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nyse:sny
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Sanofi
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Apr 26th, 2022 12:00AM
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Aug 9th, 2017 12:00AM
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https://www.uspto.gov?id=US11311675-20220426
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Medicament delivery device
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The present disclosure relates to a medicament delivery device. The medicament delivery device includes a needle for delivering a medicament and an insertion mechanism configured to urge the needle in a first direction parallel to a longitudinal axis of the needle. The insertion mechanism includes a driving mechanism and a cam. The driving mechanism is configured to exert a force in a second direction perpendicular to the first direction. The cam is coupled to the needle and is configured to receive a force from the driving mechanism and move in the first direction in response to the received force.
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11311675
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1. A device for medicament delivery, the device comprising:
a needle for delivering a medicament; and
an insertion mechanism configured to urge the needle in a first direction parallel to a longitudinal axis of the needle, wherein the insertion mechanism comprises a driving mechanism which is configured to exert a force in a second direction perpendicular to the first direction,
the insertion mechanism further comprising a cam which is coupled to the needle and is configured to receive the force from the driving mechanism and move in the first direction in response to the received force, wherein the driving mechanism comprises an insertion spring configured to expand in the second direction and a driving plunger having an angled surface to make contact with an angled surface of the cam and exert the force in the second direction on the cam upon expansion of the insertion spring; and
an injection mechanism configured to urge a stopper of the device through a chamber of the device, wherein the injection mechanism comprises a second plunger and an injection spring, the second plunger being arranged to make contact with the stopper, the injection spring being configured to expand and push against the second plunger to urge the stopper through the chamber, and the injection spring being arranged coaxially within the insertion spring.
2. The device of claim 1, wherein the angled surface of the cam is arranged at an angle between the first direction and the second direction and a guide is configured to allow movement of the angled surface of the cam in the first direction only, and wherein the driving mechanism is configured to exert the force in the second direction on the angled surface of the cam.
3. The device of claim 2, wherein the angled surface of the cam is arranged at an angle between 20 degrees and 50 degrees with respect to the first direction.
4. The device of claim 1, wherein the driving mechanism comprises an insertion spring latch; and wherein:
in a first position, the insertion spring latch is arranged to prevent the insertion spring from expanding in the second direction; and
in a second position, the insertion spring latch is arranged to allow the insertion spring to expand in the second direction.
5. The device of claim 1, further comprising:
a syringe for delivering the medicament through the needle,
wherein the chamber comprises a medicament chamber of the syringe, and the second plunger comprises a syringe plunger.
6. The device of claim 5, wherein the injection mechanism comprises an injection spring latch; and wherein:
in a first position, the injection spring latch is arranged to prevent the injection spring from expanding; and
in a second position, the injection spring latch is arranged to allow the injection spring to expand and push against the syringe plunger.
7. The device of claim 1, further comprising the medicament for delivery through the needle.
8. A device for medicament delivery, the device comprising:
a needle for delivering a medicament:
an insertion mechanism configured to urge the needle in a first direction parallel to a longitudinal axis of the needle, wherein the insertion mechanism comprises a driving mechanism which is configured to exert a force in a second direction perpendicular to the first direction;
the insertion mechanism further comprising a cam which is coupled to the needle and is configured to receive the force from the driving mechanism and move in the first direction in response to the received force, wherein the driving mechanism comprises a driving plunger having an angled surface to make contact with an angled surface of the cam and exert the force on the cam; and
an injection mechanism configured to urge a stopper of the device through a chamber of the device, wherein the injection mechanism comprises a second plunger and an injection spring, the second plunger being arranged to make contact with the stopper, the injection spring being configured to expand and push against the second plunger to urge the stopper through the chamber, and wherein the injection spring, and the second plunger are arranged internally within the driving plunger, and the driving plunger is arranged such that, on expansion of the injection spring in the second direction, the second plunger is moved into contact with the stopper of the device.
9. The device of claim 8, wherein the device comprises a syringe configured to deliver the medicament through a flexible conduit, and the flexible conduit is connected with an upper end of the needle.
10. The device of claim 8, wherein the device comprises a syringe configured to deliver the medicament through a flexible conduit, and wherein the insertion mechanism is configured to move the needle in the first direction from a first position to a second position, wherein the needle in the first position is separated from the flexible conduit, and the needle in the second position is arranged to engage with the flexible conduit.
11. The device of claim 10, wherein the needle comprises a piercing element, and the piercing element of the needle is arranged to engage with a receiving portion of the flexible conduit in the second position.
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11
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application is the national stage entry of International Patent Application No. PCT/EP2017/070154, filed on Aug. 9, 2017, and claims priority to Application No. EP 16184073.1, filed on Aug. 12, 2016, the disclosures of which are incorporated herein by reference.
FIELD OF INVENTION
The present disclosure relates to a device for delivery of medicament to a patient.
BACKGROUND
A variety of diseases exist that require regular treatment by injection of a medicament and such injections can be performed by using injection devices. Injection or infusion pumps of the type known as patch pumps for delivering injections of medicament are known in the art. Another type of injection pump that is gaining traction is the bolus injector device. Some bolus injector devices are intended to be used with relatively large volumes of medicament, typically at least 1 ml and maybe a few ml. Injection of such large volumes of medicament can take some minutes or even hours. Such high capacity bolus injector devices can be called large volume devices (LVDs). Generally such devices are operated by the patients themselves, although they may also be operated by medical personnel.
To use a patch pump or bolus injector device, such as an LVD, it is first supported on a suitable injection site on a patient's skin. Once installed, injection is initiated by the patient or another person (user). Typically, the initiation is effected by the user operating an electrical switch, which causes a controller to operate the device. Operation includes firstly injecting a needle into the user and then causing the injection of medicament into the user's tissue. Biological medicaments are being increasingly developed which comprise higher viscosity injectable liquids and which are to be administered in larger volumes than long-known liquid medicaments. LVDs for administering such biological medicaments may comprise a pre-filled disposable drug delivery device or, alternatively, a disposable drug delivery device into which a patient or medical personnel must insert a drug cartridge prior to use.
SUMMARY
According to an aspect a medicament delivery device is provided including a needle for delivering a medicament; and an insertion mechanism configured to urge the needle in a first direction parallel to a longitudinal axis of the needle; wherein the insertion mechanism includes a driving mechanism which is configured to exert a force in a second direction perpendicular to the first direction, and a cam which is coupled to the needle and is configured to receive a force from the driving mechanism and move in the first direction in response to the received force.
The cam may include comprise an angled surface arranged at an angle between the first direction and the second direction and a guide configured to allow movement of the cam surface in the first direction only.
The driving mechanism may be configured to exert a force in the second direction on the angled surface of the cam.
The angled surface of the cam may be arranged at an angle between 20 degrees and 50 degrees with respect to the first direction.
The driving mechanism may include a driving plunger having an angled surface to make contact with the angled surface of the cam and exert a force on the cam.
The driving mechanism may include an insertion spring configured to expand in the second direction and push the driving plunger against the cam.
The driving mechanism may include an insertion spring latch; wherein in a first position, the insertion spring latch is arranged to prevent the insertion spring from expanding in the second direction; and in a second position, the insertion spring latch is arranged to allow the insertion spring to expand in the second direction.
The device may include a syringe for delivering a medicament through the needle; and an injection mechanism configured to urge a stopper of the syringe through a medicament chamber of the syringe.
The injection mechanism may include a syringe plunger arranged to make contact with the stopper, and an injection spring configured to expand and push against the syringe plunger to urge the stopper through the medicament chamber.
The injection mechanism may include an injection spring latch; wherein in a first position, the injection spring latch is arranged to prevent the injection spring from expanding; and in a second position, injection spring latch is arranged to allow the injection spring to expand and push against the syringe plunger.
The injection spring may be arranged coaxially within the insertion spring.
The injection spring, syringe plunger and injection spring latch may be arranged internally within the driving plunger.
The driving plunger may be arranged such that, on expansion of the insertion spring in the second direction, the syringe plunger is moved into contact with the stopper of the syringe.
The syringe may be configured to deliver a medicament through a flexible conduit, and the flexible conduit may be connected with an upper end of the needle.
The syringe may be configured to deliver a medicament through a flexible conduit, and the insertion mechanism may be configured to move the needle in the first direction from a first position to a second position.
The needle in the first position may be separated from the flexible conduit, and the needle in the second position may be arranged to engage with the flexible conduit.
The needle may include a piercing element, and the piercing element of the needle may be arranged to engage with a receiving portion of the flexible conduit in the second position.
The device may include a medicament for delivery through the needle.
These and other aspects of the disclosure will be apparent from and elucidated with reference to the embodiments described hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
Exemplary embodiments of the present disclosure are described with reference to the accompanying drawings, in which:
FIG. 1 is a schematic side view of a first embodiment of a medicament delivery device;
FIG. 2 is a schematic side view of the FIG. 1 injection device;
FIG. 3 is a schematic side view of the FIG. 1 injection device;
FIG. 4 is a schematic side view of a second embodiment of a medicament delivery device;
FIG. 5 is a schematic side view of the FIG. 4 injection device;
FIG. 6 is a schematic side view of the FIG. 4 injection device;
FIG. 7A is a partial schematic side view of a third embodiment of a medicament delivery device; and
FIG. 7B is a partial schematic side view of the FIG. 7A device.
DETAILED DESCRIPTION
A medicament delivery device, as described herein, may be configured to inject a medicament into a patient. For example, delivery could be sub-cutaneous, intra-muscular, or intravenous. Such a device could be operated by a patient or by a care-giver, such as a nurse or physician. The device can include a cartridge-based system that requires piercing a sealed ampule before use. The device can include a large volume device (“LVD”) or patch pump, configured to adhere to a patient's skin for a period of time (e.g., about 5, 15, 30, 60, or 120 minutes) to deliver a “large” volume of medicament (typically about 2 ml to about 10 ml).
In combination with a specific medicament, the presently described devices may also be customized in order to operate within required specifications. For example, the device may be customized to inject a medicament within a certain time period (e.g. about 10 minutes to about 60 minutes for an LVD). Other specifications can include a low or minimal level of discomfort, or to certain conditions related to human factors, shelf-life, expiry, biocompatibility, environmental considerations, etc. Such variations can arise due to various factors, such as, for example, a drug ranging in viscosity from about 3 cP to about 50 cP. Consequently, a drug delivery device will often include a hollow needle ranging from about 25 to about 31 Gauge in size. Common sizes are 27 and 29 Gauge.
The medicament delivery devices described herein can also include one or more automated functions. For example, one or more of needle insertion, medicament injection, and needle retraction can be automated. Energy for one or more automation steps can be provided by one or more energy sources. Energy sources can include, for example, mechanical, pneumatic, chemical, or electrical energy. For example, mechanical energy sources can include springs, levers, elastomers, or other mechanical mechanisms to store or release energy. One or more energy sources can be combined into a single device. Devices can further include gears, valves, or other mechanisms to convert energy into movement of one or more components of a device.
The one or more automated functions of a device may each be activated via an activation mechanism. Such an activation mechanism can include one or more of a button, a lever, a needle sleeve, or other activation component. Activation of an automated function may be a one-step or multi-step process. That is, a user may need to activate one or more activation components in order to cause the automated function. For example, in a one-step process, a user may depress a trigger against their body in order to cause injection of a medicament. Other devices may require a multi-step activation of an automated function. For example, a user may be required to depress a button and deploy a needle in order to cause injection.
In addition, activation of one automated function may activate one or more subsequent automated functions, thereby forming an activation sequence. For example, activation of a first automated function may activate at least two of needle insertion, medicament injection, and needle retraction. Some devices may also require a specific sequence of steps to cause the one or more automated functions to occur. Other devices may operate with a sequence of independent steps.
Some medicament delivery devices can also include one or more functions of a safety syringe, pen-injector, or auto-injector. For example, a delivery device could include a mechanical energy source configured to automatically inject a medicament (as typically found in an auto-injector) and a dose setting mechanism (as typically found in a pen-injector).
FIGS. 1 to 3 show a medicament delivery device 10, which in the exemplary embodiment comprises a bolus injector device (hereafter simply referred to as “device 10”), according to a first embodiment comprises a housing 11 containing a needle insertion mechanism 100 and a medicament injection mechanism 200. The device 10 can include an LVD. The device 10 is only shown schematically and a number of the functional components are omitted for the sake of clarity and brevity, but the device 10 includes a needle 12 for injection of the liquid medicament into a patient's body. The liquid medicament may be provided in a syringe 13 within the housing 11, or may be provided externally of the device 10.
Although not shown in the figures, the device 10 may include one or more of the following components. A controller configured to control operation of the device 10. An energy source to power the device 10. An electrical power source in the form of a battery to power to the controller. The battery may also provide electrical power to the insertion mechanism 100 and/or the injection mechanism 200, if this is an electrically driven device.
The device 10 generally comprises a housing upper side 11a and a lower side 11b. In use, the lower side 11b of the housing 11 is intended to be a contact surface that is placed against a patient's skin during a medicament administration process. The lower side 11b forms a flat contact surface. The lower side 11b may comprise an adhesive layer to removably adhere to a patient's skin. A height of the device 10, measured between the upper side 11a and the lower side 11b, may be short with respect to the size of the lower side 11b. A length of the lower side 11b may be greater than the height of the device 10. A width of the lower side 11b may be greater than the height of the device 10. The device 10 is stable when placed in position against a patient's skin.
The contact surface or lower side 11b of the housing 11 includes an aperture 14 through which the needle 12 can project in use. A length of needle 12 defines a first axis of the device 10. The first axis is perpendicular to the contact surface with a patient's skin when the lower side 11b is placed against the patient's skin. The height of the device 10 is measured along the first axis. A second axis of the device 10 is perpendicular to the first axis. The second axis is parallel to the lower side 11b of the housing 11.
The needle 12 is moveable along the first axis. The needle 12 can be moved between a retracted position and an engaged position. In the retracted position the needle 12 is disposed within the housing 11 of the device 10. In the engaged position, the needle 12 projects from the lower side 11b of the housing 11 through the aperture 14. The needle 12 is arranged in the engaged position so as to pierce and inject a patient's skin when the device 10 is in contact with a patient.
The needle insertion mechanism 100 is configured to move the needle 12 from the retracted position to the engaged position. The needle insertion mechanism 100 comprises a driving mechanism 110 to generate a motive force to move the needle 12. The needle insertion mechanism 100 comprises a cam 120 to translate the motive force of the driving mechanism 110 to a different axis.
The driving mechanism 110 comprises an insertion spring 111, a frame 112, a driving plunger 113 and an insertion spring latch 114. The insertion spring 111 is a compressible spring. The insertion spring may be, for example, an extended coil spring. In an initial state, the insertion spring 111 is fully compressed. In an activated state, the insertion spring 111 is fully extended. When activated, the insertion spring 111 is configured to expand. The insertion spring 111 is arranged to expand along the second axis of the device 10. The insertion spring 111 is arranged between the frame 112 and the driving plunger 113. The insertion spring 111 is arranged to push against the frame 112 and the driving plunger 113 when activated.
The frame 112 is a rectangular box. The box of the frame is open at one side. The frame 112 is arranged with the open face of the box facing along the second axis of the device 10. The inner face of the frame 112 which faces the opening is the rear face of the frame 112. The insertion spring 111 is arranged inside the frame 112. The insertion spring 111 is arranged in abutment with the rear face of the frame 112. The insertion spring 111 may be fixedly attached to the rear face of the frame 112. The insertion spring 111 may lie entirely within the frame 112 when fully compressed. The insertion spring 111 may extend through the open face of the frame 112 when fully expanded.
The rear face of the frame 112 forms a reaction surface against which the insertion spring 111 can push. The frame 112 is fixed in position within the housing of the device 10. The frame 112 is not moved by the expansion of the insertion spring 111. The insertion spring 111 expands away from the rear face of the frame 112. Alternatively, the frame 112 may be formed as a flat plate to provide a reaction surface. Alternatively, the insertion spring 111 may be arranged in abutment with an inner surface of the housing 11.
The driving plunger 113 is formed having a cylindrical shape. A length of the driving plunger 113 is greater than a diameter of the driving plunger 113. The driving plunger 113 comprises a protruding part 115 at a point on the length of the cylinder. The driving plunger 113 comprises an angled surface 116 at one end of the cylinder. The angled surface 116 is at an angle with respect to the long axis of the cylinder. The angled end is called the front end of the driving plunger 113. The rear end of the cylinder, opposite to the angled surface 116, may be flat, that is, perpendicular to the long axis of the cylinder. The rear end of the cylinder may have rounded edges.
The driving plunger 113 is arranged at least partially within the insertion spring 111. An outer diameter of the cylindrical body of the driving plunger 113 is smaller than an inner diameter of the insertion spring 111. The driving plunger 113 is arranged co-axially with the insertion spring 111. The driving plunger 113 and insertion spring 111 are aligned on the second axis. The insertion spring 111 surrounds a rear portion of the driving plunger 113, including the rear end of the driving plunger 113.
The protruding part 115 extends radially outwards to engage with the insertion spring 111. The diameter of the protruding part 115 is greater than that of the insertion spring 111. The insertion spring 111 abuts against a rear face of the protruding part 115. The insertion spring 111 surrounds a rear portion of the driving plunger 113 between the protruding part 115 and the rear end of the driving plunger. The insertion spring 111 pushes against the protruding part 115 as it expands. The insertion spring 111 can move the driving plunger 113 along the second axis as it expands.
Alternatively, the diameter of the insertion spring 111 may be smaller than that of the driving plunger 113. The insertion spring may engage with the rear face of the driving plunger 113. The rear face of the driving plunger 113 may have a groove or recess to engage with the insertion spring 111. Further alternatively, the driving plunger 113 may comprise a cavity which is open at a rear end of the driving plunger 113. The insertion spring 111 may be arranged within the cavity of the driving plunger 113.
The insertion spring latch 114 is configured to retain the insertion spring 111 in the fully compressed state and to release the insertion spring 111 when the driving mechanism 110 is activated. The insertion spring latch 114 comprises one or more latching elements arranged in the opening of the frame 112. The insertion spring latch 114 has a first latched state and a second unlatched state.
In the latched state, the one or more latching elements of the insertion spring latch 114 are arranged in a forward position with respect to the protruding part 115 of the driving plunger 113. The insertion spring latch 114 engages with a forward face of the protruding part 115. The insertion spring latch 114 is fixedly attached to the frame 112. The insertion spring latch 114 is restrained from moving along the second axis. The insertion spring 111 pushes the driving plunger 113 against the insertion spring latch. The driving plunger 113 is restrained from moving along the second axis by the insertion spring latch. The insertion spring latch 114 retains the insertion spring 111 within the frame 112.
In the unlatched state, the one or more latching elements of the insertion spring latch 114 are disengaged from the protruding part 115. The insertion spring latch 114 is moved radially away from the second axis. The insertion spring latch 114 is moved away from the driving plunger 113 towards the frame 112. The driving plunger 113 can be moved along the second axis past the insertion spring latch 114. The insertion spring 111 can push against the rear face of the protruding part 115 and move the driving plunger 113 along the second axis.
The insertion spring latch 114 can be operated to move between the latched state and the unlatched state. The insertion spring latch 114 can be operated to move from the latched state to the unlatched state when the insertion mechanism 100 is activated.
The insertion spring latch 114 may alternatively be engaged with the insertion spring 111 in the latched state. The insertion spring 111 may abut with the one or more latching elements of the insertion spring latch 114. The protruding part 115 may be arranged in a forward position of the insertion spring latch 114 along the second axis. In the unlatched state the insertion spring latch 114 may allow the insertion spring 111 to expand along the second axis and engage with the protruding part 115.
The angled surface 116 of the driving plunger 113 is configured to engage with the cam 120. The angled surface 116 is formed at an angle of about 45 degrees with respect to the second axis. The angled surface 116 forms an angle of about 45 degrees with the lower side 11b of the case 11. The angle of the angled surface 116 relative to the lower side 11b may be between about 20 degrees and about 50 degrees. A width of the driving plunger 113 may be enlarged at a forward end to increase the size of the angled surface 116. The angled surface 116 may be truncated at a forward end by a flat portion, that is, a surface which is perpendicular to the second axis.
The cam 120 comprises an angled surface 121 and a guide 122. The cam 120 is formed as a triangular body. The angled surface 121 is angled between the first axis and the second axis. A lower face of the cam 120 is perpendicular to the first axis. A forward face of the cam is perpendicular to the second axis. The cam 120 is triangular in cross-section. The cam 120 may be a triangular prism having a constant cross-section. Alternatively, the cam 120 may be formed with any shape including the angled surface 121.
The angled surface 121 is formed at an angle of about 45 degrees with respect to the second axis. The angled surface 121 forms an angle of about 45 degrees with the lower side 11b of the case 11. The angle of the angled surface 121 relative to the lower side 11b may be between about 20 degrees and about 50 degrees. The angle of the angled surface 121 may be any angle which corresponds to the angled surface 116 of the driving plunger 113. The angles of the angled surface 116 and the angled surface 121 add up to 90 degrees. The driving plunger 113 is perpendicular to the first axis when the angled surface 116 is engaged with the angled surface 121. Alternatively, the angled surfaces may not add up to 90 degrees if the driving mechanism 110 is arranged at an angle within the housing of the device 10.
The angled surface 121 of the cam 120 is longer in cross section than the angled surface 116. The angled surface 116 of the driving plunger 113 can move across the angled surface 121. Alternatively, the angled surface 116 may be longer than the angled surface 121, or the surfaces may have the same length.
The guide 122 is configured to allow movement of the cam 120 along the first axis only. The guide 122 comprises one or more rails extending along the first axis, and corresponding grooves in the body of the cam 120. Alternatively, the guide 122 may include a rail passing through an opening in the body of the cam 120. Further alternatively, the guide 122 may comprise a retaining element in abutment with the forward face of the body of the cam 120 to prevent movement along the second axis.
The cam 120 is coupled to the needle 12. The needle 12 extends downwards from the cam 120 along the first axis. The needle 12 may extend out of a lower face of the body of the cam 120. The body of the cam 120 may be formed around an upper end of the needle 12. Alternatively, the needle may be arranged on an end face of the cam 120. The needle 12 may be fixedly attached to an end face of the cam 120, for example, using an adhesive.
The needle 12 is configured to move with the cam 120. The cam 120 is configured to move the needle 12 along the first axis. The first axis is the longitudinal axis of the needle 12. The first axis is perpendicular to the lower side 11b of the housing 11. As the cam 120 moves along guide 122 in the direction of the first axis, the needle is moved along the first axis.
FIG. 1 shows the device 10 in an initial state. The needle 12 is in the retracted position. The needle 12 is entirely within the housing 11 of the device 10. The aperture 14 may include a seal or septum to cover the aperture 14 in the initial state and seal the interior of the housing 11. The insertion spring 111 is fully compressed in the initial state. The insertion spring latch 114 is in the latched state. The insertion spring latch 114 is engaged with the protruding part 115. The insertion spring latch 114 prevents the driving plunger 113 from movement along the second axis. The protruding part 115 retains the insertion spring 111 in the compressed state. The insertion spring 111 is retained entirely within the frame 112. The insertion spring 111 is prevented from expanding along the second axis by the protruding part 115 and the insertion spring latch 114. Alternatively, the insertion spring latch 114 may be engaged directly with the insertion spring 111, as described above.
In the initial state, the driving plunger 113 is engaged with the cam 120. The angled surface 116 is in abutment with the angled surface 121. The driving mechanism 100 is aligned with the second axis of the device 10. The angled surface 116 is parallel to the angled surface 121. The driving plunger 113 is arranged such that movement along the second axis results in the driving plunger applying a force to the cam 120 along the second axis. The driving plunger 113 is configured to apply a force to the cam 120 along the second axis when the driving mechanism 110 is activated.
FIG. 2 shows the device 10 in an engaged state. The insertion mechanism 100 has been activated. The insertion spring 111 is in an activated state. The needle 12 is in the engaged position. The device 10 is ready to begin the medicament administration process.
The insertion mechanism 100 may be activated by, for example, a switch arranged to be pressed by the patient or care giver. The switch may be mechanical or may be electronic. An electronic switch may provide a signal to a controller which controls the activation of the insertion mechanism 100. Alternatively, a controller may control the insertion mechanism 100 automatically, in response to detecting that the device 10 has been placed in position on the patient's skin. The insertion mechanism 100 may be prevented from activating unless the device 10 is placed in position on the patient's skin.
Activation of the insertion mechanism 100 causes the insertion spring latch 114 to release the insertion spring 111. The insertion spring latch 114 is moved from the latched state to the unlatched state. The insertion spring latch 114 allows the protruding part 115 to pass the insertion spring latch 114 along the second axis. The insertion spring 111 applies a force along the second axis to the protruding part 115 of the driving plunger 113. The driving plunger 113 is caused to move along the second axis by the insertion spring 111. The insertion spring 111 expands along the second axis until fully extended in the activated state. The insertion spring 111 moves from the initial state to the activated state.
The driving mechanism 110 applies a force to the cam 120 when activated. Movement of the driving plunger 113 along the second axis causes the angled surface 116 to apply a force along the second axis to the angled surface 121 of the cam 120. The angle of the interface between the driving plunger 113 and the cam 120 causes a component of the force at the angled surface 121 to be directed along the first axis. The cam 120 is restricted from moving along the second axis by the guide 122. The cam 120 and the needle 12 are caused to move along the first axis towards the lower side 11b of the case 11.
The cam 120 is configured to move along a first axis in response to a force along a second axis. The cam 120 can translate motion along the second axis to motion along the first axis. The second axis is perpendicular to the first axis. The cam 120 is configured to move along the first axis in response to the force applied by the driving plunger 113. The cam 120 is arranged to receive a force along the second axis at the angled surface 121. A component of the force at the angled surface 121 is directed along the first axis and causes movement of the cam 120 along the first axis.
The angled surface 116 moves across the angled surface 121. Where the angled surface 121 is angled at 45 degrees to the second axis, a displacement of the driving plunger 113 along the second axis causes the same displacement of the cam 120 along the first axis. The needle 12 can be moved to the engaged position by movement of the cam 120 along the first axis. The needle 12 moves through the aperture 14 into the engaged position. The needle 12 may piece or rupture a seal covering the aperture 14 as it moved through the aperture 14 into the engaged position.
The cam 120 of the device 10 allows the driving mechanism 110 to be mounted sideways within the device 10. The driving mechanism 110 is longest in the direction along which it applies a force. By mounting the driving mechanism 110 sideways, with the longest axis parallel to the contact surface 11b of the device 10, a medicament delivery device 10 with a smaller vertical extent can be provided. The device 10 is formed to have a large contact surface 11b and a small vertical extent between the lower side 11b and the upper side 11a of the housing 11. The device 10 is stable when held against the patient's skin during a medicament administration process. The device 10 can be held securely and minimises rocking which could change the insertion angle of the needle 12. The needle 12 can be inserted perpendicular to the patient's skin and maintained in position during the medicament administration process. The increased area of the contact surface 11 provides a greater amount of friction and minimises slippage which could move the needle 12 laterally. The device 10 improves patient comfort and improves ease of use.
The injection mechanism 200 is shown in an initial state in FIG. 1 and FIG. 2. The injection mechanism 200 is configured to deliver medicament through the needle 12 when activated. The medicament is provided in the syringe 13. The syringe 13 comprises a medicament chamber 15 and a stopper 16. The medicament chamber 15 is generally cylindrical, with an opening at each end. The medicament chamber 15 may be formed of glass or a plastic material.
The stopper 16 is arranged within the medicament chamber 15. The stopper 16 forms a tight seal with the walls of the medicament chamber 16. The stopper 16 may be, for example, rubber or a synthetic rubber-like material. Alternatively, the stopper 16 may have the form of a plunger which passed through the opening and has an external component. When the injection mechanism 200 is in the initial state, the stopper 16 is disposed at one end of the medicament chamber 15.
A conduit 17 connects the medicament chamber 15 with the needle 12. The conduit 17 may be, for example, a flexible pipe or hose. One end of the conduit 17 is connected to an opening of the medicament chamber 15. The conduit 17 is connected to the end of the medicament chamber 15 which lies furthest from the needle 12. The other end of the conduit 17 is connected to the needle 12. The conduit 17 is connected to an upper end of the needle 12.
A portion of the length of the needle 12 is deflected at a right angle with respect to the first axis. The deflected portion of the needle 12 is disposed at an upper end of the needle 12 configured to receive medicament from the syringe 13. The needle 12 is configured to receive medicament through the conduit 17.
The injection mechanism 200 comprises an injection spring 211, an injection spring latch 212 and a syringe plunger 213. When activated, the injection spring 211 is configured to expand. The injection spring 211 is arranged to push the syringe plunger 213 through the medicament chamber 15 when activated.
The injection spring 211 is a compressible spring, for example, an extended coil spring. In an initial state, the injection spring 211 is fully compressed. In an activated state, the injection spring 211 is fully extended.
FIG. 2 shows the device 10 in the engaged state, ready to begin the medicament administration process. The injection spring 211 is in the initial state and is fully compressed. The injection spring latch 212 is configured to retain the injection spring 211 in the fully compressed state and to release the injection spring 211 when the injection mechanism 200 is activated. When the injection spring latch 212 releases the injection spring 211, the injection spring 211 can expand until the injection spring 211 is fully extended in the activated state.
The syringe plunger 213 comprises a protruding part 215 at a point on the length of the cylinder. The protruding part 215 extends radially outwards to engage with the injection spring 211. The injection spring 211 pushes against the protruding part 215 as it expands to move the syringe plunger 213 through the medicament chamber 15. The injection spring latch 212 may be engaged with the protruding part 215 in the initial state, to retain the injection spring 211 in the compressed state. Alternatively, the injection spring latch 212 may be engaged directly with the injection spring 211.
The syringe plunger 213 is arranged to be pushed through the medicament chamber 15 by the injection spring 211. The syringe plunger 213 is formed as a cylinder extending co-axially with the injection spring 211 and extending through the injection spring 211. One end of the syringe plunger 213 is disposed within the medicament chamber 15. The syringe plunger 213 extends through an opening of the medicament chamber 15. The syringe plunger 213 forms a tight seal with the opening to prevent the medicament from exiting the medicament chamber 15. Alternatively, the syringe plunger 213 may engage with the stopper 16 of the medicament chamber 15 outside the medicament chamber 15.
The syringe plunger 213 is coupled to the stopper 16. The syringe plunger 213 is arranged to move the stopper 16 from one end of the medicament chamber 15 to the other end as the syringe plunger 215 is pushed through the medicament chamber 15. The syringe plunger 213 is configured to move the stopper 16 through the medicament chamber 15 when the injection mechanism 200 is activated.
FIG. 3 shows the device 10 in the process of administering the medicament. The injection mechanism 200 has been activated. The injection spring 211 is partially extended, and is moving towards the activated state.
Activation of the injection mechanism 200 causes the stopper 16 to move towards the other end of the medicament chamber 15, causing medicament to be ejected from the medicament chamber through the opening at the other end of the medicament chamber 15.
The injection mechanism 200 may be activated by, for example, a switch arranged to be pressed by the patient or care giver. The switch may be mechanical or may be electronic. An electronic switch may provide a signal to a controller which controls the activation of the injection mechanism 200. Alternatively, a controller may control the injection mechanism 200 automatically, after the needle 12 has been moved to the engaged position.
Activation of the injection mechanism 200 causes the injection spring latch 212 to release the injection spring 211. The injection spring 211 moves from the initial state to the activated state. The injection spring 211 expands until fully extended in the activated state. The injection spring 211 applies a force to the protruding part 215 of the syringe plunger 213. The syringe plunger 213 is caused to move through the medicament chamber 15 by the insertion spring 211.
Movement of the syringe plunger 213 through the medicament chamber 15 causes the stopper 16 to move from one end of the medicament chamber 15 to the other end. Medicament is expelled from the medicament chamber 15 through the conduit 17 by the stopper 16. The medicament is delivered to the needle 12 through the conduit 17 and is delivered to the patient through the needle 12.
FIGS. 4 to 6 show a second embodiment of a medicament delivery device 20. The device 20 comprises a needle insertion mechanism 300 and a medicament injection mechanism 400. Other elements not described are substantially as described with respect to the first embodiment.
The needle insertion mechanism 300 is configured to move the needle 12 from the retracted position to the engaged position. The needle insertion mechanism 300 comprises a driving mechanism 310 configured to engage with the cam 120.
The driving mechanism 310 comprises an insertion spring 311, a frame 312 and an insertion spring latch 314, substantially as described with respect to the first embodiment. The driving mechanism 310 further comprises a driving plunger 313. The driving plunger 313 is formed having a cylindrical shape. The driving plunger 313 is aligned co-axially with the insertion spring 311 along the second axis. The driving plunger 313 comprises a protruding part 315 for engaging with the insertion spring 311, as described above with respect to the first embodiment. The insertion spring 311 surrounds a rear portion of the driving plunger 313 between a rear end and the protruding part 315.
The driving plunger 313 is configured to house the injection mechanism 400 in an initial state of the device 10. The driving plunger 313 is formed as a hollow cylinder. The driving plunger 313 includes an opening at one end. The forward end of the driving plunger 313, which is furthest from the insertion spring 313 is, open and the hollow interior of the cylinder is exposed. The injection mechanism 400 can be arranged in the interior of the driving plunger 313. An inner diameter of the driving plunger 313 is greater than an outer diameter of the injection mechanism.
The driving plunger 313 further comprises a cam engaging part 316. The cam engaging part 316 extends outwards from the cylindrical portion of the driving plunger 313. The cam engaging part 316 is integrally formed with the cylindrical portion. The cam engaging part extends from a forward end of the cylindrical part, which is adjacent to the opening. The cam engaging part 216 extends downwards, in the direction of the first axis.
The cam engaging part 316 is formed having a rectangular shape. The cam engaging part 316 comprises an angled surface 317. A lower face of the cam engaging part 316, furthest from the cylindrical portion of the driving plunger 313, is formed at an angle. The angled surface 317 corresponds to the angled surface 121 of the cam 120, in the same way as the angled surface 116.
The injection mechanism 400 comprises an injection spring 411, an injection spring latch 412 and a syringe plunger 413, substantially as described with respect to the first embodiment above. The outer diameters of the injection spring 411 and the syringe plunger 413 are smaller than the inner diameter of the driving plunger 313. A length of the injection spring 411 when fully compressed is shorter than a length of the interior of the driving plunger 313.
The injection spring latch 412 is configured to retain the injection spring 411 in the fully compressed state and to release the injection spring 411 when the injection mechanism 400 is activated. The injection spring latch 412 is disposed within the cylindrical walls of the driving plunger 313, to retain the injection spring 411 within the driving plunger 313. The injection spring latch 412 comprises one or more latching elements disposed in the walls of the driving plunger 313. The injection spring latch 412 is arranged adjacent to the opening of the driving plunger 313. The driving plunger 313 may include an enlarged portion with thicker cylindrical walls which accommodate the injection spring latch 412. The injection spring latch 412 has a first latched state and a second unlatched state.
In the latched state, the one or more latching elements of the injection spring latch 412 are arranged in a forward position with respect to a protruding part 415 of the syringe plunger 413. The injection spring latch 412 engages with a forward face of the protruding part 415. The injection spring latch 412 is fixedly attached to the driving plunger 313. The injection spring latch 412 is restrained from moving along the second axis. The injection spring 411 pushes the syringe plunger 413 against the injection spring latch 412. The syringe plunger 413 is restrained from moving along the second axis by the injection spring latch 412. The injection spring latch 412 retains the injection spring 411 within the driving plunger 313.
In the unlatched state, the one or more latching elements of the injection spring latch 412 are disengaged from the protruding part 415. The injection spring latch 412 is moved radially away from the second axis. The injection spring latch 412 is retracted within the wall of the driving plunger 313. The syringe plunger 413 can be moved along the second axis past the injection spring latch 412. When the injection spring latch 412 releases the injection spring 411, the injection spring 411 can push against the rear face of the protruding part 415 and move the syringe plunger 413 along the second axis.
The injection spring latch 412 can be operated to move between the latched state and the unlatched state. The injection spring latch 412 can be operated to move from the latched state to the unlatched state when the injection mechanism 400 is activated.
The injection spring latch 412 may alternatively be engaged with the injection spring 411 in the latched state. The injection spring 411 may abut with the one or more latching elements of the injection spring latch 412. The protruding part 415 may be arranged in a forward position of the injection spring latch 412 along the second axis. In the unlatched state the injection spring latch 412 may allow the injection spring 411 to expand along the second axis and engage with the protruding part 415.
FIG. 4 shows the device 20 in an initial state. The insertion spring 311 is in the initial state and is fully compressed within the frame 312. The insertion spring latch 314 is in the latched state. The insertion spring latch 314 is engaged with the protruding part 315 of the driving plunger 313. The insertion spring 311 is prevented from expanding along the second axis by the protruding part 315 and the insertion spring latch 314.
In the initial state the components of the injection mechanism 400 are housed within the driving plunger 313. The injection spring 411 is fully compressed, in an initial state. The injection spring latch 414 is in the latched state. The injection spring latch 414 is engaged with the protruding part 415 of the syringe plunger 413. The injection spring 411 is prevented from expanding along the second axis by the protruding part 415 and the injection spring latch 414. In the initial state, the injection mechanism 400 is separated from the syringe 13 by a distance along the second axis.
In the initial state, the driving plunger 313 is engaged with the cam 120. The cam engaging part 316 of the driving plunger 313 is in abutment with the cam 120. The angled surface 317 is in contact with the angled surface 121. The driving plunger 313 is arranged such that movement along the second axis results in the cam engaging part 316 applying a force to the cam 120 along the second axis. The driving plunger 313 is configured to apply a force to the cam 120 along the second axis when the driving mechanism 310 is activated.
FIG. 5 shows the device 10 in an engaged state. The insertion mechanism 300 has been activated. The insertion spring 311 is in an activated state. The needle 12 is in the engaged position. The device 10 is ready to begin the medicament administration process.
In the engaged state, the insertion spring latch 314 is moved from the latched state to the unlatched state. The insertion spring latch 314 allows the protruding part 315 to pass the insertion spring latch 314 along the second axis. The driving plunger 313 is caused to move along the second axis by the insertion spring 311. The cam engaging part 316 causes the cam 120 and the needle 12 to move along the first axis towards the lower side 11b of the case 11. The needle 12 moves through the aperture 14 into the engaged position.
The injection mechanism 400 is moved along the second axis with the driving plunger 313. The injection mechanism 400 is moved into abutment with the syringe 13. The syringe plunger 413 engages with the stopper 16 when the device 20 is in the engaged state. A forward face of the syringe plunger 413 is in abutment with the stopper 16. The syringe plunger 413 may pass through an opening of the medicament chamber 15 to engage with the stopper 16, or the stopper may include an external component for engaging with the syringe plunger 413.
The syringe plunger 413 is arranged such that further movement along the second axis exerts a force on the stopper 16 along the second axis. The syringe plunger 413 is configured to move the stopper 16 through the medicament chamber 15 when the injection mechanism 400 is activated. The driving mechanism 310 may include locking means or a ratchet mechanism configured to retain the driving plunger 313 in position after activation of the driving mechanism 310. The driving plunger 313 may provide a fixed reaction surface against which the injection spring 411 can push when the injection mechanism 400 is activated.
FIG. 6 shows the device 20 in the process of administering the medicament. The injection mechanism 400 has been activated. The injection spring 411 is partially extended, and is moving towards the activated state.
Activation of the injection mechanism 400 causes the injection spring latch 412 to release the injection spring 411. The injection spring latch 412 is moved from the latched state to the unlatched state. The injection spring latch 412 allows the protruding part 115 to pass the injection spring latch 412 along the second axis. The injection spring 411 moves from the initial state to the activated state. The injection spring 411 expands out of the driving plunger 313 and applies a force to the syringe plunger 413. The syringe plunger 413 is caused to move through the medicament chamber 15 by the insertion spring 411, causing the delivery of the medicament as described above.
The driving plunger 313 of the device 20 allows the injection mechanism 400 to be arranged within the driving mechanism 310. The nesting of components allows the device 20 to be contained within a smaller housing 11. A smaller device 20 is more convenient for the patient, as it is easier to handle and can be stored in a smaller space.
FIGS. 7A and 7B show an arrangement of a needle 512 and a conduit 517 according to a third embodiment of the device. The end of the conduit 517 is fixed in position. The needle 512 is configured to engage with the conduit 517 in the engaged position of the needle 512 only. Other elements not described are substantially as described with respect to the either of the first embodiment and the second embodiment.
The needle 512 comprises a piercing element 512a formed at an upper end. The deflected portion of the needle 512 is further deflected through a right angle so as to extend downwards along the first axis. Alternatively, the needle is formed to have a smooth curve through 180 degrees. The downward deflected portion of the needle 512 forms the piercing element 512a. The conduit 517 comprises a receiving portion 517a at an end furthest from the syringe 13. The receiving portion 517a is fixed in position. An upper face of the receiving portion 517a is formed having an opening which is initially sealed by, for example, a frangible seal or septum. The receiving portion 517a is arranged directly below the piercing element 512a along the first axis.
In the initial position of the needle 512, the piercing element 512a is separated from the receiving portion 517a along the first axis. As the needle 512 is moved into the engaged position, the piercing element 512a is caused to engage with the receiving portion 517a. The piercing element 512a pierces or ruptures the seal on the receiving portion 517a. In this way, the medicament can be delivered from the conduit 517 to the needle 512 in the engaged position.
Although a few embodiments of the present disclosure have been shown and described, it will be appreciated by those skilled in the art that changes may be made in these embodiments without departing from the invention, the scope of which is defined in the appended claims. Various components of different embodiments may be combined where the principles underlying the embodiments are compatible.
For example, the syringe of the second embodiment may be coupled to the driving plunger. The syringe may be configured to move with the driving plunger. The arrangement of the cam engaging part and the cam may be as described with respect to the second embodiment or, further alternatively, the cam engaging part may be formed on a forward end of the syringe. The cam may be arranged in a forward position with respect to the syringe. Coupled movement of the driving plunger and syringe may cause the cam engaging part to engage with the cam, as described above.
Where a spring has been described above, the insertion mechanism and the injection mechanism may be powered electrically or by a pneumatic or hydraulic drive mechanism. Alternatively, the device may be entirely user-driven.
The angled surface of the cam can be formed with a certain curvature, for example a scoop, to improve the performance of the insertion spring. Alternate cam mechanisms are also considered. For example, the cam may include a rotating part, wherein a force along the second axis causes the cam to rotate, which in turn causes a movement along the first axis.
Where the needle is described with a deflection, the needle may be straight along its entire length. The conduit may be a flexible tube coupled to an upper end of the needle. The device may include a plurality of needles coupled to the cam in any arrangement.
The terms “drug” or “medicament” are used synonymously herein and describe a pharmaceutical formulation containing one or more active pharmaceutical ingredients or pharmaceutically acceptable salts or solvates thereof, and optionally a pharmaceutically acceptable carrier. An active pharmaceutical ingredient (“API”), in the broadest terms, is a chemical structure that has a biological effect on humans or animals. In pharmacology, a drug or medicament is used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being. A drug or medicament may be used for a limited duration, or on a regular basis for chronic disorders.
As described below, a drug or medicament can include at least one API, or combinations thereof, in various types of formulations, for the treatment of one or more diseases. Examples of API may include small molecules having a molecular weight of 500 Da or less; polypeptides, peptides and proteins (e.g., hormones, growth factors, antibodies, antibody fragments, and enzymes); carbohydrates and polysaccharides; and nucleic acids, double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids may be incorporated into molecular delivery systems such as vectors, plasmids, or liposomes. Mixtures of one or more drugs are also contemplated.
The term “drug delivery device” shall encompass any type of device or system configured to dispense a drug or medicament into a human or animal body. Without limitation, a drug delivery device may be an injection device (e.g., syringe, pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for intraocular, subcutaneous, intramuscular, or intravascular delivery), skin patch (e.g., osmotic, chemical, micro-needle), inhaler (e.g., nasal or pulmonary), an implantable device (e.g., drug- or API-coated stent, capsule), or a feeding system for the gastro-intestinal tract. The presently described drugs may be particularly useful with injection devices that include a needle, e.g., a hypodermic needle for example having a Gauge number of 24 or higher.
The drug or medicament may be contained in a primary package or “drug container” adapted for use with a drug delivery device. The drug container may be, e.g., a cartridge, syringe, reservoir, or other solid or flexible vessel configured to provide a suitable chamber for storage (e.g., short- or long-term storage) of one or more drugs. For example, in some instances, the chamber may be designed to store a drug for at least one day (e.g., 1 to at least 30 days). In some instances, the chamber may be designed to store a drug for about 1 month to about 2 years. Storage may occur at room temperature (e.g., about 20° C.), or refrigerated temperatures (e.g., from about −4° C. to about 4° C.). In some instances, the drug container may be or may include a dual-chamber cartridge configured to store two or more components of the pharmaceutical formulation to-be-administered (e.g., an API and a diluent, or two different drugs) separately, one in each chamber. In such instances, the two chambers of the dual-chamber cartridge may be configured to allow mixing between the two or more components prior to and/or during dispensing into the human or animal body. For example, the two chambers may be configured such that they are in fluid communication with each other (e.g., by way of a conduit between the two chambers) and allow mixing of the two components when desired by a user prior to dispensing. Alternatively or in addition, the two chambers may be configured to allow mixing as the components are being dispensed into the human or animal body.
The drugs or medicaments contained in the drug delivery devices as described herein can be used for the treatment and/or prophylaxis of many different types of medical disorders. Examples of disorders include, e.g., diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism. Further examples of disorders are acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis. Examples of APIs and drugs are those as described in handbooks such as Rote Liste 2014, for example, without limitation, main groups 12 (anti-diabetic drugs) or 86 (oncology drugs), and Merck Index, 15th edition.
Examples of APIs for the treatment and/or prophylaxis of type 1 or type 2 diabetes mellitus or complications associated with type 1 or type 2 diabetes mellitus include an insulin, e.g., human insulin, or a human insulin analogue or derivative, a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptor agonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4 (DPP4) inhibitor, or a pharmaceutically acceptable salt or solvate thereof, or any mixture thereof. As used herein, the terms “analogue” and “derivative” refer to any substance which is sufficiently structurally similar to the original substance so as to have substantially similar functionality or activity (e.g., therapeutic effectiveness). In particular, the term “analogue” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, by deleting and/or exchanging at least one amino acid residue occurring in the naturally occurring peptide and/or by adding at least one amino acid residue. The added and/or exchanged amino acid residue can either be codeable amino acid residues or other naturally occurring residues or purely synthetic amino acid residues. Insulin analogues are also referred to as “insulin receptor ligands”. In particular, the term “derivative” refers to a polypeptide which has a molecular structure which formally can be derived from the structure of a naturally occurring peptide, for example that of human insulin, in which one or more organic substituent (e.g. a fatty acid) is bound to one or more of the amino acids. Optionally, one or more amino acids occurring in the naturally occurring peptide may have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or amino acids, including non-codeable, have been added to the naturally occurring peptide.
Examples of insulin analogues are Gly(A21), Arg(B31), Arg(B32) human insulin (insulin glargine); Lys(B3), Glu(B29) human insulin (insulin glulisine); Lys(B28), Pro(B29) human insulin (insulin lispro); Asp(B28) human insulin (insulin aspart); human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Examples of insulin derivatives are, for example, B29-N-myristoyl-des(B30) human insulin, Lys(B29) (N-tetradecanoyl)-des(B30) human insulin (insulin detemir, Levemir®); B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-gamma-glutamyl)-des(B30) human insulin, B29-N-omega-carboxypentadecanoyl-gamma-L-glutamyl-des(B30) human insulin (insulin degludec, Tresiba®); B29-N—(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyhepta-′decanoyl) human insulin.
Examples of GLP-1, GLP-1 analogues and GLP-1 receptor agonists are, for example, Lixisenatide (Lyxumia®, Exenatide (Exendin-4, Byetta®, Bydureon®, a 39 amino acid peptide which is produced by the salivary glands of the Gila monster), Liraglutide (Victoza®), Semaglutide, Taspoglutide, Albiglutide (Syncria®), Dulaglutide (Trulicity®), rExendin-4, CJC-1134-PC, PB-1023, TTP-054, Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926, NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697, DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030, CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN and Glucagon-Xten.
An example of an oligonucleotide is, for example: mipomersen sodium (Kynamro®), a cholesterol-reducing antisense therapeutic for the treatment of familial hypercholesterolemia.
Examples of DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin, Saxagliptin, Berberine.
Examples of hormones include hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.
Examples of polysaccharides include a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra-low molecular weight heparin or a derivative thereof, or a sulphated polysaccharide, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium. An example of a hyaluronic acid derivative is Hylan G-F 20 (Synvisc®), a sodium hyaluronate.
The term “antibody”, as used herein, refers to an immunoglobulin molecule or an antigen-binding portion thereof. Examples of antigen-binding portions of immunoglobulin molecules include F(ab) and F(ab′)2 fragments, which retain the ability to bind antigens. The antibody can be polyclonal, monoclonal, recombinant, chimeric, de-immunized or humanized, fully human, non-human, (e.g., murine), or single chain antibody. In some embodiments, the antibody has effector function and can fix a complement. In some embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, the antibody can be an isotype or subtype, an antibody fragment or mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region. The term antibody also includes an antigen-binding molecule based on tetravalent bispecific tandem immunoglobulins (TBTI) and/or a dual variable region antibody-like binding protein having cross-over binding region orientation (CODV).
The terms “fragment” or “antibody fragment” refer to a polypeptide derived from an antibody polypeptide molecule (e.g., an antibody heavy and/or light chain polypeptide) that does not comprise a full-length antibody polypeptide, but that still comprises at least a portion of a full-length antibody polypeptide that is capable of binding to an antigen. Antibody fragments can comprise a cleaved portion of a full length antibody polypeptide, although the term is not limited to such cleaved fragments. Antibody fragments that are useful in the present disclosure include, for example, Fab fragments, F(ab′)2 fragments, scFv (single-chain Fv) fragments, linear antibodies, monospecific or multispecific antibody fragments such as bispecific, trispecific, tetraspecific and multispecific antibodies (e.g., diabodies, triabodies, tetrabodies), monovalent or multivalent antibody fragments such as bivalent, trivalent, tetravalent and multivalent antibodies, minibodies, chelating recombinant antibodies, tribodies or bibodies, intrabodies, nanobodies, small modular immunopharmaceuticals (SMIP), binding-domain immunoglobulin fusion proteins, camelized antibodies, and VHH containing antibodies. Additional examples of antigen-binding antibody fragments are known in the art.
The terms “Complementarity-determining region” or “CDR” refer to short polypeptide sequences within the variable region of both heavy and light chain polypeptides that are primarily responsible for mediating specific antigen recognition. The term “framework region” refers to amino acid sequences within the variable region of both heavy and light chain polypeptides that are not CDR sequences, and are primarily responsible for maintaining correct positioning of the CDR sequences to permit antigen binding. Although the framework regions themselves typically do not directly participate in antigen binding, as is known in the art, certain residues within the framework regions of certain antibodies can directly participate in antigen binding or can affect the ability of one or more amino acids in CDRs to interact with antigen.
Examples of antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6 mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).
Pharmaceutically acceptable salts of any API described herein are also contemplated for use in a drug or medicament in a drug delivery device. Pharmaceutically acceptable salts are for example acid addition salts and basic salts.
Those of skill in the art will understand that modifications (additions and/or removals) of various components of the APIs, formulations, apparatuses, methods, systems and embodiments described herein may be made without departing from the full scope and spirit of the present disclosure, which encompass such modifications and any and all equivalents thereof.
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16324818
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sanofi-aventis deutschland gmbh
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 27th, 2022 08:38AM
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Apr 27th, 2022 08:38AM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 26th, 2022 12:00AM
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Jul 24th, 2019 12:00AM
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https://www.uspto.gov?id=US11315670-20220426
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Method and monitoring device for monitoring operation of a drug delivery device
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The present invention relates to a method and to a monitoring device for monitoring operation of a drug delivery device, the monitoring device comprising of at least a first and a second sensor arranged at a distance from each other with regard to a first direction and being adapted to generate a first and a second electrical signal in response to an operation of the device, a processing unit configured to determine a time delay between the first and the second electrical signals and being adapted to determine at least one state parameter of the drug delivery device on the basis of said time delay.
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11315670
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1. A monitoring device for monitoring operation of a drug delivery device, wherein the drug delivery device comprises a drive mechanism operable to set and/or to dispense a dose of a medicament, wherein at least one of setting and dispensing of the dose is accompanied by a displacement or movement of a first signal generator of the drive mechanism along a first direction, wherein the first signal generator is configured to generate a first detectable signal when moving along the first direction, the monitoring device comprising:
a first sensor configured to generate a first electrical signal in response to a detection of the first detectable signal emanating from the first signal generator when moving along the first direction;
a second sensor arranged at a distance from the first sensor with regard to the first direction and being configured to generate a second electrical signal in response to a detection of the same first detectable signal emanating from the first signal generator; and
a processing unit connected to the first sensor and to the second sensor, the processing unit being configured to receive the first electrical signal from the first sensor and the second electrical signal from the second sensor, the processing unit being configured to determine at least one of a dosing related parameter or a dispensing related status of the drug delivery device based on a time delay between receiving the first electrical signal and the second electrical signal.
2. The monitoring device according to claim 1, wherein at least one of the first sensor and the second sensor comprises at least one of an acoustic sensor, a vibration sensor, an acceleration sensor and a mechanical tension sensing element.
3. The monitoring device according to claim 1, wherein the processing unit is configured to determine a size of a dose set by the drug delivery device when the time delay is smaller than or equal to a predefined dosage value.
4. The monitoring device according to claim 1, wherein the processing unit is adapted to identify and/or to detect a dispensing operation of the drug delivery device when the time delay substantially equals a predefined injection value.
5. The monitoring device according to claim 1, wherein at least one of the first sensor, the second sensor and the processing unit is adapted to distinguish between the first detectable signal generated by the first signal generator and a second detectable signal generated by a second signal generator.
6. The monitoring device according to claim 1, wherein setting and/or dispensing of the dose is accompanied by the first detectable signal generated by the first signal generator when the first signal generator is subject to a displacement or movement along the first direction during setting of the dose and/or during dispensing of the dose.
7. The monitoring device according to claim 1, wherein the monitoring device is fastenable to a housing of the drug delivery device in a pre-defined position and/or pre-defined orientation, such that the first signal generator is movable along the first direction and is located between the first sensor and the second sensor with regard to the first direction.
8. The monitoring system according to claim 1, wherein the first signal generator is a click-sound generating component and the first detectable signal is a clicking sound.
9. The monitoring system according to claim 1, wherein the first detectable signal propagates from a housing of the drug delivery device to the monitoring device through a mechanical connection.
10. A monitoring system, comprising:
a drug delivery device comprising a housing and a drive mechanism configured to interact with a cartridge containing a medicament to dispense, wherein the drive mechanism comprises a first signal generator movably disposed along a first direction relative to the housing during at least one of a dose setting operation and a dose dispensing operation, the first signal generator configured to generate a detectable signal when moving along the first direction; and
a monitoring device, the monitoring device comprising:
a first sensor configured to generate a first electrical signal in response to a detection of a detectable signal caused by a movement of the first signal generator relative to the housing during at least one of the dose setting operation and the dose dispensing operation,
a second sensor arranged at a distance from the first sensor with regard to the first direction and configured to generate a second electrical signal in response to the detection of the same detectable signal caused by the movement of the first signal generator,
wherein the first signal generator is operable to generate a detectable signal detectable by the first sensor and by the second sensor during at least one of the dose setting operation and the dose dispensing operation, and
a processing unit connected to the first sensor and to the second sensor, the processing unit being configured to receive the first electrical signal from the first sensor and the second electrical signal from the second sensor and determine at least one of a dosing related parameter or dispensing related status of the drug delivery device based on a time delay between receiving the first electrical signal and the second electrical signal.
11. The monitoring system according to claim 10, wherein the first signal generator is adapted to generate a first audible or acoustic signal during the dose setting operation of the drive mechanism.
12. The monitoring system according to claim 10, wherein the drive mechanism comprises at least a second signal generator adapted to generate a second audible or acoustic signal during the dose dispensing operation of the drive mechanism.
13. The monitoring system according to claim 10, wherein the monitoring device is fastenable to the housing of the drug delivery device in a predefined position such that the first signal generator of the drive mechanism is located between the first sensor and the second sensor with regard to the first direction.
14. The monitoring system according to claim 10, wherein the monitoring device is fastenable to the housing of the drug delivery device in a predefined position such that the first signal generator of the drive mechanism is located outside an intermediate space between the first sensor and the second sensor of the monitoring device with regard to the first direction.
15. The monitoring system according to claim 10, wherein the first signal generator is a click-sound generating component and the detectable signal is a clicking sound.
16. The monitoring system according to claim 10, wherein the first detectable signal propagates from the housing of the drug delivery device to the monitoring device through a mechanical connection.
17. A method of monitoring operation of a drug delivery device, the drug delivery device comprising a housing and a drive mechanism, the drive mechanism comprising at least a first signal generator movably disposed along a first direction relative to the housing, the method comprising:
generating an audible or acoustic signal by the first signal generator when the first signal generator moves along the first direction during at least one of setting and dispensing of a dose;
detecting the same audible or acoustic signal by both a first sensor and by a second sensor of a monitoring device, wherein the first sensor and the second sensor are arranged at a distance from each other with regard to the first direction;
generating a first electrical signal by the first sensor and generating a second electric signal by the second sensor;
receiving the first electrical signal and the second electrical signal by a processing unit;
determining a time delay between the first electrical signal and the second electrical signal by the processing unit; and
determining at least one dosing related parameter or dispensing related status of the drug delivery device based on the time delay.
18. The method according to claim 17, further comprising:
comparing a magnitude of the time delay with at least one of a predefined dosage value and/or injection value; and
determining a size of a set dose and/or identifying and/or detecting a dispensing operation of the drug delivery device based on the comparison.
19. A monitoring system, comprising:
a drug delivery device comprising a housing and a drive mechanism configured to interact with a cartridge containing a medicament to dispense, wherein the drive mechanism comprises a first signal generator movably disposed along a first direction relative to the housing during operation of the drug delivery device; and
a monitoring device, the monitoring device comprising:
a first sensor configured to generate a first electrical signal in response to a movement of the first signal generator relative to the housing during operation of the drug delivery device,
a second sensor arranged at a distance from the first sensor and configured to generate a second electrical signal in response to the movement of the first signal generator,
wherein the first signal generator is operable to generate a detectable signal detectable by the first sensor and by the second sensor during operation of the drug delivery device,
wherein the first signal generator is adapted to generate a first audible or acoustic signal during a dose setting operation of the drive mechanism, and
a processing unit connected to the first sensor and to the second sensor, the processing unit being configured to receive the first electrical signal from the first sensor and the second electrical signal from the second sensor and determine at least one of a dosing related parameter or dispensing related status of the drug delivery device based on a time delay between receiving the first electrical signal and the second electrical signal.
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a divisional of U.S. patent application Ser. No. 14/240,796, filed Feb. 25, 2014, which is a U.S. National Phase Application pursuant to 35 U.S.C. § 371 of International Application No. PCT/EP2012/067548 filed Sep. 7, 2012, which claims priority to European Patent Application No. 11180590.9 filed Sep. 8, 2011. The entire disclosure contents of these applications are herewith incorporated by reference into the present application.
TECHNICAL FIELD
The present invention relates to the field of drug delivery devices and in particular to injection devices designed and intended for regular and long-term self-medication. In particular, the invention refers to a monitoring device adapted to monitor and to log or to record usage and handling of the drug delivery device.
BACKGROUND
Chronic diseases require administering of medicaments or drugs according to a pre-defined time schedule in order to keep the concentration level of a pharmaceutically active substance on a pre-defined level. Many medicaments require administration by way of injection by making use of syringes or syringe-like drug delivery devices. Such devices should be universally applicable and should be operable even by persons without formal medical training.
Moreover, such devices, like pen-type injectors should provide accurate, precise and reliable setting of a dose and subsequent dispensing of the respective medicament. Typically, the medicament to be dispensed and injected is provided in a disposable or replaceable cartridge, such as a vial, an ampoule or a carpule comprising a slidably disposed piston to become operably engaged with a piston rod of a drive mechanism of the drug delivery device. The drive mechanism is adapted to apply thrust to the cartridge's piston in distal direction in order to built-up a respective fluid pressure, which in turn leads to a dispensing of the liquid medicament via a dispensing or distal end of the cartridge being typically in fluid connection with a piercing element like an injection needle.
It is generally of importance, that the patient strictly follows a given prescription schedule. However, patients that already got used to the medicament for a long time or patients that suffer side effects of a chronic disease and which may be physically impaired, compliance of the prescription schedule is sometimes sub-optimal. Since a large variety of existing drug delivery devices is implemented all-mechanically, it is further rather difficult for an attending physician to control, whether the patient strictly follows the prescription schedule.
From document WO 2007/107564 A1 an electronic module is known, which is to be positioned on an outer surface of a pen-like medication delivery device. The electronic module is capable of measuring signals, such as audible, optical, vibration or electromagnetic signals, generated during operation of a pen-like medication delivery device. By way of detecting acoustic signals generated in response to setting of a dose of a medicament or generated in response to expelling a dose of the medicament, respective information can be gathered and stored in the electronic module, which allow to monitor frequent usage and operation of the drug delivery device.
Hence, the known electronic device may detect different “click-sounds” being indicative of a dose setting or of a dose dispensing procedure, respectively. However, such an electronic module is so far unable to precisely determine the size of a dose and the corresponding amount of the respective medicament dispensed from the device during an injection operation.
It is therefore an object of the present invention to provide an improved monitoring device allowing for contactless and quantitative determination of a dose set and/or to be dispensed by a drug delivery device. Moreover, the monitoring device should provide an elegant, reliable and precise approach to unequivocally detect and to identify one or more parameters, for example state parameters, or configurations of the drug delivery device, being preferably implemented in an all-mechanical way.
SUMMARY
In a first aspect, the invention provides a monitoring device for monitoring operation of a drug delivery device. The monitoring device is particularly adapted for contactless and/or wireless monitoring of subsequent device operations. The monitoring device typically provided as a separate unit to be coupled and/or interconnected with the housing of the drug delivery device comprises at least a first and a second sensor arranged at a distance from each other with regard to a first direction, e.g. a longitudinal direction. The two sensors are each adapted to generate a first and a second electrical signal in response to an operation of the device.
Typically, the two sensors are adapted to detect and/or to record one and the same detectable operation of the device. The sensors are further coupled with a processing unit of the monitoring device which is adapted to determine a time delay between the first and the second electrical signals generated by first and second sensors, respectively. On the basis of this time delay, the processing unit is further adapted to determine at least one parameter, for example a state parameter, of the drug delivery device.
The monitoring device is suitable and designed for drug delivery devices, wherein setting and/or dispensing of a dose is accompanied by device-specific or by device-characteristic features that are detectable outside the device by way of the monitoring device. Said features may express in a visual, audible and/or haptic way. They are typically generated by a particular component of the drive mechanism of the drug delivery device, which is preferably subject to a displacement or movement along the first direction during dose setting and/or dose dispensing.
By making use of two different sensors separated from each other along the first direction, a varying or moving place of origin of the detectable signal during operation of the drug delivery device and/or of its drive mechanism along the first direction can be detected. The displacement of the signal generating component of the drive mechanism reflects in a time delay between the signals detected or recorded by first and second sensors, respectively. From the detected or measured time delay, a relative position of the signal generation component of the drive mechanism relative to the position of first and second sensors can be derived. The position of the signal generating component of the drive mechanism is typically indicative of the configuration of the drive mechanism from which e.g. the actual size of a dose can be calculated or determined.
According to a preferred embodiment, the first and/or the second sensors comprise an acoustic-, a vibration-, an acceleration- and/or a mechanical tension sensing element. Preferably, the sensors are designed as acoustic or vibrational sensors by way of which a characteristic click-sound of the drive mechanism can be detected. Depending on the relative position of a click-sound generating component of the drive mechanism and the two respective sensors, for instance an audible signal provided by the drive mechanism may be almost simultaneously detected at the location of two detectors, with a time delay typically in the range of microseconds.
Operation of the drug delivery device, either for dose setting or dose dispensing typically leads to a displacement of the click-sound generating component of its drive mechanism, thus leading to a respective modification of the time delay. For instance, zero time delay between first and second electrical signals corresponds to a configuration, wherein the click-sound generating component of the drug delivery device is substantially equally spaced from first and second sensors. A positive time delay corresponds to configurations, wherein the click-sound generating component of the drive mechanism is arranged closer to the first sensor than to the second sensor. A negative time delay corresponds to a configuration, wherein the click-sound generating component is arranged nearer to the second sensor than to the first sensor.
Correspondingly, a positive time delay may be therefore indicative of a rather small dose size, zero time delay may correspond to a medium dose size and a negative time delay may represent a rather large dose size, or vice versa.
Depending on the precision of the detectors and the signal processing of the processing unit, the magnitude of the detected time delay between first and second electrical signals may be precisely correlated with the respective dose size. This way, by making use of two sensors and by evaluating a time delay between them, the size of a set dose in an all-mechanically implemented drug delivery device can be quantitatively and precisely determined in a cost-efficient way. Hence, dose size determination does not require any modifications to a mechanically implemented drug delivery device. It is only required, that the monitoring device is connected with the housing of the drug delivery device in a pre-defined and signal transferring manner.
Even though the invention is preferably described in terms of audible and acoustic signals, the basic concept of the invention can be generally implemented also on the basis of vibrational signals, as well as with acceleration- and mechanical tension-signals. Signal propagation velocity within the housing of the drug delivery device should be in a range allowing to detect a time delay.
Propagation of sound signals, vibrational signals or other mechanical waves propagating in the housing of the drug delivery device should be precisely detectable by the first and second sensors. Moreover, the type of signal to be detected as well as the material, the respective signal wave is propagating through should allow for detection of a time delay. For instance with thermoplastic housing components and with acoustic waves featuring a velocity of propagation in the range of 103 m/s, detectable time delays between first and second electrical signals are typically in the range of microseconds.
According to a further preferred aspect, the monitoring device further comprises at least one threshold circuit to detect the occurrence of of the first and/or of the second electrical signal generated by first and second sensors exceeding a threshold value, respectively. This way, arrival of e.g. a sound wave at the first or second sensor can be precisely and sharply determined. The threshold circuit, which may comprise a Schmitt-trigger or some other kind of comparator-circuit provides a kind of threshold switch. As soon as the electrical signal generated by first and/or second sensor crosses a pre-defined threshold, the respective threshold circuit generates a maximum signal or a minimum signal to be interpreted by a processing unit as logical one or logical zero.
The signals provided by first and second sensors are preferably separately processed by respective first and second threshold circuits. The signals generated by the threshold circuits are then adapted to start and/or to stop a timer module in order to determine the time delay between them.
According to a further preferred embodiment, the processing unit is adapted to determine the size of a dosage set by the drug delivery device when the time delay is smaller than or equal to a pre-defined dosage value (x). This feature typically implies, that a click-sound generating component of the drug delivery device is disposed between first and second sensors with regard to the first direction. The distance between first and second sensors is selected or determined such, that for any possible dose setting configuration of the drive mechanism the click-sound generating component remains between first and second sensors.
The predefined dosage value (x) is typically governed by the velocity of propagation of sound waves in the housing of the drug delivery device and by the distance of first and second sensors. The pre-defined dosage value is typically smaller than the distance between first and second sensors with respect to the first direction divided by the velocity of propagation of the signal generated by the click-sound generating component.
This way, any time delay being smaller than the pre-defined dosage value (x) is a clear indication that the respective signals arise from a dose-setting related displacement of a click-sound generating component of the drug delivery device.
According to a further preferred embodiment, the processing unit is also adapted to identify and/or to detect a dispensing operation of the drug delivery device when the time delay substantially equals a pre-defined injection value (y). Preferably, another click-sound generating component being indicative of an injection or dispensing operation of the drug delivery device is positioned outside the spatial region delimited by first and second sensors, respectively.
By having the dispensing click-sound generating component arranged outside the distance region of first and second sensors, a respective dispensing clicking sound may always lead to substantially identical time delays, irrespective of the actual position or configuration of the drive mechanism. The pre-defined injection value (y) substantially corresponds to or equals the distance between first and second sensors divided by the velocity of propagation.
The processing unit is accordingly adapted to distinguish and to categorize the various time delays. If the time delay ranges between zero and the predefined dosage value (x), a dose setting of the drug delivery device can be logged and monitored. When a time delay substantially equal to the pre-defined injection value (y) is detected, this is an indication, that a dispensing injection procedure takes place. Accordingly, the monitoring device which is further equipped with an electronic storage as well as with a user interface module may increment a dispensing counter.
Moreover, the processing unit may at least temporally store the actual time delay being smaller than or equal to the pre-defined dosage value. In response of subsequently detecting a dose injection procedure, the actual and/or temporarily stored time delay being smaller than or equal to the pre-defined dosage value can be stored or logged in the memory of the monitoring device, e.g. together with a time stamp, thereby allowing to size of the dose actually dispensed.
According to a further preferred embodiment, the monitoring device comprises a third sensor, adapted to individually determine the size of a dosage set by the drug delivery device. In contrast to the first and/or the second sensors, the third sensor may be implemented optically in order to acquire visual information about the size of the set dosage. Signals generated and/or acquired by the third sensor may be separately provided to the processing unit and may be processed either separately or in combination with the signals provided by the first and/or second sensors, which are preferably implemented acoustically.
Usage of a third sensor is of particular benefit in case when e.g. signals of first and second sensors are ambiguous or lie beyond a predefined range. Then, by way of the third sensor, signals obtained from first and/or second sensors can be unequivocally assigned to a particular type and/or magnitude of a state parameter of the device.
Moreover, in a further preferred embodiment, the processing unit is also able to distinguish and/or to determine the leading and/or the trailing signal of the multiplicity of signals generated by the first and/or second sensor. This way, positive and negative time delays can be obtained being further indicative on the size of the set dosage.
According to a further embodiment, the distance with regard to the first or a longitudinal direction between the first and the second sensor is smaller than or equal to the distance between a first and a second sound generating element of the drug delivery device. This way, a configuration can be attained, wherein at least one sound generating element always remains between first and second sensors for any conceivable configuration of the drive mechanism. The sound generating element sandwiched or disposed between first and second sensors is preferably designed to generate audible signals during a dose setting operation.
