Rimegepant for CGRP-related disorders

Abstract

This invention provides a method for treating CGRP-related disorders, such as migraines. [Solution] A method is provided comprising administering rimegepant or a pharmaceutically acceptable salt thereof to a patient requiring treatment. Also provided are a pharmaceutical composition containing rimegepant and a kit comprising the pharmaceutical composition and instructions for use.

Description

[Technical Field]

[0001] The present invention relates to the use of rimegepant and its salts for treating CGRP-related disorders such as migraines. [Background technology]

[0002] Migraine is a chronic, debilitating disorder characterized by recurrent attacks lasting 4 to 72 hours, typically a unilateral, pulsating headache of moderate to severe intensity, often accompanied by nausea or vomiting, and / or multiple symptoms including sensitivity to sound (phonophobia) and light (photophobia). Migraines are often preceded by a transient neurological warning symptom known as an aura, which usually involves visual disturbances such as flashing lights, but may also include numbness or tingling in a part of the body. Migraines are widespread and distressing. The Migraine Research Foundation ranks migraines as the third most prevalent disease globally, and in the Global Burden of Diseases Study 2015, it ranked migraines as the seventh most common cause of distress globally. According to the Migraine Research Foundation, approximately 36 million people in the United States experience migraine attacks. While most people experience one to two migraine attacks per month, over 4 million people suffer from chronic migraines, defined as experiencing at least 15 headache days per month for more than three months, with at least 8 of those being migraines. Others have transient migraines, characterized by experiencing fewer than 15 migraine days per month. Individuals with transient migraines may develop chronic migraines over time. Migraine attacks can last from four hours to up to three days. More than 90% of people who suffer from migraines are unable to work or function normally during an attack, and many experience comorbidities such as depression, anxiety, and insomnia. They also often experience nausea and aversion to food and fluids during attacks.

[0003] CGRP (calcitonin gene-related peptide) is a 37-amino acid neuropeptide belonging to a peptide family that includes calcitonin, adremedullin, and amylin. In humans, two types of CGRP (α-CGRP and 13-CGRP) exist, and they have similar levels of activity. They differ in three amino acids and exhibit different distributions. At least two CGRP receptor subtypes may also explain the differing activity. CGRP receptors are located in pain signaling pathways, intracranial arteries, and mast cells, and their activation is thought to be causal in the pathophysiology of migraine. For example, studies and clinical trials have shown that serum levels of CGRP increase during migraine attacks, intravenous infusion of CGRP induces persistent pain in migraine and non-migraine patients, and treatment with anti-migraine drugs normalizes CGRP activity.

[0004] The potential involvement of CGRP in migraines is suggested by, for example, olcegepant (Boehringer Ingelheim, Ridgefield, CT) and telcagepant (Merck Sharp & Dohme Corp., Kenilworth, NJ), ubrogepant (Allergan plc, Dublin, Ireland), rimegepant Biohaven Pharmaceutical Holding Company Ltd., New Haven, CT), galcanezumab Eli Lilly and Company, Indianapolis, IN), fremanezumab (Teva Pharmaceutical Industries, Petah Tikva, Israel), eptinezumab Alder Biopharmaceuticals, Inc., Bothell, WA) and erenumab (Amgen Inc., Thousand It forms the basis for the development and clinical trials of many compounds, including Oaks (CA). Another compound recently being studied for the treatment of migraines is lasmiditan (Eli Lilly and Company, Indianapolis, IN).

[0005] Currently, clinicians use several pharmacological substances for the acute treatment of migraines. A study published by the American Headache Society in 2015 concluded that drugs deemed effective for the acute treatment of migraines fall into the categories of triptans, ergotamine derivatives, nonsteroidal anti-inflammatory drugs ("NSAIDs"), opioids, and combination drugs. The current standard of treatment for the acute treatment of migraines is serotonin 5-HT. 1B / 1D The prescription involves triptans, which are receptor agonists. Triptans have been developed and approved for the acute treatment of migraines over the past 20 years. The initial introduction of triptans represented a shift towards drugs that more selectively target the pathophysiology suspected of migraine. While triptans account for nearly 80% of anti-migraine treatments prescribed in outpatient visits by healthcare providers, issues such as incomplete efficacy and headache recurrence remain significant clinical limitations. In fact, only about 30% of patients in clinical trials experienced pain relief within two hours of taking triptans. Furthermore, because their 5-HT1B-mediated action can cause systemic and cerebrovascular vasoconstriction, triptans are contraindicated in patients with cardiovascular disease, cerebrovascular disease, or any significant risk factors. Also, according to a January 2017 study published in the Headache Journal, an estimated 2.6 million migraine sufferers in the United States have cardiovascular events, symptoms, or treatments that limit the possibility of triptans as a treatment option.

