Anti-cgrp antibody formulations

Abstract

The present application relates to anti-CGRP antibody formulations. Pharmaceutical formulations of anti-CGRP antibodies and methods of their use are provided, which are useful as a treatment for migraine, episodic headache, chronic headache, chronic cluster headache, and episodic cluster headache.

Description

[0001] This application is a divisional application. The parent application number is 201680034297.0, the application date is June 8, 2016, and the invention title is "Anti-CGRP Antibody Preparation".

[0002] This invention belongs to the field of medicine. More specifically, this invention relates to antibodies against calcitonin gene-related peptide (CGRP) and pharmaceutical preparations thereof. An additional aspect of this invention relates to the use of such anti-CGRP antibodies and pharmaceutical preparations thereof for treating patients suffering from CGRP-related conditions.

[0003] CGRP is a neuropeptide secreted by nerves in the central and peripheral nervous systems and is involved in pain pathways. The role of CGRP in headache and migraine has been established in the field, and several clinical studies are currently evaluating the use of anti-CGRP antibodies for the treatment of headache and migraine. (See, for example, Dodick et al., Lancet Neurol; 13(9):885-892 (2014)).

[0004] Liquid pharmaceutical formulations of antibodies intended for human use require chemical and physical stability of the antibody over its extended shelf life (e.g., WO06083689 and WOO6096491). Chemical instability of antibodies can result from a variety of chemical reactions, including deamidation, racemization, hydrolysis, oxidation, β-elimination, and disulfide exchange. Physical instability can result from processes such as denaturation, aggregation, precipitation, and surface adsorption. Antibody instability can lead to the formation of polypeptide byproducts or derivatives with low activity, increased toxicity, and / or increased immunogenicity, which can raise concerns about the safety and efficacy of the antibody.

[0005] While the potential for protein instability is widely understood, specific instability issues for particular proteins are difficult to predict. The applicant sought to formulate an anti-CGRP antibody (PCT / US2011 / 039381) comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the amino acid sequence of the LCVR is SEQ ID NO: 1 and the amino acid sequence of the HCVR is SEQ ID NO: 2. In formulating the anti-CGRP antibody for use in a therapy, the applicant identified several factors contributing to antibody instability, such as photodegradation, polymer formation during freeze-thaw cycles, and oxidation of polysorbate-80 (PS-80) in the formulation. Therefore, a stable pharmaceutical formulation is needed to address at least one or more of the observed problems.

[0006] Therefore, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about 40 mg / mL to about 160 mg / mL, a histidine buffer at a concentration of about 5 mM to about 20 mM, sodium chloride (NaCl) at a concentration of about 50 mM to about 200 mM, PS-80 at a concentration of about 0.03% (w / v) to about 0.07% (w / v), and a pH of about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of which is given by SEQ ID NO: 1, and the amino acid sequence of which is given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of which is given by SEQ ID NO: 3, and the amino acid sequence of which is given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0007] In one alternative embodiment, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about 50 mg / mL to about 150 mg / mL, a histidine buffer at a concentration of about 5 mM to about 20 mM, sodium chloride at a concentration of about 50 mM to about 200 mM, PS-80 at a concentration of about 0.03% (w / v) to about 0.07% (w / v), and a pH of about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of which is given by SEQ ID NO: 1, and the amino acid sequence of which is given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of which is given by SEQ ID NO: 3, and the amino acid sequence of which is given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0008] In one alternative embodiment, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about 100 mg / mL to about 160 mg / mL, a histidine buffer at a concentration of about 5 mM to about 20 mM, NaCl at a concentration of about 50 mM to about 200 mM, PS-80 at a concentration of about 0.03% (w / v) to about 0.07% (w / v), and a pH of about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of which is given by SEQ ID NO: 1, and the amino acid sequence of which is given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of which is given by SEQ ID NO: 3, and the amino acid sequence of which is given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0009] Another embodiment of the invention also provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-80, wherein the concentration of the anti-CGRP antibody is selected from about 50 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 150 mg / mL, the histidine buffer concentration is about 5 mM to about 20 mM, the NaCl concentration is about 50 mM to about 200 mM, the PS-80 concentration is about 0.03% (w / v) to about 0.07% (w / v), and the pH is about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of the LCVR being given by SEQ ID NO: 1, and the amino acid sequence of the HCVR being given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of which is given by SEQ ID NO: 3, and the amino acid sequence of which is given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of which is given by SEQ ID NO: 3, and the amino acid sequence of which is given by SEQ ID NO: 4.