According to a further or alternative embodiment, the first and/or the second sensors and/or the processing unit is or are adapted to identify different sounds generated by different sound generating elements of the drug delivery device. In particular, the spectral range of for instance a first click-sound generating element is different from the spectral range of the click-sound generated by a second sound generating element. Assuming that first and second sound generating elements are exclusively adapted to generate respective sounds either during dose setting or during dose dispensing, respective dose setting and dose dispensing procedures can be easily detected by spectral analysis of the sound signals to be detected by the first and/or the second sensor.
Additionally and according to another embodiment, the monitoring device also comprises at least one fastening element to releasably fasten the monitoring device in a pre-defined manner to a housing of the drug delivery device. Monitoring device and housing of the drug delivery device may comprise mutually corresponding fastening members, by way of which the monitoring device can be attached to the drug delivery device in a pre-defined and precise way. By providing the monitoring device as a stand-alone electronic device, it can be used with a plurality of different drug delivery devices, which e.g. by the virtue of their all-mechanical implementation may even be designed as disposable pen-type injectors. This way, the monitoring device, releasably attached to the drug delivery device by the at least one fastening element can be repeatedly used with a series of e.g. disposable and cost-efficient drug delivery devices.
In another but independent aspect, the invention also refers to a monitoring system comprising a drug delivery device. The drug delivery device has a housing and a drive mechanism as well as a cartridge being at least partially filled with a medicament to be dispensed. Dispensing or injection of the medicament requires interaction of the drive mechanism, typically with a proximal seal or piston of the cartridge.
The drive mechanism, which may be implemented all-mechanically comprises at least one sound generating element movably disposed along a first direction relative to the housing. This way, during dose setting as well as during dose dispensing or dose injection, the sound generating element is subject to spatial displacement along said first direction relative to the housing. The monitoring system further comprises a monitoring device as described above being fastened to or at least acoustically coupled with the drug delivery device.
Here, first and second sensors of the monitoring device are adapted to detect the sound generated by the sound generating element of the drive mechanism in response to an operation of the same. By detecting and determining time delays between electrical signals to be generated by first and second sensors, respectively, a relative position of the sound generating element with respect to first and second sensors can be derived. Said relative position is a direct indication of the size of the dose set by the drive mechanism and can therefore at least temporally stored or logged in a storage module of the monitoring device.
In a further embodiment of the monitoring system, the drive mechanism of the drug delivery device comprises a first and a second sound generating element, wherein the first sound generating element is adapted to generate a first click-sound during a dose setting operation of the drive mechanism. In contrast to that, the second sound generating element of the drive mechanism is adapted to generate a second click-sound during a dose dispensing operation. Spectral ranges of first and second click-sounds may even coincide or may vastly overlap. Distinction between dose setting and dose dispensing may be exclusively conducted by determination of the above described time delay.
According to a further preferred embodiment, the monitoring device is fastenable to the housing of the drug delivery device in a pre-defined position and/or orientation, such that the at least one sound generating element of the drive mechanism is located between the first and the second sensors of the monitoring device with regard to the first direction. The distance between first and second sensors of the monitoring device is larger than or equal to a maximum distance, the first sound generating element can be moved during a dose dispensing operation. This way it can be ensured, that the first sound generating element always remains between the first and the second sensors in any conceivable configuration of the drive mechanism.
Moreover, the monitoring device is to be fastened to the housing in such a way that even for all conceivable positions and configurations of the drug delivery device the at least one sound generating element remains in the detection range defined by the first and second sensors. This way, the at least one, preferably both sound generating elements always remain in the spatial range of the arrangement formed by at least first and/or second sensors.
The dose setting operation can be therefore characterized in that the time delay is smaller than or equal to a pre-defined dosage value (x).
According to a further preferred embodiment, the at least one sound generating element, preferably the second sound generating element of the drive mechanism is located outside an intermediate space defined by first and second sensors of the monitoring device with regard to the first direction. The respective sound generating element is preferably located at a rather remote or proximal region of the drive mechanism, which in any conceivable configuration of the drive mechanism is beyond or outside said intermediate space.
A sound generated by this second remote sound generating element leads to a time delay which directly corresponds to the distance of first and second sensors and is therefore indicative of a dispensing operation. The time delay to be detected in response of a click-sound generation with the second sound generating element as origin is substantially constant irrespective of the position of the second sound generating element relative to the monitoring device and its first and second sensors as long as said sound generating element is positioned outside said intermediate space.
In a further independent aspect the invention also relates to a method for monitoring operation of a drug delivery device. The drug delivery device, preferably designed as pen-type injector comprises a housing and a drive mechanism, wherein the drive mechanism is to be operably engaged with a piston of a cartridge disposed in the drug delivery device. The drive mechanism further comprises at least one sound generating element moveably disposed along a first direction relative to the housing. The method of monitoring of the drug delivery device comprises the steps of generating a sound during operation of the drive mechanism and detecting said sound by a first sensor and by a second sensor arranged at a distance from each other with regard to the first direction.
In response to the sound detection, respective first and second electrical signals are generated and a time delay between first and second electrical signals is determined. On the basis of said time delay, at least one state or condition parameter of the drug delivery device is determined or derived. Said method is preferably conducted by way of a monitoring device, e.g. to be releasably fastened to the housing of the drug delivery device in such a way, that first and second sensors of the monitoring device are precisely positioned relative to the at least one sound generating element of the drive mechanism of the drug delivery device.
According to a further embodiment, the magnitude of the time delay is compared to pre-defined dosage and/or pre-defined injection values (x, y) for either determining a size of a set dosage and/or for identifying and/or for detecting a dispensing operation of the drug delivery device. Depending on whether a dose size or an injection procedure has been determined, the dose size can be associated with a time stamp and can be stored in an electronic memory module of the monitoring device. This way and by means of appropriate storage reading devices, the actual dosing schedule conducted with an all-mechanically implemented drug delivery device can be precisely monitored and displayed to e.g. an attending physician.
It is further to be noted, that all features and embodiments as described herein are understood to equally apply to the monitoring device, to the monitoring system as well as to the method of monitoring operation. In particular, a mentioning of a component being configured or arranged to conduct a particular operation is to be understood to disclose a respective method step and vice versa.
The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Arg-Leu-Phe-Ile-Phe-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro36 Exendin-4(1-39),
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
It will be further apparent to those skilled in the pertinent art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. Further, it is to be noted, that any reference signs used in the appended claims are not to be construed as limiting the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
In the following, a preferred embodiment of the invention will be described by making reference to the drawings, in which:
FIG. 1 shows a drug delivery device in form of a pen-type injector in a perspective exploded view,
FIG. 2 is illustrative of a respective drug delivery device and further indicates positions of sensors and sound generating elements,
FIG. 3 shows a diagram of a first, positive time delay,
FIG. 4 shows a diagram of substantially zero time delay,
FIG. 5 shows a diagram illustrating a negative time delay,
FIG. 6 shows a diagram with a time delay indicating a dose dispensing operation and
FIG. 7 shows a diagram representing irrelevant noise,
FIG. 8 schematically shows relative position of sensors and sound generating elements in an initial configuration of the drug delivery device and
FIG. 9 shows a comparative device after setting of a dose,
FIG. 10 shows a schematic block diagram of the monitoring device to be acoustically and/or mechanically coupled with the drug delivery device.
DETAILED DESCRIPTION
FIG. 1 is illustrative of a drug delivery device 1 designed as a pen-type injector. The device comprises a proximal housing component 10 featuring a dosage window 13 through which the size of a set dose can be visually inspected. The housing 10 accommodates a drive mechanism 21 being not further illustrated here but which is to be operated by means of a dose dial 12 and by means of a injection button 11.
The housing 10 and its drive mechanism 21 is operably engaged with a cartridge 14 being filled with the medicament to be injected. Typically, the cartridge is disposed in a cartridge holder 19 as shown in FIG. 2 featuring at least one inspection window 20 allowing to visually inspect the filling level of the cartridge 14 disposed therein. The cartridge holder 19 or the cartridge 14 itself comprises a threaded socket portion at a distal outlet section in order to threadedly engage with a needle assembly 15 comprising a double-tipped injection needle. The replaceable and disposable injection needle 15 is provided with an inner needle cap 16 protecting the needle tip and further comprises an outer needle cap 17 that may serve as a package for the needle assembly 15.
The distal section of the drug delivery device 1 comprising the cartridge 14 and/or the cartridge holder 19 is further adapted to be protected and covered by a protective cap 18.
The present type of drug delivery device 1 may be implemented either as reusable device, wherein the cartridge 14 can be replaced when its content is used up. Alternatively, the drug delivery device can be designed as a disposable and all-mechanical device which is intended to be entirely discarded after consumption of the medicament provided in the cartridge 14. The drive mechanism 21 may resemble the one as disclosed for instance in EP 1 603 611 B1. Hence, for setting of a dose, the dose dial 12 may be turned in a screwed motion, thereby displacing the dose dial 12 and the injection button 11 in proximal direction 2, in which the dose dial 12 extends in longitudinal direction from the housing 10.
As further illustrated in FIG. 2, the drive mechanism 21 comprises two sound generating elements 22, 24 that generate a respective or characteristic click-sound either during dose setting or during dose dispensing. In the present embodiment, the distally located sound generating element 22 generates multiple or subsequent click-sounds during a dose setting operation. The proximally located sound generating element 24 is in turn adapted to generate at least one click-sound at the beginning, during or at the end of a dose dispensing operation, during which a user by exerting pressure in distal direction 3 returns the dose dial 12 back into its initial configuration as shown in FIGS. 2 and 8.
In FIG. 2, two sensors 23, 25 are illustrated that are adapted to detect audible signals generated by the two sound generating elements 22, 24 of the dose mechanism 21 of the drug delivery device 1. The two sensors 23, 25 belong to a monitoring device 40 as indicated in FIGS. 8 through 10, which is to be releasably coupled or connected to the housing 10 of the drug delivery device 1.
The drive mechanism 21, at least its dose dial sleeve 12 and the two sound generating elements 22, 24 are movably disposed relative to the housing 10 in longitudinal direction 2, 3. Hence, for dose setting, the drive mechanism 21 is displaced in proximal direction 2 and for dose dispensing, the drive mechanism 21 together with its sound generating elements 22, 24 returns to its initial configuration by a movement in distal direction 3.
As shown in FIGS. 2, 8 and 9, the first or distally located sound generating element 22 is located between the first and second sensors 23, 25. In the configuration according to FIGS. 2 and 8, longitudinal distance between sound generating element 22 and sensor 23 is smaller than the distance between element 22 and sensor 25. Therefore, with the beginning of a dose setting motion, the sensor 23 will receive the sound signal generated by the sound generating element 22 earlier than the second sensor 25.
Further and as indicated in FIGS. 8 and 9, the monitoring device 40 may comprise a third sensor 46, being e.g. implemented as optical sensor to visually detected a size of a set dosage. By way of the third sensor 46 additional information about the state of the drug delivery device 1 can be obtained that may be further used to process the signals obtained from the first and/or second sensors 23, 25. Moreover, by way if the third sensor 46, calibration of the monitoring device 40 can be provided in general.
The respective sensor signals are depicted in FIG. 3. The various sketches of FIGS. 3 to 7 show various diagrams 30, 32 of a electrical signals 31, 33 being generated by first and second sensors 23, 25, respectively. The situation as illustrated in FIG. 3 corresponds to the initial setting of FIG. 2. Hence, the signal 31 received and generated by sensor 23 advances the signal 33 generated by the proximally located sensor 25.
The time delay 36 between the two signals 31, 33 is indicative of the longitudinal position of sound generating element 22 relative to sensors 23, 25. The positive time delay 36 according to FIG. 3 is therefore indicative of a rather small dose size.
The diagrams 30, 32 of FIG. 4 relate to a configuration according to FIG. 9, wherein the sound generating element 22 is located almost in the middle between sensors 23, 25. Consequently, the two sensors 23, 25 receive the acoustical or vibrational signal almost at the same time. Consequently, the time delay 36 between signals 31′ and 33′ is almost zero and is therefore not further illustrated in FIG. 4.
The situation as illustrated in FIG. 5 corresponds to a rather large dose, wherein the dose dial and its dose sleeve 26 is displaced a maximum distance relative to the housing 10. Consequently, the sound generating element 22 is still located between sensors 23, 25 but is positioned much closer to sensor 25 than to sensor 23. Correspondingly, signal 33″ of sensor 25 advances the signal 31″ of sensor 23. A corresponding negative time delay 36′ therefore arises being indicative of a rather large or maximum dose to be set by the present drive mechanism 21.
The proximally located sound generating element 24 is already located proximally from the distal sensor 25 in the initial configuration of the drive mechanism 21 as shown in FIGS. 2 and 8. It therefore lies outside the spatial region or outside the intermediate space formed by the two sensors 23 and 25. Even when the dose sleeve 26′ is pulled out in distal direction 2 as shown in FIG. 9, the time delay 36″ of a signal emanating from the sound generating element 24 substantially equals a pre-defined injection value (y), which is governed by the longitudinal distance between sensors 23, 25 and the velocity of sound propagation in the housing 10.
Typically, the pre-defined injection value (y) is larger than the maximum dosage value (x) that may originate from the distal sound generating element 22. This way, a dispensing operation accompanied by a click-sound originating from sound generating element 24 can be distinguished from dose setting operations accompanied by click-sounds originating from distal sound generating element 22 by a comparison of the time delay 36 with pre-defined dosage value x or pre-defined injection value y.
Apart from a time delay distinction it is also conceivable, that the click-sounds generated by the sound generating elements 22, 24 feature a different spectral range that can be accordingly detected by at least one of the sensors 23, 25.
FIG. 7 further shows a situation, wherein a time delay 36″′ between signals 34 and 35 of sensors 23 and 25 exceeds the pre-defined dosage value x and/or the injection value y. Moreover, the delay 36″′ is positive. Such a constellation neither matches with a dose setting operation nor with a dose dispensing operation and is therefore identified as irrelevant background noise. Since its origin must be located distally from the distal sensor 23 it may be generated in response of removal of any of the caps 16, 17, 18 of the drug delivery device 1. In particular when the detected and processed time delay exceeds a predefined value (y) or when signals derived from first and/or second sensors 23, 25 do not match with signals obtained e.g. from a third sensor 46, then the processing unit is adapted to classify the measured values as false and irrelevant.
As indicated in FIGS. 8, 9 and 10, the monitoring device 40 comprises a housing and is to be releasably connected with the housing 10 of the drug delivery device 1, e.g. by clips 28 or similar fastening members that provide sufficient sound transmission and sound propagation between the housings 10 and 40.
An example of the internal structure of the monitoring device 40 is further illustrated in FIG. 10. The two sensors 23, 25 are each coupled with a signal conditioning circuit 41, 42, for example a threshold circuit that may for instance comprise a Schmitt-trigger circuit. The output lines of the two signal conditioning circuits 41, 42 are coupled with a timer module 43 in such a way that any of the signals of sensors 23, 25 may start or stop the timer 43. If according to FIG. 3 signal 31 of sensor 23 starts the timer 43, the trailing signal 33 of sensor 25 subsequently stops the timer 43. Start and stop times are subtracted by the timer 43 to obtain a time delay 36 to be further processed by the processing unit 44. Event though the timer 43 and the processing unit 44 are illustrated separately in the present embodiment, those modules 43, 44 may also be integrated in a single processing unit, e.g. comprising a microcontroller.
The timer 43 and/or the processing unit 44 are adapted to detect and/or to distinguish temporal variations in the run-time of the signals 31, 33 in the range of nanoseconds.
The quality of the signal(s) obtained from the sensors 23, 25 depends on the kind of sensors used, the geometrical properties of involved parts like injection device, monitoring device or fastening element and also possible irrelevant noises. In order to prevent that the threshold circuit not reliably determines the acoustic signals, e.g. from sound generating elements, the monitoring device 40 may be equipped with analog signal conditioning means 41, 42 and digital signal processing means, located e.g. in the signal processing unit 44, for determination of the time delay. It if of further benefit when signals 31 and 33 are cross correlated prior and/or during signal processing to enable precise determination of run-time shifts or time delays.
The central processing unit 44 which may comprise a microcontroller or some other processing device may further be equipped with a storage module not further illustrated here for storing the time delay and/or a dose size related thereto. The processing unit 44 is further coupled with a user interface (UI) module 45. The UI module 45 may comprise one or more keys and a display, allowing to provide or to display information to the user, for example stored information or device related information, such as dose information, injection information and/or the like. For instance, the monitoring device 40 may indicate to the user, that the dose recently set should not be injected because it does not match with the prescription schedule. The user interface module 45 may therefore generate a respective alert, visually and/or audible.
Additionally, the processing unit 44 may distinguish between time delays 36, 36′ being indicative of a dose size and such time delays 36″ that correspond to an injection operation. Preferably, the processing unit 44 temporally stores those time delays 36, 36′ that represent a dose size. Only in response to detection of an injection time-delay 36″, the last dose size is transferred to the storage medium and stored therein. The storage medium is preferably of non-volatile type.
This way, even after setting of a dose, the set dosage may also be repeatedly amended. Hence, a constant or repeated but stepwise increase of the dose setting leads to a constant decrease of the time delay 36, 36′. Even in case a maximum dose has already been selected and set, corrections of the set dosage are always possible by turning the dose dial 12 in an opposite direction. Such counter-rotated movement in turn leads to a decrease of the time delay 36, 36′.
Additionally, the monitoring device 40 may be equipped with a sleeping functionality, wherein one of the sensors 23, 25 and/or an additional but not illustrated acceleration sensor can be used to observe the general handling of the drug delivery device. If the device is for instance gripped by a user, such activity can be detected by any of such sensor, thereby activating the monitoring device.
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16520732
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sanofi-aventis deutschland gmbh
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 27th, 2022 08:38AM
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Apr 27th, 2022 08:38AM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 26th, 2022 12:00AM
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Mar 5th, 2020 12:00AM
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https://www.uspto.gov?id=US11311671-20220426
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Auto-injector
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Auto-injector for administering a dose of a liquid medicament includes a housing to contain a syringe with a hollow needle and a stopper for sealing the syringe and displacing the medicament, the housing having a distal end and a proximal end with an orifice to apply against an injection site. A spring means, upon activation, can push the needle from inside the housing through the orifice and past the proximal end, operate the syringe to supply the dose of medicament, and retract the syringe with the needle after delivering the medicament. An activating means can lock the spring means in a pressurized state prior to manual operation and capable of, upon manual operation, releasing the spring means for injection.
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11311671
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1. An auto-injector for administering a dose of a liquid medicament, the auto-injector comprising:
an elongate housing;
a tubular interlock sleeve configured to telescope in the elongate housing, the tubular interlock sleeve biased against the elongate housing to protrude from the elongate housing, the tubular interlock sleeve configured to translate into the elongate housing against the bias;
a syringe comprising a hollow injection needle;
a drive spring;
a plunger configured to transmit a force of the drive spring to a stopper of the syringe; and
a trigger button abutted against the elongate housing to prevent actuation of the auto-injector, the trigger button at least initially coupled to the tubular interlock sleeve, the trigger button being configured to emerge from the elongate housing in response to the tubular interlock sleeve being translated into the elongate housing against the bias,
wherein the tubular interlock sleeve is translatable in a longitudinal direction between a proximal position and a distal position and biased in a proximal direction to protrude from the elongate housing in the proximal position, wherein the tubular interlock sleeve is configured to be translated from the proximal position into an intermediate position when pressed against an injection site, and wherein the trigger button is configured such that movement of the trigger button causes the tubular interlock sleeve to move from the intermediate position into the distal position thereby releasing the drive spring.
2. The auto-injector of claim 1, wherein the trigger button is pivotable in the elongate housing and configured to rotate when operated.
3. The auto-injector of claim 1, wherein the tubular interlock sleeve is translatable in a longitudinal direction between a proximal position and a distal position and biased in a proximal direction to protrude from the elongate housing in the proximal position, wherein the tubular interlock sleeve is arranged to be translated from the proximal position into an intermediate position when pressed against the injection site.
4. The auto-injector of claim 3, wherein the tubular interlock sleeve is configured to, in the intermediate or distal position, prevent release of a distal ground of the drive spring.
5. The auto-injector of claim 3, wherein the tubular interlock sleeve comprises a ramp, wherein the trigger button comprises a pin configured to engage the ramp in response to the trigger button being pressed with the tubular interlock sleeve in its intermediate position, wherein the pin is configured to slide along the ramp and translate the tubular interlock sleeve into the distal position.
6. The auto-injector of claim 3, further comprising a tubular syringe carrier configured to hold the syringe and to support the syringe at a proximal end of the syringe, wherein the syringe and the tubular syringe carrier are configured to axially translate jointly, wherein the tubular syringe carrier is configured to telescope in the tubular interlock sleeve.
7. The auto-injector of claim 1, further comprising a retraction sleeve slidably arranged in the elongate housing, wherein the drive spring is arranged inside the retraction sleeve, wherein a distal end of the drive spring bears against a distal end face of the retraction sleeve, wherein a proximal end of the drive spring bears against a thrust face of a decoupling member, wherein a resilient lug on the tubular interlock sleeve is arranged to be engaged with the retraction sleeve by the trigger button being depressed when the tubular interlock sleeve is in its intermediate or distal position so as to prevent the retraction sleeve from translating in a distal direction.
8. The auto-injector of claim 7, wherein the resilient lug is configured to engage between a first ramp and a second ramp on the trigger button, wherein, the trigger button is configured such that in response to translation of the tubular interlock sleeve into the proximal position, the trigger button is pulled into a depressed position by the resilient lug sliding along the first ramp and the trigger button is pushed into a ready position by the resilient lug sliding along the second ramp.
9. The auto-injector of claim 7, wherein the elongate housing comprises at least one latch configured to axially fix the retraction sleeve in a maximum proximal position, wherein the decoupling member is configured to decouple the at least one latch when the decoupling member is moved in a proximal direction towards a maximum proximal position, wherein, in response to the decoupling member moving in the proximal direction, the retraction sleeve is moved in a distal direction to retract the hollow injection needle.
10. The auto-injector of claim 7, wherein the decoupling member comprises at least two resilient decoupling arms, the at least two resilient decoupling arms having inner ramped surfaces bearing against a first shoulder of the plunger in the proximal direction, wherein the at least two resilient decoupling arms are supportable by an inner wall of the retraction sleeve to prevent the at least two resilient decoupling arms from being flexed outward and slipping past the first shoulder, wherein at least one aperture is arranged in the retraction sleeve to allow the at least two resilient decoupling arms to be flexed outward by the first shoulder to allow the first shoulder to slip through the at least two resilient decoupling arms in the proximal direction, wherein the plunger is arranged to push the syringe or the stopper in the proximal direction.
11. The auto-injector of claim 7, wherein the syringe is configured to move jointly with a syringe holder which is slidably arranged in the retraction sleeve, wherein the syringe holder is provided with at least two resilient syringe holder arms arranged distally, the at least two resilient syringe holder arms having a respective inclined surface for bearing against a second shoulder arranged at the plunger proximally from a first shoulder, wherein the at least two resilient syringe holder arms are supportable by an inner surface of the elongate housing in order to prevent the at least two resilient syringe holder arms from being flexed outward, and wherein the elongate housing comprises a widened portion configured to allow the at least two resilient syringe holder arms to flex outwards when the syringe holder moves towards a maximum proximal position thus allowing the second shoulder to slip through the at least two resilient syringe holder arms and to switch load of the drive spring from the syringe to the stopper.
12. The auto-injector of claim 11, wherein the syringe holder has at least one stop configured to be engaged by a resilient first clip on the elongate housing to prevent translation of the syringe holder in the proximal direction, wherein the resilient first clip is arranged to decouple from the stop upon translation of the tubular interlock sleeve into the distal position.
13. The auto-injector of claim 1, further comprising a cap configured to attach to a proximal end of the housing, wherein a sheet metal clip is attached to the cap for joint axial movement and independent rotation, the sheet metal clip arranged to extend through an orifice into the tubular interlock sleeve when the cap is attached to the tubular interlock sleeve, wherein the sheet metal clip incorporates at least two barbs snapped into a circumferential notch or behind a shoulder of a protective needle shield attached to the hollow injection needle.
14. The auto-injector of claim 13, wherein the cap is configured to attach to the tubular interlock sleeve by a screw connection.
15. The auto-injector of claim 1, wherein the syringe contains a medicament.
16. The auto-injector of claim 15, wherein the medicament is an analgesic, an anticoagulant, insulin, an insulin derivate, heparin, Lovenox, a vaccine, a growth hormone, a peptide hormone, a protein, antibodies, or complex carbohydrates.
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16
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. patent application Ser. No. 15/880,251, filed on Jan. 25, 2018, which is a continuation of U.S. patent application Ser. No. 15/165,720, filed May 26, 2016, now U.S. Pat. No. 9,931,471, which is a continuation of U.S. patent application Ser. No. 13/806,324 filed Dec. 21, 2012, now U.S. Pat. No. 9,352,088, which is a U.S. National Phase Application pursuant to 35 U.S.C. § 371 of International Application No. PCT/EP2011/060726 filed Jun. 27, 2011, which claims priority to European Patent Application No. 10167506.4 filed Jun. 28, 2010. The entire disclosure contents of these applications are herewith incorporated by reference into the present application.
TECHNICAL FIELD
The invention relates to an auto-injector for administering a dose of a liquid medicament according to the preamble of claim 1.
BACKGROUND
Administering an injection is a process which presents a number of risks and challenges for users and healthcare professionals, both mental and physical.
Injection devices (i.e. devices capable of delivering medicaments from a medication container) typically fall into two categories—manual devices and auto-injectors.
In a manual device—the user must provide the mechanical energy to drive the fluid through the needle. This is typically done by some form of button/plunger that has to be continuously pressed by the user during the injection. There are numerous disadvantages to the user from this approach. If the user stops pressing the button/plunger then the injection will also stop. This means that the user can deliver an underdose if the device is not used properly (i.e. the plunger is not fully pressed to its end position). Injection forces may be too high for the user, in particular if the patient is elderly or has dexterity problems.
The extension of the button/plunger may be too great. Thus it can be inconvenient for the user to reach a fully extended button. The combination of injection force and button extension can cause trembling/shaking of the hand which in turn increases discomfort as the inserted needle moves.
Auto-injector devices aim to make self-administration of injected therapies easier for patients. Current therapies delivered by means of self-administered injections include drugs for diabetes (both insulin and newer GLP-1 class drugs), migraine, hormone therapies, anticoagulants etc.
Auto-injectors are devices which completely or partially replace activities involved in parenteral drug delivery from standard syringes. These activities may include removal of a protective syringe cap, insertion of a needle into a patient's skin, injection of the medicament, removal of the needle, shielding of the needle and preventing reuse of the device. This overcomes many of the disadvantages of manual devices. Injection forces/button extension, hand-shaking and the likelihood of delivering an incomplete dose are reduced. Triggering may be performed by numerous means, for example a trigger button or the action of the needle reaching its injection depth. In some devices the energy to deliver the fluid is provided by a spring.
US 2002/0095120 A1 discloses an automatic injection device which automatically injects a pre-measured quantity of fluid medicine when a tension spring is released. The tension spring moves an ampoule and the injection needle from a storage position to a deployed position when it is released. The content of the ampoule is thereafter expelled by the tension spring forcing a piston forward inside the ampoule. After the fluid medicine has been injected, torsion stored in the tension spring is released and the injection needle is automatically retracted back to its original storage position.
The spring means is a single compression spring arranged to be grounded at a distal end in the housing for advancing the needle and for injecting the dose of medicament via a plunger and wherein the compression spring is arranged to have its ground in the housing switched to its proximal end for retracting the syringe.
SUMMARY
It is an object of the present invention to provide an improved auto-injector.
The object is achieved by an auto-injector according to claim 1.
Preferred embodiments of the invention are given in the dependent claims.
In the context of this specification the term proximal refers to the direction pointing towards the patient during an injection while the term distal refers to the opposite direction pointing away from the patient.
According to the invention, an auto-injector for administering a dose of a liquid medicament comprises:
an elongate housing arranged to contain a syringe with a hollow needle and a stopper for sealing the syringe and displacing the medicament, the housing having a distal end and a proximal end with an orifice intended to be applied against an injection site, wherein the syringe is slidably arranged with respect to the housing,
spring means capable of, upon activation:
pushing the needle from a covered position inside the housing into an advanced position through the orifice and past the proximal end,
operating the syringe to supply the dose of medicament, and
retracting the syringe with the needle into the covered position after delivering the medicament,
activating means arranged to lock the spring means in a pressurized state prior to manual operation and capable of, upon manual operation, releasing the spring means for injection.
According to the invention the spring means is a single drive spring in the shape of a compression spring arranged to be grounded at a distal end in the housing for advancing the needle and for injecting the dose of medicament. The force of the drive spring is forwarded to the needle and/or the syringe via a plunger. The drive spring is arranged to have its ground in the housing switched to its proximal end for retracting the syringe when the injection of the medicament is at least nearly finished.
The single drive spring is used for inserting the needle, fully emptying the syringe and retracting the syringe and needle to a safe position after injection. Thus a second spring for withdrawing the syringe and needle, which is a motion with an opposite sense compared to advancing the syringe and injecting the dose, is not required. While the distal end of the drive spring is grounded the proximal end moves the syringe forward for inserting the needle and carries on to the injection by pushing on the stopper. When the injection is at least nearly finished the drive spring bottoms out at its proximal end, resulting in the proximal end being grounded in the housing. At the same time the distal end of the drive spring is released from its ground in the housing. The drive spring is now pulling the syringe in the opposite direction.
According to the invention the activating means is arranged as a trigger button laterally arranged on the housing. A lateral trigger button can be easier to operate for people with dexterity problems.
The auto-injector according to the invention has a particularly low part count compared to most conventional auto-injectors. The use of just one drive spring reduces the amount of metal needed and thus consequently reduces weight and manufacturing costs.
The trigger button is preferably pivoted in the housing and arranged to be rotated when operated.
An interlock sleeve may be telescoped in the proximal end of the housing, the interlock sleeve translatable in longitudinal direction between a proximal position and a distal position and biased in proximal direction in a manner to protrude from the housing in the proximal position. The interlock sleeve is arranged to be translated from its proximal position into an intermediate position when pressed against the injection site. The trigger button is arranged to push the interlock sleeve from the intermediate position into the distal position thus releasing the drive spring. Before the syringe and needle translate in proximal direction the activating means, i.e. the lateral trigger button has to be operated so as to release the drive spring. The probability for inadvertent operation of the auto-injector thus decreases due to the requirement of two user actions, pressing the auto-injector against the injection site and operating the trigger button.
In its proximal position the interlock sleeve may be arranged to hold the trigger button in a depressed position, e.g. flush with the housing. Translation of the interlock sleeve into the intermediate position causes the trigger button to emerge from the housing into a ready position. This provides a sequenced operation in a manner that the trigger button cannot be operated before the interlock sleeve is pressed against the injection site.
It is desirable to trigger the retraction of the needle when the contents of the syringe have been entirely delivered to the patient, i.e. when the stopper has bottomed out in the syringe. Automatically triggering the retraction when the stopper exactly reaches the end of its travel is a problem due to tolerances when manufacturing the syringe and stopper. Due to these tolerances the position of the stopper at the end of its travel relative to the retracting means is not repeatable. Consequently, in some cases the stopper would prematurely bottom out so the retraction would not be triggered at all. In other cases the retraction would be triggered before the stopper bottomed so residual medicament would remain in the syringe.
The retraction could automatically be triggered a certain amount of time or travel before the stopper bottoms out in the syringe. However this reliable retraction would be traded off for residual medicament in the syringe.
Thus, in a preferred embodiment the interlock sleeve is furthermore arranged to prevent release of the distal ground of the drive spring when in its intermediate and/or distal position. This means, the drive spring remains distally grounded as long as the auto-injector is kept pressed against the injection site so the needle retraction can only start when the auto-injector is removed from the injection site and the interlock sleeve consequently returns into its proximal position and thus releases the distal ground.
A retraction sleeve may be axially movable arranged in the housing, wherein the drive spring is arranged inside the retraction sleeve with its distal end bearing against a distal end face and with its proximal end bearing against a thrust face of a decoupling member. A resilient lug on the interlock sleeve is arranged to be engaged with the retraction sleeve by the trigger button being depressed when the interlock sleeve is in its intermediate or distal position so as to prevent the retraction sleeve from translating in distal direction. Thus, when the interlock sleeve is pressed against the injection site, the retraction sleeve is kept from retracting. Only after removal of the auto-injector from the injection site and consequent translation of the interlock sleeve into its proximal position the retraction sleeve may translate in distal direction and retract the needle into the housing.
The lug may be engaged between two ramps on the trigger button in such a manner that the trigger button is pulled into the depressed position upon translation of the interlock sleeve into its proximal position by the lug sliding along the first ramp. The trigger button is pushed into its ready position by the lug sliding along the second ramp.
A third ramp may be arranged on the interlock sleeve for being engaged by a pin on the trigger button when the trigger button is being pressed when the interlock sleeve is in its intermediate position. When the trigger button is being pressed the pin slides along the third ramp and translates the interlock sleeve into its distal position for triggering the injection.
A tubular syringe carrier may be arranged for holding the syringe and supporting it at its proximal end. Supporting the syringe at the proximal end is preferred over support at the finger flanges since the finger flanges are more frangible under load while the proximal or front end of the syringe is more robust. The syringe and the syringe carrier are arranged for joint axial translation. The syringe carrier is telescoped in the interlock sleeve.
In a preferred embodiment at least one latch is provided for axially fixing the retraction sleeve in a maximum proximal position. The decoupling member is arranged to decouple the latch when being moved in proximal direction nearly into a maximum proximal position. When decoupled, the retraction sleeve is allowed to move in distal direction and retract the needle by means of the spring force which is no longer grounded at its distal end. Thus, retraction can only occur if the latches have been released and if the auto-injector has been removed from the injection site.
Preferably the plunger is arranged for pushing the syringe and/or the stopper in proximal direction. At least one but preferably two or more resilient decoupling arms are arranged at the decoupling member. The decoupling arms exhibit inner ramped surfaces bearing against a first shoulder of the plunger in proximal direction. The resilient decoupling arms are supportable by an inner wall of the retraction sleeve in order to prevent the decoupling arms from being flexed outward and slip past the first shoulder. In this state the plunger may be pushed in proximal direction by the decoupling member pushing against the first shoulder in order to insert the needle and inject the dose. At least one aperture is arranged in the retraction sleeve allowing the decoupling arms to be flexed outward by the first shoulder thus allowing the first shoulder to slip through the decoupling arms in proximal direction. This may happen when the injection is at least nearly finished. The decoupled plunger allows the syringe and needle to be retracted since it is no longer bearing against the decoupling member.
The syringe may be arranged for joint axial movement with a syringe holder which is slidably arranged in the retraction sleeve. The syringe holder is provided with at least two resilient syringe holder arms arranged distally, the syringe holder arms having a respective inclined surface for bearing against a second shoulder, which is arranged at the plunger proximally from the first shoulder. The syringe holder arms are supportable by an inner surface of the housing in order to prevent them from being flexed outward. Thus, when the trigger button is pressed the spring force forwarded by the plunger does not yet press against the stopper but against the syringe for forwarding it. Consequently, a so called wet injection is avoided, i.e. the liquid medicament is not leaking out of the hollow needle before the needle is inserted. A widened portion is provided in the housing for allowing the syringe holder arms to flex outwards when the syringe holder has nearly reached a maximum proximal position thus allowing the second shoulder to slip through the syringe holder arms and to switch load of the drive spring from the syringe to the stopper. This allows for defining the moment to start injecting the medicament.
The syringe holder may have at least one stop for being engaged by a resilient first clip on the housing in a manner to prevent translation of the syringe holder in proximal direction. The first clip may be arranged to decouple from the stop upon translation of the interlock sleeve into its distal position in order to release the drive spring and start the injection.
Usually the hollow needle is equipped with a protective needle shield for keeping the needle sterile and preventing it from being mechanically damaged. The protective needle shield is attached to the needle when the auto-injector or the syringe is assembled.
Preferably a cap is provided at the proximal end of the housing. A sheet metal clip is attached to the cap for joint axial movement and independent rotation. The sheet metal clip is arranged to extend through an orifice into the interlock sleeve when the cap is attached to the interlock sleeve. The sheet metal clip incorporates at least two barbs snapped into a circumferential notch or behind a shoulder of the protective needle shield. This allows for automatically engaging the sheet metal clip with the protective needle shield during assembly. When the cap is removed from the interlock sleeve in preparation of an injection the protective needle shield is reliably removed without exposing the user too high a risk to injure themselves.
The cap may be attachable to the housing by a screw connection. This allows for a low force removal of the protective needle shield.
The housing may have at least one viewing window for inspecting the syringe.
The auto-injector may preferably be used for subcutaneous or intra-muscular injection, particularly for delivering one of an analgetic, an anticoagulant, insulin, an insulin derivate, heparin, Lovenox, a vaccine, a growth hormone, a peptide hormone, a proteine, antibodies and complex carbohydrates.
The cap with the sheet metal spring may also be applied with other auto-injectors and injection devices.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus, are not limitive of the present invention, and wherein:
FIGS. 1A-B are two longitudinal sections of an auto-injector with a single drive spring for advancing a syringe with a needle, injecting a dose of medicament and retracting the syringe and needle, the auto-injector as-delivered,
FIG. 2 is a longitudinal section of the auto-injector with a skin interlock sleeve translated in distal direction and a lateral trigger button ready to be operated, and
FIG. 3 is a detail of the auto-injector with the trigger button depressed.
Corresponding parts are marked with the same reference symbols in all figures.
DETAILED DESCRIPTION
FIGS. 1A-B show two longitudinal sections in different section planes of an auto-injector 1, the different section planes approximately 90° rotated to each other. The auto-injector 1 comprises an elongate housing 2. A syringe 3, e.g. a Hypak syringe, with a hollow needle 4 is arranged in a proximal part of the auto-injector 1. When the auto-injector 1 or the syringe 3 is assembled a protective needle shield may be attached to the needle (not illustrated). A stopper 6 is arranged for sealing the syringe 3 distally and for displacing a liquid medicament M through the hollow needle 4. The syringe 3 is held in a tubular syringe carrier 7 and supported at its proximal end therein. A single drive spring 8 in the shape of a compression spring is arranged in a distal part of the auto-injector 1. A plunger 9 is arranged for forwarding the spring force of the drive spring 8.
Inside the housing 2 a retraction sleeve 10 is slidably arranged. Before the injection is triggered the retraction sleeve 10 is in a maximum proximal position and prevented from moving in distal direction D by means of stops 11 caught behind latches 12 in the housing 2. A distal end of the drive spring 8 bears against an end face 13 of the retraction sleeve 10. Due to the stops 11 and latches 12 the force of the drive spring 8 is reacted into the housing 2. The proximal end of the drive spring 8 bears against a decoupling member 14 arranged around the plunger 9.
The decoupling member 14 comprises a thrust face 17 for bearing against a proximal end of the drive spring 8. Proximally from the thrust face 17 two or more resilient decoupling arms 18 are provided at the decoupling member 14, the decoupling arms 18 having inner ramped surfaces bearing against a first shoulder 19 in the plunger 9 in proximal direction P. The resilient decoupling arms 18 are supported by an inner wall of the retraction sleeve 10 in this situation so they cannot flex outward and slip past the first shoulder 19.
The syringe carrier 7 is engaged for joint axial movement with a syringe holder 22 which is slidably arranged in the retraction sleeve 10. The syringe holder 22 is provided with two or more resilient syringe holder arms 23 arranged distally. The syringe holder arms 23 have a respective inclined surface for bearing against a second shoulder 24 in the plunger 9 arranged proximally from the first shoulder 19. In the initial position shown in FIGS. 1A-B the syringe holder arms 23 are supported by an inner surface (not illustrated) of the housing 2 so they cannot flex outward and the second shoulder 24 cannot slip through. In order to support the syringe holder arms 23 at the housing 2 a respective number of apertures are provided in the retraction sleeve 10.
Two resilient first clips 2.1 are arranged in the housing 2 which engage stops 22.1 on the syringe holder 22 so as to prevent translation of the syringe holder 22, the syringe carrier 7, the syringe 3 and the needle 4 in proximal direction P. Since the syringe holder arms 23 are kept from flexing out, the load of the drive spring 8 is statically resolved through the decoupling member 14, the plunger 9 and the syringe holder 22 into the first clips 2.1 in the housing 2.
A lateral trigger button 20 is arranged laterally on the housing 2 with a pivot 20.1 near its proximal end. In the as delivered configuration in FIGS. 1A-B the trigger button 20 is flush with the housing 2 so it cannot be depressed.
A skin interlock sleeve 25 is telescoped in the proximal end P of the housing 2. An interlock spring 26 for biasing the interlock sleeve 25 in proximal direction P is arranged between the housing 2 and the interlock sleeve 25. The syringe carrier 7 is telescoped in a proximal portion 25.1 of the interlock sleeve 25. A distal portion 25.2 of the interlock sleeve 25 has a greater diameter than the proximal portion 25.1. The syringe holder 22 is telescoped in the distal portion 25.2. The distal portion 25.2 exhibits a lug 25.3 and a third ramp 25.4 for interacting with the trigger button 20. The lug 25.3 is caught between two ramps 20.2, 20.3 arranged inwardly in the trigger button 20.
In order to start an injection the proximal end P of the auto-injector 1 has to be pressed against the injection site, e.g. a patient's skin. As a result the interlock sleeve 25 translates in distal direction D into the housing 2 (see FIG. 2) until the interlock sleeve 25 is flush with the proximal end P of the housing 2. The lug 25.3 also moves in distal direction D along the second ramp 20.3 of the trigger button 20 thus rotating the trigger button outwardly in such a manner that the trigger button 20 laterally emerges from the housing 2 (see FIG. 2).
The trigger button 20 has now been moved to a position where if pushed it will release the drive spring 8 in order to insert the needle 4 into the injection site and to inject the medicament M.
If the auto-injector 1 is removed from the injection site without operating the trigger button 20 the interlock sleeve 25 will translate back into its proximal position under load of the interlock spring 26. The lug 25.3 will slide along the first ramp 20.2 and pull the trigger button 20 back into the position as in FIGS. 1A-B.
The lug 25.3 is resiliently arranged in the interlock sleeve 25 in such a manner that it may be pushed radially inwards. As long as the interlock sleeve 25 is in its proximal position as in FIGS. 1A-B the lug 25.3 is prevented from flexing inwards by the retraction sleeve 10. When the interlock sleeve 25 is pushed into the housing 2 as in FIG. 2 the lug 25.3 reaches an aperture 10.1 in the retraction sleeve 10 allowing it to flex inwards. If the interlock sleeve 25 is kept pressed against the injection site and the trigger button 20 is being depressed the lug 25.3 will be pushed inwards through the aperture 10.1. The resilience of the lug 25.3 has to be chosen so as to ensure that the force required to keep the interlock sleeve 25 pressed does not exceed a convenient level for the user since the counteracting force is the sum of the spring force of the interlock spring 26 and the force created by the lug 25.3 trying to slide along the second ramp 20.3.
When the lug 25.3 has entered the aperture 10.1 the skin interlock sleeve 25 is prevented from returning into its proximal position.
If the trigger button 20 was depressed with the interlock sleeve 25 only partially translated into the housing 2 the lug 25.3 would not yet have reached the aperture 10.1 so it could not flex inwards. Instead, depressing the trigger button 20 would force the interlock sleeve 25 back into its proximal position due to the engagement of the lug 25.3 with the second ramp 20.3.
When the trigger button 20 is pushed in the situation shown in FIG. 2, the lug 25.3 is pushed radially inwards. A pin 20.4, inwardly arranged on the trigger button 20, is pressed against the third ramp 25.4 in such a manner that the interlock sleeve 25 is translated further in distal direction D into the housing 2, as shown in FIG. 3. This movement will result in a further flexing of the lug 25.3, as it slides along the second ramp 20.3. This position cannot be reached by just pushing the interlock sleeve 25 against the injection site. A distal end of the distal portion 25.2 now reaches the clips 2.1 and pushes them outwards thus decoupling the syringe holder 22 from the housing 2 and releasing the drive spring 8.
The second shoulder 24 pushes the syringe holder 22, syringe carrier 7 and syringe 3 forward in proximal direction P while no load is exerted onto the stopper 6. The hollow needle 4 appears from the proximal end P and is inserted into the injection site.
The forward movement continues until the syringe holder 22 bottoms out at a front face 35 of the retraction sleeve 10. The travel from the initial position up to this point defines an injection depth, i.e. needle insertion depth.
When the syringe holder 22 has nearly bottomed out, the resilient syringe holder arms 23 have reached a widened portion 2.2 of the housing 2 where they are no longer supported by the inner wall of the housing 2. However, since the force required to insert the needle 4 is relatively low the second shoulder 24 will continue to drive forward the syringe holder 22 until proximal travel is halted at the front face 35. At this point the syringe holder arms 23 are flexed out by the continued force of the second shoulder 24 and allow it to slip through. Now the plunger 9 no longer pushes against the syringe holder 22 but against the stopper 6 for expelling the medicament M from the syringe 3 and injecting it into or through the patient's skin.
When the stopper 6 has nearly bottomed out in the syringe 3 the decoupling member 14 has reached a position where it pushes against the latches 12 in a manner to decouple the retraction sleeve 10 from the housing 2. Thus the drive spring 8 is no longer grounded with its distal end in the housing 2 by the latches 12. Instead, as soon as the decoupling member 14 has bottomed out at a second abutment 33 in the housing 2 the proximal end of the drive spring 8 gets grounded in the housing 2 while its distal end is pulling the retraction sleeve 10 in distal direction D.
Just before the decoupling member 14 decouples the retraction sleeve 10 from the housing 2 the decoupling arms 18 reach an aperture 10.1, 10.2 in the retraction sleeve 10 so they are no longer kept from being flexed outward. The decoupling arms 18 are thus pushed outward by the first shoulder 19 pushing against its ramped surfaces so the first shoulder 19 can slip through in distal direction D as soon as the decoupling member 14 has hit the second abutment 33.
Although the latches 12 are disengaged now, the retraction sleeve 10 may not yet slide in distal direction D because of the lug 25.3 engaged in the aperture 10.1 so the retraction sleeve 10 is trying to pull the interlock sleeve 25 in distal direction D which is prevented by the third ramp 25.4 distally abutting against the housing 2.
If the auto-injector 1 is taken away from the injection site and the user releases the trigger button 20 the lug 25.3 re-emerges from inside the retraction sleeve 10 so the retraction sleeve 10 gets disengaged from the interlock sleeve 25 and may now translate in distal direction D. A spring means may be arranged for actively pulling the trigger button 20 outwards in this situation. In an alternative embodiment the lug 25.3 may project outwards with an inclination in proximal direction P so as to allow the retraction sleeve 10 to push it outwards on retraction.
The syringe holder 22 is taken along in distal direction D by the retraction sleeve 10, e.g. by a front face 35. Thus the syringe 3 and needle 4 are retracted into a safe position inside the housing 2, e.g. into the initial position. The plunger 9, no longer bearing against the decoupling arms 18 is pulled back, too.
The housing 2 may have at least one viewing window for inspecting the syringe 3.
The auto-injector 1 may preferably be used for subcutaneous or intra-muscular injection, particularly for delivering one of an analgesic, an anticoagulant, insulin, an insulin derivate, heparin, Lovenox, a vaccine, a growth hormone, a peptide hormone, a protein, antibodies and complex carbohydrates.
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16809669
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sanofi-aventis deutschland gmbh
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 27th, 2022 08:38AM
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Apr 27th, 2022 08:38AM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 19th, 2022 12:00AM
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Dec 9th, 2019 12:00AM
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https://www.uspto.gov?id=US11306155-20220419
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Methods for treating patients with heterozygous familial hypercholesterolemia (heFH) with an anti-PCSK9 antibody
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The present invention provides methods for treating hypercholesterolemia. The methods of the present invention comprise administering to patients with heterozygous familial hypercholesterolemia a pharmaceutical composition comprising a PCSK9 inhibitor. In certain embodiments, the PCSK9 inhibitor is an anti-PCSK9 antibody such as the exemplary antibody referred to herein as mAb316P. The methods of the present invention are useful for treating patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy.
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11306155
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1. A method for reducing low density lipoprotein cholesterol (LDL-C) comprising:
administering to a patient in need thereof one or more doses of 75 mg at a frequency of once every two weeks of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR) having the amino acid sequences of SEQ ID NOs: 1 and 6, respectively,
wherein the patient has heterozygous familial hypercholesterolemia (heFH), and wherein prior to treatment the patient has a serum LDL-C concentration of greater than or equal to 100 mg/dL without a history of documented cardiovascular disease.
2. The method of claim 1, wherein the diagnosis of heFH is made either by genotyping or clinical criteria, and wherein the clinical criteria is either the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, or the WHO/Dutch Lipid Network criteria with a score >8.
3. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered to the patient in combination with the maximally tolerated dose of statin therapy.
4. The method of claim 1, wherein the maximally tolerated dose of statin therapy comprises a daily dose of 40 mg to 80 mg of atorvastatin, a daily dose of 20 mg to 40 mg of rosuvastatin, or a daily dose of 80 mg of simvastatin.
5. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered to the patient in combination with at least one other lipid lowering therapy.
6. The method of claim 1, wherein treatment with the antibody or antigen-binding fragment thereof for 24 weeks reduces the patient's low density lipoprotein cholesterol (LDL-C) by at least 40%.
7. A method for reducing low density lipoprotein cholesterol (LDL-C) comprising:
administering to a patient in need thereof one or more doses of 75 mg at a frequency of once every two weeks of an antibody or antigen-binding fragment thereof that specifically binds human proprotein convertase subtilisin/kexin type 9 (PCSK9), wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR) having the amino acid sequences of SEQ ID NOs: 1 and 6, respectively,
wherein the patient has heterozygous familial hypercholesterolemia (heFH) that is inadequately controlled by a maximally tolerated dose of statin therapy, wherein prior to treatment the patient has a serum LDL-C concentration of greater than or equal to 100 mg/dL without a history of documented cardiovascular disease, and wherein:
(a) the 75 mg dose is maintained if the patient's LDL-C measured after five or more doses is lower than 70 mg/dL; or
(b) the 75 mg dose is discontinued if the patient's LDL-C measured after five or more doses is greater than or equal to 70 mg/dL, and the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is subsequently administered to the patient at a dose of 150 mg at a frequency of once every two weeks.
8. The method of claim 7, wherein the diagnosis of heFH is made either by genotyping or clinical criteria, and wherein the clinical criteria is either the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, or the WHO/Dutch Lipid Network criteria with a score >8.
9. The method of claim 7, wherein the antibody or antigen-binding fragment thereof is administered to the patient in combination with the maximally tolerated dose of statin therapy.
10. The method of claim 7, wherein the maximally tolerated dose of statin therapy comprises a daily dose of 40 mg to 80 mg of atorvastatin, a daily dose of 20 mg to 40 mg of rosuvastatin, or a daily dose of 80 mg of simvastatin.
11. The method of claim 7, wherein the antibody or antigen-binding fragment thereof is administered to the patient in combination with at least one other lipid lowering therapy.
12. The method of claim 7, wherein treatment with the antibody or antigen-binding fragment thereof for 24 weeks reduces the patient's low density lipoprotein cholesterol (LDL-C) by at least 40%.
13. The method of claim 1, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.
14. The method of claim 7, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.
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14
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RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 14/801,384, filed Jul. 16, 2015, which claims the benefit of U.S. Provisional Application No. 62/080,717, filed on Nov. 17, 2014, U.S. Provisional Application No. 62/043,144, filed on Aug. 28, 2014, U.S. Provisional Application No. 62/025,362, filed on Jul. 16, 2014, and European Patent Application No. 15305419.2, filed on Mar. 23, 2015, the contents of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to the field of therapeutic treatments of diseases and disorders that are associated with elevated levels of lipids and lipoproteins. More specifically, the invention relates to the use of PCSK9 inhibitors to treat patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy.
BACKGROUND
Heterozygous familial hypercholesterolemia (heFH) is a hereditary lipid metabolism disorder that predisposes affected individuals to cardiovascular (CV) disease. Patients with heFH typically have very high low-density lipoprotein cholesterol (LDL-C) levels—often >190 mg/dL at the time of diagnosis—that are associated with high risk for premature CV disease. Findings from observational studies have shown that the risk of coronary heart disease (CHD) is reduced in heFH patients receiving statin therapy; however, even with treatment, the risk of CHD is still greater in heFH patients than in the general population. Despite the availability of lipid-lowering therapy (LLT), approximately 80% of patients with heFH do not reach the recommended levels of LDL-C. Given the increased CV risk in the heFH population, there is a need to provide patients with more intensive cholesterol-lowering therapy.
Current LDL-C lowering medications include statins, cholesterol absorption inhibitors (e.g., ezetimibe [EZE]), fibrates, niacin, and bile acid sequestrants. Statins are the most commonly prescribed, as they have shown a greater ability to lower LDL-C and reduce CHD events. However, many patients at risk of cardiovascular disease (CVD) have poorly controlled low-density lipoprotein cholesterol (LDL-C) despite statin therapy.
BRIEF SUMMARY OF THE INVENTION
The present invention provides methods for treating hypercholesterolemia. In particular, the methods of the present invention are useful for treating patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy.
According to one aspect, the methods of the present invention comprise administering one or more doses of a PCSK9 inhibitor to a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy (i.e., hypercholesterolemia that is not adequately controlled by maximum tolerated dose statin therapy in the absence of a PCSK9 inhibitor, with or without other lipid modifying therapy). According to certain embodiments of the present invention, the PCSK9 inhibitor is administered to the patient with heterozygous familial hypercholesterolemia as an add-on therapy to the patient's existing statin therapy with or without other lipid lowering therapy.
According to another aspect, the methods of the present invention comprise selecting a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy (e.g., a maximum tolerated dose statin therapy), and administering to the patient one or more doses of a PCSK9 inhibitor in combination with (i.e., “on top of”) the statin therapy.
Another aspect of the invention includes a method for treating a patient with heterozygous familial hypercholesterolemia (heFH) who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy by administering one or more doses of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to the patient, wherein the patient exhibits inadequate control of the hypercholesterolemia despite treatment with the maximum tolerated dose statin therapy with or without other lipid lowering therapy in the absence of the PCSK9 inhibitor.
Another aspect of the invention includes a method for reducing low-density lipoprotein cholesterol (LDL-C) in a patient with heterozygous familial hypercholesterolemia (heFH) who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy by administering one or more doses of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to the patient, wherein the patient exhibits inadequate control of the hypercholesterolemia despite treatment with the maximum tolerated dose statin therapy with or without other lipid lowering therapy in the absence of the PCSK9 inhibitor.
Another aspect of the invention includes a method for treating hypercholesterolemia in a patient with heterozygous familial hypercholesterolemia (heFH) who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy by administering one or more doses of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to the patient, wherein the patient exhibits inadequate control of the hypercholesterolemia despite treatment with the maximum tolerated dose statin therapy with or without other lipid lowering therapy in the absence of the PCSK9 inhibitor.
Another aspect of the invention includes a method for improving the serum level of one or more lipid components in a patient with heterozygous familial hypercholesterolemia (heFH) who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy by administering one or more doses of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to the patient, wherein the patient exhibits inadequate control of the lipid component despite treatment with the maximum tolerated dose statin therapy with or without other lipid lowering therapy in the absence of the PCSK9 inhibitor. In certain aspects, the invention provides a decrease in the serum level of a lipid component selected from the group consisting of LDL-C, Apo B, non-HDL-C, total cholesterol, Lp(a), and triglycerides. In certain aspects, the invention provides an increase in the serum level of a lipid component selected from the group consisting of HDL-C and Apo A1.
In certain aspects of the invention, the diagnosis of heFH is made by either genotyping or by clinical criteria. In some aspects, the clinical criteria is either the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, or the WHO/Dutch Lipid Network criteria with a score >8.
In certain aspects of the invention, the PCSK9 inhibitor is an antibody or an antigen-binding fragment thereof that specifically binds PCSK9.
In certain aspects of the invention, the antibody or antigen-binding fragment thereof comprises the heavy and light chain complementarity determining regions (CDRs) of a heavy chain variable region/light chain variable region (HCVR/LCVR) amino acid sequence pair selected from the group consisting of SEQ ID NOs: 1/6 and 11/15. In some aspects, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:12, 13, 14, 16, 17, and 18. In some aspects, the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO:11 and an LCVR having the amino acid sequence of SEQ ID NO:15. In some aspects, the antibody or antigen-binding fragment thereof comprises heavy and light chain CDR amino acid sequences having SEQ ID NOs:2, 3, 4, 7, 8, and 10. In some aspects, the antibody or antigen-binding fragment thereof comprises an HCVR having the amino acid sequence of SEQ ID NO:1 and an LCVR having the amino acid sequence of SEQ ID NO:6.
In certain aspects of the invention, the antibody or antigen-binding fragment thereof binds to the same epitope on PCSK9 as an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:12, 13, 14, 16, 17, and 18; or SEQ ID NOs: 2, 3, 4, 7, 8, and 10.
In certain aspects of the invention, the antibody or antigen-binding fragment thereof competes for binding to PCSK9 with an antibody comprising heavy and light chain CDR amino acid sequences having SEQ ID NOs:12, 13, 14, 16, 17, and 18; or SEQ ID NOs: 2, 3, 4, 7, 8, and 10.
In certain aspects of the invention, the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a dose of about 75 mg at a frequency of once every two weeks. In some aspects, the about 75 mg dose is maintained if the patient's LDL-C measured after five or more doses is <70 mg/dL. In some aspects, the about 75 mg dose is discontinued if the patient's LDL-C measured after five or more doses remains ≥70 mg/dL, and the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is subsequently administered to the patient at a dose of about 150 mg at a frequency of once every two weeks. In some aspects, the antibody or antigen-binding fragment thereof that specifically binds PCSK9 is administered to the patient at a dose of about 150 mg at a frequency of once every two weeks.
In certain aspects of the invention, the PCSK9 inhibitor is administered to the patient in combination with the maximum tolerated dose statin therapy. In some aspects, the maximum tolerated dose statin therapy comprises a daily dose of about 40 mg to about 80 mg of atorvastatin. In some aspects, the maximum tolerated dose statin therapy comprises a daily dose of about 20 mg to about 40 mg of rosuvastatin. In some aspects, the maximum tolerated dose statin therapy comprises a daily dose of about 80 mg of simvastatin.
In certain aspects of the invention, the PCSK9 inhibitor is administered to the patient in combination with the other lipid lowering therapy.
In certain aspects of the invention, the method improves at least one hypercholesterolemia-associated parameter selected from the group consisting of: (a) reduction of the patient's low density lipoprotein cholesterol (LDL-C) by at least 40%; (b) reduction of the patient's apolipoprotein B (ApoB) by at least 30%; (c) reduction of the patient's non-high density lipoproprotein cholesterol (non-HDL-C) by at least 40%; (d) reduction of the patient's total cholesterol by at least 20%; (e) increase of the patient's high density lipoprotein cholesterol (HDL-C) by at least 3%; (f) reduction of the patient's triglycerides by at least 5%; (g) reduction of the patient's lipoprotein a (Lp(a)) by at least 20%; and (h) increase of the patient's apolipoprotein A1 by at least 1%.
Other embodiments of the present invention will become apparent from a review of the ensuing detailed description.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a graphic representation of the study design for ODYSSEY FH I (Example 2).
FIG. 2 is a graph showing the calculated LDL-C LS mean percent change from baseline over time for treatment with alirocumab or placebo in the ITT population in the ODYSSEY FH I study (Example 2). The least-squares (LS) means and standard errors (SD) are taken from MMRM (mixed-effect model with repeated measures) analysis.
FIG. 3 is a graphic representation of the study design for ODYSSEY FH II (Example 3).
FIG. 4 is a graph showing the LDL-C LS mean (+/−SE) percent change from baseline over time for the ITT population in the ODYSSEY FH II study (Example 3). The Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis.
FIG. 5 is a graph showing the LDL-C LS mean (+/−SE) percent change from baseline during efficacy treatment period over time for the mITT Population in the ODYSSEY FH II study (Example 3).
FIG. 6 is a graphic representation of the study design for ODYSSEY HIGH FH (Example 4). Labels in the study design are defined as follows: FU: follow up; HeFH, heterozygous familial hypercholesterolemia; LLT, lipid-lowering therapy; OLE, open-label extension.
FIG. 7 is a graph showing the calculated LDL-C LS mean percent change from baseline over time for treatment with alirocumab or placebo in the ITT population in the ODYSSEY HIGH FH study (Example 4). The least-squares (LS) means and standard errors (SE) are taken from MMRM (mixed-effect model with repeated measures) analysis.
FIG. 8 is a graph showing the LS mean (SE) calculated LDL-C values versus time for the ODYSSEY FH I and FH II studies. The values indicted on the graph are the LS mean % change from baseline to week 24 and week 52.
FIG. 9 is a graph showing the LS mean (SE) calculated LDL-C values versus time for the ODYSSEY FH I and FH II studies. The values indicated below the graph are the numbers of patients analyzed at the various timepoints.
FIG. 10 is a graph showing LDL-C levels over time in alirocumab patients according to whether dose was increased to 150 mg Q2W or maintained at 75 mg Q2W (ITT analysis).
FIGS. 11A, 11B, and 11C depict charts showing subgroup analysis of LDL-C reductions from baseline to week 24 (alirocumab vs. placebo) according to demographics and baseline characteristics (FIG. 11A), statin/LLT use (FIG. 11B), and baseline lipids (FIG. 11C) (ITT analysis; pooled data from FH I and FH II). Moderate chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate of ≥30 and ≤60 mL/min/1.73 m2. In FH I, 20/323 and 9/163 patients in alirocumab and placebo arms had moderate CKD at baseline. Corresponding values in FH II were 2/167 and 1/82. “High intensity” statin dose refers to atorvastatin 40-80 mg or rosuvastatin 20-40 mg.
FIG. 12 is a graphic representation of patient disposition in the ODYSSEY HIGH FH study.
FIG. 13 is a graph showing the percent change from baseline to week 24 in LDL-C levels by individual patients in the ODYSSEY HIGH FH study. All patients were on a background statin (at the maximum tolerated level). A subset of patients also received a further lipid lowering therapy.
FIGS. 14A-14B depict graphs showing the LS mean (SE) calculated LDL-C values versus time for the ODYSSEY HIGH FH study. In FIG. 14A, the values indicted on the graph are the LS mean % values (in mg/dL) at week 24 and week 52. In FIG. 14B, the values indicated on the graph are the LS mean % values (in mg/dL) at week 24 and week 78. All patients were on a background statin (at the maximum tolerated level). A subset of patients also received a further lipid lowering therapy.
DETAILED DESCRIPTION
Before the present invention is described, it is to be understood that this invention is not limited to the particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the term “about,” when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression “about 100” includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to describe in their entirety.
Heterozygous Familial Hypercholesterolemia not Adequately Controlled by Maximum Tolerated Dose Statin Therapy with or without Other Lipid Lowering Therapy
The present invention relates generally to methods and compositions for treating patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy, i.e., hypercholesterolemia not adequately controlled by a therapeutic regimen comprising a daily maximum tolerated dose of a statin. As used herein, the expression “not adequately controlled,” in reference to hypercholesterolemia, means that the patient's serum low-density lipoprotein cholesterol (LDL-C) concentration, total cholesterol concentration, and/or triglyceride concentration is not reduced to a recognized, medically-acceptable level (taking into account the patient's relative risk of coronary heart disease) after at least 4 weeks on a therapeutic regimen comprising a stable daily dose of a statin. For example, “a patient with hypercholesterolemia that is not adequately controlled by a statin” includes patients with a serum LDL-C concentration of greater than about 70 mg/dL, 100 mg/dL, 130 mg/dL, 140 mg/dL, or more (depending on the patient's underlying risk of heart disease) after the patient has been on a stable daily statin regimen for at least 4 weeks.
According to certain embodiments, the patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy who are treatable by the methods of the present invention have hypercholesterolemia (e.g., a serum LDL-C concentration of greater than or equal to 70 mg/dL in patients with a history of documented cardiovascular disease or a serum LDL-C≥100 mg/dL in patients without a history of documented cardiovascular disease) despite taking a stable daily dose of a statin (with or without other lipid modifying therapy) for at least 4 weeks, 5 weeks, 6 weeks, or more. In certain embodiments, the heterozygous familial hypercholesterolemia patient's hypercholesterolemia is inadequately controlled by a maximum tolerated dose statin therapy (also referred to herein as “a daily maximum tolerated dose therapeutic statin regimen”).
As used herein, “maximum tolerated dose statin therapy” means a therapeutic regimen comprising the administration of daily dose of a statin that is the maximally tolerated dose for a particular patient. Maximally tolerated dose means the highest dose of statin that can be administered to a patient without causing unacceptable adverse side effects in the patient. Maximum tolerated dose statin therapy includes, but is not limited to, e.g., 40-80 mg of atorvastatin daily, 20-40 mg of rosuvastatin daily, or 80 mg of simvastatin (if already on this dose for >1 year). However, patients not able to tolerate the above statin doses could take a lower dose of daily atorvastatin, rosuvastatin, or simvastatin provided there was an acceptable reason for not using the higher dose. Some examples of acceptable reasons for a patient taking a lower statin dose include: adverse effects on higher doses, advanced age, low body mass index (BMI), regional practices, local prescribing information, concomitant medications, and comorbid conditions such as impaired glucose tolerance/impaired fasting glucose.
The present invention also includes methods for treating patients with heterozygous familial hypercholesterolemia that are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy comprising daily administration of other statins such as cerivastatin, pitavastatin, fluvastatin, lovastatin, and pravastatin.
Patient Selection
The present invention includes methods and compositions useful for treating patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy.
Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria with a criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score >8 points.
According to the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, definite familial hypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) or LDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child <16 years or Total-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment); plus either A) tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt); or B) DNA-based evidence of an LDL receptor mutation or familial defective apo B-100.
According to the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, possible familial hypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) or LDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child <16 years or Total-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment); and at least one of the following: A) family history of MI below 50 years of age in 2nd degree relative or below 60 years of age in 1st degree relative; and B) family history of raised cholesterols >7.5 mmol/l (290 mg/dL) in adult 1st or 2nd degree relative or >6.7 mmol/l (260 mg/dL) in child or sibling under 16 years of age.
The WHO Criteria (Dutch Lipid Network clinical criteria) for diagnosis of Heterozygous Familial Hypercholesterolemia (heFH) is set forth in the Examples, such as in Table 2.
According to certain embodiments, the heterozygous familial hypercholesterolemia patient may be selected on the basis of having one or more additional risk factors selected from the group consisting of age (e.g., older than 40, 45, 50, 55, 60, 65, 70, 75, or 80 years), race, national origin, gender (male or female), exercise habits (e.g., regular exerciser, non-exerciser), other preexisting medical conditions (e.g., type-II diabetes, high blood pressure, myocardial infarction, ischemic stroke, etc.), and current medication status (e.g., currently taking beta blockers, niacin, ezetimibe, fibrates, omega-3 fatty acids, bile acid resins, etc.).
According to the present invention, heterozygous familial hypercholesterolemia patients may be selected on the basis of a combination of one or more of the foregoing selection criteria or therapeutic characteristics.
Administration of a PCSK9 Inhibitor as Add-on Therapy to Maximum Tolerated Dose Statin Therapy
The present invention includes methods wherein a heterozygous familial hypercholesterolemia patient who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy in the absence of a PCSK9 inhibitor is administered a PCSK9 inhibitor according to a particular dosing amount and frequency, and wherein the PCSK9 inhibitor is administered as an add-on to the patient's therapeutic statin regimen. For example, according to certain embodiments, if a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy comprising, e.g., 40-80 mg of atorvastatin, the patient with heterozygous familial hypercholesterolemia may be administered a PCSK9 inhibitor at a particular amount and dosing interval while the patient continues his or her stable daily therapeutic statin regimen.
The methods of the present invention include add-on therapeutic regimens wherein the PCSK9 inhibitor is administered as add-on therapy to the same stable daily maximum tolerated dose therapeutic statin regimen (i.e., same dosing amount of statin) that the heterozygous familial hypercholesterolemia risk patient was on prior to receiving the PCSK9 inhibitor. In other embodiments, the PCSK9 inhibitor is administered as add-on therapy to a daily maximum tolerated dose therapeutic statin regimen comprising a statin in an amount that is more than or less than the dose of statin the patient was on prior to receiving the PCSK9 inhibitor. For example, after starting a therapeutic regimen comprising a PCSK9 inhibitor administered at a particular dosing frequency and amount, the daily dose of statin administered or prescribed to the patient may (a) stay the same, (b) increase, or (c) decrease (e.g., up-titrate or down-titrate) in comparison to the daily statin dose the high cardiovascular risk patient was taking before starting the PCSK9 inhibitor therapeutic regimen, depending on the therapeutic needs of the patient.
Therapeutic Efficacy
The methods of the present invention will result in the improvement in the serum level of one or more lipid components selected from the group consisting of LDL-C, ApoB, non-HDL-C, total cholesterol, HDL-C, triglycerides, Apo A-1, and Lp(a). For example, according to certain embodiments of the present invention, administration of a pharmaceutical composition comprising a PCSK9 inhibitor to a heterozygous familial hypercholesterolemia patient who is not adequately controlled by a stable daily maximum tolerated dose therapeutic statin regimen (e.g., administration of the PCSK9 inhibitor on top of the patient's maximum tolerated dose statin therapy) will result in a mean percent reduction from baseline in serum low density lipoprotein cholesterol (LDL-C) of at least about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, or greater; a mean percent reduction from baseline in ApoB of at least about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, or greater; a mean percent reduction from baseline in non-HDL-C of at least about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, or greater; a mean percent reduction from baseline in total cholesterol of at least about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, or greater; a mean percent increase from baseline in HDL-C of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or greater; a mean percent reduction from baseline in triglycerides of at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or greater; a mean percent increase from baseline in Apo A-1 of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or greater; and/or a mean percent reduction from baseline in Lp(a) of at least about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, or greater.