[0006] Therefore, there remains a significant unmet medical need for migraine treatments that could enhance patient benefits compared to existing therapies. Furthermore, CGRP receptor antagonists may be useful drugs for other disorders involving CGRP dysfunction. In addition to migraine, such disorders include cluster headache (Doods (2001) Curr. Opin. Invest. Drugs 2, 1261-1268; Edvinsson et al.). al. (1994) Cephalalgia 14, 320-327); chronic tension-type headache (Ashina et al. (2000) Neurology 14, 1335-1340); pain (Yu et al. (1998) Eur. J Pharmacol. 347, 275-282); chronic pain (Hulsebosch et al. (2000) Pain 86, 163-175); neurogenic and inflammatory pain (Holzer (1988) Neuroscience 24, 739-768; Delay-Goyet et al. (1992) Acta Physiol. Scanda. 146, 537-538; Salmon et al. (2001) Nature Neurosci. 4, 357-358); eye pain (May et al. (2002) Cephalalgia (22, 195-196), toothache (Awawdeh et al. (2002) Int. Endocrin. J 35, 30-36), non-insulin-dependent diabetes (Molina et al.) al. (1990) Diabetes 39, 260-265); Vascular disorders; inflammation (Zhang et al. (2001) Pain 89, 265); arthritis, increased bronchial reactivity, asthma, (Foster et al. (1992) Ann. NY Acad. Sci. 657, 397-404; Schini et al. (1994) Am. J Physiol. 267, H2483-H2490; Zheng et al. (1993) J Viral. 67, 5786-5791); shock, sepsis (Beer et al. (2002) Crit. Care Med. 30, 1794-1798); Opiate withdrawal syndrome (Salmon et al. (2001) Nature Neurosci. 4, 357-358); Morphine tolerance (Menard et al. al. (1996) J Neurosci. 16, 2342-2351); Hot flashes in men and women (Chen et al. (1993) Lancet 342, 49; Spetz et al. (2001) J Urology 166, 1720-1723); Allergic dermatitis (Wallengren (2000) Contact Dermatitis 43, 137-143); Psoriasis; Encephalitis, brain injury, ischemia, stroke, epilepsy and neurodegenerative diseases (Rohrenbeck et al. (1999) Neurobiol. Dis. 6, 15-34); Skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic skin redness Skin redness, skin rosaceousness, and erythema; tinnitus (Herzog et al. (2002) J Membr. Biol. 189,225); obesity (Walker et al. (2010)) Endocrinology 151, 4257-4269); Inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al. (2002) Scand. J Gastroenterol. 37, 414-422) and cystitis are possible causes. [Overview of the project]

[0007] The present invention particularly aims to treat CGRP-related disorders, such as migraine, using rimegepant and its salts. The present invention enables the provision of more effective GCRP-related treatments to patients. Patients suffering from migraine can experience improved responses in one or more areas, including, for example, a reduction in the number of migraines, relief from pain, or improvement in relief from the most bothersome symptoms.

[0008] In one aspect of the present invention, there is provided a method of treating migraine in a patient who needs treatment, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof so as to reduce by at least 20% the number of migraines per month in the patient.

[0009] In one aspect of the present invention, the number of migraines per month in the patient is reduced by at least 30%. In one aspect of the present invention, the number of migraines per month in the patient is reduced by at least 40%.

[0010] In one aspect of the present invention, there is provided a method of treating migraine in a patient who needs treatment, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition can provide relief from pain that is about 30% higher than that of a placebo.

[0011] In one aspect of the present invention, the relief from pain is about 50% higher than that of a placebo. In one aspect of the present invention, the relief from pain of the pharmaceutical composition is 30 - 75% higher than that of a placebo. In one aspect of the present invention, the relief from pain is 35 - 65% higher than that of a placebo.

[0012] In one aspect of the present invention, there is provided a method of treating migraine in a patient who needs treatment, the method comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition can provide relief from MBS that is about 30% higher than that of a placebo.

[0013] In one embodiment of the present invention, the release from MBS is about 40% higher than that from placebo. In one embodiment of the present invention, the release from MBS is about 30 - 50% higher than that from placebo. In one embodiment of the present invention, the release from MBS is about 35 - 65% higher than that from placebo.

[0014] In one embodiment of the present invention, the method provides an AUC of about 80 - 125% of 5000 (hr*ng / mL). 0-t In one embodiment of the present invention, the method provides an AUC of about 85 - 115% of 5000 (hr*ng / mL). 0-t In one embodiment of the present invention, the method provides an AUC of about 90 - 105% of 5000 (hr*ng / mL). 0-t In one embodiment of the present invention, the method provides an AUC of about 90 - 105% of 5000 (hr*ng / mL).

[0015] In one embodiment of the present invention, the method provides a C of about 80 - 125% of 835 (ng / mL). max In one embodiment of the present invention, the method provides a C of about 85 - 120% of 835 (ng / mL). max In one embodiment of the present invention, the method provides a C of about 95 - 115% of 835 (ng / mL). max In one embodiment of the present invention, the method provides a C of about 95 - 115% of 835 (ng / mL).

[0016] In one embodiment of the present invention, the pharmaceutical composition is administered orally, sublingually or buccally.

[0017] In one aspect of the present invention, the pharmaceutical composition contains about 10 to 600 mg of rimegepant or a pharmaceutically acceptable salt thereof. In one aspect of the present invention, the pharmaceutical composition contains about 25 to 300 mg of rimegepant or a pharmaceutically acceptable salt thereof. In one aspect of the present invention, the pharmaceutical composition contains about 25 to 150 mg of rimegepant or a pharmaceutically acceptable salt thereof. In one aspect of the present invention, the pharmaceutical composition contains about 50 to 100 mg of rimegepant or a pharmaceutically acceptable salt thereof. In one aspect of the present invention, the pharmaceutical composition contains 70 to 80 mg of rimegepant or a pharmaceutically acceptable salt thereof. In one aspect of the present invention, the pharmaceutical composition contains about 75 mg of rimegepant or a pharmaceutically acceptable salt thereof. In one aspect of the present invention, the pharmaceutical composition contains about 150 mg of rimegepant or a pharmaceutically acceptable salt thereof. In one aspect of the present invention, the pharmaceutical composition contains about 37.5 mg of rimegepant or a pharmaceutically acceptable salt thereof.

