Pharmaceutical composition comprising a CGRP receptor antagonist for the treatment of acute migraine

Abstract

The present invention relates to a calcitonin gene-related peptide (CGRP) receptor antagonist of formula (I) or a or equivalent net peptide weight of a pharmaceutically active salt thereof, namely AXN-001, which is also known as FE 205030 A pharmaceutical composition comprising AXN-001 can be used in the treatment of acute migraine.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING A CGRP RECEPTOR ANTAGONIST FOR THE TREATMENT OF ACUTE MIGRAINE

[0002] Field of the Invention

[0003] The present invention relates to a calcitonin gene-related peptide (CGRP) receptor antagonist which may be used for the acute treatment of migraine and other CGRP-dependent conditions.

[0004] Background

[0005] Migraine is a highly prevalent and disabling neurological disease, disproportionally impacting women. Migraine affects >1 billion people worldwide, more than >700 million of whom are women. In 2016, migraine was responsible globally for >45 million years of life lived with disability (YLDs).

[0006] Acute treatments for migraine, taken as needed during attacks, are the mainstay of migraine management. Most patients (>90%) on existing oral acute therapies report at least one unmet treatment need, in particular the needs for faster onset of action and higher efficacy.

[0007] Most frequently prescribed acute treatments of migraine include (i) previously approved triptans (small molecule agonists for serotonin 5-HT1 B / 1 D receptors), and (ii) recently approved gepants (small molecule antagonists for the CGRP receptor). Triptans are more effective than gepants but are associated with safety concerns (cardiovascular contraindications, medication overuse headache) and tolerability issues (“triptans sensations” characterized by chest pressure and difficulty to breathe). Whereas gepants are safer and better tolerated than triptans they are markedly less effective. Triptans are available as oral (PO), intranasal (IN), and subcutaneous (SC) products. Gepants are currently available only as oral tablet (ubrogepant, rimegepant) and nasal spray (zavegepant) products that are both marginally effective (i.e., -10% treatment effect on 2-hour pain freedom endpoint, with treatment effect being defined as % of drug responders minus % of placebo responders). There is currently no approved SC formulation of a CGRP receptor antagonist, most likely due to solubility or tolerability limitations.

[0008] Thus, there is a need for a pharmaceutical composition for the treatment of acute migraine which exhibits advantageous properties of triptans such as rapid onset of action and high efficacy, as well as advantageous properties of gepants such as high safety and tolerability. Summary of the Invention

[0009] According to a first aspect of the invention, there is provided a pharmaceutical composition comprising 1 mg to 18 mg of a compound of formula (I) or pharmaceutically active salt thereof, based on the weight of the formula (I) moiety: wherein the concentration of the compound of formula (I) or pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL, based on the weight of the formula (I) moiety.

[0010] The compound of formula (I) is also known as AXN-001 or FE 205030 and is described in Srinivasan, et al. J Pharm Sci. 2022;111 (1):247-261 , hereby incorporated by reference.

[0011] The compound also is disclosed in WO 2016 / 110499 A1 (Example 30), which also is incorporated by reference.

[0012] The compound of formula (I) may also be represented by the name “Oxazole-2- carbonyl-D-Val-Phe(2-Cbm)-c(Cys-Orn (iPr)-Asp-Val-Gly-Pro-Phe-Cys)-3Pal-NH2”. 3Pal refers to 3-pyridylalanine. Phe(2-Cbm) refers to 3-(2-carbamoyl)phenylalanine.

[0013] Structurally, AXN-001 is a 11-mer monocyclic, branched peptide, which may be isolated as a hydrochloride salt. AXN-001 is a neuropeptide CGRP receptor antagonist; more specifically, AXN-001 is a highly potent, selective CGRP receptor antagonist having a combination of pharmacological properties which provide a rapid onset of action upon subcutaneous administration and with an ideal duration of response when delivered in a specific manner / composition, for example, between 3 and 8 hours. Advantageously, the pharmaceutical compositions described herein, comprising 1 mg to 18 mg of AXN-001 or a pharmaceutically active salt thereof, wherein the concentration of AXN-001 or a pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL (both based on the weight of the AXN-001 moiety), supports an unprecedented target product profile (TPP), which addresses an unmet medical need for patients and prescribers: speed of action, rapid return to function, and reduced recurrence of migraine, as well as safety, tolerability, efficacy, consistency, and lack of drug-drug interactions.