PCSK9 Inhibitors
The methods of the present invention comprise administering to a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy a therapeutic composition comprising a PCSK9 inhibitor. As used herein, a “PCSK9 inhibitor” is any agent that binds to or interacts with human PCSK9 and inhibits the normal biological function of PCSK9 in vitro or in vivo. Non-limiting examples of categories of PCSK9 inhibitors include small molecule PCSK9 antagonists, peptide-based PCSK9 antagonists (e.g., “peptibody” molecules), and antibodies or antigen-binding fragments of antibodies that specifically bind human PCSK9.
The term “human proprotein convertase subtilisin/kexin type 9” or “human PCSK9” or “hPCSK9”, as used herein, refers to PCSK9 having the nucleic acid sequence shown in SEQ ID NO:197 and the amino acid sequence of SEQ ID NO:198, or a biologically active fragment thereof.
The term “antibody”, as used herein, is intended to refer to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the invention, the FRs of the anti-PCSK9 antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.
The term “antibody,” as used herein, also includes antigen-binding fragments of full antibody molecules. The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.
Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab′)2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment,” as used herein.
An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.
In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).
As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using routine techniques available in the art.
The constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.
The term “human antibody”, as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term “human antibody”, as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
The term “recombinant human antibody”, as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These forms have been extremely difficult to separate, even after affinity purification.
The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using a human IgG1 hinge. The instant invention encompasses antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.
An “isolated antibody,” as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an “isolated antibody” for purposes of the present invention. An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.
The term “specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that “specifically binds” PCSK9, as used in the context of the present invention, includes antibodies that bind PCSK9 or portion thereof with a KD of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM, as measured in a surface plasmon resonance assay. An isolated antibody that specifically binds human PCSK9, however, have cross-reactivity to other antigens, such as PCSK9 molecules from other (non-human) species.
The anti-PCSK9 antibodies useful for the methods of the present invention may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes methods involving the use of antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies of the present invention may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.
The present invention also includes methods involving the use of anti-PCSK9 antibodies comprising variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present invention includes the use of anti-PCSK9 antibodies having HCVR, LCVR, and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein.
The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIAcore™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, N.J.).
The term “KD”, as used herein, is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.
The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.
According to certain embodiments, the anti-PCSK9 antibody used in the methods of the present invention is an antibody with pH-dependent binding characteristics. As used herein, the expression “pH-dependent binding” means that the antibody or antigen-binding fragment thereof exhibits “reduced binding to PCSK9 at acidic pH as compared to neutral pH” (for purposes of the present disclosure, both expressions may be used interchangeably). For example, antibodies “with pH-dependent binding characteristics” includes antibodies and antigen-binding fragments thereof that bind PCSK9 with higher affinity at neutral pH than at acidic pH. In certain embodiments, the antibodies and antigen-binding fragments of the present invention bind PCSK9 with at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, or more times higher affinity at neutral pH than at acidic pH.
According to this aspect of the invention, the anti-PCSK9 antibodies with pH-dependent binding characteristics may possess one or more amino acid variations relative to the parental anti-PCSK9 antibody. For example, an anti-PCSK9 antibody with pH-dependent binding characteristics may contain one or more histidine substitutions or insertions, e.g., in one or more CDRs of a parental anti-PCSK9 antibody. Thus, according to certain embodiments of the present invention, methods are provided comprising administering an anti-PCSK9 antibody which comprises CDR amino acid sequences (e.g., heavy and light chain CDRs) which are identical to the CDR amino acid sequences of a parental anti-PCSK9 antibody, except for the substitution of one or more amino acids of one or more CDRs of the parental antibody with a histidine residue. The anti-PCSK9 antibodies with pH-dependent binding may possess, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or more histidine substitutions, either within a single CDR of a parental antibody or distributed throughout multiple (e.g., 2, 3, 4, 5, or 6) CDRs of a parental anti-PCSK9 antibody. For example, the present invention includes the use of anti-PCSK9 antibodies with pH-dependent binding comprising one or more histidine substitutions in HCDR1, one or more histidine substitutions in HCDR2, one or more histidine substitutions in HCDR3, one or more histidine substitutions in LCDR1, one or more histidine substitutions in LCDR2, and/or one or more histidine substitutions in LCDR3, of a parental anti-PCSK9 antibody.
As used herein, the expression “acidic pH” means a pH of 6.0 or less (e.g., less than about 6.0, less than about 5.5, less than about 5.0, etc.). The expression “acidic pH” includes pH values of about 6.0, 5.95, 5.90, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. As used herein, the expression “neutral pH” means a pH of about 7.0 to about 7.4. The expression “neutral pH” includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.
Preparation of Human Antibodies
Methods for generating human antibodies in transgenic mice are known in the art. Any such known methods can be used in the context of the present invention to make human antibodies that specifically bind to human PCSK9.
Using VELOCIMMUNE® technology (see, for example, U.S. Pat. No. 6,596,541, Regeneron Pharmaceuticals) or any other known method for generating monoclonal antibodies, high affinity chimeric antibodies to PCSK9 are initially isolated having a human variable region and a mouse constant region. The VELOCIMMUNE® technology involves generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to endogenous mouse constant region loci such that the mouse produces an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation. The DNA encoding the variable regions of the heavy and light chains of the antibody are isolated and operably linked to DNA encoding the human heavy and light chain constant regions. The DNA is then expressed in a cell capable of expressing the fully human antibody.
Generally, a VELOCIMMUNE® mouse is challenged with the antigen of interest, and lymphatic cells (such as B-cells) are recovered from the mice that express antibodies. The lymphatic cells may be fused with a myeloma cell line to prepare immortal hybridoma cell lines, and such hybridoma cell lines are screened and selected to identify hybridoma cell lines that produce antibodies specific to the antigen of interest. DNA encoding the variable regions of the heavy chain and light chain may be isolated and linked to desirable isotypic constant regions of the heavy chain and light chain. Such an antibody protein may be produced in a cell, such as a CHO cell. Alternatively, DNA encoding the antigen-specific chimeric antibodies or the variable domains of the light and heavy chains may be isolated directly from antigen-specific lymphocytes.
Initially, high affinity chimeric antibodies are isolated having a human variable region and a mouse constant region. The antibodies are characterized and selected for desirable characteristics, including affinity, selectivity, epitope, etc, using standard procedures known to those skilled in the art. The mouse constant regions are replaced with a desired human constant region to generate the fully human antibody of the invention, for example wild-type or modified IgG1 or IgG4. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.
In general, the antibodies that can be used in the methods of the present invention possess high affinities, as described above, when measured by binding to antigen either immobilized on solid phase or in solution phase. The mouse constant regions are replaced with desired human constant regions to generate the fully human antibodies of the invention. While the constant region selected may vary according to specific use, high affinity antigen-binding and target specificity characteristics reside in the variable region.
Specific examples of human antibodies or antigen-binding fragments of antibodies that specifically bind PCSK9 which can be used in the context of the methods of the present invention include any antibody or antigen-binding fragment which comprises the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 and 11, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Alternatively, specific examples of human antibodies or antigen-binding fragments of antibodies that specifically bind PCSK9 which can be used in the context of the methods of the present invention include any antibody or antigen-binding fragment which comprises the three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs 37, 45, 53, 61, 69, 77, 85, 93, 101, 109, 117, 125, 133, 141, 149, 157, 165, 173, 181, and 189, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. The antibody or antigen-binding fragment may comprise the three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 and 15, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity. Alternatively, the antibody or antigen-binding fragment may comprise the three light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of SEQ ID NOs 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 161, 169, 177, 185, and 193, or a substantially similar sequence thereof having at least 90%, at least 95%, at least 98% or at least 99% sequence identity.
In certain embodiments of the present invention, the antibody or antigen-binding fragment thereof comprises the six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) from the heavy and light chain variable region amino acid sequence pairs (HCVR/LCVR) selected from the group consisting of SEQ ID NOs:1/6 and 11/15. Alternatively, in certain embodiments of the present invention, the antibody or antigen-binding protein comprises the six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) from the heavy and light chain variable region amino acid sequence pairs (HCVR/LCVR) selected from the group consisting of SEQ ID NOs:37/41, 45/49, 53/57, 61/65, 69/73, 77/81, 85/89, 93/97, 101/105, 109/113, 117/121, 125/129, 133/137, 141/145, 149/153, 157/161, 165/169, 173/177, 181/185, and 189/193.
In certain embodiments of the present invention, the anti-PCSK9 antibody, or antigen-binding fragment thereof, that can be used in the methods of the present invention has HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 amino acid sequences selected from SEQ ID NOs: 2/3/4/7/8/10 (mAb316P) and 12/13/14/16/17/18 (mAb300N) (See U.S. Patent App. Publ No. 2010/0166768).
In certain embodiments of the present invention, the antibody or antigen-binding fragment thereof comprises HCVR/LCVR amino acid sequence pairs selected from the group consisting of SEQ ID NOs: 1/6 and 11/15. Alternatively, in certain embodiments of the present invention, the antibody or antigen-binding protein comprises HCVR/LCVR amino acid sequence pairs selected from the group consisting of SEQ ID NOs:37/41, 45/49, 53/57, 61/65, 69/73, 77/81, 85/89, 93/97, 101/105, 109/113, 117/121, 125/129, 133/137, 141/145, 149/153, 157/161, 165/169, 173/177, 181/185, and 189/193.
Pharmaceutical Compositions and Methods of Administration
The present invention includes methods which comprise administering a PCSK9 inhibitor to a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy, wherein the PCSK9 inhibitor is contained within a pharmaceutical composition. The pharmaceutical compositions of the invention are formulated with suitable carriers, excipients, and other agents that provide suitable transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. “Compendium of excipients for parenteral formulations” PDA (1998) J Pharm Sci Technol 52:238-311.
Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents.
A pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present invention. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.
Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present invention. Examples include, but are not limited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but are not limited to the SOLOSTAR™ pen (sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park Ill.), to name only a few.
In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Fla. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.
The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by known methods. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared is preferably filled in an appropriate ampoule.
Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.
Dosage
The amount of PCSK9 inhibitor (e.g., anti-PCSK9 antibody) administered to a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy according to the methods of the present invention is, generally, a therapeutically effective amount. As used herein, the phrase “therapeutically effective amount” means a dose of PCSK9 inhibitor that results in a detectable improvement (at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more from baseline) in one or more parameters selected from the group consisting of LDL-C, ApoB, non-HDL-C, total cholesterol, HLDL-C, triglycerides, Apo A-1, and Lp(a).
In the case of an anti-PCSK9 antibody, a therapeutically effective amount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg, of the anti-PCSK9 antibody.
The amount of anti-PCSK9 antibody contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of patient body weight (i.e., mg/kg). For example, the anti-PCSK9 antibody may be administered to a patient at a dose of about 0.0001 to about 10 mg/kg of patient body weight.
Combination Therapies
As described elsewhere herein, the methods of the present invention may comprise administering a PCSK9 inhibitor to patients with heterozygous familial hypercholesterolemia in combination with the patient's previously prescribed stable daily maximum tolerated dose therapeutic statin regimen. According to certain embodiments of the present invention, additional therapeutic agents, besides a statin, may be administered to the patient in combination with the PCSK9 inhibitor. Examples of such additional therapeutic agents include e.g., (1) an agent which inhibits cholesterol uptake and or bile acid re-absorption (e.g., ezetimibe); (2) an agent which increases lipoprotein catabolism (such as niacin); and/or (3) activators of the LXR transcription factor that plays a role in cholesterol elimination such as 22-hydroxycholesterol.
Administration Regimens
According to certain embodiments of the present invention, multiple doses of a PCSK9 inhibitor (i.e., a pharmaceutical composition comprising a PCSK9 inhibitor) may be administered to a subject over a defined time course (e.g., on top of a daily therapeutic statin regimen). The methods according to this aspect of the invention comprise sequentially administering to a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy multiple doses of a PCSK9 inhibitor. As used herein, “sequentially administering” means that each dose of PCSK9 inhibitor is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering to the patient with heterozygous familial hypercholesterolemia a single initial dose of a PCSK9 inhibitor, followed by one or more secondary doses of the PCSK9 inhibitor, and optionally followed by one or more tertiary doses of the PCSK9 inhibitor.
The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the individual doses of a pharmaceutical composition comprising a PCSK9 inhibitor. Thus, the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of the PCSK9 inhibitor, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of PCSK9 inhibitor contained in the initial, secondary and/or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses”).
According to exemplary embodiments of the present invention, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more) weeks after the immediately preceding dose. The phrase “the immediately preceding dose,” as used herein, means, in a sequence of multiple administrations, the dose of antigen-binding molecule which is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.
The methods according to this aspect of the invention may comprise administering to a patient with heterozygous familial hypercholesterolemia any number of secondary and/or tertiary doses of a PCSK9 inhibitor. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.
In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient with heterozygous familial hypercholesterolemia 1 to 2, 4, 6, 8 or more weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 1 to 2, 4, 6, 8 or more weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.
The present invention includes administration regimens comprising an up-titration option (also referred to herein as “dose modification”). As used herein, an “up-titration option” means that, after receiving a particular number of doses of a PCSK9 inhibitor, if a patient has not achieved a specified reduction in one or more defined therapeutic parameters, the dose of the PCSK9 inhibitor is thereafter increased. For example, in the case of a therapeutic regimen comprising administration of 75 mg doses of an anti-PCSK9 antibody to a patient with heterozygous familial hypercholesterolemia who is not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy at a frequency of once every two weeks, if after 8 weeks (i.e., 5 doses administered at Week 0, Week 2 and Week 4, Week 6 and Week 8), the patient has not achieved a serum LDL-C concentration of less than 70 mg/dL, then the dose of anti-PCSK9 antibody is increased to e.g., 150 mg administered once every two weeks thereafter (e.g., starting at Week 12).
In certain embodiments, the anti-PCSK9 antibody is administered to a subject at a dose of about 75 mg every two weeks, for example for at least six doses.
In some embodiments, the antibody is administered to a subject at a dose of about 75 mg every two weeks for 12 weeks, and the dose remains at 75 mg every two weeks if, at week 8, the subject's LDL-C value was less than 70 mg/dl.
In other embodiments, the antibody is administered to a subject at a dose of about 75 mg every two weeks for 12 weeks, and the dose is titrated up to about 150 mg every two weeks if, at week 8, the subject's LDL-C value was greater than or equal to 70 mg/dl. In certain embodiments, the anti-PCSK9 antibody is administered to a subject at a dose of about 150 mg every two weeks, for example for at least six doses.
EXAMPLES
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
Example 1. Generation of Human Antibodies to Human PCSK9
Human anti-PCSK9 antibodies were generated as described in U.S. Pat. No. 8,062,640. The exemplary PCSK9 inhibitor used in the following Examples is the human anti-PCSK9 antibody designated “mAb316P,” also known as “Alirocumab.” mAb316P has the following amino acid sequence characteristics: heavy chain variable region (HCVR) comprising SEQ ID NO:1; light chain variable domain (LCVR) comprising SEQ ID NO:6; heavy chain complementarity determining region 1 (HCDR1) comprising SEQ ID NO:2; HCDR2 comprising SEQ ID NO:3; HCDR3 comprising SEQ ID NO:4; light chain complementarity determining region 1 (LCDR1) comprising SEQ ID NO:7; LCDR2 comprising SEQ ID NO:8; and LCDR3 comprising SEQ ID NO:10.
Example 2: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia not Adequately Controlled with their Lipid-Modifying Therapy
Introduction
This study included patients with heterozygous familial hypercholesterolemia (heFH) with or without a history of documented myocardial infarction (MI) or ischemic stroke.
The objective of the study was to assess the efficacy and safety of Alirocumab in patients with heFH and who require additional pharmacological management since their current lipid-modifying therapy (LMT) failed to achieve the LDL-C treatment goal.
This study (FIG. 1) was undertaken to demonstrate in heFH patients who are not at their LDL-C goal that Alirocumab 75 mg Q2W or 75 mg Q2W/150 mg Q2W as add-on therapy to statin±other LMT causes a statistically significant and clinically meaningful reduction in LDL-C. This population that is not at LDL-C goal on optimized LMT represents the highest risk group with a well identified unmet medical need that can be addressed by adding Alirocumab to their LDL-C lowering therapies.
Study Objectives
The primary objective of the study was to demonstrate the reduction of LDL-C by Alirocumab as add-on therapy to stable maximally tolerated daily statin therapy with or without other LMT in comparison with placebo after 24 weeks of treatment in patients with heFH.
The secondary objectives of the study were: 1) to evaluate the effect of Alirocumab 75 mg in comparison with placebo on LDL-C after 12 weeks of treatment; 2) to evaluate the effect of Alirocumab on other lipid parameters (i.e., Apo B, non-HDL-C, total-C, Lp (a), HDL-C, TG levels, and Apo A-1 levels); 3) to evaluate the long-term effect of Alirocumab on LDL-C; 4) to evaluate the safety and tolerability of Alirocumab; 5) to evaluate the development of anti-Alirocumab antibodies; and 6) to evaluate the PK of Alirocumab.
Study Design
This was a randomized, double-blind, placebo-controlled, parallel-group, unbalanced (2:1, Alirocumab:placebo), multi-center, multi-national study to assess the efficacy and the safety of Alirocumab in patients with heFH not adequately controlled with their LMT (i.e., stable maximally tolerated daily statin therapy±other LMT). Not adequately controlled was defined as an LDL-C≥70 mg/dL (1.81 mmol/L) at the screening visit (Week-3) in patients with a history of documented cardiovascular disease or LDL-C≥100 mg/dL (2.59 mmol/L) at the screening visit (Week-3) in patients without a history of documented cardiovascular disease. Randomization was stratified according to prior history of MI or ischemic stroke [Yes/No], statin treatment (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily vs. simvastatin whatever the daily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily) and geographic region. After randomization, patients received double-blind study treatment (either Alirocumab or placebo) Q2W over a period of 18 months (78 weeks) on top of stable maximally tolerated daily statin therapy±other LMT. A dose up-titration depending on Week 8 LDL-C levels may occur at Week 12 for patients randomized to Alirocumab. After completion of the 18-month double-blind treatment period, all patients who successfully completed the study had the opportunity to participate in an open-label extension study. Consequently all patients received Alirocumab at entry in the open-label extension study regardless of the study treatment they received during the 18-month double-blind treatment period.
The study consisted of 3 periods: screening, double-blind treatment, and follow-up.
The screening period was up to 3 weeks in duration including an intermediate visit during which the patient (or another designated person such as spouse, relative, etc.) was trained to self-inject/inject with placebo for Alirocumab. Eligibility assessments were performed to permit the randomization of patients into the study.
The double blind treatment period (DBTP) was a randomized, double-blind study treatment period of 18 months. The first injection during the double-blind period was done at the site on the day of randomization (Week 0 [D1]-V3). The subsequent injections were done by the patient (self-injection) or another designated person (such as spouse, relative, etc.) at a patient-preferred location (home . . . ). Patients randomized to Alirocumab received a dose of 75 mg of the Investigational Medicinal Product (IMP) from randomization (V3) up to Week 12 (V6) (i.e., Weeks 0, 2, 4, 6, 8, and 10). At the Week 12 visit (V6) these patients, in a blinded manner, either: 1) continued Alirocumab 75 mg Q2W from Week 12 onwards until the last injection at Week 76, if the Week 8 LDL-C was <70 mg/dL (1.81 mmol/L); OR 2) dose up-titrated to Alirocumab 150 mg Q2W from Week 12 onwards until the last injection at Week 76, if the Week 8 LDL-C was ≥70 mg/dL (1.81 mmol/L).
The follow-up period (if applicable) was a period of 8 weeks after the end of the DBTP for patients not consenting to participate in the open-label extension study or if prematurely discontinuing study treatment.
The laboratory measurement of lipid parameters were performed by a central laboratory (central lab) during the study.
Patients who achieved 2 consecutive calculated LDL-C levels<25 mg/dL (0.65 mmol/L) during the study were monitored and managed.
Statin and other LMT (if applicable) should be stable (including dose) during the first 24 weeks of the DBTP barring exceptional circumstances whereby overriding concerns warrant such changes. At Week 24 onwards, background LMT may be modified only under certain conditions as described below.
Patients should be on a stable diet (NCEP-ATPIII therapeutic lifestyle changes [TLC] diet or equivalent) throughout the entire study duration from screening. Table 1 provides a summary of the TLC diet for high cholesterol.
TABLE 1
Total Fat
25%-35% total calories*
Saturated fat*
<7% total calories
Polyunsaturated fat
up to 10% total calories
Monounsaturated fat
up to 20% total calories
Carbohydrates†
50%-60% total calories*
Protein
~15% total calories
Cholesterol
<200 mg/day (5.172 mmol/day)
Plant Sterols
2 g
Soluble Fiber such as psyllium
10 g-25 g
*ATP III allows an increase of total fat to 35 percent of total calories and a reduction in carbohydrate to 50 percent for persons with the metabolic syndrome. Any increase in fat intake should be in the form of either polyunsaturated or monounsaturated fat. Trans-fatty acids are another LDL-raising fat that should be kept at a low intake.
†Carbohydrate should derive predominantly from foods rich in complex carbohydrates including grains-especially whole grains-fruits, and vegetables.
The study duration included a screening period of up to 3 weeks, a 78-week DBTP for efficacy and safety assessment, and an 8-week post-treatment follow-up period after the last visit of the DBTP for patients not consenting to participate in the open-label extension study or if prematurely discontinuing study treatment. Thus, the maximum study duration per patient was about 89 weeks (i.e., 20 months) (up to 3 weeks screening+78 weeks double-blind treatment+8 weeks follow-up). The end of the study per patient was the last protocol planned visit or the resolution/stabilization of all SAEs, and AESI, whichever came last.
Selection of Patients
The inclusion criteria were: 1) patients with heFH* who were not adequately controlled with a maximally tolerated daily dose of statin** with or without other LMT, at stable dose prior to the screening visit (Week-3).
*Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria with a criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score >8 points.
According to the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, definite familial hypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) or LDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child <16 years or Total-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment); plus either A) tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 2nd degree relative (grandparent, uncle, aunt); or B) DNA-based evidence of an LDL receptor mutation or familial defective Apo B.
According to the Simon Broome Register Diagnostic Criteria for Heterozygous Familial Hypercholesterolemia, possible familial hypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) or LDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child <16 years or Total-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190 mg/dL) in an adult. (Levels either pre-treatment or highest on treatment); and at least one of the following: A) family history of MI below 50 years of age in 2nd degree relative or below 60 years of age in 1st degree relative; and B) family history of raised cholesterols >7.5 mmol/l (290 mg/dL) in adult 1st or 2nd degree relative or >6.7 mmol/l (260 mg/dL) in child or sibling under 16 years of age.
The WHO Criteria (Dutch Lipid Network clinical criteria) for diagnosis of Heterozygous Familial Hypercholesterolemia (heFH) is set forth in Table 2.
TABLE 2
Diagnostic Scoring for Heterozygous
Familial Hypercholesterolemia
Family history
a First degree relative with known premature (men <55
1
yrs, women <60 yrs) coronary and vascular disease.
b First degree relative with known LDL-cholesterol >95th
percentile for age and sex.
and/or
a First degree relative with tendon xanthomata
2
and/or arcus cornealis.
b Children below 18 yrs. with LDL-cholesterol >95th
percentile for age and sex.
Clinical history
a Patient has premature (men <55 yrs, women <60
2
yrs) coronary artery disease
b Patient has premature (men <55 yrs, women <60
1
yrs) cerebral or peripheral vascular disease.
Physical examination
a Tendon xanthomata
6
b Arcus cornealis below the age of 45 yrs.
4
Laboratory analysis
mmol/L
mg/dL
a LDL-cholesterol
>8.5
>330
8
b LDL-cholesterol
6.5-8.4
250-329
5
c LDL-cholesterol
5.0-6.4
190-249
3
d LDL-cholesterol
4.0-4.9
155-189
1
(HDL-cholesterol and triglycerides are normal)
DNA-analysis
a Functional mutation low-density lipoprotein receptor gene present
8
Diagnosis of heFH is:
Certain When
>8 points
Probable When
6-8 points
Possible When
3-5 points
**Definition of maximally tolerated dose (any of the following were acceptable):
1) rosuvastatin 20 mg or 40 mg daily;
2) atorvastatin 40 mg or 80 mg daily;
3) simvastatin 80 mg daily (if already on this dose for >1 year); or
4) patients not able to be on any of the above statin doses, should be treated with the dose of daily atorvastatin, rosuvastatin or simvastatin that is considered appropriate for the patient as per the investigator's judgment or concerns. Some examples of acceptable reasons for a patient taking a lower statin dose included, but were not limited to: adverse effects on higher doses, advanced age, low body mass index, regional practices, local prescribing information, concomitant medications, co-morbid conditions such as impaired glucose tolerance/ impaired fasting glucose.
Patients who met all of the above inclusion criteria were screened for the following exclusion criteria, which are sorted and numbered in the following 3 subsections: exclusion criteria related to study methodology, exclusion criteria related to the active comparator and/or mandatory background therapies, and exclusion criteria related to Alirocumab.
Exclusion criteria related to study methodology were: 1) patient without diagnosis of heFH made either by genotyping or by clinical criteria; 2) LDL-C<70 mg/dL (<1.81 mmol/L) at the screening visit (Week-3) and patient with history of documented cardiovascular disease. Cardiovascular disease was defined as coronary heart disease, ischemic stroke or peripheral arterial disease; 3) LDL-C<100 mg/dL (<2.59 mmol/L) at the screening visit (Week-3) and patient without history of documented cardiovascular disease; 4) not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (Week-3) and from screening to randomization; 5) currently taking a statin other than simvastatin, atorvastatin, or rosuvastatin; 6) simvastatin, atorvastatin, or rosuvastatin is not taken daily or not taken at a registered dose; 7) daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for patients on simvastatin 80 mg for more than one year, who are eligible); 8) use of fibrates, other than fenofibrate within 6 weeks of the screening visit (Week-3) or between screening and randomization visits; 9) use of nutraceutical products or over-the-counter therapies that may affect lipids which have not been at a stable dose/amount for at least 4 weeks prior to the screening visit (Week-3) or between screening and randomization visits; 10) use of red yeast rice products within 4 weeks of the screening visit (Week-3) or between screening and randomization visits; 11) patient who has received plasmapheresis treatment within 2 months prior to the screening visit (Week-3), or has plans to receive it during the study; 12) recent (within 3 months prior to the screening visit [Week-3] or between screening and randomization visits) MI, unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack (TIA), carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease; 13) planned to undergo scheduled PCI, CABG, carotid, or peripheral revascularization during the study; 14) systolic BP>160 mmHg or diastolic BP>100 mmHg at screening visit or randomization visit; 15) history of New York Heart Association (NYHA) Class III or IV heart failure within the past 12 months; 16) known history of a hemorrhagic stroke; 17) age <18 years or legal age of majority at the screening visit (Week-3), whichever is greater; 18) patients not previously instructed on a cholesterol-lowering diet prior to the screening visit (Week-3); 19) newly diagnosed (within 3 calendar months prior to randomization visit [Week 0]) or poorly controlled (glycated haemoglobin A1c [HbA1c]>9% at the screening visit [Week-3] diabetes); 20) presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins. Note that patients on thyroid replacement therapy can be included if the dosage has been stable for at least 12 weeks prior to screening and between screening and randomization visits, and TSH level is within the normal range of the Central Laboratory at the screening visit; 21) history of bariatric surgery within 12 months prior to the screening visit (Week-3); 22) unstable weight defined by a variation >5 kg within 2 months prior to the screening visit (Week-3); 23) known history of homozygous FH; 24) known history of loss of function of PCSK9 (i.e., genetic mutation or sequence variation); 25) use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization visit (Week 0). Note that topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies were not considered as ‘systemic’ and were allowed; 26) use of continuous estrogen or testosterone hormone replacement therapy unless the regimen has been stable in the past 6 weeks prior to the Screening visit (Week-3) and no plans to change the regimen during the study; 27) history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer or in situ cervical cancer; 28) known history of a positive HIV test; 29) patient who has taken any investigational drugs other than the Alirocumab training placebo kits within 1 month or 5 half lives, whichever is longer; 30) patient who has been previously treated with at least one dose of Alirocumab or any other anti-PCSK9 monoclonal antibody in other clinical trials; 31) patient who withdraws consent during the screening period (patient who is not willing to continue or fails to return); 32) conditions/situations such as: a) any clinically significant abnormality identified at the time of screening that, in the judgment of the Investigator or any sub-Investigator, would preclude safe completion of the study or constrain endpoints assessment; e.g., major systemic diseases, patients with short life expectancy; or b) considered by the Investigator or any sub-Investigator as inappropriate for this study for any reason, e.g.: deemed unable to meet specific protocol requirements, such as scheduled visits; deemed unable to administer or tolerate long-term injections as per the patient or the Investigator; Investigator or any sub-Investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol, etc; presence of any other conditions (eg, geographic or social), either actual or anticipated, that the Investigator feels would restrict or limit the patient's participation for the duration of the study; or 33) laboratory findings during screening period (not including randomization Week 0 labs): positive test for Hepatitis B surface antigen or Hepatitis C antibody; positive serum beta-hCG or urine pregnancy test (including Week 0) in women of childbearing potential (WOCBP); triglycerides >400 mg/dL (>4.52 mmol/L) (1 repeat lab is allowed); estimated glomerular filtration rate (eGFR)<30 mL/min/1.73 m2 according to 4-variable modification of diet in renal disease (MDRD) Study equation (calculated by central lab); alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>3× upper limit of normal range (ULN) (1 repeat lab is allowed); CPK>3×ULN (1 repeat lab is allowed); TSH<lower limit of normal (LLN) or >ULN (1 repeat lab is allowed).
Exclusion criteria related to the active comparator and/or mandatory background therapies were: 1) all contraindications to the background therapies or warnings/precautions of use (when appropriate) as displayed in the respective National Product Labeling.
Exclusion criteria related to Alirocumab were: 1) known hypersensitivity to monoclonal antibody or any component of the drug product; 2) pregnant or breast-feeding women; or 3) women of childbearing potential not protected by highly-effective method(s) of birth control (as defined in the informed consent form and/or in a local protocol addendum) and/or who are unwilling or unable to be tested for pregnancy. Note that women of childbearing potential must have a confirmed negative pregnancy test at screening and randomization visits. They must use an effective contraceptive method throughout the entire duration of the study treatment, and for 10 weeks after the last intake of IMP, and agree to repeat urine pregnancy test at designated visits. Postmenopausal women must be amenorrheic for at least 12 months.
Coronary heart disease, ischemic stroke, and peripheral arterial disease, as defined in exclusion criteria number 2 related to study methodology was as follows. Documented history of CHD (includes one or more of the following): acute myocardial infarction (MI); silent myocardial infarction; unstable angina; coronary revascularization procedure (eg, percutaneous coronary intervention [PCI] or coronary artery bypass graft surgery [CABG]); clinically significant CHD diagnosed by invasive or non-invasive testing (such as coronary angiography, stress test using treadmill, stress echocardiography or nuclear imaging).
Documented previous ischemic stroke with a focal ischemic neurological deficit that persisted more than 24 hours, considered as being of atherothrombotic origin. CT or MRI must have been performed to rule out hemorrhage and non-ischemic neurological disease.
Documented peripheral arterial disease (one of the following criteria must be satisfied): 1) current intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) of presumed atherosclerotic origin together with ankle-brachial index equal to or less than 0.90 in either leg at rest or 2) history of intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) together with endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease or 3) history of critical limb ischemia together with thrombolysis, endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease.
Study Treatments
Sterile Alirocumab drug product was supplied at a concentration of 75 mg/mL and 150 mg/mL both as 1 mL volume in an auto-injector. The drug substance was formulated in histidine, pH 6.0, polysorbate 20, and sucrose.
Sterile placebo for Alirocumab was prepared in the same formulation as Alirocumab without the addition of protein as 1 mL volume in an auto-injector.
During the double-blind treatment period, Alirocumab or placebo was administered subcutaneously Q2W, starting at Week 0 continuing up to the last injection (Week 76) 2 weeks before the end of the double blind treatment period (DBTP). If the injection was scheduled to take place on the same date as the site visit, then the IMP was administered after the blood sampling was completed.
Investigational Medicinal Product (IMP) should ideally have been administered Q2W subcutaneously at approximately the same time of the day; however it was acceptable to have a window period of ±3 days. The time of the day was based on the patient's preference.
The following classes of drugs were identified as non-NIMP because the medication was either a background therapy or a potential rescue medication: statins (rosuvastatin, atorvastatin, simvastatin); cholesterol absorption inhibitors (ezetimibe); bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam); nicotinic acid; fenofibrate; and omega-3 fatty acids (≥1000 mg daily).
Patients were randomized to receive either placebo or Alirocumab during the double-blind study treatment period using a ratio 1:2, with permuted-block randomization. Randomization was stratified according to prior history of MI or ischemic stroke [Yes/No], statin treatment (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily vs. simvastatin whatever the daily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily) and geographic region.
A concomitant medication was any treatment received by the patient concomitantly to the study (until follow-up visit). Concomitant medications should be kept to a minimum during the study. However, if these are considered necessary for the patient's welfare and are unlikely to interfere with the IMP, they may be given at the discretion of the Investigator, with a stable dose (when possible). Besides the specific information related to concomitant medications provided in this section, any other concomitant medication(s) will be allowed. If the patient has an LDL-C≥160 mg/dL (4.14 mmol/L) at the screening visit (Week-3) and is treated with a statin only, i.e., without additional LMT, the investigator will have to report the reason for the patient not being on a second LMT. For background LMT, including statins, sites must follow the national product label for the safety monitoring and management of patients.
Nutraceutical products or over-the-counter therapies that may affect lipids were allowed only if they had been used at a stable dose for at least 4 weeks prior to screening visit, during the screening period and maintained during the first 24 weeks of the double-blind treatment period. After the Week 24 visit, modification to these nutraceutical products or over-the-counter therapies was allowed but in general should be avoided. Examples of such nutraceutical products or over-the-counter therapies include omega-3 fatty acids at doses <1000 mg, plant stanols such as found in Benecol, flax seed oil, and psyllium.
Patients must have been on stable maximally tolerated daily registered doses of statins with or without other LMT for at least 4 weeks (6 weeks for fenofibrate) before screening visit. During the study, the patients should stay on these stable maximally tolerated registered daily doses of statins with or without other LMT. From the screening visit (Week-3) until Week 24 of the double-blind treatment period, the background LMT should not be changed. No dose adjustment, discontinuation or initiation of other statins or other LMT should take place during this time, barring exceptional circumstances whereby overriding concerns (including but not limited to triglyceride alert posted by the central lab) warrant such changes, as per the Investigator's judgment.
For a rescue notification of LDL-C at the Week 24 visit and later, i.e., LDL-C increase >25% as compared to randomization visit LDL-C on two consecutive occasions, the Investigator should have ensured that no reasonable explanation existed for insufficient LDL-C control (such as an alternative medical cause like corticosteroid use, etc) and in particular that: compliance with diet was appropriate; compliance with background LMT was appropriate; and study treatment was given as planned. If any of the above could reasonably explain the insufficient LDL-C control, the Investigator should have undertaken appropriate action, i.e., stress on the absolute need to be compliant with treatment, if needed organize a specific interview with a qualified nutrition professional and stress on the absolute need to be compliant with diet, and perform a blinded LDL-C assessment within 1 to 2 months. If none of the above mentioned reasons were found, or if appropriate action failed to decrease LDL-C under the alert value, rescue medication may have been introduced.
If no reason for LDL-C above the threshold value could be found, or if appropriate action failed to decrease LDL-C below the threshold value, rescue medication may have been introduced. The effectiveness of any such changes was to be made based on lack of rescue threshold from blinded lipid testing at the next routinely scheduled lab draw. Patients per protocol already received a maximum tolerated dose of statin, so statin uptitration or switch was not an option. For further LDL-C lowering, the investigator could consider adding: a cholesterol absorption inhibitor (ezetimibe), or a bile acid-binding sequestrant (the resins cholestyramine and colestipol, or colesevelam, a nonabsorbable polymer). The following lipid-modifying agents could also be considered: fibrate (Note: Caution should be exercised when combining fibrates with other cholesterol-lowering medications such as statins because of the risk of myopathy. When a fibrate is combined with a statin, fenofibrate is the fibrate of choice because it does not affect statin glucuronidation. The only fibrate allowed per protocol was fenofibrate); nicotinic acid (niacin) (Note: Niacin raises blood glucose but has been shown to be effective in modifying lipid disorders in people with diabetes if glucose control is maintained).
In summary, background LMT should not be modified from screening to the follow-up visit. However, up to Week 24, if a confirmed TG alert was reached or if there was an overwhelming clinical concern (at the discretion of the Investigator) then modification of the background LMT was allowed. At Week 24 onwards, if a confirmed TG alert was reached, or if a rescue threshold for LDL-C was attained (and no other reasonable explanation exists), or if there was an overwhelming clinical concern (at the discretion of the Investigator) then modification of the background LMT was allowed.
Women of childbearing potential must take an effective contraceptive method throughout the study treatment and for 10 weeks after the last IMP injection (e.g., Follow-up visit).
Forbidden concomitant medications from the initial screening visit until the follow-up visit included the following: statins other than simvastatin, atorvastatin and rosuvastatin; fibrates, other than fenofibrate; and red yeast rice products.
Study Endpoints
The primary efficacy endpoint was the percent change in calculated LDL-C from baseline to Week 24, which was defined as: 100×(calculated LDL-C value at Week 24-calculated LDL-C value at baseline)/calculated LDL-C value at baseline. The baseline calculated LDL-C value was the last LDL-C level obtained before the first double-blind IMP injection. The calculated LDL-C at Week 24 was the LDL-C level obtained within the Week 24 analysis window and during the main efficacy period. The main efficacy period was defined as the time from the first double-blind IMP injection up to 21 days after the last double-blind IMP injection or up to the upper limit of the Week 24 analysis window, whichever came first. All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used to provide a value for the primary efficacy endpoint if appropriate according to above definition.
The key secondary efficacy endpoints were: 1) the percent change in calculated LDL-C from baseline to Week 12: similar definition and rules as for primary efficacy endpoint, except that the calculated LDL-C at Week 12 was the LDL-C level obtained within the Week 12 analysis window and during the 12-week efficacy period. The 12-week efficacy period was defined as the time from the first double-blind IMP injection up to the Visit 6 re-supply IVRS contact or up to 21 days after the last double-blind IMP injection, whichever came first. Blood sampling collected the day of the Visit 6 re-supply IVRS contact was considered as before titration; 2) the percent change in Apo B from baseline to Week 24, using the same definition and rules as for the primary endpoint; 3) the percent change in non-HDL-C from baseline to Week 24, using the same definition and rules as for the primary endpoint; 4) the percent change in total-C from baseline to Week 24, using the same definition and rules as for the primary endpoint; 5) the percent change in Apo B from baseline to Week 12, using the same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 6) the percent change in non-HDL-C from baseline to Week 12, using the same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 7) the percent change in total-C from baseline to Week 12, using the same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 8) the percent change in calculated LDL-C from baseline to Week 52, using definitions and rules that were similar to the ones used for the primary endpoint replacing Week 24 by Week 52. Note that the 52-week efficacy period was defined as the time from the first double-blind IMP injection up to 21 days after the last double-blind IMP injection, or up to the upper limit of the Week 52 analysis window, whichever came first; 9) the proportion of patients reaching LDL-C goal at Week 24, i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patients without prior CVD, defined as: (number of patients whose calculated LDL-C value at Week 24 reach LDL-C goal/number of patients in the modified intent-to-treat (mITT) population)*100, using definition and rules used for the primary endpoint; 10) the proportion of patients reaching LDL-C<70 mg/dL (1.81 mmol/L) at Week 24; 11) the percent change in Lp(a) from baseline to Week 24, using the same definition and rules as for the primary endpoint; 12) the percent change in HDL-C from baseline to Week 24, using the same definition and rules as for the primary endpoint; 13) the percent change in HDL-C from baseline to Week 12, using the same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 14) the percent change in Lp(a) from baseline to Week 12, using the same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 15) the percent change in fasting TG from baseline to Week 24, using the same definition and rules as for the primary endpoint; 16) the percent change in fasting TG from baseline to Week 12, using the same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 17) the percent change in Apo A-1 from baseline to Week 24, using the same definition and rules as for the primary endpoint; and 18) the percent change in Apo A-1 from baseline to Week 12, using the same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12.
Other secondary efficacy endpoints were: 1) the percent change in calculated LDL-C from baseline to Week 78, using definitions and rules that were similar to the ones used for the primary endpoint replacing Week 24 by Week 78. The 78-week efficacy period was defined as the time from the first double-blind IMP injection up to 21 days after the last double-blind IMP injection, or up to the upper limit of the Week 78 analysis window, whichever came first; 2) the proportion of patients reaching LDL-C goal at Weeks 12, 52, and 78, i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patients without prior CVD; 3) the proportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L) at Week 24; 4) the proportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L) at Week 12; 5) the proportion of patients reaching LDL-C<70 mg/dL (1.81 mmol/L) at Week 12; 6) the absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline to Weeks 12, 24, 52, and 78; 7) the percent change in Apo B, non-HDL-C, total-C, Lp (a), HDL-C, fasting TG, and Apo A-1 from baseline to Weeks 52 and 78; 8) the change in ratio Apo B/Apo A-1 from baseline to Weeks 12, 24, 52, and 78; 9) the proportion of patients with Apo B<80 mg/dL (0.8 g/L) at Weeks 12, 24, 52, and 78; 10) the proportion of patients with non-HDL-C<100 mg/dL at Weeks 12, 24, 52, and 78; and 11) the proportion of patients with calculated LDL-C<70 mg/dL (1.81 mmol/L) and/or ≥50% reduction in calculated LDL-C (if calculated LDL-C≥70 mg/dL [1.81 mmol/L]) at Weeks 12, 24, 52, and 78.
Other endpoints were: anti-Alirocumab antibody assessments, high-sensitivity C-reactive protein, glycated haemoglobin A1c, EQ-5D Questionnaire, pharmacogenetics, and pharmacokinetics. Anti-Alirocumab antibodies included the antibody status (positive/negative) and antibody titers. Serum samples for anti-Alirocumab antibody determination were drawn periodically throughout the study. The first scheduled sample at randomization visit was obtained before IMP injection (predose). Patients who had a titer at or above 240 for anti-Alirocumab antibody at follow-up visit had additional antibody sample(s), at 6 to 12 months after the last dose and thereafter, about every 3 to 6 months until titer returns below 240. The percent change in high-sensitivity C-reactive protein (hs-CRP) was measured at baseline and Weeks 24, 52, and 78. EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D as a measure of health-related quality of life defines health in terms of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension can take one of three responses (3 ordinal levels of severity): “no problem” (1); “some problems” (2); “severe problems” (3); Overall health state is defined as a 5-digit number. Health states defined by the 5-dimensional classification can be converted into corresponding index scores that quantify health status, where 0 represents ‘death’ and 1 represents “perfect health”.
Study Procedures
For all visits after Day 1/Week 0 (randomization visit), a timeframe of a certain number of days was allowed. The window period for visits at Weeks 12 and 24 were ±3 days, at Weeks 52 and 78 was ±5 days, and for all other site visits it was ±7 days during the double-blind treatment period, and follow-up period. A window period of +3 days was allowed for the randomization visit (Day 1/Week 0) and ±7 days for the injection training visit during the screening period (Week-1). For all visits after Day 1/randomization visit, if one visit date is changed, then the next visit should take place according to the original schedule.
Safety
Occurrence of treatment emergent adverse events (TEAEs) reported by the patient or noted by the investigator, serious adverse events (SAEs), TEAEs leading to treatment discontinuation, AEs of special interest (local Injection site reactions, allergic events, selected neurological events and cardiovascular events confirmed by adjudication result), occurrence of PCSA (potentially clinically significant abnormalities) in laboratory parameters, exploratory analysis for patients with 2 consecutive calculated LDL-C<25 mg/dL (<0.65 mmol/L) and for changes in blood glucose control, including diabetes.
Statistical Methods
Sample Size Determination:
A total sample size of 45 patients (30 in alirocumab and 15 in placebo) had 95% power to detect a difference in mean percent change in LDL-C of 30% with a 0.05 two-sided significance level and assuming a common standard deviation of 25%, and all these 45 patients having an evaluable primary endpoint. Nevertheless, to meet regulatory requirements across the program, the sample size was increased to assess the safety of alirocumab. In order to have at least 225 patients on alirocumab followed for 12 months in this study, and assuming a drop-out rate of 10% over the first 3-month period and a drop-out rate of 20% over the remaining 9-month period, the final total sample size was increased to 471 with a randomization ratio 2:1 (alirocumab 314: placebo 157).
Timing of Analyses:
The first step analysis included efficacy endpoints up to Week 52 (final efficacy analysis) and interim safety analysis, which was performed on all safety data up to the common study cut-off date (last patient Week 52 visit). Analysis of lipid data beyond Week 52 was descriptive. These results are presented herein.
The second step (final) analysis will be conducted at the end of the study and will consist in the final analysis of efficacy endpoints up to Week 78 and final safety analysis.
Analysis Populations:
The primary efficacy analysis population was the intent-to-treat (ITT) population, defined as all randomized patients who had an evaluable primary endpoint, that is, those with an available baseline calculated LDL-C value, and at least one available calculated LDL-C value within one of the analysis windows up to Week 24 (including all calculated LDL-C values on-treatment and off-treatment).
The secondary efficacy analysis population was the modified intent-to-treat (mITT) population, defined as all randomized patients who took at least one dose or part of a dose of the double-blind investigational medicinal product (IMP) and who had an available calculated LDL-C value at baseline and at least one within one of the analysis windows up to Week 24 during the efficacy treatment period. The efficacy treatment period was defined as the time from the first double-blind IMP injection up to 21 days after the last double-blind injection.
The safety population included all randomized patients who received at least one dose or part of a dose of the double-blind IMP.
Efficacy Analyses:
Primary analyses of efficacy endpoints were conducted using an ITT approach (based on the ITT population defined above), including all lipid data, regardless of whether the patient was continuing therapy or not. This corresponds to ITT estimands, defined for primary and key secondary endpoints. In addition, analyses were also conducted using an on-treatment approach (based on the mITT population defined above), including lipid data collected during the efficacy treatment period. This corresponds to on-treatment estimands of key secondary endpoints.
The ITT approach analyzed all patients, irrespective of their adherence to the treatment; it assessed the benefit of the treatment strategy and reflected as much as possible the effect in a population of patients. The on-treatment approach analyzed the effect of treatment, restricted to the period during which patients actually received the treatment. It assessed the benefit that a treatment would achieve in patients adherent to treatment up to the considered time point.
Efficacy analyses were performed according to treatment as-randomized.
All measurements, scheduled or unscheduled, fasting or not fasting, were assigned to analysis windows in order to provide an assessment for Week 4 to Week 78 time points.
With regards to the primary efficacy analysis (ITT approach), the percent change in calculated LDL-C from baseline to Week 24 was analyzed using a mixed-effect model with repeated measures (MMRM) approach. All post-baseline data available from Week 4 to Week 52 analysis windows were used and missing data were accounted for by the MMRM. The model included the fixed categorical effects of treatment group (placebo versus alirocumab), randomization strata (as per IVRS), time point (Week 4 to Week 52), treatment-by-time point interaction and strata-by-time point interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline value-by-time-point interaction. This model provided baseline adjusted least-squares means (LSmeans) estimates at Week 24 for both treatment groups with their corresponding standard errors and 95% confidence intervals. To compare the alirocumab to the placebo group, an appropriate contrast statement was used to test the differences of these estimates at the 5% alpha level.
A hierarchical procedure was defined to test key secondary endpoints while controlling for multiplicity (using above order of key secondary endpoints). The first key secondary endpoint was the percent change in calculated LDL-C from baseline to Week 24 using an on-treatment approach.
Continuous secondary variables anticipated to have a normal distribution (i.e., lipids other than TGs and Lp(a)) were analyzed using the same MMRM model as for the primary endpoint. Continuous endpoints anticipated to have a non-normal distribution (i.e., TGs and Lp(a)) were analyzed using multiple imputation approach for handling of missing values followed by robust regression model with endpoint of interest as response variable using M-estimation (using SAS ROBUSTREG procedure) with treatment group, randomization strata (as per IVRS) and corresponding baseline value(s) as effects to compare treatment effects. Combined estimate for mean in both treatment groups, as well as the differences of these estimates, with their corresponding SEs, 95% CIs and p-value were provided (through SAS MIANALYZE procedure).
Binary secondary efficacy endpoints were analyzed using multiple imputation approach for handling of missing values followed by stratified logistic regression with treatment group as main effect and corresponding baseline value(s) as covariate, stratified by randomization factors (as per IVRS). Combined estimates of odds ratio versus placebo, 95% CI, and p-value were provided (through SAS MIANALYZE procedure).
Safety Analyses:
Safety analyses were descriptive, performed on the safety population according to treatment actually received. The safety analysis focused on the TEAE period defined as the time from the first dose of double-blind IMP up to 70 days after the last double-blind injection. TEAE which developed, worsened or became serious or PCSA occurring after the patient inclusion in the open-label extension study (LTS13643) were not considered in the TEAE period. TEAE period was truncated at the common study cut-off date.
Results
Study Patients
Patient Accountability
Of the 486 randomized patients (323 patients and 163 patients in the alirocumab and the placebo groups, respectively), one patient in the alirocumab group was not treated and was therefore not included in the safety population. This patient was also excluded from the ITT population (no LDL-C value within one of the analysis windows up to Week 24 as the patient withdrew consent on Day 1).
Two randomized patients in the alirocumab group were excluded from the mITT population (one patient excluded from the ITT population and one patient with no LDL-C value within one of the analysis windows up to Week 24 during the efficacy treatment period).
TABLE 3
Analysis populations
Alirocumab 75
Q2W/Up150
Placebo
Q2W
All
Randomized population
163 (100%)
323 (100%)
486 (100%)
Efficacy populations
Intent-to-Treat (ITT)
163 (100%)
322 (99.7%)
485 (99.8%)
Modified Intent-to-
163 (100%)
321 (99.4%)
484 (99.6%)
Treat (mITT)
Safety population
163
322
485
Note:
The safety population patients are tabulated according to treatment actually received (as treated). For the other populations, patients are tabulated according to their randomized treatment.
In the alirocumab group, among the 311 patients who received at least one injection after Week 12, 135 (43.4%) patients received automatic up-titration at Week 12 from alirocumab 75 mg Q2W to 150 mg Q2W in a blinded manner.
Study Disposition
Study disposition, exposure and safety analyses were assessed using all data up to the study common cut-off date (defined as the date of the last patient's Week 52 visit). Therefore, this first step analysis includes data beyond Week 52 and up to Week 78 or Follow-up visit for some patients.
There were in total 7 (1.4%) randomized patients who completed the 78-week double-blind study treatment period and 424 (87.2%) randomized patients with treatment ongoing at the time of the first-step analysis cut-off date. The double-blind IMP was prematurely discontinued before Week 78 for 18 (11.0%) randomized patients in the placebo group and 36 (11.1%) randomized patients in the alirocumab group. The main reasons for study treatment discontinuation were adverse event and other reasons.
In addition, among these patients 34 (10.5%) randomized patients had prematurely discontinued the double-blind IMP before the Week 52 visit in the alirocumab group and 15 (9.2%) patients in the placebo group.
In this first step analysis, final results are available for the primary efficacy endpoint at Week 24 and key secondary efficacy endpoints were assessed at Week 12, Week 24 and Week 52. The primary endpoint was missing for 46 patients at the week 24 visit for the following reasons: 18 samples were not done due to earlier study discontinuation, 14 samples were done outside the analysis time window, 4 missing samples while visit Week 24 was done, and 10 samples were done but the measurement could not be done (lipemia, insufficient quantity, TGs>400 mg/dL[>4.52 mmol/L], sample lost, . . . ).
Demographics, Baseline, and Summary Population Characteristics
Demographic characteristics, disease characteristics and lipid parameters at baseline were similar in the alirocumab group as compared to the placebo group (see Table 4). 486 heFH patients diagnosed by genotyping (39%) or WHO or Simon Broome criteria (61%) were randomized (2:1) to alirocumab (75 mg Q2W potentially uptitrated to 150 mg Q2W) or placebo (323 versus 163, respectively). Half of the randomized population (51%) had a history of at least one coronary heart disease (CHD) or multiple CHD risk factors that defined these patients being at very high cardiovascular risk. Demographics characteristics, disease characteristics and lipid parameters at baseline were similar in the alirocumab group as compared to the placebo group. All patients were treated with a statin, 82% receiving a dose defined as high intensity statin (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily) and 57% receiving ezetimibe in addition to the statin. Mean (SD) calculated LDL-C at baseline was 144.6 (49.7) mg/dL [3.75 (1.29) mmol/L].
Exposure to injections was similar across treatment groups with a mean exposure of 59 weeks. In the alirocumab group, among the 311 patients who received at least one injection after Week 12, 135 (43.4%) patients received automatic up-titration at Week 12 from alirocumab 75 mg Q2W to 150 mg Q2W in a blinded manner.
TABLE 4
Baseline Characteristics of FHI Patient Population
Characteristic
Diagnosis of heFH†, % (n)
Alirocumab (N = 323)
Placebo (N = 163)
Genotyping
39.9%
(129)
38.0%
(62)
Clinical criteria
59.8%
(193)
62.0%
(101)
Age, mean (SD), yrs
52.1
(12.9)
51.7
(12.3)
Male
55.7%
(180)
57.7%
(94)
Race, white
92.9%
(300)
88.3%
(144)
BMI, mean (SD), kg/m2
29.0
(4.6)
30.0
(5.4)
CHD history
45.5%
(147)
47.9%
(78)
CHD risk equivalents†
16.7%
(54)
15.3%
(25)
Current smoker
12.1%
(39)
18.4%
(30)
Hypertension
43.0%
(139)
43.6%
(71)
Type 2 diabetes
9.6%
(31)
15.3%
(25)
% (N) of patients unless statedAll pts on background of max tolerated statin ± other lipid-lowering therapy.
†Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score of >8 points. In FH I, one patient was categorised as “probable” FH by clinical criteria - genotyping results for this patient are pending.
TABLE 5
Disease characteristics and other relevant baseline data - Randomized population
Alirocumab 75
Q2W/Up150
Placebo
Q2W
All
(N = 163)
(N = 323)
(N = 486)
Type of hypercholesterolemia
Heterozygous Familial
163
323
486
Hypercholesterolemia (heFH)
(100%)
(100%)
(100%)
Non-Familial
0
0
0
Hypercholesterolemia (non-FH)
Time from hypercholesterolemia
diagnosis (years)
Number
163
323
486
Mean (SD)
13.28
12.19
12.55
(11.38)
(11.38)
(11.38)
Median
9.43
8.82
9.03
Min:Max
0.0:42.6
0.0:60.7
0.0:60.7
Confirmation of diagnosis
By genotyping
62
129
191
(38.0%)
(39.9%)
(39.3%)
By WHO/Simon Broomea
101
193
294
(62.0%)
(59.8%)
(60.5%)
afor heFH diagnosis not confirmed by genotyping.
Note:
at time of screening, one patient was included based on clinical criteria with a score of 8 for the WHO criteria. As the clinical score characterized the patient as probable heFH rather than certain, a genotyping was performed to confirm heFH status but these results are still pending.
TABLE 6
Cardiovascular History and Risk Factors Breakdown
Alirocumab
Placebo
Characteristic
(N = 323)
(N = 163)
CHD history
45.5%
(147)
47.9%
(78)
Acute MI
22.0%
(71)
26.4%
(43)
Silent MI
2.5%
(8)
1.2%
(2)
Unstable angina
11.1%
(36)
15.3%
(25)
Coronary revasc.
31.6%
(102)
34.4%
(56)
Other clinically significant CHD
26.9%
(87)
29.4%
(48)
CHD risk equivalents
16.7%
(54)
15.3%
(25)
Ischemic stroke
4.0%
(13)
1.8%
(3)
Peripheral arterial disease
2.8%
(9)
2.5%
(4)
Moderate CKD
6.2%
(20)
5.5%
(9)
Diabetes + 2 or more risk factors
5.9%
(19)
6.1%
(10)
% (N) of patients unless stated. All pts on background of max tolerated statin ± other lipid-lowering therapy
Table 7
Background LMT at randomization - Randomized population
Alirocumab 75
Q2W/Up150
Placebo
Q2W
All
(N = 163)
(N = 323)
(N = 486)
Any statin
163
(100%)
323
(100%)
486
(100%)
Taking high intensity statin
135
(82.8%)
261
(80.8%)
396
(81.5%)
Atorvastatin daily dose (mg)
64
(39.3%)
113
(35.0%)
177
(36.4%)
10
1
(0.6%)
3
(0.9%)
4
(0.8%)
20
2
(1.2%)
7
(2.2%)
9
(1.9%)
40
23
(14.1%)
23
(7.1%)
46
(9.5%)
80
38
(23.3%)
77
(23.8%)
115
(23.7%)
Other doses
0
3
(0.9%)
3
(0.6%)
Rosuvastatin daily dose (mg)
81
(49.7%)
172
(53.3%)
253
(52.1%)
5
4
(2.5%)
7
(2.2%)
11
(2.3%)
10
2
(1.2%)
5
(1.5%)
7
(1.4%)
20
19
(11.7%)
44
(13.6%)
63
(13.0%)
40
55
(33.7%)
116
(35.9%)
171
(35.2%)
Other doses
1
(0.6%)
0
1
(0.2%)
Simvastatin daily dose (mg)
18
(11.0%)
38
(11.8%)
56
(11.5%)
10
2
(1.2%)
2
(0.6%)
4
(0.8%)
20
1
(0.6%)
5
(1.5%)
6
(1.2%)
40
10
(6.1%)
25
(7.7%)
35
(7.2%)
80
3
(1.8%)
6
(1.9%)
9
(1.9%)
Other doses
2
(1.2%)
0
2
(0.4%)
Any LMT other than statinsa
107
(65.6%)
198
(61.3%)
305
(62.8%)
Any LMT other than nutraceuticals
105
(64.4%)
192
(59.4%)
297
(61.1%)
Ezetimibe
97
(59.5%)
180
(55.7%)
277
(57.0%)
Nutraceuticals
8
(4.9%)
20
(6.2%)
28
(5.8%)
ain combination with statins or not.
High intensity statin corresponds to atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily.
TABLE 8
Lipid efficacy parameters at baseline - Quantitative
summary in conventional units - Randomized population
Alirocumab 75
Q2W/Up150
Placebo
Q2W
All
(N = 163)
(N = 323)
(N = 486)
Calculated LDL-C
(mg/dL)
Number
163
323
486
Mean (SD)
144.4
(46.8)
144.8
(51.1)
144.6
(49.7)
Median
138.0
135.0
135.5
Q1:Q3
112.0:166.0
112.0:163.0
112.0:165.0
Min:Max
66:354
39:384
39:384
Measured LDL-C
(mg/dL)
Number
140
272
412
Mean (SD)
140.0
(43.5)
140.2
(49.7)
140.1
(47.6)
Median
135.0
130.5
132.0
Q1:Q3
111.0:164.0
108.0:159.5
108.5:161.0
Min:Max
68:356
37:378
37:378
Non-HDL-C (mg/dL)
Number
163
323
486
Mean (SD)
169.6
(50.6)
170.3
(54.6)
170.1
(53.3)
Median
161.0
158.0
160.0
Q1:Q3
132.0:195.0
134.0:198.0
133.0:196.0
Min:Max
78:390
58:426
58:426
Total-C (mg/dL)
Number
163
323
486
Mean (SD)
217.6
(50.3)
221.1
(54.3)
219.9
(53.0)
Median
210.0
212.0
211.0
Q1:Q3
185.0:240.0
184.0:244.0
185.0:243.0
Min:Max
137:445
123:482
123:482
HDL-C (mg/dL)
Number
163
323
486
Mean (SD)
48.0
(14.4)
50.8
(15.7)
49.8
(15.3)
Median
45.0
47.0
46.5
Q1:Q3
36.0:56.0
39.0:59.0
38.0:58.0
Min:Max
24:116
22:115
22:116
Fasting TGs
(mg/dL)
Number
163
323
486
Mean (SD)
126.5
(62.9)
128.4
(66.7)
127.8
(65.4)
Median
111.0
113.0
112.0
Q1:Q3
85.0:151.0
82.0:153.0
83.0:152.0
Min:Max
45:431
35:566
35:566
Lipoprotein-
(a)(mg/dL)
Number
161
317
478
Mean (SD)
47.2
(51.6)
51.7
(50.2)
50.2
(50.7)
Median
23.0
34.0
28.0
Q1:Q3
8.0:72.0
12.0:82.0
11.0:80.0
Min:Max
2:223
2:229
2:229
Apo-B (mg/dL)
Number
161
317
478
Mean (SD)
113.4
(28.5)
114.4
(30.8)
114.1
(30.0)
Median
109.0
108.0
109.0
Q1:Q3
94.0:128.0
94.0:130.0
94.0:129.0
Min:Max
64:249
45:250
45:250
Apo-A1 (mg/dL)
Number
161
317
478
Mean (SD)
137.6
(27.2)
142.8
(27.4)
141.1
(27.4)
Median
134.0
138.0
137.0
Q1:Q3
121.0:151.0
124.0:158.0
122.0:155.0
Min:Max
84:292
79:278
79:292
Apo-B/Apo-A1
(ratio)
Number
161
317
478
Mean (SD)
0.859
(0.292)
0.830
(0.269)
0.839
(0.277)
Median
0.810
0.780
0.800
Q1:Q3
0.640:0.990
0.650:0.960
0.650:0.970
Min:Max
0.36:2.42
0.26:1.84
0.26:2.42
Total-C/HDL-C
(ratio)
Number
163
323
486
Mean (SD)
4.907
(1.838)
4.707
(1.756)
4.774
(1.785)
Median
4.658
4.321
4.444
Q1:Q3
3.661:5.658
3.537:5.649
3.542:5.649
Min:Max
1.86:13.64
1.73:15.14
1.73:15.14
Note:
Measured LDL-C was assessed via the beta-quantification method.
The collection of measured LDL-C was not planned in the initial protocol and was added in an amendment. Therefore, measured LDL-C values are available for fewer patients compared to calculated LDL-C values.
Dosage and Duration
Exposure to injections was similar across treatment groups with a mean exposure of 59 weeks.
In the alirocumab group, among the 311 patients who received at least one injection after Week 12, 135 (43.4%) patients received automatic up-titration from 75 mg Q2W to 150 mg Q2W at Week 12 in a blinded manner.
Efficacy
Primary Efficacy Endpoint
The ITT analysis includes all calculated LDL-C values collected on-treatment and off-treatment up to Week 52. The primary endpoint (percent change in calculated LDL-C from baseline to Week 24) analysis is provided based on a MMRM model on the ITT population, using LS means estimates at Week 24. Thirty-two (9.9%) patients in the alirocumab group and 14 (8.6%) patients in the placebo group did not have a calculated LDL-C value at Week 24. These missing values were accounted for by the MMRM model.
Results of the primary endpoint analysis are presented in Table 9, in mmol/L and mg/dL.
Primary Efficacy Analysis
A statistically significant decrease in percent change in LDL-C from baseline to Week 24 was observed in the alirocumab group (LS mean versus baseline−48.8%) compared to the placebo group (LS mean versus baseline+9.1%) (LS mean difference vs. placebo of −57.9%, p<0.0001). In the alirocumab group, LDL-C reduction from baseline was observed from Week 4 and maintained throughout the study up to Week 78 (see FIG. 2 and Table 10).
TABLE 9
Percent change from baseline in calculated LDL-C
at Week 24: MMRM - ITT analysis - ITT population
Alirocumab 75
Q2W/Up150
Calculated LDL
Placebo
Q2W
Cholesterol
(N = 163)
(N = 322)
Baseline (mmol/L)
Number
163
322
Mean (SD)
3.739
(1.213)
3.748
(1.326)
Median
3.574
3.497
Min:Max
1.71:9.17
1.01:9.95
Baseline (mg/dL)
Number
163
322
Mean (SD)
144.4
(46.8)
144.7
(51.2)
Median
138.0
135.0
Min:Max
66:354
39:384
Week 24 percent change
from baseline (%)
LS Mean (SE)
9.1
(2.2)
−48.8
(1.6)
LS mean difference (SE)
−57.9
(2.7)
vs placebo
95% CI
(−63.3 to −52.6)
p-value vs placebo
<0.0001*
Note:
Least-squares (LS) means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis. The model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, treatment-by-time point and strata-by-time point interaction, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline calculated LDL-C value-by-time point interaction
MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
The p-value is followed by a ‘*’ if statistically significant according to the fixed hierarchical approach used to ensure a strong control of the overall type-1 error rate at the 0.05 level
TABLE 10
Calculated LDL-C over time - ITT analysis - ITT population
Alirocumab 75 Q2W/Up150
Placebo
Q2W
(N = 163)
(N = 322)
Percent
Percent
Change
change
Change
change
Calculated
from
from
from
from
LDL-C
Value
baseline
baseline
Value
baseline
baseline
LS Mean (SE)
(mmol/L)
Baseline a
3.739
(0.095)
NA
NA
3.748
(0.074)
NA
NA
Week 4
3.819
(0.070)
0.074
(0.070)
4.3
(2.1)
1.996
(0.050)
−1.749
(0.050)
−46.7
(1.5)
Week 8
3.805
(0.073)
0.059
(0.073)
3.6
(1.8)
1.986
(0.052)
−1.759
(0.052)
−46.4
(1.3)
Week 12
3.898
(0.074)
0.153
(0.074)
5.7
(2.0)
2.078
(0.053)
−1.668
(0.053)
−43.5
(1.4)
Week 16
3.892
(0.080)
0.147
(0.080)
5.6
(2.1)
1.763
(0.057)
−1.982
(0.057)
−51.7
(1.5)
Week 24
4.029
(0.084)
0.284
(0.084)
9.1
(2.2)
1.846
(0.060)
−1.899
(0.060)
−48.8
(1.6)
Week 36
3.965
(0.091)
0.220
(0.091)
8.5
(2.4)
1.997
(0.066)
−1.748
(0.066)
−45.1
(1.8)
Week 52
4.000
(0.092)
0.255
(0.092)
9.0
(2.6)
1.925
(0.066)
−1.821
(0.066)
−47.1
(1.9)
Week 64
3.947
(0.086)
1.962
(0.063)
Week 78
4.082
(0.101)
2.177
(0.073)
LS Mean (SE)
(mg/dL)
Baseline a
144.4
(3.7)
NA
NA
144.7
(2.9)
NA
NA
Week 4
147.5
(2.7)
2.9
(2.7)
4.3
(2.1)
77.1
(1.9)
−67.5
(1.9)
−46.7
(1.5)
Week 8
146.9
(2.8)
2.3
(2.8)
3.6
(1.8)
76.7
(2.0)
−67.9
(2.0)
−46.4
(1.3)
Week 12
150.5
(2.9)
5.9
(2.9)
5.7
(2.0)
80.2
(2.0)
−64.4
(2.0)
−43.5
(1.4)
Week 16
150.3
(3.1)
5.7
(3.1)
5.6
(2.1)
68.1
(2.2)
−76.5
(2.2)
−51.7
(1.5)
Week 24
155.6
(3.2)
11.0
(3.2)
9.1
(2.2)
71.3
(2.3)
−73.3
(2.3)
−48.8
(1.6)
Week 36
153.1
(3.5)
8.5
(3.5)
8.5
(2.4)
77.1
(2.5)
−67.5
(2.5)
−45.1
(1.8)
Week 52
154.4
(3.5)
9.8
(3.5)
9.0
(2.6)
74.3
(2.6)
−70.3
(2.6)
−47.1
(1.9)
Week 64
152.4
(3.3)
75.8
(2.4)
Week 78
157.6
(3.9)
84.0
(2.8)
a Baseline is described using means and standard errors.
Note:
Least-squares (LS) means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis. The model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline LDL-C value-by-time point interaction
MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
Key Secondary Efficacy Endpoints
Table 11 summarizes analysis results on key secondary endpoints in the hierarchical order. All key secondary endpoints are statistically significant according to the hierarchical testing procedure.
TABLE 11
Endpoint
Analysis
Results
P-value
Calculated LDL-C - Percent change
On-treatment
LS mean difference vs.
<0.0001
from baseline to Week 24
placebo −58.1%
Calculated LDL-C - Percent change
ITT
LS mean difference vs.
<0.0001
from baseline to Week 12
placebo of −49.2%
Calculated LDL-C - Percent change
On-treatment
LS mean difference vs.
<0.0001
from baseline to Week 12
placebo of −49.5%
Apo-B - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −45.8%
Apo-B - Percent change from
On-treatment
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −45.9%
Non-HDL-C - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −52.4%
Non-HDL-C - Percent change from
On-treatment
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −52.6%
Total-C - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −38.7%
Apo-B - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 12
placebo of −37.5%
Non-HDL-C - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 12
placebo of −43.7%
Total-C - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 12
placebo of −32.5%
Calculated LDL-C - Percent change
ITT
LS mean difference vs.
<0.0001
from baseline to Week 52
placebo of −56.2%
Proportion of very high CV risk
ITT
combined estimate for odds-
<0.0001
patients reaching calculated LDL-
ratio vs. placebo of 155.1
C <70 mg/dL (1.81 mmol/L) or
high CV risk patients reaching
calculated LDL-C <100 mg/dL
(2.59 mmol/L) at Week 24
Proportion of very high CV risk
On-treatment
combined estimate for odds-
<0.0001
patients reaching calculated LDL-
ratio vs. placebo of 149.1
C <70 mg/dL (1.81 mmol/L) or
high CV risk patients reaching
calculated LDL-C <100 mg/dL
(2.59 mmol/L) at Week 24
Proportion of patients reaching
ITT
combined estimate for odds-
<0.0001
calculated LDL-C <70 mg/dL (1.81
ratio vs. placebo of 237.1
mmol/L) at Week 24
Proportion of patients reaching
On-treatment
combined estimate for odds-
<0.0001
calculated LDL-C <70 mg/dL (1.81
ratio vs. placebo of 237.9
mmol/L) at Week 24
Lp(a) - Percent change from
ITT
combined estimate for
<0.0001
baseline to Week 24
adjusted mean difference
vs. placebo of −17.7%
HDL-C - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of 8%
Fasting TGs - Percent change from
ITT
combined estimate for
<0.0001
baseline to Week 24
adjusted mean difference
vs. placebo of −16.1%
Apolipoprotein A1 - Percent change
ITT
LS mean difference vs.