[0018] In one aspect of the present invention, rimegepant is in the form of the hemisulfate sesquihydrate salt.

[0019] In one aspect of the present invention, a pharmaceutical composition containing a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof is provided to provide an AUC of about 80 to 125% of 5000 (hr*ng / mL). 0-t To provide an AUC of about 80 to 125% of 5000 (hr*ng / mL), a pharmaceutical composition containing a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof is provided.

[0020] In one aspect of the present invention, a pharmaceutical composition containing a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof is provided to provide a C of about 80 to 125% of 835 (ng / mL). max To provide a C of about (ng / mL) of 835, a pharmaceutical composition containing a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof is provided.

[0021] In one aspect of the present invention, the pharmaceutical composition is provided in the form of a tablet. In one aspect of the present invention, the pharmaceutical composition comprises about 50-60 wt% rimegepanthemisulfate sesquihydrate, about 30-35 wt% microcrystalline cellulose, about 2-7 wt% hydroxypropyl cellulose, about 3-7 wt% croscarmellose sodium, and about 0.1-1.0 wt% magnesium stearate. In one aspect of the present invention, the pharmaceutical composition comprises about 57.1 wt% rimegepanthemisulfate sesquihydrate, about 33.4 wt% microcrystalline cellulose, about 4.0 wt% hydroxypropyl cellulose, about 5.0 wt% croscarmellose sodium, and about 0.5 wt% magnesium stearate.

[0022] In one aspect of the present invention, the pharmaceutical composition is provided in the form of an oral solid-molded fast-dispersing dosage form. In one aspect of the present invention, the pharmaceutical composition comprises about 70-80 wt% rimegepanthemisulfate sesquihydrate, about 10-20 wt% fish gelatin, about 10-20 wt% filler, and 0.1-5.0 wt% flavorant. In one aspect of the present invention, the filler is mannitol.

[0023] In one embodiment of the present invention, a method for treating symptoms associated with abnormal levels of CGRP in a patient requiring treatment, comprising administering to the patient a pharmaceutical composition containing a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, thereby achieving an AUC of approximately 80-125% of 5000 (hr*ng / mL). 0-t We will provide a way to provide this.

[0024] In one aspect of the present invention, a method for treating symptoms associated with abnormal levels of CGRP in a patient requiring treatment, comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, thereby reducing approximately 80-125% of 835 (ng / mL) of C maxThe present invention provides a method that can provide [something]. In one aspect of the present invention, the disorder is selected from migraine and cluster headache; chronic tension headache; chronic pain; neurogenic inflammation and inflammatory pain; eye pain; toothache; non-insulin-dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial reactivity; asthma; shock; sepsis; opioid withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis, brain injury, ischemia, stroke, epilepsy and neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, rosacea and erythema; tinnitus; obesity; inflammatory bowel disease; irritable bowel syndrome; and cystitis.

[0025] In one aspect of the present invention, a kit for treating symptoms associated with abnormal levels of CGRP in a patient, (a) A pharmaceutical composition comprising a therapeutically effective dose of rimegepant or a pharmaceutically acceptable salt thereof; (b) Instructions for use for administering the pharmaceutical composition; including, Here, we provide a kit that delivers approximately 80-125% of the therapeutically effective dose of 5000 (hr*ng / mL). [Brief explanation of the drawing]

[0026] [Figure 1] Figure 1 shows the probability of pain relief over time in the clinical trial titled "BHV3000-301: Phase 3: A double-blind, randomized, placebo-controlled safety and efficacy trial of BHV-3000 (rimegepant) for the acute treatment of migraine" (clinicaltrials.gov identifier: NCT03235479).

[0027] [Figure 2] Figure 2 shows the probability of pain relief over time in the clinical trial titled "BHV3000-302: Phase 3: A double-blind, randomized, placebo-controlled safety and efficacy trial of BHV-3000 (rimegepant) for the acute treatment of migraine" (clinicaltrials.gov identifier: NCT03237845).

[0028] [Figure 3] Figure 3 shows the time to pain relief up to 8 hours after administration in the clinical trial titled "BHV3000-301: Phase 3: Double-blind, randomized, placebo-controlled safety and efficacy trial of BHV-3000 (rimegepant) for the acute treatment of migraine" (clinicals.gov identifier: NCT03235479).

[0029] [Figure 4] Figure 4 shows the time to pain relief up to 8 hours after administration in the clinical trial titled "BHV3000-302: Phase 3: Double-blind, randomized, placebo-controlled safety and efficacy trial of BHV-3000 (rimegepant) for the acute treatment of migraine" (clinicals.gov identifier: NCT03237845).