[0014] Advantageously, the combination of (i) the dose of AXN-001 or a pharmaceutically active salt thereof and (ii) the concentration of AXN-001 or a pharmaceutically active salt thereof of the compositions described herein provides for a differentiated and superior pharmacokinetic (PK) profile.

[0015] In more specific embodiments, pharmaceutical compositions formulated with 6 mg to 18 mg of AXN-001 or a pharmaceutically active salt thereof at a concentration of 12 mg / mL to 36 mg / mL (both based on the weight of the AXN-001 moiety), may provide faster, higher, and more consistent free plasma concentrations than any approved gepant. In turn, this may provide faster, higher, and more reliable efficacy than any approved gepant. In more specific embodiments, pharmaceutical compositions as described herein providing a dose of 3 mg to 5 mg of AXN-001 or a pharmaceutically active salt thereof (based on the weight of the AXN- 001 moiety) may provide an advantageous PK profile. Advantageously, such doses are fast acting and long acting. Advantageously, such doses at a concentration of 12 mg / mL to 36 mg / mL achieve the desired plasma levels in a minimum amount for efficacy.

[0016] Brief Description of the Drawings

[0017] Embodiments are described, by way of illustration only, with reference to the accompanying figures, in which:

[0018] FIG. 1 is a plot relating to AXN-001 degradation rates.

[0019] FIG. 2 is a plot relating to AXN-001 plasma concentrations measured in the clinical PK study (linear scale).

[0020] FIG. 3 is a plot relating to AXN-001 plasma concentrations measured in the clinical PK study (logarithmic scale). FIG. 4A is a plot relating to AXN-001 AUC(o-t).

[0021] FIG. 4B is a plot relating to AXN-001 Cmax.

[0022] FIG. 5 is a plot relating to PK profiles of AXN-001 and gepants.

[0023] Detailed Description

[0024] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined.

[0025] As used herein, the singular forms “a,” “an,” and “the” designate both the singular and the plural, unless expressly stated to designate the singular only.

[0026] As used herein, the term “about” when qualifying a number or range means that the number or range is not limited to the exact number or range set forth, but encompass values around the stated number or range as will be understood by persons of ordinary skill in the art depending on the context in which the number or range is used. When not otherwise apparent from the context or convention in the art, “about” means up to plus or minus 10% of the particular term (± 10%).

[0027] As used herein, a phrase in the form “A / B” or in the form “A and / or B” means (A), (B), or (A and B); a phrase in the form “at least one of A, B, and C” means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0028] As used herein, the terms “comprising,” “including,” and “containing” are used expansively to mean that the described compositions, methods, or kits include at least the stated elements, and may include other elements that are not specified.

[0029] The terms “administer,” “administration,” or “administering” as used herein refer to providing, giving, dosing and / or prescribing, such as by either a health professional or his or her authorized agent or under his or her direction, and putting into, taking or consuming, such as by a health professional or the subject or patient.

[0030] "Subject" and “patient” as used herein includes any mammal. In any embodiments described herein, the subject is human. The terms “pharmaceutical composition” and “composition” and “formulation” are used interchangeably herein.

[0031] It should be understood that disclosure herein pertaining to AXN-001 or a pharmaceutically active salt thereof also may apply to other species based on the AXN-001 moiety, including esters of AXN-001 , complexes comprising AXN-001 , AXN-001 clathrates, etc.

[0032] The pharmaceutical compositions described herein are injectable compositions. An injectable composition may provide for subcutaneous or intravenous administration, for example, to a patient. An injectable composition may be formulated for subcutaneous or intravenous administration. Preferably, the composition is for subcutaneous administration, e.g., the composition is formulated for subcutaneous administration.

[0033] The amounts and concentrations discussed herein are based on the weight of the formula (l) / AXN-001 moiety, meaning that a pharmaceutical composition as described herein comprises the stated amount of AXN-001 (the compound of formula (I)) or an equivalent net peptide weight of a pharmaceutically active salt thereof. Thus, as used herein, any weight provided in mg relating to AXN-001 (the compound of formula (I)) is understood to include the equivalent net peptide weight of a pharmaceutically active salt thereof. In other words, “6 mg AXN-001 or a pharmaceutically active salt thereof” is understood to refer, for salt embodiments, to the equivalent net peptide weight of the salt to AXN-001.

[0034] In this context, the skilled person is readily aware that any dry peptide powder usually contains the peptide and other components, for example, water, absorbed solvents, counterions, and salts, which constitutes the gross peptide weight. In contrast, the net peptide weight is actual weight of only the peptide component.