<0.05
from baseline to Week 24
placebo of 4.7%
The on-treatment analysis of LDL-C percent change from baseline to Week 24 shows very consistent results with the ITT analysis (LS mean difference vs. placebo of −58.1% in the on-treatment analysis versus −57.9% in the ITT analysis). Indeed, few patients had LDL-C values collected post-treatment (i.e., more than 21 days after last injection) at Week 24: 6 patients (3.7%) in the placebo group and 2 patients (0.6%) in the alirocumab group. A statistically significant decrease in percent change in LDL-C from baseline to Week 12 (i.e. before possible up-titration) in the ITT analysis was observed in the alirocumab group (LS mean versus baseline −43.5%) compared to the placebo group (LS mean versus baseline+5.7%) (LS mean difference vs. placebo of −49.2%, p<0.0001).
The key secondary endpoints of Apo B, non-HDL-C, Total-C, Lp(a), HDL-C, and TGs at various time points as well as the proportion of patients reaching their LDL-C goals and the proportion of patients reaching calculated LDLD-C<70 mg/dL at Week 24 were statistically significant according to the hierarchical testing procedure. For the alirocumab group the baseline mean (SD) LDL-C, Non-LDL-C, ApoB and the median (IQR) Lp(a) levels were 144.7 (51.3), 170.3 (54.6), 114.3 (30.8), and 34 (12:82) mg/dl respectively. For the placebo group the baseline mean (SD) LDL-C, Non-LDL-C, ApoB and the median (IQR) Lp(a) levels were 144.4 (46.8), 169.6 (50.6), 113.4 (28:5), and 23 (8.72) mg/dl respectively. After 24 weeks, LS mean (SE) % change from baseline to Week 24 for Non-LDL-C, ApoB Lp(a) levels in the alirocumab group was −42.8%, −41.1%, and −25.2%, respectively. The LS mean (SE) % change from baseline to Week 24 for Non-LDL-C, ApoB Lp(a) levels for the placebo group was 9.6%, 4.7%, and −7.5%, respectively. The LS mean difference vs. placebo for Non-LDL-C, ApoB and Lp(a) was −52.4%, −45.8%, and 17.7%, respectively.
The proportion of very high cardiovascular (CV) risk patients reaching calculated LDL-C<70 mg/dL (1.81 mmol/L) or high CV risk patients reaching calculated LDL-C<100 mg/dL (2.59 mmol/L) at Week 24 was significantly higher in the alirocumab than in the placebo group (combined estimate for proportion of 72.1% in the alirocumab group vs 2.4% in the placebo group, p<0.0001).
Two consecutive calculated LDL-C values<25 mg/dL (<0.65 mmol/L) were observed in 16 (5.0%) patients. No particular safety concern has been observed in these patients.
TABLE 12
Number (%) of patients with 2 consecutive calculated
LDL-C <25 mg/dL (<0.65 mmol/L) during the
treatment period- Safety population
Alirocumab 75
Q2W/Up150
Placebo
Q2W
(N = 163)
(N = 322)
Patients with 2 consecutive calculated
0/163
16/317
(5.0%)
LDL-C value <25 mg/dL 1
Time to the first calculated LDL-C
value <25 mg/dL (weeks) 2
Number
0
16
Mean (SD)
14.79
(11.37)
Median
14.14
Min:Max
3.1:36.1
Patients with 2 consecutive calculated
0/163
6/317
(1.9%)
LDL-C value <15 mg/dL 1
Time to the first calculated LDL-C
value <15 mg/dL (weeks) 2
Number
0
6
Mean (SD)
18.31
(12.35)
Median
20.14
Min:Max
4.6:36.1
The number (n) represents the subset of the total number of patients who met the criteria
The denominator (/N) within a treatment group is the number of patients for the treatment group who had at least two calculated LDL-C values assessed at least 21 days apart in the efficacy period
1 2 consecutive values are considered if spaced out by at least 21 days
2 First calculated LDL-C value <25 or <15 mg/dL among the first 2 consecutive calculated LDL-C values <25 or <15 mg/dL per patient
Summary Safety Results:
Alirocumab was well tolerated during the treatment period.
TABLE 13
Overview of adverse event profile: Treatment
emergent adverse events - Safety population
Alirocumab 75
Q2W/Up150
Placebo
Q2W
n(%)
(N = 163)
(N = 322)
Patients with any TEAE
122 (74.8%)
249 (77.3%)
Patients with any treatment
15 (9.2%)
39 (12.1%)
emergent SAE
Patients with any TEAE leading to
0
4 (1.2%)
death
Patients with any TEAE leading to
8 (4.9%)
10 (3.1%)
permanent treatment discontinuation
n (%) = number and percentage of patients with at least one TEAE
Overall, the proportions of patients reporting at least one treatment emergent adverse event (TEAE) (77.3% in the alirocumab group and 74.8% in the placebo group) or at least one TEAE leading to permanent discontinuation (3.1% in the alirocumab group and 4.9% in the placebo group) were similar in both groups. “Musculoskeletal and connective tissue disorders” SOC was reported in 22.4% of patients in the alirocumab group vs. 25.2% in the placebo group. The most frequently reported TEAEs in both treatment groups were “injection site reaction” (11.8% vs. 9.8% in alirocumab vs. placebo group, respectively) and “nasopharyngitis” (9.9% vs 6.7% in alirocumab vs. placebo group, respectively). Among the events of interest, no particular signal was detected for TEAEs related to allergic events, neurological events, neurocognitive disorders and diabetes. The SOC “neoplasms benign, malignant and unspecified” was observed in 2.8% of patients in the alirocumab group vs 0.6% in the placebo group with no particular clinical pattern on individual events (all these events were reported as not related to IMP by the investigator). TEAEs “cardiovascular events confirmed by adjudication” were reported for 1.9% of patients in the alirocumab group and 1.2% in the placebo group.
Six deaths (1.9%) were reported as not related to IMP by the investigator in the alirocumab group versus none in the placebo group: two myocardial infarctions (MI) (one classified as acute MI and one classified as sudden cardiac death), two metastatic cancers (non-small cell lung cancer and pancreatic carcinoma with secondary Trousseau syndrome causing multiple embolic strokes), a colonic pseudo-obstruction following abdominal surgery in one patient, and sudden cardiac death in one patient due to congestive cardiac failure and coronary artery disease. Both patients with MI had multiple risk factors for coronary artery disease. With regards to cancers, the time to onset of first symptoms (about 3.5 and 7.5 months after starting the investigational product) is not suggestive of a causal role of the investigational product.
No relevant abnormalities were observed for PCSA.
Example 3: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia not Adequately Controlled with their Lipid-Modifying Therapy
Introduction
The objective of the study was to assess the efficacy and safety of Alirocumab in improving lipid parameters in patients with heterozygous familial hypercholesterolemia (heFH) who have failed to reach their LDL-C treatment goal on maximally-tolerated statin therapy, with or without additional lipid-modifying therapy (LMT). Patients not at goal on a maximally-tolerated dose of daily statin therapy, with or without other LMT, were enrolled in this study, and that their background treatment was maintained throughout the study.
This specific study (FIG. 3) was undertaken to demonstrate in heFH patients who were not at their LDL-C goal, that Alirocumab 75 mg q2w or 75 mg q2w/150 mg q2w as add-on therapy to statin+/−other LMT, causes a statistically significant and clinically meaningful reduction in LDL-C. This population that is not at LDL-C goal on optimized LMT represents a highest risk group with a well-identified unmet medical need that can be addressed by adding Alirocumab to their LDL-C lowering therapies.
Study Objectives
The primary objective of the study was to demonstrate the reduction of LDL-C by Alirocumab as add-on therapy to stable, maximally-tolerated daily statin therapy with or without other LMT in comparison with placebo after 24 weeks of treatment in patients with heFH.
The secondary objectives of the study were: 1) to evaluate the effect of Alirocumab 75 mg in comparison with placebo on LDL-C after 12 weeks of treatment; 2) to evaluate the effect of Alirocumab on other lipid parameters (e.g., ApoB, non-HDL-C, total-C, Lp[a], HDL-C, TG levels, and ApoA-1 levels); 3) to evaluate the long-term effect of Alirocumab on LDL-C; 4) to evaluate the safety and tolerability of Alirocumab; and 5) to evaluate the development of anti-Alirocumab antibodies.
Study Design
This was a randomized, double-blind, placebo-controlled, parallel-group, multi-national study in patients with heFH who were not adequately controlled with their LMT (i.e., stable maximally-tolerated daily statin therapy+/−other LMT). Not adequately controlled was defined as an LDL-C≥70 mg/dL (1.81 mmol/L) at the screening visit (week 2) in patients with a history of documented CVD or LDL-C≥100 mg/dL (2.59 mmol/L) at the screening visit (week-2) in patients without a history of documented CVD. Patients were randomized in a 2:1 ratio to receive either 75 mg of Alirocumab or placebo by SC injection, every 2 weeks, on top of stable, maximally-tolerated daily statin therapy (atorvastatin, rosuvastatin, or simvastatin) with or without other LMT. Randomization was stratified according to prior history of either myocardial infarction (MI) or ischemic stroke, and statin treatment (atorvastatin 40 mg to 80 mg daily or rosuvastatin 20 mg to 40 mg daily vs. simvastatin whatever the daily dose, atorvastatin below 40 mg daily, or rosuvastatin below 20 mg daily).
The study consisted of three periods: a screening period, a treatment period, and a follow-up period.
The screening period was up to 2 weeks, including an intermediate visit during which the patient or caregiver was trained to self-inject/inject using a dose of placebo.
The double-blind treatment period was 78 weeks. The first injection of study drug was administered at the clinical site on day 1, after study assessments were completed, and as soon as possible after the patient was randomized into the study. The patient/caregiver administered subsequent injections outside of the clinic according to the dosing schedule. On days where the clinic study visit coincides with dosing, the dose of study drug was administered after all study assessments were performed and all laboratory samples collected. The last dose of study drug was administered at week 76. At week 12, patients randomized to Alirocumab were, in a blinded manner, either: 1) continued Alirocumab 75 mg every 2 weeks, if the week 8 LDL-C was <70 mg/dL (1.81 mmol/L), or 2) dose up-titrated to Alirocumab 150 mg every 2 weeks, if the week 8 LDL-C was ≥70 mg/dL (1.81 mmol/L).
The follow-up period (if applicable) was 8 weeks after the end of the DBTP for patients not consenting to participate in the open-label extension study, or if prematurely discontinuing study treatment.
Patients were asked to follow a stable diet (equivalent to the National Cholesterol Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes [NCEP ATP III TLC] diet/Appendix 5) from screening to the end of study visit. The daily dose of statin or other LMT (if applicable) should remain stable from screening to the end of study visit. Starting at week 24, background LMT may be modified under certain conditions as described later. Table 1 from Example 2 is relevant to this Example and provides a summary of the TLC diet for high cholesterol.
An independent external physician was notified by the central laboratory for any patient who achieved 2 consecutive calculated LDL-C levels<25 mg/dL (0.65 mmol/L). Patients who meet this criterion were monitored.
Selection of Patients
The study population consisted of patients with heFH who were not adequately controlled with a maximally-tolerated stable daily dose of a statin for at least 4 weeks before the screening visit (week-2), with or without other LMT.
A patient must have met the following criteria to be eligible for inclusion in the study: 1) patients with heFH* who were not adequately controlled** with a maximally-tolerated daily dose*** of statin with or without other LMT, at a stable dose prior to the screening visit (week-2).
*Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score of >8 points.
Definite familial hypercholesterolemia was defined herein the same as it was in Example 2. Possible familial hypercholesterolemia was defined herein the same as it was in Example 2. The WHO Criteria (Dutch Lipid Network clinical criteria) for Diagnosis of Heterozygous Familial Hypercholesterolemia (heFH) set forth in Table 2 in Example 2 was the same for this Example.
**“Not adequately controlled” was defined herein the same as it was in Example 2.
A Documented History of CHD was defined herein the same as in Example 2.
CHD Risk Equivalents (includes 1 or more of the following criteria): 1) documented peripheral arterial disease (one of the following criteria must be satisfied): A) current intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) of presumed atherosclerotic origin together with ankle-brachial index equal to or less than 0.90 in either leg at rest, or B) history of intermittent claudication (muscle discomfort in the lower limb produced by exercise that is both reproducible and relieved by rest within 10 minutes) together with endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease, or C) history of critical limb ischemia together with thrombolysis, endovascular procedure or surgical intervention in one or both legs because of atherosclerotic disease; 2) documented previous ischemic stroke with a focal ischemic neurological deficit that persisted more than 24 hours, considered as being of atherothrombotic origin. CT or MRI must have been performed to rule out hemorrhage and non-ischemic neurological disease.
***“Maximally-tolerated dose” was defined herein the same as it was in Example 2.
Patients who met all of the above inclusion criteria were screened for the following exclusion criteria, which are sorted in the following three subsections: exclusion criteria related to study methodology, exclusion criteria related to the active comparator and/or mandatory background therapies, and exclusion criteria related to the current knowledge of Alirocumab.
Exclusion criteria related to the study methodology were: 1) patient without diagnosis of heFH made either by genotyping or by clinical criteria; 2) LDL-C<70 mg/dL (<1.81 mmol/L) at the screening visit (week-2) in patients with history of documented CVD. NOTE: CVD is defined as CHD, ischemic stroke, or peripheral arterial disease as described above; 3) LDL-C<100 mg/dL (<2.59 mmol/L) at the screening visit (week2) in patients without history of documented CVD; 4) not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (week-2) and from screening to randomization; 5) currently taking another statin than simvastatin, atorvastatin, or rosuvastatin; 6) simvastatin, atorvastatin, or rosuvastatin is not taken daily or not taken at a registered dose; 7) daily doses above atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg (except for patients on simvastatin 80 mg for more than 1 year, who are eligible); 8) use of fibrates, other than fenofibrate within 6 weeks of the screening visit (week-2) or between screening and randomization visits; 9) use of nutraceutical products or over-the-counter therapies that may affect lipids which have not been at a stable dose/amount for at least 4 weeks prior to the screening visit (week-2) or between screening and randomization visits; 10) use of red yeast rice products within 4 weeks of the screening visit (week-2), or between screening and randomization visits; 11) patient who has received plasmapheresis treatment within 2 months prior to the screening visit (week-2), or has plans to receive it during the study; 12) recent (within 3 months prior to the screening visit [week-2] or between screening and randomization visits) MI, unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease; 13) planned to undergo scheduled PCI, CABG, carotid, or peripheral revascularization during the study; 14) systolic blood pressure>160 mm Hg or diastolic blood pressure>100 mm Hg at screening visit or randomization visit; 15) history of New York Heart Association (NYHA) Class III or IV heart failure within the past 12 months; 16) known history of a hemorrhagic stroke; 17) age <18 years or legal age of majority at the screening visit (week-2), whichever is greater; 18) patients not previously instructed on a cholesterol-lowering diet prior to the screening visit (week-2); 19) newly diagnosed (within 3 calendar months prior to randomization visit [week 0]) or poorly controlled (hemoglobin A1c [HbA1c]>9% at the screening visit [week-2]) diabetes; 20) presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins. Note: Patients on thyroid replacement therapy can be included if the dosage has been stable for at least 12 weeks prior to screening and between screening and randomization visits, and thyroid-stimulating hormone (TSH) level is within the normal range of the central laboratory at the screening visit; 21) history of bariatric surgery within 12 months prior to the screening visit (week- 2); 22) unstable weight defined by a variation >5 kg within 2 months prior to the screening visit (week-2); 23) known history of homozygous FH; 24) known history of loss-of-function of PCSK9 (ie, genetic mutation or sequence variation); 25) use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization visit (week 0). Note: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered as ‘systemic’ and are allowed; 26) use of continuous estrogen or testosterone hormone replacement therapy unless the regimen has been stable in the past 6 weeks prior to the screening visit (week-2) and no plans to change the regimen during the study; 27) history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer; 28) known history of a positive HIV test; 29) patient who has taken any investigational drugs other than the Alirocumab training placebo kits within 1 month or 5 half-lives, whichever is longer; 30) patient who has been previously treated with at least 1 dose of Alirocumab or any other anti-PCSK9 monoclonal antibody in other clinical studies; 31) conditions/situations such as: a) any clinically significant abnormality identified at the time of screening that, in the judgment of the investigator or any sub-investigator, would preclude safe completion of the study or constrain endpoints assessment; eg, major systemic diseases, patients with short life expectancy; or b) considered by the investigator or any sub-investigator as inappropriate for this study for any reason, e.g.: i) deemed unable to meet specific protocol requirements, such as scheduled visits; ii) those deemed unable to administer or tolerate long-term injections as per the patient or the investigator; iii) investigator or any sub-investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol, etc.; iv) presence of any other conditions (eg, geographic or social), either actual or anticipated, that the investigator feels would; 32) laboratory findings during screening period (not including randomization week 0 labs, unless otherwise noted): i) positive test for hepatitis B surface antigen or hepatitis C antibody (confirmed by reflexive testing); ii) positive serum beta-hCG or urine pregnancy test (including week 0) in women of childbearing potential; iii) TG>400 mg/dL (>4.52 mmol/L) (1 repeat lab is allowed); iv) eGFR<30 mL/min/1.73 m2 according to 4-variable MDRD study equation (calculated by central lab); v) alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>3× upper limit of normal (ULN) (1 repeat lab is allowed); vi) CPK>3×ULN (1 repeat lab is allowed); vii) TSH<lower limit of normal (LLN) or >ULN (1 repeat lab is allowed).
Exclusion criteria related to the active comparator and/or mandatory background therapies were: 1) all contraindications to the background therapies or warnings/precautions of use (when appropriate) as displayed in the respective National Product Labeling.
Exclusion criteria related to the current knowledge of Alirocumab were: 1) known hypersensitivity to monoclonal antibody or any component of the drug product; 2) pregnant or breast-feeding women; 3) women of childbearing potential who are not protected by highly-effective method(s) of birth control (as defined in the informed consent form and/or in a local protocol addendum) and/or who are unwilling or unable to be tested for pregnancy. Note: Women of childbearing potential must have a confirmed negative pregnancy test at screening and randomization visits. They must use an effective contraceptive method throughout the entire duration of study treatment and for 10 weeks after the last dose of study drug, and agree to repeat urine pregnancy test at designated visits. The applied methods of contraception have to meet the criteria for a highly effective method of birth control according to the “Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95)”. Postmenopausal women must be amenorrheic for at least 12 months.
Study Treatments
The study treatment was a single SC injection of 1 mL for a 75 mg or 150 mg dose of Alirocumab or placebo provided in an auto-injector, administered in the abdomen, thigh, or outer area of the upper arm. The first injection of study drug was administered at the clinical site, as soon as possible after the patient was randomized into the study. The patient was monitored at the clinical site for 30 minutes following the first injection. The patient/caregiver administered subsequent injections outside of the clinic, according to the dosing schedule. On days where the clinic study visit coincided with dosing, the dose of study drug was administered after all study assessments were performed and all laboratory samples collected. Subcutaneous dosing of study drug should be administered every 2 weeks at approximately the same time of day (based upon patient preference); it was acceptable for dosing to fall within a window of +/−3 days.
Sterile Alirocumab drug product was supplied at a concentration of 75 mg/mL or 150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose in an auto-injector.
Placebo matching Alirocumab was supplied in the same formulation as Alirocumab, without the addition of protein, in an auto-injector.
All patients were on a maximally-tolerated stable daily statin (atorvastatin, rosuvastatin, or simvastatin)+/−other LMT throughout the duration of the study. Statin dose and the dose of other LMT (if applicable) should have remained stable throughout the whole study duration, from screening to the end of study visit.
During the double-blind treatment period, modification to the background LMT was allowed before week 24 only under certain conditions: 1) exceptional circumstances—overriding concerns (including, but not limited to, TG alert, below, posted by the central lab) warrant such changes, per the investigator's judgment; or 2) a confirmed TG alert—the patient meets the pre-specified TG alert (TG≥500 mg/dL [5.65 mmol/L]).
During the double-blind treatment period, modification to the background LMT was allowed after week 24 only under certain conditions: 1) exceptional circumstances, per the investigator's judgment; 2) a confirmed TG alert—the patient meets the pre-specified TG alert (TG≥500 mg/dL [5.65 mmol/L], or 3) LDL-C increased by at least 25% as compared to the randomization visit LDL-C (and no other reasonable explanation exists).
For a laboratory rescue alert of LDL-C increase >25% as compared to the randomization visit LDL-C on 2 consecutive occasions, the investigator should have ensured that no reasonable explanation exists for insufficient LDL-C control (such as an alternative medical cause like corticosteroid use, etc.) and in particular that: compliance with diet was appropriate; compliance with background LMT was appropriate; and study treatment was given as planned. If any of the above could reasonably explain the insufficient LDL-C control, the investigator should have stressed the absolute need to be compliant with treatment and, if needed, organized a specific interview with a qualified nutrition professional and stressed the absolute need to be compliant with diet, and performed a blinded LDL-C assessment within 1 to 2 months. Rescue treatment may be initiated in the event that no reason for LDL-C above the threshold value could be found.
If no reason for LDL-C above the threshold value could be found, or if appropriate action failed to decrease LDL-C below the threshold value, rescue medication may have been introduced. The effectiveness of any such changes would be made based on lack of rescue threshold from blinded lipid testing at the next routinely scheduled lab draw. Patients per protocol already received a maximum tolerated dose of statin, so statin up-titration or switch would not be an option. For further LDL-C lowering, the investigator may have considered adding: a cholesterol absorption inhibitor (ezetimibe), or a bile acid-binding sequestrant (the resins cholestyramine and colestipol, or colesevelam, a nonabsorbable polymer). The following lipid modifying agents may have also been considered: fibrate (Note: Caution should be exercised when combining fibrates with other cholesterol-lowering medications such as statins because of the risk of myopathy. When a fibrate is combined with a statin, fenofibrate is the fibrate of choice because it does not affect statin glucuronidation. The only fibrate allowed per protocol was fenofibrate); nicotinic acid (niacin) (Note: Niacin raises blood glucose but has been shown to be effective in modifying lipid disorders in people with diabetes if glucose control is maintained).
The dose of study drug was increased (up-titrated) from 75 mg to 150 mg SC every 2 weeks, starting at week 12, for an individual patient in the event LDL-C≥70 mg/dL at the week 8 visit.
Patients were randomized to receive either Alirocumab or placebo in a ratio of 2:1, with permuted-block randomization. Randomization was stratified according to prior history of MI or ischemic stroke (Yes/No), and statin dose (“Yes” as atorvastatin 40 mg to 80 mg daily or rosuvastatin 20 mg to 40 mg daily and “No” as simvastatin whatever the daily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily) as fixed effects; and the baseline calculated LDL-C as covariate.
Concomitant medications should have been kept to a minimum during the study. If considered necessary for the patient's welfare and unlikely to interfere with study drug, concomitant medications (other than those that are prohibited during the study) could have been given at the discretion of the investigator, with a stable dose (when possible).
Nutraceutical products or over-the-counter therapies that may affect lipids were allowed only if they had been used at a stable dose for at least 4 weeks before the screening visit, during the screening period, and maintained during the first 24 weeks of the double-blind treatment period. After the week 24 visit, modification to these nutraceutical products or over-the-counter therapies was allowed, but in general should have been avoided. Examples of such nutraceutical products or over-the-counter therapies include omega-3 fatty acids at doses <1000 mg, plant stanols such as found in Benecol, flax seed oil, and psyllium.
Women of childbearing potential must have used an effective contraception method throughout study treatment, and for 10 weeks after the last dose of study drug.
Prohibited concomitant medications from the initial screening visit until the end of the study visit included the following: statins, other than atorvastatin, rosuvastatin, or simvastatin; fibrates, other than fenofibrate; and red yeast rice products.
Study Endpoints
Baseline characteristics included standard demography (e.g., age, race, weight, height, etc.), disease characteristics including medical history, and medication history for each patient.
The primary efficacy endpoint was the percent change in calculated LDL-C from baseline to week 24, which was defined as: 100×(calculated LDL-C value at week 24-calculated LDL-C value at baseline)/calculated LDL-C value at baseline. The baseline calculated LDL-C value was the last LDL-C level obtained before the first dose of study drug. The calculated LDL-C at week 24 was the LDL-C level obtained within the week 24 analysis window and during the main efficacy period. The main efficacy period was defined as the time from the first double-blind study drug injection up to 21 days after the last double-blind study drug injection or up to the upper limit of the week 24 analysis window, whichever came first.
The key secondary efficacy endpoints were: 1) the percent change in calculated LDL-C from baseline to week 12: similar definition and rules as for primary efficacy endpoint, except that the calculated LDL-C at week 12 was the LDL-C level obtained within the week 12 analysis window and during the 12-week efficacy period. The 12-week efficacy period was defined as the time from the first double-blind study drug injection up to the visit 6 re-supply IVRS contact or up to 21 days after the last study drug injection, whichever came first. Blood sampling collected the day of the visit 6 re-supply IVRS contact will be considered as before titration; 2) the percent change in ApoB from baseline to week 24. Same definition and rules as for the primary endpoint; 3) the percent change in non-HDL-C from baseline to week 24. Same definition and rules as for the primary endpoint; 4) the percent change in total-C from baseline to week 24. Same definition and rules as for the primary endpoint; 5) the percent change in ApoB from baseline to week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to week 12; 6) the percent change in non-HDL-C from baseline to week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to week 12; 7) the percent change in total-C from baseline to week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to week 12; 8) the percent change in calculated LDL-C from baseline to week 52. Definitions and rules are similar to the ones used for the primary endpoint replacing week 24 by week 52; 9) the proportion of patients reaching LDL-C goal at week 24, i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patients without prior CVD, defined as: (number of patients whose calculated LDL-C value at week 24 reach LDL-C goal/number of patients in the [modified intent-to-treat (mITT population)]*100, using definition and rules used for the primary endpoint; 10) the proportion of patients reaching LDL-C<70 mg/dL (1.81 mmol/L) at week 24; 11) the percent change in Lp(a) from baseline to week 24. Same definition and rules as for the primary endpoint; 12) the percent change in HDL-C from baseline to week 24. Same definition and rules as for the primary endpoint; 13) the percent change in HDL-C from baseline to week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to week 12; 14) the percent change in Lp(a) from baseline to week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to week 12; 15) the percent change in fasting TG from baseline to week 24. Same definition and rules as for the primary endpoint; 16) the percent change in fasting TG from baseline to week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to week 12; 17) the percent change in ApoA-1 from baseline to week 24. Same definition and rules as for the primary endpoint; 18) the percent change in ApoA-1 from baseline to week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to week 12.
Other secondary efficacy endpoints were: 1) the percent change in calculated LDL-C from baseline to week 78. Definitions and rules are similar to the ones used for the primary endpoint replacing week 24 by week 78; 2) the proportion of patients reaching LDL-C goal at weeks 12, 52, and 78, i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patients without prior CVD; 3) the proportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L) at week 24; 4) the proportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L) at week 12; 5) the proportion of patients reaching LDL-C<70 mg/dL (1.81 mmol/L) at week 12; 6) the absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline to weeks 12, 24, 52, and 78; 7) the percent change in ApoB, non-HDL-C, total-C, Lp(a), HDL-C, fasting TG, and ApoA-1 from baseline to weeks 52 and 78; 8) the change in ratio ApoB/ApoA-1 from baseline to weeks 12, 24, 52, and 78; 9) the proportion of patients with ApoB<80 mg/dL (0.8 g/L) at weeks 12, 24, 52, and 78; 10) the proportion of patients with non-HDL-C<100 mg/dL at weeks 12, 24, 52, and 78; 11) the proportion of patients with calculated LDL-C<70 mg/dL (1.81 mmol/L) and/or ≥50% reduction in calculated LDL-C (if calculated LDL-C≥70 mg/dL [1.81 mmol/L]) at weeks 12, 24, 52, and 78.
Other endpoints were: 1) anti-Alirocumab antibody status (positive/negative) and titers assessed throughout the study; 2) the percent change in high sensitivity C-reactive protein (hs-CRP) from baseline to weeks 24, 52, and 78; 3) the absolute change in HbA1c (%) from baseline to weeks 24, 52, and 78; and 4) response of each EQ-SD item, index score, and change of index score from baseline through week 52.
Study Visits
The following visits were scheduled:
At Visit 1/Screening/Day —14 to −8; Visit 2/Screening/Day −7 (+/−3 days); Visit 3/Baseline/Week 0/Day 1; Visit 4/Week 4/Day 29 (+/−7 days); Visit 6/Week 12/Day 85 (+/−3 days); Visit 7/Week 16/Day 113 (+/−7 days); Visit 8/Week 24/Day 169 (+/−3 days)/Primary Endpoint Assessment; Visit 9/Week 36/Day 253 (+/−7 days); Visit 10/Week 52/Day 365 (+/−5 days); Visit 11/Week 64/Day 449 (+/−7 days); Visit 12/Week 78/Day 547 (+/−5 days); and the End of Study/Visit 13/Week 86/Day 603 (+/−7 days).
Medical/surgical history, medication history, demographics, height, hepatitis B surface antigen, and serum pregnancy testing were performed for the purpose of determining study eligibility or characterizing the baseline population.
All laboratory samples were collected before the dose of study drug was administered.
Blood samples for lipid panels should be collected in the morning, in fasting condition (i.e., overnight at least 10 hours fast, only water, and refrain from smoking) for all clinic visits. Alcohol consumption within 48 hours, and intense physical exercise and smoking within 24 hours preceding blood sampling were discouraged. Note: if the patient was not in fasting condition, the lipid blood samples were collected and a new appointment was scheduled the day after (or as close as possible to this date), with a reminder for the patient to be fasted.
Sample Size And Power Considerations
A total sample size of 45 patients (30 in alirocumab and 15 in placebo) will have 95% power to detect a difference in mean percent change in LDL-C of 30% with a 0.05 two-sided significance level; assuming a common standard deviation of 25% and that all 45 patients have an evaluable primary endpoint.
To meet regulatory requirements across the program, the sample size was increased to 126 patients on alirocumab, with the intent to understand safety in a larger population. In order to have at least 126 patients on alirocumab treated for 12 months in this study, and assuming a drop-out rate of 10% over the first 3-month period and a drop-out rate of 20% over the remaining 9-month period, the final total sample size was increased and rounded to 250 patients, with a randomization ratio 2:1 (alirocumab: 167, placebo: 83).
Analysis Populations
Intent-to-Treat Population
The randomized population included all randomized patients, and was analyzed according to the treatment allocated by randomization.
The ITT population (also known as the full analysis set [FAS]) was defined as all randomized patients who had an evaluable primary endpoint. The endpoint was evaluable when the following two conditions were met: 1) availability of a baseline calculated LDL-C value; and 2) availability of at least 1 calculated LDL-C value within 1 of the analysis windows up to week 24.
Patients in the ITT population were analyzed according to the treatment group allocated by randomization (i.e., as-randomized treatment group).
Modified Intent-to-Treat
The mITT population was defined as the all randomized population who took at least 1 dose or part of a dose of study drug and had an evaluable primary endpoint. The endpoint was considered as evaluable (i.e. efficacy treatment period) when both of the following conditions were met: 1) availability of a baseline calculated LDL-C value; and 2) availability of at least 1 calculated LDL-C value during the efficacy treatment period and within one of the analysis windows up to week 24. The efficacy treatment period is defined as the time from the first double-blind study drug injection up to 21 days after the last double-blind study drug injection.
Patients in the mITT population were analyzed according to the treatment group allocated by randomization.
Safety Analysis Set
The safety population considered for safety analyses was the randomized population who received at least 1 dose or part of a dose of study drug. Patients were analyzed according to the treatment actually received (i.e. as-treated treatment group, placebo or alirocumab).
Results
Description of Study Populations
A total of 249 patients were randomized (82 to the placebo group and 167 to the alirocumab group) in this study. One patient in the placebo group was randomized but did not receive study treatment due to the reason of withdrew consent prior to receiving the first IMP injection. Therefore, the patient was excluded from the safety population. Two patients among the randomized patients (the one in the placebo group above and one in the alirocumab group) were excluded from the ITT and mITT populations due to lack of post-baseline LDL-C assessments.
TABLE 14
Analysis Populations
Alirocumab 75
Q2W/Up150
Placebo
Q2W
All
(N = 82)
(N = 167)
(N = 249)
Randomized population
82 (100%)
167 (100%)
249 (100%)
Efficacy population:
Intent-to-Treat (ITT)
81 (98.8%)
166 (99.4%)
247 (99.2%)
Modified Intent-to-Treat
81 (98.8%)
166 (99.4%)
247 (99.2%)
(mITT)
Quality-of-life population
80 (97.6%)
164 (98.2%)
244 (98.0%)
Anti-alirocumab antibody
77 (93.9%)
166 (99.4%)
243 (97.6%)
population
Safety population
81 (98.8%)
167 (100%)
248 (99.6%)
Note:
The safety, and anti-alirocumab antibody population patients are tabulated according to treatment actually received (as treated). For the other populations, patients are tabulated according to their randomized treatment
In the alirocumab group, among the 158 patients who received at least one injection after Week 12, 61 (38.6%) patients received automatic up-titration at Week 12 in a blinded manner from alirocumab 75 mg Q2W to 150 mg Q2W.
Subject Dispositions
As of the first-step analyses data cut-off date, patient status is presented below for the 249 randomized patients: 1) 0 (0.0%) patients completed the 78-week double-blind treatment period, due to ongoing patients not yet reaching the week 78 visit; 2) 234 (94.0%) patients were still treatment-ongoing: 78 (95.1%) in the placebo group and 156 (93.4%) in the alirocumab group; 3) 9 (3.6%) randomized and treated patients prematurely discontinued study treatments before Week 24: 1 (1.2%) in the placebo group and 8 (4.8%) in the alirocumab group. 4 (1.6%) patients prematurely terminated study treatments due to adverse events: 0 in the placebo group vs. 4 (2.4%) in the alirocumab group. 3 (1.2%) patients prematurely terminated study treatments due to poor protocol compliance: 1 (1.2%) in the placebo group and 2 (1.2%) in the alirocumab group. 2 (0.8%) patients prematurely terminated study treatments due to various other reasons: 0 in the placebo group vs. 2 (1.2%) in the alirocumab group; 4) 13 (5.2%) randomized and treated patients prematurely discontinued study treatments before Week 52: 2 (2.4%) in the placebo group and 11 (6.6%) in the alirocumab group. 5 (2.0%) patients prematurely terminated study treatments due to adverse events: 0 in the placebo group vs. 5 (3.0%) in the alirocumab group. 3 (1.2%) patients prematurely terminated study treatments due to poor protocol compliance: 1 (1.2%) in the placebo group and 2 (1.2%) in the alirocumab group. 5 (0.8%) patients prematurely terminated study treatments due to various other reasons: 1 (1.2%) in the placebo group and 4 (2.4%) in the alirocumab group; 5) 14 (5.6%) patients prematurely terminated study treatments before completing the 78-week treatment period: 3 (3.7%) in the placebo group and 11 (6.6%) in the alirocumab group. 6 (2.4%) patients prematurely terminated study treatments due to adverse events: 1 (1.2%) in the placebo group and 5 (3.0%) in the alirocumab group. 3 (1.2%) patients prematurely terminated study treatments due to poor protocol compliance: 1 (1.2%) in the placebo group and 2 (1.2%) in the alirocumab group. 5 (2.0%) patients prematurely terminated study treatments due to various other reasons: 1 (1.2%) in the placebo group and 4 (2.4%) in the alirocumab group.
The following table provides the availability of LDL-C values over time. At Week 24, the primary efficacy endpoint was available for 78 (96.3%) patients in the placebo group and 157 (94.5%) in the alirocumab group. There were 77 (95.1%) on-treatment assessments and 1 (1.2%) off-treatment assessments in the placebo group, as compared with 155 (93.4%) on-treatment assessments and 2 (1.2%) off-treatment assessments in the alirocumab group. At Week 52, the key secondary efficacy endpoint was available for 78 (96.3%) patients in the placebo and 158 (95.2%) patients in the alirocumab groups.
TABLE 15
Calculated LDL-C Availability over Time - ITT Population
Placebo
Alirocumab 75 Q2W/Up150
(N = 81)
Q2W (N = 166)
Post-
On-
Post-
Calculated
On-treatment
treatment
Missing
treatment
treatment
Missing
LDL-C
value
value
value
value
value
value
WEEK 4
79 (97.5%)
0
2 (2.5%)
162 (97.6%)
0
4 (2.4%)
WEEK 8
79 (97.5%)
0
2 (2.5%)
156 (94.0%)
0
10 (6.0%)
WEEK 12
76 (93.8%)
0
5 (6.2%)
151 (91.0%)
1 (0.6%)
14 (8.4%)
WEEK 16
77 (95.1%)
0
4 (4.9%)
149 (89.8%)
3 (1.8%)
14 (8.4%)
WEEK 24
77 (95.1%)
1 (1.2%)
3 (3.7%)
155 (93.4%)
2 (1.2%)
9 (5.4%)
WEEK 36
73 (90.1%)
0
8 (9.9%)
153 (92.2%)
2 (1.2%)
11 (6.6%)
WEEK 52
78 (96.3%)
0
3 (3.7%)
155 (93.4%)
3 (1.8%)
8 (4.8%)
An on-treatment value was obtained after the first study treatment injection and within 21 days after the last study treatment injection.
A post-treatment value was obtained more than 21 deays after the last study treatment injection.
The primary endpoint was missing for 12 (4.9%) patients at Week 24. At the Week 24 visit, the reasons for missing values were as follows: 1) 4 subjects with samples not obtained due to earlier study discontinuation; 2) 2 subjects were still ongoing, but Week 24 LDL-C was not done; 3) 6 samples were obtained at Week 24, but the LDL-C could not be calculated (5 with TGs>400 mg/dL and measured LDL-C reported, 1 with >400 mg/dL but measured LDL-C not reported).
Demographic and Baseline Characteristics
Overall, demographic characteristics, baseline disease characteristics, baseline efficacy lipid parameters, LMT history and background LMT use were homogeneous between patients randomized to the alirocumab group and patients randomized to the placebo group (see Table 16). Particularly, the mean baseline LDL-C in the alirocumab group was 134.6 mg/dL (SD=41.1 mg/dL) compared to that in the placebo group being 134.0 mg/dL (SD=41.4 mg/dL) with an overall mean of 134.4 mg/dL (SD=41.1 mg/dL). One potentially notable exception is the difference observed in baseline BMI, with a mean BMI of 28.6 kg/m2 (SD=4.6 kg/m2) in the alirocumab group compared to 27.7 kg/m2 (SD=4.7 kg/m2) in the placebo group.
TABLE 16
Baseline Characteristics of FHII Patient Population
Alirocumab
Placebo
Characteristic
(N = 167)
(N = 82)
Age, mean (SD), yrs
53.2
(12.9)
53.2
(12.5)
Diagnosis of heFH†, % (n)
Genotyping
70.1%
(117)
81.7%
(67)
Clinical criteria
29.9%
(50)
18.3%
(15)
Male
51.5%
(86)
54.9%
(45)
Race, white
98.2%
(164)
97.6%
(80)
BMI, mean (SD), kg/m2
28.6
(4.6)
27.7
(4.7)
CHD history
34.1%
(57)
37.8%
(31)
CHD risk equivalents†
9.0%
(15)
4.9%
(4)
Current smoker
21.6%
(36)
15.9%
(13)
Hypertension
34.1%
(57)
29.3%
(24)
Type 2 diabetes
4.2%
(7)
3.7%
(3)
% (N) of patients unless stated. All pts on background of max tolerated statin ± other lipid-lowering therapy.
†Diagnosis of heFH must be made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may be based on either the Simon Broome criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score of >8 points.
TABLE 17
Disease Characteristics and Other Relevant
Baseline Data - Randomized Population
Alirocumab 75
Q2W/Up150
P Value
Placebo
Q2W
All
vs.
(N = 82)
(N = 167)
(N = 249)
Placebo
Type of hypercholesterolemia
Heterozygous Familial
82
167
249
Hypercholesterolemia (heFH)
(100%)
(100%)
(100%)
Non-Familial Hypercholesterolemia
0
0
0
(non-FH)
Time from hypercholesterolemia
diagnosis (years)
Number
82
167
249
0.4938
Mean (SD)
12.7
12.9
12.8
(8.8)
(7.9)
(8.2)
Median
10.8
12.3
11.5
Min:Max
0:42
0:40
0:42
Confirmation of diagnosis*
By genotyping
67
117
184
(81.7%)
(70.1%)
(73.9%)
By WHO/Simon Broome
18
52
70
(22.0%)
(31.1%)
(28.1%)
Definite/Certain
18
52
70
(22.0%)
(31.1%)
(28.1%)
*heFH diagnosis can be confirmed by both genotyping and WHO or Simon Broome criteria.
Note:
p-values comparing baseline data between treatment groups are provided for descriptive purpose, as a screening tool, using Fisher exact test for qualitative data and the asymptotic one-way ANOVA test for Wilcoxon scores (Krukal-Wallis test) for continuous data.
TABLE 18
Background LMT at Randomization - Randomized Population
Alirocumab 75
Q2W/Up150
P = Value
Placebo
Q2W
All
vs.
(N = 82)
(N = 167)
(N = 249)
Placebo
Any statin
82
(100%)
167
(100%)
249
(100%)
Taking high intensity
72
(87.8%)
144
(86.2%)
216
(86.7%)
0.8434
statin
Atorvastatin daily dose
(mg)
10
2
(2.4%)
2
(1.2%)
4
(1.6%)
20
0
8
(4.8%)
8
(3.2%)
40
13
(15.9%)
27
(16.2%)
40
(16.1%)
80
16
(19.5%)
28
(16.8%)
44
(17.7%)
Other doses
1
(1.2%)
0
1
(0.4%)
Rosuvastatin daily dose
(mg)
5
1
(1.2%)
1
(0.6%)
2
(0.8%)
10
2
(2.4%)
4
(2.4%)
6
(2.4%)
20
8
(9.8%)
30
(18.0%)
38
(15.3%)
40
33
(40.2%)
59
(35.3%)
92
(36.9%)
Other doses
1
(1.2%)
1
(0.6%)
2
(0.8%)
Simvastatin daily dose
(mg)
10
1
(1.2%)
0
1
(0.4%)
20
1
(1.2%)
3
(1.8%)
4
(1.6%)
40
0
3
(1.8%)
3
(1.2%)
80
3
(3.7%)
1
(0.6%)
4
(1.6%)
Other doses
0
0
0
Any LMT other than
57
(69.5%)
117
(70.1%)
174
(69.9%)
1.0000
statins*
Any LMT other than
54
(65.9%)
115
(68.9%)
169
(67.9%)
nutraceuticals
Ezetimibe
53
(64.6%)
112
(67.1%)
165
(66.3%)
Nutraceuticals
7
(8.5%)
8
(4.8%)
15
(6.0%)
Note:
p = values comparing baseline data between treatment groups are provided for descriptive purpose, as a screening tool, using Fisher exact test.
*in combination with statins or not.
TABLE 19
Cardiovascular History and Risk Factors Breakdown
Alirocumab
Placebo
Characteristic
(N = 323)
(N = 163)
CHD history
34.1%
(57)
37.8%
(31)
Acute MI
16.2%
(27)
17.1%
(14)
Silent MI
0.6%
(1)
2.4%
(2)
Unstable angina
9.0%
(15)
9.8%
(8)
Coronary revasc.
27.5%
(46)
29.3%
(24)
Other clinically significant CHD
16.2%
(27)
20.7%
(17)
CHD risk equivalents
9.0%
(15)
4.9%
(4)
Ischemic stroke
3.0%
(5)
1.2%
(1)
Peripheral arterial disease
3.0%
(5)
1.2%
(1)
Moderate CKD
1.2%
(2)
1.2%
(1)
Diabetes + 2 or more risk factors
3.0%
(5)
2.4%
(2)
% (N) of patients unless stated. All pts on background of max tolerated statin ± other lipid-lowering therapy
TABLE 20
Lipid Efficacy Parameters at Baseline - Quantitative
Summary in Conventional Units - Randomized Population
Alirocumab 75
P Value
Placebo
Q2W/Up150 Q2W
All
vs.
(N = 82)
(N = 167)
(N = 249)
Placebo
Calculated LDL-C (mg/dL)
Number
82
167
249
0.8507
Mean (SD)
134.0
(41.4)
134.6
(41.1)
134.4
(41.1)
Median
126.0
128.0
126.0
Q1:Q3
109.0:151.0
107.0:154.0
108.0:151.0
Min:Max
74:295
58:303
58:303
Measured LDL-C (mg/dL)
Number
70
149
219
0.6375
Mean (SD)
130.2
(36.6)
132.6
(40.6)
131.8
(39.3)
Median
125.5
126.0
126.0
Q1:Q3
104.0:145.0
104.0:149.0
104.0:147.0
Min:Max
71:249
49:310
49:310
HDL-C (mg/dL)
Number
82
167
249
0.4437
Mean (SD)
54.2
(15.7)
52.6
(15.7)
53.1
(15.7)
Median
51.0
50.0
51.0
Q1:Q3
42.0:63.0
42.0:61.0
42.0:62.0
Min:Max
25:103
24:110
24:110
Total-C (mg/dL)
Number
82
167
249
0.9589
Mean (SD)
211.7
(45.6)
211.6
(45.8)
211.6
(45.6)
Median
200.0
205.0
202.0
Q1:Q3
179.0:237.0
178.0:242.0
179.0:239.0
Min:Max
133:376
123:391
123:391
Non-HDL-C (mg/dL)
Number
82
167
249
0.8208
Mean (SD)
157.5
(43.7)
159.0
(44.8)
158.5
(44.4)
Median
150.5
147.0
149.0
Q1:Q3
129.0:170.0
127.0:181.0
127.0:177.0
Min:Max
93:320
76:326
76:326
Fasting TGs (mg/dL)
Number
82
167
249
0.6593
Mean (SD)
116.6
(56.8)
123.2
(69.3)
121.0
(65.4)
Median
100.5
105.0
104.0
Q1:Q3
81.0:136.0
81.0:144.0
81.0:141.0
Min:Max
47:366
46:581
46:581
Apo-B (mg/dL)
Number
81
167
248
0.9533
Mean (SD)
107.7
(23.9)
107.9
(27.4)
107.9
(26.3)
Median
103.0
102.0
102.0
Q1:Q3
91.0:116.0
91.0:122.0
91.0:121.0
Min:Max
74:187
57:208
57:208
Apo-A1 (mg/dL)
Number
81
167
248
0.3472
Mean (SD)
148.9
(29.6)
146.3
(29.4)
147.2
(29.4)
Median
150.0
142.0
144.5
Q1:Q3
129.0:166.0
127.0:160.0
128.0:162.5
Min:Max
82:223
90:252
82:252
Apo-B/Apo-A1 (ratio)
Number
81
167
248
0.7518
Mean (SD)
0.8
(0.2)
0.8
(0.2)
0.8
(0.2)
Median
0.7
0.7
0.7
Q1:Q3
0.6:0.8
0.6:0.9
0.6:0.9
Min:Max
0:1
0:2
0:2
Lipoprotein-(a) (mg/dL)
Number
81
167
248
0.9910
Mean (SD)
50.9
(59.7)
49.8
(69.2)
50.2
(66.1)
Median
21.0
22.0
22.0
Q1:Q3
7.0:76.0
8.0:70.0
7.5:75.0
Min:Max
2:232
2:555
2:555
Total-C/HDL-C (ratio)
Number
82
167
249
0.6572
Mean (SD)
4.2
(1.3)
4.3
(1.5)
4.3
(1.5)
Median
3.9
3.9
3.9
Q1:Q3
3.3:4.8
3.3:5.0
3.3:4.9
Min:Max
2:9
2:11
2:11
Note:
p-values comparing baseline data between treatment groups are provided for descriptive purpose, as a screening tool, using the asymptotic one-way ANOVA test for Wilcoxon scores (Kruskal-Wallis test).
The collection of measured LDL-C was not planned in the initial protocol and was added in an amendment. Therefore, measured LDL-C values are available for fewer patients compared to calculated LDL-C values.
Extent of Exposure
Exposure to injections was similar across treatment groups with a mean exposure of approximately 58-60 weeks. Alirocumab treated patients were exposed for 2-75.9 weeks and placebo treated patients for 11.6-75.7 weeks. The majority (93.5%:97.5%, alirocumab:placebo, respectively) of patients were treated for more than 52 weeks.
In the alirocumab group, among the 158 patients who received at least one injection after Week 12, 61 (38.6%) patients received automatic up-titration in a blinded manner at Week 12 from alirocumab 75 mg Q2W to 150 mg Q2W. 26 patients were not given the opportunity to up-titrate at Week 12 due to missing Week 8 LDL-C values at the time of the up-titration decision. Of the 26 patients missing the Week 8 LDL-C value, 4 alirocumab patients should have been up-titrated based on the now available Week 8 LDL-C data. The remaining patients were either in the placebo treatment group, or the Week 8 LDL-C visits for the alirocumab patients were below the LDL-C<70 mg/dL cut-off for up-titration.
Efficacy Analyses
Primary Efficacy Analysis in the ITT Population
The primary endpoint (percent change in calculated LDL-C from baseline to Week 24) analysis is provided based on a MMRM model on the ITT population, using LS means estimates at Week 24. This repeated measures approach includes all LDL-C values collected on-treatment and off-treatment up to Week 52. At Week 24, 3 (3.7%) patients in the placebo group and 9 (5.4%) patients in the alirocumab group did not have a calculated LDL-C value (Table 15). These missing values were accounted for by the MMRM model.
The primary efficacy analysis showed a statistically significant decrease in percent change from baseline calculated LDL-C at Week 24 in the ITT analysis for the alirocumab treatment group (LS mean=−48.7%) as compared to placebo (LS mean=2.8%). The LS mean difference between the alirocumab treatment group and the placebo treatment groups is −51.4% (p<0.0001). 81.4% of HeFH patients in the alirocumab group achieved the LDL-C goals at 24 weeks, compared to 11.3% for the placebo group.
TABLE 21
Percent Change from Baseline in Calculated LDL-C at Week
24 (ITT Analysis): MMRM Analysis - ITT Population
Alirocumab 75
Calculated LDL
Placebo
Q2W/Up150 Q2W
Cholesterol
(N = 81)
(N = 166)
Baseline (mmol/L)
Number
81
166
Mean (SD)
3.470
(1.078)
3.486
(1.069)
Median
3.263
3.289
Min:Max
1.92:7.64
1.50:7.85
Baseline (mg/dL)
Number
81
166
Mean (SD)
134.0
(41.6)
134.6
(41.3)
Median
126.0
127.0
Min:Max
74:295
58:303
Week 24 percent change
from baseline (%)
LS Mean (SE)
2.8
(2.8)
−48.7
(1.9)
LS mean difference (SE) vs
−51.4
(3.4)
Placebo
95% Cl
(−58.1 to −44.8)
p-value vs. Placebo
<.0001
Note:
Lean-squares (LS) means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis. The model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline value by time-point interaction.
MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
The p-value is followed by a ‘*’ if statistically significant according to the fixed hierarchical approach used to ensure a strong control of the overall type-1 error rate at the 0.05 level.
Calculated LDL-C Over Time
FIG. 4 is a graph that shows the LDL-C LS mean (+/−SE) percent change from baseline over time for the ITT population. Note: Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis.
The model includes the fixed categorical effects of treatment group, time point, treatment-by-time point interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline LDL-C-by-time point interaction.
TABLE 22
Calculated LDL-C Over Time - ITT Population
Placebo
Alirocumab 75 Q2W/Up150
(N = 81)
Q2W (N = 166)
Percent
Percent
Change
change
Change
change
Calculated
from
from
from
from
LDL-C
Value
baseline
baseline
Value
baseline
baseline
LS mean (SE)
(mmol/L)
Baseline
3.470 (0.120)
NA
NA
3.486 (0.083)
NA
NA
Week 4
3.485 (0.077)
0.004 (0.077)
1.1 (2.0)
1.924 (0.054)
−1.56 (0.054)
−45.2 (1.4)
Week 8
3.561 (0.090)
0.081 (0.090)
3.3 (2.4)
1.913 (0.063)
−1.57 (0.063)
−45.3 (1.7)
Week 12
3.585 (0.097)
0.104 (0.097)
4.6 (2.6)
1.960 (0.068)
−1.52 (0.068)
−43.8 (1.8)
Week 16
3.508 (0.101)
0.028 (0.101)
2.4 (2.7)
1.649 (0.071)
−1.83 (0.071)
−51.9 (1.9)
Week 24
3.537 (0.103)
0.057 (0.103)
2.8 (2.8)
1.754 (0.072)
−1.73 (0.072)
−48.7 (1.9)
Week 36
3.603 (0.117)
0.122 (0.117)
5.1 (3.2)
1.788 (0.081)
−1.69 (0.081)
−48.0 (2.2)
Week 52
3.718 (0.125)
0.237 (0.125)
8.4 (3.3)
1.708 (0.088)
−1.77 (0.088)
−50.3 (2.3)
Week 64
3.601 (0.107)
1.657 (0.075)
Week 78
3.574 (0.109)
1.806 (0.076)
LS mean (SE)
(mg/dL)
Baseline
134.0 (4.6)
NA
NA
134.6 (3.2)
NA
NA
Week 4
134.6 (3.0)
0.2 (3.0)
1.1 (2.0)
74.3 (2.1)
−60.1 (2.1)
−45.2 (1.4)
Week 8
137.5 (3.5)
3.1 (3.5)
3.3 (2.4)
73.9 (2.4)
−60.5 (2.4)
−45.3 (1.7)
Week 12
138.4 (3.7)
4.0 (3.7)
4.6 (2.6)
75.7 (2.6)
−58.7 (2.6)
−43.8 (1.8)
Week 16
135.5 (3.9)
1.1 (3.9)
2.4 (2.7)
63.7 (2.7)
−70.7 (2.7)
−51.9 (1.9)
Week 24
136.6 (4.0)
2.2 (4.0)
2.8 (2.8)
67.7 (2.8)
−66.7 (2.8)
−48.7 (1.9)
Week 36
139.1 (4.5)
4.7 (4.5)
5.1 (3.2)
69.0 (3.1)
−65.3 (3.1)
−48.0 (2.2)
Week 52
143.6 (4.8)
9.2 (4.8)
8.4 (3.3)
65.9 (3.4)
−68.4 (3.4)
−50.3 (2.3)
Week 64
139.0 (4.1)
64.0 (2.9)
Week 78
138.0 (4.2)
69.7 (2.9)
* Baseline is described using means and standard errors.
Note:
Least-squares (LS) means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis. The model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline LDL-C value by time point interaction.
MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
Sensitivity to Serious GCP Non-Compliance
There was no site with serious GCP non-compliance in this study.
Key Secondary Efficacy Analysis
The following table summarizes analysis results on all key secondary endpoints in the hierarchical order for statistical testing at the 0.05 significance level. This study has achieved statistically significant effects in favor of the alirocumab treated patients for all but the last one in the hierarchy (i.e., Apo A-1—Percent change from baseline to Week 12) of the key secondary efficacy endpoints.
For clarification, the ITT analysis is defined for patients in the ITT population and includes all endpoint assessments in an analysis window, regardless of study treatment dosing status (i.e. includes post-treatment assessments). The on-treatment analysis is defined for patients in the mITT population and includes all endpoint assessments from the first double-blind study drug injection up to the day of last injection +21 days (i.e. includes assessments in the efficacy treatment period).
TABLE 23
Summary of Key Secondary Efficacy Endpoints
Alirocumab
Endpoint/Analysis
Placebo Result
Result
Comparison
P-value
1. LDL-C at WK 24 - ITT
LS mean: 2.8%
LS mean: −48.7%
Diff: −51.4%
<.0001
analysis
2. LDL-C at WK 24 - on-
LS mean: 2.7%
LS mean: −49.4%
Diff: −52.2%
<.0001
treatment analysis
3. LDL-C at WK 12 - ITT
LS mean: 4.6%
LS mean: −43.8%
Diff: −48.4%
<.0001
analysis
4. LDL-C at WK 12 - on-
LS mean: 4.6%
LS mean: −44.2%
Diff: −48.8%
<.0001
treatment analysis
5. Apo B at WK 24 - ITT
LS mean: −3.5%
LS mean: −42.8%
Diff: −39.3%
<.0001
analysis
6. Apo B at WK 24 - on-
LS mean: −3.5%
LS mean: −43.2%
Diff: −39.8%
<.0001
treatment analysis
7. Non-HDL-C at WK 24 -
LS mean: 3.1%
LS mean: −42.6%
Diff: −45.7%
<.0001
ITT analysis
8. Non-HDL-C at WK 24 -
LS mean: 3.1%
LS mean: −43.2%
Diff: −46.4%
<.0001
on-treatment analysis
9. Total Cholesterol at WK
LS mean: 2.1%
LS mean: −30.6%
Diff: −32.8%
<.0001
24 - ITT analysis
10. Apo B at WK 12- ITT
LS mean: −0.9%
LS mean: −35.4%
Diff: −34.5%
<.0001
analysis
11. Non-HDL-C at WK 12-
LS mean: 4.1%
LS mean: −37.9%
Diff: −42.0%
<.0001
ITT analysis
12. Total Cholesterol at
LS mean: 3.4%
LS mean: −26.6%
Diff: −29.9%
<.0001
WK 12 - ITT analysis
13. LDL-C at WK 52 - ITT
LS mean: 8.4%
LS mean: −50.3%
Diff: −58.8%
<.0001
analysis
14. Very High CV LDL-C <70
Proportion = 11.3%
Proportion = 81.4%
Odds Ratio = 52.2
<.0001
mg/dL OR High CV LDL-C <100
mg/dL at WK 24 - ITT
analysis
15. Very High CV LDL-C <70
Proportion = 11.6%
Proportion = 82.1%
Odds Ratio = 53.3
<.0001
mg/dL OR High CV LDL-C <100
mg/dL at WK 24 - on-
treatment analysis
16. LDL-C <70 mg/dL at
Proportion = 1.2%
Proportion = 68.2%
Odds Ratio = 239.7
<.0001
WK 24 - ITT analysis
17. LDL-C <70 mg/dL at
Proportion = 1.3%
Proportion = 68.8%
Odds Ratio = 240.6
<.0001
WK 24 - on-treatment
analysis
18. Lp(a) at WK 24 - ITT
LS mean: −10.0%
LS mean: −30.3%
Diff: −20.3%
<.0001
analysis
19. HDL-C at WK 24 - ITT
LS mean: −0.8%
LS mean: 6.0%
Diff: 6.8%
0.0009
analysis
20. Fasting Triglycerides at
LS mean: 0.4%
LS mean: −10.5%
Diff: −10.9%
0.0017
WK 24 - ITT analysis
19. Apo A-1 at WK 24 - ITT
LS mean: −1.6%
LS mean: 2.8%
Diff: 4.4%
0.0062
analysis
20. Lp(a) at WK 12 - ITT
LS mean: −5.6%
LS mean: −24.7%
Diff: −19.1%
<.0001
analysis
21. HDL-C at WK 12 - ITT
LS mean: 1.7%
LS mean: 6.0%
Diff: 4.3%
0.0147
analysis
22. Fasting Triglycerides at
LS mean: 0.9%
LS mean: −8.0%
Diff: −8.9%
0.0258
WK 12 - ITT analysis
Apo A-1 at WK 12 - ITT
LS mean: −1.9%
LS mean: 0.4%
Diff: 2.3%
0.1475
analysis
Hierarchical Testing Terminated
All the key secondary efficacy endpoints, except for percent change in Apo A-1 from baseline to Week 12 in ITT population, achieved statistically significant effects in favor of the alirocumab treated patients according to the hierarchical testing procedure.
The key secondary efficacy analysis for percent change from baseline of calculated LDL-C to week 24 in the mITT population (on-treatment analysis) showed consistent results with the ITT analysis with a statistically significant decrease in calculated LDL-C in the alirocumab treatment group (LS mean=−49.4%) as compared to placebo (LS mean=2.7%). The LS mean treatment difference between the alirocumab-treated patients and the placebo-treated patients is −52.2% (p<0.0001). Indeed, few patients had LDL-C values collected post-treatment (i.e., more than 21 days after last injection) at Week 24: 1 patient (1.2%) in the placebo group and 2 patients (1.2%) in the alirocumab group.
The decrease in percent change in Apo A-1 from baseline to Week 24 in the ITT analysis was non-statistically significant: LS mean versus baseline was 0.4% in the alirocumab group and −1.9% in the placebo group (LS mean difference vs. placebo of 2.3%, p=0.1475).
Calculated Ldl-C Over Time (Includes Observed Data)
FIG. 5 is a graph that shows the LDL-C LS mean (+/−SE) percent change from baseline during the efficacy treatment period over time for the mITT Population.
Summary
Overall, demographic characteristics, baseline disease characteristics, baseline efficacy lipid parameters, LMT history and background LMT use were comparable between patients randomized to the alirocumab group and patients randomized to the placebo group. Particularly, the mean (SD) baseline LDL-C in the alirocumab group was 134.6 (41.1) mg/dL compared to that in the placebo group being 134.0 (41.4) mg/dL.
The primary efficacy endpoint and all the key secondary endpoints, except for percent change in Apo A-1 from baseline to Week 12 in ITT population (ITT analysis), achieved statistically significant benefit in favor of Alirocumab-treated patients according to the hierarchical testing procedure.
Summary Safety Results
A total of 248 patients were randomized and received at least a partial dose of study treatment (Safety Population). Below is a high-level summary of adverse events and events of interest.
TABLE 24
Overview of Adverse Event Profile: Treatment
Emergent Adverse Events - Safety Population
Alirocumab 75
Placebo
Q2W/Up150 Q2W
(N = 81)
(N = 167)
Patients with any TEAE
62 (76.5%)
117 (70.1%)
Patients with any treatment
7 (8.6%)
10 (6.0%)
emergent SAE
Patients with any TEAE leading
0
0
to death
Patients with any TEAE leading
1 (1.2%)
5 (3.0%)
to permanent treatment
discontinuation
TEAE: Treatment emergent adverse event,
SAE: Serious adverse event
n(%) = number and percentage of patients with at least one TEAE
Treatment-emergent SAEs occurred in a total of 17 patients, specifically 10 (6.0%) patients in the alirocumab treatment group and 7 (8.6%) patients in the placebo treatment group. There were no more than 2 reports in any SOC for either treatment group and no individual SAE was reported more than once in either treatment group.
No patient deaths were reported at the time of this first-step analysis.
A total of 6 patients prematurely discontinued study treatment due to a TEAE. Specifically, 5 (3.0%) patients in the alirocumab treatment group discontinued treatment early for rectal adenocarcinoma, diarrhoea, nausea, angioedema, asthenia, and alanine aminotransferase increased. One (1.2%) patient in the placebo treatment group discontinued due to syncope.
TEAEs occurred in 117 (70.1%) patients in the alirocumab treatment group and 62 (76.5%) patients in the placebo treatment group. The TEAEs that occurred in ≥5% of patients in any treatment group are: injection site reaction (10.8% vs. 7.4% in alirocumab and placebo group, respectively), headache (8.4% vs. 8.6% in alirocumab and placebo group, respectively), myalgia (6.0% vs. 6.2% in alirocumab and placebo group, respectively), and diarrhoea (5.4% vs. 1.2% in alirocumab and placebo group, respectively).
For TEAEs of special interest (AESIs), results are presented by pre-defined SMQ preferred term groupings.
Treatment-emergent injection site reactions (ISRs) occurred in 18 (10.8%) patients in the alirocumab treatment group and 6 (7.4%) patients in the placebo treatment group. None of the AEs were serious.
General Allergic TEAEs, identified through the MedDRA SMQ of “Hypersensitivity” occurred in 17 (10.2%) patients in the alirocumab treatment group and 6 (7.4%) patients in the placebo treatment group. None of the AEs were serious.
Treatment-emergent neurologic disorders occurred in 7 (4.2%) patients in the alirocumab treatment group and 2 (2.5%) patients in the placebo treatment group. In the alirocumab group, the PTs were: hypoaesthesia in 4 (2.4%) patients, paraesthesia in 2 (1.2%), and balance disorder in 1 (0.6%). None of the AEs were serious.
Treatment-emergent neurocognitive disorders occurred in 0 (0.0%) patients in the alirocumab treatment group and 1 (1.2%) patients in the placebo treatment group. The AE was not serious.
A total of 9 (5.4%) patients in the alirocumab treatment group and 0 (0.0%) patients in the placebo treatment group had 2 consecutive calculated LDL-C measurements below 25 mg/dL. For those patients with 2 consecutive calculated LDL-C measurements below 25 mg/dL, TEAEs occurred in 3 (33.3%) patients in the alirocumab treatment. The PTs were: influenza, influenza like illness, and nasopharyngitis. None of these AEs were serious, nor were they AESIs.
Conclusion
The following conclusions can be drawn from this early review of the study data: 1) the study achieved the primary efficacy endpoint with a statistically significant reduction in calculated LDL-C in the alirocumab treated patients; 2) this study also achieved all of the key secondary efficacy endpoints, except for the last endpoint (Apo A-1 at Week 12 in the ITT population (ITT analysis)); and 3) based on the available data at the time of this first step analysis, subcutaneous administration of alirocumab to patients with heterozygous familial hypercholesterolemia and an LDL-C>70 mg/dL or LDL-C>100 mg/dL, depending on history of MI or stroke at baseline, was generally safe and well tolerated.
Summary of Pooled Data from FH I and FH II Studies
From the pooled data of the FHI and FHII studies the following conclusions can be drawn: 1) self-administered alirocumab produced significantly greater LDL-C reductions vs. placebo after 24 weeks (LS mean difference of 51.4-57.9%); 2) the majority of patients (>70%) achieved their LDL-C goals at Week 24; 3) LDL-C reductions of 47.1-50.3% at Week 52 were achieved with alirocumab; 4) mean LDL-C levels of 1.7-1.9 mmol/L (65.9-74.3 mg/dL) at Week 52 were achieved with alirocumab; 5) approximately 50% of patients did not require uptitration to alirocumab 150 mg Q2W suggesting that 75 mg Q2W may be sufficient for many patients; and 6) TEAEs occurred in a similar frequency in the alirocumab and placebo arms.
Specifically, the combined data of the FHI and FHII studies shows that alirocumab produced a significant reduction in LDL-C at week 24 relative to placebo. The LS mean (SE) % change from baseline at week 24 was −48.8% for the alirocumab group (N=488), compared to 7.1% for the placebo group (N=244). The LS mean difference (SE) vs. placebo was −55.8% (2.1) (P<0.0001). Moreover, only 42% of alirocumab patients required uptitration at Week 12 to the 150 mg Q2W dose.
The LS mean (SE) calculated LDL-C values versus time for the ODYSSEY FH I and FH II studies are shown in FIG. 8. The values indicted on the graph are the LS mean % change from baseline to week 24 and week 52. FIG. 9 is a graph showing the LS mean (SE) calculated LDL-C values versus time for the ODYSSEY FH I and FH II studies. The values indicted below the graph are the numbers of patients analyzed at the various timepoints.
Among patients who received double-blind treatment for at least 12 weeks, 176/311 (56.6%) in FH I and 97/158 (61.4%) in FH II had LDL-C levels<1.8 mmol/L at week 8 and were maintained on alirocumab 75 mg Q2W. LDL-C levels were stable over time in these patients (FIG. 10). For patients in FH I who received dose increase to 150 mg Q2W, mean LDL-C levels were 2.7 mmol/L (104.3 mg/dL) at week 12 and 2.0 mmol/L (78.5 mg/dL) at week 24. Corresponding values in FH II were 2.6 mmol/L (98.6 mg/dL) at week 12 and 1.9 mmol/L (71.8 mg/dL) at week 24.
Subgroup analyses of the primary efficacy endpoint showed consistent reduction of calculated LDL-C across a range of demographic and baseline characteristics (FIGS. 11A-11C). The percentage reduction in LDL-C (alirocumab vs placebo) was 60.1% in males and 50.6% in females (pooled data from FH I and FH II), with a P-value for interaction of 0.0267. In the individual studies, LDL-C reductions (vs placebo) were 62.6% for males and 51.9% for females in FH I, and 53.5% for males and 49.2% for females in FH II.
A summary of interim safety data pooled from the FH I and FH II studies is set forth in Table 25A. All data was collected up to last patient visit at week 52. The percentage of patients who experienced TEAEs, serious AEs, and TEAEs leading to treatment discontinuation were comparable between treatment groups in the individual studies (Table 25B). A higher proportion of patients experienced injection site reactions in the alirocumab groups vs placebo in FH I (12.4% vs 11.0%) and FH II (11.4% vs 7.4%). Most of the injection site reactions were classified as mild in intensity. No injection site reaction led to study drug discontinuation. None of the reported neurological or allergic events (Table 3) were serious. Pruritus was reported in two (0.6%) and three (1.8%) alirocumab-treated patients in FH I and II, respectively, and one placebo-treated patient in each study (0.6% and 1.2%, respectively). Few neurocognitive events were reported with alirocumab (2 [0.6%] in FH I, none in FH II) or placebo (2 [1.2%] in FH I, 1 [1.2%] in FH II; Table 3). In FH I and FH II, respectively, 85.8% and 91.6% of alirocumab-treated patients (87.7% and 90.1% of placebo) received study treatment for ≥76 weeks.