[0030] [Figure 5] Figure 5 shows the Kaplan-Meier curve for pain relief during the 2-hour period following a single dose of rimegepant 75 mg Zydis ODT in the clinical trial titled "BHV3000-303: Phase 3: A double-blind, randomized, placebo-controlled safety and efficacy trial of BHV-3000 (rimegepant) in the acute treatment of migraine" (clinicals.gov identifier: NCT03461757).

[0031] [Figure 6] Figure 6 shows pain relief 2 to 8 hours after a single dose of rimezepant 75 mg Zydis ODT in the clinical trial titled "BHV3000-303: Phase 3: A double-blind, randomized, placebo-controlled safety and efficacy trial of BHV-3000 (rimegepant) in the treatment of acute migraine" (clinicals.gov identifier: NCT03461757).

[0032] Detailed description of the invention The following detailed description is provided to assist those skilled in the art in carrying out the invention. Those skilled in the art can modify and alter the embodiments described herein to the extent that they do not deviate from the spirit or scope of this disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the invention pertains. The terms used herein are merely descriptive and not intended to limit any particular embodiment.

[0033] To use as in this application, unless otherwise expressly provided herein, the following terms have the meanings set forth below. Further definitions are provided throughout this application. Where a term is not specifically defined herein, it shall be given the meaning that is technically recognizable to a person skilled in the art in applying the term in the context in which it is used to describe the present invention.

[0034] The articles "a" and "an" mean one or more (i.e., at least one) grammatical objects of the article unless the context explicitly indicates otherwise. For example, "element" means one or more elements.

[0035] The term “about” means a value or composition that falls within the tolerance range of a particular value or composition as determined by those skilled in the art, and this will depend in part on how the value or composition is measured or determined, i.e., on the limitations of the measuring system. For example, “about” may mean one or more standard deviations for each practice in the art. Alternatively, “about” may mean a range of up to 1%, 5%, 10%, or 20% (i.e., ±10% or ±20%), depending on the context of this application. For example, about 3 mg may include any number from 2.7 mg to 3.3 mg (in the case of 10%), or from 2.4 mg to 3.6 mg (in the case of 20%). Furthermore, particularly with respect to biological systems or processes, the term may mean up to one decimal place, or up to five times the value. Where a particular value or composition is provided in this application and claims, unless otherwise specified, the meaning of “about” should be assumed to be within the tolerance range for that particular value or composition.

[0036] The term "administration" means the physical introduction of a composition containing a therapeutic agent into a target using any of the various methods and delivery systems known to those skilled in the art. Administration can also be carried out, for example, once, multiple times, and / or over one or more long periods, and may be a therapeutically effective dose or less than a therapeutic dose.

[0037] The term "AUC" (Area Under the Curve) refers to the total amount of drug absorbed or exposed to a subject. Generally, AUC can be obtained mathematically from a plot of drug concentrations over time until the concentration in the subject becomes negligible. The term "AUC" can also refer to a partial AUC at a specific time interval.

[0038] The term “C max "C" refers to the maximum concentration of the drug in the subject's blood, serum, a specific compartment, or a test area between the first and second doses. max "When specified, this may also mean the dose-normalized ratio.

[0039] The term "dosing interval" refers to the amount of time that elapses between multiple administrations of the formulations disclosed herein to a subject. Thus, the dosing interval can be expressed as a range.

[0040] The term "dosage frequency" means the frequency with which the dose of the formulation disclosed herein is administered within a given time period. Dosage frequency may be expressed as the number of doses per given time period, for example, once a week or once every two weeks.

[0041] The terms "in combination with" and "in conjunction with" mean administering one therapeutic modality in addition to another. Thus, "in combination with" and "in conjunction with" mean administering one therapeutic modality before, during, or after administration of another therapeutic modality to the target organism.

[0042] The term “pharmaceutically acceptable salt” generally means one or more salt forms of the compounds described herein that are indicated to increase the solubility of the compound in gastric or gastrointestinal fluids of a patient’s digestive tract in order to promote the dissolution and bioavailability of the compound. Pharmaceutically acceptable salts include, where applicable, those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include, for example, those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, and many other acids and bases that are particularly well known in the pharmaceutical field.

[0043] The terms “subject” and “patient” mean either a human or a non-human animal. The term “non-human animal” includes, but is not limited to, vertebrates, e.g., non-human primates, sheep, dogs, and rodents, e.g., mice, rats, guinea pigs. In some embodiments, the subject is a human. The terms “subject” and “patient” are used interchangeably herein.

[0044] The terms “effective dose,” “therapeutic effective dose,” “therapeutic effective dose,” and “therapeutic effective dose” of a drug (which may be referred to herein as “drug”) mean any amount of a drug, when used alone or in combination with other drugs, that protects a subject from the onset of the disease, or promotes disease relief as demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or relief from functional impairment or disability due to the distress of the disease. The therapeutic effective dose of a drug can be evaluated using a variety of methods known to those skilled in the art, such as evaluating the activity of a drug in human subjects in clinical trials, animal model systems to predict efficacy in humans, or assaying the activity of a drug in an in vitro assay.

[0045] The term “T max "This refers to the highest concentration (C) in the blood, serum, specific compartment, or test area of ​​the subject after drug administration. max It means the time or period of time that reaches ).

