Patent Description:
CGRP is a neuropeptide secreted by the nerves of the central and peripheral nervous systems and is implicated in pain pathways. The role of CGRP in headache and migraine has been established in the art and a number of clinical studies are currently evaluating the use of anti-CGRP antibodies for the treatment of headaches and migraine. (see, for example, <NPL>)).

Liquid pharmaceutical formulations for antibodies intended for human use require the chemical and physical stability of the antibody over its extended shelf life (e.g. <CIT> and in <CIT>). Chemical instability of the antibody can result from a number of chemical reactions including deamidation, racemization, hydrolysis, oxidation, beta elimination and disulfide exchange. Physical instability can result from processes such as denaturation, aggregation, precipitation, and adsorption to surfaces. Instability of the antibody can result in the formation of a polypeptide by-product or derivatives having low activity, increased toxicity, and/or increased immunogenicity, which can pose concerns about the safety and efficacy of the antibody.

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While the possible occurrence of protein instabilities is widely appreciated, it is difficult to predict particular instability issues for a particular protein. Applicants sought to formulate an anti-CGRP antibody (<CIT>), wherein said antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the amino acid sequence of said LCVR is SEQ ID NO: <NUM> and the amino acid sequence of said HCVR is SEQ ID NO: <NUM>. In formulating the anti-CGRP antibody for use in therapy, applicants discovered several factors that contributed to the instability of the antibody, such as photo degradation, polymer formation during freeze-thaw, and oxidation of polysorbate-<NUM> (PS-<NUM>) in the formulation. Therefore, a stable pharmaceutical formulation was needed to overcome at least one or more of the observed issues.

Accordingly, the present invention provides a pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of <NUM>/mL to <NUM>/mL, histidine buffer at a concentration of <NUM>, sodium chloride (NaCl) at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at <NUM> to <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

In one embodiment, the pharmaceutical formulation provided comprises an anti-CGRP antibody at a concentration of <NUM>/mL to <NUM>/mL, histidine buffer at a concentration of <NUM>, sodium chloride at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at about <NUM> to about <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

In one embodiment, the pharmaceutical formulation provided is one comprising an anti-CGRP antibody at a concentration of <NUM>/mL to <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at <NUM> to <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

In a further embodiment of the present invention the pharmaceutical formulation provided is one comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-<NUM>, wherein the concentration of anti-CGRP antibody is selected from the group consisting of about <NUM>/mL, about <NUM>/mL, about <NUM>/mL or about <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at <NUM> to <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

Another embodiment of the present invention also provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-<NUM>, wherein the concentration of anti-CGRP antibody is selected from the group consisting of about <NUM>/mL, about <NUM>/mL, about <NUM>/mL or about <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at <NUM> to <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

In another embodiment, the present invention also provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-<NUM>, wherein the concentration of anti-CGRP antibody is selected from the group consisting of about <NUM>/mL, about <NUM>/mL, about <NUM>/ml or about <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at <NUM> to <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

In another embodiment, the present invention also provides a pharmaceutical formulation comprising an anti-CGRP antibody in a histidine buffer, NaCl, and PS-<NUM>, wherein the concentration of anti-CGRP antibody is selected from the group consisting of about <NUM>/mL, about <NUM>/mL, about <NUM>/ml or about <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at <NUM> to <NUM>, wherein the anti-CGRP antibody comprises a a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

More particularly, the present invention provides for a pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of about <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and pH of about <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>. More preferably, the pharmaceutical formulation comprises an anti-CGRP antibody with two LCs and two HCs, the amino acid sequence of each LC given by SEQ ID NO: <NUM> and the amino acid sequence of each HC given by SEQ ID NO: <NUM>.

Preferably, the concentration of the anti-CGRP antibody in the pharmaceutical composition provided is about <NUM>/mL to about <NUM>/mL. More preferably, the concentration of the anti-CGRP antibody is about <NUM>/mL, about <NUM>/mL, about <NUM>/mL, or about <NUM>/mL.

Most preferably, the pharmaceutical formulation comprises a pH of about <NUM>.

Most preferably, the pharmaceutical formulation comprises an anti-CGRP antibody at a concentration in the range of about <NUM>/mL to about <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v) and a pH of about <NUM>.