TABLE 25A
Interim Safety Analysis (Pooled Data from FH I and FH II Studies)
% (N) of patients
All pts on background of max
tolerated statin ± other
Alirocumab
Placebo
lipid-lowering therapy
(N = 489)
(N = 244)
TEAEs
74.8%
(366)
75.4%
(184)
Treatment-emergent SAEs
10.0%
(49)
9.0%
(22)
TEAEs leading to death
0.8%
(4)
0
TEAEs leading to
3.1%
(15)
3.7%
(9)
discontinuation
Adverse Events of Interest
Adjudicated CV events
1.6%
(8)
1.2%
(3)
Injection-site reactions
11.5%
(56)
9.0%
(22)
Neurocognitive disorders
0.2%
(1)
1.2%
(3)
ALT >3 × ULN
2.1%
(10/488)
1.2%
(3/244)
Creatine kinase >3 × ULN
3.5%
(17/483)
6.2%
(15/243)
Other Adverse Events
Nasopharyngitis
10.2%
(50)
11.1%
(27)
Influenza
8.8%
(43)
6.1%
(15)
Headache
5.5%
(27)
6.6%
(16)
Back pain
4.9%
3.7%
Upper respiratory tract
4.3%
4.9%
infection
arthralgia
3.9%
4.9%
urinary tract infection
3.9%
2.5%
Diarrhoea
3.7%
2.5%
Myalgia
3.5%
4.9%
gastroenteritis
3.3%
3.3%
sinusitis
3.3%
2.9%
muscle spasms
3.1%
0.4%
dizziness
2.9%
3.7%
nausea
2.5%
3.7%
pain in extremities
1.8%
3.3%
fatigue
3.1%
2.5%
influenza like illness
2.9%
2.0%
bronchitis
2.7%
2.5%
abdominal pain
2.5%
1.6%
blood creatinine
2.5%
2.9%
phosphokinase
cough
1.6%
2.5%
hypertension
1.6%
2.5%
cystitis
1.2%
1.6%
neck pain
0.4%
2.0%
TABLE 25B
Final Safety Analysis (Pooled Data from FHI and FHII Studies)
FH I
FH II
Alirocumab
Placebo
Alirocumab
Placebo
n (%)
(n = 322)
(n = 163)
(n = 167)
(n = 81)
TEAEs
263
(81.7)
129
(79.1)
125
(74.9)
66
(81.5)
Treatment-emergent SAEs
44
(13.7)
22
(13.5)
15
(9.0)
8
(9.9)
TEAEs leading to deatha
6
(1.9)
0
0
0
TEAEs leading to treatment
11
(3.4)
10
(6.1)
6
(3.6)
1
(1.2)
discontinuation
TEAEs occurring in ≥5% patients (in any group)
Injection site reaction
40
(12.4)
18
(11.0)
19
(11.4)
6
(7.4)
Exact Fisher test p-valueb
0.77
0.38
Nasopharyngitis
36
(11.2)
12
(7.4)
21
(12.6)
18
(22.2)
Upper respiratory tract infection
22
(6.8)
14
(8.6)
5
(3.0)
1
(1.2)
Arthralgia
20
(6.2)
9
(5.5)
8
(4.8)
7
(8.6)
Influenza
20
(6.2)
10
(6.1)
24
(14.4)
7
(8.6)
Back pain
18
(5.6)
7
(4.3)
12
(7.2)
6
(7.4)
Sinusitis
17
(5.3)
7
(4.3)
1
(0.6)
2
(2.5)
Headache
15
(4.7)
9
(5.5)
16
(9.6)
7
(8.6)
Diarrhoea
10
(3.1)
5
(3.1)
11
(6.6)
1
(1.2)
Bronchitis
10
(3.1)
9
(5.5)
4
(2.4)
1
(1.2)
Dizziness
7
(2.2)
6
(3.7)
8
(4.8)
5
(6.2)
Myalgia
6
(1.9)
11
(6.7)
10
(6.0)
5
(6.2)
Influenza like illness
6
(1.9)
1
(0.6)
9
(5.4)
5
(6.2)
Safety events of interest
Positively adjudicated CV events
8
(2.5)
3
(1.8)
2
(1.2)
1
(1.2)
General allergic TEAEsc
28
(8.7)
16
(9.8)
19
(11.4)
5
(6.2)
Neurological TEAEsc
12
(3.7)
7
(4.3)
7
(4.2)
2
(2.5)
Neurocognitive disordersc
2
(0.6)
2
(1.2)
0
1
(1.2)
Development/worsening of
6
(1-9)
4
(2.5)
4
(2.4)
2
(2.5)
diabetesb
Ophthalmologic disordersc
3
(0.9)
4
(2.5)
3
(1.8)
1
(1.2)
Alanine aminotransferase >3 ×
5/322
(1.6)
2/163
(1.2)
6/166
(3.6)
1/81
(1.2)
ULN
Creatine kinase >3 ×
13/318
(4.1)
10/163
(6.1)
8/165
(4.8)
6/80
(7.5)
ULN
Example 4: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C Higher or Equal to 160 mg/dL with their Lipid-Modifying Therapy
Introduction
This study included patients with heterozygous familial hypercholesterolemia (heFH) with or without a history of documented MI or ischemic stroke.
The objective of the present study was to assess the efficacy and safety of Alirocumab in patients with heFH whose LDL-C level was higher than or equal to 160 mg/dL (4.14 mmol/L) on maximally tolerated statin therapy with or without additional LMT.
This specific study (FIG. 6) was undertaken to demonstrate in heFH patients, with LDL-C higher or equal to 160 mg/dL, that Alirocumab 150 mg Q2W as add-on therapy to statin+/−other LMT causes a statistically significant and clinically meaningful reduction in LDL-C. This population with such a high LDL-C level despite an optimized LMT represents a highest risk group with a well-identified unmet medical need that may be addressed by adding Alirocumab to their LDL-C lowering therapies.
Study Objectives
The primary objective of the study was to demonstrate the reduction of LDL-C by Alirocumab as add-on therapy to stable maximally tolerated daily statin therapy with or without other LMT in comparison with placebo after 24 weeks of treatment in patients with heterozygous familial hypercholesterolemia (heFH) and LDL-C higher than or equal to 160 mg/dL (4.14 mmol/L).
The secondary objectives were: 1) to evaluate the effect of Alirocumab in comparison with placebo on LDL-C after 12 weeks of treatment; 2) to evaluate the effect of Alirocumab on other lipid parameters (i.e., Apo B, non-HDL-C, total-C, Lp (a), HDL-C, TG, and Apo A-1 levels); 3) to evaluate the long-term effect of Alirocumab on LDL-C; 4) to evaluate the safety and tolerability of Alirocumab; 5) to evaluate the development of anti-Alirocumab antibodies.
Study Design
This was a randomized, double-blind, placebo-controlled, parallel-group, unbalanced (2:1, Alirocumab: placebo), multi-center, multi-national study to assess the efficacy and the safety of Alirocumab in patients with heterozygous familial hypercholesterolemia (heFH) and LDL-C higher or equal to 160 mg/dL with or without their LMT (i.e., stable maximally tolerated daily statin therapy+/−other LMT). Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke [Yes/No], and statin treatment (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily vs. simvastatin whatever the daily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily). After randomization, patients received double-blind study treatment (either Alirocumab or placebo) every 2 weeks over a period of 78 weeks on top of stable maximally tolerated daily statin therapy+/−other LMT.
After completion of the 18-month double-blind treatment period, all patients who successfully completed the ODYSSEY High FH study had the opportunity to participate in an open-label extension study. Consequently all patients will receive Alirocumab at entry in the open-label extension study regardless the study treatment they received during the 18-month double-blind treatment period.
The study consisted of 3 periods: screening, double-blind treatment, and follow up.
The screening period was up to 3 weeks in duration including an intermediate visit during which the patient (or another designated person such as spouse, relative, etc.) was trained to self-inject/inject with placebo for Alirocumab. Eligibility assessments were performed to permit the randomization of the patients into the study.
The double-blind treatment period was a randomized, double-blind study treatment period of 18 months. The first injection during the double-blind period was done at the site on the day of randomization (Week 0 [D1]-V3) and as soon as possible after the call to IVRS/IWRS for randomization into the study. The subsequent injections were done by the patient (self-injection) or another designated person (such as spouse, relative, etc.) at a patient-preferred location (home . . . ). Patients randomized to Alirocumab received a dose of 150 mg of the IMP from randomization (V3) up to Week 76 (i.e., Weeks 0, 2, 4, 6, 8 . . . to 76).
The follow-up period (if applicable) was a period of 8 weeks after the end of the DBTP for patients not consenting to participate in the open-label extension study or if prematurely discontinuing study treatment.
The laboratory measurement of lipid parameters were performed by a central laboratory (central lab) during the study.
Patients who achieved 2 consecutive calculated LDL-C levels<25 mg/dL (0.65 mmol/L) during the study were monitored and managed.
Statin and other LMT (if applicable) should have been stable (including dose) during the first 24 weeks of the DBTP barring exceptional circumstances whereby overriding concerns (including but not limited to TG alert posted by the central lab) warrant such changes, as per the Investigator's judgment. From Week 24 onwards, background LMT was modified only under certain conditions as described below.
Patients should have been on a stable diet (NCEP-ATPIII TLC diet or equivalent) throughout the entire study duration from screening, as described above in Example 2 (see Table 1). The dietician or site staff with appropriate training reviewed the patient's diet at the screening visit and periodically throughout the study.
The study duration included a screening period of up to 3 weeks, a 78-week DBTP for efficacy and safety assessment, and an 8-week post-treatment follow-up period after the last visit of the DBTP for patients not consenting to participate in the open-label extension study or if prematurely discontinuing study treatment. Thus, the maximum study duration per patient was about 89 weeks (i.e., 20 months) (up to 3 weeks screening+78 weeks double-blind treatment+8 weeks follow-up). The end of the study per patient was the last protocol planned visit or the resolution/stabilization of all SAEs, and AESI, whichever came last.
Selection of Patients
The inclusion criteria were: 1) patients with heterozygous familial hypercholesterolemia (heFH)* who were not adequately controlled with a maximally tolerated daily dose of statin,** with or without other lipid-modifying therapy (LMT) at stable dose prior to the screening visit (Week-3).
Diagnosis of heFH must have been made either by genotyping or by clinical criteria. For those patients not genotyped, the clinical diagnosis may have been based on either the Simon Broome criteria with a criteria for definite FH or the WHO/Dutch Lipid Network criteria with a score >8 points. See criteria described above in Example 2.
Definition of maximally tolerated dose: any of the following were acceptable): 1) rosuvastatin 20 mg or 40 mg daily; 2) atorvastatin 40 mg or 80 mg daily; 3) simvastatin 80 mg daily (if already on this dose for >1 year—see exclusion criterion E 06); or 4) patients not able to be on any of the above statin doses, should have been treated with the dose of daily atorvastatin, rosuvastain or simvastatin that was considered appropriate for the patient as per the investigator's judgment or concerns. Some examples of acceptable reasons for a patient taking a lower statin dose included, but were not limited to: adverse effects on higher doses, advanced age, low body mass index, regional practices, local prescribing information, concomitant meds, co-morbid conditions such as impaired glucose tolerance/impaired fasting glucose.
Patients who met all the above inclusion criteria were screened for the following exclusion criteria, which are sorted and numbered in the following 3 subsections: exclusion criteria related to study methodology, exclusion criteria related to the background therapies, and exclusion criteria related to Alirocumab.
Exclusion criteria related to study methodology were: 1) patient without diagnosis of heFH made either by genotyping or by clinical criteria; 2) LDL-C<160 mg/dL (<4.14 mmol/L) at the screening visit (Week-3); 3) not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks as applicable, prior to the screening visit (Week-3) or from screening to randomization; 4) currently taking a statin other than simvastatin, atorvastatin, or rosuvastatin; 5) simvastatin, atorvastatin, or rosuvastatin is not taken daily or not taken at a registered dose; 6) daily doses above atorvastatin 80 mg, rosuvastatin 40 mg or simvastatin 40 mg, (except for patients on simvastatin 80 mg for more than one year, who are eligible); 7) use of fibrates, other than fenofibrate within 6 weeks of the screening visit (Week-3) or between screening and randomization visits; 8) use of nutraceutical products or over-the-counter therapies that may affect lipids which have not been at a stable dose/amount for at least 4 weeks prior to the screening visit (Week-3) or between screening and randomization visits; 9) use of red yeast rice products within 4 weeks of the screening visit (Week-3) or between screening and randomization visits; 10) patient who has received plasmapheresis treatment within 2 months prior to the screening visit (Week-3), or has plans to receive it during the study; 11) recent (within 3 months prior to the screening visit [Week-3] or between screening and randomization visits) MI, unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack (TIA), carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease; 12) planned to undergo scheduled PCI, CABG, carotid, or peripheral revascularization during the study; 13) systolic blood pressure>160 mmHg or diastolic blood pressure>100 mmHg at screening visit or randomization visit; 14) history of New York Heart Association (NYHA) Class III or IV heart failure within the past 12 months; 15) known history of a hemorrhagic stroke; 16) age <18 years or legal age of majority at the screening visit (Week-3), whichever is greater; 17) patients not previously instructed on a cholesterol-lowering diet prior to the screening visit (Week-3); 18) newly diagnosed (within 3 calendar months prior to randomization visit [Week 0]) or poorly controlled (HbA1c>9% at the screening visit [Week-3]) diabetes; 19) presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins. Note: patients on thyroid replacement therapy can be included if the dosage has been stable for at least 12 weeks prior to screening and between screening and randomization visits, and TSH level is within the normal range of the Central Laboratory at the screening visit; 20) history of bariatric surgery within 12 months prior to the screening visit (Week-3); 21) unstable weight defined by a variation >5 kg within 2 months prior to the screening visit (Week-3); 22) known history of homozygous FH; 23) known history of loss of function of PCSK9 (i.e., genetic mutation or sequence variation); 24) use of systemic corticosteroids, unless used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization visit (Week 0). Note: topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not considered as “systemic” and are allowed; 25) use of continuous estrogen or testosterone hormone replacement therapy unless the regimen has been stable in the past 6 weeks prior to the Screening visit (Week-2) and no plans to change the regimen during the study; 26) history of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer or in situ cervical cancer; 27) known history of positive HIV test; 28) patient who has taken any investigational drugs other than the Alirocumab training placebo kits within 1 month or 5 half lives, whichever is longer; 29) patient who has been previously treated with at least one dose of Alirocumab or any other anti-PCSK9 monoclonal antibody in other clinical trials; 30) patient who withdraws consent during the screening period (patient who is not willing to continue or fails to return); 31) conditions/situations such as any clinically significant abnormality identified at the time of screening that, in the judgment of the Investigator or any sub-Investigator, would preclude safe completion of the study or constrain endpoints assessment; eg, major systemic diseases, patients with short life expectancy considered by the Investigator or any sub-Investigator as inappropriate for this study for any reason, e.g.: a) deemed unable to meet specific protocol requirements, such as scheduled visits; b) deemed unable to administer or tolerate long-term injections as per the patient or the Investigator; c) investigator or any sub-Investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol, etc.; d) presence of any other conditions (e.g., geographic or social . . . ) actual or anticipated, that the Investigator feels would restrict or limit the patient's participation for the duration of the study; 32) laboratory findings during screening period (not including randomization Week 0 labs): a) positive test for Hepatitis B surface antigen or Hepatitis C antibody; b) positive serum beta-hCG or urine pregnancy (including Week 0) in women of childbearing potential; c) triglycerides >400 mg/dL (>4.52 mmol/L) (1 repeat lab is allowed); d) eGFR<30 mL/min/1.73 m2 according to 4-variable MDRD Study equation (calculated by central lab); e) ALT or AST>3×ULN (1 repeat lab is allowed); f) CPK>3×ULN (1 repeat lab is allowed); g) TSH<lower limit of normal (LLN) or >upper limit of normal (ULN) (1 repeat lab is allowed).
Exclusion criteria related to the background therapies were: 1) all contraindications to the background therapies or warnings/precautions of use (when appropriate) as displayed in the respective National Product Labeling.
Exclusion criteria related to Alirocumab were: 1) known hypersensitivity to monoclonal antibody or any component of the drug product; 2) pregnant or breast-feeding women; and 3) women of childbearing potential not protected by highly-effective method(s) of birth control (as defined in the informed consent form and/or in a local protocol addendum) and/or who are unwilling or unable to be tested for pregnancy. Note: Women of childbearing potential must have had a confirmed negative pregnancy test at screening and randomization visits. They must have used an effective contraceptive method throughout the entire duration of the study treatment, and for 10 weeks after the last intake of IMP, and agreed to repeat urine pregnancy test at designated visits. The applied methods of contraception had to meet the criteria for a highly effective method of birth control according to the “Note for guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (CPMP/ICH/286/95)”. Postmenopausal women must have been amenorrheic for at least 12 months.
Study Treatments
Sterile Alirocumab drug product was supplied at a concentration of 150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose. Drug product was supplied as 1 mL volume in an auto-injector.
Sterile placebo for Alirocumab was prepared in the same formulation as Alirocumab without the addition of protein as 1 mL volume in an auto-injector.
During the double-blind treatment period, Alirocumab or placebo was administered subcutaneously every 2 weeks, starting at Week 0 continuing up to the last injection (Week 76) 2 weeks before the end of the double blind treatment period. If the injection was scheduled to take place on the same date as the site visit, then the IMP should have been administered after the blood sampling had been completed.
IMP should ideally have been administered every 2 weeks subcutaneously at approximately the same time of the day; however it was acceptable to have a window period of ±3 days. The time of the day was based on patient's preference.
The following classes of drugs were identified as non-investigational medicinal products (NIMP) because the medication was either a background therapy or a potential rescue medication: statins (rosuvastatin, atorvastatin, simvastatin); cholesterol absorption inhibitors (ezetimibe); bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam); nicotinic acid; fenofibrate; omega-3 fatty acids (≥1000 mg daily).
Patients who achieved 2 consecutive calculated LDL-C<25 mg/dL (0.65 mmol/L) were monitored.
Patients who had titers at or above 240 for anti-Alirocumab antibodies at follow-up visit had additional antibody sample(s) at 6 to 12 months after the last dose, and thereafter about every 3 to 6 months until titer returned below 240.
Patients were randomized to receive either placebo or Alirocumab during the double-blind study treatment period using a ratio 1:2, with permuted-block randomization. Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke [Yes/No], and statin treatment (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily vs. simvastatin whatever the daily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mg daily).
A concomitant medication was any treatment received by the patient concomitantly to the study (until follow-up visit). Concomitant medications were to be kept to a minimum during the study. However, if these were considered necessary for the patient's welfare and were unlikely to interfere with the IMP, they could be given at the discretion of the Investigator, with a stable dose (when possible). Besides the specific information related to concomitant medications provided in this section, any other concomitant medication(s) will be allowed. If the patient had an LDL-C>or equal 160 mg/dL (4.14 mmol/L) at the screening visit (Week-3) and was treated with a statin only, i.e. without additional LMT, the investigator was to report the reason for the patient not being on a second LMT. For background LMT, including statins, sites must have followed the national product label for the safety monitoring and management of patients.
Nutraceutical products or over-the-counter therapies that may affect lipids were allowed only if they had been used at a stable dose for at least 4 weeks prior to screening visit, during the screening period and maintained during the first 24 weeks of the double-blind treatment period. After the Week 24 visit, modification to these nutraceutical products or over-the-counter therapies was allowed but in general should have been avoided. Examples of such nutraceutical products or over-the-counter therapies included omega-3 fatty acids at doses <1000 mg, plant stanols such as found in Benecol, flax seed oil, and psyllium.
Patients must have been on stable maximally tolerated daily registered doses of statins with other LMT for at least 4 weeks (6 weeks for fenofibrate) before screening visit. During the study, the patients should have stayed on these stable maximally tolerated registered daily doses of statins with other LMT. Lipid profile values from samples obtained after randomization were blinded. Nevertheless, sites were made aware of triglyceride alert, as well as rescue threshold of LDL-C value in order to make decisions on the patient's background LMT. From the screening visit (Week-3) until Week 24 of the double-blind treatment period, the background LMT should not have been changed. No dose adjustment, discontinuation or initiation of other statins or other LMT should have taken place during this time, barring exceptional circumstances whereby overriding concerns (including but not limited to triglyceride alert posted by the central lab) warranted such changes, as per the investigator's judgment.
For a triglyceride alert (TG≥500 mg/dL (5.65 mmol/L)) that was confirmed by repeat testing, the investigator was to perform investigations, manage the patient, and modify the background LMT as per his/her medical judgment.
For a rescue notification of LDL-C at the Week 24 visit and later, i.e., LDL-C increase >25% as compared to randomization visit LDL-C on two consecutive occasions, the investigator should have ensured that no reasonable explanation existed for insufficient LDL-C control (such as an alternative medical cause like corticosteroid use, etc.) and in particular that: compliance with diet was appropriate, compliance with background LMT was appropriate, and study treatment was given as planned. If any of the above could have reasonably explained the insufficient LDL-C control, the investigator should have undertaken appropriate action, i.e. stressed the absolute need to be compliant with treatment, if needed organized a specific interview with a qualified nutrition professional and stressed the absolute need to be compliant with diet, and performed a blinded LDL-C assessment within 1 to 2 months. If none of the above mentioned reasons could be found, or if appropriate action failed to decrease LDL-C under the alert value, rescue medication may have been introduced. The effectiveness of any such changes were made based on the absence of rescue notification of LDL-C sent on the blinded lipid testing at the next scheduled lab draw.
If no reason for LDL-C above the threshold value could be found, or if appropriate action failed to decrease LDL-C below the threshold value, rescue medication may have been introduced. The effectiveness of any such changes would be made based on lack of rescue threshold from blinded lipid testing at the next routinely scheduled lab draw. Patients per protocol already received a maximum tolerated dose of statin, so statin up-titration or switch was not an option. For further LDL-C lowering, the investigator may have considered: a cholesterol absorption inhibitor (ezetimibe), or a bile acid-binding sequestrant (the resins cholestyramine and colestipol, or colesevelam, a nonabsorbable polymer). The following lipid modifying agents may have also been considered: fibrate (Note: Caution should be exercised when combining fibrates with other cholesterol-lowering medications such as statins because of the risk of myopathy. When a fibrate is combined with a statin, fenofibrate is the fibrate of choice because it does not affect statin glucuronidation.); the only fibrate allowed per protocol was fenofibrate; nicotinic acid (niacin) (Note: Niacin raises blood glucose but has been shown to be effective in modifying lipid disorders in people with diabetes if glucose control is maintained).
In summary, background LMT should not have been modified from screening to the follow up visit. However, up to Week 24, if a confirmed TG alert was reached or if there was an overwhelming clinical concern (at the discretion of the Investigator) then modification of the background LMT was allowed. From Week 24 onwards, if a confirmed TG alert was reached, or if a rescue threshold for LDL-C was attained (and no other reasonable explanation exists), or if there was an overwhelming clinical concern (at the discretion of the Investigator) then modification of the background LMT was allowed.
Women of childbearing potential were required to take an effective contraceptive method throughout the study treatment and for 10 weeks after the last IMP injection (i.e., Follow-up visit).
Forbidden concomitant medications from the initial screening visit until the follow-up visit included the following: statins other than simvastatin, atorvastatin and rosuvastatin; fibrates, other than fenofibrate; and red yeast rice products.
Study Endpoints
The primary efficacy endpoint was the percent change in calculated LDL-C from baseline to Week 24, which was defined as: 100×(calculated LDL-C value at Week 24-calculated LDL-C value at baseline)/calculated LDL-C value at baseline. The baseline calculated LDL-C value was the last LDL-C level obtained before the first double-blind IMP injection. The calculated LDL-C at Week 24 was the LDL-C level obtained within the Week 24 analysis window and during the main efficacy period. The main efficacy period was defined as the time from the first double-blind IMP injection up to 21 days after the last double-blind IMP injection or up to the upper limit of the Week 24 analysis window, whichever came first. All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used to provide a value for the primary efficacy endpoint if appropriate according to above definition.
The key secondary efficacy endpoints were: 1) The percent change in calculated LDL-C from baseline to Week 12: similar definition and rules as for primary efficacy endpoint, except that the calculated LDL-C at Week 12 was the LDL-C level obtained within the Week 12 analysis window and during the 12-week efficacy period. The 12-week efficacy period was defined as the time from the first double-blind IMP injection up to the Visit 6 re-supply IVRS contact or up to 21 days after the last double-blind IMP injection, whichever came first. Blood sampling collected the day of the Visit 6 re-supply IVRS contact was considered as before titration; 2) the percent change in Apo B from baseline to Week 24. Same definition and rules as for the primary endpoint; 3) the percent change in non-HDL-C from baseline to Week 24. Same definition and rules as for the primary endpoint; 4) the percent change in total-C from baseline to Week 24. Same definition and rules as for the primary endpoint; 5) the percent change in Apo B from baseline to Week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 6) the percent change in non-HDL-C from baseline to Week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 7) the percent change in total-C from baseline to Week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 8) the percent change in calculated LDL-C from baseline to Week 52. Definitions and rules were similar to the ones used for the primary endpoint replacing Week 24 by Week 52. The 52-week efficacy period was defined as the time from the first double-blind IMP up to 21 days after the last double-blind IMP injection, or up to the upper limit of the Week 52 analysis window whichever came first; 9) the proportion of patients reaching LDL-C goal at Week 24, i.e. LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patients without CVD, defined as: (number of patients whose calculated LDL-C value at Week 24 reach LDL-C goal/number of patients in the mITT population)*100, using definition and rules used for the primary endpoint; 10) the percent change in Lp(a) from baseline to Week 24. Same definition and rules as for the primary endpoint; 11) the percent change in HDL-C from baseline to Week 24. Same definition and rules as for the primary endpoint; 12) the percent change in HDL-C from baseline to Week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 13) the percent change in Lp(a) from baseline to Week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 14) the percent change in fasting TG from baseline to Week 24. Same definition and rules as for the primary endpoint; 15) the percent change in fasting TG from baseline to Week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12; 16) the percent change in Apo A-1 from baseline to Week 24. Same definition and rules as for the primary endpoint; 17) the percent change in Apo A-1 from baseline to Week 12. Same definition and rules as for the percent change in calculated LDL-C from baseline to Week 12.
Other secondary efficacy endpoints were: 1) the percent change in calculated LDL-C from baseline to Week 78: Definitions and rules were similar to the ones used for the primary endpoint replacing Week 24 by Week 78; 2) the proportion of patients reaching LDL-C goal at Weeks 12, 52 and 78, i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patients without prior CVD; 3) the proportion of patients reaching LDL C<100 mg/dL (2.59 mmol/L) at Week 24; 4) the proportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L) at Week 12; 5) the proportion of patients reaching LDL-C<70 mg/dL (1.81 mmol/L) at Week 24; 6) the proportion of patients reaching LDL-C<70 mg/dL (1.81 mmol/L) at Week 12; 7) the absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline to Weeks 12, 24, 52 and 78; 8) the percent change in Apo B, non-HDL-C, total-C, Lp (a), HDL-C, fasting TG, and Apo A-1 from baseline to Week 52 and 78; 9) the change in ratio Apo B/Apo A-1 from baseline to Weeks 12, 24, 52 and 78; 10) the proportion of patients with Apo B<80 mg/dL (0.8 g/L) at Weeks 12, 24, 52 and 78; 11) the proportion of patients with non-HDL-C<100 mg/dL at Weeks 12, 24, 52 and 78; 12) the proportion of patients with calculated LDL-C<70 mg/dL (1.81 mmol/L) and/or ≥50% reduction in calculated LDL-C (if calculated LDL-C≥70 mg/dL [1.81 mmol/L]) at Weeks 12, 24, 52 and 78.
Total-C, HDL-C, TG, Apo B, Apo A-1, and Lp (a) were directly measured by the Central Laboratory. LDL-C was calculated using the Friedewald formula at all visits (except Week-1 and Follow Up visit). If TG values exceeded 400 mg/dL (4.52 mmol/L) then the central lab reflexively measured (via the beta quantification method) the LDL-C rather than calculating it. Non-HDL-C was calculated by subtracting HDL-C from the total-C. Ratio Apo B/Apo A-1 was calculated.
The clinical laboratory data consisted of urinalysis, hematology (red blood cell count, hemoglobin, red blood cell distribution width (RDW), reticulocyte count, hematocrit, platelets, white blood cell count with differential blood count), standard chemistry (glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, total protein, LDH, albumin, γ Glutamyl Transferase [γGT]), Hepatitis C antibody, liver panel (ALT, AST, ALP, and total bilirubin), and CPK.
Vital signs included: heart rate, systolic and diastolic blood pressure in sitting position.
Other endpoints included: anti-Alirocumab antibody assessments, hs-CRP, HbA1c, EQ-5D Questionnaire, and pharmacogenetic samples.
Anti-Alirocumab antibodies included the antibody status (positive/negative) and antibody titers. Serum samples for anti-Alirocumab antibody determination were drawn periodically throughout the study. The first scheduled sample at randomization visit was obtained before IMP injection (predose). Patients who had titers at or above 240 for anti-Alirocumab antibodies at the follow-up visit had additional antibody sample(s) at 6 to 12 months after the last dose, and thereafter about every 3 to 6 months until titer returned below 240. Anti-Alirocumab antibody samples were analyzed using a validated non-quantitative, titer-based bridging immunoassay. It involved an initial screen, a confirmation assay based on drug specificity, and a measurement of the titer of anti-Alirocumab antibodies in the sample. The lower limit of detection was approximately 1.5 ng/mL. Samples that were positive in the ADA assay were assessed for neutralizing antibodies using a validated, non-quantitative, competitive ligand binding assay. The lower limit of detection based on a monoclonal positive control neutralizing antibody was 390 ng/mL.
The percent change in hs-CRP from baseline to Week 24, 52 and 78.
The absolute change in HbA1c (%) from baseline to Week 24, 52 and 78.
EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D as a measure of health-related quality of life defines health in terms of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension can take one of three responses (3 ordinal levels of severity): ‘no problem’ (1), “some problems” (2), “severe problems” (3). Overall health state was defined as a 5-digit number. Health states defined by the 5-dimensional classification can be converted into corresponding index scores that quantify health status, where 0 represents ‘death’ and 1 represents “perfect health”.
Study Procedures
For all visits after Day 1/Week 0 (randomization visit), a timeframe of a certain number of days was allowed. The window period for visits at Weeks 12 and 24 was ±3 days, at Week 52 and 78 was ±5 days, and for all other site visits it was ±7 days during the double-blind treatment period, and follow-up period. A window period of +3 days was allowed for the randomization visit (Day 1/Week 0) and ±7 days for the injection training visit at screening (Week-1).
The blood sampling for determination of lipid parameters (i.e. total-C, LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio Apo B/Apo A-1, Lp [a]) was to be performed in the morning, in fasting condition (i.e. overnight, at least 10-12 hours fast and refrain from smoking) for all site visits throughout the study. Alcohol consumption within 48 hours and intense physical exercise within 24 hours preceding the blood sampling were discouraged. Note: if the patient was not in fasting conditions, the blood sample was not be collected and a new appointment was given the day after (or as close as possible to this date) to the patient with instruction to be fasted (see above conditions).
Only patients who met the inclusion criteria were screened. The screening period took place up to 3 weeks or 21 days (and as short as possible, upon receipt of laboratory eligibility criteria) prior to randomization/Day 1 visit. The first screening visit (Week-3) took place from 21 to 8 days before the randomization visit. If it was planned to have another designated person administer the injections to the patient during the study, then this person should have been present at the injection training visit (Week-1).
The following visits were scheduled: Screening Visit (Visit 1/Week-3/Day−21 up to −8); Screening (Visit 2/Week-1/Day−7 ±7); Randomization visit (Visit 3/Week 0/Day 1 +3); Visit 4/Week 4/Day 29 ±7); Visit 5/Week 8/Day 57 ±7); Visit 6/Week 12/Day 85 ±3; Visit 7/Week 16/Day 113 ±7): Visit 8/Week 24/Day 169 ±3; Visit 9/Week 36/Day 253 ±7; Visit 10/Week 52/Month 12/Day 365 ±5; Visit 11/Week 64/Day 449 ±7; Visit 12/Week 78/Month 18/Day 547 ±5 (end of treatment visit); and Visit 13/Week 86/Day 603 ±7 (follow up visit).
Safety
Monitored safety events were the occurrence of treatment emergent adverse events (TEAEs) reported by the patient or noted by the investigator, serious adverse events (SAEs), TEAEs leading to treatment discontinuation, AEs of special interest (local Injection site reactions, allergic events, selected neurological events and cardiovascular events with adjudication result), occurrence of PCSA (potentially clinically significant abnormalities) in laboratory parameters, specific analysis for diabetes or impaired glucose control and patients with 2 consecutives LDL-C<25 mg/dL.
Statistical Methods
Sample Size Determination:
A total sample size of 45 patients (30 in alirocumab and 15 in placebo) had 95% power to detect a difference in mean percent change in LDL-C of 30% with a 0.05 two-sided significance level and assuming a common standard deviation of 25%, and all these 45 patients having an evaluable primary endpoint. A final total sample size of 105 patients with a randomization ratio 2:1 (alirocumab 70: placebo 35) has been selected in order to provide at least 50 patients exposed to alirocumab for 12 months at the first step analysis and assuming a drop-out rate of 10% over the first 3-month period and a drop-out rate of 20% over the 3-12-month period.
Timing of Analyses:
The first step analysis included efficacy endpoints up to Week 52 (final efficacy analysis) and interim safety analysis, which was performed on all safety data up to the common study cut-off date (last patient Week 52 visit). Analysis of lipid data beyond Week 52 was descriptive. Results of the first step analysis are presented herein.
Second step (final) analysis will be conducted at the end of the study and will consist in the final analysis of efficacy endpoints up to Week 78 and final safety analysis.
Analysis Populations:
The primary efficacy analysis population was the intent-to-treat (ITT) population, defined as all randomized patients who had an evaluable primary efficacy endpoint, that is, those with an available baseline calculated LDL-C value, and at least one available calculated LDL-C value within one of the analysis windows up to Week 24 (including all calculated LDL-C on-treatment and off-treatment).
The secondary efficacy analysis population was the modified intent-to-treat (mITT) population, defined as all randomized patients who took at least one dose or part of a dose of the double-blind investigational medicinal product (IMP) and who had an available calculated LDL-C value at baseline and at least one within one of the analysis windows up to Week 24 during the efficacy treatment period. The efficacy treatment period was defined as the time from the first double-blind IMP administration up to 21 days after the last double-blind injection.
The safety population included all randomized patients who received at least one dose or part of a dose of the double-blind IMP.
Efficacy Analyses:
Primary analyses of efficacy endpoints were conducted using an ITT approach (based on the ITT population defined above), including all lipid data, regardless of whether the patient was continuing therapy or not. This corresponds to ITT estimands, defined for primary and key secondary endpoints. In addition, analyses were also conducted using an on-treatment approach (based on the mITT population defined above), including lipid data collected during the efficacy treatment period. This corresponds to on-treatment estimands of key secondary endpoints.
The ITT approach analyzed all patients, irrespective of their adherence to the treatment; it assessed the benefit of the treatment strategy and reflected as much as possible the effect in a population of patients. The on-treatment approach analyzed the effect of treatment, restricted to the period during which patients actually received the treatment. It assessed the benefit that a treatment would achieve in patients adherent to treatment up to the considered time point.
Efficacy analyses were performed according to treatment as-randomized.
All measurements, scheduled or unscheduled, fasting or not fasting, were assigned to analysis windows in order to provide an assessment for Week 4 to Week 78 time points.
With regards to the primary efficacy analysis (ITT approach), the percent change in calculated LDL-C from baseline to Week 24 was analyzed using a mixed-effect model with repeated measures (MMRM) approach. All post-baseline data available from Week 4 to Week 52 analysis windows were used and missing data were accounted for by the MMRM. The model included the fixed categorical effects of treatment group (placebo versus alirocumab), randomization strata (as per IVRS), time point (Week 4 to Week 52), treatment-by-time point interaction and strata-by-time point interaction, as well as, the continuous fixed covariates of baseline LDL-C value and baseline value-by-time-point interaction. This model provided baseline adjusted least-squares means (LSmeans) estimates at Week 24 for both treatment groups with their corresponding 95% confidence interval. To compare the alirocumab to the placebo group, an appropriate statement was used to test the differences of these estimates at the 5% alpha level.
A hierarchical procedure has been defined to test key secondary endpoints while controlling for multiplicity (using above order of key secondary endpoints). The first key secondary endpoint was the percent change in calculated LDL-C from baseline to Week 24 using an on-treatment approach.
Continuous secondary variables anticipated to have a normal distribution (i.e., lipids other than TG and Lp(a)) were analyzed using the same MMRM model as for the primary endpoint. Continuous endpoints anticipated to have a non-normal distribution (i.e., TG and Lp(a)) were analyzed using multiple imputation approach for handling of missing values followed by robust regression model with endpoint of interest as response variable using M-estimation (using SAS ROBUSTREG procedure) with treatment group, randomization strata (as per IVRS) and corresponding baseline value(s) as effects to compare treatment effects. Combined estimate for mean in both treatment groups, as well as the differences of these estimates, with their corresponding SEs, 95% CIs and p-value were provided (through SAS MIANALYZE procedure).
Binary secondary efficacy endpoints were analyzed using multiple imputation approach for handling of missing values followed by stratified logistic regression with treatment group as main effect and corresponding baseline value(s) as covariate, stratified by randomization factors (as per IVRS). Combined estimates of odds ratio versus placebo, 95% CI, and p-value were provided (through SAS MIANALYZE procedure).
Safety Analyses:
Safety analyses were descriptive, performed on the safety population according to treatment actually received. The safety analysis focused on the TEAE period defined as the time from the first dose of double-blind up to 70 days after the last double-blind injection. TEAE which developed, worsened or became serious or PCSA occurring after the patient inclusion in the open-label extension study (LTS13643) were not considered in the TEAE period. TEAE period was truncated at the common study cut-off date.
Results
Study Patients
Patient Accountability
Of the 107 randomized patients (72 and 35 patients in the alirocumab and the placebo groups, respectively), one patient in the alirocumab group did not have any baseline calculated LDL-C value and was therefore not included in the ITT and mITT populations.
TABLE 26
Analysis populations
Alirocumab
Placebo
150 Q2W
All
Randomized population
35 (100%)
72 (100%)
107 (100%)
Efficacy populations
Intent-to-Treat (ITT)
35 (100%)
71 (98.6%)
106 (99.1%)
Modified Intent-to-Treat (mITT)
35 (100%)
71 (98.6%)
106 (99.1%)
Safety population
35
72
107
Note:
The safety population patients are tabulated according to treatment actually received (as treated).
For the other populations, patients are tabulated according to their randomized treatment.
Study Disposition
Study disposition, exposure, efficacy and safety analyses were assessed using all data up to the common cut-off date of the study (defined as the date of last patient's Week 52 visit). Therefore, this first step analysis includes efficacy data up to Week 52 and safety data beyond Week 52 and up to Week 78 or Follow-up visit for some patients. Patient disposition is shown in FIG. 12.
In this study, one site with 7 patients randomized and a second site with 6 patients randomized were identified with serious GCP non-compliance, and the sites were closed. For the first closed site, one of the key findings was related to IMP injections reported as having been received by some patients whereas corresponding kits were discovered in the fridge. The reporting of these injections was corrected in the database but other issues on injections could not be excluded. For the second site, persistent concerns with the conduct of the study and associated documentation related to the study were observed during routine monitoring.
Among these 13 patients, one was still ongoing at the cut-off date, one discontinued for adverse event, one patient moved, 3 patients discontinued for poor compliance to protocol and 7 patients discontinued due to decision of site closure.
There were in total 10 (9.3%) randomized patients who completed the 78 weeks double-blind study treatment period and 76 (71.0%) randomized patients with treatment ongoing at the time of the first-step analysis cut-off date. The double-blind IMP was prematurely discontinued before Week 78 for 6 (17.1%) patients in the placebo group and 15 (20.8%) patients in the alirocumab group. All these patients actually prematurely discontinued before Week 52. The main reasons for study treatment discontinuation were “other reasons”, poor compliance and adverse events. These “other reasons” included the 7 patients who discontinued due to the decision of site closure as mentioned above, 1 patient withdrawal not otherwise specified, 1 patient withdrew due to cholesterol results obtained independently and 1 patient moved.
In this first step analysis, final results are available for primary efficacy endpoint at Week 24 and key secondary efficacy endpoints assessed at Week 12, Week 24 and Week 52. The following table provides the availability of LDL-C over time. At Week 24, the primary efficacy endpoint was available for 33 (94.3%) in the placebo and 63 (88.7%) in the alirocumab group.
TABLE 27
Calculated LDL-C availability over time - ITT population
Placebo
Alirocumab 150 Q2W
(N = 235)
(N = 271)
On-
Post-
Post-
Calculated
treatment
treatment
On-treatment
treatment
LDL-C
value
value
Missing value
value
value
Missing value
Week 4
31 (88.6%)
0
4 (11.4%)
67 (94.4%)
0
4 (5.6%)
Week 8
34 (97.1%)
0
1 (2.9%)
66 (93.0%)
0
5 (7.0%)
Week 12
33 (94.3%)
0
2 (5.7%)
68 (95.8%)
0
3 (4.2%)
Week 16
28 (80.0%)
0
7 (20.0%)
66 (93.0%)
0
5 (7.0%)
Week 24
33 (94.3%)
0
2 (5.7%)
62 (87.3%)
1 (1.4%)
8 (11.3%)
Week 36
30 (85.7%)
1 (2.9%)
4 (11.4%)
60 (84.5%)
3 (4.2%)
8 (11.3%)
Week 52
27 (77.1%)
0
8 (22.9%)
52 (73.2%)
2 (2.8%)
17 (23.9%)
The primary endpoint was missing for 10 patients at Week 24 (2 and 8 patients in placebo and alirocumab groups, respectively). At the Week 24 visit (as per CRF monitoring), the reasons for missingness were as follows: 3 samples not done due to earlier study discontinuation; 3 samples done outside analysis time window; 2 samples not done due to Week 24 visit not done; and 2 samples available but measurement could not be done (lipemia, insufficient quantity, TGs>400 mg/dL[>4.52 mmol/L], sample lost, etc.).
The higher number of missing data at Week 52 is mainly due to the decision to close the two sites due to serious GCP non-compliance.
The LDL-C endpoint at Week 52 was missing for 25 out of 106 patients. The reasons for missing results were as follows: 17 samples not done due to earlier study discontinuation including 11 patients from the two closed sites; 3 samples done outside analysis time window; 1 sample not done due to Week 52 not done; 1 missing sample while visit Week 52 was done; and 3 samples available but measurement could not be done (TGs>400 mg/dL[>4.52 mmol/L] and hemolysis).
Demographics and Baseline Characteristics
Summary Population Characteristics:
107 HeFH patients diagnosed by genotyping (17.8%) and WHO/Dutch Lipid Network criteria (score of >8 points) or Simon Broome criteria for definite FH (82.2%) were randomized 2:1 to alirocumab (150 mg Q2W) or placebo.
Demographics characteristics, disease characteristics and lipid parameters at baseline were generally similar in the alirocumab group as compared to the placebo group: diagnosis of HeFH through genotyping in the alirocumab (19.4%) vs the placebo group (14.3%); diagnosis of HeFH through clinical criteria in the alirocumab (80.6%) vs the placebo group (85.7%); a mean age (SD) in the alirocumab group of 49.8 years (14.2) vs a mean age of the placebo group of 52.1 years (11.2); percentage of white race in the alirocumab (88.9%) vs the placebo (85.7%) group; and a mean BMI (SD) in the alirocumab group of 28.8 kg/m2 (5.2) vs a mean BMI in the placebo group of 28.9 kg/m2 (4.2). Some imbalances were noted due to the small sample size of the study: a higher proportion of female patients in the alirocumab group (51.4%) vs the placebo group (37.1%); more recent hypercholesterolemia diagnosis in the alirocumab group (median of 9.8 years) vs the placebo group (median of 17.4 years); a lower proportion of patients considered as very high CV risk in the alirocumab group (52.8%) than in the placebo group (65.7%) mainly driven by a medical history of coronary revascularization procedure; and a lower proportion of patients received ezetimibe at randomization in the alirocumab group (19.4%) than in the placebo group (34.3%). The cardiovascular history and risk factors of patients in both the alirocumab and placebo groups are shown in Table 28.
TABLE 28
Cardiovascular history and risk factors
All patients on
background of maximally
Alirocumab
tolerated statin ±
Placebo
150 Q2W
All
other LLT
(N = 35)
(N = 72)
(N = 107)
CHD history, % (n)
43.1%
(31)
62.9%
(22)
49.5% (53)
Acute MI, % (n)
22.1%
(16)
22.9%
(8)
22.4% (24)
Silent MI, % (n)
1.4%
(1)
0
0.9% (1)
Unstable angina, % (n)
9.7%
(7)
17.1%
(6)
12.1% (13)
Coronary
15.3%
(11)
40.0%
(14)
23.4% (25)
revascularization
procedures, % (n)
Other clinically
27.8%
(20)
28.6%
(10)
28.0% (30)
significant CHD, % (n)
Current smoker, % (n)
16.7%
(12)
25.7%
(9)
19.6% (21)
Hypertension, % (n)
55.6%
(40)
60.0%
(21)
57.0% (61)
Type 2 diabetes, % (n)
12.5%
(9)
17.1%
(6)
14.0% (15)
At randomization, all patients were treated with a statin, 72.9% receiving high intensity statin (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily) and 6.5% receiving simvastatin 80 mg. In addition to the statin, 19.4% and 34.3% of patients were receiving ezetimibe in the alirocumab and placebo groups respectively. Table 30 shows the background lipid modifying therapies (LMTs) of the alirocumab and placebo treated populations at randomization as well as those of the total randomized population.
Table 31 shows the lipid efficacy parameters at baseline of the alirocumab and placebo treated populations as well as the total randomized population. Mean (SD) calculated LDL-C at baseline was 197.8 (53.4) mg/dL (5.123 (1.38) mmol/L). Mean (SD) non-HDL-C at baseline was 226.4 (55.3) mg/dL. Mean (SD) Total-C at baseline was 274.4 (54.0) mg/dL. Mean (SD) HDL-C at baseline was 48.1 (13.3) mg/dL. The mean (SD) Total-C/HDL-C ratio at baseline was 6.135 (2.119). Mean (SD) fasting triglycerides (TGs) at baseline was 149.8 (86.6) mg/dL. Mean (SD) Lipoprotein-(a) at baseline was 41.2 (46.6) mg/dL. Mean (SD) Apo-B at baseline was 140.9 (31.0) mg/dL. Mean (SD) Apo-A1 at baseline was 137.5 (23.3) mg/dL. The mean (SD) Apo-B/Apo-A1 ratio at baseline was 1.061 (0.323) mg/dL.
Exposure to injections was similar across treatment groups with a mean exposure of 60.7 weeks in placebo group and 58.3 weeks in alirocumab group.
TABLE 29
Disease characteristics and other relevant
baseline data - Randomized population
Alirocumab
Placebo
150 Q2W
All
(N = 35)
(N = 72)
(N = 107)
Type of
hypercholesterolemia
Heterozygous Familial
35
(100%)
72
(100%)
107
(100%)
Hypercholesterolemia
(heFH)
Non-Familial
0
0
0
Hypercholesterolemia
(non-FH)
Time from
hypercholesterolemia
diagnosis (years)
Number
35
72
107
Mean (SD)
16.41
(12.62)
11.48
(10.48)
13.09
(11.41)
Median
17.42
9.76
11.70
Min:Max
0.0:42.8
0.0:39.9
0.0:42.8
Confirmation of
diagnosis
By genotyping
5
(14.3%)
14
(19.4%)
19
(17.8%)
By WHO/Simon
30
(85.7%)
58
(80.6%)
88
(82.2%)
Broomea
afor heFH diagnosis not confirmed by genotyping.
TABLE 30
Background LMT at randomization - Randomized population
Alirocumab
Placebo
150 Q2W
All
(N = 35)
(N = 72)
(N = 107)
Any statin
35
(100%)
72
(100%)
107
(100%)
Taking high dose statin
28
(80.0%)
57
(79.2%)
85
(79.4%)
Taking high intensity statin
25
(71.4%)
53
(73.6%)
78
(72.9%)
Atorvastatin daily dose
10
(28.6%)
22
(30.6%)
32
(29.9%)
(mg)
10
0
0
0
20
0
0
0
40
3
(8.6%)
10
(13.9%)
13
(12.1%)
80
7
(20.0%)
11
(15.3%)
18
(16.8%)
Other doses
0
1
(1.4%)
1
(0.9%)
Rosuvastatin daily dose
16
(45.7%)
33
(45.8%)
49
(45.8%)
(mg)
5
1
(2.9%)
2
(2.8%)
3
(2.8%)
10
0
0
0
20
3
(8.6%)
8
(11.1%)
11
(10.3%)
40
12
(34.3%)
23
(31.9%)
35
(32.7%)
Other doses
0
0
0
Simvastatin daily dose (mg)
10
(28.6%)
19
(26.4%)
29
(27.1%)
10
1
(2.9%)
4
(5.6%)
5
(4.7%)
20
1
(2.9%)
2
(2.8%)
3
(2.8%)
40
5
(14.3%)
9
(12.5%)
14
(13.1%)
80
3
(8.6%)
4
(5.6%)
7
(6.5%)
Other doses
0
0
0
Any LMT other than
13
(37.1%)
16
(22.2%)
29
(27.1%)
statinsa
Any LMT other than
12
(34.3%)
16
(22.2%)
28
(26.2%)
nutraceuticals
Ezetimibe
12
(34.3%)
14
(19.4%)
26
(24.3%)
Nutraceuticals
1
(2.9%)
0
1
(0.9%)
ain combination with statins or not.
High intensity statin corresponds to atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily.
High dose statin corresponds to atorvastatin 40 to 80 mg daily, rosuvastatin 20 to 40 mg daily, or simvastatin 80 mg daily.
TABLE 31
Lipid efficacy parameters at baseline - Quantitative
summary in conventional units - Randomized population
Alirocumab
Placebo
150 Q2W
All
(N = 35)
(N = 72)
(N = 107)
Calculated LDL-C
(mg/dL)
Number
35
71
106
Mean (SD)
201.0
(43.4)
196.3
(57.9)
197.8
(53.4)
Median
201.0
180.0
181.0
Q1:Q3
166.0:240.0
165.0:224.0
165.0:224.0
Min:Max
137:279
89:402
89:402
Non-HDL-C (mg/dL)
Number
35
72
107
Mean (SD)
231.5
(47.6)
223.9
(58.8)
226.4
(55.3)
Median
226.0
204.0
209.0
Q1:Q3
194.0:274.0
189.5:251.0
191.0:260.0
Min:Max
153:326
117:419
117:419
Total-C (mg/dL)
Number
35
72
107
Mean (SD)
276.4
(46.8)
273.5
(57.5)
274.4
(54.0)
Median
272.0
256.0
259.0
Q1:Q3
237.0:313.0
242.5:300.5
241.0:310.0
Min:Max
202:364
171:458
171:458
HDL-C (mg/dL)
Number
35
72
107
Mean (SD)
44.9
(11.3)
49.6
(14.0)
48.1
(13.3)
Median
42.0
45.5
45.0
Q1:Q3
39.0:51.0
39.5:57.5
39.0:55.0
Min:Max
24:72
28:84
24:84
Fasting TGs (mg/dL)
Number
35
72
107
Mean (SD)
156.3
(89.3)
146.6
(85.6)
149.8
(86.6)
Median
122.0
131.5
129.0
Q1:Q3
95.0:193.0
87.5:160.5
94.0:171.0
Min:Max
62:455
40:512
40:512
Lipoprotein-
(a)(mg/dL)
Number
34
71
105
Mean (SD)
46.2
(50.3)
38.8
(44.9)
41.2
(46.6)
Median
30.0
22.0
26.0
Q1:Q3
11.0:42.0
8.0:50.0
10.0:48.0
Min:Max
2:201
2:189
2:201
Apo-B (mg/dL)
Number
34
71
105
Mean (SD)
146.6
(28.3)
138.2
(32.0)
140.9
(31.0)
Median
143.0
130.0
134.0
Q1:Q3
121.0:173.0
118.0:154.0
119.0:158.0
Min:Max
99:208
81:255
81:255
Apo-A1 (mg/dL)
Number
34
71
105
Mean (SD)
131.5
(19.2)
140.3
(24.6)
137.5
(23.3)
Median
127.5
137.0
134.0
Q1:Q3
120.0:142.0
122.0:155.0
122.0:151.0
Min:Max
97:181
97:211
97:211
Apo-B/Apo-A1 (ratio)
Number
34
71
105
Mean (SD)
1.141
(0.287)
1.023
(0.334)
1.061
(0.323)
Median
1.170
0.950
1.020
Q1:Q3
0.900:1.300
0.800:1.170
0.850:1.230
Min:Max
0.58:1.86
0.49:2.32
0.49:2.32
Total-C/HDL-C (ratio)
Number
35
72
107
Mean (SD)
6.540
(1.986)
5.938
(2.167)
6.135
(2.119)
Median
6.417
5.647
5.863
Q1:Q3
4.936:7.600
4.399:6.878
4.545:7.370
Min:Max
3.29:11.19
2.92:13.48
2.92:13.48
Dosage and Duration
Exposure to injections was similar across treatment groups with a mean exposure of 60.7 weeks in the placebo group and 58.3 weeks in the alirocumab group. Duration of exposure for injection could not be calculated for 1 patient in alirocumab group due to unknown last injection date.
Efficacy
Primary Efficacy Endpoint
The ITT analysis includes all calculated LDL-C values collected on-treatment and off-treatment up to Week 52. The primary endpoint (percent change in calculated LDL-C from baseline to Week 24) analysis is provided based on a MMRM model on the ITT population, using LS means estimates at Week 24. Nine (11.3%) patients in the alirocumab group and 2 (5.7%) patients in the placebo group did not have a calculated LDL-C value at Week 24. These missing values were accounted for by the MMRM model.
Results of the primary endpoint analysis are presented in Table 32, in mmol/L and mg/dL.
Primary Efficacy Analysis
A statistically significant decrease in percent change in LDL-C from baseline to Week 24 was observed in the alirocumab group (LS mean versus baseline −45.7%) compared to the placebo group (LS mean versus baseline −6.6%) (LS mean difference vs. placebo (SE) of −39.1% (6.0%), p<0.0001) (see Table 31). This represents an absolute reduction (SD) of −90.8 (6.7) mg/dL in the alirocumab group and −15.5 (9.5) mg/dL in the placebo group (see Table 33). Percent change from baseline to Week 24 in LDL-C by individual patients are set forth in FIG. 13. All patients were on a background statin (at the maximum tolerated level). A subset of patients also received a further lipid lowering therapy.
In the alirocumab group, LDL-C reduction from baseline was observed from Week 4 to Week 52 (see FIG. 7, FIGS. 14A-14B and Table 33). A slight decrease in LDL-C reduction over time was observed in the alirocumab group (LS mean versus baseline at Week 52 of −42.1 versus −45.7 at Week 24), although the overall amount of the decrease stayed the same (75 mg/dL; see FIGS. 14A-14B). Furthermore, significant numbers of patients on alirocumab achieved LDL-C levels of <100 mg/dL (57% vs 11% of placebo patients) and <70 mg/dL (<1.81 mmol/L; 32% vs 3% of placebo patients) at Week 24 despite baseline LDL-C levels of >190 mg/dL (mean (SD) baseline calculated LDL-C 196.3 (57.9) mg/dL for alirocumab group; 201 (43.4) mg/dL for placebo group). At week 12, 31.0% of alirocumab group patients (vs. 0.0% of placebo group; ITT analysis) reached calculated LDL-C levels of <70 mg/dL (<1.81 mmol/L). Similarly, at Week 52, 31.0% of alirocumab group patients (vs 5.7% of placebo group; ITT analysis) reached calculated LDL-C levels of <70 mg/dL (<1.81 mmol/L).
A sensitivity analysis of the primary efficacy endpoint was performed excluding 13 patients from 2 sites with serious GCP non compliance. The decrease in percent change in LDL-C from baseline to Week 24 was still statistically significant in the alirocumab group (LS mean versus baseline −50.3%) compared to the placebo group (LS mean versus baseline −2.3%) (LS mean difference vs. placebo (SE) of −48.0% (5.8%), p<0.0001) (see Table 34).
TABLE 32
Percent change from baseline in calculated LDL-C
at Week 24: MMRM - ITT analysis - ITT population
Alirocumab
Placebo
150 Q2W
Calculated LDL Cholesterol
(N = 35)
(N = 71)
Baseline (mmol/L)
Number
35
71
Mean (SD)
5.205
(1.125)
5.083
(1.499)
Median
5.206
4.662
Min:Max
3.55:7.23
2.31:10.41
Baseline (mg/dL)
Number
35
71
Mean (SD)
201.0
(43.4)
196.3
(57.9)
Median
201.0
180.0
Min:Max
137:279
89:402
Week 24 percent change from
baseline (%)
LS Mean (SE)
−6.6
(4.9)
−45.7
(3.5)
LS mean difference (SE) vs placebo
−39.1
(6.0)
95% CI
(−51.1 to −27.1)
p-value vs placebo
<0.0001*
Note:
Least-squares (LS) means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis. The model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, treatment-by-time point and strata-by-time point interaction, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline calculated LDL-C value-by-time point interaction
MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
The p-value is followed by a ‘*’ if statistically significant according to the fixed hierarchical approach used to ensure a strong control of the overall type-I error rate at the 0.05 level
TABLE 33
Calculated LDL-C over time - ITT analysis - ITT population
Placebo
Alirocumab 150 Q2W
(N = 35)
(N = 71)
Percent
Percent
Change
change
Change
change
from
from
from
from
Calculated LDL-C
Value
baseline
baseline
Value
baseline
baseline
LS Mean
(SE) (mmol/L)
Baseline a
5.205 (0.190)
NA
NA
5.083 (0.178)
NA
NA
Week 4
4.537 (0.221)
−0.586 (0.221)
−11.5 (4.1)
2.522 (0.154)
−2.601 (0.154)
−52.9 (2.8)
Week 8
4.435 (0.229)
−0.688 (0.229)
−12.4 (4.3)
2.647 (0.161)
−2.477 (0.161)
−48.6 (3.1)
Week 12
4.702 (0.234)
−0.422 (0.234)
−6.6 (4.6)
2.692 (0.164)
−2.432 (0.164)
−46.9 (3.2)
Week 16
4.779 (0.235)
−0.344 (0.235)
−6.1 (4.8)
2.633 (0.161)
−2.490 (0.161)
−48.0 (3.3)
Week 24
4.722 (0.246)
−0.401 (0.246)
−6.6 (4.9)
2.771 (0.174)
−2.352 (0.174)
−45.7 (3.5)
Week 36
4.666 (0.251)
−0.457 (0.251)
−8.9 (5.0)
2.832 (0.176)
−2.292 (0.176)
−44.0 (3.5)
Week 52
4.862 (0.275)
−0.262 (0.275)
−3.0 (5.9)
2.921 (0.197)
−2.202 (0.197)
−42.1 (4.2)
Week 78
1.2 (6.4)
−37.9 (4.5)
LS Mean
(SE) (mg/dL)
Baseline a
201.0 (7.3)
NA
NA
196.3 (6.9)
NA
NA
Week 4
175.2 (8.5)
−22.6 (8.5)
−11.5 (4.1)
97.4 (5.9)
−100.4 (5.9)
−52.9 (2.8)
Week 8
171.2 (8.8)
−26.6 (8.8)
−12.4 (4.3)
102.2 (6.2)
−95.6 (6.2)
−48.6 (3.1)
Week 12
181.5 (9.0)
−16.3 (9.0)
−6.6 (4.6)
103.9 (6.3)
−93.9 (6.3)
−46.9 (3.2)
Week 16
184.5 (9.1)
−13.3 (9.1)
−6.1 (4.8)
101.7 (6.2)
−96.1 (6.2)
−48.0 (3.3)
Week 24
182.3 (9.5)
−15.5 (9.5)
−6.6 (4.9)
107.0 (6.7)
−90.8 (6.7)
−45.7 (3.5)
Week 36
180.2 (9.7)
−17.7 (9.7)
−8.9 (5.0)
109.3 (6.8)
−88.5 (6.8)
−44.0 (3.5)
Week 52
187.7 (10.6)
−10.1 (10.6)
−3.0 (5.9)
112.8 (7.6)
−85.0 (7.6)
−42.1 (4.2)
a Baseline is described using means and standard errors.
Note:
Least-squares (LS) means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis. The model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of baseline LDL-C value and baseline LDL-C value-by-time point interaction
MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
Sensitivity Analysis of Primary Endpoint
TABLE 34
Percent change from baseline in calculated LDL-C
at Week 24: MMRM - ITT analysis - ITT population
excluding sites with serious GCP non compliance
Alirocumab
Placebo
150 Q2W
Calculated LDL Cholesterol
(N = 31)
(N = 62)
Baseline (mmol/L)
Number
31
62
Mean (SD)
5.310
(1.146)
5.101
(1.460)
Median
5.258
4.675
Min:Max
3.55:7.23
2.31:10.41
Baseline (mg/dL)
Number
31
62
Mean (SD)
205.0
(44.2)
197.0
(56.4)
Median
203.0
180.5
Min:Max
137:279
89:402
Week 24 percent change from
baseline (%)
LS Mean (SE)
−2.3
(4.7)
−50.3
(3.3)
LS mean difference (SE) vs placebo
−48.0
(5.8)
95% CI
(−59.4 to −36.6)
p-value vs placebo
<0.0001
Note:
Least-squares (LS) means, standard errors (SE) and p-value taken from MMRM (mixed-effect model with repeated measures) analysis. The model includes the fixed categorical effects of treatment group, randomization strata as per IVRS, time point, treatment-by-time point and strata-by-time point interaction, as well as the continuous fixed covariates of baseline calculated LDL-C value and baseline calculated LDL-C value-by-time point interaction
MMRM model and baseline description run on patients with a baseline value and a post-baseline value in at least one of the analysis windows used in the model.
The p-value is not adjusted for multiplicity and provided for descriptive purpose only
Note:
Sites No. 643-710 and No. 840-743 were excluded from analysis
Key Secondary Efficacy Endpoints
The following table summarizes analysis results on key secondary endpoints in the hierarchical order. All key secondary endpoints are statistically significant according to the hierarchical testing procedure up to Lp(a) endpoint at Week 24 (ITT estimand) included.
Statistically significance was not reached for HDL-C at Week 24 (ITT estimand) and therefore the testing procedure was stopped, p-values are provided from this endpoint for descriptive purpose only.
TABLE 35
Endpoint
Analysis
Results
P-value
Calculated LDL-C - Percent
On-treatment
LS mean difference vs.
<0.0001
change from baseline to Week
placebo of −38.9%
24
Calculated LDL-C - Percent
ITT
LS mean difference vs.
<0.0001
change from baseline to Week
placebo of −40.3%
12
Calculated LDL-C - Percent
On-treatment
LS mean difference vs.
<0.0001
change from baseline to Week
placebo of −40.3%
12
Apo-B - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −30.3%
Apo-B - Percent change from
On-treatment
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −30.2%
Non-HDL-C - Percent change
ITT
LS mean difference vs.
<0.0001
from baseline to Week 24
placebo of −35.8%
Non-HDL-C - Percent change
On-treatment
LS mean difference vs.
<0.0001
from baseline to Week 24
placebo of −35.5%
Total-C - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 24
placebo of −28.4%
Apo-B - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 12
placebo of −30.2%
Non-HDL-C - Percent change
ITT
LS mean difference vs.
<0.0001
from baseline to Week 12
placebo of −34.5%
Total-C - Percent change from
ITT
LS mean difference vs.
<0.0001
baseline to Week 12
placebo of −27.8%
Calculated LDL-C - Percent
ITT
LS mean difference vs.
<0.0001
change from baseline to Week
placebo of −39.1%
52
Proportion of very high CV
ITT
combined estimate for odds-
0.0016
risk patients reaching
ratio vs. placebo of 11.7
calculated LDL-C <70
mg/dL (1.81 mmol/L) or high
CV risk patients reaching
calculated LDL-C <100
mg/dL (2.59 mmol/L) at
Week 24
Proportion of very high CV
On-treatment
combined estimate for odds-
0.0014
risk patients reaching
ratio vs. placebo of 11.9
calculated LDL-C <70
mg/dL (1.81 mmol/L) or high
CV risk patients reaching
calculated LDL-C <100
mg/dL (2.59 mmol/L) at
Week 24
Lp(a) - Percent change from
ITT
combined estimate for adjusted
0.0164
baseline to Week 24
mean difference vs. placebo
of −14.8%
HDL-C - Percent change from
ITT
LS mean difference vs. placebo
0.2745
baseline to Week 24
of 3.7%
Fasting TGs - Percent change
ITT
combined estimate for adjusted
0.1386
from baseline to Week 24
mean difference vs. placebo
of −8.7%
The on-treatment analysis of the LDL-C percent change from baseline to Week 24 shows very consistent results with the ITT analysis (LS mean difference vs. placebo of −38.9% in the on-treatment analysis versus −39.1% in the ITT analysis). Indeed, only 3 patients (2 in placebo and 1 in alirocumab) had LDL-C values collected post-treatment (ie more than 21 days after last injection) at Week 24.
The key secondary endpoints including Apo B, non-HDL-C, Total-C, Lp(a) at various time points as well as the proportion of patients reaching their LDL-C goals at Week 24 were statistically significant according to the hierarchical testing procedure. Significant reductions were seen in non-HDL-C, Apo B, and Lp(a) levels at Week 24. The alirocumab vs placebo LS mean percent change from baseline to week 24 was −41.9 vs −6.2 for non-HDL-C (p value<0.0001), −39.0 vs −8.7 for Apo B (p value<0.0001), and −23.5 vs −8.7 for Lp(a) (p value=0.0164).
The proportion of very high cardiovascular (CV) risk patients reaching calculated LDL-C<70 mg/dL (1.81 mmol/L) or high CV risk patients reaching calculated LDL-C<100 mg/dL (2.59 mmol/L) at Week 24 was significantly higher in the alirocumab than in the placebo group (combined estimate for proportion of 41.0% in the alirocumab group vs 5.7% in the placebo group, p=0.0016).
Analyses performed with on-treatment approach were consistent with these analyses.
The differences in percent change in HDL-C and fasting TGs from baseline to Week 24 in the ITT analysis were non-statistically significant: HDL-C at Week 24: LS mean versus baseline was +7.5% in the alirocumab group and +3.9% in the placebo group (LS mean difference vs. placebo of +3.7%, p=0.2745); and Fasting TGs at Week 24: LS mean versus baseline was −10.5% in the alirocumab group and −1.1% in the placebo group (LS mean difference vs. placebo of −9.4%, p=0.1299).
Four (5.6%) patients experienced two consecutive calculated LDL-C values<25 mg/dL. No particular safety concern has been observed in these patients.
Summary Safety Results:
The proportion of patients who experienced a treatment emergent adverse event (TEAE) was lower in the alirocumab group (61.1%) compared to placebo group (71.4%) in the present study. The proportion of patients who experienced a serious TEAE was similar between treatment groups. A similar proportion of patients experienced TEAEs leading to treatment discontinuation (1 patient (2.9%) and 3 patients (4.2%) in the placebo and alirocumab groups, respectively). These results are consistent with the proportion of patients who have experienced TEAEs in previous alirocumab Phase 2/3 placebo-controlled studies (results from 2476 and 1276 patients in the alirocumab and placebo groups, respectively). Specifically, in this study TEAEs were 75.8% vs 76.4%, treatment-emergent SAEs were 13.7% vs 14.3%, TEAEs leading to death were 0.5% vs 0.9%, and TEAEs leading to discontinuation were 5.3% vs 5.1%, for alirocumab vs. placebo groups, respectively.
The most frequently reported SOC (and PT) in both treatment groups of the present study were: “infections and infestations”: 40.3% in the alirocumab group vs 34.3% in the placebo group (with influenza reported in 11.1% vs 2.9% and urinary tract infection in 6.9% vs 0 in alirocumab vs placebo group respectively); “cardiac disorders”: 12.5% in the alirocumab group vs no case in the placebo group. Among the events sent to adjudication, events were confirmed for 6 patients presenting: 4 MI, 1 heart failure requiring hospitalization and 5 ischemia driven coronary revascularization procedures; “nervous system disorders”: 11.1% in the alirocumab group vs 8.6% in the placebo group (with headache reported in 5.6% vs 0 and dizziness 4.2% vs 0 in alirocumab vs placebo group respectively); and “musculoskeletal and connective tissue disorders”: 16.7% in the alirocumab group vs 28.6% in the placebo group. No death was reported during the study in either group.
SAEs were reported by 11.1% patients in the alirocumab group and 11.4% in the placebo group. There is no particular clinical pattern among SAEs preferred terms which were individually reported. The most frequently reported SOC (system organ class) for SAEs is “cardiac disorders”.
Seven patients, 6 (8.3%) in the alirocumab group and 1 (2.9%) in the placebo group experienced a treatment-emergent local injection site reaction. These events were of mild intensity except one of moderate intensity. Two patients, one (1.4%) in the alirocumab group and one (2.9%) in the placebo group experienced neurocognitive disorders. Four patients, three (4.2%) in the alirocumab group and one (2.9%) in the placebo group experienced ALT>3×ULN. Two patients out of 71 analysed (2.8%, in comparison to 0 patients in the placebo group) experienced a creatine kinase level>3×ULN. None of the events were serious or led to treatment discontinuation. TEAEs occurring in alirocumab and placebo patient groups were collected until the last patient visit at Week 52 and are categorized in Table 36.
TABLE 36
TEAE safety analysis through week 52.
% (n) of patients
All patients on background of
Alirocumab
maximally tolerated statin ±
Placebo
150 Q2W
other LLT
(N = 35)
(N = 72)
Nasopharyngitis
11.4% (4)
11.1% (8)
Influenza
2.9% (1)
11.1% (8)
Injection-site reaction
2.9% (1)
8.3% (6)
Urinary tract infection
0
6.9% (5)
Diarrhea
8.6% (3)
5.6% (4)
Sinusitis
5.7% (2)
5.6% (4)
Bronchitis
2.9% (1)
5.6% (4)
Headache
0
5.6% (4)
Fatigue
0
5.6% (4)
Myalgia
8.6% (3)
4.2% (3)
Nausea
5.7% (2)
1.4% (1)
Vertigo
5.7% (2)
1.4% (1)
Dyspepsia
5.7% (2)
0
Increased Blood Uric Acid
5.7% (2)
0
Rheumatoid arthritis
5.7% (2)
0
Among the events of interest no particular signal was detected for TEAE related to neurological events, general allergic events and diabetes.
No relevant abnormality for PCSA was observed.
The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.