[0010] Another embodiment of the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-80, wherein the concentration of the anti-CGRP antibody is selected from about 50 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 150 mg / mL; the histidine buffer concentration is about 10 mM; the NaCl concentration is about 50 mM to about 200 mM; the PS-80 concentration is about 0.03% (w / v) to about 0.07% (w / v); and the pH is about 5.0 to about 6.5. The anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of which is given by SEQ ID NO: 1, and the amino acid sequence of which is given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of which is given by SEQ ID NO: 3, and the amino acid sequence of which is given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0011] In another embodiment, the present invention also provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-80, wherein the concentration of the anti-CGRP antibody is selected from about 50 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 150 mg / mL, the histidine buffer concentration is about 10 mM, the NaCl concentration is about 150 mM, the PS-80 concentration is about 0.03% (w / v) to about 0.07% (w / v), and the pH is about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of the LCVR being given by SEQ ID NO: 1, and the amino acid sequence of the HCVR being given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of the LC being given by SEQ ID NO: 3, and the amino acid sequence of the HC being given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0012] In another embodiment, the present invention also provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-80, wherein the concentration of the anti-CGRP antibody is selected from about 50 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 150 mg / mL, the histidine buffer concentration is about 10 mM, the NaCl concentration is about 150 mM, the PS-80 concentration is about 0.05% (w / v), and the pH is about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of the LCVR being given by SEQ ID NO: 1, and the amino acid sequence of the HCVR being given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of the LC being given by SEQ ID NO: 3, and the amino acid sequence of the HC being given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0013] More specifically, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about 120 mg / mL, a histidine buffer at a concentration of about 10 mM, NaCl at a concentration of about 150 mM, PS-80 at a concentration of about 0.05% (w / v) and a pH of about 5.8, wherein the anti-CGRP antibody comprises LCVR and HCVR, the amino acid sequence of LCVR being given by SEQ ID NO: 1 and the amino acid sequence of HCVR being given by SEQ ID NO: 2. Preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC being given by SEQ ID NO: 3 and the amino acid sequence of HC being given by SEQ ID NO: 4. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody having two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3 and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0014] In another embodiment, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, wherein the concentration of the anti-CGRP antibody is from about 40 mg / mL to about 160 mg / mL. Preferably, the concentration of the anti-CGRP antibody is from about 50 mg / mL to about 150 mg / mL. More preferably, the concentration of the anti-CGRP antibody is from about 50 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 150 mg / mL. In a specific embodiment, the pharmaceutical formulation comprises an anti-CGRP antibody in a histidine buffer at a concentration of from about 40 mg / mL to about 160 mg / mL, wherein the concentration of the histidine buffer is from about 5 mM to about 20 mM. Preferably, the concentration of the histidine buffer is about 10 mM.

[0015] In another embodiment, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody and NaCl, wherein the concentration of NaCl is from about 50 mM to about 200 mM. Preferably, the concentration of NaCl is from about 125 mM to about 175 mM. More preferably, the concentration of NaCl is about 150 mM. Even more preferably, the pharmaceutical formulation comprises an anti-CGRP antibody, 10 mM of histidine buffer, and NaCl, wherein the concentration of NaCl is from about 50 mM to about 200 mM. Most preferably, the pharmaceutical formulation comprises an anti-CGRP antibody at a concentration ranging from about 40 mg / mL to about 160 mg / mL, a histidine buffer at a concentration of about 10 mM, and NaCl at a concentration of about 50 mM to about 200 mM, with a pH of about 5.8. Preferably, the NaCl concentration is about 150 mM.

[0016] In another embodiment, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody and PS-80, wherein the concentration of PS-80 is from about 0.03% (w / v) to about 0.07% (w / v). Preferably, the concentration of PS-80 in the pharmaceutical formulation is about 0.05% (w / v). In a preferred embodiment, the pharmaceutical formulation comprises an anti-CGRP antibody at a concentration ranging from about 40 mg / mL to about 160 mg / mL, and PS-80 at a concentration ranging from about 0.03% (w / v) to about 0.07% (w / v). More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody at a concentration ranging from about 40 mg / mL to about 160 mg / mL, a histidine buffer at a concentration ranging from about 5 mM to 20 mM, and PS-80 at a concentration of about 0.05% (w / v). Even more preferably, the pharmaceutical formulation comprises an anti-CGRP antibody at a concentration ranging from about 40 mg / mL to about 160 mg / mL, NaCl at a concentration ranging from about 50 mM to about 200 mM, and PS-80 at a concentration of about 0.05% (w / v). Most preferably, the pharmaceutical formulation comprises an anti-CGRP antibody at a concentration ranging from about 100 mg / mL to about 150 mg / mL, a histidine buffer at a concentration ranging from about 125 mM to about 175 mM, PS-80 at a concentration of about 0.05% (w / v), and a pH of about 5.8.

[0017] The present invention also provides methods for treating or preventing conditions (preferably headaches and / or migraines) associated with elevated CGRP levels, comprising administering a therapeutically effective amount of the pharmaceutical preparation of the present invention to a patient in need. Some embodiments of the present invention provide methods for treating or preventing migraines, episodic headaches, chronic headaches, chronic cluster headaches, and / or episodic cluster headaches, comprising administering a therapeutically effective amount of the pharmaceutical preparation of the present invention to a patient in need. According to some embodiments, a method for treating or preventing chronic and episodic cluster headaches is provided, comprising administering a dose of 300 mg of anti-CGRP antibody to a patient in need. Other embodiments provide a method for treating or preventing chronic and episodic cluster headaches, comprising administering a dose of 360 mg of anti-CGRP antibody to a patient in need. In other embodiments, the present invention provides a method for treating or preventing chronic and episodic migraines, comprising administering a dose of 120 mg of anti-CGRP antibody to a patient in need. Other embodiments provide a method for treating or preventing chronic and episodic migraines, comprising administering a dose of 240 mg of anti-CGRP antibody to a patient in need. Another embodiment provides a method for treating or preventing chronic and episodic migraines, comprising administering an initial loading dose of 240 mg of anti-CGRP antibody to a patient in need, followed by a monthly maintenance dose of 120 mg of anti-CGRP antibody. Preferably, the dose is administered at weekly, bi-weekly, monthly, or quarterly intervals. More preferably, it is administered monthly.