The present invention also provides a pharmaceutical formulation of the present invention for use in the treatment or prevention of at least one of migraine, episodic headache, chronic headache, chronic cluster headache, and episodic cluster headache. A patient in need thereof is administered a therapeutically effective amount of a pharmaceutical formulation of the present invention. According to some embodiments, the present invention provides a pharmaceutical formulation of the present invention for use in a method of treating or preventing chronic and episodic cluster headaches comprising administering to a patient in need thereof a dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition. Further embodiments provide a pharmaceutical formulation of the present invention for use in method of treating or preventing chronic and episodic cluster headaches comprising administering to a patient in need thereof a dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition. In other embodiments, the present invention provides a pharmaceutical formulation of the present invention for use in a method of treating or preventing chronic and episodic migraines comprising administering to a patient in need thereof a dose of <NUM> of an anti-CGRP antibody. Further embodiments provide the pharmaceutical formulation of the present invention for use in a method of treating or preventing chronic and episodic migraine comprising administering to a patient in need thereof a dose of <NUM> of an anti-CGRP antibody. Another embodiment provides a pharmaceutical formulation of the present invention for use in a method of treating or preventing chronic and episodic migraine comprising administering to a patient in need thereof an initial loading dose of <NUM> of an anti-CGRP antibody followed by a monthly maintenance dose of <NUM> of an anti-CGRP antibody. Preferably, the dose is administered at weekly, semi-monthly, monthly or quarterly intervals. More preferably, the administration is monthly.

In another embodiment, the present invention also provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent cluster headache in a patient in need by administering a monthly subcutaneous dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition, wherein the anti-CGRP antibody binds to an epitope comprising amino acids VTHRLAGLLSR of SEQ ID NO: <NUM>. In a further embodiment, the present invention provides a pharmaceutical formulation of the present invention for use in method to treat or prevent episodic migraine in a patient in need by administering a monthly subcutaneous dose of <NUM> of an anti-CGRP antibody in the pharmaceutical formulation Preferably, the pharmaceutical formulation has a pH of about <NUM>. In another embodiment, the present invention also provides a pharmaceutical formulation of the present invention for use in method to treat or prevent cluster headache in a patient in need by administering a monthly subcutaneous dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition. Preferably, the pharmaceutical formulation has a pH of about <NUM>.

In another embodiment, the present invention also provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent cluster headache in a patient in need thereof by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition. In a particular embodiment, the anti-CGRP antibody is in a pharmaceutical composition of the present invention comprising a histidine buffer at a pH of about <NUM>-<NUM>. Preferably the pharmaceutical composition has a pH of about <NUM>-<NUM>. More preferably, the pharmaceutical composition has a pH of about <NUM>.

In another particular embodiment, the present invention also provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent cluster headache in a patient in need thereof by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition More preferably, the anti-CGRP antibody is in a pharmaceutical composition of the invention at a pH of about <NUM>-<NUM>. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>.

In another particular embodiment, the present invention also provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent cluster headache in a patient in need thereof by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition. More preferably, the anti-CGRP antibody is in a pharmaceutical composition of the present invention at a pH of about <NUM>-<NUM>. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition of the present invention at a pH of about <NUM>.

In a further embodiment, the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent episodic migraine in a patient in need by administering a monthly subcutaneous dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition, wherein the anti-CGRP antibody binds to an epitope comprising amino acids VTHRLAGLLSR of SEQ ID NO: <NUM>. In a further embodiment, the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent episodic migraine in a patient in need by administering a monthly subcutaneous dose of <NUM> of an anti-CGRP antibody in the pharmaceutical formulation. Preferably, the anti-CGRP antibody is in a pharmaceutical formulation of the present invention having a pH of about <NUM>. In a further embodiment, the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent episodic migraine in a patient in need by administering a monthly subcutaneous dose of <NUM> of an anti-CGRP, wherein the anti-CGRP antibody is in the pharmaceutical composition. Preferably, the anti-CGRP antibody is in a pharmaceutical formulation of the present invention at a pH of about <NUM>.

In another embodiment the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent episodic migraine in a patient in need thereof by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition of the present invention. In a particular embodiment, the anti-CGRP antibody is in a pharmaceutical composition of the present invention comprising a histidine buffer at a pH of about <NUM>-<NUM>. Preferably the pharmaceutical composition has a pH of about <NUM>-<NUM>. More preferably, the pharmaceutical composition has a pH of about <NUM>.

In another particular embodiment, the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent episodic migraine in a patient in need thereof by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition More preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>-<NUM>. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>.

In another particular embodiment the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent episodic migraine in a patient in need by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition More preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>-<NUM>. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>.