Conclusion:
The following conclusions regarding patients with HeFH and high baseline levels of LDL-C despite maximally tolerated statin with or without another LLT can be drawn from the ODYSSEY HIGH FH study: 1) self-administered alirocumab produced significantly greater LDL-C reductions vs. placebo after 24 weeks, with absolute mean decreasing from baseline in LDL-C was −90.8 mg/dL at Week 24 with alirocumab versus −15.5 mg/dL with placebo, and resultant LDL-C levels of 107 mg/dL with alirocumab at Week 24 versus 182 mg/dL with placebo; 2) 32% of alirocumab patients reached LDL-C<70 mg/dL despite baseline LDL-C>190 mg/dL; 3) 57% of alirocumab patients achieved LDL-C<100 mg/dL at Week 24; 4) alirocumab was generally well tolerated and TEAEs occurred in a similar frequency in the alirocumab and placebo arms.
Example 5: Efficacy and Safety of the PCSK9 Monoclonal Antibody Alirocumab Vs Placebo in 1254 Patients with Heterozygous Familial Hypercholesterolemia (HeFH): Analyses Up to 78 Weeks from Four ODYSSEY Trials
Background:
Previous studies have shown that only ˜20% of heterozygous familial hypercholesterolemia (HeFH) patients treated with lipid-lowering therapies (LLTs) achieved pre-defined LDL-C target levels of ≤2.5 mmol/L [97 mg/dL]. The efficacy and safety of alirocumab vs placebo was studied in 1254 HeFH pts on maximally-tolerated statin±other LLT from four, 18-month, placebo-controlled ODYSSEY trials (FHI, FHII, HIGH FH, LONG TERM). This represents the single largest collection of patients with HeFH studied in a Phase 3 clinical trials program. A description of the LONG TERM study is set forth in Robinson et al., (2015) NEJM 372:16 pg 1489-99, which is incorporated by reference herein in its entirety.
Methods:
Data were pooled by initial alirocumab dose. In FH I/II, patients with LDL-C levels≥1.81/2.59 mmol/L [70/100 mg/dL], depending on CV risk, received placebo (N=244) or alirocumab 75 mg Q2W (N=488); the alirocumab dose was increased to 150 mg Q2W at week 12 if LDL-C at week 8≥1.81 mmol/L [70 mg/dL] (41.8% of patients). Separately, data was pooled from HIGH FH (LDL-C≥4.14 mmol/L [160 mg/dL]) and the subset of patients with HeFH from LONG TERM (LDL-C≥1.81 mmol/L [70 mg/dL]), where patients received placebo (N=180) or alirocumab 150 mg Q2W (N=342). All doses were 1-mL subcutaneous (SC) injections. Data for change in LDL-C from baseline was pooled through week 52.
Results:
Baseline LDL-C levels and changes from baseline with treatment are shown in Table 37. Compared to placebo, alirocumab reduced LDL-C by 49% and 61% (p<0.0001) at week 12 for the 75 and 150 mg Q2W doses, respectively. At week 24, LDL-C reductions with alirocumab vs placebo were 56% (alirocumab 75 mg Q2W with a possible week 12 dose increase) and 59% (alirocumab 150 mg Q2W), respectively (p<0.0001). For both dose regimens, despite high baseline LDL-C levels, LS mean LDL-C levels of ˜2 mmol/L [77 mg/dL] were achieved by week 12 (Table 37), with reductions maintained through Week 52. Additional beneficial effects were observed in other parameters including non-HDL-C and Apo B.
In the individual studies to date, generally similar rates of treatment-emergent adverse events (TEAEs) were observed in alirocumab and placebo-treated patients. Across placebo-controlled studies in the ODYSSEY Program (patients both with and without HeFH), TEAEs (preferred terms) reported in ≥5% of alirocumab or placebo patients include nasopharyngitis (11.3% and 11.1% of alirocumab and placebo-treated patients, respectively), upper respiratory tract infection (URI) (6.1% vs 7.0%), injection site reaction (6.7% vs 4.8%), influenza (5.7% vs 4.6%), headache (4.8% vs 5.2%) and arthralgia (4.0% vs 5.5%).
TABLE 37
Least-squares (LS) mean (SE) calculated LDL-C at week 12 (W12), week 24
(W24) and week 52 (W52) (intent-to-treat analyses)
Change
%
Change
%
%
Calculated
from
change
Calculated
from
change
difference
LDL-C,
baseline,
from
LDL-C,
baseline,
from
versus
mmol/L
mmol/L
baseline
mmol/L
mmol/L
baseline
placebo
Pool of FHI
and FHII
studies†
Placebo (N = 244)
Alirocumab 75/150 mg Q2W (N = 488)
Baseline,
3.65 (0.08)
—
—
3.66 (0.06)
—
—
—
mean (SE)
W12
3.80 (0.06)
0.14 (0.06)
5.4 (1.6)
2.04 (0.04)
−1.62 (0.04)
−43.6 (1.1)*
−49.0 (1.9)*
W24
3.86 (0.07)
0.21 (0.07)
7.1 (1.7)
1.82 (0.05)
−1.84 (0.05)
−48.8 (1.2)*
−55.8 (2.1)*
W52
3.90 (0.07)
0.25 (0.07)
8.8 (2.0)
1.85 (0.05)
−1.81 (0.05)
−48.2 (1.5)*
−57.0 (2.5)*
Pool of
LONG TERM
(HeFH
patients
only) and
HIGH FH‡
Placebo (N = 180)
Alirocumab 150 mg Q2W (N = 342)
Baseline,
3.99 (0.11)
—
—
4.16 (0.09)
—
—
—
mean (SE)
W12
4.03 (0.08)
−0.07 (0.08)
1.9 (1.7)
1.75 (0.06)
−2.35 (0.06)
−58.8 (1.3)*
−60.7 (2.1)*
W24
4.03 (0.08)
−0.07 (0.08)
2.6 (1.9)
1.86 (0.06)
−2.24 (0.06)
−56.3 (1.4)*
−58.9 (2.4)*
W52
4.19 (0.10)
0.09 (0.10)
6.2 (2.5)
1.94 (0.07)
−2.16 (0.07)
−53.4 (1.8)*
−59.6 (3.1)*
†alirocumab dose 75 mg Q2W, increasing to 150 mg Q2W at W12 if LDL-C at W8 ≥ 1.81 mmol/L;
‡alirocumab dose 150 mg Q2W; *p < 0.0001 vs placebo
Conclusions:
In this large cohort of 1254 pts with HeFH, alirocumab reduced mean LDL-C levels to <2 mmol/L [77 mg/dL] at week 24-52 of treatment, levels hitherto unobtainable with current LLTs.
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16707492
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sanofi biotechnology
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USA
|
B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
|
Open
|
|
|
Apr 20th, 2022 02:27PM
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Apr 20th, 2022 02:27PM
|
Sanofi
|
Health Care
|
Pharmaceuticals & Biotechnology
|
|
nyse:sny
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Sanofi
|
Apr 19th, 2022 12:00AM
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Jun 23rd, 2016 12:00AM
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https://www.uspto.gov?id=US11305005-20220419
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Methods of use of influenza vaccine for prevention of pneumonia
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This application relates to the field of prevention of pneumonia by administration of a high-dose influenza vaccine.
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11305005
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1. A method for preventing pneumonia in a subject comprising: (a) identifying a subject at risk of serious pneumonia; and (b) administering an influenza vaccine to the subject, wherein the dose of influenza vaccine administered to the subject is higher than a standard-dose influenza vaccine, wherein the vaccine is administered for active immunization against pneumonia in the subject, wherein the pneumonia is caused by a virus, bacterium, or fungus, and wherein the pneumonia is serious pneumonia.
2. A method of preventing pneumonia in a subject comprising: (a) identifying a subject at risk of serious pneumonia; and (b) administering an influenza vaccine to the subject, wherein (i) the content of one or more influenza protein(s) in the influenza vaccine is higher than the content of the influenza protein(s) in a standard-dose influenza vaccine, wherein said influenza protein(s) are selected from HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and NP; and/or (ii) the influenza vaccine provides more antigen to the subject as compared to a standard-dose influenza vaccine, wherein the antigen is one or more of HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and NP, wherein the pneumonia is caused by a virus, bacterium, or fungus, and wherein the pneumonia is serious pneumonia.
3. The method of claim 1, wherein the pneumonia is caused by a virus selected from influenza virus, respiratory syncytial virus (RSV), metapneumovirus, adenovirus, rhinovirus, coronavirus varicella-zoster virus, and parainfluenza virus; the pneumonia is caused by a bacterium selected from Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitides, Mycoplasma pneumonia, Haemophilus influenae, Legionella pneumonia, Legionella spp., Chlamydia spp., including Chlamydia pneumonia and Chlamydia psittaci, Moraxella spp., including Moraxella catarrhalis, Streptococcus pyogenes, including Streptococcus pyogenes Pseudomonas aeruginosa, gram-negative enteric bacilli, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, Haemophilus parainfluenae, Haemophilus parahaemolyticus, Pseudomonas alcaligenes, Citrobacter freundii, Staphylococcus haemolyticus, Clostridium perfringens, anaerobes, including Fusobacterium sp., Prevotella sp., Gemella morbillorum, Peptostreptococcus prevotii, Veillonella sp., Nocardia sp., coagulase-negative Staphylococci, and Acinetobacter baumannii; the pneumonia is caused by a fungus associated with at least one of histoplasmosis, coccidioidomycosis, blastomycosis, pneumocystis pneumonia, sporotrichosis, cryptococcosis, aspergillosis, candidiasis, or scedoporiosis; the pneumonia is caused by a virus and a bacterium; or the pneumonia is caused by infection with influenza virus.
4. The method of claim 1, wherein the pneumonia is a community-acquired pneumonia (CAP).
5. The method of claim 1, wherein the pneumonia is a healthcare-associated pneumonia.
6. The method of claim 1, wherein the pneumonia is not preceded by influenza.
7. The method of claim 3, wherein the pneumonia is preceded by, or concurrent with influenza.
8. The method of claim 2, wherein the vaccine administered to the subject has a haemagglutinin (HA) content that is higher than the HA content of a standard-dose influenza vaccine, and/or the vaccine administered to the subject has a neuraminidase (NA) content that is higher than the NA content of a standard-dose influenza vaccine.
9. The method of claim 1, wherein the vaccine administered to the subject is a trivalent vaccine or a quadrivalent vaccine.
10. The method of claim 1, wherein the vaccine administered to the subject is produced in avian eggs, is made by recombinant DNA techniques, is inactivated or live attenuated, and/or is administered intradermally, intramuscularly, or intranasally.
11. The method of claim 1, wherein the vaccine administered to the subject contains adjuvant.
12. The method of claim 2, wherein the vaccine administered to the subject is a reformulated version of a vaccine selected from Fluzone (Trivalent or Quadrivalent; Sanofi Pasteur), Fluarix (Trivalent or Quadrivalent; intradermal; GlaxoSmithKline), FluLaval (Trivalent or Quadrivalent; ID Biomedical Corporation of Quebec; distributed by GlaxoSmithKline), Alfluria (bioCSL), Fluvirin (Novartis Vaccines and Diagnostics), Flucelvax (Novartis Vaccines and Diagnostics), FluMist (MedImmune), and FluBlok (Protein Sciences), wherein the reformulated vaccine has a higher dose than the standard dose version.
13. The method of claim 2, wherein the HA content of the vaccine administered to the subject is higher than about 15, 20, 24, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 micrograms of HA per strain per dose.
14. The method of claim 2, wherein the vaccine administered to the subject is formulated to have a higher HA content than the HA content of a standard-dose vaccine.
15. The method of claim 2, wherein the vaccine administered to the subject is formulated to have a higher NA content than the NA content of a standard-dose vaccine.
16. The method of claim 1, wherein the subject is about 65 years of age or older or the subject is a child that is about 18 years of age or younger.
17. The method of claim 1, wherein the subject is an adult that is about 18 years of age or older and younger than about 65 years of age.
18. The method of claim 1, wherein the subject is immune-compromised, the subject is a pregnant woman, the subject has or had asthma, diabetes, heart disease, HIV, AIDS, or cancer, and/or the subject is younger than 5 years, 4 years, 3 years, 2 years, 1 year, or 6 months.
19. The method of claim 1 wherein the pneumonia is caused by a non-influenza pathogen.
20. A method for preventing pneumonia caused by a non-influenza pathogen in a subject comprising: (a) identifying a subject at risk of pneumonia; and (b) administering an influenza vaccine to the subject, wherein the dose of influenza vaccine administered to the subject is higher than a standard-dose influenza vaccine, wherein the vaccine is administered for active immunization against pneumonia in the subject, and wherein the pneumonia is caused by a non-influenza virus, bacterium, or fungus.
21. The method of claim 20, wherein the pneumonia is not preceded by or concurrent with influenza.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a national phase entry pursuant to 35 U.S.C. § 371 of International Application No. PCT/US2016/038963, filed Jun. 23, 2016, which claims the benefit of priority of U.S. Provisional Application No. 62/183,888, filed Jun. 24, 2015, all of which are incorporated by reference in their entirety for any purpose.
FIELD
This application relates to compositions and methods for preventing pneumonia.
INTRODUCTION AND SUMMARY
Pneumonia is an infection of one or both of a patient's lungs that can be caused by a number of different pathogens, including viruses, bacteria, and fungi. Symptoms of pneumonia include cough, chest pain, fever, and difficulty breathing. Serious complications of pneumonia can include respiratory failure, sepsis, and lung abscesses. When a patient develops pneumonia outside of a hospital without having had recent contact with a healthcare facility (like a hospital, long-term care facility, or dialysis center), it is termed community-acquired pneumonia (CAP). When a patient develops pneumonia following a stay in a healthcare facility, it is termed healthcare-associated pneumonia. The infectious agents that cause CAP and healthcare-associated pneumonia are often different.
Respiratory viruses are recognized as common causes of CAP, particularly among children and the elderly (see Pavia A T (2013) Infect Dis Clin North Am 27(1): 57-175). Additionally, respiratory viruses are an important cause of severe pneumonia and respiratory failure in immunocompromised patients. In patients with CAP, respiratory viruses can be the sole cause of viral pneumonia (i.e., primary viral pneumonia), can be present as a co-infection with a bacteria or another virus (i.e., viral-bacterial pneumonia or viral-viral pneumonia), or can act as predisposing factors to facilitate or worsen bacterial pneumonia.
Influenza virus can cause primary viral pneumonia or predispose a patient to bacterial pneumonia. Influenza is a common cause of pneumonia particularly among young children, the elderly, pregnant women, those with chronic health conditions, and those who live in a nursing home. Radiographic pneumonia can be confirmed in approximately 16%-55% of patients hospitalized for influenza. Patients with influenza who are admitted to the hospital are more likely to die or be admitted to the ICU if they also have pneumonia. The American Lung Association reports that flu and pneumonia was the ninth leading cause of death in the United States in 2010 and the seventh leading cause of death among individuals 65 years of age and older.
Many different types of bacteria can also cause pneumonia. The most common cause of bacterial pneumonia in adults is Streptococcus pneumoniae (pneumococcus). Available vaccines have decreased the prevalence of pneumococcal diseases, including pneumonia caused by Streptococcus pneumoniae (CDC: Pneumococcal vaccination).
The Centers for Disease Control estimates that one million people per year are hospitalized with pneumonia in the US, and approximately 50,000 people die from pneumonia (CDC: Pneumonia Prevention). Most hospitalizations and deaths from pneumonia in the US are in adults. Globally, pneumonia causes nearly one million deaths in children under 5 years of age, which is greater than that from any other infectious agent, including HIV infection, malaria, or tuberculosis. While certain vaccinations and preventative practices can decrease its risk, pneumonia remains a significant healthcare concern in the US and globally.
The inventors have discovered that when influenza vaccine is administered at a higher than normal dose, it can prevent pneumonia in addition to preventing influenza. In one embodiment, the influenza vaccine's effect on pneumonia is mediated directly through cross-pathogen immune responses. In another embodiment, the influenza vaccine's effect on pneumonia is mediated indirectly through alterations of the nasopharyngeal microbiome. In another embodiment, the influenza vaccine's effect on pneumonia is mediated through a combination of effects.
In one embodiment, the influenza vaccine exerts an effect on pneumonia protection that is independent from its prevention of influenza infection or its corresponding disease modulation. In other embodiments, the influenza vaccine elicits an immune response that prevents pneumonia caused by non-influenza pathogens, like, for example, Streptococcus pneumoniae.
In accordance with the description, methods for preventing pneumonia comprising administering an influenza vaccine or a component or components of an influenza vaccine are encompassed. In some embodiments, use of an influenza vaccine or a component or components of an influenza vaccine for preventing pneumonia is provided. In some embodiments, use of an influenza vaccine or a component or components of an influenza vaccine for the manufacture of a medicament for the prevention of pneumonia is provided. In some embodiments, an influenza vaccine or a component or components of an influenza vaccine for use in the prevention of pneumonia is provided.
In some embodiments, the dose of the influenza vaccine administered to a subject is higher than a standard dose influenza vaccine. In some embodiments, the subject is provided with a greater volume of a standard dose vaccine, thereby providing the subject with a higher dose. In other embodiments, the influenza vaccine is formulated to contain a higher dose. In other embodiments, the influenza vaccine has a higher neuraminidase (NA) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher haemagglutinin (HA) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher matrix 1 (M1) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher matrix 2 (M2) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher polymerase basic 1 (PB1) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher polymerase basic 2 (PB2) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher polymerase acidic (PA) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher non-structural 1 (NS1) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher non-structural 2 (NS2) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher nucleoprotein (NP) content when compared to standard dose vaccines. In other embodiments, the influenza vaccine has a higher amount of any combination of one or more of the influenza virus proteins HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and NP when compared to standard dose vaccines.
In some embodiments, the pneumonia is caused by a virus, bacteria, or fungi. In some embodiments, the pneumonia is caused by a virus selected from influenza virus, respiratory syncytial virus (RSV), metapneumovirus, adenovirus, rhinovirus, coronavirus varicella-zoster virus, and parainfluenza virus. In some embodiments, the pneumonia is caused by a bacteria selected from the group consisting of Streptococcus pneumonia, Staphylococcus aureus, Neisseria meningitides, Mycoplasma pneumonia, Haemophilus influenza, Legionella pneumonia, Legionella spp., Chlamydia spp., including Chlamydia pneumonia, and Chlamydia psittaci, Moraxella spp., including Moraxella catarrhalis, Streptococcus pyogenes, including Streptococcus pyogenes (Group A), Pseudomonas aeruginosa, gram-negative enteric bacilli, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, Haemophilus parainfluenzae, Haemophilus parahaeolyticus, Pseudomonas alcaligenes, Citrobacter freundii, Staphylococcu haemolyticus, Clostridium perfringens, anaerobes, including Fusobacterium sp., Prevotella sp., Gemella morbillorum, Peptostreptococcus prevotii, and Veillonella sp., nocardia sp., coagulase-negative Staphylococci, and Acinetobacter baumannii. In some embodiments, the pneumonia is caused by a fungus associated with at least one of histoplasmosis, coccidioidomycosis, blastomycosis, pneumocystis pneumonia, sporotrichosis, cryptococcosis, aspergillosis, candidiasis, and scedoporiosis. In some embodiments, the pneumonia is caused by a virus and a bacterium.
In some embodiments, the pneumonia is a community-acquired pneumonia (CAP). In some embodiments, the pneumonia is a healthcare-associated pneumonia.
In some embodiments, the pneumonia is caused by infection with influenza virus. In some embodiments, the pneumonia is not preceded by influenza. In some embodiments, the pneumonia is preceded by, or concurrent with influenza.
In some embodiments, the vaccine is administered to a subject at a dose that is higher than that in a standard-dose influenza vaccine. In some embodiments, the vaccine administered to a subject has a hemaeglutinin (HA) content that is higher than the HA content of a standard-dose influenza vaccine. In some embodiments, the vaccine administered to a subject has a neuraminidiase (NA) content that is higher than the NA content of a standard-dose influenza vaccine. In some embodiments, the vaccine administered to the subject has a content of one or more influenza proteins that is higher than the content in a standard-dose influenza vaccine, wherein said influenza protein(s) is selected from HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and NP.
In some embodiments, the influenza vaccine is a trivalent vaccine. In some embodiments, the influenza vaccine is a quadrivalent vaccine.
In some embodiments, the vaccine is produced in avian eggs. In some embodiments, the vaccine is not produced in avian eggs. In some embodiments, the vaccine is made by recombinant DNA techniques. In some embodiments, the vaccine is inactivated or live attenuated.
In some embodiments, the vaccine is administered intradermally, intramuscularly, or intranasally.
In some embodiments, the vaccine contains adjuvant. In some embodiments, the vaccine does not contain adjuvant.
In some embodiments, the vaccine is selected from Fluzone (Trivalent or Quadrivalent; Sanofi Pasteur), Fluarix (Trivalent or Quadrivalent; intradermal; GlaxoSmithKline), FluLaval (Trivalent or Quadrivalent; ID Biomedical Corporation of Quebec; distributed by GlaxoSmithKline), Alfluria (bioCSL), Fluvirin (Novartis Vaccines and Diagnostics), Flucelvax (Novartis Vaccines and Diagnostics), FluMist (MedImmune), and FluBlok (Protein Sciences). In some embodiments, the vaccine is a reformulated version of a vaccine selected from the group consisting of Fluzone (Trivalent or Quadrivalent; Sanofi Pasteur), Fluarix (Trivalent or Quadrivalent; intradermal; GlaxoSmithKline), FluLaval (Trivalent or Quadrivalent; ID Biomedical Corporation of Quebec; distributed by GlaxoSmithKline), Alfluria (bioCSL), Fluvirin (Novartis Vaccines and Diagnostics), Flucelvax (Novartis Vaccines and Diagnostics), FluMist (MedImmune), and FluBlok (Protein Sciences), wherein the reformulated vaccine has a higher dose than the standard dose version.
In some embodiments, the influenza vaccine is marketed as a high-dose influenza vaccine.
In some embodiments, a dose is considered high if the dose provided to the subject for prevention of pneumonia is increased as compared to the dose in a standard-dose influenza vaccine.
In some embodiments, the vaccine is Fluzone High-Dose, which contains 60 micrograms HA per strain per dose (0.5 mL).
In some embodiments, the vaccine is an inactivated or recombinant vaccine.
In some embodiments, the vaccine has an HA content that is higher than 15 micrograms of HA per strain per each 0.5 mL. In some embodiments, the vaccine is higher than about 15, 20, 24, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 micrograms of HA per strain for each 0.5 mL.
In some embodiments, the vaccine is similar to Fluzone ID except that its HA content is higher than about 9, 10, 15, 20, 24, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 micrograms of HA per strain for each 0.1 mL. In some embodiments, the vaccine is similar to Flublok except that its HA content is higher than about 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 micrograms of HA per strain for each 0.5 mL. In some embodiments, the vaccine that is administered to a subject for the prevention of influenza is formulated to have a higher HA content than the HA content of a standard dose vaccine. In some embodiments, the vaccine that is administered to a subject for the prevention of influenza is formulated to have a higher NA content than the NA content of a standard dose vaccine.
In some embodiments, the vaccine is a live-attenuated vaccine.
In some embodiments, the vaccine is similar to Flumist except that it contains more than about 106.5-107.5 FFU (fluorescent focus units) of live attenuated influenza virus reassortants.
In some embodiments, the subject is elderly. In some embodiments, the subject is older than about 65 years. In some embodiments, the subject is an adult that is older than about 18 years and younger than about 65 years. In some embodiments, the subject is a child that is younger than about 18 years. In some embodiments, the subject is younger than 5 years, 4 years, 3 years, 2 years, 1 year, or 6 months. In some embodiments, the subject is immune-compromised. In some embodiments, the subject is a pregnant woman.
In some embodiments, the subject has asthma, diabetes, heart disease, HIV, AIDS, or cancer. In some embodiments, the subject had asthma, diabetes, heart disease, HIV, AIDS, or cancer.
In some embodiments, the subject is non-human. In some embodiments, the subject is a horse, poultry, pig, dog, or cat.
Headings are provided in this description for organizational purposes and as an aid to the reader only and are not to be construed as limiting the disclosure in any way.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the trial design of the FIM12 study. FIM12 compared two influenza vaccines, standard-dose inactivated influenza vaccine IIV-SD (Fluzone®) and high-dose inactivated influenza vaccine IIV-HD (Fluzone High-Dose), over two influenza seasons. This randomized-controlled trial (RCT) enrolled patients 65 years of age or older.
FIGS. 2A and 2B shows the comparison of risk ratio for pneumonia within 30 days of respiratory illness (Pneumonia 30D, FIG. 2A) and serious pneumonia (FIG. 2B) in Trial FIM12 for IIV-SD (labeled as Fluzone®) and IIV-HD (labeled as Fluzone® High-Dose). Analysis was done by year (Y1=year 1; Y2=year 2), and total data for both years are also shown. Heterogeneity is a test of whether the risk ratios are the same in Y1 and Y2; for both pneumonia 30D and serious pneumonia the p-values do not indicate statistically significant differences between the years in this respect, and one therefore concludes there is no strong evidence for a difference in the effect in the two years. CI=confidence interval; M-H=Mantel-Haenszel.
FIG. 3 shows the relative vaccine efficacy of IIV-HD against pneumonia relative to IIV-SD. Pneumonia classification were pneumonia occurring within 30 days of lab-confirmed influenza, pneumonia occurring with 30 days of respiratory illness (RI) regardless of influenza confirmation, and serious pneumonia regardless of influenza confirmation. Efficacy data are presented as (95% confidence interval).
FIG. 4 presents pneumococcus vaccination rates prior to FIM12 randomization and during the trial for IIV-HD and IIV-SD for Y1, Y2, and combined (Y1+Y2).
FIG. 5 presents data on the number of serious pneumonia events and the rate of these events following vaccination with IIV-HD or IIV-SD based on the timing of events in relation to the defined level of influenza incidence for the week based on the number of laboratory-confirmed influenza illness observed in the trial. The categories of high, moderate, and low influenza incidence are described in the footnotes.
FIG. 6 presents rates of all-cause hospitalization and serious cardio-respiratory events possibly related to influenza within the intent-to-treat population for IIV-HD and IIV-SD for Y1, Y2, and combined (Y1+Y2) combined analysis.
FIG. 7 presents the relative vaccine effectiveness (rVE) of IIV-HD compared with IIV-SD in preventing all-cause hospitalization and serious cardio-respiratory events possibly related to influenza within the intent-to-treat population for Y1, Y2, and combined (Y1+Y2) analysis.
FIG. 8 shows the rate ratios (IIV-HD/IIV-SD) for all-cause hospitalization and serious cardio-respiratory events possibly related to influenza (intent-to-treat analysis). Each horizontal line represents the 95% confidence interval of the rate ratio for each comparison, with the center being the corresponding point estimate. The vertical line represents the null value of 1. Horizontal lines that do not intersect with the vertical line are statistically significant. Point estimates to the left of vertical line favor IIV-HD, and those to the right favor IIV-SD. “Influenza Events” refer to serious laboratory-confirmed influenza diagnosed outside study procedures by a participant's health-care provider.
FIG. 9 shows the etiology of the “Serious Pneumonia” narrated in the FIM12 study, based on SAE narratives. Note that for one event, S. pneumonia was isolated from blood cultures, and respiratory cultures revealed E. coli, Pseudomonas, and Group C streptococci (only S. pneumonia counted in the table for this event).
DESCRIPTION OF CERTAIN EMBODIMENTS
Influenza Vaccine for Preventing Pneumonia
The invention comprises vaccine compositions useful in preventing influenza and pneumonia, regardless of the cause of pneumonia.
In one embodiment, a method of preventing pneumonia in a subject comprising administering an influenza vaccine to a subject, wherein the dose of the influenza vaccine is higher than a standard dose influenza vaccine, is encompassed. In one embodiment, use of an influenza vaccine for preventing pneumonia in a subject, wherein the dose of the influenza vaccine is higher than a standard dose influenza vaccine, is encompassed. In one embodiment, use of an influenza vaccine for the manufacture of a medicament for preventing pneumonia in a subject, wherein the dose of the influenza vaccine is higher than a standard dose influenza vaccine, is encompassed. In one embodiment, an influenza vaccine for use in preventing pneumonia in a subject, wherein the dose of the influenza vaccine is higher than a standard dose influenza vaccine, is encompassed.
In one embodiment, a method of preventing pneumonia in a subject comprising administering an influenza vaccine to a subject, wherein the influenza vaccine provides the subject with a higher level of antigen than a standard dose influenza vaccine, is encompassed. In one embodiment, use of an influenza vaccine for preventing pneumonia in a subject, wherein the influenza vaccine provides the subject with a higher level of antigen than a standard dose influenza vaccine, is encompassed. In one embodiment, use of an influenza vaccine for the manufacture of a medicament for preventing pneumonia in a subject, wherein the influenza vaccine provides the subject with a higher level of antigen than a standard dose influenza vaccine, is encompassed. In one embodiment, an influenza vaccine for use in preventing pneumonia in a subject, wherein the influenza vaccine provides the subject with a higher level of antigen than a standard dose influenza vaccine, is encompassed.
In other embodiments, methods of preventing pneumonia in a subject comprising administering an influenza vaccine to a subject, wherein the neuraminidase (NA) content of the influenza vaccine is higher than the NA content of a standard dose influenza vaccine is encompassed. In one embodiment, use of an influenza vaccine for preventing pneumonia in a subject, wherein the NA content of the influenza vaccine is higher than the NA content of a standard dose influenza vaccine, is encompassed. In one embodiment, use of an influenza vaccine for the manufacture of a medicament for preventing pneumonia in a subject, wherein the NA content of the influenza vaccine is higher than the NA content of a standard dose influenza vaccine, is encompassed. In one embodiment, an influenza vaccine for use in preventing pneumonia in a subject, wherein the NA content of the influenza vaccine is higher than the NA content of a standard dose influenza vaccine, is encompassed.
In other embodiments, a method of preventing pneumonia in a subject comprising administering an influenza vaccine to a subject, wherein the haemagglutinin (HA) content of the influenza vaccine is higher than the HA content of a standard dose influenza, is encompassed. In one embodiment, use of an influenza vaccine for preventing pneumonia in a subject, wherein the HA content of the influenza vaccine is higher than the HA content of a standard dose influenza vaccine, is encompassed. In one embodiment, use of an influenza vaccine for the manufacture of a medicament for preventing pneumonia in a subject, wherein the HA content of the influenza vaccine is higher than the HA content of a standard dose influenza vaccine, is encompassed. In one embodiment, an influenza vaccine for use in preventing pneumonia in a subject, wherein the HA content of the influenza vaccine is higher than the HA content of a standard dose influenza vaccine, is encompassed.
The description below applies to the methods, uses, and products disclosed herein. Terms such as “administering,” e.g., with respect to doses, particular subjects, etc., encompass products and uses of products “to be administered” at the indicated doses and/or to the indicated subjects, etc.
In other embodiments, the influenza vaccine has a higher amount of one or more of the influenza virus proteins (HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and/or NP) when compared to standard dose vaccines.
Types of Pneumonia
In one embodiment the pneumonia is caused by a virus, bacteria, or fungi. In the case of viral pneumonia, the virus may be any virus known to cause pneumonia, including an influenza virus, a respiratory syncytial virus (RSV), a metapneumovirus, an adenovirus, a rhinovirus, a coronavirus, a varicella-zoster virus, and a parainfluenza virus.
In the case of bacterial pneumonia, the bacteria may be any bacteria known to cause pneumonia, including Streptococcus pneumonia, Staphylococcus aureus, Neisseria meningitides, Mycoplasma pneumonia, Haemophilus influenza, Legionella pneumonia, Legionella spp., Chlamydia spp., including Chlamydia pneumonia, and Chlamydia psittaci, Moraxella spp., including Moracella catarrhalis, Streptococcus pyogenes, including Streptococcus pyogenes (Group A), Pseudomonas aeruginosa, gram-negative enteric bacilli, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, Haemophilus parainfluenzae, Haemophilus parahaeolyticus, Pseudomonas alcaligenes, Citrobacter freundii, Staphylococcu haemolyticus, Clostridium perfringens, anaerobes, including Fusobacterium Prevotella sp., Gemella morbillorum, Peptostreptococcus prevotii, and Veillonella sp., nocardia sp., coagulase-negative Staphylococci, and Acinetobacter baumannii.
In the case of fungal pneumonia, the fungus may be any fungus known to cause pneumonia, including a fungus responsible for any of histoplasmosis, coccidioidomycosis, blastomycosis, pneumocystis pneumonia, sporotrichosis, cryptococcosis, aspergillosis, candidiasis, or scedoporiosis.
In some embodiments, the cause of the pneumonia is unknown. In other embodiments, the cause of the pneumonia is determined to be viral and bacterial.
In one embodiment the pneumonia is characterized as community-acquired pneumonia (CAP). In other embodiments the pneumonia is a healthcare-associated pneumonia, which is a pneumonia that develops following a stay in a healthcare facility, including a hospital, long-term care facility, or dialysis center.
In some embodiments, the pneumonia to be prevented by the methods, uses, and products of the invention is not preceded by influenza.
Influenza Vaccines
The influenza vaccine composition, as well as the influenza vaccine used in accordance with the invention, may be any influenza vaccine approved by a body that governs the type of vaccines that may be administered to the public. In certain embodiments, a high-dose vaccine contains high levels of one or more influenza protein(s) (HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and/or NP).
In one embodiment, the influenza vaccine is a trivalent vaccine. In another embodiment, the influenza is a quadrivalent vaccine.
The trivalent or quadrivalent vaccine may be produced in avian eggs or may be “egg-free” or “recombinant”.
The trivalent or quadrivalent vaccine may be inactivated or live attenuated.
The trivalent or quadrivalent vaccine may be administered intradermally, intramuscularly, or intranasally.
The trivalent or quadrivalent vaccine may be adjuvanted or non-adjuvanted.
The trivalent or quadravalent vaccine may be selected from the group consisting of Fluzone® (Trivalent or Quadrivalent; Sanofi Pastuer), Fluarix (Trivalent or Quadrivalent; intradermal; GlaxoSmithKline), FluLaval (Trivalent or Quadrivalent; ID Biomedical Corporation of Quebec; distributed by GlaxoSmithKline), Alfluria (bioCSL), Fluvirin (Novartis Vaccines and Diagnostics), Flucelvax (Novartis Vaccines and Diagnostics), FluMist (MedImmune), and FluBlok (Protein Sciences).
Dosages
In one embodiment, the influenza vaccine composition of the invention, as well as the influenza vaccine for use in accordance with the invention, are high-dose. A dose of an influenza vaccine is considered high if the amount of antigen provided to the subject is increased as compared to the amount of antigen in a standard dose influenza vaccine. The dose may be increased by administering a greater volume of a vaccine formulated in a standard dosage or by specifically formulating a higher dose vaccine.
Dosages are typically based on HA content. For example, the only high-dose influenza vaccine on the market as of the filing date is Fluzone High-Dose, which contains 60 micrograms HA per strain per dose (0.5 mL). All other currently approved influenza vaccines are considered standard dose. Fluzone High-Dose is contemplated for use in accordance with this invention.
For inactivated and recombinant vaccines (all vaccines named above except Flumist) the HA content is typically 15 micrograms of HA per strain for each 0.5 mL. Thus, in one embodiment, the influenza vaccine of this invention has an HA content that is higher than 15 micrograms of HA per strain per each 0.5 mL. In one embodiment, the influenza vaccine of the invention has an HA content that is higher than about 15, 20, 24, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 micrograms of HA per strain for each 0.5 mL.
Standard dose Fluzone ID has an HA content of about 9 micrograms per strain per dose (0.1 mL). For Fluzone ID to be used in the present invention, it must have an HA content that is higher than about 9, 10, 15, 20, 24, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 micrograms of HA per strain for each 0.1 mL.
Standard dose Flublok has an HA content of about 45 micrograms per strain per dose (0.5 mL). Despite the higher HA content as compared to other vaccines, Flublok is not considered a “high-dose” vaccine by the FDA because of the lack of comparative clinical trial data for it against standard-dose influenza vaccines. In one embodiment, Flublok is considered a high dose vaccine capable of being used in accordance with the invention. In other embodiments, for Flublok to be used in the present invention, it must have an HA content that is higher than about 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 micrograms of HA per strain for each 0.5 mL.
Thus, the standard dose vaccines described herein and known to those of skill in the art (those today marketed and those marketed in the future) may be used in accordance with the invention to prevent pneumonia as long as they are reformulated to have a higher HA content than the HA content of a standard-dose influenza vaccine.
Flumist is a live-attenuated vaccine that is administered intranasally. Each 0.2 mL dose of Flumist contains about 10E6.5-7.5 FFU (fluorescent focus units) of live attenuated influenza virus reassortants. For Flumist to be used in the present invention, it must have an FFU content that is higher than about 10E6.5-7.5 FFU per live attenuated influenza virus reassortants.
In some embodiments of the present invention, the influenza virus used in preventing pneumonia have an increased neuraminidase (NA) content as compared to a standard-dose influenza vaccine.
The NA content of the high-dose Fluzone® is also increased versus the standard-dose vaccine. An NA activity assay (optical density [O.D] obtained with a microplate reader assay) determined that the mean NA activity in standard dose influenza vaccine was 23,373. In comparison, the mean NA activity in the high-dose influenza vaccine was 179,454, representing approximately 7.7 times the NA activity in the standard dose influenza vaccine (Cate T R et al. Vaccine 2010; 28:2076-2079).
Thus, in one embodiment, the influenza vaccine of this invention has a NA content that is higher than the NA content of a standard dose influenza vaccine. In one embodiment, the influenza vaccine of the invention has a NA content that has an O.D. higher than about 23,000, 23,373, 23,500, 24,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, 100,000, 105,000, 110,000, 115,000, 120,000, 125,000, 130,000, 135,000, 140,000, 145,000, 150,000, 155,000, 160,000, 165,000, 170,000, and 175,000.
In some embodiments of the present invention, the influenza vaccine used in preventing pneumonia have an increased HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and/or NP content as compared to a standard dose vaccine.
Treatment Groups
Subjects to be treated by the methods, products, and uses of the invention include any subject capable of receiving an influenza vaccine. In one embodiment, the subject is considered elderly. An elderly human subject is older than about 65 years. In other embodiments, the subject is a healthy adult (older than 18 years), a healthy child (younger than 18 years), an immune-compromised adult or child, a pregnant woman, or an adult or child with asthma, diabetes, heart disease, HIV, AIDS, or cancer. The subject may also be a child younger than 5 years, 4 years, 3 years, 2 years, 1 year, and 6 months.
In other embodiments, the subjects to be treated by the methods, products, and uses of the invention are non-human, including horses, poultry, pigs, dogs, and cats.
Combination Therapy
The high-dose influenza vaccine used in accordance with the invention may be administered alone, or co-administered with at least one additional therapeutic or prophylactic agent. In one embodiment, the at least one additional therapeutic or prophylactic agent is a pneumonia vaccine. Thus, methods of preventing pneumonia, or methods of preventing pneumonia and influenza, comprising co-administering a high-dose influenza vaccine and a pneumonia vaccine are encompassed. Uses of a high-dose influenza vaccine and a pneumonia vaccine for preventing pneumonia, or preventing pneumonia and influenza, wherein the influenza vaccine and pneumonia vaccine are co-administered, are also encompassed. A high-dose influenza vaccine and a pneumonia vaccine for use in preventing pneumonia, or preventing pneumonia and influenza, wherein the influenza vaccine and pneumonia vaccine are co-administered, are also encompassed. Uses of a high-dose influenza vaccine and a pneumonia vaccine for the manufacture of a medicament for preventing pneumonia, or preventing pneumonia and influenza, wherein the influenza vaccine and pneumonia vaccine are co-administered, are also encompassed. The co-administration may be concurrent or sequential. The sequential administration may occur on the same day or on different days. As described herein, the high-dose influenza vaccine may contain more than one influenza protein including combinations of HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and/or NP, and any one or all of these proteins may be present at a higher level than in a standard-dose vaccine. Thus, in one embodiment the high-dose influenza vaccine used in accordance with the invention has high HA, NA, M1, M2, PB1, PB2, PA, NS1, NS2, and/or NP, and is given in combination with at least one additional therapeutic or prophylactic agent, such as a pneumonia vaccine.
EXAMPLES
Example 1. Efficacy of Vaccination with High-Dose Inactivated Influenza Vaccine Versus Standard Dose in Prevention of Pneumonia in Elderly Patients
A high-dose inactivated influenza vaccine (IIV-HD) has been shown to produce more robust antibody responses and improves protection against influenza illness compared to a standard-dose vaccine (IIV-SD) in elderly patients. In this study, IIV-HD was 24.2% more efficacious than IIV-SD in preventing laboratory-confirmed symptomatic influenza in elderly patients. (DiazGranados C A, et al. N Engl J Med (2014) 371 (7):635-645). Herein, IIV-HD was compared with IIV-SD in regards to the ability to decrease the risk of pneumonia, a common and dangerous sequelae or complication to influenza, and also a common and very burdensome infectious illness that can be caused by many other microorganisms in addition to influenza.
The FIM12 study was a double-blind, randomized, active-controlled, multicenter trial that enrolled adults≥65 years. Participants were randomized to receive either IIV-HD or IIV-SD and were followed for 6-8 months post-vaccination for the occurrence of influenza, pneumonia, and serious adverse events (SAEs). SAEs were defined as events leading to death or hospitalization (or its prolongation); considered as life-threatening or medically important; or resulting in disability. The trial was conducted during the 2011-2012 (Year 1) and 2012-2013 (Year 2) influenza seasons. The trial compared IIV-HD (containing 60 micrograms of hemagglutinin per vaccine strain, Fluzone® High-Dose) versus IIV-SD (containing 15 micrograms of hemagglutinin per vaccine strain, Fluzone®).
The FIM12 trial (NCT01427309) included 31,989 participants with 15,991 participants randomized to IIV-HD and 15,998 participants randomized to IIV-SD. The design of the FIM12 trial is presented in FIG. 1; note that the actual numbers of patients enrolled in the trial differ slightly from the projected design. Participants were vaccinated in September-October of each season (i.e., Year 1 and Year 2), and participants were followed for 6-8 months post-vaccination (until April 30th, which would be past the normal end of annual influenza season) for the occurrence of influenza, pneumonia, and SAEs.
Results
To determine whether IIV-HD protects against pneumonia, the number of pneumonia events occurring within 30 days of a respiratory illness (Pneumonia 30D) for Y1 and Y2 was evaluated, with results shown in FIG. 2A. In combined data from Y1 and Y2, there were 169 events of Pneumonia 30D in the IIV-HD (i.e., Fluzone® High-Dose) and 232 events in the IIV-SD (i.e., Fluzone®). These combined data indicated a relative risk of 0.72 for IIV-HD versus IIV-SD for pneumonia within 30 days of a respiratory illness. As shown in FIG. 3, this corresponds with a 27% relative vaccine efficacy/effectiveness (i.e., 27% reduction in relative risk) in preventing pneumonia within 30 days of a respiratory infection (labeled RI) for IIV-HD versus IIV-SD. Statistical analysis shown in FIG. 2A indicates that this reduction in pneumonia within 30 days of a respiratory infection was statistically significant for IIV-HD versus IIV-SD (P=0.05, test for overall effect). The significance of the finding is further confirmed by the confidence intervals of the vaccine effectiveness estimate (FIG. 3), which indicated a lower bound of the 95% confidence interval of 11%, well above the null value of 0.
The number of cases of serious pneumonia (irrespective of confirmed influenza infection) was also evaluated. Serious pneumonia was defined as events of pneumonia resulting in death or hospitalization, considered life-threatening or medically important, or resulting in disability. As shown in FIG. 2B, there were a total of 71 events of serious pneumonia in the IIV-HD group compared to 118 events in the IIV-SD group in combined data for Y1 and Y2. These combined data indicated a relative risk of 0.60 for IIV-HD versus IIV-SD for serious pneumonia. As shown in FIG. 3, this corresponded to a relative vaccine efficacy/effectiveness of 40% (i.e., 40% reduction in relative risk) of serious pneumonia for IIV-HD versus IIV-SD. Results shown in FIG. 2B indicate that the efficacy in preventing serious pneumonia was statistically significant for IIV-HD versus IIV-SD (P=0.0007, test for overall effect). The significance of the finding is further confirmed by the confidence intervals of the vaccine effectiveness estimate (FIG. 3), which indicated a lower bound of the 95% confidence interval of 19%, well above the null value of 0.
The relative reduction in pneumonia within 30 days of lab-confirmed influenza was also evaluated. As shown in FIG. 3, there was a 60% relative vaccine efficacy (i.e. reduction in relative risk) of IIV-HD versus IIV-SD for prevention of pneumonia within 30 days of lab-confirmed influenza. However, given the low number of cases, the estimate did not reach statistical significance.
The potential for pneumococcal vaccination rates to have impacted efficacy measurements of pneumonia prevention for IIV-HD versus IIV-SD was also evaluated, as pneumococcal vaccination is suggested for patients 65 years of age or older and can reduce the risk of pneumonia (see CDC: Prevention of Pneumonia). As shown in FIG. 4, vaccination rates for the IIV-HD and IIV-SD groups were essentially the same, indicating that differences in pneumococcal vaccination rates cannot explain the differences in efficacy/effectiveness in preventing pneumonia for IIV-HD versus IIV-SD.
The relative vaccine efficacy of IIV-HD versus IIV-SD was determined based on differences in the rate of incidence of influenza at the time when the pneumonia event occurred. The actual FIM12 study influenza incidence data was used to determine periods of high, moderate, and low incidence of influenza, as described in FIG. 5. Data confirmed that IIV-HD had greater relative vaccine efficacy compared with IIV-SD for periods of high, moderate, and low incidence. Therefore, the higher relative vaccine efficacy of IIV-HD versus IIV-SD was consistent during all incidence periods.
The data presented in FIGS. 1-5 indicated significant reductions in the incidence of pneumonia, including serious pneumonia, following vaccination with IIV-HD compared with IIV-SD. As data from the same trial indicated that IIV-HD was 24.2% more efficacious than IIV-SD in preventing laboratory-confirmed symptomatic influenza in elderly patients, the data on reduction of risk of pneumonia shown in FIGS. 2 and 3 support an unexpectedly large effect of IIV-HD to reduce pneumonia compared with IIV-SD. The efficacy of IIV-HD significantly reduced the risk of serious pneumonia (relative vaccine efficacy of 40%, see FIG. 3). These data support the use of high-dose influenza vaccine, including IIV-HD, to reduce the risk of pneumonia. These data also support the use of high-dose influenza vaccine, including IIV-HD, to reduce the risk of pneumonia in elderly patients who have increased risk of pneumonia and complications resulting from pneumonia.
The FIM12 study was characterized by intensive surveillance for detection of influenza respiratory illness. The study surveillance included active surveillance, by which a call-center called all study participants twice weekly (during periods of high influenza activity) or weekly (at other times during the influenza season) to inquire about the occurrence of any new or exacerbated respiratory illnesses. If a new or exacerbated illness was reported, the study sites were to collect a nasopharyngeal sample within 5 days of the illness start for influenza testing and detection. We therefore believe that the study had the appropriate design to detect most of the illnesses due to influenza infection occurring in the study participants. This provides an opportunity to evaluate how likely is to attribute the pneumonias reported during the study to influenza (directly as “influenza pneumonias” or indirectly as pneumonias complicating influenza illness). To evaluate this, we ascertained how many of the Pneumonia 30D and serious pneumonias reported in the study occurred within 30 days of laboratory-confirmed influenza. It turns out that only 14 of the 401 reported Pneumonia 30D (3.5%) occurred within 30 days after laboratory-confirmed influenza illness. For the Pneumonias 30D that occurred after a respiratory illness that was not confirmed to be influenza by laboratory methods, the relative vaccine efficacy/effectiveness was 26% and still statistically significant. Similarly and even more importantly, only 4 of the 189 reported Serious Pneumonias (2.1%) occurred within 30 days after laboratory-confirmed influenza illness (with 3 of these confirmations occurring outside of study procedures). For the Serious Pneumonias reported at any time during study surveillance that did not occurred within 30 days of laboratory-confirmed influenza, the relative vaccine efficacy/effectiveness was 38% and highly statistically significant. Therefore, the high-dose influenza vaccine is showing an effect in preventing pneumonia for pneumonias that cannot be classified as related to laboratory-confirmed influenza illness. This indicates that even if the study missed some laboratory-confirmed influenza infections, the high-dose influenza vaccine is very likely having an important preventive effect on pneumonia etiologies other than influenza.
Example 2. Reductions in Hospitalizations and Serious Adverse Events Following Administration of IIV-HD Versus IIV-SD
Based on results on the reduction in risk of pneumonia, the efficacy of IIV-HD versus IIV-SD was also determined for the potential to reduce all-cause hospitalization and serious cardio-respiratory events for the 6-8 month post-vaccination period of the trial (as described in FIG. 1). SAEs were defined as events that lead to death or hospitalization (or its prolongation); that are considered as life-threatening or medically important; or that result in disability. Based on available medical information, the diagnoses associated with all SAEs were reported.
As shown in FIG. 6, there were a total of 3,173 all-cause hospitalization events with a combined rate (events per 1,000 participant-seasons for Y1+Y2) of 95.68 for IIV-HD and 102.73 for IIV-SD. FIG. 7 shows the relative vaccine efficacy of IIV-HD versus IIV-SD for Y1, Y2, and combined data for all-cause hospitalization. Data indicated that while there was very little difference between the rates for Y1, there was a 13.6% relative vaccine efficacy for the all-cause hospitalization rates for IIV-HD versus IIV-SD in Y2. The greater relative vaccine efficacy seen in Y2 may be due to the higher influenza virulence and the greater mismatch between the strains in the vaccine in Y2 versus the predominant circulating strains in that influenza season (as previously discussed in DiazGranados 2014).
Serious adverse events were also assessed in the FIM12 trial. A total of 1,347 SAE preferred terms in the trial for Y1 and Y2 were independently reviewed by two physicians (blinded to the participant's treatment group) using the Medical Dictionary for Regulatory Activities versions 14.0 (for Year 1) and 15.0 (for Year 2) (see Brown E G, et al. (1999) Drug Saf 20(2):109-17). A total of 948 serious cardio-respiratory events were adjudicated as possibly related to influenza. Rates of serious cardio-respiratory events for IIV-HD and IIV-SD are shown in FIG. 6; note that the data on serious pneumonia events were also presented in FIG. 3. The rates of influenza in FIG. 6 correspond to serious laboratory-confirmed influenza diagnosed outside study procedures by a participant's health-care provider; therefore, these are different values than those that were used to determine efficacy of the vaccine.
The relative vaccine efficacy (rVE) to reduce serious cardio-respiratory events of IIV-HD compared with IIV-SD is shown in FIG. 7. Rates of serious cardio-respiratory events were lower for IIV-HD than for IIV-SD in both Y1 and Y2 for the events of pneumonia, other selected respiratory events, and heart failure, as evidenced by an rVE greater than 30% for the combined data of Y1 and Y2 for IIV-HD versus IIV-SD. Also the aggregate occurrence of any serious cardio-respiratory event possibly related to influenza was also lower for IIV-HD versus IIV-SD with an rVE of 17.7% for combined data from Y1 and Y2.
The data in FIGS. 6 and 7 support the greater relative efficacy of high-dose influenza vaccine, including IIV-HD, versus IIV-SD for reducing all-cause hospitalization and some serious cardio-pulmonary events in elderly patients. Compared with IIV-SD, IIV-HD produced greater reduction in all-cause hospitalization and pneumonia, other selected respiratory events, and heart failure over two influenza seasons.
EQUIVALENTS
The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and Examples detail certain embodiments and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the embodiment may be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.
As used herein, the term about refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term about generally refers to a range of numerical values (e.g., +/−5-10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). In some instances, the term about may include numerical values that are rounded to the nearest significant figure.
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15738417
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sanofi pasteur inc.
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 20th, 2022 02:26PM
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Apr 20th, 2022 02:26PM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 19th, 2022 12:00AM
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Jul 20th, 2020 12:00AM
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https://www.uspto.gov?id=US11305068-20220419
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Autoinjector
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An autoinjector includes a case having a rib, a needle shroud telescopically coupled to the case, a carrier slidably arranged in the case and adapted to hold a medicament container, and a collar rotatably and slidably disposed in the case and coupled to the needle shroud and the carrier. The needle shroud is movable between a first extended position, a retracted position and a locked second extended position. The carrier is movable from a first axial position to a second axial position relative to the case. The collar abuts the rib when the needle shroud is in the first extended position and the carrier is in the first axial position, and the collar disengages the rib when the needle shroud is in the retracted position and the carrier is in the second axial position.
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11305068
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1. An autoinjector comprising:
a case,
a needle shroud telescopically coupled to the case and movable between a first extended position and a retracted position, and
a collar rotatably and slidably disposed in the case and coupled to the needle shroud, wherein the collar abuts a rib when the needle shroud is in the first extended position, wherein the collar disengages the rib when the needle shroud is in the retracted position, and wherein the collar translates distally relative to the case when the needle shroud is in the retracted position.
2. The autoinjector of claim 1, wherein the case is configured to receive a medicament container.
3. The autoinjector of claim 2, wherein the medicament container is a syringe with a needle at a distal end of the syringe.
4. The autoinjector of claim 3, wherein the syringe is arranged in the case.
5. The autoinjector of claim 2, wherein the medicament container contains a medicament.
6. The autoinjector of claim 1, wherein the autoinjector further comprises a spring configured to bias the collar relative to the case.
7. The autoinjector of claim 6, wherein the spring is proximally grounded in the case.
8. The autoinjector of claim 6, wherein the spring is proximally grounded in the case at a location proximal from the collar.
9. The autoinjector of claim 6, wherein when the needle shroud is in the first extended position, a boss of the collar abuts an angled rib of the case, wherein the collar is biased distally by a spring force of the spring, wherein the spring force, the rib, and the boss cooperate to apply a rotational and axial force to the collar.
10. The autoinjector of claim 9, wherein the needle shroud is arranged and configured to resolve at least part of the spring force.
11. The autoinjector of claim 10, wherein a shroud boss of the collar abuts the needle shroud to resolve at least part of the spring force.
12. The autoinjector of claim 11, wherein an extension of the needle shroud distally beyond the case is limited by the shroud boss abutting a transversal surface on the needle shroud.
13. The autoinjector of claim 9, wherein a movement of the needle shroud from the first extended position to the retracted position triggers an injection operation of the autoinjector.
14. The autoinjector of claim 6, wherein a cap is removably coupled to a distal end of the case.
15. The autoinjector of claim 14, wherein the first extended position and the retracted position are positions relative to the distal end of the case, wherein the needle shroud protrudes from the distal end of the case farther in the first extended position than in the retracted position.
16. An autoinjector comprising:
a case,
a needle shroud telescopically coupled to the case and movable between a first extended position and a retracted position,
a collar rotatably and slidably disposed in the case and coupled to the needle shroud, wherein the collar abuts a rib when the needle shroud is in the first extended position, wherein the collar disengages the rib when the needle shroud is in the retracted position, and wherein the collar translates axially relative to the case when the needle shroud is in the retracted position.
17. The autoinjector of claim 16, wherein the case is configured to receive a medicament container, wherein the medicament container contains a medicament.
18. The autoinjector of claim 16, wherein the autoinjector further comprises a spring configured to bias the collar relative to the case.
19. The autoinjector of claim 18, wherein when the needle shroud is in the first extended position, a boss of the collar abuts an angled rib of the case, wherein the collar is biased distally by a spring force of the spring, wherein the spring force, the rib, and the boss cooperate to apply a rotational and axial force to the collar.
20. The autoinjector of claim 16, wherein the first extended position and the retracted position of the needle shroud are positions relative to a distal end of the case, wherein the needle shroud protrudes from the distal end of the case farther in the first extended position than in the retracted position.
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20
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 16/163,388, filed Oct. 17, 2018, which is a continuation of U.S. patent application Ser. No. 14/903,351, filed Jan. 7, 2016, now U.S. Pat. No. 10,137,255, which is a U.S. national stage application under 35 USC § 371 of International Application No. PCT/EP2014/064425, filed on Jul. 7, 2014, which claims priority to European Patent Application No. 13175662.9, filed on Jul. 9, 2013, the entire contents of which are incorporated herein by reference.
TECHNICAL FIELD
The invention relates to an autoinjector.
BACKGROUND
Administering an injection is a process which presents a number of risks and challenges for users and healthcare professionals, both mental and physical. Injection devices typically fall into two categories—manual devices and autoinjectors. In a conventional manual device, manual force is required to drive a medicament through a needle. This is typically done by some form of button/plunger that has to be continuously pressed during the injection. There are numerous disadvantages associated with this approach. For example, if the button/plunger is released prematurely, the injection will stop and may not deliver an intended dose. Further, the force required to push the button/plunger may be too high (e.g., if the user is elderly or a child). And, aligning the injection device, administering the injection and keeping the injection device still during the injection may require dexterity which some patients (e.g., elderly patients, children, arthritic patients, etc.) may not have.
Autoinjector devices aim to make self-injection easier for patients. A conventional autoinjector may provide the force for administering the injection by a spring, and trigger button or other mechanism may be used to activate the injection. Autoinjectors may be single-use or reusable devices.
There remains a need for an improved autoinjector.
SUMMARY
It is an object of the present invention to provide an improved autoinjector.
In an exemplary embodiment, an autoinjector according to the present invention comprises a case having a rib, a needle shroud telescopically coupled to the case and movable between a first extended position, a retracted position and a locked second extended position, a carrier slidably arranged in the case, adapted to hold a medicament container, and movable from a first axial position to a second axial position relative to the case, and a collar rotatably and slidably disposed in the case and coupled to the needle shroud and the carrier. The collar abuts the rib when the needle shroud is in the first extended position and the carrier is in the first axial position, and the collar disengages the rib when the needle shroud is in the retracted position and the carrier is in the second axial position.
In an exemplary embodiment, the autoinjector further comprises a plunger slidably coupled to the carrier, and a drive spring biasing the plunger relative to the carrier. The carrier includes a compliant beam having a boss adapted to engage an opening in the plunger when the carrier is in the first axial position. The boss is adapted to engage the case when the carrier is in the second axial position.
In an exemplary embodiment, the collar includes a shroud boss adapted to engage a shroud slot in the needle shroud, a carrier boss adapted to engage a carrier slot in the carrier and a case boss adapted to engage the rib in the case. The shroud boss, the carrier boss and the case boss are disposed in approximately a same plane on the collar.
In an exemplary embodiment, the collar is in a first angular position relative to the case when the needle shroud is in the first extended position and the carrier is in the first axial position. The collar rotates to a second angular position relative to the case and translates proximally relative to the case when the needle shroud moves from the first extended position to the retracted position. The collar translates distally relative to the case when the needle shroud is in the retracted position and the carrier moves from the first axial position to the second axial position. The boss disengages the opening when the carrier is in the second axial position and wherein the plunger translates axially relative to the carrier under the force of the drive spring advancing the carrier from the second axial position to a third axial position relative to the case. The collar rotates to a third angular position relative to the case and translates with the needle shroud distally relative to the case when the carrier is in the third axial position. The collar rotates to a fourth angular position relative to the case when the needle shroud is in the locked second extended position. The shroud boss engages a shroud slot notch in the shroud slot and the carrier boss engages a carrier slot notch in the carrier slot when the collar is in the fourth angular position and the needle shroud is in the locked second extended position. The engagement of the carrier boss and the carrier slot notch substantially fixes the collar in an axial position relative to the case.
In an exemplary embodiment, the autoinjector further comprises a control spring biasing the collar relative to the case.
In an exemplary embodiment, the autoinjector further comprises a trigger button coupled to or integral with the carrier.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus, are not limitive of the present invention, and wherein:
FIG. 1A is a side view of an exemplary embodiment of an autoinjector according to the present invention prior to use,
FIG. 1B is a side view of an exemplary embodiment of an autoinjector according to the present invention prior to use,
FIG. 1C is a side view of an exemplary embodiment of an autoinjector according to the present invention prior to use,
FIG. 1D is a side view of an exemplary embodiment of an autoinjector according to the present invention prior to use,
FIG. 1E is a semi-transparent side view of an exemplary embodiment of an autoinjector according to the present invention prior to use,
FIG. 1F is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention prior to use,
FIG. 1G is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention prior to use,
FIGS. 2A to 2I are schematic views of an exemplary embodiment of a control mechanism for an autoinjector according to the present invention,
FIG. 3A is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 3B is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 3C is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 3D is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 3E is a semi-transparent side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 3F is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 3G is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 4A is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 4B is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 4C is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 4D is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 4E is a semi-transparent side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 4F is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 4G is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 5A is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 5B is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 5C is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 5D is a side view of an exemplary embodiment of an autoinjector according to the present invention during use larity,
FIG. 5E is a semi-transparent side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 5F is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 5G is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 6A is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 6B is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 6C is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 6D is a side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 6E is a semi-transparent side view of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 6F is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 6G is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention during use,
FIG. 7A is a side view of an exemplary embodiment of an autoinjector according to the present invention after use,
FIG. 7B is a side view of an exemplary embodiment of an autoinjector according to the present invention after use,
FIG. 7C is a side view of an exemplary embodiment of an autoinjector according to the present invention after use,
FIG. 7D is a side view of an exemplary embodiment of an autoinjector according to the present invention after use,
FIG. 7E is a semi-transparent side view of an exemplary embodiment of an autoinjector according to the present invention after use,
FIG. 7F is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention after use, and
FIG. 7G is a longitudinal section of an exemplary embodiment of an autoinjector according to the present invention after use.
Corresponding parts are marked with the same reference symbols in all figures.
DETAILED DESCRIPTION
FIGS. 1A-1F and 1B are different views of an exemplary embodiment of an autoinjector 1 according to the present invention prior to use. In an exemplary embodiment, the autoinjector 1 includes a case 2 telescopically coupled to a needle shroud 7. FIGS. 1C and 1D are related side views of the autoinjector 1 with the case 2 removed for clarity. FIG. 1E is a related semi-transparent side view of the case 2. FIGS. 1F and 1G are related longitudinal sections of the autoinjector 1.
In an exemplary embodiment as shown in FIGS. 1F and 1G, the case 2 is adapted to receive a medicament container, such as a syringe 3 containing a medicament M. The syringe 3 may be a pre-filled syringe and have a needle 4 arranged at a distal end. When the autoinjector 1 or the syringe 3 is assembled, a protective needle sheath 5 is removably attached to the needle 4. A stopper 6 is arranged for sealing the syringe 3 proximally and for displacing the medicament M contained in the syringe 3 through the needle 4. In other exemplary embodiments, the medicament container may be a cartridge or an ampoule, and the needle 4 may be removably coupled to the medicament container. In an exemplary embodiment, the syringe 3 is held in a syringe carrier 8 and supported at its proximal end therein. The syringe carrier 8 is slidably arranged within the case 2.
In an exemplary embodiment, a cap (not illustrated) may be removably coupled to a distal end of the case 2. The case 2 may include a viewing window 2.7 for providing visual access to contents of the syringe 3.
In an exemplary embodiment, the needle shroud 7 is telescoped in the distal end of the case 2. A control spring 9 is arranged to bias the needle shroud 7 in a distal direction D relative to the case 2.
In an exemplary embodiment, a drive spring 10 (which may be a compression spring) is arranged within a proximal part 8.1 of the syringe carrier 8. A plunger 12 serves for forwarding a force of the drive spring 10 to the stopper 6. In an exemplary embodiment, the plunger 12 is hollow and telescoped within the proximal part 8.1 of the syringe carrier 8 wherein the drive spring 10 is arranged within the plunger 12 biasing the plunger 12 in the distal direction D relative to the syringe carrier 8. In an exemplary embodiment, the proximal part 8.1 of the syringe carrier 8 protrudes through an opening in a proximal end of the case 2 and serves as a trigger button 13. In other exemplary embodiments, a button overmold may be coupled to or integralled formed with the trigger button 13.
In an exemplary embodiment, a plunger release mechanism 15 is arranged for preventing release of the plunger 12 prior to the needle 4 reaching an insertion depth and for releasing the plunger 12 once the needle 4 reaches its insertion depth. The plunger release mechanism 15 may comprise one or more compliant beams 8.3 with a respective first boss 8.4 arranged on the syringe carrier 8, a respective first opening 12.1 (best seen in FIG. 5F) laterally arranged in the plunger 12 for engaging the first boss 8.4, a proximal narrow section 2.4 of the case 2 adapted to radially outwardly support the first boss 8.4 and prevent it from disengaging the first opening 12.1, a wide section 2.5 in the case 2 distal of the narrow section 2.4 adapted to allow radially outward deflection of the first boss 8.4 once the first boss 8.4 is axially aligned with the wide section 2.5. At least one of the first boss 8.4 and the first opening 12.1 may be ramped such that the plunger 12 under load from the drive spring 10 deflects the first boss 8.4 radially outwards.
In an exemplary embodiment, a control mechanism 21 (best seen in FIGS. 2A to 21) is arranged for selectively applying the force of the control spring 9 to the syringe carrier 8 or to the needle shroud 7. Furthermore, the control mechanism 21 is arranged for locking the trigger button 13 such that it cannot be operated prior to depression of the needle shroud 7 against an injection site and for unlocking the trigger button 13 on depression of the needle shroud 7 against the injection site, thus allowing operation of the trigger button 13.
In an exemplary embodiment, the control mechanism 21 comprises a collar 16 having a shroud boss 18 adapted to engage a shroud slot 17 in the needle shroud 7, a carrier boss 20 adapted to engage a carrier slot 19 in the syringe carrier 8, and a case boss 22 adapted to engage an angled case rib 2.9 on the case 2.
In an exemplary embodiment, the control spring 9 is proximally grounded in the case 2 and distally bears against the collar 16 which is movable axially and rotationally relative to the case 2. In the initial state prior to use, the control spring 9 may be compressed between the case 2 and the collar 16.
FIGS. 2A to 21 are schematic views of exemplary embodiments of the components of the control mechanism 21 corresponding to different states of operation of the autoinjector 1. Although the case boss 22, the carrier boss 20 and the shroud boss 18 are shown at different axial positions for clarity in FIGS. 2A to 21, in an exemplary embodiment, all of the bosses 18, 20, 22 on the collar 16 are disposed in the same plane as shown in FIG. 1E. In an exemplary embodiment, the shroud slot 17 comprises a transversal first surface 17.1, a transversal second surface 17.2, a longitudinal third surface 17.3, a transversal fourth surface 17.4, an angled fifth surface 17.5, a transversal sixth surface 17.6 and a transversal seventh surface 17.7. In an exemplary embodiment, the carrier slot 19 comprises a transversal first surface 19.1, an angled second surface 19.2, an angled third surface 19.3, a longitudinal fourth surface 19.4 and a transversal fifth surface 19.5.
A exemplary sequence of operation of the autoinjector 1 is as follows:
Prior to use the autoinjector 1 is in the state as illustrated in FIGS. 1A to 1G, and the control mechanism 21 is in the state illustrated in FIG. 2A. If applicable, the autoinjector 1 is removed from a packaging. The medicament M in the syringe 3 may be visually examined through the viewing window 2.7.
If the cap (not illustrated) is attached to the case 2 and/or the protective needle sheath 5, the cap may be removed by pulling it in the distal direction D away from the case 2 thereby also removing the protective needle sheath 5 from the needle 4. The load exerted by pulling the cap 11 is resolved in the case 2, because the case boss 22 on the collar 16 abuts the angled case rib 2.9 in the distal direction D. The collar 16 is in a first angular position relative to the case 2. As the case rib 2.9 is angled, a rotational force in a first rotational direction R1 and an axial force in the distal direction Dare applied to the collar 16 due to the control spring 9 biasing the collar 16 in the distal direction D. The rotational and axial forces are resolved by the shroud boss 18 abutting the shroud slot 17 and/or the carrier boss 20 abutting the carrier slot 19 (in the illustrated embodiment both are used) such that the collar 16 cannot rotate or translate axially relative to the case 2. The syringe carrier 8 is in a first axial position relative to the case 2.
Movement of the syringe carrier 8 in the distal direction Dis prevented by the carrier boss 20 being in contact with the angled second surface 19.2 of the carrier slot 19. Thus, depression of the trigger button 13 is prevented. Movement of the syringe carrier 8 in the proximal direction P is prevented by a backstop (not illustrated) on the case 2. Furthermore, the force of the control spring 9 on the collar 16 prevents the syringe carrier 8 from moving in the proximal direction P.
The needle shroud 7 is in a first extended position EP, protruding from the case 2 in the distal direction D. The extension of the needle shroud 7 distally beyond the case 2 is limited by the shroud boss 18 abutting the transversal first surface 17.1 and the transversal second surface 17.2 on the shroud slot 17. Due to the collar 16 being prevented from moving in the distal direction D by the case rib 2.9, the needle shroud 7 cannot move in the distal direction D either. Movement of the needle shroud 7 in the proximal direction P relative to the case 2 results in a corresponding axial translation of the collar 16 relative to the case 2, compressing the control spring 9.
The plunger release mechanism 15 prevents the plunger 12 from being released.
When the autoinjector 1 is pressed against an injection site, the needle shroud 7 is pressed into the case 2 into a retracted position RP against the force of the control spring 9.
FIGS. 3A and 3B are different views of an exemplary embodiment of the autoinjector 1 with the needle shroud 7 in the retracted position RP. FIGS. 3C and 3D are related side views of the autoinjector 1 with the case 2 removed for clarity. FIG. 3E is a related semi-transparent side view of the case 2 with the collar 16. FIGS. 3F and 3G are related longitudinal sections of the autoinjector 1. FIG. 2B shows the control mechanism 21 as the needle shroud 7 is translating from the extended position EP to the retracted position RP. FIG. 2C shows the control mechanism 21 when the needle shroud 7 is in the retracted position RP.