[0035] Preferably, the pharmaceutical composition comprises 4 mg to 18 mg of a compound of formula (I) or pharmaceutically active salt thereof, preferably 6 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In the pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 8 mg / mL to 36 mg / mL, preferably 12 mg / mL to 36 mg / mL, based on the weight of the formula (i) moiety.

[0036] Advantageously, the pharmaceutical composition comprising a dose of 6 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety) may provide a rapid onset of action and a long duration of action, i.e., an advantageous PK profile. Advantageously, the pharmaceutical composition comprising a dose of 6 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety) may provide the formation of a depot, e.g., may form a depot in vivo after administration.

[0037] Preferably, the pharmaceutical composition comprises 4 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In such a pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof may be 8 mg / mL, based on the weight of the formula (i) moiety.

[0038] Preferably, the pharmaceutical composition comprises 8 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In such a pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof may be 16 mg / mL, based on the weight of the formula (i) moiety.

[0039] Preferably, the pharmaceutical composition comprises 12 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In such a pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof may be 24 mg / mL, based on the weight of the formula (i) moiety.

[0040] Without wanting to be bound by theory, the present inventors believe that the combination of 6 mg to 18 mg of AXN-001 or a pharmaceutically active salt thereof at a concentration (of AXN-001 or a pharmaceutically active salt thereof) of 12 mg / mL to 36 mg / mL (both based on the weight of the AXN-001 moiety) administered subcutaneously advantageously creates a depot (e.g., in vivo after administration)_which results in longer duration of action. In turn, provision of a depot comprising AXN-001 or a pharmaceutically active salt thereof facilitates an improved pharmaceutical composition.

[0041] Preferably, the pharmaceutical composition comprises 1 mg to 6 mg of a compound of formula (I) or a pharmaceutically active salt thereof, preferably 3 mg to 5 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In such a pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof may be 2 mg / mL to 12 mg / mL, preferably 6 mg / mL to 10 mg / mL, based on the weight of the formula (i) moiety.

[0042] Advantageously, the pharmaceutical composition comprising a dose of 3 mg to 5 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety) may provide an desirable PK profile. Advantageously, such doses are fast acting and long acting. Advantageously, such doses achieve the desired plasma levels in a minimum amount for efficacy.

[0043] Preferably, the pharmaceutical composition comprises 1 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In such a pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof may be 2 mg / mL, based on the weight of the formula (i) moiety.

[0044] Preferably, the pharmaceutical composition comprises 2 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In such a pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof may be 4 mg / mL, based on the weight of the formula (i) moiety.

[0045] Preferably, the pharmaceutical composition comprises 4 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (i) moiety. In such a pharmaceutical composition, the concentration of the compound of formula (I) or a pharmaceutically active salt thereof may be 8 mg / mL, based on the weight of the formula (i) moiety.

[0046] Optionally, the pharmaceutical composition comprises 6 mg to 18 mg of AXN-001 or a pharmaceutically active salt thereof, for example, 7 mg to 17 mg, 8 mg to 16 mg, 9 mg to 15 mg, 10 mg to 14 mg, 11 mg to 13 mg, 12 mg, based on the weight of the AXN-001 moiety, or any amount of AXN-001 within any range defined by any combination of the above-listed endpoints. For example, the pharmaceutical composition may comprise at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 11 mg, at least 12 mg, at least 13 mg, at least 14 mg, at least 15 mg, at least 16 mg of AXN-001 or a pharmaceutically active salt thereof, based on the weight of the AXN-001 moiety; for example, the pharmaceutical composition may comprise no more than 18 mg, no more than 17 mg, no more than 16 mg, no more than 15 mg, no more than 14 mg, no more than 13 mg, no more than 12 mg, no more than 11 mg, no more than 10 mg, no more than 9 mg of AXN-001 or a pharmaceutically active salt thereof, based on the weight of the AXN-001 moiety.

[0047] Preferably, the composition comprises 8 mg to 16 mg of AXN-001 or a pharmaceutically active salt thereof, based on the weight of the AXN-001 moiety.