[0018] In another embodiment, the invention also provides a method for treating or preventing cluster headaches in a patient in need by administering a monthly subcutaneous dose of 300 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody binds to an epitope comprising the amino acid VTHRLAGLLSR of SEQ ID NO: 7. In another embodiment, the invention provides a method for treating or preventing episodic migraines in a patient in need by administering a monthly subcutaneous dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO: 1 and HCVR as given by the amino acid sequence of SEQ ID NO: 2. Preferably, the anti-CGRP antibody is in a pharmaceutical formulation comprising about 10 mM histidine buffer, about 150 mM NaCl, about 0.05% PS-80, and a pH of about 5.8. In another embodiment, the present invention also provides a method for treating or preventing cluster headaches in patients of need by administering a monthly subcutaneous dose of 300 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LC as given by the amino acid sequence of SEQ ID NO: 3 and HC as given by the amino acid sequence of SEQ ID NO: 4. Preferably, the anti-CGRP antibody is in a pharmaceutical preparation comprising about 10 mM of histidine buffer, about 150 mM of NaCl, about 0.05% PS-80, and a pH of about 5.8.

[0019] In another embodiment, the present invention also provides a method for treating or preventing cluster headaches in patients of need by administering a monthly dose of 300 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO: 1 and HCVR as given by the amino acid sequence of SEQ ID NO: 2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a histidine buffer. In one specific embodiment, the anti-CGRP antibody is in a pharmaceutical composition comprising a histidine buffer at a pH of about 5.5-6.1. In another specific embodiment, the anti-CGRP antibody is in a pharmaceutical composition comprising about 5 mM to about 20 mM of a histidine buffer. Preferably, the pharmaceutical composition has a pH of about 5.7-6.0. More preferably, the pharmaceutical composition has a pH of about 5.8.

[0020] In another specific embodiment, the present invention also provides a method for treating or preventing cluster headaches in patients of need by administering a monthly dose of 300 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO:1 and HCVR as given by the amino acid sequence of SEQ ID NO:2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, NaCl, and a surfactant. Preferably, the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, about 50 mM to about 200 mM of NaCl, and a surfactant. More preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.7-6.0. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.8.

[0021] In another specific embodiment, the present invention also provides a method for treating or preventing cluster headaches in patients of need by administering a monthly dose of 300 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO:1 and HCVR as given by the amino acid sequence of SEQ ID NO:2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, a salt, and PS-80 as a surfactant. Preferably, the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, a salt, and about 0.03% (w / v) to about 0.07% (w / v) of PS-80. More preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.7 to 6.0. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.8.

[0022] In another embodiment, the present invention provides a method for treating or preventing episodic migraine in a patient in need by administering a monthly subcutaneous dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody binds to an epitope comprising the amino acid VTHRLAGLLSR of SEQ ID NO: 7. In another embodiment, the present invention provides a method for treating or preventing episodic migraine in a patient in need by administering a monthly subcutaneous dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR given by the amino acid sequence of SEQ ID NO: 1 and HCVR given by the amino acid of SEQ ID NO: 2. Preferably, the anti-CGRP antibody is in a pharmaceutical formulation comprising about 10 mM histidine buffer, about 150 mM NaCl, about 0.05% PS-80, and a pH of about 5.8. In another embodiment, the present invention provides a method for treating or preventing episodic migraine in a patient of need by administering a monthly subcutaneous dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LC as given by the amino acid sequence of SEQ ID NO: 3 and HC as given by the amino acid sequence of SEQ ID NO: 4. Preferably, the anti-CGRP antibody is in a pharmaceutical preparation comprising about 10 mM histidine buffer, about 150 mM NaCl, about 0.05% PS-80, and a pH of about 5.8.

[0023] In another embodiment, the present invention provides a method for treating or preventing episodic migraine in a patient of need by administering a monthly dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO: 1 and HCVR as given by the amino acid sequence of SEQ ID NO: 2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a histidine buffer. In one specific embodiment, the anti-CGRP antibody is in a pharmaceutical composition comprising a histidine buffer at a pH of about 5.5-6.1. In another specific embodiment, the anti-CGRP antibody is in a pharmaceutical composition comprising about 5 mM to about 20 mM of histidine buffer. Preferably, the pharmaceutical composition has a pH of about 5.7-6.0. More preferably, the pharmaceutical composition has a pH of about 5.8.

[0024] In another specific embodiment, the present invention provides a method for treating or preventing episodic migraine in a patient of need by administering a monthly dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO:1 and HCVR as given by the amino acid sequence of SEQ ID NO:2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, NaCl, and a surfactant. Preferably, the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, about 50 mM to about 200 mM of NaCl, and a surfactant. More preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.7-6.0. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.8.

[0025] In another specific embodiment, the present invention provides a method for treating or preventing episodic migraine in a patient of need by administering a monthly dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO:1 and HCVR as given by the amino acid sequence of SEQ ID NO:2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, a salt, and PS-80 as a surfactant. Preferably, the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, a salt, and about 0.03% (w / v) to about 0.07% (w / v) of PS-80. More preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.7 to 6.0. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.8.

[0026] In another embodiment, the present invention provides a method for treating or preventing chronic migraine in a patient of need by administering a monthly dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO: 1 and HCVR as given by the amino acid sequence of SEQ ID NO: 2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a histidine buffer. In one specific embodiment, the anti-CGRP antibody is in a pharmaceutical composition comprising a histidine buffer at a pH of about 5.5-6.1. In another specific embodiment, the anti-CGRP antibody is in a pharmaceutical composition comprising about 5 mM to about 20 mM of a histidine buffer. Preferably, the pH of the pharmaceutical composition is about 5.7-6.0. More preferably, the pH of the pharmaceutical composition is about 5.8.

[0027] In another specific embodiment, the present invention provides a method for treating or preventing chronic migraine in a patient of need by administering a monthly dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO: 1 and HCVR as given by the amino acid sequence of SEQ ID NO: 2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, NaCl, and a surfactant. Preferably, the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, about 50 mM to about 200 mM of NaCl, and a surfactant. More preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.7 to 6.0. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.8.