[0046] The term “treatment” means either treatment of symptoms or disease in an organism, and includes (i) preventing the onset of disease or symptoms in an organism prone to disease, but not yet diagnosed with disease; (ii) suppressing disease or symptoms, i.e., halting its progression; alleviating disease or symptoms, i.e., causing a reduction in its symptoms; or (iii) improving or alleviating symptoms caused by disease, i.e., symptoms of disease. Treatment may be used in combination with other standard treatments or alone. Treatment or “therapy” of an organism includes any intervention or process of any kind performed on the organism, or administration of drugs to the organism, with the aim of reversing, reducing, improving, suppressing, slowing or preventing the onset, progression, development, severity or recurrence of symptoms, complications, or symptoms or biochemical indicators associated with the disease.

[0047] With respect to headaches, “treatment” is an approach to obtain a beneficial or desirable outcome for the subject. For the purposes of this invention, beneficial or desirable clinical outcomes include, but are not limited to, one or more of the following: reduction in severity, relief of pain intensity and other associated symptoms, reduction in the frequency of recurrence, improvement in the quality of life of persons suffering from headaches, reduction in the dosage of other medications required to treat headaches, and improvement in any aspect of headache, including a reduction in the number of headache days per month. In the case of migraines, other associated symptoms include, but are not limited to, nausea, vomiting, and sensitivity to light, sound, and / or movement. In the case of cluster headaches, other associated symptoms include, but are not limited to, swelling under or around the eyes, excessive tearing, red eyes, runny or congested nose, and facial flushing.

[0048] For the purposes of this disclosure, publications by the U.S. Food and Drug Administration (FDA) https: / / www.fda.gov / downloads / drugs / guidances / ucm419465.pdf Guidance available from This information is based on Industry, “Migraine: Developing Drugs for Acute Treatment”, February 2018. Terms used in the examples, such as most troublesome symptoms (MBS) and pain relief, are described in the FDA guidance.

[0049] Starting materials useful for the production of the pharmaceutical compositions of the present invention are commercially available and readily obtainable, or can be prepared by those skilled in the art.

[0050] The chemical formula for rimegepant is C 28 H 28 It is F2N6O3, and its IUPAC name is [(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-9-yl]4-(2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate. Limegepant is also referred to herein as BHV-3000.

[0051] The structure of the rimegepant is, [ka] That is the case.

[0052] Limegepanth is described, for example, in WO2011 / 046997, published on April 21, 2011.

[0053] In a preferred embodiment of the present invention, the rimegepant exists in the form of a hemisulfate sesquihydrate salt. This preferred salt is described in WO2013 / 130402, published on September 6, 2013.

[0054] The chemical formula for the salt form is C 28 H 28 The formula is F2N6O3·0.5H2SO4·1.5H2O, and the structure is [ka] That is the case.

[0055] The pharmaceutical compositions of the present invention can be prepared in any suitable dosage form, such as tablets, capsules, nasal sprays, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microsphere aerosols, and the like.

[0056] The pharmaceutical compositions of the present invention, comprising rimegepant, generally also include other pharmaceutically acceptable carriers (also called additives), such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, flow enhancers, colorants, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizers, suspending agents, flavoring agents, preservatives, and mixtures thereof. The selection of additives depends on the desired properties of the composition and the properties of other pharmacologically active compounds in the formulation. Suitable additives are known to those skilled in the art ("Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by..."). See Rowe et al., McGraw Hill.

[0057] Pharmaceutically acceptable carriers that can be used in the preparation of the pharmaceutical compositions of the present invention may include, but are not limited to, fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), talc, calcium sulfate, vegetable oil, synthetic oil, polyol, alginic acid, phosphate buffer, emulsifier, isotonic saline, pyrogenic substance removal water, and combinations thereof. Disintegrants may also be added as needed, and exemplary disintegrants may include, but are not limited to, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate. In embodiments of the present invention, flavorings are selected from mint, peppermint, berry, cherry, menthol, and sodium chloride flavorings and combinations thereof. In aspects of the present invention, the sweetener is selected from sugars, sucralose, aspartame, acesulfame, neotame, and combinations thereof.

[0058] Generally, the pharmaceutical compositions of the present invention can be produced by conventional methods known in the art, such as conventional mixing steps, dissolving steps, granulation steps, dragee-making steps, levigating steps, emulsification steps, sealing steps, encapsulation steps, and freeze-drying steps.

[0059] In one embodiment of the present invention, the pharmaceutical composition is prepared in the form of an oral solid-molded, high-speed dispersible formulation as described in U.S. Patent No. 9,192,580 issued on November 24, 2015.

[0060] The expression "high-speed dispersibility formulation" means a composition that decomposes or disperses within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds, and particularly preferably 2 to 8 seconds, after contact with a fluid. The fluid is preferably what is found in the oral cavity, i.e., saliva, in the case of oral administration.