[0048] Optionally, the pharmaceutical composition has a concentration of AXN-001 or a pharmaceutically active salt thereof of 16 mg / mL to 32 mg / mL, for example, 17 mg / mL to 31 mg / mL, 18 mg / mL to 30 mg / mL, 19 mg / mL to 29 mg / mL, 20 mg / mL to 28 mg / mL, 21 mg / mL to 27 mg / mL, 22 mg / mL to 26 mg / mL, 23 mg / mL to 25 mg / mL, 24 mg / mL, all based on the weight of the AXN-001 moiety, or any concentration of AXN-001 within any range defined by any combination the above-listed endpoints. For example, the pharmaceutical composition may comprise at least 16 mg / mL, at least 17 mg / mL, at least 18 mg / mL, at least

[0049] 19 mg / mL, at least 20 mg / mL, at least 21 mg / mL, at least 22 mg / mL, at least 23 mg / mL, at least 24 mg / mL, at least 25 mg / mL, at least 26 mg / mL, at least 27 mg / mL, at least 28 mg / mL, at least 29 mg / mL, at least 30 mg / mL, at least 31 mg / mL of AXN-001 or a pharmaceutically active salt thereof, based on the weight of the AXN-001 moiety; for example, the pharmaceutical composition may comprise no more than 32 mg / mL, no more than 31 mg / mL, no more than 30 mg / mL, no more than 29 mg / mL, no more than 28 mg / mL, no more than 27 mg / mL, no more than 26 mg / mL, no more than 25 mg / mL, no more than 24 mg / mL, no more than 23 mg / mL, no more than 22 mg / mL, no more than 21 mg / mL, no more than

[0050] 20 mg / mL, no more than 19 mg / mL, no more than 18 mg / mL, no more than 17 mg / mL of AXN- 001 or a pharmaceutically active salt thereof, all based on the weight of the AXN-001 moiety.

[0051] Optionally, the pharmaceutical composition comprises a concentration of AXN-001 or a pharmaceutically active salt thereof, which is twice the dose per ml, for example 32 mg / ml for a 16 mg dose, etc. (based on the weight of the AXN-001 moiety).

[0052] Preferably, the pharmaceutical composition comprises 8 mg of AXN-001 or a pharmaceutically active salt thereof and the concentration of AXN-001 or a pharmaceutically active salt thereof is 16 mg / mL, both based on the weight of the AXN-001 moiety.

[0053] Preferably, the pharmaceutical composition comprises 16 mg of AXN-001 or a pharmaceutically active salt thereof and the concentration of AXN-001 or a pharmaceutically active salt thereof is 32 mg / mL, both based on the weight of the AXN-001 moiety. The pharmaceutical composition is an injectable composition. An injectable composition may provide for subcutaneous or intravenous administration, for example, to a patient. For example, an injectable composition may be formulated for subcutaneous or intravenous administration.

[0054] Optionally, the pharmaceutical composition is aqueous, e.g., is formulated with water. For example, the pharmaceutical composition may comprise water, e.g. water for injection (WFI).

[0055] Optionally, the pharmaceutical composition has a pH between 4.5 to 5.5. For example, the pH of the pharmaceutical composition may be 4.5 to 5.5, 4.6 to 5.4, 4.7 to 5.3, 4.8 to 5.2, 4.9 to 5.1 , or 5.0, or may be a pH within any range defined by any combination of the above endpoints.

[0056] Advantageously, the pharmaceutical composition having a pH between 4.5 to 5.5 provides for reduced or no injection site reactions.

[0057] Optionally, the pharmaceutical composition comprises a buffering agent. Preferably, the buffering agent is sodium acetate trihydrate. Advantageously, the buffering agent maintains the pharmaceutical composition at the desired pH value or range. More specifically, the buffering agent modulates the rapid pH adjustment in the subcutaneous space and allows AXN-001 be absorbed rapidly prior to gel / depot formation due to neutral pH. This is particularly important because solubility of AXN-001 is low at neutral pH. In turn, the presence of a buffering agent such as sodium acetate trihydrate in the pharmaceutical composition may be particularly important.

[0058] Optionally, the pharmaceutical composition comprises an isotonicity agent. Preferably, the isotonicity agent is mannitol. Advantageously, the isotonicity agent adjusts the tonicity of the pharmaceutical composition to be isotonic with blood. The presence of an isotonicity agent such as mannitol may be particularly important for good tolerability.

[0059] Preferably, the pharmaceutical composition comprises 32.0 mg AXN-001 , 1.36 mg sodium acetate trihydrate, 45.0 mg mannitol, hydrochloric acid or sodium hydroxide q.s. to pH 5.0, and Water For Injection to 1.0 mL. According to a further aspect of the invention, there is provided a kit of parts comprising a pharmaceutical composition comprising 1 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety): wherein the concentration of the compound of formula (I) or pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL (based on the weight of the formula (i) moiety).