[0028] In another specific embodiment, the present invention provides a method for treating or preventing chronic migraine in a patient of need by administering a monthly dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LCVR as given by the amino acid sequence of SEQ ID NO: 1 and HCVR as given by the amino acid sequence of SEQ ID NO: 2, and wherein the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, a salt, and PS-80 as a surfactant. Preferably, the anti-CGRP antibody is in a pharmaceutical composition comprising a buffer, a salt, and about 0.03% (w / v) to about 0.07% (w / v) of PS-80. More preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.7 to 6.0. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition with a pH of about 5.8. The present invention also provides pharmaceutical formulations for use in therapies, preferably for treating or preventing migraine and / or headache. In specific embodiments, the present invention provides pharmaceutical preparations for treating or preventing at least one or more of the following conditions: episodic migraine, chronic migraine, episodic headache, chronic headache, chronic cluster headache, and / or episodic cluster headache. Preferably, the dose of anti-CGRP antibody administered to the patient for episodic and / or chronic migraine is 120 mg or 240 mg, and the dose of anti-CGRP antibody for episodic and / or chronic cluster headache is 300 mg or 360 mg. Furthermore, the present invention provides the use of the pharmaceutical preparations of the present invention in the manufacture of medicaments for treating or preventing migraine and / or headache. Specifically, the present invention provides the use of the pharmaceutical preparations in the manufacture of medicaments for treating at least one or more of the following conditions: episodic migraine, chronic migraine, episodic headache, chronic headache, chronic cluster headache, and / or episodic cluster headache.

[0029] As used herein, the term "patient" refers to a person. In some embodiments, a patient is a person diagnosed with a condition or ailment for which treatment or administration of the pharmaceutical preparations of the present invention is indicated. In some embodiments, a patient is a person characterized as being at risk of a condition or ailment for which treatment or administration of the pharmaceutical preparations of the present invention is indicated.

[0030] As used herein, the term "treating" (or "treat") refers to a process involving the reduction, interruption, prevention, control, cessation, decrease, or reversal of the progression or severity of symptoms, conditions, illnesses, or diseases, but does not necessarily involve the complete elimination of all disease-related symptoms, conditions, or illnesses associated with CGRP activity. As used herein, the term "prevention" (or "prevent") refers to the inhibition, prevention, avoidance, cessation, or reduction of the onset of diseases, conditions, and / or illnesses, or the cessation or prevention of symptoms of diseases, conditions, and / or illnesses. Prevention includes administration to subjects who do not exhibit symptoms of diseases, conditions, and / or illnesses at the time of administration.

[0031] As used herein, the term "therapeutic effective amount" refers to the amount or dose of anti-CGRP antibody in the pharmaceutical formulation of the present invention, which provides the desired pharmacological effect in a patient after administration of a single or multiple doses. A dose may include a higher initial loading dose followed by lower doses. "Dose" refers to a predetermined amount of therapeutic medicine calculated to produce the desired therapeutic effect in a patient. Therapeutic effective amount can be determined by the attending physician (as those skilled in the art) by considering a number of factors, such as the patient's body type, age and general health, the specific disease or surgical procedure involved, the degree or severity of the disease or ailment, the individual patient's response, the route of administration, the bioavailability characteristics of the administered formulation, the chosen dosing regimen, and the use of any concomitant medications.

[0032] As used herein, the term "month" or its derivatives refer to a period of time comprising 28 to 31 consecutive days. The term "about," as used herein, means within a reasonable range of the stated value, such as plus or minus 10%.

[0033] The general structure of an antibody is known in the art. Anti-CGRP antibodies are disclosed in WO2011 / 156324. As used herein, a "drug substance" (DS) is a formulation comprising an antibody, a buffer (e.g., histidine), an excipient (e.g., NaCl), and a surfactant (e.g., PS-80) and situated within a specific pH range or at a specific pH. A "drug product" (DP) is a formulation comprising a buffer, an excipient, a surfactant, and an antibody, wherein the antibody concentration in the DP may be lower than the antibody concentration in the DS.

[0034] The pharmaceutical formulation of the present invention is a liquid dosage form of a solution. The pharmaceutical formulation of the present invention can be administered via parenteral administration. As used herein, parenteral administration may include injecting the dosage form into the body using a sterile syringe or other mechanical device such as an infusion pump. Parenteral routes may include intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Subcutaneous administration is the preferred route. The pharmaceutical formulation of the present invention is intended for pharmaceutical use in humans.

[0035] The present invention is further illustrated by the following embodiments, which should not be construed as limiting. Example

[0036] Antibody production The antibodies of this invention can be prepared and purified as follows. Suitable host cells (such as CHO cells) are transiently or stably transfected with an expression system that secretes the antibody using an optimal predetermined HC:LC vector ratio, or a single vector system encoding two LCs and two HCs (such as SEQ ID NO: 3 for each LC and SEQ ID NO: 4 for each HC). The clarified culture medium (in which the antibody has been secreted) is purified using any of many commonly used techniques. For example, the culture medium can be conveniently applied to a Protein A or G Sepharose FF column that has been equilibrated with a compatibility buffer (such as phosphate-buffered saline (pH 7.4)). The column is washed to remove non-specifically bound components. For example, bound antibodies are eluted by a pH gradient. Antibody fractions are detected, for example, by SDS-PAGE and then pooled. Further purification is optional, depending on the intended use. The antibody can be concentrated and / or sterilely filtered using common techniques. Soluble aggregates and polymers can be efficiently removed using common techniques, including size exclusion, hydrophobic interactions, ion exchange, or hydroxyapatite chromatography. After these chromatographic steps, the purity of the antibody is greater than 99%. This product can be immediately frozen at -70°C in the formulation matrix of this invention or can be lyophilized. The amino acid and nucleic acid sequences of exemplary antibodies are provided below.