In another embodiment the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent chronic migraine in a patient in need thereof by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition. In a particular embodiment, the anti-CGRP antibody is in a pharmaceutical composition comprising a histidine buffer at a pH of about <NUM>-<NUM>. Preferably the pharmaceutical composition has a pH of about <NUM>-<NUM>. More preferably, the pharmaceutical composition has a pH of about <NUM>.

In another particular embodiment, the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent chronic migraine in a patient in need by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP antibody, wherein the anti-CGRP antibody is in the pharmaceutical composition,. More preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>-<NUM>. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>.

In another particular embodiment the present invention provides a pharmaceutical formulation of the present invention for use in a method to treat or prevent chronic migraine in a patient in need by administering a monthly dose of <NUM> of an anti-CGRP antibody, wherein the anti-CGRP, wherein the anti-CGRP antibody is in the pharmaceutical composition. More preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>-<NUM>. Most preferably, the anti-CGRP antibody is in a pharmaceutical composition at a pH of about <NUM>.

The present invention also provides a pharmaceutical formulation of the present invention for use in therapy, preferably for use in the treatment or prevention of migraines and/or headaches. In particular embodiments, the present invention provides a pharmaceutical formulation of the present invention for use in the treatment or prevention of at least one or more of the following conditions: episodic migraine, chronic migraine, episodic headaches, chronic headaches, chronic cluster headaches, and/or episodic cluster headaches. Preferably, the dose of anti-CGRP antibody that is administered to a patient is <NUM> or <NUM> for episodic and/or chronic migraine and <NUM> or <NUM> for episodic and/or chronic cluster headaches.

As used herein, the term "patient" refers to a human. In some embodiments, a patient is a human who has been diagnosed as having a condition or disorder for which treatment or administration with a pharmaceutical formulation of the present invention is indicated. In some embodiments, a patient is a human that is characterized as being at risk of a condition or disorder for which treatment or administration with a pharmaceutical formulation of the present invention is indicated.

As used herein, the term "treating" (or "treat" or "treatment") refers to processes involving a slowing, interrupting, arresting, controlling, stopping, reducing, or reversing the progression or severity of a symptom, disorder, condition, or disease, but does not necessarily involve a total elimination of all disease-related symptoms, conditions, or disorders associated with CGRP activity. As used herein, the term "prevention" (or "prevent" or "preventing") refers to precluding, averting, obviating, forestalling, reducing the incidence of, stopping, or hindering the symptoms of a disease, disorder and/or condition. Prevention includes administration to a subject who does not exhibit symptoms of a disease, disorder, and/or condition at the time of administration.

As used herein, the term "therapeutically effective amount" refers to the amount or dose of an anti-CGRP antibody in a pharmaceutical formulation of the present invention, which upon single or multiple dose administration to the patient, provides the desired pharmacological effect in the patient. A dose can include a higher initial loading dose, followed by a lower dose. A "dose" refers to a predetermined quantity of a therapeutic drug calculated to produce the desired therapeutic effect in a patient. A therapeutically effective amount can be determined by the attending diagnostician, as one skilled in the art, by considering a number of factors such as the patient's size, age, and general health, the specific disease or surgical procedure involved, the degree or severity of the disease or malady, the response of the individual patient, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, and the use of any concomitant medications.

As used herein, the term "month" or derivations thereof, refers to a time period that includes <NUM> to <NUM> consecutive days. The term "about" as used herein, means in reasonable vicinity of the stated numerical value, such as plus or minus <NUM>% of the stated numerical value.

The general structure of an "antibody" is known in the art. Anti-CGRP antibodies are disclosed in <CIT>. As used herein, a "drug substance" ("DS") is a formulation that comprises an antibody, buffer (e.g. histidine), excipient (e.g. NaCl), and surfactant (e.g. PS-<NUM>), and is within a certain pH range or at a specified pH. A "drug product" ("DP") is a formulation comprising a buffer, excipient, surfactant, and antibody, wherein the antibody in the DP may be at a lower concentration than the antibody concentration in the DS.

The pharmaceutical formulations of the present invention are in the liquid dosage form of a solution. Administration of the pharmaceutical formulations of the present invention may be via parenteral administration. Parenteral administration, as used herein, may include injection of a dosage form into the body by a sterile syringe or some other mechanical device such as an infusion pump. Parenteral routes can include intravenous, intramuscular, subcutaneous, and intraperitoneal routes of administration. Subcutaneous administration is a preferred route. The pharmaceutical formulations of the present invention are intended for pharmaceutical use in a human.