[0060] The kit of parts may comprise a means for administration, for example, a means for injection. The kit of parts may comprise syringe, e.g., a 1 mL syringe, for comprising the pharmaceutical composition. The kit of parts may comprise an injector, e.g., an autoinjector, preferably a subcutaneous autoinjector, for administering the pharmaceutical composition.

[0061] According to a further aspect of the invention, there is provided a pharmaceutical composition comprising 1 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety):

[0062] wherein the concentration of the compound of formula (I) or pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL (based on the weight of the formula (i) moiety) for use in the treatment of acute migraine.

[0063] Acute migraine treatment is understood to mean relieving migraine symptoms, in contrast to preventive treatment which is aimed at reducing the frequency and severity of migraine events. Advantageously, the pharmaceutical composition for use in the treatment of acute migraine provides for patient well-being characterized by one or more or all of (a) rapid improvement of headache, (b) relief of non-pain symptoms, and (c) absence of adverse events.

[0064] Optionally, the pharmaceutical composition is for use in the treatment of acute migraine in a patient in need thereof. The pharmaceutical composition may be for use in the treatment of acute migraine in a human patient or in a human subject.

[0065] Optionally, the pharmaceutical composition is administered subcutaneously, i.e., by subcutaneous injection. For example, the pharmaceutical composition is administered via subcutaneous (SC) autoinjector. Advantageously, this provides for a patient-friendly delivery.

[0066] Optionally, the pharmaceutical composition is for administration at a dose of 6 mg to 18 mg of AXN-001 or pharmaceutically active salt thereof per subject (per episode) (based on the weight of the AXN-001 moiety), for example, 7 mg to 17 mg, 8 mg to 16 mg, 9 mg to 15 mg, 10 mg to 14 mg, 11 mg to 13 mg, 12 mg, or any dose within any range defined by any combination of the above endpoints. Preferably, the pharmaceutical composition is for administration at a dose of 8 mg to 16 mg per subject (based on the weight of the AXN-001 moiety).

[0067] Preferably, the pharmaceutical composition is for administration at a dose of 1 mg AXN-001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) by subcutaneous administration. Preferably, the pharmaceutical composition is for administration at a dose of 2 mg AXN-001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) by subcutaneous administration. Preferably, the pharmaceutical composition is for administration at a dose of 4 mg AXN-001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) by subcutaneous administration. Preferably, the pharmaceutical composition is for administration at a dose of 8 mg AXN-001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) by subcutaneous administration. Preferably, the pharmaceutical composition is for administration at a dose of 16 mg AXN-001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) by subcutaneous administration. Preferably, the pharmaceutical composition is for administration at a dose of 32 mg AXN-001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) by subcutaneous administration.

[0068] According to a further aspect of the invention, there is provided the use in the manufacture of a medicament for the treatment of acute migraine, of 1 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety): wherein the concentration of the compound of formula (I) or pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL (based on the weight of the formula (I) moiety).

[0069] According to a further aspect of the invention, there is provided a method of treatment of acute migraine comprising a step of administering to a patient in need thereof a pharmaceutical composition comprising 1 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety): wherein the concentration of the compound of formula (I) or pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL(based on the weight of the formula (i) moiety).

[0070] According to a further aspect of the invention, there is provided a method of manufacturing a pharmaceutical composition comprising 1 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof (based on the weight of the formula (i) moiety):

[0071] wherein the concentration of the compound of formula (I) or pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL (based on the weight of the formula (i) moiety).

[0072] Optionally, the method of manufacturing the pharmaceutical composition of 32 mg / mL ANX-001 and other concentrations comprises the steps of:

[0073] 1) Preparing formulation buffer (10 mM Sodium Acetate, 45 mg / mL Mannitol, pH 5.0)

[0074] 2) Formulating 32 mg / mL AXN-001 in the formulation buffer a. adding approximately 12 mL formulation buffer. b. adding 480 mg of AXN-001 peptide (net peptide weight) and mixing until the peptide is dissolved. c. adjusting the pH of the formulation to pH 5.0 ±0.1 with hydrochloric acid or sodium hydroxide solution. d. adding additional formulation buffer to the reaction mixture to final volume of 15mL and mixing.

[0075] 3) Formulations of more dilute concentrations of AXN-001 may be prepared by appropriate dilution of the 32 mg / mL formulation in formulation buffer: a. 16 mg / mL AXN-001 may be prepared by adding 8 mL of the 32 mg / mL formulation from step 2 to 8 mL of formulation buffer. b. 8 mg / mL AXN-001 may be prepared by adding 4 mL of the 32 mg / mL formulation from step 2 to 12 mL of formulation buffer. c. 4 mg / mL AXN-001 may be prepared by adding 2 mL of the 32 mg / mL formulation from step 2 to 14 mL of formulation buffer. d. 2 mg / mL AXN-001 may be prepared by adding 1 mL of the 32 mg / mL formulation from step 2 to 15 mL of formulation buffer.