[0061] In a preferred embodiment, the composition of the present invention is a solid high-speed dispersibility formulation comprising a solid network of a fish gelatin-containing water-soluble or water-dispersible carrier, which is an active ingredient. The carrier is therefore inert to the active ingredient. The network is obtained by sublimating a solvent from a solid composition, and the composition comprises a solution of the active ingredient and the carrier in the solvent. The formulation according to the present invention can be prepared by the method disclosed in British Patent No. 1,548,022 by Gregory et al., which uses fish gelatin as the carrier. Thus, a composition (or admixture) comprising a solution of the active ingredient and the carrier in the solvent is prepared and then sublimated. Sublimation is preferably carried out by freeze-drying the composition. The composition can be contained in a mold during the freeze-drying process to produce a solid form of any desired shape. The mold can be cooled with liquid nitrogen or solid carbon dioxide in a preliminary step before the composition is deposited therein. After freezing the mold and composition, they are then subjected to reduced pressure, with controlled application of heat as needed to aid in the sublimation of the solvent. The reduced pressure applied during this process is less than approximately 4 mmHg, preferably less than approximately 0.3 mmHg. The freeze-dried composition may then be removed from the mold as needed, or stored there until later use.

[0062] When this process is used with fish gelatin as an active ingredient and carrier, a solid high-speed dispersion formulation is produced that has the advantages associated with the use of fish gelatin described herein. Fish gelatin is generally classified into varieties from cold and hot water fish sources, and into gelling and non-gelling varieties. Non-gelling varieties of fish gelatin have lower proline and hydroxyproline amino acid content compared to gelling fish gelatin and bovine gelatin, which are known to be associated with crosslinking properties and gelling ability. Non-gelling fish gelatin can survive at solution concentrations up to about 40% and temperatures down to 20°C. In one embodiment of the present invention, the fish gelatin used by the present invention is preferably obtained from a cold water fish source and is a non-gelling type of fish gelatin. More preferably, in one embodiment of the present invention, a non-hydrolyzed form of non-gelling fish gelatin may be used. In an alternative embodiment, spray-dried non-hydrolyzed non-gelling fish gelatin may be used. Fish gelatin suitable for use in the present invention is commercially available.

[0063] The compositions according to the present invention may also contain other matrix-forming agents and secondary components in addition to the active ingredient and fish gelatin carrier. Suitable matrix-forming agents for use in the present invention include animal or plant proteins, such as other gelatins, dextrins, substances derived from soybean, wheat, and psyllium seed proteins; gums, such as acacia, guar, agar, and xanthan gum; polysaccharides; alginates; carboxymethylcellulose; carrageenan; dextran; pectin; synthetic polymers, such as polyvinylpyrrolidone; and polypeptide / protein or polysaccharide complexes, such as gelatin-acacia complexes.

[0064] Other substances that may be incorporated into the rapidly soluble compositions of the present invention include sugars, e.g., mannitol, dextrose, lactose, galactose, and trehalose; cyclic sugars, e.g., cyclodextrin; inorganic salts, e.g., sodium phosphate, sodium chloride, and aluminum silicate; and amino acids having 2 to 12 carbon atoms, e.g., glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, and L-phenylalanine. One or more matrix-forming agents may be incorporated into the solution or suspension before solidification (freezing). The matrix-forming agent may be present in addition to the surfactant or in the absence of the surfactant. In addition to forming a matrix, the matrix-forming agent can help maintain the dispersion of any of the active ingredients in the suspension solution. This is particularly useful for surfactants that do not dissolve well in water and are therefore meant to be suspended rather than dissolved. Secondary components, such as preservatives, antioxidants, surfactants, viscosity improvers, colorants, flavorings, pH adjusters, sweeteners, or taste-masking agents, may also be incorporated into the rapidly dissolving composition. Suitable colorants include red, black, and yellow iron oxides, and FD&C dyes available from Ellis & Everard, such as FD&C Blue No. 2 and FD&C Red No. 40. Suitable flavorings include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavorings, as well as combinations thereof. Suitable pH adjusters include edible acids and bases, such as citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, and sodium hydroxide. Suitable sweeteners include, for example, sucralose, aspartame, acetone potassium, and thaumatin. Suitable taste-masking agents include, for example, sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents, or microencapsulated active substances.

[0065] Typical routes of administration of the pharmaceutical compositions of the present invention include, but are not limited to, oral, topical, transdermal, inhalation, non-enteral, sublingual, rectal, vaginal, and intranasal administration. The term "non-enteral" as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection, or infusion methods. Pharmaceutical compositions according to specific embodiments of the present invention are formulated so that the active ingredients contained therein are bioavailable when the composition is administered to a patient. The subject or composition administered to a patient may take one or more unit dosage forms. Practical methods for preparing such dosage forms will be known or evident to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).

[0066] Solid compositions are typically formulated in dosage units that provide approximately 1 to 10,000 mg of the active ingredient per dose. Some examples of solid dosage units include 0.1 mg, 1 mg, 10 mg, 37.5 mg, 75 mg, 100 mg, 150 mg, 300 mg, 500 mg, 600 mg, and 1,000 mg. Typical dose ranges according to the present invention are approximately 10 to 600 mg, 25 to 300 mg, 25 to 150 mg, 50 to 100 mg, 60 to 90 mg, and 70 to 80 mg. Liquid compositions generally have a unit dosage range of 1 to 100 mg / mL. Some examples of liquid dosage units include 0.1 mg / mL, 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, and 100 mg / mL.