[0037] Manufacturing of anti-CGRP drug formulations The manufacturing process of the anti-CGRP antibody drug formulation of the present invention includes a complex buffer excipient composition and the addition of an anti-CGRP antibody drug (DS).

[0038] The buffer excipient composition comprises L-histidine, L-histidine hydrochloride monohydrate, NaCl, PS-80, and water (Table 1). The anti-CGRP antibody contains the light chain of SEQ ID NO: 3 and the heavy chain of SEQ ID NO: 4.

[0039] Table 1. Buffer Excipient Compositions *Weight / Volume.

[0040] Preparation and filtration of the buffer excipient composition. Weigh an appropriate amount of water at a temperature not exceeding 25°C into a suitably sized, balanced empty container. Add and mix appropriate amounts of L-histidine, L-histidine hydrochloride monohydrate, and NaCl. Weigh PS-80 into a glass container and add an appropriate amount of water to the glass container to obtain the indicated final concentration and mix the solution. Add the PS-80 solution to the other excipients, mix the solution, and prepare the solution to adjust the pH and osmotic pressure concentration to within 5.8 ± 0.3 and 254–344 mOsm / kg, respectively. Pass the buffer excipient composition through a filter to reduce the bioburden.

[0041] Anti-CGRP antibody DS was prepared as follows: antibody expression in cells, purification, concentration, and freezing of the antibody in a solution of 10 mM histidine buffer, 150 mM NaCl, 0.05% PS-80, and a pH of approximately 5.8. The DS solution was stored at -70°C. The frozen DS was equilibrated to 20 ± 5°C and mixed with an appropriate amount of buffer excipient solution to achieve an intermediate antibody DP concentration. The pH of the solution was checked to be within 5.8 ± 0.3.

[0042] Mix the solutions and take a sample for in-process UV assay to determine the antibody DP concentration. Add an appropriate amount of buffer excipient solution to achieve the final target batch weight. After mixing, check the pH of the solution to be within 5.8 ± 0.3. Pass the antibody DP solution through a filter to reduce bioload, then aseptically filter and fill into vials or syringes. The final concentration of antibody DP can be between approximately 40 mg / mL and approximately 160 mg / mL.

[0043] Light stability Light can affect the active molecules in pharmaceutical formulations, as well as the final product or packaging, leading to photodegradation that can result in a loss of product efficacy. The effects of light on anti-CGRP antibodies formulated in pre-filled glass syringes at pH 5.8 with citrate or histidine buffer were assessed using size exclusion chromatography (SEC). For visible light, the exposure level was approximately 20% of ICH Q1B, and for UV light, the exposure level was 10% of ICH Q1B.

[0044] Divide approximately 165 mg / mL of anti-CGRP antibody (in 10 mM histidine, 150 mM NaCl, pH 6.0) into two aliquots. Dialyze one aliquot to a buffer of 10 mM histidine, 150 mM NaCl, pH 5.8, and dialyze the other aliquot to a buffer of 10 mM citrate, 150 mM NaCl, pH 5.8. After dialysis, dilute the antibody to 50 mg / mL or 120 mg / mL with an appropriate buffer (histidine or citrate). Add PS-80 to each formulation to a final concentration of 0.05%. Filter the formulation through a 0.22 μm sterile PVDF filter and fill it into pre-filled glass syringes. Use eight syringes per formulation for size exclusion chromatography (SEC) analysis. Place the syringes in the light chamber for exposure to ultraviolet (UV), visible, or both UV and visible light. Syringes in the opaque cartridge are also included as a “dark” control. The temperature was kept constant at 20°C. Total polymer was measured by SEC. The results are summarized in Table 2.

[0045] Table 2. Comparison of total polymer percentage between histidine and citrate buffers DP concentration and light conditions Total polymer of histidine buffer (%) Total polymer of citrate buffer (%) 50 mg / mL in the dark 1.44 1.70 50 mg / mL UV 1.63 2.06 50 mg / mL VIS 1.88 2.60 50 mg / mL UV / VIS 2.33 3.47 120 mg / mL in the dark 1.54 1.98 120 mg / mL UV 2.18 2.89 120 mg / mL VIS 2.38 3.66 120 mg / mL UV / VIS 2.86 4.20 .

[0046] Under essentially the conditions described above, the results presented in Table 2 indicate that the total polymer percentage in the histidine buffer is lower than that observed with the citrate buffer. These data suggest that formulations containing histidine buffers provide better stability upon light exposure compared to formulations containing citrate.

[0047] Excipient compatibility study The stability of the anti-CGRP antibody formulation was evaluated in an excipient compatibility study. The pH 6.0 formulation contained 120 mg / mL anti-CGRP antibody, 0.04% PS-80, 10 mM or 20 mM histidine buffer, and 150 mM NaCl, 5% mannitol, or a combination of 100 mM NaCl and 1.5% mannitol. The formulation was prepared by dialysis and stored in HDPE containers at the indicated temperatures, protected from light. Total polymers were determined by SEC at the start of the study, 1 month, and 2 months.

[0048] Table 3. Comparison of total polymer percentages among mannitol, NaCl, and combinations of mannitol and NaCl.