[0076] 4) Filtering the formulation with a 0.2 pm polyether sulfone membrane filter into a sterile syringe.

[0077] 5) Storing at 2-8 °C.

[0078] Also provided is a method of treating a patient by administering a dose of AXN-001 or a pharmaceutically active salt thereof by subcutaneous administration, e.g., by subcutaneous injection. Preferably, a dose of 1 mg AXN-001 or a pharmaceutically active salt thereof is administered to the patient by subcutaneous administration. Preferably, a dose of 2 mg AXN- 001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) is administered to the patient by subcutaneous administration. Preferably, a dose of 4 mg AXN- 001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) is administered to the patient by subcutaneous administration. Preferably, a dose of 8 mg AXN- 001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) is administered to the patient by subcutaneous administration. Preferably, a dose of 16 mg AXN- 001 or a pharmaceutically active salt thereof (based on the weight of the AXN-001 moiety) is administered to the patient by subcutaneous administration.

[0079] Unless otherwise stated or evident from the context, features described above in relation to any one aspect of the disclosure are equally applicable, mutatis mutandis, to every other aspect of the disclosure.

[0080] Examples

[0081] The following specific examples are included as illustrative examples of the compositions and methods described herein. These examples are in no way intended to limit the scope of the disclosure. Other aspects of the disclosure will be apparent to those skilled in the art.

[0082] Drug substance

[0083] AXN-001 is a 11-mer monocyclic, branched peptide, which may be isolated as a hydrochloride salt. The drug substance used in the development of the pharmaceutical composition and for the clinical studies described herein was prepared by solid phase peptide synthesis. Screening and stability studies of the drug product confirm the compatibility of AXN- 001 with the excipients used.

[0084] Excipients

[0085] Mannitol may be used as isotonicity agent. Sodium acetate trihydrate may be used as buffering agent. Water for injection may be used as solvent. Hydrochloric acid and sodium hydroxide may be used as pH adjusting agents if required.

[0086] Method of Manufacturing

[0087] The method of manufacturing the pharmaceutical composition of 32 mg / mL ANX-001 and other concentrations may comprise the steps of:

[0088] 1) Preparing formulation buffer (10 mM Sodium Acetate, 45 mg / mL Mannitol, pH 5.0)

[0089] 2) Formulating 32 mg / mL AXN-001 in formulation buffer a. adding approximately 12 mL formulation buffer b. adding 480 mg of AXN-001 peptide (content and purity adjusted) and mixing until the peptide is dissolved c. adjusting pH of the formulation to pH 5.0 ±0.1 with hydrochloric acid or sodium hydroxide solution d. adding additional formulation buffer to the reaction mixture to final volume of 15mL and mixing.

[0090] 3) Formulations of more dilute concentrations of AXN-001 may be prepared by appropriate dilution of the 32 mg / mL formulation in formulation buffer: a. 16 mg / mL AXN-001 may be prepared by adding 8 mL of the 32 mg / mL formulation from step 2 to 8 mL of formulation buffer. b. 8 mg / mL AXN-001 may be prepared by adding 4 mL of the 32 mg / mL formulation from step 2 to 12 mL of formulation buffer c. 4 mg / mL AXN-001 may be prepared by adding 2 mL of the 32 mg / mL formulation from step 2 to 14 mL of formulation buffer d. 2 mg / mL AXN-001 may be prepared by adding 1 mL of the 32 mg / mL formulation from step 2 to 15 mL of formulation buffer.

[0091] 4) Filtering the formulation with a 0.2 pm polyether sulfone membrane filter into a sterile syringe

[0092] 5) Storing at 2-8 °C.

[0093] Development of pharmaceutical composition

[0094] Formulation of comparable peptides typically involves isotonic acetate buffer solutions at approximately pH 4.5. However, the Applicant surprisingly identified pharmaceutical compositions having higher pH values which in turn relate more closely to physiological pH levels. To achieve formulations having higher pH values, an isotonic 10 mM phosphate buffer was used.