The invention is further illustrated by the following examples which should not be construed as limiting.

Antibodies of the invention can be made and purified as follows. An appropriate host cell, such as CHO, is either transiently or stably transfected with an expression system for secreting antibodies using an optimal predetermined HC:LC vector ratio or a single vector system encoding both LC and both HC, such as each LC being SEQ ID NO: <NUM> and each HC being SEQ ID NO: <NUM>. Clarified media, into which the antibody has been secreted, is purified using any of many commonly-used techniques. For example, the medium may be conveniently applied to a Protein A or G Sepharose FF column that has been equilibrated with a compatible buffer, such as phosphate buffered saline (pH <NUM>). The column is washed to remove nonspecific binding components. The bound antibody is eluted, for example, by pH gradient. Antibody fractions are detected, such as by SDS-PAGE, and then are pooled. Further purification is optional, depending on the intended use. The antibody may be concentrated and/or sterile filtered using common techniques. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The purity of the antibody after these chromatography steps is greater than <NUM>%. The product may be immediately frozen at -<NUM> in the formulation matrix of the invention or may be lyophilized. The amino acid and nucleic acid sequences for the exemplified antibody are provided below.

The manufacturing process for an anti-CGRP antibody pharmaceutical formulation of the present invention includes compounding of the buffer excipient composition, and adding the anti-CGRP antibody drug substance (DS).

The buffer excipient composition consists of L-Histidine, L-Histidine Hydrochloride Monohydrate, NaCl , PS-<NUM>, and water (Table <NUM>). The anti-CGRP antibody comprises a light chain of SEQ ID NO: <NUM>, and a heavy chain of SEQ ID NO: <NUM>.

The buffer excipient composition is prepared and filtered. An appropriate quantity of water at a temperature not more than <NUM> is weighed into a tared empty vessel of appropriate size. The appropriate quantities of L-Histidine, L-Histidine Hydrochloride Monohydrate and NaCl are added and mixed. PS-<NUM> is weighed out in a glass container and an appropriate quantity of water is added into the glass container to give the indicated final concentration, and the solution is mixed. The PS-<NUM> solution is added to the other excipients, the solution is mixed, and the solution is prepared to have a pH and osmolality adjusted to within <NUM> ± <NUM> and <NUM>-<NUM> mOsm/Kg, respectively. The buffer excipient composition is passed through a filter for bioburden reduction.

The anti-CGRP antibody DS is prepared by expressing the antibody in cells, purifying, concentrating, and freezing the antibody in solution in <NUM> histidine buffer, <NUM> NaC1, <NUM>% PS-<NUM>, and pH of about <NUM>. The DS solution is stored at -<NUM>. The frozen DS is equilibrated to a temperature of <NUM> ± <NUM> and mixed with an appropriate amount of the buffer excipient solution to achieve the intermediate antibody DP concentration. The pH of the solution is checked to be within <NUM> ± <NUM>.

The solution is mixed and a sample is taken for an in-process UV assay to determine the antibody DP concentration. An appropriate quantity of the buffer excipient solution is added to reach the final target batch weight. After mixing, the pH of the solution is checked to be within <NUM>± <NUM>. The antibody DP solution is passed through a filter for bioburden reduction prior to sterile filtration and filling into vials or syringes. The final concentration of the antibody DP can be between about <NUM>/mL to about <NUM>/mL.

Light can influence the active molecule in a drug formulation, as well as the final product or package resulting in photodegradation that may result in the loss of potency of the product. The effect of light on anti-CGRP antibody formulated in citrate buffer or histidine buffer at pH <NUM> in glass prefilled syringes is evaluated by size exclusion chromatography (SEC). The light exposure levels are approximately <NUM>% of ICH Q1B for visible light and <NUM>% for the UV light.

Anti-CGRP antibody, at approximately <NUM>/mL (in <NUM> Histidine, <NUM> NaCl, pH <NUM>), is divided into two aliquots. One aliquot is dialyzed into <NUM> histidine, <NUM> NaCl, pH <NUM> buffer, and the other aliquot is dialyzed into <NUM> citrate, <NUM> NaCl, pH <NUM> buffer. Following dialysis, the antibody is diluted with the appropriate buffer (histidine or citrate) to <NUM>/mL or to <NUM>/mL. PS-<NUM> is added to each formulation to a final concentration of <NUM>%. The formulations are filtered through a <NUM> sterilizing grade PVDF filter and filled into glass prefilled syringes. Eight syringes per formulation for size exclusion chromatography (SEC) analysis are utilized. Syringes are placed in light chambers for exposure to either ultraviolet (UV), visible or both UV and visible light. Syringes in an opaque box are also included as "dark" controls. The temperature is constant at <NUM>. Total polymer is measured by SEC. The results are summarized in Table <NUM>.