[0049] Under essentially the conditions described above, the total polymer percentage in the formulation containing 5% mannitol was higher than that in the formulation containing 150 mM NaCl or the formulation containing 100 mM NaCl and 1.5% mannitol. This demonstrates that the addition of NaCl and / or the combination of NaCl and mannitol positively affects protein stability.

[0050] Stability after freeze-thaw cycle Freezing is a common processing step used during protein development and production to maintain protein stability and quality, and can allow for longer shelf life. However, freezing can induce complex physical and chemical changes under solvent / solute conditions, leading to protein denaturation, which has the potential to form aggregates over time. The stability of drug formulations in histidine buffers after freeze-thaw (FT) was determined by SEC. Eight different formulations were prepared and stored in HDPE containers. Each formulation was pH 6.0 and contained 0.02% PS-80, 10 mM histidine, and 150, 120, 100, or 20 mg / mL anti-CGRP antibody DP, and 5% mannitol, 150 mM NaCl or 1.5% mannitol and 100 mM NaCl.

[0051] Each formulation in the HDPE container underwent three freeze-thaw cycles. For each cycle, each formulation was frozen at -70°C and thawed at room temperature. The formulations in the HDPE container were then subjected to slow freeze-thaw cycles in a lyophilizer chamber. The control was stored at 5°C during the study. The percentage of total polymer was assessed by SEC after the third cycle or after the slow freeze-thaw cycle.

[0052] Table 4. Comparison of total polymer percentages among mannitol, NaCl, and combinations of mannitol and NaCl. ND: Not determined.

[0053] Under the conditions described above, the total polymer percentage in the formulation containing 5% mannitol and 20 mg / mL DP increased during FT cycles 3 and slow FT, compared to the total polymer percentage in all other formulations. The polymer percentage also increased in the formulation containing 20 mg / mL DP and 150 mM NaCl. This indicates that NaCl and / or the combination of NaCl and mannitol in the formulation, as well as antibody concentrations greater than 20 mg / mL, have a stabilizing effect on the frozen-thawed protein.

[0054] Capillary shearing device The capillary shear device (CSD) is a high-shear stress simulation device that uses a peristaltic pump and capillary tube to study the physical stress on formulated pharmaceutical preparations (DPs). The CSD is used to evaluate the shear physical stress of the pharmaceutical preparations of the present invention, wherein the preparations contain 10 mM histidine, 150 mM NaCl, anti-CGRP antibody at concentrations of 5 mg / mL, 40 mg / mL, or 120 mg / mL, different concentrations of PS-80, and a pH of 6.0.

[0055] The anti-CGRP antibody DP is pumped using a peristaltic pump through a 0.5 mm inner diameter stainless steel capillary tube, with or without air, at a rate of approximately 3.3 mL / sec. This pumping rate results in approximately 10⁵ sec of delivery. -1 The shear value. The calculated energy dissipation is approximately 10⁵ W / kg. The control group did not undergo pumping.

[0056] Three different capillary shearing device settings were used in this study. Stainless steel and PTFE capillaries were chosen because these materials are commonly used in manufacturing. Both air-free stainless steel and air-free PTFE capillaries represent nominal stress conditions. Nominal stress is encountered when pumping solution via a filling needle using a peristaltic pump. Stainless steel capillaries with air retention represent high stress conditions because proteins can relatively easily unfold at the air-liquid interface. Total polymers were determined by SEC, and particulate matter was determined by a high-precision particle counter (HIAC). SEC data are shown in Table 5, and HIAC data are shown in Table 6.

[0057] Table 5. Total Polymer Percentage – SEC .

[0058] Table 6. Particulate Matter – HIAC .

[0059] The SEC data in Table 5 show that, under essentially the conditions described above, adding PS-80 to the air-containing stainless steel group (high stress conditions) resulted in a reduction in total polymer.

[0060] Compared to formulations lacking PS-80, the addition of 0.005%, 0.02%, 0.03%, or 0.05% PS-80 resulted in a reduction in particle formation in most groups, as determined by HIAC (Table 6). These studies suggest that the addition of PS-80 to solution reduces particulate matter present in anti-CGRP antibody formulations.

[0061] PS-80 Oxidation A formulation containing anti-CGRP antibody (120 mg / ml), 10 mM histidine, 150 mM NaCl, and 0.05% PS-80 at pH 6.0 was used to determine PS-80 oxidation at various temperatures and time points. Each formulation was filled into vials or pre-filled glass syringes and placed in chambers at room temperature (at the start of the study), 5°C, 25°C, or 40°C. Antibody-free corresponding buffers (10 mM histidine, 150 mM NaCl, 0.05% PS-80, pH 6.0) served as controls. A PS-80 hydrolysis method was used to determine the percentage of PS-80. The amounts of free oleic acid and total oleic acid were determined. PS-80 hydrolysis resulted in total oleic acid (TOA), which was measured by high-performance liquid chromatography (HPLC). To obtain the percentage of intact PS-80, free oleic acid was subtracted from total oleic acid.

[0062] Table 7. Percentage of PS-80 in the formulation at various time points and temperatures .

[0063] Following procedures substantially as described above, oxidation of PS-80 was most significant in the 2.25 mL control group at 25°C at 3 and 6 months (Table 7). Oxidation of PS-80 was confirmed by mass spectrometry (data not shown).

[0064] In similar studies, such as Figure 1 The formulations were prepared as shown. DS was dialyzed into each matrix and PS-80 was added or diluted to achieve the indicated final concentrations. Each formulation was filled into a pre-filled glass syringe and stored in a chamber at room temperature, 5°C, 25°C, 30°C, or 40°C. PS-80 concentrations were determined at room temperature at the start of the study, after 1, 2, or 3 months at 5°C, 25°C, or 30°C, and after 6 months at 5°C or 25°C. Results are shown in... Figure 1 middle.