[0095] Degradation rates were determined for 1 mg / mL solutions of AXN-001 at pH 3.5, 4.5, 5.5, 6.5, and 7.5, when kept at 2-8°C, 25°C, 40°C, or 60°C for 30 days. The degradation rates for various pH values and temperatures are shown in Table 1 and FIG. 1.

[0096] Table 1 : Degradation rates Degradation Rates (% / day)

[0097] Legend: n.d. = degradation too slow, not measurable

[0098] Degradation rates at 2-8° C were not determined (“n.d.”) because degradation could not be measured at thirty days (with the exception of pH 7.5).

[0099] The preliminary conclusions were that:

[0100] • Pharmaceutical compositions at 40 and 60°C were the most stable at pH 4.5

[0101] • Pharmaceutical compositions at 25°C were the most stable at pH 5.5 A pH of 5 was selected as the target pH for a clinical trial formulation. The composition of the 32 mg / mL pharmaceutical composition used as a clinical trial formulation is presented in Table 2 below.

[0102] Table 2: Composition of AXN-001 Clinical Formulation, 32 mg / mL

[0103] For Phase I clinical studies, the 32 mg / mL pharmaceutical composition described above was administered subcutaneously.

[0104] The Phase I clinical trial was a randomised, double-blind, placebo-controlled, first-in- human study of the safety, tolerability and pharmacokinetics of AXN-001 in healthy volunteers under Protocol No. AXN-001-01 .

[0105] Physiochemical and Biological Properties

[0106] As noted in Table 2 above, the pH of the pharmaceutical composition was 5.0, which was ensured by measuring and adjusting pH as an in-process control. pH also was a release specification. Isotonicity was achieved by addition of mannitol. The density was determined to be 1.015 g / cm3(32 mg / mL).

[0107] Clinical Trial

[0108] The pharmacokinetic objective of the Phase I clinical trial was to provide pharmacokinetic analysis of AXN-001 following single ascending subcutaneous doses of AXN- 001 . The study design included the following cohorts:

[0109] - Cohort 1 : Dose 1 mg (2 mg / mL formulation);

[0110] - Cohort 2: Dose 2 mg (4 mg / mL formulation);

[0111] - Cohort 3: Dose 4 mg (8 mg / mL formulation);

[0112] - Cohort 4: Dose 8 mg (16 mg / mL formulation);

[0113] - Cohort 5: Dose 16 mg (32 mg / mL formulation). Participants were administered a single dose (0.5 mL) of AXN-001 or placebo via subcutaneous (SC) injection into the abdomen. Blood samples were collected at specified time points for pharmacokinetic analysis (5,10,15,20,30,45,60 minutes; 2,3,4,6,8,12,24 hours). Individual plasma concentrations of ANX-001 were determined and used for analyses.

[0114] Pharmacokinetic (PK) parameters of AXN-001 were determined using Phoenix WinNonlin version 8.3. All concentrations below the limit of quantification (BLQ) were set to zero for the purpose of the PK analysis. All AUC determinations were made using linear trapezoidal method. The following parameters were determined:

[0115] Cmax Maximum observed concentration, as read directly from the observed data.

[0116] Tmax Time to maximum concentration

[0117] T nM Time to 10 nM

[0118] Tsornvi Time to 30 nM

[0119] T onM Time to 100 nM

[0120] AllCo-t Area under the concentration-time curve from time zero to the time of the last measurable concentration, calculated using linear trapezoidal rule

[0121] AUCo-inf Area under the concentration-time curve from time zero to infinity, calculated using linear trapezoidal rule

[0122] %AUCextraPThe portion of AUC determined by extrapolation ti / 2 Apparent terminal elimination half-life

[0123] CL / F or CL Total apparent body clearance

[0124] VZ / F or VzApparent volume of distribution

[0125] Az Terminal elimination rate constant

[0126] Table 3 summarizes the mean plasma concentration of AXN-001 measured at various time points following a single subcutaneous dose. FIG. 2 illustrates the plasma concentrations measured in this experiment on a linear scale; FIG. 3 illustrates the plasma concentrations on a logarithmic scale.

[0127] Table 3

[0128] Table 4 provides the summary mean plasma PK Parameters for Cohorts 1 to 5.

[0129] Table 4

[0130] Table 5 shows the time required for blood levels to reach certain target concentrations of AXN- 001 after subcutaneous administration.

[0131] Table 5

[0132] As shown in Table 5, all subjects at all doses were able to achieve plasma concentrations of 10nM AXN-001 in less than 15 minutes. All subjects in the 4, 8, and 16 mg cohort, 5 of 6 subjects in the 2 mg cohort, and 1 of 6 subjects in the 1 mg cohort achieved plasma concentrations of 30nM. All subjects in the 8 and 16 mg cohorts, and 2 / 5 of the 4 mg cohort, achieved 100nM plasma concentrations.