Under conditions essentially as described above, the results provided in Table <NUM> demonstrate that the percent total polymer in histidine buffer were lower than that observed with citrate buffer. These data demonstrate that the formulations comprising the histidine buffer provide for better stability following exposure to light compared to formulations comprising citrate.

Stability of anti-CGRP antibody pharmaceutical formulations is evaluated in an excipient compatibility study. The formulations, at pH <NUM>, comprise <NUM>/mL anti-CGRP antibody, <NUM>% PS-<NUM>, either <NUM> or <NUM> histidine buffer, and either <NUM> NaCl, <NUM>% mannitol, or a combination of <NUM> NaCl and <NUM>% mannitol. Formulations are prepared by dialysis, and stored in HDPE containers at indicated temperatures, and are protected from light. Total polymer is determined by SEC at the beginning of the study, at <NUM> month, and at <NUM> months.

Under conditions essentially as described above, the percent total polymer in the formulation comprising <NUM>% mannitol was higher compared to the percent total polymer for the formulation comprising <NUM> NaCl, or the formulation comprising <NUM> NaCl and <NUM>% mannitol. The addition of NaCl and/or a combination of NaCl and mannitol is shown to positively affect the stability of the protein.

Freezing is a common processing step used to maintain stability and quality of a protein during development and production, and may allow for a longer shelf life. However, freezing can induce complex physical and chemical changes in the solvent/solute conditions, resulting in denaturation of proteins with the possibility of generation of aggregates over time. The stability of pharmaceutical formulations in histidine buffer following freeze-thaw (FT) is determined by SEC. Eight different formulations are prepared and stored in HDPE containers. Each formulation is at pH <NUM>, comprises <NUM>% PS-<NUM>,<NUM> histidine, and either <NUM>, <NUM>, <NUM>, or <NUM>/mL anti-CGRP antibody DP, and either <NUM>% mannitol, <NUM> NaCl, or <NUM>% mannitol and <NUM> NaCl.

Respective formulations in HDPE containers undergo three freeze-thaw cycles. For one cycle, each formulation is frozen at -<NUM> and thawed at room temperature. Respective formulations in HDPE containers undergo a slow freeze-thaw in a lyophilizer chamber. Controls are stored at <NUM> for the duration of the study. Following the third cycle or following the slow freeze-thaw, percent total polymer is assessed by SEC.

Under conditions described above, the percent total polymer in the formulation comprising <NUM>% mannitol and <NUM>/mL DP was increased in FT cycle <NUM> and in the slow FT, compared to the percent total polymer in all other formulations. The percent polymer was also increased in the formulation comprising <NUM>/mL DP and <NUM> NaCl. NaCl and/or a combination of NaCl and mannitol, together with concentrations of antibody greater than <NUM>/mL in the formulation are shown to have a stabilizing effect on the protein following freeze-thaw.

The capillary shear device (CSD) is a high shear force simulating stress device that uses a peristaltic pump and a capillary tube to study physical stress on a formulated DP. A CSD is used to evaluate shear force physical stress of pharmaceutical formulations of the present invention, wherein said formulations comprise <NUM> histidine, <NUM> NaCl, anti-CGRP antibody at a concentration of <NUM>/mL, <NUM>/mL, or <NUM>/mL, varying concentrations of PS-<NUM>, and pH of <NUM>.

Anti-CGRP antibody DP is pumped through a <NUM> inner diameter stainless steel capillary tube, with or without air, at a rate of approximately <NUM>/sec using a peristaltic pump. This pump rate results in a shear value of approximately <NUM> sec-<NUM>. Calculated energy dissipation is approximately <NUM> W/Kg. Controls do not undergo pumping.

Three different capillary shear device set-ups are utilized in this study. Stainless steel and PTFE capillary tubes are chosen because these materials are commonly used in manufacturing. Stainless steel capillary tubes without air in the system or PTFE capillary tubes without air in the system both represent a nominal stress condition. Nominal stress will be encountered when the solution is pumped using a peristaltic pump through a filling needle. Stainless steel capillary tubes with air entrapment in the system represent a high stress condition because the protein can unfold relatively easy in the air-liquid interface. Total polymer is determined by SEC, and particulate matter is determined by high accuracy particle counter (HIAC). SEC data are shown in Table <NUM>, and HIAC data are shown in Table <NUM>.