[0067] In some embodiments, the method may involve administering one or more additional agents to the subject simultaneously with or sequentially with rimegepant. In some embodiments, the additional agents may be antiheading agents known in the art, such as exemplary antiheading agents (e.g., 5-HT1 agonists, triptans, ergot alkaloids, opiates, adrenaline antagonists, NSAIDs, or antibodies). In some embodiments, the therapeutic effect may be higher than that of using rimegepant or one or more additional agonists alone. Thus, a synergistic effect can be achieved between rimegepant and one or more additional agents. In some embodiments, one or more additional agents may be administered prophylactically to the subject.

[0068] In addition to migraines, other CGRP-related disorders that can be treated by the pharmaceutical compositions and methods of the present invention include, for example, cluster headaches; chronic tension headaches; chronic pain; neurogenic inflammation and inflammatory pain; eye pain; toothache; non-insulin-dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial reactivity; asthma; shock; sepsis; opioid withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis, brain injury, ischemia, stroke, epilepsy and neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, rosacea and erythema; tinnitus; obesity; inflammatory bowel disease; irritable bowel syndrome; and cystitis.

[0069] In one embodiment, the present invention also provides a kit for use in an instant method. The kit may include one or more containers containing the pharmaceutical composition described herein and instructions for use by any of the methods described herein. Generally, these instructions for use include instructions for administering the pharmaceutical composition by any of the methods described herein to treat, improve or prevent headaches (such as migraines) or other CRGP disorders. The kit may also include instructions for selecting an individual suitable for treatment, for example, based on identifying whether the individual has a headache or is at risk of developing a headache. Instructions for use are generally provided in the form of a package insert or label, in accordance with the requirements of the competent regulatory authority for the jurisdiction in which the pharmaceutical composition is to be delivered to the patient.

[0070] In the present invention, administering a pharmaceutical composition containing rimegepant to a subject may promote a reduction in severity (e.g., a reduction in the need for and / or amount (e.g., exposure to) other drugs and / or treatments commonly used for this condition, including ergotamine, dihydroergotamine, or triptans for migraines), duration, and / or frequency (e.g., a reduction in the time to the next transient attack in the individual).

[0071] Furthermore, administering a pharmaceutical composition containing rimegepant to a subject may promote the reduction or improvement of one or more headache symptoms, or a decrease in the duration of symptoms, compared to not administering the composition.

[0072] Furthermore, administering a pharmaceutical composition containing rimegepant to a subject can promote a reduction in the frequency of headache attacks in an individual over a specific period, for example, per month (compared to pre-treatment levels). For example, the frequency of attacks may be reduced in an individual by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, or 70% compared to pre-treatment levels.

[0073] Furthermore, administering a pharmaceutical composition containing rimegepant to a subject can facilitate the delay of headache onset, i.e., prolong, slow, delay, stabilize, and / or prolong the progression of the disease. The length of this delay may vary depending on the medical history and / or the individual receiving treatment.

[0074] Furthermore, administering a pharmaceutical composition containing rimegepant to a subject can delay the onset or progression of headache, that is, delay the progression of initial symptoms and / or subsequent disorders. The onset of headache can be detected and evaluated using standard clinical techniques well known in the art. [Examples]

[0075] The following examples illustrate the present invention and are not intended to limit its scope.

[0076] Example 1 Tablet manufacturing - Prepare a batch as follows to produce tablets containing a 75 mg dose of rimegepant. The batch composition is shown in Table 1 below. Produce tablets from the batch as shown.

[0077] [Table 1]

[0078] 1. Weigh out the rimegepanthemisulfate sesquihydrate and all additives. 2. Pass rimegepanthemisulfate sesquihydrate, microcrystalline cellulose (inside the granules), hydroxypropyl cellulose, and croscarmellose sodium (inside the granules) through a 20-mesh screen. 3. Load the sifted mixture from step 2 into a suitable granulator equipped with a bowl of appropriate size and dry mix for 10 minutes. 4. While mixing, equip the granulator with a spray tip and add purified water until it reaches the endpoint. 5. With the impeller and chopper set to low, mix the wet mass for 30 seconds. 6. Discharge the wet mass into the expansion chamber of the fluid bed dryer. Dry to a target LOD < 2%. 7. Grind the dry granules using a Comil equipped with a suitable screen (0.075R) and spacer (0.050). Perform analysis of bulk and tap density and particle size distribution. Record the results. Calculate the Carr index and the average Carr index from two samples. 8. Calculate the fractionation yield. Recalculate the amount of off-grain material. 9. Pass the microcrystalline cellulose and croscarmellose through a 20-mesh screen. 10. Using a 2-cubic foot tote & blend, combine the ground granules with recalculated microcrystalline cellulose (external component of granules) and croscarmellose sodium (external component of granules), and rotate 150 times. 11. Pass the magnesium stearate through a 30-mesh screen. 12. Place the screened magnesium stearate into a 2-cubic foot tote & blend and rotate 75 times. 13. Collect a mixed homogeneous sample for each plan. 14. Analyze bulk and tap densities and particle size distribution, and calculate the Carr index. 15. Discard into a suitable container and weigh. Install a 716-station rotary tablet press with 16.7mm round concave plain woolen linings. Adjust the number of stations as needed. 17. Adjust the press to achieve the following tablet specifications: abrasion loss ≤ 0.3%; hardness: 10-14kP; thickness: 3.60-4.10mm; disintegration ≥ 2:30 min. 18. Conduct in-process testing on the following items: • Degree of wear and collapse at the start, middle, and end of the work. • Tablet hardness, tablet thickness, individual tablet weight, average tablet weight, appearance at 15-minute intervals 19. Pass the tablets through a dust remover and a metal detector. 20. Package the tablets in a double polyethylene bag inside an appropriate container.