[0133] FIG. 4A and 4B relate to the summary of AXN-001 plasma concentrations. More specifically, FIG. 4A relates to the summary plasma concentrations of AXN-001 following single ascending subcutaneous dose of AXN-001 for Cohort 1 to 5 on a linear scale and FIG. 4B presents the data on a semi-log scale. FIG. 5 shows the differentiated / superior PK profile of AXN-001. More specifically, the data shown in FIG. 5 demonstrates that within 30 minutes, the AXN-001 achieves a much higher increase in free plasma concentration when compared with olcegepant, zavegepant, rimegepant and Ubrogepant, whilst maintaining a consistent free plasma concentration for up to 120 minutes.

[0134] Summarising, the human PK analyses of subcutaneous injection of AXN-001 demonstrated:

[0135] Faster, higher, and more consistent free plasma concentrations than any approved gepant

[0136] Faster, higher, and more reliable efficacy than any approved gepant.

Claims

Claims1. A pharmaceutical composition comprising 1 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (I) moiety:wherein the concentration of the compound of formula (I) or pharmaceutically active salt thereof is 2 mg / mL to 36 mg / mL, based on the weight of the formula (I) moiety.

2. The pharmaceutical composition according to claim 1 comprising 4 mg to 18 mg of a compound of formula (I) or a pharmaceutically active salt thereof, preferably 6 mg to 18 mg of a compound of formula (I) or pharmaceutically active salt thereof, all based on the weight of the formula (I) moiety.

3. The pharmaceutical composition according to claim 1 comprising 1 mg to 6 mg of a compound of formula (I) or pharmaceutically active salt thereof, preferably 3 mg to 5 mg of a compound of formula (I) or pharmaceutically active salt thereof, all based on the weight of the formula (I) moiety.

4. The pharmaceutical composition according to any preceding claim, wherein the pharmaceutical composition comprises the compound of formula (I) or an equivalent net peptide weight of a pharmaceutically active salt thereof:

5. The pharmaceutical composition according to claim 2, wherein the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 8 mg / mL to 36 mg / mL, preferably 12 mg / mL to 36 mg / mL, based on the weight of the formula (I) moiety.

6. The pharmaceutical composition according to claim 3, wherein the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 2 mg / mL to 12 mg / mL, preferably 6 mg / mL to 10 mg / mL, based on the weight of the formula (I) moiety.

7. The pharmaceutical composition according to any preceding claim, comprising:(i) 1 mg of a compound of formula (I) or a pharmaceutically active salt thereof based on the weight of the formula (I) moiety, wherein the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 2 mg / mL based on the weight of the formula (I) moiety;(ii) 2 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (I) moiety, wherein the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 4 mg / mL based on the weight of the formula (I) moiety;(iii) 4 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (I) moiety, wherein the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 8 mg / mL based on the weight of the formula (I) moiety;(iv) 8 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (I) moiety, wherein the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 16 mg / mLbased on the weight of the formula (I) moiety; or(v) 16 mg of a compound of formula (I) or a pharmaceutically active salt thereof, based on the weight of the formula (I) moiety, wherein the concentration of the compound of formula (I) or a pharmaceutically active salt thereof is 32 mg / mL based on the weight of the formula (I) moiety.

8. The pharmaceutical composition according to any preceding claim, wherein the composition is an injectable pharmaceutical composition.

9. The pharmaceutical composition according to any preceding claim, wherein the composition is aqueous.

10. The pharmaceutical composition according to any preceding claim, wherein the pH of the composition is 4.5 to 5.5.

11. The pharmaceutical composition according to any preceding claim, comprising a buffering agent, preferably wherein the buffering agent is sodium acetate trihydrate.

12. The pharmaceutical composition according to any preceding claim, comprising an isotonicity agent, preferably wherein the isotonicity agent is mannitol.

13. The pharmaceutical composition according to any preceding claim for use in the treatment of acute migraine.

14. The pharmaceutical composition according to any preceding claim, wherein the composition is for administration at a dose of 1 mg to 16 mg / subject based on the weight of the formula (I) moiety.

15. The pharmaceutical composition according to any preceding claim, wherein the composition is administered subcutaneously.

16. A method of treatment of acute migraine comprising a step of administering to a patient in need thereof a composition according to any preceding claim.

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