The SEC data in Table <NUM> show that under conditions essentially described above, the addition of PS-<NUM> to the stainless steel with air groups (high stress conditions) led to a reduction in the total polymer.

Compared to formulations lacking PS-<NUM>, the addition of <NUM>%, <NUM>%, <NUM>%, or <NUM>% of PS-<NUM> led to a reduction in particle formation in most of the groups as determined by HIAC (Table <NUM>). These studies demonstrate that the addition of PS-<NUM> to the solution reduces the particulate matter present in the anti-CGRP antibody formulation.

Formulations at pH <NUM> comprising the anti-CGRP antibody (<NUM>/ml), <NUM> histidine, <NUM> NaCl, and <NUM>% PS-<NUM> are used to determine PS-<NUM> oxidation at various temperatures and time-points. Respective formulations are filled into vials or glass prefilled syringes and placed in chambers at room temperature (at the beginning of the study), <NUM>, <NUM>, or <NUM>. The corresponding buffer (<NUM> histidine, <NUM> NaCl, <NUM>% PS-<NUM>, pH <NUM>) without the antibody is used as a control. PS-<NUM> hydrolysis method is used to determine percent PS-<NUM>. Amount of free oleic acid and amount of total oleic acid are determined. PS-<NUM> hydrolysis results in total oleic acid (TOA), and TOA is measured by high-performance liquid chromatography (HPLC). To obtain the percent of intact PS-<NUM>, free oleic acid is subtracted from the total oleic acid.

Following a procedure essentially as described above, oxidation of PS-<NUM> was most pronounced in the <NUM> control groups at <NUM> at <NUM> and <NUM> months (Table <NUM>). Oxidation of PS-<NUM> was confirmed by mass spectrometry (data not shown).

In a similar study, formulations are prepared as indicated in Figure <NUM>. DS is dialyzed into the respective matrix and PS-<NUM> is added or diluted to achieve the indicated final concentration. Respective formulations are filled into glass prefilled syringes and stored in chambers at room temperature, <NUM>, <NUM>, <NUM>, or <NUM>. The concentration of PS-<NUM> is determined at the beginning of the study at room temperature, after <NUM>, <NUM>, or <NUM> months at <NUM>, <NUM>, or <NUM>, and at <NUM> months at <NUM> or <NUM>. The results are shown in Figure <NUM>.

Following a procedure as essentially described above, oxidation of PS-<NUM> was observed in formulations comprising <NUM>/mL antibody. These data show that antibody at a concentration greater than <NUM>/mL prevents oxidation of PS-<NUM>.

A phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study was conducted with <NUM> patients aged <NUM>-<NUM> years with <NUM> to <NUM> migraine headache days and at least <NUM> migraine attacks per month. The patients were randomly assigned (<NUM>:<NUM>:<NUM>:<NUM>:<NUM>) to placebo or <NUM> of <NUM> LY2951742 dose groups. Subcutaneous injections of LY2951742 doses of <NUM>, <NUM>, <NUM>, <NUM> or placebo were given once every <NUM> days for <NUM> weeks. The primary objective was to assess whether at least one dose of LY2951742 was superior to placebo in the prevention of migraine headache. Superiority was defined as a ≥<NUM>% posterior probability of greater improvement for any LY2951742 dose compared with placebo, as measured by the mean change from baseline in the number of migraine headache days in the last <NUM>-day period of the <NUM>-week treatment phase.

The results showed that all <NUM> dose arms were numerically superior to placebo on primary outcome measures at all-time points. One dose arm (<NUM>) of LY2951742 met the primary objective (p = <NUM>) with a significantly greater reduction compared to placebo in the number of migraine headache days in the last <NUM> day period of the <NUM> week treatment phase.

Claim 1:
A pharmaceutical formulation comprising an anti-CGRP antibody at a concentration of <NUM>/mL to <NUM>/mL, histidine buffer at a concentration of <NUM>, NaCl at a concentration of <NUM>, PS-<NUM> at a concentration of <NUM>% (w/v), and a pH at <NUM> to <NUM>, wherein the anti-CGRP antibody comprises a light chain (LC) and a heavy chain (HC), the amino acid sequence of LC given by SEQ ID NO: <NUM> and the amino acid sequence of HC given by SEQ ID NO: <NUM>.