[0065] Figure 1 The PS-80 percentage is displayed.

[0066] Following the procedure essentially as described above, the oxidation of PS-80 in formulations containing 5 mg / mL antibody was observed. These data show that antibody concentrations greater than 5 mg / mL prevent the oxidation of PS-80.

[0067] Clinical trials of dosage ranges for migraines This phase IIb, randomized, double-blind, placebo-controlled, dose-range study enrolled 410 patients aged 18–65 years with migraine days of 4–14 days and at least two migraine attacks per month. Patients were randomized (2:1:1:1:1) to either the placebo group or one of four LY2951742 dose groups. Subcutaneous injections of 5 mg, 50 mg, 120 mg, or 300 mg of LY2951742 or placebo were administered every 28 days for 12 weeks. The primary objective was to assess whether at least one dose of LY2951742 was superior to placebo in migraine prevention. Superiority was defined as a ≥95% posterior probability of a greater improvement at any LY2951742 dose compared to placebo, as measured by the mean change from baseline in the number of migraine days during the last 28 days of the 12-week treatment period.

[0068] Results showed that all four dose groups were superior to placebo in the primary outcome measure at all time points. One dose group of LY2951742 (120 mg) achieved the primary objective (p=0.004): a significantly reduced number of migraine days in the last 28 days of the 12-week treatment period compared with placebo.

[0069] Clinical trials of episodic cluster headache This phase III, randomized, double-blind clinical trial enrolled 162 patients aged 18–65 years with at least two cluster headache cycles lasting 7 days to 1 year (in treatment-naïve) and separated by pain-free remission cycles of ≥ 1 month. Patients were randomized to either placebo or treatment. Subcutaneous injections of either a pharmaceutical composition containing 300 mg of LY2951742 or placebo were administered every 30 days for 8 weeks. The primary objective was to assess whether 300 mg of LY2951742 was superior to placebo in the prevention of episodic cluster headache. The primary outcome measured was the mean change from baseline in weekly cluster headache episodes after treatment.

[0070] sequence SEQ ID NO: 1 - (Exemplary LCVR of the anti-CGRP antibody of the present invention) SEQ ID NO: 2 - (Exemplary HCVR of the anti-CGRP antibody of the present invention) SEQ ID NO: 3 - (Exemplary LC of the anti-CGRP antibody of the present invention) SEQ ID NO: 4 - (Exemplary HC of the anti-CGRP antibody of the present invention) SEQ ID NO: 5 - Exemplary nucleotide sequence (LC encoding the anti-CGRP antibody of the present invention) SEQ ID NO: 6 - Exemplary nucleotide sequence (encoding the HC of the anti-CGRP antibody of the present invention) SEQ ID NO: 7-human αCGRP peptide .

[0071] This application relates to the following implementation scheme: 1. A pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about 40 mg / mL to about 160 mg / mL, a histidine buffer at a concentration of about 5 mM to about 20 mM, NaCl at a concentration of about 50 mM to about 200 mM, PS-80 at a concentration of about 0.03% (w / v) to about 0.07% (w / v) and a pH of about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of the LCVR being given by SEQ ID NO: 1 and the amino acid sequence of the HCVR being given by SEQ ID NO: 2.

[0072] 2. The formulation of embodiment 1, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC being given by SEQ ID NO: 3, and the amino acid sequence of HC being given by SEQ ID NO: 4.

[0073] 3. The formulation of embodiment 1, wherein the anti-CGRP antibody comprises two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0074] 4. The formulation of any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is about 50 mg / mL to about 150 mg / mL.

[0075] 5. The formulation of any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is about 100 mg / mL to about 160 mg / mL.

[0076] 6. The formulation of any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is selected from about 40 mg / mL, about 50 mg / mL, about 100 mg / mL, about 120 mg / mL and about 150 mg / mL.

[0077] 7. The formulation of any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is about 50 mg / mL.

[0078] 8. The formulation of any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is about 100 mg / mL.

[0079] 9. The formulation of any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is about 120 mg / mL.

[0080] 10. The formulation of any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is about 150 mg / mL.

[0081] 11. The formulation of any one of embodiments 1 to 10, wherein the concentration of the histidine buffer is about 10 mM to about 15 mM.

[0082] 12. The formulation of embodiment 11, wherein the concentration of the histidine buffer is about 10 mM.

[0083] 13. The formulation of any one of embodiments 1 to 12, wherein the concentration of NaCl is about 125 mM to about 175 mM.

[0084] 14. The formulation of embodiment 13, wherein the concentration of NaCl is about 150 mM.

[0085] 15. A formulation according to any one of embodiments 1 to 14, wherein the concentration of PS-80 is about 0.05% (w / v).

[0086] 16. The formulation of any one of embodiments 1 to 15, wherein the pH is about 5.8.

[0087] 17. A formulation according to any one of embodiments 1 to 3, wherein the concentration of the anti-CGRP antibody is selected from about 50 mg / mL, about 100 mg / mL, about 120 mg / mL and about 150 mg / mL, the concentration of the histidine buffer is about 10 mM, the concentration of NaCl is about 150 mM, and the concentration of PS-80 is about 0.05%, and the pharmaceutical formulation has a pH of about 5.5 to about 6.0.

[0088] 18. The formulation of embodiment 17, wherein the concentration of the anti-CGRP antibody is about 100 mg / mL.

[0089] 19. The formulation of embodiment 17, wherein the concentration of the anti-CGRP antibody is about 120 mg / mL.