The force opposing depression of the needle shroud 7 is provided by the control spring 9 through the collar 16 and the shroud boss 18 engaging the transversal first surface 17.1. During depression of the needle shroud 7 towards the retracted position RP, the shroud boss 18 abuts the transversal first surface 17.1 of the shroud slot 17 (cf. FIG. 2B) causing the collar 16 to translate axially in the proximal direction P relative to the case 2. The carrier boss 20 disengages the transversal first surface 19.1 of the carrier slot 19 in the proximal direction P. As the angled second surface 19.2 of the carrier slot 19 is angled relative to a transverse axis of the case 2, a rotational force is applied to the collar 16 in a second rotational direction R2 opposite the first rotational direction R1, causing the collar 16 to rotate to a second angular position relative to the case 2. If the autoinjector 1 were removed from the injection site, the collar 16 and needle shroud 7 would return in the distal direction D into the positions shown in FIGS. 1A to 1G and the control mechanism 21 would return into the state shown in FIG. 2A due to the engagement of the case boss 22 to the angled case rib 2.9 applying the rotational force to the collar 16 in the first rotational direction R1.
When the needle shroud 7 is in the retracted position RP, the case boss 22 remains abutting the case rib 2.9 (cf. FIG. 3E) and the shroud boss 18 remains abutting the transversal first surface 17.1 of the shroud slot 17 (cf. FIG. 3C). Thus, the collar 16 is prevented from moving axially relative to the case 2.
FIGS. 4A and 4B are different side views of an exemplary embodiment of the autoinjector 1 after depression of the trigger button 13. FIGS. 4C and 4D are related side views of the autoinjector 1 with the case 2 removed for clarity. FIG. 4E is a related semi-transparent side view of the case 2 with the collar 16. FIGS. 4F and 4G are related longitudinal sections of the autoinjector 1.
When the trigger button 13 is pressed, the syringe carrier 8 moves in the distal direction D from the first axial position to a second axial position relative to the case 2, causing the carrier boss 20 to ride further along the angled second surface 19.2 and thereby rotating the collar 16 relative to the case 2 in the second rotational direction R2 to a third angular position relative to the case 2. After sufficient rotation of the collar 16 relative to the case 2, the shroud boss 18 comes clear of the transversal first surface 17.1 of the shroud slot 17, and the case boss 22 comes clear of the case rib 2.9. As the collar 16 is thus axially neither supported by the case 2 nor by the shroud slot 17, the collar 16 moves in the distal direction D guided by the shroud boss 18 along the longitudinal third surface 17.3 (cf. FIG. 2D), wherein the carrier boss 20 disengages the angled second surface 19.2 and moves in the distal direction D towards the angled third surface 19.3 of the carrier slot 19. As the carrier boss 20 engages the angled third surface 19.3 of the carrier slot 19, a rotational force in the second rotational direction R2 is applied to the collar 16 which is resolved by the shroud boss 18 abutting the third longitudinal surface 17.3 such that the carrier boss 20 cannot disengage the angled third surface 19.3. The collar 16 and the control spring 9 are thus axially coupled to the syringe carrier 8. The control spring 9 coupled to the syringe carrier 8 through the collar 16 advances the syringe carrier 8 from the second axial position to a third axial position in the distal direction D relative to the case 2 such that the needle 4 is extended from the case 2 and inserted into the injection site.
FIGS. 5A and 5B are different side views of an exemplary embodiment of the autoinjector 1 with the needle 4 extending from the case 2. FIGS. 5C and 5D are related side views of the autoinjector 1 with the case 2 removed for clarity. FIG. 5E is a related semi-transparent side view of the case 2 with the collar 16. FIGS. 5F and 5G are related longitudinal sections of the autoinjector 1.
The translation of the syringe carrier 8 relative to the case 2 is limited when the shroud boss 18 abuts the transversal fourth surface 17.4 of the shroud slot 17 (cf. FIG. 2F). The transversal fourth surface 17.4 thus defines a penetration depth of the needle 4.
In an exemplary embodiment, prior to the shroud boss 18 abutting the transversal fourth surface 17.4 of the shroud slot 17, the plunger 12 is released by the plunger release mechanism 15. As the syringe carrier 8 translates in the distal direction D relative to the case 2, the compliant beams 8.3 reach the wide section 2.5, and the plunger 12, under load from the drive spring 10, deflects the first boss 8.4 on the compliant beam 8.3 radially outwards such that the first boss 8.4 disengages the first opening 12.1 in the plunger 12. The plunger 12 is thus released and advanced by the drive spring 10 displacing the stopper 6 within the syringe 3 and ejecting the medicament M through the needle 4. The release of the plunger release mechanism 15 may provide an audible and/or tactile feedback to the user. The progress of delivery of the medicament M can be observed through the viewing window 2.7 by examining the movement of the plunger 12 within the syringe 3. The plunger 12 is visible in the viewing window 2.7 thus helping the user differentiate between a used and an un-used autoinjector 1.
If the autoinjector 1 is removed from the injection site at any time after the needle 4 has reached insertion depth, the needle shroud 7 moves in the distal direction D driven by the control spring 9 which is coupled to the needle shroud 7 through the collar 16 and the shroud boss 18 abutting the transversal fourth surface 17.4 of the shroud slot 17.
FIGS. 6A and 6B are different side views of an exemplary embodiment of the autoinjector 1 with the syringe 3 emptied. FIGS. 6C and 6D are related side views of the autoinjector 1 with the case 2 removed for clarity. FIG. 6E is a related semi-transparent side view of the case 2 with the collar 16. FIGS. 6F and 6G are related longitudinal sections of the autoinjector 1.
When the syringe carrier 8 abuts a front stop (not illustrated) on the case 2, the shroud boss 18 disengages the longitudinal third surface 17.3 and abuts the transversal fourth surface 14. The force of the control spring 9 causes the collar 16 to translate axially and ride along the angled third surface 19.3. Because the shroud boss 18 does not abut the longitudinal third surface, the collar 16 rotates relative to the case 2 in the second rotational direction R2 to a fourth angular position relative to the case 2 due to the angled third surface 19.3. After sufficient rotation of the collar 16 in the second rotational direction R2, the carrier boss 20 disengages the angled third surface 19.3, and the shroud boss 18 moves from contact with the transversal fourth surface 17.4 to the angled fifth surface 17.5 (cf. FIG. 2G). After further rotation of the collar 16 in the second rotational direction R2, the carrier boss 20 abuts the longitudinal fourth surface 19.4, preventing further rotation of the collar 16 in the second rotational direction R2 but allowing for axial translation of the collar 16. The shroud boss 18 applies an axial force on the angled fifth surface 17.5 to push the needle shroud 7 in the distal direction D relative to the case 2. When the carrier boss 20 disengages the longitudinal fourth surface 19.4, the force of the control spring 9 causes the collar 16 to rotate in the second rotational direction R2, because the shroud boss 18 abuts the angled fifth surface 17.5 of the shroud slot 17.
The collar 16 rotates as the shroud boss 18 moves along the angled fifth surface 17.5 from the position shown in FIG. 2H until it abuts the transversal sixth surface 17.6, and the rotation results in the carrier boss 20 engaging a notch adjacent a transversal fifth surface 19.5 in the carrier slot 19 (cf. FIG. 21). At this point, the needle shroud 7 may abut a front stop (not illustrated) in the case 2. The needle shroud 7 is now in a second extended position SEP extending further from the case 2 in the distal direction D than in the extended position EP thus hiding the extended needle 4. If the needle shroud 7 is attempted to move proximally from the second extended position SEP, the collar 16 is substantially prevented from moving axially relative to the case 2, which prevents the needle shroud 7 from moving proximally relative to the case 2 from the second extended position SEP. The syringe carrier 8 has locked in an axial position relative to the case 2 (see FIG. 5F in which the first boss 8.4 proximally abuts the narrow section 2.4 of the case 2), and the collar 16 is substantially axially locked relative to the syringe carrier 8 via the engagement of the carrier boss 20 in the notch. If the needle shroud 7 is depressed, the shroud boss 18 will abut the sixth transversal surface 17.6 and prevent the needle shroud 7 from retracting. Thus, the needle shroud 7 is prevented from being retracted and is locked in the second extended position SEP to cover the needle 4. This action is activated as soon as the needle 4 reaches insertion depth, and hence the needle 4 will always be shrouded upon removal from the injection site. This reduces the risk of needle stick injury.
FIGS. 7A and 7B are different side views of an exemplary embodiment of the autoinjector 1 removed from the injection site with the needle shroud 7 in the second extended position SEP. FIGS. 7C and 7D are related side views of the autoinjector 1 with the case 2 removed for clarity. FIG. 7E is a related semi-transparent side view of the case 2 with the collar 16. FIGS. 7F and 7G are related longitudinal sections of the autoinjector 1.
In an exemplary embodiment, the shroud boss 18 could be arranged on the needle shroud 7 and engaged in the shroud slot 17, which would be arranged in the collar 16. Likewise the carrier boss 20 could be arranged on the syringe carrier 8 and engaged in the carrier slot 19, which would be arranged in the collar 16. Likewise the angled case rib 2.9 could be arranged on the collar 16 and the case boss 22 on the case 2.
In another exemplary embodiment, the control mechanism 21 could be adapted to be applied in an autoinjector 1 without the trigger button 13, but which is activated based on depression of the needle shroud 7. For example, the a modified control mechanism 21 could include, e.g. a steeper angle of the angled second surface 19.2 of the carrier slot 19, a reduced length of the transversal first surface 17.1 of the shroud slot 17, and/or a reduced length of the angled case rib 2.9.
In an exemplary embodiment, the case 2 may comprise a front case and a rear case which are attached to form the case 2, in order to facilitate assembly.
The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a protein, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein praline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(w-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37Exendin-4(1-39)-NH2,
des Pro36 Exendin-4(1-39),
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two 13 sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by a, o, £, y, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; a and y contain approximately 450 amino acids and O approximately 500 amino acids, while p and £ have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH)— In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains y, a and o have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and £ have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by 'A and K. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, K or 'A, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystallizable fragment (Fe). The Fe contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
Those of skill in the art will understand that modifications (additions and/or removals) of various components of the apparatuses, methods and/or systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.
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16933661
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sanofi-aventis deutschland gmbh
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 20th, 2022 02:26PM
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Apr 20th, 2022 02:26PM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 19th, 2022 12:00AM
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Jul 30th, 2020 12:00AM
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https://www.uspto.gov?id=USD0949195-20220419
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Display panel portion with an animated computer icon
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D949195
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The ornamental design for a display panel portion with an animated computer icon, substantially as shown and described.
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1
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FIG. 1 is a first image in a sequence for the display panel portion with an animated computer icon.
FIG. 2 is second image in the sequence thereof.
FIG. 3 is a third image in the sequence thereof.
FIG. 4 is a fourth image in the sequence thereof.
FIG. 5 is a fifth image in the sequence thereof.
FIG. 6 is a sixth image in the sequence thereof.
FIG. 7 is a seventh image in the sequence thereof.
FIG. 8 is an eighth image in the sequence thereof.
FIG. 9 is a ninth image in the sequence thereof; and,
FIG. 10 is a tenth image in the sequence thereof.
The appearance of the transitional image sequentially transitions between the images shown in FIGS. 1-10.
The process or period in which one image transitions to another forms no part of the claimed design.
The broken lines showing a display panel portion and portions of the animated computer icon in FIGS. 1-10 form no part of the claimed design.
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29744622
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sanofi
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USA
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S1
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Design Patent
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Open
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D14/488
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15
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Apr 20th, 2022 02:26PM
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Apr 20th, 2022 02:26PM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 19th, 2022 12:00AM
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Jun 20th, 2019 12:00AM
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https://www.uspto.gov?id=US11305069-20220419
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Safety device for a medicament container
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A safety device for a medicament container includes a first sheath having a first ledge and a second ledge, a second sheath telescopically arranged with the first sheath and releasably coupled to the first ledge, and a finger flange having at least one resilient clip adapted to engage the second ledge first sheath.
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11305069
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1. A safety device for a medicament container, the safety device comprising:
a first sheath comprising a first ledge and a second ledge;
a second sheath telescopically arranged with the first sheath and releasably coupled to the first ledge; and
a finger flange comprising:
a resilient clip adapted to engage the second ledge of the first sheath,
a central portion comprising a substantially flat proximal surface and a distal surface that is concave or substantially flat, and
a support portion extending radially from the central portion;
wherein the resilient clip comprises a transverse beam extending in a radial inward direction and a longitudinal beam extending from the transverse beam in a proximal direction, and
wherein the transverse beam comprises a hinge in the shape of a section with a reduced thickness compared to a remaining portion of the transverse beam.
2. The safety device of claim 1, wherein the resilient clip comprises:
a hook comprising a slope surface and a block surface extending from the longitudinal beam in the radial inward direction,
wherein during insertion of the second ledge in a distal direction, the second ledge engages the slope surface and increasingly deflects the resilient clip in a radial outward direction, and
wherein after the second ledge has passed the slope surface, the resilient clip relaxes and the second ledge engages the block surface to prevent the second ledge from returning in the proximal direction.
3. The safety device of claim 1, wherein the hinge has a thickness of approximately 30% to 70% of a thickness of the remaining portion of the transverse beam.
4. The safety device of claim 1, wherein a protrusion is arranged on one of the finger flange and the first sheath, and wherein the protrusion is arranged to engage a recess in the other one of the finger flange and the first sheath so as to limit relative rotation between the first sheath and the finger flange.
5. The safety device of claim 1, wherein the finger flange comprises:
a hole adapted to receive the first sheath; and
a central recess disposed adjacent to the hole adapted to receive the second ledge.
6. The safety device of claim 1, wherein the finger flange comprises a retaining wall adapted to abut the second ledge.
7. The safety device of claim 6, wherein the retaining wall abuts an entire periphery of the second ledge.
8. The safety device of claim 1, wherein the finger flange comprises:
a hole adapted to receive the first sheath; and
a lateral recess disposed adjacent the hole.
9. The safety device of claim 1, wherein the support portion comprises a support surface, wherein the support surface is made of a first material, wherein the support portion is made of a second material, and wherein the first material has a lower durometer than the second material.
10. The safety device of claim 9, wherein the support surface comprises one or more frictional features.
11. The safety device of claim 10, wherein the support surface is formed by overmolding or by two-shot injection molding.
12. The safety device of claim 1, wherein the finger flange comprises a hole adapted to receive the first sheath, and wherein a radial distance between an outer radial surface and an outer diameter of the hole is approximately 20 mm.
13. The safety device of claim 1, wherein the support portion comprises a substantially flat proximal surface and a concave distal surface or a concave proximal surface and a concave distal surface.
14. A medicament delivery device, comprising:
a medicament container; and
a safety device for the medicament container, the safety device comprising:
a first sheath comprising a first ledge and a second ledge,
a second sheath telescopically arranged with the first sheath and releasably coupled to the first ledge, and
a finger flange comprising:
a resilient clip adapted to engage the second ledge of the first sheath,
a central portion comprising a substantially flat proximal surface and a distal surface that is concave or substantially flat, and
a support portion extending radially from the central portion,
wherein the resilient clip comprises a transverse beam extending in a radial inward direction and a longitudinal beam extending from the transverse beam in a proximal direction, and
wherein the transverse beam comprises a hinge in the shape of a section with a reduced thickness compared to a remaining portion of the transverse beam.
15. A safety device for a medicament container, the safety device comprising:
a first sheath comprising a first ledge and a second ledge;
a second sheath telescopically arranged with the first sheath and releasably coupled to the first ledge;
a finger flange comprising a resilient clip adapted to engage the second ledge of the first sheath; and
a cap comprising a cylindrical portion having a first outer diameter and a disc portion having a second outer diameter larger than the first outer diameter,
wherein the resilient clip comprises a transverse beam extending in a radial inward direction and a longitudinal beam extending from the transverse beam in a proximal direction, and
wherein the transverse beam comprises a hinge in the shape of a section with a reduced thickness compared to a remaining portion of the transverse beam.
16. The safety device of claim 15, wherein the cylindrical portion comprises a through hole adapted to accommodate a needle shield.
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16
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 14/914,759, filed Feb. 26, 2016, which is a U.S. national stage application under 35 USC § 371 of International Application No. PCT/EP2014/068130, filed on Aug. 27, 2014, which claims priority to European Patent Application No. 13306179.6, filed on Aug. 29, 2013, the entire contents of which are incorporated herein by reference.
TECHNICAL FIELD
This disclosure relates to a safety device for a medicament container.
BACKGROUND
Administering an injection is a process which presents a number of risks and challenges for users and healthcare professionals, both mental and physical. Medicament delivery devices typically fall into two categories—manual devices and auto-injectors. In a conventional manual device, manual force is required to drive a medicament through a needle. This is typically done by some form of button/plunger that has to be continuously pressed during the injection. A conventional auto-injector may provide the force for administering the medicament by a spring, and a trigger button or other mechanism may be used to activate the injection.
For use of manual devices and autoinjectors, safety and usability are of the utmost importance. Thus, there remains a need for improved medicament delivery devices which include components or mechanisms for user and patient safety (e.g., to prevent misuse, needlestick, etc.) and enhanced usability (e.g., making the device easier to user before, during and after an injection to improve dose accuracy and compliance).
SUMMARY
Certain embodiments of the present invention provide improved safety devices for a medicament containers.
In an exemplary embodiment according to the present invention, a safety device for a medicament container comprises a first sheath having a first ledge and a second ledge, a second sheath telescopically arranged with the first sheath and releasably coupled to the first ledge, and a finger flange having at least one resilient clip adapted to engage the second ledge first sheath.
In an exemplary embodiment the resilient clip comprises a transverse beam extending in a radial inward direction, a longitudinal beam extending from the transverse beam in a proximal direction, a hook comprising a slope surface and a block surface extending from the longitudinal beam in the radial inward direction, wherein during insertion of the outer ledge in a distal direction the second ledge engages the slope surface increasingly deflecting the resilient clip in a radial outward direction, wherein, after the second ledge has passed the slope surface the resilient clip relaxes and the second ledge (36) engages the block surface preventing the second ledge from returning in the proximal direction.
In an exemplary embodiment of the transverse beam comprises a hinge in the shape of a section with a reduced thickness compared to the rest of the transverse beam.
In an exemplary embodiment the hinge has a thickness of approximately 30% to 70%, in particular 40% to 60% of the thickness of the rest of the transverse beam.
In an exemplary embodiment a protrusion is arranged on one of the finger flange and the first sheath, the protrusion arranged to engage a recess in the other one of the finger flange and the first sheath so as to limit relative rotation between the first sheath and the finger flange.
In an exemplary embodiment, the finger flange comprises a hole adapted to receive the first sheath. The finger flange comprises a central recess disposed adjacent to the hole adapted to receive the second ledge.
In an exemplary embodiment, the finger flange comprises a retaining wall adapted to abut the second ledge. The retaining wall abuts an entire periphery of the second ledge.
In an exemplary embodiment, the finger flange comprises at least one lateral recess disposed adjacent the hole.
In an exemplary embodiment, the finger flange comprises a central portion and at least one support portion extending radially from the central portion. The at least one support portion includes a support surface and wherein the support surface is made from a first material and the support portion is made from a second material, and wherein the first material has a lower durometer than the second material. The support surface may include one or more frictional features.
In an exemplary embodiment the support surface is formed by overmolding or by two-shot injection molding.
In an exemplary embodiment, a radial distance between an outer radial surface and an outer diameter of the hole is approximately 20 mm.
In an exemplary embodiment, the central portion comprises a substantially flat proximal surface and a concave distal surface, and the at least one support portion comprises a substantially flat proximal surface and a concave distal surface.
In an exemplary embodiment, the central portion comprises a substantially flat proximal surface and a substantially flat distal surface, and the at least one support portion comprises a concave proximal surface and a concave distal surface.
In an exemplary embodiment according to the present invention, a medicament delivery device comprises a medicament container and a safety device according to any one of the exemplary embodiments.
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
Certain embodiments of the present invention will become more fully understood from the detailed description given herein below and the accompanying drawings which are given by way of illustration only, and thus, are not limitive of the present invention, and wherein:
FIG. 1 shows a medicament delivery device according to certain embodiments of the present invention,
FIG. 2 shows a medicament container according to the present invention,
FIG. 3 shows a safety device according to the present invention,
FIGS. 4A and 4B show a plunger according to the present invention,
FIGS. 5A and 5B show a cap according to certain embodiments of the present invention,
FIG. 6 shows a cap according to certain embodiments of the present invention,
FIG. 7 shows a finger flange according to certain embodiments of the present invention,
FIG. 8 shows another finger flange according to certain embodiments of the present invention, and
FIG. 9 shows a finger flange according to certain embodiments of the present invention, and
FIG. 10 shows a finger flange according to certain embodiments of the present invention,
FIG. 11 shows a sectional detail view of a finger flange according to certain embodiments of the present invention, and
FIG. 12 shows a sectional detail view of a finger flange according to certain embodiments of the present invention.
Corresponding parts are marked with the same reference symbols in all figures.
DETAILED DESCRIPTION
FIG. 1 shows a medicament delivery device 10 according to certain embodiments of the present invention. In an exemplary embodiment, the delivery device 10 comprises a medicament container 20, a safety device 30 and a plunger 40. The delivery device 10 may further include a finger flange 50 and/or a cap 60.
FIG. 2 shows an exemplary of a medicament container 20 according to the present invention. In the exemplary embodiment, the medicament container 20 includes a barrel 22, a stopper 24 slidably disposed in the barrel 22 and a needle 26 coupled to a distal end of the barrel 22. In an exemplary embodiment, the stopper 24 may be made from a rubber material. A proximal end of the barrel 22 includes a flange 28 which may be fully or partial circular, elliptical, square, rectangular or any other shape. The barrel 22 may be any size (e.g., 0.5 ml, 1 ml, 2 ml, etc.) and be made of any suitable material (e.g., plastic, glass). In an exemplary embodiment, the barrel 22 may be manufactured from Type I clear glass. In an exemplary embodiment, the stopper 24 is made from a rubber material. In an exemplary embodiment, the needle 26 is made from stainless steel. The needle 26 may be any gauge or length.
In an exemplary embodiment, a needle shield 29 may be removably coupled to the distal end of the barrel 22 to cover the needle 26. In an exemplary embodiment, the needle shield 29 may be a sheath 29.1 made of, for example, rubber or elastomer latex.
In another exemplary embodiment, the needle shield 29 may further include a casing 29.2 made of, for example, polypropylene or any other similar material. The casing 29.2 may be disposed partially or entirely on an outer surface of the sheath 29.1. The casing 29.2 may provide further support to the sheath 29.1 to, for example, prevent the needle 26 from bending or puncturing the sheath 29.1. When the needle shield 29 is removed, the needle 26 is exposed.
FIG. 3 shows a safety device 30 according to certain embodiments of the present invention. In the exemplary embodiment, the safety device 30 comprises a first sheath 31 arranged telescopically with a second sheath 32, and the sheaths 31, 32 which are biased relative to each other by a spring 33. Prior to use, one of the sheaths is in a retracted position relative to the other sheath, and after use, the one of the sheaths is in an extended position relative to the other sheath to cover the needle 26. In the extended position, the one of the sheaths is locked in the extended position to prevent retraction and uncovering of the needle 26.
In the exemplary embodiment shown in FIG. 3, the first sheath 31 is an outer sheath, and the second sheath 32 is an inner sheath, and the second sheath 32 is movable from the retracted position to the extended position relative to the first sheath 31. The first sheath 31 comprises an open distal end allowing the second sheath 32 to move from the retracted position to the distal position. A proximal end of the first sheath 31 includes an engagement arrangement 34 adapted to engage the flange 28 of the medicament container 20. In an exemplary embodiment, the engagement arrangement 34 includes a support surface 34.1 adapted to abut a distal surface of the flange 28 to prevent distal movement of the medicament container 20 relative to the first sheath 31, and one or more resilient hooks 34.2 adapted to engage the flange 28 to prevent proximal movement of the medicament container 20 relative to the first sheath 31. When the medicament container 20 is inserted into the first sheath 31, the flange 28 causes the resilient hooks 34.2 to deflect until the flange 28 is distal of the hooks 34.2, at which point the hooks 34.2 return to a non-deflected position and can abut a proximal surface of the flange 28.
In an exemplary embodiment, the proximal end of the first sheath 31 includes an inner ledge 35 and an outer ledge 36. The inner ledge 35 may be formed partially or entirely around a proximal opening of the first sheath 31. The outer ledge 36 may be formed partially or entirely around an outer surface of the first sheath 31. As shown in the exemplary embodiment in FIG. 3, the first sheath 31 may have a distal portion having a first outer diameter and a proximal portion having a second outer diameter which is larger than the first outer diameter. The outer ledge 36 may be formed partially or entirely around the larger second outer diameter to provide a support surface for a user's fingers.
In an exemplary embodiment, the second sheath 32 comprises an open distal end allowing the needle 26 to pass through when the second sheath 32 is in the retracted position. A proximal end of the second sheath 32 includes one or more resilient arms 37 adapted to releaseably engage the inner ledge 35 to maintain the second sheath 32 in the retracted position against the force of the spring 33 which biases the second sheath 32 towards the extended position. When the second sheath 32 is in the retracted position, the resilient arms 37 are radially biased to engage the inner ledge 35.
In an exemplary embodiment, the first sheath 31 is made from polycarbonate, the second sheath is made from copolyesther, and the spring 33 is made from stainless steel.
FIGS. 4A and 4B show a plunger 40 according to certain embodiments of the present invention. In the exemplary embodiment, the plunger 40 includes a distal end 41 adapted to engage the stopper 24, a proximal end 42 adapted to be pressed by a user, and a stem 43 connecting the distal and proximal ends 41, 42. FIG. 4B shows a partial cross-section of an exemplary embodiment of the proximal end 42 of the plunger 40. In the exemplary embodiment, the proximal end 42 includes a bearing surface 42.1 adapted to receive a user's finger. The bearing surface 42.1 may be flat (perpendicular relative to a longitudinal axis of the medicament container 20) or have a partially or entirely concave or convex surface. In another exemplary embodiment, the bearing surface 42.1 may have one or more surface elements (e.g., ridges, bumps, etc.) adapted to frictionally engage the user's finger to prevent it from slipping off the bearing surface 42.1 during use. The proximal end 42 further includes a radial surface 42.2 having a distal end that is adapted to engage one or more resilient projections on the first sheath 31 that deflect upon engagement with the radial surface 42.2 to engage the one or more resilient arms 37 on the second sheath 32 when the plunger 40 has been pressed a sufficient distance relative to the medicament container 20. In an exemplary embodiment, the distal end of the radial surface 42.2 may comprise one or more ramps 42.3 adapted to engage the resilient projections such that the resilient rejections resilient arms 37 deflect and disengage the inner ledge 35.
In an exemplary use, when the plunger 40 is pressed a sufficient distance, the ramps 42.3 engage the resilient projections which engage the resilient arms 37 such that the resilient arms 37 deflect and disengage the inner ledge 35. The force of the spring 33 pushes the second sheath 32 distally relative to the first sheath 31 from the retracted position to the extended position. The second sheath 32 is locked in the extended position, because the resilient arms 37 abut a stop surface 31.1 (shown in FIG. 3) on the first sheath 31 preventing the second sheath 32 from moving proximally relative to the first sheath 31 from the extended position.
In an exemplary embodiment, the plunger 40 is made from polypropylene.
In an exemplary embodiment, the safety device 30 and the plunger 40 may be as described in U.S. Patent Application Publication No. 2002/0193746, the entire disclosure of which is expressly incorporated herein by reference.
FIGS. 5A and 5B show a cap 60 according to certain embodiments of the present invention. In the exemplary embodiment, the cap 60 comprises cylindrical portion 61 having a first outer diameter and a disc portion 62 having a second outer diameter larger than the second outer diameter. The cylindrical portion 61 includes a thru hole 61.1 adapted to accommodate the needle shield 29. The disc portion 62 may include a thru hole coaxial with the thru hole 61.1 or may include a full or partial cover to fully or partially enclose the thru hole 61.1. When assembled a proximal end of the cylindrical portion 61 may abut a distal end of the first sheath 31.
In an exemplary embodiment, the cap 60 may be made from polypropylene.
In an exemplary embodiment, a gripping surface 63 may be coupled to the cap 60. In the exemplary embodiment, the gripping surface 63 includes a proximal portion 63.1 and a distal portion 63.2. The proximal portion 63.1 may be coupled to all or part of an outer surface of the cylindrical portion 61 of the cap 60 and/or all or part of a proximal surface of the disc portion 62. The distal portion 63.2 may be coupled to all of part of an inner surface of the cylindrical portion 61 of the cap 60 and/or all or part of a distal surface of the disc portion 62. In another exemplary embodiment, the proximal portion 63.1 or the distal portion 63.2 may be disposed partially or entirely around a circumference of the disc portion 62.
In an exemplary embodiment, the gripping surface 63 may be made from a material having a lower durometer than the material comprising the cap 60. In an exemplary embodiment, the gripping surface 63 may be elastomer thermoplastic. The gripping surface 63 may provide an easily grippable and supportive surface for a user to grip to remove the cap 60 from the medicament delivery device 10. In an exemplary embodiment, any part of the gripping surface 63 may include one or more frictional features (e.g., ridges, bumps, etc.) to ensure that the user's fingers do not slip when gripping and removing the cap 60.
FIG. 6 shows an exemplary embodiment of a cap 60 coupled to the medicament delivery device 10. In the exemplary embodiment, the distal portion 63.2 of the gripping surface 63 is partially disposed on the inner surface of the cylindrical portion 61 of the cap 60. In an exemplary embodiment, a thickness of the distal portion 63.2 may decrease along the length of the inner surface in the proximal direction. A proximal end of the distal portion 63.2 along the length of the inner surface may include a ramp feature 63.2.1 adapted to receive and guide the needle shield 29, e.g., during assembly. The distal portion 63.2 of the gripping surface 63 is adapted to frictionally engage the needle shield 29, such that when the cap 60 is pulled away from the medicament delivery device 10, the needle shield 29 is removed. In another exemplary embodiment, all or part of the distal portion 63.2 may include one or more engagement features (e.g., a barb, a hook, a projection, etc.) adapted to engage the needle shield 29 (or any feature thereof, e.g., a slot, a channel, a recess, etc.) when the needle shield 29 is inserted into the cap 60. In an exemplary embodiment, the distal portion 63.2 may include one or more separate pieces of material. For example, a first piece of material may be disposed on the inner surface of the cylindrical portion 61 and a second piece of material may be disposed on the distal surface of the disc portion 62. A thru-hole 62.1 may be formed in the disc portion 62, e.g., for molding the gripping surface 63.
In an exemplary embodiment, the cap 60 and/or the gripping surface 63 may include one or more indicia for indicating how to remove the cap 60. For example, all or part of the cap 60 may be a first color and all or part of the gripping surface 63 may be a second color different from the first color to signify that this is the needle end of the device 10. In another exemplary embodiment, one or more words or symbols may be disposed on the cap 60 and/or the gripping surface 63. For example, an arrow point in the distal direction and/or the words “PULL” or “DO NOT TWIST” may be disposed on the cap 60 and/or the gripping surface 63.
FIG. 7 shows a finger flange 50 according to certain embodiments of the present invention. FIG. 8 shows another finger flange 500 according to certain embodiments of the present invention. FIG. 9 shows a proximal view of a finger flange 50/500 according to certain embodiments of the present invention.
As shown in the exemplary embodiment in FIG. 9, a proximal surface of the finger flange 50/500 include a hole 70 adapted to receive the first sheath 31. In an exemplary embodiment, a diameter of the hole 70 is approximately equal to an outer diameter of the first sheath 31. A central recess 71 may be formed around the hole 70 and be adapted to accommodate a proximal portion of the first sheath 31. For example, the central recess 71 may include a bearing surface 71.1 adapted to abut a distal face of the outer ledge 36. The central recess 71 may further include a retaining wall 71.2 adapted to abut at least a portion of the outer ledge 36 to prevent rotation of the first sheath 31 relative to the finger flange 50/500. One or more resilient clips 72 are disposed within or adjacent the central recess 71 and adapted to engage the outer ledge 36. When the finger flange 50/500 is coupled to the first sheath 31, the clips 72 deflect to accommodate the outer ledge 36 and then return to a non-deflected position to engage the outer ledge 36.
In another exemplary embodiment, the bearing surface 71.1 may not be recessed but may be in plane with the proximal surface of the finger flange 50/500. In this exemplary embodiment, the retaining wall 71.2 and the clips 72 may extend proximally from the flat surface.
In an exemplary embodiment, the proximal surface of the finger flange 50/500 may include one or more lateral recesses 73 adjacent the central recess 71. The lateral recesses 73 may be formed to create a hinge effect when supporting the user's fingers. The lateral recesses 73 may further decrease weight of the finger flange 50/500 and reduce constraints on molding.
FIG. 7 shows an exemplary embodiment of the finger flange 50 disposed on the outer sheath 31. In the exemplary embodiment, the finger flange 50 includes one or more support portions 51 extending radially from a central portion 52. The proximal surface of the finger flange 50 is substantially flat and distal surfaces of the support portions 51 and the central portion 52 are concave relative to the proximal surface (e.g., when the finger flange 50 is placed on a flat surface such that the proximal surface engages the flat surface). The support portion 51 may include a support surface 53. In an exemplary embodiment, the support surface 53 may be made, e.g. by overmolding or by two-shot injection molding, from a material having a lower durometer than the material comprising the finger flange 50. In an exemplary embodiment, the support surface 53 may be elastomer thermoplastic. The gripping surface 53 may provide a surface for a user's finger when administering an injection. In an exemplary embodiment, any part of the support surface 53 may include one or more frictional features (e.g., ridges, bumps, etc.) to ensure that the user's fingers do not slip when administering the injection. Likewise, the support surface 53 may be formed without such surface structures. While the exemplary embodiment of the invention shows two support portions 51 extending radially in a wing-like fashion from the central portion 52, those of skill in the art will understand that any number of support portions 51 in any shape, size or dimension may be utilized based on the intended application. For example, a radial distance R between an outer radial surface 54 and an inner radial surface 55 may be approximately 20 mm. However, for use with elderly or arthritic patients, the radial distance may be increased, and the support portions may be larger.
In an exemplary embodiment, the finger flange 50 may be made from polypropylene or acrylonitrile butadiene styrene and the support surfaces 53 may be made from elastomer thermoplastic.
FIG. 8 shows an exemplary embodiment of the finger flange 500 disposed on the outer sheath 31. In the exemplary embodiment, the finger flange 500 includes one or more support portions 501 extending radially from a central portion 502. Proximal and distal surfaces of the support portions 501 are concave, and proximal and distal surfaces of the central portion 502 are substantially flat (e.g., approximately perpendicular to a longitudinal axis of the first sheath 31). The support portion 501 may include a support surface 503. In an exemplary embodiment, the support surface 503 may be made, e.g. by overmolding or by two-shot injection molding, from a material having a lower durometer than the material comprising the finger flange 500. In an exemplary embodiment, the support surface 503 may be elastomer thermoplastic. The gripping surface 503 may provide a surface for a user's finger when administering an injection. In an exemplary embodiment, any part of the support surface 503 may include one or more frictional features (e.g., ridges, bumps, etc.) to ensure that the user's fingers do not slip when administering the injection. Likewise, the support surface 53 may be formed without such surface structures. While the exemplary embodiment of the invention shows two support portions 501 extending radially in a wing-like fashion from the central portion 502, those of skill in the art will understand that any number of support portions 501 in any shape, size or dimension may be utilized based on the intended application. For example, a radial distance R between an outer radial surface 504 and an inner radial surface 505 may be approximately 20 mm. However, for use with elderly or arthritic patients, the radial distance may be increased, and the support portions may be larger.
In an exemplary embodiment, the finger flange 500 may be made from polypropylene or acrylonitrile butadiene styrene and the support surfaces 503 may be made from elastomer thermoplastic.
FIG. 10 shows a finger flange 50 according to certain embodiments of the present invention. A proximal surface of the finger flange 50 includes a hole 70 adapted to receive the first sheath 31. In an exemplary embodiment, a diameter of the hole 70 is approximately equal to an outer diameter of the first sheath 31. A central recess 71 may be formed around the hole 70 and be adapted to accommodate a proximal portion of the first sheath 31. For example, the central recess 71 may include a bearing surface 71.1 adapted to abut a distal face of the outer ledge 36. The central recess 71 may further include a retaining wall 71.2 adapted to abut at least a portion of the outer ledge 36 to prevent rotation of the first sheath 31 relative to the finger flange 50. One or more resilient clips 72 are disposed within or adjacent the central recess 71 and adapted to engage the outer ledge 36. When the finger flange 50 is coupled to the first sheath 31, the clips 72 deflect to accommodate the outer ledge 36 and then return to a non-deflected position to engage the outer ledge 36.
In another exemplary embodiment, the bearing surface 71.1 may not be recessed but may be in plane with the proximal surface of the finger flange 50. In this exemplary embodiment, the retaining wall 71.2 and the clips 72 may extend proximally from the flat surface.
In an exemplary embodiment, the proximal surface of the finger flange 50 may include one or more lateral recesses 73 adjacent the central recess 71. The lateral recesses 73 may be formed to create a hinge effect when supporting the user's fingers. The lateral recesses 73 may further decrease weight of the finger flange 50 and reduce constraints on molding.
In an exemplary embodiment a protrusion 71.3 is arranged in the retaining wall 71.2 in a manner to engage a respective recess (not illustrated) in the outer ledge 36 so as to avoid and/or limit relative rotation between the first sheath 31 and the finger flange 50.
In another exemplary embodiment the protrusion 71.3 could be arranged in the hole 70 in a manner to engage a respective recess (not illustrated) in the first sheath 31. In the illustrated embodiment the protrusion 71.3 has an arcuate shape. Those skilled in the art will understand that the protrusion 71.3 may take any other form. Likewise, it would be possible to arrange the protrusion 71.3 on the first sheath 31 or on the outer ledge 36 in a manner to let it engage a corresponding recess in the retaining wall 71.2 or in the hole 70.
FIG. 11 shows a sectional detail view of an exemplary embodiment of a finger flange 50 according to certain embodiments of the present invention. The resilient clip 72 comprises a transverse beam 72.1 originating from the finger flange 50 and extending in a radial inward direction I. The transverse beam 72.1 may be arranged substantially in parallel with the finger flange 50, i.e. substantially at right angles with respect to the first sheath 31 to be received within the hole 70. The resilient clip 72 furthermore comprises a longitudinal beam 72.2 originating from a radial inward end of the transverse beam 72.1 and extending in a proximal direction P. A hook comprising a slope surface 72.3 and a block surface 72.4 is arranged on the proximal end of the longitudinal beam 72.2 and extends in the radial inward direction I. The slope surface 72.3 allows for inserting the outer ledge 36 of the first sheath 31 in a distal direction D, wherein the outer ledge 36 engages the slope surface 72.3 increasingly deflecting it in a radial outward direction O due to the resilient properties of the transverse beam 72.1 and/or the longitudinal beam 72.2. Once the outer ledge 36 has passed the slope surface 72.3 during insertion the resilient clip 72 relaxes and returns in the radial inward direction I. The distally facing block surface 72.4 thus engages a proximal face of the outer ledge 36 preventing it from returning in the proximal direction P.
FIG. 12 shows a sectional detail view of an exemplary embodiment of a finger flange 50 according to certain embodiments of the present invention. The embodiment substantially corresponds to the embodiment of FIG. 11. However, the embodiment of FIG. 12 differs from the embodiment of FIG. 11 in that the transverse beam 72.1 comprises a hinge 72.1.1, i.e. a section in which a thickness of the transverse beam 72.1 is reduced with respect to the rest of the transverse beam 72.1. In an exemplary embodiment the hinge 72.1.1 has a thickness of approximately 30% to 70%, in particular 40% to 60% of the thickness of the rest of the transverse beam 72.1. In an exemplary embodiment the hinge 72.1.1 is arranged adjacent the longitudinal beam 72.2.
While exemplary embodiments of the components and/or portions of the cap 60 are described as having certain shapes (e.g., cylinders, discs, etc.) with certain properties that connote a shape (e.g., a diameter, circumference, etc.), those of skill in the art will understand that the cap 60 according to present invention is not limited to any shape or size, but may be adapted for any application or use.
While exemplary embodiments of the present invention are described as being made from certain materials, those of skill in the art will understand that other materials (and/or combinations of materials) may be utilized based on the intended application or use.
The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound, wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound, wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis, wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro36 Exendin-4(1-39),
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ ωntain approximately 450 amino acids and δ approximately 500 amino acids, while p and E have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
Those of skill in the art will understand that modifications (additions and/or removals) of various components of the apparatuses, methods and/or systems and embodiments described herein may be made without departing from the full scope and spirit of the present invention, which encompass such modifications and any and all equivalents thereof.
REFERENCES
10 medicament delivery device
20 medicament container
22 barrel
24 stopper
26 needle
28 flange
29 needle shield
29.1 sheath
29.2 casing
30 safety device
31 first sheath
31.1 stop surface
32 second sheath
33 spring
34 engagement arrangement
34.1 support surface
34.2 resilient hook
35 inner ledge
36 outer ledge
37 resilient arm
40 plunger
41 distal end
42 proximal end
42.1 bearing surface
42.2 radial surface
42.3 ramp
43 stem
50 finger flange
51 support portion
52 central portion
53 support surface
54 outer radial surface
55 inner radial surface
60 cap
61 cylindrical portion
61.1 thru hole
62 disc portion
62.1 thru hole
63 gripping surface
63.1 proximal portion
63.2 distal portion
63.2.1 ramp feature
70 hole
71 central recess
71.1 bearing surface
71.2 retaining wall
71.3 protrusion
72 resilient clip
72.1 transverse beam
72.1.1 hinge
72.2 longitudinal beam
72.3 slope surface
72.4 block surface
73 lateral recess
500 finger flange
501 support portion
502 central portion
503 support surface
504 outer radial surface
505 inner radial surface
D distal direction
I radial inward direction
O radial outward direction
P proximal direction
R radial distance
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16446755
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sanofi
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 20th, 2022 02:26PM
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Apr 20th, 2022 02:26PM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 12th, 2022 12:00AM
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Sep 5th, 2016 12:00AM
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https://www.uspto.gov?id=US11298458-20220412
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Drug delivery device
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The present disclosure relates to a drug delivery device for dispensing of a liquid medicament, the device comprising:
a housing to accommodate a cartridge filled with the medicament and having a piston slidably displaced inside the cartridge and sealing a proximal end of the cartridge,
at least one resilient member having a first end arranged at an inside facing side wall portion of the housing and having a second end (opposite to the first end to abut with the piston of the cartridge.
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11298458
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1. A drug delivery device for dispensing of a liquid medicament, the drug delivery device comprising:
a housing to accommodate a cartridge filled with the liquid medicament and having a piston slidably displaced inside the cartridge and sealing the cartridge;
a resilient member having a first end arranged at an inside facing side wall portion of the housing and having a second end opposite to the first end to abut the piston of the cartridge; and
an electronic suction pump to connect to a distal end of the cartridge for a suction-based extraction of the liquid medicament from the cartridge.
2. The drug delivery device according to claim 1, wherein the first end of the resilient member is firmly attached to the side wall portion of the housing.
3. The drug delivery device according to claim 1, wherein the resilient member protrudes substantially perpendicular from the side wall portion, and the second end extends into an interior of the housing.
4. The drug delivery device according to claim 1, further comprising a pressure piece attached to the second end of the resilient member, wherein the pressure piece is complementary shaped to a cross section of the piston.
5. The drug delivery device according to claim 1, wherein the resilient member is integrally formed with the side wall portion.
6. The drug delivery device according to claim 1, wherein the resilient member comprises a compression spring.
7. The drug delivery device according to claim 1, wherein the resilient member is made of a plastic material, an elastomeric material, or a combination thereof.
8. The drug delivery device according to claim 1, further comprising a tube with a connector to establish a fluid transferring interconnection with an interior of the cartridge.
9. The drug delivery device according to claim 1, further comprising the cartridge firmly assembled inside the housing with the piston axially abutting the resilient member, wherein a magnitude of a force exerted by the resilient member onto the piston is smaller than or substantially equal to a breakaway force necessary to displace the piston relative to a barrel of the cartridge when the piston is initially resting.
10. The drug delivery device according to claim 1, wherein the side wall portion of the housing is pivotably or detachably connected to another portion of the housing.
11. The drug delivery device according to claim 10, wherein:
the side wall portion forms a lid to cover an access opening of the housing,
a first end of the lid is pivotably attached to the other portion of the housing via a hinge, and
a second end of the lid comprises a fastener to releasably engage with a complementary shaped fastening structure of the housing when in a closed configuration in which the lid covers the access opening.
12. The drug delivery device according to claim 1, wherein the housing comprises a reusable housing part and a disposable housing part that are detachably connectable.
13. The drug delivery device according to claim 12, wherein the cartridge is assembled inside the disposable housing part.
14. The drug delivery device according to claim 12, wherein the first end of the resilient member is attached to the reusable housing part or to the disposable housing part.
15. A method of assembling a drug delivery device, the drug delivery device comprising a housing to accommodate a cartridge filled with the liquid medicament and having a piston slidably displaced inside the cartridge and sealing the cartridge, a resilient member having a first end arranged at an inside facing side wall portion of the housing and having a second end opposite to the first end to abut the piston of the cartridge, and an electronic suction pump to connect to a distal end of the cartridge for a suction-based extraction of the liquid medicament from the cartridge, the method comprising:
inserting the cartridge into an opening of the housing of the drug delivery device; and
placing a sidewall portion of the housing into a closed configuration to cover the opening and cause the second end of the resilient member of the drug delivery device to abut the piston of the cartridge.
16. The method of claim 15, wherein the sidewall portion comprises a pivotable lid, wherein placing the sidewall portion of the housing into the closed configuration comprises closing the lid to cover the opening and cause the resilient member of the drug delivery device to abut the piston of the cartridge.
17. The method of claim 15, wherein placing the sidewall portion of the housing into the closed configuration comprises causing the resilient member to exert a magnitude of force onto the piston smaller than or substantially equal to a breakaway force necessary to displace the piston relative to a barrel of the cartridge when the piston is initially resting.
18. The method of claim 15, wherein inserting the cartridge into the opening of the housing comprises placing the cartridge into fluid communication with a suction pump configured to deliver medicament from the cartridge.
19. The method of claim 15, wherein:
inserting the cartridge into the opening of the housing comprises inserting the cartridge into a disposable portion of the housing, and
the resilient member is arranged on the disposable portion or a reusable portion of the housing.
20. A drug delivery device for dispensing of a liquid medicament, the drug delivery device comprising:
a housing to accommodate a cartridge filled with the liquid medicament and having a piston slidably displaced inside the cartridge and sealing the cartridge;
a resilient member having a first end arranged at an inside facing side wall portion of the housing and having a second end opposite to the first end to abut the piston of the cartridge;
a suction pump to connect to a distal end of the cartridge for a suction-based extraction of the liquid medicament from the cartridge; and
a tube with a connector to establish a fluid transferring interconnection with an interior of the cartridge, wherein the tube extends through the suction pump and is connected to a dispensing outlet to allow the liquid medicament, transported through the tube, to be directly injected into a biological tissue.
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CROSS REFERENCE TO RELATED APPLICATIONS
The present application is the national stage entry of International Patent Application No. PCT/EP2016/070882, filed on Sep. 5, 2016, and claims priority to Application No. EP 15185785.1, filed in on Sep. 18, 2015, the disclosures of which are expressly incorporated herein in entirety by reference thereto.
TECHNICAL FIELD
The present disclosure relates to the field of drug delivery devices and in particular to the field of injection devices for delivery of a liquid medicament by way of injection.
BACKGROUND
Drug delivery devices for setting and dispensing a single or multiple doses of a liquid medicament are as such well-known in the art. Generally, such devices have substantially a similar purpose as that of an ordinary syringe.
Drug delivery devices and in particular injection devices have to meet a number of user-specific requirements. For instance, with patient's suffering chronic diseases, such like diabetes, the patient may be physically infirm and may also have impaired vision. Suitable drug delivery devices especially intended for home medication therefore need to be robust in construction and should be easy to use. Furthermore, manipulation and general handling of the device and its components should be intelligible and easy understandable. Moreover, a dose setting as well as a dose dispensing procedure must be easy to operate and has to be unambiguous.
The medicament to be dispensed by the drug delivery device is provided and contained in a multi-dose cartridge. Such cartridges typically comprise a vitreous barrel sealed in distal direction by means of a pierceable seal and being further sealed in proximal direction by the piston. With reusable drug delivery devices an empty cartridge is replaceable by a new one. In contrast to that, drug delivery devices of disposable type are to be entirely discarded when the cartridge is empty.
Automated medicament delivery devices, such like auto-injectors provide a rather easy and convenient approach to inject a predefined dose of a liquid medicament into biological tissue.
With some automatically or semi-automatically driven drug delivery or injection devices it is hence convenient to connect a suction pump to a distal outlet of the cartridge whereas the proximal end of the cartridge is sealed by the piston. Extraction and withdrawal of the medicament due to a suction effect of the suction pump is then typically accompanied by a distally-directed but suction-based displacement of the piston relative to the barrel.
Delivery devices equipped with an electric drive and hence with an electrically-operated pump are typically configured as a reusable device allowing to replace an empty cartridge by a new one. Such electrical pump-driven devices comprise at least a reusable unit to be connected with a disposable unit, wherein the cartridge is typically located inside the disposable unit. Upon deploying the device and prior to extract an initial dose from a new cartridge the cartridge has to be mounted inside the drug delivery device or the disposable device unit has to be connected with the reusable device unit. In either case the time interval between a manufacturing and filling of a cartridge and an initial use of the cartridge by means of the drug delivery device or injection device may be comparatively long. At least some days, weeks, months or even years may have passed from the manufacturing of the cartridge and its initial use in or with a suitable drug delivery device.
Depending on a storage time or the shelf life of a cartridge a breakaway or break-loose force to be applied onto the piston may be substantially high for driving the piston in distal direction relative to the barrel of the cartridge. Therefore, the suction force of a pump to be used with such a cartridge in connection with such drug delivery devices needs to be quite large. This requires implementation of rather large and powerful pumps and requires implementation of tubes or comparable fluid-guiding structures that are capable to transfer and to withstand such comparatively large suction forces.
The implementation of rather large, powerful and also heavy weight pumps in drug delivery devices is of particular disadvantage when the drug delivery device is intended for a mobile use, where weight, space and storage of electric energy are of particular relevance.
It is therefore an object of the present disclosure to provide an improved drug delivery device for dispensing of a liquid medicament, typically by way of injection. The drug delivery device or the injection device should provide an effective and simple means to overcome an initial breakaway force or break-loose force necessary to displace a piston inside a barrel of a cartridge after the piston has been subject to a short-term or long-term storage prior to its use in the drug delivery device. The improvements to be made to the drug delivery device should be rather simple and cost-efficient and should be easy to implement into existing designs of drug delivery devices. Optionally, the improvements to be made to the drug delivery device should be suitable for retrofitting of existing drug delivery devices.
SUMMARY DISCLOSURE
In one aspect the disclosure relates to a drug delivery device for dispensing of a liquid medicament. The disclosure particularly relates to an injection device that provides dispensing of a single or multiple well-defined doses of a liquid medicament and further provides injection of the liquid medicament into biological tissue of a patient. The drug delivery device comprises a housing to accommodate a cartridge filled with the liquid medicament. The cartridge to be assembled in the housing has a piston slidably displaced inside the cartridge, wherein said piston seals a proximal end of the cartridge. Typically, an opposite end, hence a distal end of the cartridge comprises or forms an outlet through which the liquid medicament can be extracted from the interior of the cartridge.
In addition, the drug delivery device comprises at least one resilient member having a first end that is arranged at an inside-facing sidewall portion of the housing. The resilient member further has a second end opposite to the first end. The second end is configured to abut with or to abut against the piston of the cartridge. In particular, the second end of the resilient member is configured to abut with a proximally-facing surface of the piston so as to exert a pressure onto the piston that acts in distal direction.
By means of the at least one resilient member typically sandwiched between an inside-facing sidewall portion of the housing and the piston of the cartridge, the piston can be somewhat pre-tensed in distal direction. With a suction-based withdrawal or extraction of the medicament from the cartridge via its distal outlet the resilient member supports an initial displacement of the piston relative to the cartridge, hence, relative to a tubular-shaped barrel of the cartridge in which the piston is slidably arranged.
Investigations have revealed that a first or an initial displacement of the piston inside the cartridge after long-term or even short-term storage of the cartridge requires an initial force level that is much larger than a force level normally to be applied to a non-moving piston at the beginning of frequent dispensing procedures. In typical application scenarios the piston might be subject to a single continuous displacement for emptying the cartridge in one go. In such a scenario the cartridge is only subject to dynamic friction after it has set in motion initially. In other typical scenarios of use the medicament is dispensed or injected in accordance with a predefined administering schedule according to which several doses of the medicament are dispensed and extracted from the cartridge at consecutive times, wherein the time intervals between consecutive dispensing procedures are rather small compared to the storage time between manufacturing of the cartridge and its initial use with the drug delivery device.
Hence, it is only at the very beginning and with an initial displacement of the piston inside the cartridge that a rather large force has to be applied to the piston in order to overcome the comparatively large break-loose or breakaway force of the piston relative to the barrel of the cartridge. A rather powerful pump for extracting the medicament from the cartridge would be only needed at the very beginning of the extraction of the medicament from the cartridge.
By means of the resilient member supporting an initial displacement of the piston relative to the barrel of the cartridge a very simple but rather effective means is provided to overcome the comparatively large breakaway or break-loose force of the piston. Consequently, the drug delivery device can be equipped with a less powerful pump that requires less assembly space, which comes along with a reduced weight and which is operable with reduced electrical power compared to conventional pump-driven drug delivery devices, where the suction force provided by the pump alone has to overcome the initial breakaway force of the piston inside the cartridge.
Accordingly, the resilient member configured to provide a well-defined force effect or pressure onto the piston of the cartridge in an initial configuration of the cartridge is of particular use to reduce the dimensions, the weight, the costs as well as the overall energy consumption of the drug delivery device.
According to another embodiment the resilient member is firmly attached to the sidewall portion of the housing with its first end. In this way the position of the resilient member inside the housing is rather fixed. Hence, the resilient member is inherently in a correct position inside the housing in order to engage and to abut with the piston of the cartridge as the piston is correctly arranged inside the housing of the drug delivery device. Generally, the resilient member is configured to get biased as the cartridge is assembled inside the drug delivery device. Hence, the longitudinal extension of the resilient member, hence its extension between the first end and the second end is selected such that in an unbiased or non-compressed configuration the axial or longitudinal extension of the resilient member is larger than a longitudinal or axial gap between a proximal end face of the piston and the inside-facing sidewall portion of the housing, to which the resilient member is attached.
In this way and upon correct assembly of the cartridge inside the housing the resilient member is at least partially biased or compressed in order to store mechanical energy. Depending on the degree of compression and the specific implementation and configuration of the resilient member, said member serves to exert a permanent force effect onto the proximal end face of the piston in order to support is displacement in distal direction relative to the barrel of the cartridge during an initial dispensing process.
According to another embodiment the resilient member protrudes substantially perpendicular from the sidewall portion. The second end of the resilient member furthermore extends into the interior of the housing. The second end of the resilient member protrudes into an area of the interior of the housing, which is typically occupied by the cartridge, in particular by its piston.
When in a final assembly configuration inside the housing the inside of the sidewall portion to which the resilient member is attached typically extends substantially parallel to the proximal face of the piston of the cartridge. Then and since the resilient member protrudes substantially perpendicular from the sidewall the resilient member with its second end also extends substantially perpendicular to the proximal end face of the piston. In this way, a force effect exerted by the resilient member towards and onto the piston is directed substantially parallel to the elongation of the piston. This is particularly beneficial for a smooth and longitudinal displacement of the piston inside the cartridge at the beginning of a first or initial dispensing procedure.
According to another embodiment the drug delivery device further comprises a pressure piece attached to the second end of the resilient member. The pressure piece is complementary-shaped to the cross-section of the piston. In a final assembly configuration it is intended that the pressure piece substantially covers the entire proximal face of the piston so as to exert a spatially homogeneous force effect onto the piston. By making use of a pressure piece, a punctual and spatially localized force provided by the resilient member can be evenly homogeneously distributed across the proximal end face of the piston.
In this way a rather homogeneous force effect acting on the piston can be provided, which is beneficial for a smooth displacement of the piston relative to the barrel of the cartridge at the beginning of an initial dispensing procedure. The pressure piece may be provided as a separate piece and may be detachably connected to the second end of the resilient member. Having the pressure piece replaceably assembled to the resilient member allows making use of different pressure pieces with one and the same resilient member. This allows reconfiguring the drug delivery device for a use of cartridges of different diameter. Alternatively and according to another embodiment the pressure piece and the resilient member are integrally formed. Then, the pressure piece actually forms the second end of the resilient member to get in direct axial abutment with the proximal face of the piston of the cartridge.
In another embodiment the resilient member is integrally formed with the sidewall portion of the housing. Typically, the sidewall portion of the housing or the entire housing is made of an injection-molded plastic material. By an integral formation of the resilient member and the sidewall portion a mutual assembly and a mutual attachment and fixing of resilient member and sidewall of the housing becomes somewhat superfluous. The integral and single piece embodiment of resilient member and sidewall portion of the housing is particularly suitable for a cost-efficient mass production of the drug delivery device. By integrally forming the resilient member with the sidewall portion of the housing any geometric tolerances with regard to the resilient member, the sidewall portion and their mutual assembly that would arise otherwise can be reduced to a minimum.
In another embodiment the resilient member comprises a compression spring. Here, a first longitudinal end of the compression spring is connected to the inside of the housing's sidewall portion whereas an opposite longitudinal end of the compression spring is configured to get either in direct or indirect axial abutment with the piston of the cartridge as the cartridge is correctly assembled inside the housing of the drug delivery device. As already mentioned, the distal end, hence the second end of the resilient member and hence the second end of the compression spring may be connected to a pressure piece having a geometric shape that commutates with the geometric shape of the proximal face of the piston of the cartridge. In typical embodiments the distal face of the pressure piece as well as the proximal face of the piston are substantially even or flat-shaped.
When implemented as a compression spring the resilient member may still be integrally formed with the sidewall portion or with the housing of the drug delivery device.
In another embodiment the resilient member is made of a plastic material, of an elastomeric material or of a combination thereof. Alternatively, it is also conceivable that the resilient member comprises a metal spring. When made of a plastic and/or an elastomeric material the resilient member is particularly light-weight and provides a well-defined elasticity in order to store mechanical energy when getting in abutment with the piston of the cartridge. By making use of a suitable plastic or elastomeric material a well-defined spring force or a well-defined elastic or resilient behavior of the resilient member in response to an axial compression between the piston of the cartridge and the sidewall of the housing can be provided.
According to a further embodiment the sidewall portion of the housing to which the resilient member is attached to is pivotably or detachably connected to the housing. A pivotable or detachable connection of the sidewall portion to the rest of the housing provides the possibility to insert the cartridge into the housing without any interference with the resilient member. With a pivotable embodiment the sidewall portion together with the resilient member attached thereto can be simply pivoted aside so as to give way for inserting the cartridge through an access opening of the housing into a respective cartridge compartment inside the housing.
Thereafter and by pivoting the sidewall portion together with the resilient member into a closed configuration the resilient member starts to exert a distally-directed pressure onto the piston of the cartridge. The same may be attainable with the sidewall portion of the housing being detachably connected to the housing. In either case the sidewall portion to which the resilient member is attached to can be fixed and interlocked to the housing, typically by way of various fastening members, such like mutually-corresponding positive locking members, such like clip fasteners or by means of a screwed connection.
According to a further embodiment the sidewall portion forms a lid to cover an access opening of the housing when said sidewall portion is pivotably connected to the housing. Then, one end of said lid is pivotably attached to the housing via a hinge while an opposite end of the lid comprises a fastener to releasably engage with a complementary-shaped fastening structure of the housing thereby keeping the lid in a closed configuration in which it closes the access opening. By making use of a hinged connection of the particular sidewall portion and the housing the lid formed by said sidewall portion is permanently connected to the housing and cannot get lost when in an open configuration, in which the access opening is accessible for insertion or replacement of a cartridge.
In another embodiment the drug delivery device further comprises a suction pump to connect to a distal end of the cartridge for a suction-based extraction of the liquid medicament therefrom. The pump may be configured as a peristaltic pump or other types of suction pumps by way of which the medicament can be withdrawn and extracted from the interior of the cartridge by way of suction. With a suction pump the drug delivery device does not require any drive mechanism operable to displace the piston of the cartridge actively, e.g. by way of providing a constant driving force from the proximal end to the piston for driving the same in a distal direction.
By means of a suction pump in combination with the resilient member a rather moderate suction effect can be applied to the liquid medicament while a comparatively large breakaway force of the piston is exerted only in combination with the force effect of the resilient member. Once the piston has at least slightly moved in distal direction at the very beginning of a dispensing procedure the cartridge is either subject to a continuous or stepwise emptying and extraction of its entire content. Since the time period for the complete emptying of the cartridge is rather small compared to a previous storage time of the cartridge any repeatedly arising static friction force between the sidewall of the cartridge's barrel and the piston slidably disposed therein will be substantially smaller and may be conquered exclusively by the suction effect arising from the pump of the drug delivery device.
In a further embodiment the drug delivery device also comprises a tube with a connector to establish a fluid transferring interconnection with the interior of the cartridge. The tube may be configured as a flexible tube and may belong to a disposable tube system mechanically interacting with, e.g. a peristaltic pump, such that through repeated squeezing of the flexible tube a well-defined amount of the medicament can be extracted from the interior of the cartridge by way of suction. The connector of the tube may be a standardized connector to connect to a complementary-shaped standardized connector at the distal outlet of the cartridge. Such standardized connector may be of male and female type e.g. of male and female Luer type.
It is also conceivable that the connector comprises a tipped cannula to pierced and to intersect a pierceable seal at the distal outlet of the cartridge. Typically, it is the proximal end of the tube that is provided with the connector to establish a fluid transferring interconnection with the cartridge's interior. Moreover, a distal end of the tube may be provided with a comparable connector. The distal end of the tube may be alternatively provided with an injection needle by way of which the medicament withdrawn from the cartridge can be directly dispensed and injected into biological tissue of a patient.
In another embodiment the drug delivery device is equipped with a cartridge filled with the medicament to be dispensed. The cartridge is firmly assembled inside the housing of the drug delivery device, in particular in a suitable cartridge compartment of the housing. When firmly assembled in a final assembly configuration inside the housing the piston of the cartridge is in axial abutment with the resilient member. Then, a level or a magnitude of a force exerted by the resilient member onto the piston is smaller than or substantially equal to a breakaway or break-loose force that is necessary to displace an initially resting piston relative to the barrel of the cartridge.
Typically, the cartridge is firmly assembled inside the housing, hence inside a particular cartridge compartment in a rather well-defined way, so that the piston, in particular its proximal end face is located in a well-defined axial position relative to the housing of the drug delivery device. It is either upon a correct assembly of the cartridge inside the drug delivery device or by closing a lid of the housing equipped with the at least one resilient member that a distally-directed pressure is permanently exerted onto the piston as long as the dispensing progress, hence the extraction or withdrawal of the medicament from the cartridge actually begins.
It is of particular use that the force level exerted by the resilient member is below the typical threshold of the initial breakaway or break-loose force so that the resilient member hardly influences the extraction or dispensing process. In addition and since the resilient member is typically attached to the inside of the housing of the drug delivery device the force exerted by the resilient member is only present during an initial stage of medicament extraction. As the piston of the cartridge moves in distal direction either continuously or stepwise the force effect of the resilient member will permanently decrease until the piston loses contact to the resilient member. Then the piston displacement is only and exclusively governed by the suction effect provided by the suction pump of the drug delivery device. As the piston and the resilient member lose mutual contact the level of the force provided by the resilient member abruptly drops to zero.
It is even also conceivable that the magnitude or level of the force exerted by the resilient member onto the piston is even larger than a breakaway or break-loose force that is necessary to displace the piston relative to the barrel. In this case the piston is at least slightly displaced in a distal direction upon a final assembly of the drug delivery device or upon insertion of the cartridge into the housing of the drug delivery device. The medicament located inside the cartridge may thus be slightly pressurized. This may help to fill the tube when the cartridge gets in fluid communication with the distally-located outlet end of the cartridge.
According to a further embodiment the housing of the drug delivery device comprises a reusable housing part and a disposable housing part, wherein the reusable housing part and the disposable housing part are detachably connectable. The disposable housing part may comprise all those components of the drug delivery device that are intended for a single use. Those components together with the disposable housing part are thus intended to be discarded after they have been used. The reusable housing part typically comprises those components of the drug delivery device that are intended for multiple uses. Typically, these are for instance the pump or at least an electric drive for driving the pump, an energy source, such like a battery and a control interacting with the drive and hence with the pump for extracting the medicament from the cartridge and for conducting the dispensing or injection process.
By splitting of the housing of the drug delivery device into a reusable part and into a disposable part a rather user friendly handling of the housing and hence of the entire drug delivery device can be provided. In a further embodiment the cartridge is assembled inside the disposable housing part. Upon emptying of the cartridge the disposable housing part is to be disconnected from the reusable housing part. It is then to be discarded together with the cartridge located therein. Typically, the disposable housing part also houses the tube or other components of the drug delivery device that get in direct contact with the liquid medicament or with the biological tissue of the patient. It is then rather practical and for the benefit of maintaining a high level of hygiene that the disposable housing part is intended to be discarded in its entirety.
In another embodiment the first end of the resilient member is attached to the reusable housing part or to the disposable housing part. When attached to the reusable housing part the resilient member may extend into the disposable housing part as the disposable housing part is attached to the reusable housing part. In this way the second end of the resilient member actually extends into the disposable housing part in which also the cartridge is located. In an alternative embodiment it is also conceivable, that the cartridge is not completely accommodated inside the disposable housing part but extends from the disposable housing part at least with its proximal end. Upon a final assembly of disposable and reusable housing parts the proximal end of the cartridge may then extend into a portion of the reusable housing part in which the resilient member is located.
In the present context the distal direction denotes a dispensing end of the drug delivery device. When the drug delivery device is implemented as an injection device the distal end of the drug delivery device faces towards an injection site of a patient. The proximal end or the proximal direction faces in the opposite longitudinal direction of the device. When implemented as an injection device, the proximal end of the drug delivery device is typically operable by a hand of a user so as to configure, to set and to conduct an injection procedure.
The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue or derivative of exendin-3 or exendin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro36 Exendin-4(1-39),
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(02)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(02)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exendin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
It will be further apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit and scope of the invention as it is defined by the claims. Further, it is to be noted, that any reference numerals used in the appended claims are not to be construed as limiting the scope of the invention.
BRIEF DESCRIPTION OF THE FIGURES
In the following, an embodiment of the display arrangement, the drive mechanism and the drug delivery device is described in detail by making reference to the drawings, in which:
FIG. 1 shows a schematic illustration of a portion of the drug delivery device before the resilient member axially engages with the piston of the cartridge,
FIG. 2 shows the portion of the drug delivery device according to FIG. 1, wherein the cartridge and the housing of the drug delivery device are in a final assembly configuration in which the resilient member axially engages with the piston of the cartridge,
FIG. 3 shows a schematic diagram illustrating various force levels,
FIG. 4 shows a complete schematic illustration of the drug delivery device and
FIG. 5 shows an alternative implementation of the drug delivery device.
DETAILED DESCRIPTION
The drug delivery device 10 as illustrated in FIGS. 1, 2 and 4 comprises a housing 20 having a reusable housing part 22 and a disposable housing part 24. The reusable housing part 22 and the disposable housing part 24 are detachably connected via fasteners 34, 36 by way of which the two housing parts 22, 24 can be detached and disconnected if required. The reusable housing part 22 accommodates various reusable components of the drug delivery device 10, such like an electric drive 17, a battery 18 as well as a control 19. The electric drive 17 is in mechanical interconnection with a pump 12, typically comprising a pump head by way of which a liquid medicament can be extracted and withdrawn from the interior 45 of a cartridge 40.
The pump 12 is connected to the interior 45 of the cartridge 40 by means of a tube 14 in a fluid-guiding way. The tube 14 may extend through the pump 12 and may be directly connected with a dispensing outlet 16. The tube 14 may be even integrally formed with the outlet 16. The dispensing outlet 16 may be configured as an injection needle by way of which the medicament transported through the tube 14 can be directly injected into biological tissue. Instead of a tipped cannula or an injection needle the dispensing outlet 16 may be also provided with a standardized connector by way of which the drug delivery device 10 is detachably connectable to a transfusion system or the like medicament transportation means.
Inside the disposable housing part 24 there is located a cartridge 40 comprising a tubular-shaped barrel 43 having a distal end 41 and having a proximal end 42. The cartridge 40, in particular its tubular shape defines a longitudinal or axial direction. At the distal end 41 the cartridge 40 comprises a pierceable seal 47 that is pierceable or penetrable by a connector 15 in fluid communication with the tube 14. The connector 15 may be firmly and non-moveably assembled inside the disposable housing part 24 while the cartridge 40 is insertable into the housing along a distal longitudinal direction, hence from the right to the left direction according to the illustration of FIG. 1, 2 or 4.
When arriving at a predefined position inside the disposable housing part 24 the cartridge 40 is firmly fastened inside the housing 20. An axial but also a radial fastening may be obtained by a mutual axial abutment of a cartridge's shoulder portion 48 getting in axial abutment with a correspondingly-shaped mount 38 at the inside of the housing part 24 of the housing 20 of the drug delivery device. In this way, the cartridge 40 can be firmly fixed inside the housing 20. The interaction of the mount 38 with the shoulder portion 48 at least delimits or confines a displacement of the cartridge 40 relative to the housing 20 in distal direction 1.
The housing 20 of the drug delivery device 10 further comprises a sidewall portion 26 with an inside 28 facing towards the proximal end 42 of the cartridge 40 when assembled inside the disposable housing portion 24. The sidewall portion may get in direct axial abutment with a proximal end of the cartridge, in particular with a proximal end 42 of its barrel 43. There is further provided a resilient member 60 which is configured as a type of a compression spring in the embodiment according to FIGS. 1, 2 and 4. The resilient member 60 comprises a first end 61 by way of which it is firmly attached to the inside 28 of the sidewall portion 26 of the housing 20 of the drug delivery device 10. With its opposite second end 62 the resilient member 60 points towards a proximal end face 46 of a piston 44 of the cartridge 40. The second end 62 therefore points into the interior 21 of the housing 20. The piston 44 serves as a proximal seal for the interior of the cartridge 45 filled with a liquid medicament. The piston 44 typically made of an elastic material is displaceable in longitudinal direction inside the tubular-shaped barrel 43 of the cartridge.
Optionally, the second end 62 of the resilient member 60 is provided with a pressure piece 64. In the present embodiment as shown in FIGS. 1 and 2 the pressure piece 64 is shaped as a flat disc that matches in contour and size with the proximal end face 47 of the piston 44. As it is apparent from a comparison of FIGS. 1 and 2 the sidewall portion 26 of the housing, in particular of the disposable housing part 24 is configured as a pivotable lid 30 that is pivotably attached to the disposable housing part 24 by means of a hinge 31.
The hinge 31, which may be configured as a film hinge, e.g. integrally formed with the sidewall portion 26, provides a permanent connection between the sidewall portion 26, hence of the lid 30 and the housing 20 of the drug delivery device 10. By pivoting the lid 30 in a clockwise direction as indicated in FIG. 1 an access opening 29 of the housing part 24 gets accessible for removal and for insertion of a cartridge 40 into a respective cartridge compartment inside the housing 20. Once a cartridge 40 has been correctly assembled inside the housing part 24 the lid 30 can be pivoted in a counter-clockwise direction so that a fastener 32 located at an end opposite to the hinge 31 can detachably or releasably engage with a correspondingly or complementary-shaped fastening structure 33 in a sidewall portion of the housing part 24.
This configuration is shown in FIG. 2. By closing the lid 30 the sidewall portion 26 approaches the proximal surface 46 of the piston 44 so that the pressure piece 64 gets in direct abutment with the piston 44. Upon a mutual engagement of the fastener 32 with the fastening structure 33 the resilient member 60 is subject to an axial compression. Hence, the windings 63 of the substantially unbiased or relaxed compression spring are subject to an axial compression. Consequently, the windings 63′ as shown in FIG. 2 comprise a much smaller axial distance compared to the windings as illustrated in FIG. 1. In the fully assembled configuration as shown in FIG. 2 the resilient member 60 is compressed to a predefined degree and permanently exerts a distally-directed pressure onto the piston 44 of the cartridge 40.
Typically, the level of the force effect provided by the biased or compressed resilient member 60 is substantially smaller, substantially equal to or even slightly larger than a force level 202 that is required for an initial breakaway of the piston 44 relative to the barrel 43 of the cartridge 40. In FIG. 3 a force level diagram 200 versus time is illustrated. In an initial configuration and after the cartridge 40 has been subject to a short term or long term storage a breakaway or break-loose force for setting the piston 40 in motion relative to the barrel 43 of the cartridge 40 is substantially high. This initial breakaway force 202 may be even higher than the force level 204 that is typically required during subsequent dose dispensing procedures for displacing the piston in distal direction.
In the diagram 200 according to FIG. 3 various consecutive dose dispensing procedures are illustrated as a kind of a rectangle or square function. Once the piston 44 has been in motion and has stopped at the end of a particular dispensing procedure a repeated displacement of the piston 44 inside the barrel 43 is accompanied by a substantially smaller level of a breakaway force as it is apparent from the consecutive peaks 204 in the diagram of FIG. 3.
In the diagram 200 of FIG. 3 there is further illustrated the force effect 206 that is provided by the resilient member 60. The initial force effect 206 at the beginning of a dispensing action may be fairly large. The level of the force effect provided by the resilient member 60 may be located between the force level 204 and the force level 202. But as the piston 44 is subject to a displacement in distal direction 1 the resilient member 60 is subject to expansion. Consequently, the force provided by the resilient member 60 decreases and even drops to zero when the piston 44 gets out of contact with the resilient member 60.
Even though the lid 30 has been shown to belong to a disposable housing portion 24 it is also implementable with a reusable housing part 22. Moreover, the resilient member 60 and its sandwiched configuration between a sidewall portion 26 of the housing 20 of the drug delivery device and a piston 44 of the cartridge 40 is universally implementable with a large variety of drug delivery devices and respective housings. The resilient member can be equally applied to reusable and disposable housing parts and respective drug delivery devices.
The embodiment according to FIG. 5 slightly differs from the embodiment as shown in FIG. 4. Also here, the drug delivery device 100 comprises a housing 120, wherein the housing 120 comprises a reusable housing part 122 and a disposable housing part 124. Even though not particularly illustrated the structure and configuration of the reusable housing part 122 is highly similar or even identical to that one of the reusable housing part 22 as shown in FIG. 4. The same is also valid for the components and the functionality of the disposable housing part 124.
The cartridge 40 can be assembled inside the disposable housing part 124 as described in connection with the embodiment as shown in FIG. 4. In the embodiment of FIG. 5, the cartridge 40 may be fixed with regard to the disposable housing part 124 in proximal direction 2 by means of a resilient member 160. Here and in contrast to the configuration according to FIG. 4 the resilient member 160 is implemented as a dome-shaped pin extending in distal direction 1 from the inside of a sidewall portion of a lid 130. Depending on the mutual interconnection of reusable housing part 122 and disposable housing part 124 the lid 130 may be rigidly connected to the reusable housing part 122.
It does not need to be pivotably attached thereto. The lid 130 may be configured as a protruding or flange-like housing portion extending from a sidewall of the reusable housing part 122. The mutually corresponding fasteners 34, 36 of the reusable housing part 122 and the disposable housing part 124 are configured such that upon reaching of a final assembly configuration the piston 44 of the cartridge 40 operably engages with the second end 162 of the resilient member 160. It does not only get in contact with the resilient member 160 but also serves to squeeze or compress the resilient member 160 in longitudinal or proximal direction so that the resilient member 160 is somewhat biased and resiliently compressed. The first end 161 of the resilient member 160 is firmly attached or fastened to the inside of the lid 130. The second end 162 therefore points into the interior 121 of the housing 120 and towards the proximal end face 46 of the piston 44. In this way the resilient member 160 generally provides a distally-directed pressure onto the piston 44 until an initial dispensing action takes place. In the embodiment according to FIG. 5 it is actually the resilient member 160 that is attached to the reusable housing part 122.
LIST OF REFERENCE NUMBERS
1 distal direction
2 proximal direction
10 drug delivery device
12 pump
14 tube
15 connector
16 dispensing outlet
17 drive
18 battery
19 control
20 housing
21 interior
22 reusable housing portion
24 disposable housing portion
26 sidewall portion
28 inside
29 access opening
30 lid
31 hinge
32 fastener
33 fastening structure
34 fastener
36 fastener
38 mount
40 cartridge
41 distal end
42 proximal end
43 barrel
44 piston
45 interior
46 proximal surface
47 pierceable seal
48 shoulder portion
60 resilient member
61 first end
62 second end
63 winding
64 pressure piece
100 drug delivery device
120 housing
121 interior
122 reusable housing part
124 disposable housing part
130 lid
160 resilient member
161 first end
162 second end
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15760879
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sanofi-aventis deutschland gmbh
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 12th, 2022 11:48AM
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Apr 12th, 2022 11:48AM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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nyse:sny
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Sanofi
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Apr 12th, 2022 12:00AM
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May 1st, 2019 12:00AM
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https://www.uspto.gov?id=US11298471-20220412
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Limiting life time of dispense assembly
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The technical problem of the present invention to provide a medical device, which exhibits an increased safety of the device and facilitates a safe use is solved by medical device for delivering at least one drug agent, comprising a sensor, a control unit and an attachable dispense assembly, wherein the sensor is configured to detect attachment of the dispense assembly to the medical device, wherein the control unit is configured to determine at least based on a signal from the sensor whether the end of life of the dispense assembly is reached and wherein the medical device is configured to indicate the end of life of the dispense assembly. The technical problem is further solved by a method according to the invention.
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11298471
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1. A drug delivery device configured to deliver at least one medicament, the drug delivery device comprising:
a main body;
a cartridge retainer configured to receive a cartridge of a medicament, the cartridge retainer including a hinged connection to the main body and being moveable between an open position and a closed position;
one or more first sensors configured to detect the presence of the cartridge in the cartridge retainer, wherein the one or more first sensors are pressure activated switches; and
one or more second sensors configured to detect that the cartridge retainer is in the closed position, wherein the one or more second sensors are selected from the group of sensors consisting of a light barrier sensor, a camera, a barcode reader, and a proximity sensor.
2. The drug delivery device according to claim 1, wherein the drug delivery device further comprises a controller including the one or more first sensors.
3. The drug delivery device according to claim 2, wherein the one or more first sensors are each connected to digital inputs of the controller.
4. The drug delivery device according to claim 2, wherein the controller is configured to control at least one motor drive for expulsion of the medicament from the cartridge.
5. The drug delivery device according to claim 4, wherein the at least one motor drive is a stepper motor.
6. The drug delivery device according to claim 2, wherein the controller is operatively coupled to a plurality of human interface elements or push buttons.
7. The drug delivery device according to claim 2, further comprising a display, wherein the controller is configured to provide device information to the display.
8. The drug delivery device according to claim 7, wherein the device information includes information regarding the medicament contained within the cartridge.
9. The drug delivery device according to claim 7, wherein the display comprises a liquid crystal display (LCD) or an organic light emitting diode display (OLED).
10. The drug delivery device according to claim 1, further comprising a second cartridge retainer configured to receive a second cartridge of a second medicament, the second cartridge retainer comprising a second hinged connection to the main body and being moveable between an open position and a closed position.
11. A system comprising:
a replaceable cartridge containing a medicament; and
a drug delivery device configured to deliver at least one medicament, the drug delivery device comprising:
a main body;
a cartridge retainer configured to receive the replaceable cartridge of the medicament, the cartridge retainer including a hinged connection to the main body and being moveable between an open position and a closed position;
one or more first sensors configured to detect the presence of the replaceable cartridge in the cartridge retainer, wherein the one or more first sensors are pressure activated switches; and
one or more second sensors configured to detect that the cartridge retainer is in the closed position, wherein the one or more second sensors are selected from the group of sensors consisting of a light barrier sensor, a camera, a barcode reader, and a proximity sensor.
12. A method of detecting the presence of a cartridge of a medicament in a cartridge retainer of a drug delivery device, the method comprising:
providing the drug delivery device including:
a main body;
the cartridge retainer configured to receive the cartridge of medicament, the cartridge retainer including a hinged connection to the main body and being moveable between an open position and a closed position; and
a controller including:
one or more first sensors configured to detect the presence of the cartridge in the cartridge retainer, wherein the one or more first sensors are pressure activated switches; and
one or more second sensors configured to detect that the cartridge retainer is in the closed position, wherein the one or more second sensors are selected from the group of sensors consisting of a light barrier sensor, a camera, a barcode reader, and a proximity sensor;
the controller receiving signals from the one or more first sensors and the one or more second sensors via digital inputs of the controller; and
the controller determining from the received signals whether the cartridge is present in the cartridge retainer and whether the cartridge retainer is in the closed position.
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12
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This application is a continuation of U.S. patent application Ser. No. 14/373,088 filed Jul. 18, 2014, which is a U.S. National Stage entry of PCT Application Number PCT/EP2013/051901 filed Jan. 31, 2013, which claims priority to European Patent Application Number 12153382.2 filed Jan. 31, 2012, the contents of each of which is incorporated by reference in its entirety.
The present patent application relates to medical devices for delivering at least one drug agent, in particular two drug agents from separate reservoirs. Such drug agents may comprise a first and a second medicament. The medical device includes a dose setting mechanism for delivering the drug agents automatically or manually by the user.
The medical device can be an injector, for example a hand-held injector, especially a pen-type injector, that is an injector of the kind that provides for administration by injection of medicinal products from one or more multidose cartridges. In particular, the present invention relates to such injectors where a user may set the dose.
The drug agents may be contained in two or more multiple dose reservoirs, containers or packages, each containing independent (single drug compound) or pre-mixed (co-formulated multiple drug compounds) drug agents.
Certain disease states require treatment using one or more different medicaments. Some drug compounds need to be delivered in a specific relationship with each other in order to deliver the optimum therapeutic dose. The present patent application is of particular benefit where combination therapy is desirable, but not possible in a single formulation for reasons such as, but not limited to, stability, compromised therapeutic performance and toxicology.
For example, in some cases it may be beneficial to treat a diabetic with a long acting insulin (also may be referred to as the first or primary medicament) along with a glucagon-like peptide-1 such as GLP-1 or GLP-1 analog (also may be referred to as the second drug or secondary medicament).
Accordingly, there exists a need to provide devices for the delivery of two or more medicaments in a single injection or delivery step that is simple for the user to perform without complicated physical manipulations of the drug delivery device. The proposed drug delivery device provides separate storage containers or cartridge retainers for two or more active drug agents. These active drug agents are then combined and/or delivered to the patient during a single delivery procedure. These active agents may be administered together in a combined dose or alternatively, these active agents may be combined in a sequential manner, one after the other.
The drug delivery device also allows for the opportunity of varying the quantity of the medicaments. For example, one fluid quantity can be varied by changing the properties of the injection device (e.g., setting a user variable dose or changing the device's “fixed” dose). The second medicament quantity can be changed by manufacturing a variety of secondary drug containing packages with each variant containing a different volume and/or concentration of the second active agent.
The drug delivery device may have a single dispense interface. This interface may be configured for fluid communication with a primary reservoir and with a secondary reservoir of medicament containing at least one drug agent. The drug dispense interface can be a type of outlet that allows the two or more medicaments to exit the system and be delivered to the patient.
The combination of compounds from separate reservoirs can be delivered to the body via a double-ended needle assembly. This provides a combination drug injection system that, from a user's perspective, achieves drug delivery in a manner that closely matches the currently available injection devices that use standard needle assemblies. One possible delivery procedure may involve the following steps:
1. Attach a dispense interface to a distal end of the electro-mechanical injection device. The dispense interface comprises a first and a second proximal needle. The first and second needles pierce a first reservoir containing a primary compound and a second reservoir containing a secondary compound, respectively.
2. Attach a dose dispenser, such as a double-ended needle assembly, to a distal end of the dispense interface. In this manner, a proximal end of the needle assembly is in fluidic communication with both the primary compound and secondary compound.
3. Dial up/set a desired dose of the primary compound from the injection device, for example, via a graphical user interface (GUI).
4. After the user sets the dose of the primary compound, the micro-processor controlled control unit may determine or compute a dose of the secondary compound and preferably may determine or compute this second dose based on a previously stored therapeutic dose profile. It is this computed combination of medicaments that will then be injected by the user. The therapeutic dose profile may be user selectable. Alternatively, the user can dial or set a desired dose of the secondary compound.
5. Optionally, after the second dose has been set, the device may be placed in an armed condition. The optional armed condition may be achieved by pressing and/or holding an “OK” or an “Arm” button on a control panel. The armed condition may be provided for a predefined period of time during which the device can be used to dispense the combined dose.
6. Then, the user will insert or apply the distal end of the dose dispenser (e.g. a double ended needle assembly) into the desired injection site. The dose of the combination of the primary compound and the secondary compound (and potentially a third medicament) is administered by activating an injection user interface (e.g. an injection button).
Both medicaments may be delivered via one injection needle or dose dispenser and in one injection step. This offers a convenient benefit to the user in terms of reduced user steps compared to administering two separate injections.
As described above, since the dispense interface provides at least a part of the fluid channel for the fluids to be dispensed, the dispense interface is on the one hand in fluid communication with at least one reservoir of the medical device and thus one or more drug agents. On the other hand, over a needle assembly attached to or integrated in the dispense interface, the dispense interface is also in contact with the ambient air, the patients skin and/or the patients blood. However, it is problematic that the dispense interface is in direct contact with these latter non-sterile or contaminated fluids, gases and/or particles.
In general, a part of the fluid to be dispensed remains in the fluidic channels of the dispense interface. Over time the probability of the remaining fluid being contaminated increases. Moreover, after a certain time microbial growth can occur.
Additionally, the quality of the fluidic channels may deteriorate over time and/or certain substances present in the materials used for the fluidic channels of the dispense interface may migrate into the remaining fluid within the dispense interface.
The probability of too high levels of contamination of the remaining fluids in the dispense interface can be reduced by preservative agents present in the drug agents. However, these preservative agents can lose efficacy or can be absorbed over time by the material of the dispense interface.
It is, however, not desired to let a user of the medical device inject these remaining contaminated fluids into his or her body with a subsequent dispense step, since this constitutes risks and may be harmful for the user's health.
It is also possible, that the channels of the dispense interface are blocked, due to dried and/or clotted channels in the dispense interface. This can result in malfunctions of the medical device. In particular, this can make the user believe that a certain dose has been delivered even though there was no dose delivered. Hence, even life threatening situations can occur.
For these risks not to occur, the user would have to laboriously rinse the fluidic channels, wasting part of the medicaments or check somehow whether the medical device still ejects fluids. But even then, the user cannot be sure that both medicaments will be delivered or that the fluid dispensed will be sterile enough.
In view of the aforementioned, the invention faces the technical problem of providing a medical device which minimizes the risks described above. In particular it is an object of the present invention to provide a medical device, which exhibits an increased safety of the device and facilitates a safe use.
The technical problem is solved by a medical device for delivering at least one drug agent, comprising a sensor, a control unit and an attachable dispense assembly, wherein the sensor is configured to detect attachment of the dispense assembly to the medical device, wherein the control unit is configured to determine at least based on a signal from the sensor whether the end of life of the dispense assembly is reached and wherein the medical device is configured to indicate the end of life of the dispense assembly. The end of life of the dispense assembly may for example be determined by expiry of a timer that is started when the dispense assembly is attached.
By providing a medical device according to the invention, the beginning of the service life of the dispense assembly is detected by utilizing the point in time of attachment of the dispense assembly for determining the beginning of the service life of the dispense assembly. When the end of life or service life of the dispense assembly is reached, the medical device indicates the end of life of the dispense assembly and the user does not need to care about whether the dispense assembly may have deteriorated or is contaminated due to microbial growth or the like. As a result the medical device exhibits an increased safety of the device and facilitates a safe use.
When utilizing the point in time of attachment of the medical device to determine the end of life of the dispense assembly and indicating the end of life, the risk of dispensing a fluid with too high contamination can be reliably minimized.
A dispense assembly according to the invention is understood to be a separate element from the rest of the medical device being a main body or a cartridge holder, for example. The dispense assembly in particular exhibits one or more channels to be able to guide the fluids of the medical device to the users body. The dispense assembly can already exhibit an appropriate injection needle or cannula to pierce the user's skin. Though, it is also conceivable that the injection needle is designed as a separate element from the dispense assembly. In the latter case the dispense assembly is generally referred to as dispense interface with an attachable needle or cannula. A dispense assembly can in particular comprise a manifold and valves to further increase safety of the device and reduce the amount of undesired fluids in the channels.
The main body or the cartridge holder is then configured to receive the dispense assembly. The attachment of the dispense assembly to the main body can be realized in different ways. For instance, the dispense assembly can be attached via form fit or force fit, in particular the dispense assembly can be latched or screwed to the main body. A quick and reliable attachment can be realized in this way.
The control unit is preferably positioned in the main body or cartridge holder of the medical device and is configured to receive a signal from the sensor. Control unit is understood to be or comprise any kind of micro-processor or micro-controller, for example.
The sensor can be designed in various ways. It is possible to provide a mechanical switch, which is activated when the dispense assembly is attached. The sensor can also be designed as an electrical contact, such that a current or a voltage can be detected as soon as the dispense assembly is attached. It is further conceivable to design the sensor as a optical instrument. This may be a light barrier, a camera, a barcode reader, a proximity sensor or the like. In order to further increase safety and/or functionality, multiple identical or different sensors can be provided.
By determining the end of life of the dispense assembly based at least partially on the signal from the sensor it is meant that the signal of the sensor and hence for example the time of attachment of the dispense assembly influences the end of life of the dispense assembly. For instance, it is possible to start a timer when the dispense assembly is attached and to use the time as single criterion, whether the end of life of the dispense assembly is reached.
It is alternatively or additionally also possible to use different information for example, whether the temperature rose over a certain limit since the dispense assembly was attached or how often the dispense assembly was used since the dispense assembly was attached. For this, an additional temperature sensor or a counter is necessary, respectively. Combinations of these criterions are possible, as well.
The signal of the sensor can be an electrical pulse or a constant signal. A pulse can indicate the point in time of attachment and/or detachment of the dispense assembly, while a constant signal can constantly indicate, whether the dispense assembly is still attached.
The dispense assembly can be configured to determine the end of life of the dispense assembly in certain intervals and/or before each dispense.
Finally, by indicating the end of life of a dispense assembly, the user can be made aware, that the dispense assembly should not or cannot be used anymore. Such an indication can be provided by the medical device via a display or by means of a sound signal, for instance. It is also possible to implicitly indicate the end of life of the dispense assembly by preventing the use of the medical device.
According to a preferred embodiment of the medical device according to the invention, the control unit is configured to prevent further usage of the medical device when the end of life of the dispense assembly is reached. A particular safe usage of the medical device can be realized in this way, since the user cannot accidentally or on purpose use the medical device with the dispense assembly which end of life has already been reached.
The prevention of usage can be achieved by the software not allowing any executions of dispense actions, for example. It is also possible to mechanically lock the device in order to prevent any dispense of fluids from the medical device.
It is possible that only the dispense function of the device is disabled, preferably in combination with an indication on a display of the device. Hence, the device can still be used to access information saved on the device, such as the history of previous dispenses.
It is particularly preferred though that the user is guided through the exchange procedure of a dispense assembly, for example by displayed information such as “dispense interface expired” and/or “please remove dispense interface”, and that during this exchange procedure the user cannot access any further information on the device.
The usage of the medical device is only prevented until a new dispense assembly is attached. To make sure that the same dispense assembly is not attached twice, it is conceivable to provide the dispense assembly with identification tags, which can be read by the medical device, for example with a barcode reader. A re-attachment of the same dispense assembly will then not lead to a reactivation of the dispense function.
It is further preferred that the control unit is configured to start a timer when the sensor indicates attachment of a dispense assembly. When the timer reaches or exceeds a certain time limit, the dispense assembly has reached its end of life. This is a particular easy possibility to determine the end of life of the dispense assembly. Such a period can be several days or weeks, for example. The time limit can be predetermined, for example. The timer can be implemented in the control unit, for instance.
That the total time of attachment is used to determine the end of life of the dispense assembly does not mean that other factors can be used to further improve the determination of the end of life. For example, as already mentioned above, further information, such as the number of dispenses or the temperature, can be used to modify the point in time, when the end of life has been reached.
In case there are different types of dispense assemblies, it is also conceivable to modify the time limit, after which the end of life has been reached, in dependence of the dispense assembly used. For this purpose an identification tag on the dispense assembly can provide information from which a time limit for the end of life can be deduced.
However, it can be economical and sufficient to exclusively use a fixed time limit to determine the end of life of the dispense assembly.
In case the timer is still running when a new dispense assembly is attached, the timer can be stopped and started again or simply reset.
According to a next embodiment of a medical device according to the invention, the sensor is configured to detect detachment of the dispense assembly from the medical device. This facilitates a safe use of the medical device, because the user can explicitly be instructed to attach a new dispense assembly, for example over a display of the medical device. The detachment can also be used to reset the timer of the medical device.
Depending on the kind of sensor used, the detachment of the dispense assembly can be realized by the sensor either by a second actuation of a switch or by disconnecting an electrical contact, for example.
It is preferred that the medical device further comprises at least a first reservoir containing a first fluid and a second reservoir containing a second fluid. The dispense assembly is in that case fluidly connected to both reservoirs. However, valves can be provided to reduce or eliminate mutual fluid connections between the reservoirs. At least one, preferably both of these fluids are drug agents and contain a medicament.
Particularly for medical devices containing more than one fluid, the device according to the invention can improve safety and facilitate safe use. The two fluids which normally need to be stored in different reservoirs are in contact with each other in the dispense assembly. The mixture remaining in the dispense assembly can further promote contamination, microbial growth or clotting of the dispense assembly.
It is advantageous, if the dispense assembly comprises a mechanical lock-out mechanism to prevent re-attachment of the dispense assembly to the medical device. This allows the dispense assembly to be attached only once by simple mechanical means. After the dispense assembly has been detached for the first time, the lock out mechanism is brought in a state that prevents any re-attachment. Expensive systems such as barcode readers and identification tags on the dispense assemblies to assure no second use of a dispense assembly are not necessary. The combination of indicating the end of life and preventing the re-attachment of the same dispense assembly by a mechanical lock-out mechanism has the effect of providing a particular safe medical device, which facilitates safe handling of the device.
The lock-out mechanism can generally be realized by certain locking elements provided by the dispense assembly, which locking elements are brought into an interference position when removing the dispense assembly from the medical device. The lock-out mechanism can be implemented by a lock-out spring integrated in the dispense assembly, for example. This spring is configured such that it first allows for attaching the dispense assembly. The attachment can then trigger or bend the lock-out spring in such a way, that spring arms of the lockout spring when detaching the dispense assembly move in a position preventing a second attachment.
The medical device according to the invention is particularly advantageous when the medical device is a portable drug delivery device. Portable devices are designed and intended to be used in a variety of situations and locations. This makes a portable drug delivery device particularly prone to contaminations of the fluids in the dispense assembly.
According to a second aspect of the invention the technical problem is further solved by a method comprising the steps of detecting an attachment of a dispense assembly to a medical device, in particular a medical device according to the invention, determining whether the end of life of the dispense assembly is reached and indicating the end of life of the dispense assembly.
By providing a method according to the invention, the beginning of the service life of the dispense assembly is detected by utilizing the point in time of attachment of the dispense assembly for determining the beginning of the service life of the dispense assembly. When the end of life or service life of the dispense assembly is reached, the method allows for indicating the end of life of the dispense assembly and the user does not need to care about whether the dispense assembly may have deteriorated or is contaminated due to microbial growth or the like. As a result the medical device exhibits an increased safety of the device and facilitates a safe use.
When utilizing the point in time of attachment of the medical device to determine the end of life of the dispense assembly and indicating the end of life, the risk of dispensing a fluid with too high contamination can be reliably minimized.
The detection of the attachment can be realized by a sensor, while the indication of the end of life of the dispense assembly is preferably realized by displaying such information on a screen of the medical device.
The determination whether the end of life of the dispense assembly has been reached can be performed constantly, regularly and/or before a dispense takes place, for instance.
It is preferred that the method according to the invention, further comprises the step of preventing further usage of the medical device when the end of life of the dispense assembly is reached.
The prevention of further usage can by realized by a control unit preventing any further dispense of the fluids, for example, as long as the dispense assembly is not exchanged.
It is further preferred that the method according to the invention further comprises the step of starting a timer when the dispense assembly is attached.
The end of life of the dispense assembly can thus be determined on how long the dispense assembly is attached to the medical device. The starting of the timer is initiated by the signal from the sensor, signaling an attachment of a dispense assembly. When a certain time limit, which may be fixed or adjustable, is reached or exceeded the end of life of the dispense assembly is indicated.
For further advantages and preferred embodiments of the method according to the invention it is referred to the description of the medical device according to the invention.
According to a third aspect of the present invention, further a program is disclosed comprising program code for performing the method according to the present invention and all exemplary embodiments thereof, when the program is executed on a processor.
The program may for instance be distributed via a network, such as for instance the Internet. The program may for instance be stored or encoded on a readable medium, for instance a computer-readable or processor-readable medium. The readable medium may for instance be embodied as an electric, magnetic, electro-magnetic, optic or other storage medium, and may either be a removable medium or a medium that is fixedly installed in an apparatus or device. The readable medium may for instance be a tangible medium, for instance a tangible storage medium.
BRIEF DESCRIPTION OF THE DRAWINGS
These as well as other advantages of various aspects of the present invention will become apparent to those of ordinary skill in the art by reading the following detailed description, with appropriate reference to the accompanying drawings, in which:
FIG. 1 illustrates a perspective view of an exemplary embodiment of a delivery device according to the invention with an end cap of the device removed;
FIG. 2 illustrates a perspective view of the delivery device distal end showing the cartridge;
FIG. 3 illustrates a perspective view of the delivery device illustrated in FIG. 1 with one cartridge retainer in an open position;
FIG. 4 illustrates an exemplary embodiment of a dispense interface and an exemplary embodiment of a dose dispenser that can be removably mounted on a distal end of the delivery device illustrated in FIG. 1;
FIG. 5 illustrates the dispense interface and the dose dispenser illustrated in FIG. 4 mounted on a distal end of the delivery device illustrated in FIG. 1;
FIG. 6 illustrates one arrangement of a needle assembly that may be mounted on a distal end of the delivery device;
FIG. 7 illustrates a perspective view of the dispense interface illustrated in FIG. 4;
FIG. 8 illustrates another perspective view of the dispense interface illustrated in FIG. 4;
FIG. 9 illustrates a cross-sectional view of another embodiment of a dispense interface similar to the one illustrated in FIG. 4;
FIG. 10 illustrates an exploded view of the dispense interface illustrated in FIG. 4;
FIG. 11 illustrates a cross-sectional view of another exemplary embodiment of a dispense interface and needle assembly mounted onto a drug delivery device, similar to the device illustrated in FIG. 1;
FIG. 12a-c illustrate a cross-sectional view of an exemplary embodiment of an attachable dispense interface and a sensor;
FIG. 13 illustrates a block diagram functional description of a control unit for operation off the drug delivery device illustrated in FIG. 1;
FIG. 14 illustrates a printed circuit board assembly of the drug delivery device illustrated in FIG. 1;
FIG. 15 schematically illustrates an exemplary embodiment of a tangible storage medium according to the present invention;
FIG. 16 illustrates a cross sectional view of the another exemplary embodiment of a dispense interface with a mechanical lock-out mechanism;
FIG. 17 illustrates a perspective view of a lock-out spring of the dispense interface illustrated in FIG. 16;
FIG. 18 illustrates a perspective view of the dispense interface illustrated in FIG. 16 about to be mounted onto a drug delivery device;
FIG. 19 illustrates a perspective view of the dispense interface illustrated in FIG. 16 in a partially seated position onto a drug delivery device;
FIG. 20 illustrates a perspective view of the dispense interface illustrated in FIG. 16 in a fully seated position on a drug delivery device; and
FIG. 21 illustrates a perspective view of the dispense interface illustrated in FIG. 16 in a partially removed position from a drug delivery device;
FIG. 22 illustrates in a flow chart an exemplary embodiment of a method according to the invention.
DETAILED DESCRIPTION
The drug delivery device as an exemplary embodiment of medical device according to the invention illustrated in FIG. 1 comprises a main body 14 that extends from a proximal end 16 to a distal end 15. At the distal end 15, a removable end cap or cover 18 is provided. This end cap 18 and the distal end 15 of the main body 14 work together to provide a snap fit or form fit connection so that once the cover 18 is slid onto the distal end 15 of the main body 14, this frictional fit between the cap and the main body outer surface 20 prevents the cover from inadvertently falling off the main body.
The main body 14 contains a micro-processor control unit, an electro-mechanical drive train, and at least two medicament reservoirs. When the end cap or cover 18 is removed from the device 10 (as illustrated in FIG. 1), a dispense interface 200 is mounted to the distal end 15 of the main body 14, and a dose dispenser (e.g., a needle assembly) is attached to the interface. The drug delivery device 10 can be used to administer a computed dose of a second medicament (secondary drug compound) and a variable dose of a first medicament (primary drug compound) through a single needle assembly, such as a double ended needle assembly.
The drive train may exert a pressure on the bung of each cartridge, respectively, in order to expel the doses of the first and second medicaments. For example, a piston rod may push the bung of a cartridge forward a pre-determined amount for a single dose of medicament. When the cartridge is empty, the piston rod is retracted completely inside the main body 14, so that the empty cartridge can be removed and a new cartridge can be inserted.
A control panel region 60 is provided near the proximal end of the main body 14. Preferably, this control panel region 60 comprises a digital display 80 along with a plurality of human interface elements that can be manipulated by a user to set and inject a combined dose. In this arrangement, the control panel region comprises a first dose setting button 62, a second dose setting button 64 and a third button 66 designated with the symbol “OK.” Further buttons, such as a “back” button can be provided, as well. In addition, along the most proximal end of the main body, an injection button 74 is also provided (not visible in the perspective view of FIG. 1).
The cartridge holder 40 can in this case be removably attached to the main body 14 and may contain at least two cartridge retainers 50 and 52. Each retainer is configured so as to contain one medicament reservoir, such as a glass cartridge. Preferably, each cartridge contains a different medicament.
In addition, at the distal end of the cartridge holder 40, the drug delivery device illustrated in FIG. 1 includes a dispense interface 200 as an exemplary embodiment of a dispense assembly. The dispense interface 200 is attachable to the cartridge holder 40. As will be described in relation to FIG. 4, in one arrangement, this dispense interface 200 includes a main outer body 210 that is removably attached to a distal end 42 of the cartridge holder 40. As can be seen in FIG. 1, a distal end 214 of the dispense interface 200 preferably comprises a mounting hub 216. This mounting hub 216 may be configured so as to allow a dose dispenser, such as a conventional pen type injection needle assembly, to be removably mounted to the drug delivery device 10. The dispense interface 200 and the dose dispenser can also be designed as one piece.
Once the device is turned on, the digital display 80 shown in FIG. 1 illuminates and provides the user certain device information, preferably information relating to the medicaments contained within the cartridge holder 40. For example, the user is provided with certain information relating to both the primary medicament (Drug A) and the secondary medicament (Drug B).
As shown in FIG. 3, the first and second cartridge retainers 50, 52 may be hinged cartridge retainers. These hinged retainers allow user access to the cartridges. FIG. 3 illustrates a perspective view of the cartridge holder 40 illustrated in FIG. 1 with the first hinged cartridge retainer 50 in an open position. FIG. 3 illustrates how a user might access the first cartridge 90 by opening up the first retainer 50 and thereby having access to the first cartridge 90.
As mentioned above when discussing FIG. 1, a dispense interface 200 is coupled to the distal end of the cartridge holder 40. FIG. 4 illustrates a flat view of the dispense interface 200 unconnected to the distal end of the cartridge holder 40. A dose dispenser or needle assembly that may be used with the interface 200 is also illustrated and is provided in a protective outer cap 420.
FIG. 4 also shows a sensor 43 at the distal end 42 of the cartridge holder 40. The sensor may be a light barrier, a camera, a barcode reader or a proximity sensor, for example. The sensor 43 is preferably of such design that it can substantially only be actuated by the dispense interface 200 being attached to the cartridge holder 40. The sensor 43 may be a switch situated in a recess for this purpose, which cannot accidentally be pressed or activated by the user directly, but activated by a latch on the dispense interface 200, which is adapted to the recess of the switch.
In FIG. 5, the dispense interface 200 illustrated in FIG. 4 is shown coupled to the cartridge holder 40. The axial attachment means between the dispense interface 200 and the cartridge holder 40 can be any known axial attachment means to those skilled in the art, including snap locks, snap fits, snap rings, keyed slots, and combinations of such connections. The connection or attachment between the dispense interface and the cartridge holder may also contain additional features (not shown), such as connectors, stops, splines, ribs, grooves, pips, clips and the like design features, that ensure that specific hubs are attachable only to matching drug delivery devices. Such additional features would prevent the insertion of a non-appropriate secondary cartridge to a non-matching injection device.
Since the dispense interface 200 is now properly attached to the cartridge holder 40 of the device 10, the sensor 43 will send a signal to a control unit, for example the micro-controller 302 (see FIGS. 13 and 14). The micro-controller 302 may start a timer, for example, in order to be able to determine the end of life of the dispense interface 200 in the future. In case a predetermined time limit is reached, the medical device will indicate the end of life of the dispense interface, for example on the display 80. The user can be requested to remove the dispense interface 200. To prevent any further use after the end of life of the dispense interface has been reached, the micro-controller 302 can prevent any further dose delivery.
When the sensor 43 detects that the dispense interface 200 was removed, the user can be requested to attach an unused dispense interface 200. In case the sensor is a barcode reader and the dispense interfaces are provided with barcodes containing identity information, it is possible to prevent reuse of the same dispense interface, by reading the barcode and checking whether a new dispense interface has been attached before allowing further use of the device.
FIG. 5 also illustrates the double ended needle assembly 400 and protective cover 420 coupled to the distal end of the dispense interface 200 that may be screwed onto the needle hub of the interface 200. FIG. 6 illustrates a cross sectional view of the double ended needle assembly 400 mounted on the dispense interface 200 in FIG. 5.
The double ended needle assembly 400 illustrated in FIG. 6 comprises a double ended needle 406 and a needle hub 401. The double ended needle or cannula 406 is fixedly mounted in the needle hub 401. This needle hub 401 comprises a circular disk shaped element which has along its periphery a circumferential depending sleeve 403. Along an inner wall of this needle hub 401, a thread 404 is provided. This thread 404 allows the needle hub 401 to be screwed onto the dispense interface 200 which, in one preferred arrangement, is provided with a corresponding outer thread along a distal hub. At a center portion of the needle hub 401 there is provided a protrusion 402. This protrusion 402 projects from the hub in an opposite direction of the sleeve member. A double ended needle 406 is mounted centrally through the protrusion 402 and the needle hub 401. This double ended needle 406 is mounted such that a first or distal piercing end 405 of the double ended needle forms an injecting part for piercing an injection site (e.g., the skin of a user).
Similarly, a second or proximal piercing end 407 of the double ended needle assembly 400 protrudes from an opposite side of the circular disc so that it is concentrically surrounded by the sleeve 403. In one needle assembly arrangement, the second or proximal piercing end 407 may be shorter than the sleeve 403 so that this sleeve to some extent protects the pointed end of the back sleeve. The needle cover cap 420 illustrated in FIGS. 4 and 5 provides a form fit around the outer surface 403 of the needle hub 401.
Referring now to FIGS. 8 to 11, one preferred arrangement of this interface 200 will now be discussed. In this one preferred arrangement, this interface 200 comprises:
a. a main outer body 210,
b. an first inner body 220,
c. a second inner body 230,
d. a first piercing needle 240,
e. a second piercing needle 250,
f. a valve seal 260, and
g. a septum 270.
The main outer body 210 comprises a main body proximal end 212 and a main body distal end 214. At the proximal end 212 of the outer body 210, a connecting member is configured so as to allow the dispense interface 200 to be attached to the distal end of the cartridge holder 40. Preferably, the connecting member is configured so as to allow the dispense interface 200 to be removably connected the cartridge holder 40. In one preferred interface arrangement, the proximal end of the interface 200 is configured with an upwardly extending wall 218 having at least one recess. For example, as may be seen from FIG. 8, the upwardly extending wall 218 comprises at least a first recess 217 and a second recess 219.
Preferably, the first and the second recesses 217, 219 are positioned within this main outer body wall so as to cooperate with an outwardly protruding member located near the distal end of the cartridge holder 40 of the drug delivery device 10. For example, this outwardly protruding member 48 of the cartridge holder may be seen in FIGS. 4 and 5. A second similar protruding member is provided on the opposite side of the cartridge holder. As such, when the interface 200 is axially slid over the distal end of the cartridge holder 40, the outwardly protruding members will cooperate with the first and second recess 217, 219 to form an interference fit, form fit, or snap lock. Alternatively, and as those of skill in the art will recognize, any other similar connection mechanism that allows for the dispense interface and the cartridge holder 40 to be axially coupled could be used as well.
The main outer body 210 and the distal end of the cartridge holder 40 act to form an axially engaging snap lock or snap fit arrangement that could be axially slid onto the distal end of the cartridge holder. In one alternative arrangement, the dispense interface 200 may be provided with a coding feature so as to prevent inadvertent dispense interface cross use. That is, the inner body of the hub could be geometrically configured so as to prevent an inadvertent cross use of one or more dispense interfaces.
As can be further seen from the FIGS. 8, 9 and 10, the dispense interface 200 comprises an area 201, which can correlate with a sensor 43 as illustrated in FIG. 4. Such an specifically adapted area 201 can comprise a barcode for example, which is read by the sensor 43 in order to detect attachment of a dispense interface 200 or to detect whether the dispense interface 200 has already been used. Such an area 201 can also be a conductive area, for instance. The sensor 43 can in this case be two electrical contacts which detect the attachment of the dispense interface 200 when a current or voltage between the two contacts of the sensor 43 can be detected, which will be possible when the conductive area touches both electrical contacts of the sensor 43. When the dispense interface is removed and the contacts of the sensor 43 is interrupted the detachment of the dispense interface 200 can be detected.
A mounting hub 216 is provided at a distal end of the main outer body 210 of the dispense interface 200. Such a mounting hub 216 can be configured to be releasably connected to a needle assembly. As just one example, this mounting hub 216 may comprise an outer thread that engages an inner thread provided along an inner wall surface of a needle hub of a needle assembly, such as the needle hub 401 and the double ended needle assembly 400 illustrated in FIG. 6. Alternative mounting hubs 216 may also be provided such as a snap lock, a snap lock released through threads, a bayonet lock, a form fit, or other similar connection arrangements.
The dispense interface 200 further comprises a first inner body 220. Certain details of this inner body are illustrated in FIG. 8-11. Preferably, this first inner body 220 is coupled to an inner surface 215 of the extending wall 218 of the main outer body 210. More preferably, this first inner body 220 is coupled by way of a rib and groove form fit arrangement to an inner surface of the outer body 210. For example, as can be seen from FIG. 9, the extending wall 218 of the main outer body 210 is provided with a first rib 213a and a second rib 213b. This first rib 213a is also illustrated in FIG. 10. These ribs 213a and 213b are positioned along the inner surface 215 of the wall 218 of the outer body 210 and create a form fit or snap lock engagement with cooperating grooves 224a and 224b of the first inner body 220. In a preferred arrangement, these cooperating grooves 224a and 224b are provided along an outer surface 222 of the first inner body 220.
In addition, as can be seen in FIG. 8-10, a proximal surface 226 near the proximal end of the first inner body 220 may be configured with at least a first proximally positioned piercing needle 240 comprising a proximal piercing end portion 244. Similarly, the first inner body 220 is configured with a second proximally positioned piercing needle 250 comprising a proximally piercing end portion 254. Both the first and second needles 240, 250 are rigidly mounted on the proximal surface 226 of the first inner body 220.
Preferably, this dispense interface 200 further comprises a valve arrangement. Such a valve arrangement could be constructed so as to prevent cross contamination of the first and second medicaments contained in the first and second reservoirs, respectively. A preferred valve arrangement may also be configured so as to prevent back flow and cross contamination of the first and second medicaments.
In one preferred system, dispense interface 200 includes a valve arrangement in the form of a valve seal 260. Such a valve seal 260 may be provided within a cavity 231 defined by the second inner body 230, so as to form a holding chamber 280. Preferably, cavity 231 resides along an upper surface of the second inner body 230. This valve seal comprises an upper surface that defines both a first fluid groove 264 and second fluid groove 266. For example, FIG. 9 illustrates the position of the valve seal 260, seated between the first inner body 220 and the second inner body 230. During an injection step, this seal valve 260 helps to prevent the primary medicament in the first pathway from migrating to the secondary medicament in the second pathway, while also preventing the secondary medicament in the second pathway from migrating to the primary medicament in the first pathway. Preferably, this seal valve 260 comprises a first non-return valve 262 and a second non-return valve 268. As such, the first non-return valve 262 prevents fluid transferring along the first fluid pathway 264, for example a groove in the seal valve 260, from returning back into this pathway 264. Similarly, the second non-return valve 268 prevents fluid transferring along the second fluid pathway 266 from returning back into this pathway 266.
Together, the first and second grooves 264, 266 converge towards the non-return valves 262 and 268 respectively, to then provide for an output fluid path or a holding chamber 280. This holding chamber 280 is defined by an inner chamber defined by a distal end of the second inner body both the first and the second non return valves 262, 268 along with a pierceable septum 270. As illustrated, this pierceable septum 270 is positioned between a distal end portion of the second inner body 230 and an inner surface defined by the needle hub of the main outer body 210.
The holding chamber 280 terminates at an outlet port of the interface 200. This outlet port 290 is preferably centrally located in the needle hub of the interface 200 and assists in maintaining the pierceable seal 270 in a stationary position. As such, when a double ended needle assembly is attached to the needle hub of the interface (such as the double ended needle illustrated in FIG. 6), the output fluid path allows both medicaments to be in fluid communication with the attached needle assembly.
The hub interface 200 further comprises a second inner body 230. As can be seen from FIG. 9, this second inner body 230 has an upper surface that defines a recess, and the valve seal 260 is positioned within this recess. Therefore, when the interface 200 is assembled as shown in FIG. 9, the second inner body 230 will be positioned between a distal end of the outer body 210 and the first inner body 220. Together, second inner body 230 and the main outer body hold the septum 270 in place. The distal end of the inner body 230 may also form a cavity or holding chamber that can be configured to be fluid communication with both the first groove 264 and the second groove 266 of the valve seal.
Axially sliding the main outer body 210 over the distal end of the drug delivery device attaches the dispense interface 200 to the multi-use device. In this manner, a fluid communication may be created between the first needle 240 and the second needle 250 with the primary medicament of the first cartridge and the secondary medicament of the second cartridge, respectively.
FIG. 11 illustrates the dispense interface 200 after it has been mounted onto the distal end 42 of the cartridge holder 40 of the drug delivery device 10 illustrated in FIG. 1. A double ended needle 406 is also mounted to the distal end of this interface. The cartridge holder 40 is illustrated as having a first cartridge containing a first medicament and a second cartridge containing a second medicament.
When the interface 200 is first mounted over the distal end of the cartridge holder 40, the proximal piercing end 244 of the first piercing needle 240 pierces the septum of the first cartridge 90 and thereby resides in fluid communication with the primary medicament 92 of the first cartridge 90. A distal end of the first piercing needle 240 will also be in fluid communication with a first fluid path groove 264 defined by the valve seal 260.
Similarly, the proximal piercing end 254 of the second piercing needle 250 pierces the septum of the second cartridge 100 and thereby resides in fluid communication with the secondary medicament 102 of the second cartridge 100. A distal end of this second piercing needle 250 will also be in fluid communication with a second fluid path groove 266 defined by the valve seal 260.
FIG. 11 illustrates a preferred arrangement of such a dispense interface 200 that is coupled to a distal end 15 of the main body 14 of drug delivery device 10. Preferably, such a dispense interface 200 is removably coupled to the cartridge holder 40 of the drug delivery device 10.
As illustrated in FIG. 11, the dispense interface 200 is coupled to the distal end of a cartridge holder 40. This cartridge holder 40 is illustrated as containing the first cartridge 90 containing the primary medicament 92 and the second cartridge 100 containing the secondary medicament 102. Once coupled to the cartridge holder 40, the dispense interface 200 essentially provides a mechanism for providing a fluid communication path from the first and second cartridges 90, 100 to the common holding chamber 280. This holding chamber 280 is illustrated as being in fluid communication with a dose dispenser. Here, as illustrated, this dose dispenser comprises the double ended needle assembly 400. As illustrated, the proximal end of the double ended needle assembly is in fluid communication with the chamber 280.
In one preferred arrangement, the dispense interface is configured so that it attaches to the main body in only one orientation, that is it is fitted only one way round. As such as illustrated in FIG. 11, once the dispense interface 200 is attached to the cartridge holder 40, the primary needle 240 can only be used for fluid communication with the primary medicament 92 of the first cartridge 90 and the interface 200 would be prevented from being reattached to the holder 40 so that the primary needle 240 could now be used for fluid communication with the secondary medicament 102 of the second cartridge 100. Such a one way around connecting mechanism may help to reduce potential cross contamination between the two medicaments 92 and 102.
As can be further seen from FIG. 11, the cartridge holder 40 of medical device 10 further comprises two switches 43a and 43b as sensors at its distal end 42. The switches 43a, 43b will be activated, in this case pushed towards the reservoirs 90 and 100 respectively, when the dispense interface 200 is attached to the cartridge holder 40. The switches 43a, 43b indicate correct attachment of the dispense interface 200, when both switches 43a, 43b are activated and the attachment can be detected and a signal can be send to the control unit, for example the micro-controller 302. When the dispense interface is removed again, the switches may jump back into a state further away from the cartridges by the force of a spring (not shown), for example. In this way, the switches 43a, 43b can readily detect the next attachment of a dispense interface 200.
FIG. 12a to c illustrate a further embodiment of a sensor or a mechanism in order to detect a complete attachment of an attachable dispense assembly and a cross-sectional view of the attaching of the dispense interface 200 onto the drug delivery device 10 is illustrated. The drug delivery device 10 comprises a sensor in form of a detecting arrangement 600 comprising a push rod 601. For instance, the detecting arrangement 600 is at least partially arranged in a cavity formed by the cartridge holder 40.
At the proximal end of the push rod 601, a spring 602 is arranged which is connected to the cartridge holder 40 such that the push rod 601 is resiliently hold in the drug delivery device 10 and is at least longitudinally movable in the drug delivery device.
The detecting arrangement 600 further comprises a first switch 603 and a second switch 604 which are longitudinally arranged at a side-wall of the cavity 43. Therein, the first switch 603 is arranged closer to the distal end 42 of the cartridge holder 40 than the second switch. In other words, the first switch 603 is distally positioned and the second switch 604 is proximally positioned in the drug delivery device 10. The first switch 603 and the second switch 604 are pressure activated switches forming a first and a second detecting unit. In particular, the first switch 603 and the second switch 604 are only activated, when pressure is applied on the respective switch, and otherwise deactivated. The switches may be connected to a micro-processor control unit, such as the microcontroller 302 in FIG. 13, of the drug delivery device 10, logically signalling activation and deactivation to the micro-processor control unit.
A lateral surface of the push rod 601 oriented towards the first switch 603 and the second switch 604 is formed from three portions, two parallel surface portions 605, 606 and an inclined surface portion 607. The inclined surface portion 607 is arranged between the parallel surface portions 605, 606 such that the parallel surface portion 605 at the proximal end of the push rod is set back. A rod 608 is arranged at the distal end of the push rod 601.
In FIG. 12a, the dispense interface 200 is not attached to the drug delivery device 10. In particular, there is no contact between the rod 608 and the surface 226 of the dispense interface 200. Accordingly, the spring 602 is relaxed and the push rod 601 is hold in a first position in the drug delivery device 10. In this first position of the push rod 601 in the drug delivery device 10, the first switch 603 and the second switch 604 face the set back parallel surface portion 605 and the spring 602, respectively. In particular, there is no contact between the lateral surface of the push rod 601 and the first switch 603 and the second switch 604. Both switches are deactivated.
In FIG. 12b, attaching of the dispense interface 200 to the drug delivery device 10 is initiated such that the dispense interface 200 is aligned to the distal end 42 of the cartridge holder 40 and pushed towards the drug delivery device 10 to axially slid over the distal end 42 of the cartridge housing 40 of the drug delivery device 10. Thereby, the distal end of the rod 608 resides on the surface 226 of the dispense interface 200 and is also pushed towards the drug delivery device 10 such that, during attaching the dispense interface 200 to the drug delivery device 10, the movement of the dispense interface 200 towards the drug delivery device facilitates a corresponding movement of the push rod 601 and a compression of the spring 602.
When the push rod 601 is correspondingly moved, the first switch 603 and the second switch 604 slide along the inclined surface portion 607 of the lateral surface of the push rod 601 towards the parallel surface portion 606 and, thereby, increasing pressure is applied on the switches. When a pressure threshold is overcome, the first switch 603 and the second switch 604 are activated, for instance, the switches are activated, when residing on the parallel surface portion 606 (i.e. an activating portion of the push rod).
Due to its distal position, the first switch 603 resides on the parallel surface portion 606 before the second switch 604 resides thereon and is, thus, earlier activated. When the attaching is initiated as illustrated in FIG. 12b, the first switch 603 resides on the parallel surface portion 606 and is activated.
In FIG. 12c, attaching of the dispense interface 200 to the drug delivery device 10 is completed such that the dispense interface resides in fluid communication with the primary medicament 92 of the first cartridge 90 and the secondary medicament 102 of the second cartridge 100. Furthermore, the protruding members of the cartridge housing (e.g. protruding member 48) may cooperate with the first and second recess 217, 219 of the dispense interface 200 to form a secured mechanical connection such as a snap lock.
When the attaching of the dispense interface 200 to the drug delivery device 10 is completed as illustrated in FIG. 12c, the second switch 604 also resides on the parallel surface portion 606 and is activated. The spring 602 is compressed and the push rod is in a second position.
In this position the dispense interface 200 is considered as completely attached to the cartridge housing 40 and a timer for measuring the life time of the dispense interface 200 can be started.
When the dispense interface 200 is released from the drug delivery device 10, the compressed spring 602 relaxes and moves the push rod 601 back to the first position and optionally the dispense interface 200 to a detent position (i.e. the position illustrated in FIG. 12b). Thereby, firstly the second switch 604 and then the first switch 603 slide along the inclined surface portion 607 towards the set back parallel surface 605 and are subsequently deactivated.
When the first and/or the second switch are deactivated, to completely remove the dispense interface and be forced to attach a new dispense interface 200.
FIG. 13 illustrates a functional block diagram of a control unit to operate and control the drug delivery device illustrated in FIG. 1. FIG. 14 illustrates one arrangement of a printed circuit board (PCB) or printed circuit board assembly (PCBA) 350 that may comprise certain portions of the control unit illustrated in FIG. 13. The components described in the following can also be provided by separate circuit boards.
Referring now to both FIGS. 13 and 14, it may be seen that the control unit 300 comprises a microcontroller 302. The microcontroller is used to control the electronic system for the drug delivery device 10.
The control unit further comprises a power management module 304 coupled to the microcontroller 302 and other circuit elements. The power management module 304 receives a supply voltage from a main power source such as the battery 306 and regulates this supply voltage to a plurality of voltages required by other circuit components of the control unit 300.
The battery 306 provides power to the control unit 300 and is preferably supplied by a single lithium-ion or lithium-polymer cell. This cell may be encapsulated in a battery pack that contains safety circuitry to protect against overheating, overcharging and excessive discharge. A battery charger 308 may be coupled to the battery 306.
Preferably, the control unit further comprises a plurality of switches 316. In the illustrated arrangement, the control unit 300 may comprise two switches 316 and these switches may be distributed around the device. These switches 316 may be used to detect and/or confirm in particular whether the dispense interface 200 has been properly attached to the drug delivery device 10. Such switches are exemplarily illustrated in FIG. 11. There may further be additional switches in order to detect and/or confirm whether the removable cap 18 has been properly attached to the main body 20 of the drug delivery device 10, whether the first cartridge retainer 50 of the cartridge holder 40 for the first cartridge 90 has been properly closed, whether the second cartridge retainer 52 of the cartridge holder 40 for the second cartridge 100 has been properly closed, or to detect the presence of the first cartridge 90 and/or of the second cartridge 100.
In order to detect whether the dispense interface 200 has been properly attached to the drug delivery device 10, there may alternatively or additionally to the switches also be provided further sensors, for example a light barrier, a camera, a barcode reader, a proximity sensor or the like.
These switches and/or sensors 316 are connected to digital inputs, for example to general purpose digital inputs, on the microcontroller 302. Preferably, these digital inputs may be multiplexed in order to reduce the number of input lines required. Interrupt lines may also be used appropriately on the microcontroller 302 so as to ensure timely response to changes in switch status.
In addition, and as described in greater detail above, the control unit may also be operatively coupled to a plurality of human interface elements or push buttons 318. In one preferred arrangement, the control unit 300 comprises eight push buttons 318 and these are used on the device for user input for different user input functions.
These buttons 318 are connected to digital inputs, for example to general purpose digital inputs, on the microcontroller. Again, these digital inputs may be multiplexed so as to reduce the number of input lines required. Interrupt lines will be used appropriately on the microcontroller to ensure timely response to changes in switch status. In an example embodiment, the function of one or more buttons may be replaced by a touch screen.
In addition, the control unit 300 comprises a real time clock 320. The real-time clock 320 may communicate with the microcontroller 302 using a serial peripheral interface or similar. The real time clock may be used as a timer in order to determine the end of life of the dispense interface, for example. For this, the time when the dispense interface 200 is attached to the medical device 10 is saved, for example in the memory device 324. The difference between the current time and the saved time yields the time period of attachment of the dispense interface. The real time clock can alternatively be integrated into the microcontroller 302. This further saves space and components for realizing a timer to measure life time of a dispense assembly.
A digital display module 322 in the device preferably uses LCD or OLED technology and provides a visual signal to the user, for example of the display 80. The display module incorporates the display itself and a display driver integrated circuit. This circuit communicates with the microcontroller 302 using a serial peripheral interface or parallel bus. The end of life of the dispense interface 200 can be indicated over the display. The user can also be requested to remove the current dispense interface 200 or attach a new dispense interface 200.
As previously mentioned, a sounder 330 may also be provided in the drug delivery device 10. The proposed sounder may be used to provide an audible signal to the user. Instead of or additional to the visual indication relating to the end of life of the dispense interface, audible information may be provided for the same reason.
The control unit 300 further comprises a first motor driver 332 and a second motor driver 334. For example, where the motor drive comprises a stepper motor drive, the drive may be controlled using general purpose digital outputs. Alternatively, where the motor drive comprises a brushless DC motor drive, the drive may be controlled using a Pulse Width Modulated (PWM) digital output. These signals control a power stage, which switches current through the motor windings. The power stage requires continuous electrical commutation. This may for example increase device safety, decreasing the probability of erroneous drug delivery.
The motor drivers 332, 334 may also be controlled by a separate motor drive microcontroller (not shown) being in communication with the microcontroller 302.
The power stage may consist of a dual H-bridge per stepper motor, or three half-bridges per brushless DC motor. These may be implemented using either discrete semiconductor parts or monolithic integrated circuits.
The control unit 300 further comprises a first and a second motor 336, 338, respectively. The first motor 336 may be used to move the stopper (not shown) in the first cartridge 90. Similarly, the second motor 338 may be used to move the stopper (not shown) in the second cartridge. The motors can be stepper motors, brushless DC motors, or any other type of electric motor. The type of motor may determine the type of motor drive circuit used. The electronics for the device may be implemented with one main, rigid printed circuit board assembly, potentially with additional smaller flexible sections as required, e.g., for connection to motor windings and switches.
In order to prevent usage of the device, the micro-processor 302 can prevent usage of the device 10 by not allowing signals to be sent to the motor drivers 332, 334, for instance. In this way, the device is still usable for other actions than dispensing.
FIG. 15 schematically illustrates an exemplary embodiment of a tangible storage medium 340 according to the present invention. Tangible storage medium 340 may for instance store a computer program 342, with program code 344 for detecting an attachment of a dispense assembly to a medical device, in particular a medical device according to the invention, determining whether the end of life of the dispense interface is reached and indicating the end of life of the dispense assembly. Tangible storage medium 340 is a readably medium, for instance a computer-readable or processor-readable medium. Accordingly, the computer program 342 stored on tangible storage medium 340 may be executable by a computer or a processor. Tangible storage medium 340 may for instance be embodied as an electric, magnetic, electro-magnetic, optic or other tangible storage medium, and may either be a removable medium or a medium that is fixedly installed in an apparatus or device, such as for instance medical device 10 of FIG. 1.
FIG. 16 shows a cross section of another embodiment of a dispense interface 1200. The dispense interface may as well be adapted such that it actuates the sensors discussed in connection with dispense interface 200.
As may be seen from FIG. 16, the dispense interface 1200 further comprises a mechanical lock-out mechanism in form of dispense interface lockout member in the form of a lockout spring 2600. FIG. 17 illustrates a perspective view of such one arrangement of such a lock out member 2600 in an initial, unbiased or unstressed state. One reason that a lock out member may be incorporated into a dispense interface, such as the interface 200 illustrated in FIG. 1, is to ensure that once the dispense interface is removed from the drug delivery device, the dispense interface cannot be re-attached and used a second time. Preventing re-attachment tends to ensure that medicament is not allowed to reside in the dispense interface 1200 indefinitely and contaminate the drug delivered to the patient. This is particularly advantageous in combination with a life time limitation of the dispense interface.
In the illustrated arrangement in FIGS. 16 and 17, the lock out spring resides in a first or an initial position. As illustrated, the lock out spring 2600 extends from a distal spring end 2604 to a proximal spring end 2620. Near its distal end 2604, the lock out spring 2600 comprises a spring tip 2620. This spring tip 2620 comprises a tab 2622 defining a recess 2624.
Near its proximal end 2610, the lock out spring 2600 comprises a first spring arm 2630 and a second spring arm 2340. For example, the first spring arm 2630 extends proximally from a first pivot point 2632 of the spring 2632. Similarly, the second spring arm 2340 extends proximally from a second pivot point 2642 of the spring 2600. In the initial spring position illustrated in FIG. 16, both the first and the second spring arms 2630, 2640 reside in an unstressed state. That is, both arms flex radially outward, away from one another a spaced amount defining an initial distance DM1 2644 (cf. FIG. 17) of a mouth created between the first and the second spring arm 2630, 2640. When the spring 2600 is placed within a stressed state (so as to lock out the spring preventing re-attachment), the first and second spring arms 2630, 2640 flex towards one another at the first and second pivot points 2632, 2642, respectively. This flexing causes the arms 2630, 2640 to reduce the initial distance DM1 of the mouth to a smaller second mouth distance DM2.
FIG. 18 illustrates the dispense interface 1200 illustrated in FIG. 16 about to be mounted onto a distal end of a drug delivery device, such as the drug delivery device 1150 in FIG. 18. In this pre-attachment illustration, the lock out spring contained within the dispense interface 1200 resides in the first or initial position, as illustrated in FIG. 16.
FIG. 19 illustrates the dispense interface 1200 illustrated in FIG. 18 after the dispense interface has been moved to a first attached position. For ease of explanation, certain component parts of the dispense interface 1200 have been removed, such as the outer body 1210, so that the various configurations of the lock out spring may be illustrated and/or explained. For example, in this illustrated initial attached position, the outer body 1210 of the dispense interface 1200 has been removed so as to illustrate the lock out spring 2600 and how it changes state during attachment of the dispense interface to the drug delivery device 1150. As illustrated, both the first and the second spring knuckles 2650, 2660 have entered the distal end 1152 of the drug delivery device and have made contact with a face of the cartridge holder. For example, the first spring knuckle 2650 has made contact with a first cartridge holder face 1175b and the second spring knuckle 2660 has made contact with a second cartridge holder face 1175a. As also illustrated, both the first and second lock out spring arms 2630, 2640 have entered the distal end of the drug delivery device and reside between the outer body of the device and the cartridge holders. However, as the dispense interface continues to move in the proximal direction from this initial illustrated position, the cartridge holder faces 1175 a,b begin to exert pressure on the first and second spring knuckles 2650, 2660. This exerted pressure tends to bend the first and second spring arms 2630, 2640 inwardly, towards one another so as to reduce the initial diameter DM1 of mouth.
Once the proximal end of the dispense interface 1200 enters the distal end of the drug delivery device 1150, when mounted onto the inner body 2000 of the dispense interface, the spring tip 2620 will be mounted on a retention rib provided on the inner body 2000. For example, FIG. 19 shows the lock out spring 2600 mounted on the inner body 2000 in a first or initial position. In this initial position, the spring tip 2620 resides over the retention rib 2090 on the inner body 2000. In addition, a bottom flat surface 2622 of the spring tip 2620 resides adjacent a flat distal surface of the first outer protrusion 2006 of the inner body 2000.
When in this initial condition, the arms of the spring are disposed to flex outwards, away from the center of the spring assembly. As such, as the dispense interface 1200 is fitted onto the distal end of the drug delivery device, the distal face of the device pushes on the lock out spring 2600, forcing the spring to move in the distal direction. This axial movement of the spring 2600 causes the spring to flex about its spring arms 2630, 2640. As these arms are restrained from rotating by the presence of the cartridge doors of the drug delivery device, the spring slides in the distal direction. This distal movement occurs until the spring tip 2622 snaps over the retention rib 2090 on the inner body 2000.
FIG. 20 illustrates the dispense interface 1200 illustrated in FIG. 19 in a fully seated position. As illustrated, in this fully seated position, both the first and second spring arms 2630, 2640 now reside along an outer surface of the cartridge holders and thereby exert an inwardly directed pressure against these cartridge holders. In addition, the first spring portion residing between first pivot point 2632 and the first knuckle 2650 flattens out along the first cartridge holder face 1175b. Similarly, the second spring portion residing between the second pivot point and the second knuckle 2660 also flattens out along the second cartridge holder face 1175a. Once the spring tip 2620 has snapped over the retention tip 2090 of the inner body 2000, the spring tip 2620 cannot be easily retracted in the proximal direction so as to allow the spring tip 2620 to move back over the retention rib 2090. As such, a spring force is built up in the first and second spring arms 2630, 2640 as they are forced against the cartridge holder until such a time as the dispense interface is removed from the device.
A release button (not shown) on the drug delivery device may be pushed or manually activated to as to allow the user to remove the attached dispense interface 1200. FIG. 21 illustrates the dispense interface 1200 in a first position as it is being removed from the distal end of the drug delivery device 1150. As the dispense interface 1200 is removed from the device, the distal ends of the cartridge doors move out of engagement with the inwardly biased first and second spring arms 2630, 2640. As such, both spring arms 2630, 2640 are able to rotate as they relax and flex back towards one another.
Once the spring arms 2630, 2640 of the spring 2600 have rotated, they reside in an interference position which is illustrated in FIG. 21. For example, in this interference position, if one were to try to reattach the dispense interface 1200 onto the drug delivery device 1150, the spring arms 2630, 2640 would interfere with the distal end of the cartridge holders of the drug delivery device since these arms are no longer spaced apart the larger mouth distance DM1 as illustrated in FIG. 19 but are spaced apart a smaller mouth distance DM2. As such, the dispense interface 1200 is prevented from being reattached to the drug delivery device and thereby locks out or prevents the dispense interface 1200 from further attachment. The shape of the inner body 2000 and the support it gives to the spring help to ensure that the lock out spring 2600 cannot be easily forced or pushed out of the way by a user attempting to refit the dispense interface back onto the drug delivery device.
FIG. 22 illustrates in a flow chart an exemplary embodiment of a method according to the invention. In step 350 the attachment of the dispense interface to the medical device is detected. This can be realized by the sensors 43, 43a and/or 43b for example. When the corresponding sensor sends a signal the control unit, for example the micro-controller 302, a timer is started. In case the timer was already running because of an earlier attached dispense interface or assembly, the timer is reset.
The steps 354 and 356 now illustrate the behavior of exemplary embodiment of a medical device according to the invention during the use of the device for dispensing one or two medicaments. Each time the user requests a dose to be dispensed, the micro-controller checks in step 354 whether the timer is still less than a maximum allowed period of life time “timermax” for the attached dispense interface, in order to determine whether the end of life of the dispense interface is reached or has already been reached. It is additionally or alternatively conceivable that this criterion is checked regularly, independent of the use of the device or the dispense of the medicament. In case the timer is still less than the maximum allowed time, the dispense of the medicaments can be performed in step 356. The user can continue to use the same dispense interface as long as the timer is less than the maximum allowed time.
In case the timer is not less than the maximum allowed time, the medical device prevents further usage of the device in step 358, since it can not be guaranteed that the remaining fluids in the dispense interface are harmless for the user. Preventing further usage can mean to only prevent any further dispense of the medicaments. It can also mean that the user is prevented from any further input to the device.
Over a display the detachment of the dispense interface is the requested from the user in step 360. It is possible to reset the timer when the sensors detect detachment of the dispense interface. It is also possible to keep the timer running and reset the timer in step 352.
When the user has detached the used dispense interface and attaches a new dispense interface, the method will start again with step 350.
The term “drug” or “medicament”, as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exedin-3 or exedin-4 or an analogue or derivative of exedin-3 or exedin-4.
Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30 human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyhepta-idecanoyl) human insulin.
Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exedin-4 derivative.
Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed in Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
Antibodies are globular plasma proteins (˜150 kDa) that are also known as immunoglobulins which share a basic structure. As they have sugar chains added to amino acid residues, they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin (Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM, or pentameric with five Ig units, like mammalian IgM.
The Ig monomer is a “Y”-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chains connected by disulfide bonds between cysteine residues. Each heavy chain is about 440 amino acids long; each light chain is about 220 amino acids long. Heavy and light chains each contain intrachain disulfide bonds which stabilize their folding. Each chain is composed of structural domains called Ig domains. These domains contain about 70-110 amino acids and are classified into different categories (for example, variable or V, and constant or C) according to their size and function. They have a characteristic immunoglobulin fold in which two β sheets create a “sandwich” shape, held together by interactions between conserved cysteines and other charged amino acids.
There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and μ. The type of heavy chain present defines the isotype of antibody; these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
Distinct heavy chains differ in size and composition; α and γ contain approximately 450 amino acids and δ approximately 500 amino acids, while μ and ε have approximately 550 amino acids. Each heavy chain has two regions, the constant region (CH) and the variable region (VH). In one species, the constant region is essentially identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains. The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain.
In mammals, there are two types of immunoglobulin light chain denoted by λ and κ. A light chain has two successive domains: one constant domain (CL) and one variable domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody in mammals.
Although the general structure of all antibodies is very similar, the unique property of a given antibody is determined by the variable (V) regions, as detailed above. More specifically, variable loops, three each the light (VL) and three on the heavy (VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity. These loops are referred to as the Complementarity Determining Regions (CDRs). Because CDRs from both VH and VL domains contribute to the antigen-binding site, it is the combination of the heavy and the light chains, and not either alone, that determines the final antigen specificity.
An “antibody fragment” contains at least one antigen binding fragment as defined above, and exhibits essentially the same function and specificity as the complete antibody of which the fragment is derived from. Limited proteolytic digestion with papain cleaves the Ig prototype into three fragments. Two identical amino terminal fragments, each containing one entire L chain and about half an H chain, are the antigen binding fragments (Fab). The third fragment, similar in size but containing the carboxyl terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding sites. Limited pepsin digestion yields a single F(ab′)2 fragment containing both Fab pieces and the hinge region, including the H—H interchain disulfide bond. F(ab′)2 is divalent for antigen binding. The disulfide bond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, the variable regions of the heavy and light chains can be fused together to form a single chain variable fragment (scFv).
Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1 C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in “Remington's Pharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
Pharmaceutically acceptable solvates are for example hydrates.
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16401007
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sanofi-aventis deutschland gmbh
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USA
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B2
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Utility Patent Grant (with pre-grant publication) issued on or after January 2, 2001.
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Open
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Apr 12th, 2022 11:48AM
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Apr 12th, 2022 11:48AM
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Sanofi
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Health Care
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Pharmaceuticals & Biotechnology
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