[0090] 20. The formulation of embodiment 17, wherein the concentration of the anti-CGRP antibody is about 150 mg / mL.

[0091] 21. The formulation of embodiment 17, wherein the formulation is suitable for subcutaneous injection.

[0092] 22. A method for treating or preventing migraine, episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache, comprising administering to a patient a therapeutically effective amount of a pharmaceutical preparation of any one of embodiments 1-21.

[0093] 23. The method of implementation scheme 22, wherein the dose of anti-CGRP antibody administered to the patient is approximately 300 mg.

[0094] 24. The method of implementation scheme 22, wherein the dose of anti-CGRP antibody administered to the patient is approximately 240 mg.

[0095] 25. The method of implementation scheme 22, wherein the dose of anti-CGRP antibody administered to the patient is approximately 120 mg.

[0096] 26. The method of embodiments 22-25, wherein the dosage is administered at weekly, bi-weekly, or monthly intervals.

[0097] 27. A method for treating or preventing episodic migraine in a patient, comprising administering a monthly subcutaneous dose of 120 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LC as given by the amino acid sequence of SEQ ID NO: 3 and HC as given by the amino acid sequence of SEQ ID NO: 4.

[0098] 28. A method for treating or preventing cluster headaches in a patient, comprising administering a monthly subcutaneous dose of 300 mg of an anti-CGRP antibody, wherein the anti-CGRP antibody comprises LC as given by the amino acid sequence of SEQ ID NO: 3 and HC as given by the amino acid sequence of SEQ ID NO: 4.

[0099] 29. The method according to embodiments 27-28, wherein the anti-CGRP antibody is in a pharmaceutical formulation containing a histidine buffer.

[0100] 30. The method according to embodiments 27-29, wherein the concentration of the histidine buffer is about 10 mM to about 15 mM.

[0101] 31. The method according to embodiments 27-30, wherein the anti-CGRP antibody is in a pharmaceutical formulation at a pH of about 5.7-6.0.

[0102] 32. The method according to embodiment 31, wherein the pharmaceutical preparation has a pH of about 5.8.

[0103] 33. The method according to embodiments 27-32, wherein the anti-CGRP antibody is in a pharmaceutical formulation comprising about 10 mM histidine buffer, about 150 mM NaCl, about 0.05% PS-80 and having a pH of about 5.8.

[0104] 34. A pharmaceutical preparation according to any one of embodiments 1 to 21, used for the treatment or prevention of at least one of migraine, episodic headache, chronic headache, chronic cluster headache and episodic cluster headache.

[0105] 35. The pharmaceutical preparation of embodiment 34, wherein the dose of anti-CGRP antibody administered to the patient is 300 mg.

[0106] 36. The pharmaceutical preparation of embodiment 34, wherein the dose of anti-CGRP antibody administered to the patient is 240 mg.

[0107] 37. The pharmaceutical preparation of embodiment 34, wherein the dose of anti-CGRP antibody administered to the patient is 120 mg.

[0108] 38. A pharmaceutical preparation according to any one of embodiments 35-37, wherein the dosage is administered at monthly intervals.

[0109] 39. Use of a pharmaceutical composition according to any one of embodiments 1 to 21 for the preparation of a medicament for the treatment or prevention of at least one of migraine, episodic headache, chronic headache, chronic cluster headache, and episodic cluster headache.

[0110] 40. A pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about 120 mg / mL, a histidine buffer at a concentration of about 10 mM, NaCl at a concentration of about 150 mM, and PS-80 at a concentration of about 0.05% (w / v), the pharmaceutical formulation having a pH of about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO: 4.

[0111] 41. The pharmaceutical formulation according to embodiment 40, wherein the pharmaceutical formulation has a pH of 5.8.

Claims

1. A pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about 40 mg / mL to about 160 mg / mL, a histidine buffer at a concentration of about 5 mM to about 20 mM, NaCl at a concentration of about 50 mM to about 200 mM, PS-80 at a concentration of about 0.03% (w / v) to about 0.07% (w / v) and a pH of about 5.0 to about 6.5, wherein the anti-CGRP antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the amino acid sequence of the LCVR being given by SEQ ID NO: 1 and the amino acid sequence of the HCVR being given by SEQ ID NO:

2.

2. The formulation of claim 1, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC being given by SEQ ID NO: 3, and the amino acid sequence of HC being given by SEQ ID NO:

4.

3. The formulation of claim 1, wherein the anti-CGRP antibody comprises two LCs and two HCs, the amino acid sequence of each LC being given by SEQ ID NO: 3, and the amino acid sequence of each HC being given by SEQ ID NO:

4.

4. The formulation of any one of claims 1 to 3, wherein the concentration of the anti-CGRP antibody is from about 50 mg / mL to about 150 mg / mL.

5. The formulation of any one of claims 1 to 3, wherein the concentration of the anti-CGRP antibody is from about 100 mg / mL to about 160 mg / mL.

6. The formulation of any one of claims 1 to 3, wherein the concentration of the anti-CGRP antibody is selected from about 40 mg / mL, about 50 mg / mL, about 100 mg / mL, about 120 mg / mL and about 150 mg / mL.

7. The formulation of any one of claims 1 to 3, wherein the concentration of the anti-CGRP antibody is about 50 mg / mL.

8. The formulation of any one of claims 1 to 3, wherein the concentration of the anti-CGRP antibody is about 100 mg / mL.

9. The formulation of any one of claims 1 to 3, wherein the concentration of the anti-CGRP antibody is about 120 mg / mL.

10. The formulation of any one of claims 1 to 3, wherein the concentration of the anti-CGRP antibody is about 150 mg / mL.

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