[0079] Example 2 Clinical trials -BHV3000-301: Phase 3: A double-blind, randomized, placebo-controlled safety and efficacy trial of BHV-3000 (rimegepant) for the acute treatment of migraine (clinicals.gov identifier: NCT03235479)

[0080] A Phase 3 clinical trial was conducted with 1,490 participants, as described below.

[0081] Research Description The purpose of this study was to compare the efficacy of BHV-3000 (rimezepant) with placebo in patients with acute migraine.

[0082] [Table 2]

[0083] [Table 3]

[0084] [Table 4]

[0085] Evaluation items and measurement criteria Primary outcome criteria: 1. Pain relief from rimegepant (75 mg tablets) in the acute treatment of migraine will be measured compared to placebo using the number of evaluable subjects who reported pain-free status 2 hours after administration. [Time frame: 2 hours after administration] Pain is measured using a 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe). 2. Relief from the most troublesome symptoms (MBS) with rimegepant (75 mg tablets) will be measured compared to placebo using the number of evaluable subjects who reported no MBS 2 hours after administration. [Time frame: 2 hours after administration] MBS (Nausea, Soundphobia, or Photophobia) is measured using binary code (0 = Absence, 1 = Presence).

[0086] Secondary outcome criteria: 1. Using the number of subjects who did not experience headache pain during the study period, we will measure the difference between rimegepant (75 mg tablet) and placebo from 2 hours to 24 hours after administration. [Time frame: 2 hours to 24 hours after administration] Relief from persistent pain, measured by a 4-point numerical rating scale (none, mild, moderate, severe). 2. Differences between rimegepant (75 mg tablet) and placebo, calculated by counting the absence of photophobia at 2 hours post-administration in a subset of subjects who reported the presence of photophobia at baseline for headache. [Time frame: 2 hours post-administration] photophobia 3. In a subset of subjects who reported the presence of phonophobia at baseline for headache, rimegepant (75 mg tablet) was evaluated compared to placebo by counting the number of subjects who reported the absence of phonophobia 2 hours after administration. [Time frame: 2 hours after administration] phonophobia 4. Measure the difference in pain relief between rimegepant (75 mg tablet) and placebo at 2 hours post-administration in patients who reported moderate or severe pain at baseline and subsequently reported no or mild pain. [Time frame: 2 hours post-administration] Pain relief is measured using a 4-point numerical rating scale (none, mild, moderate, severe). 5. Relief from nausea by counting the number of subjects who reported the absence of nausea 2 hours after administration in a subset of subjects who reported the presence of nausea at baseline for headache. [Time frame: 2 hours after administration] Liberation from evil thoughts 6. Differences between rimegepant (75 mg tablet) and placebo in the probability of needing emergency medication, using the number of subjects who took emergency medication (BHV3000 or placebo) within 24 hours after administration of the study drug. [Time frame: up to 24 hours after administration] Emergency medicine is needed.

[0087] 7. Using the number of subjects who did not experience headache pain during the study period, the difference between rimegepant (75 mg tablet) and placebo in relief from persistent pain for 2 to 48 hours will be measured. [Time frame: 2 to 24 hours after administration] Relief from persistent pain 8. Rimegepant (75 mg tablets) compared to placebo in sustained pain relief over 2 to 24 hours, using a number of subjects who did not use any emergency medication and did not experience moderate or severe headache pain during that period. [Time frame: 2 to 24 hours after administration] Sustained pain relief measured by a 4-point numerical rating scale (none, mild, moderate, severe) 9. Using a number of subjects who did not use any emergency medication and did not experience moderate to severe headache pain, measure the difference between rimegepant (75 mg tablet) and placebo in sustained pain relief from 2 hours to 48 hours. [Time frame: 2 hours to 48 hours after administration] Sustained pain relief measured by a 4-point numerical rating scale (none, mild, moderate, severe) 10. Using the number of subjects who self-reported "normal" on the functional impairment scale, the relative difference between rimegepant (75 mg tablet) and placebo will be measured in the proportion of subjects who were able to function normally after 2 hours. Functional impairment score 11. The difference in pain recurrence between rimegepant (75 mg tablet) and placebo will be measured using the number of subjects who were painless 2 hours after administration of the study drug and subsequently experienced headache of any severity within 48 hours. [Time frame: 2 hours to 48 hours after administration] Pain recurrence (none, mild, moderate, severe) is measured using a 4-point numerical rating scale.

[0088] For details on the clinical trial, including eligibility criteria, contact information and location, and more information, please see below. www.clinicaltrials.gov This can be confirmed using the clinical trials.gov identifier: NCT03235479.

[0089] Example 3 Clinical trials - BHV3000-302: Phase 3: A double-blind, randomized, placebo-controlled safety and efficacy study of BHV-3000 (rimegepant) in the acute treatment of migraine (clinicals.gov identifier: NCT03237845)

[0090] A Phase 3 clinical trial was conducted with 1,503 participants, as described below.

[0091] Exam Description overview: The purpose of this study was to compare the efficacy of BHV-3000 (rimegepant) with placebo in subjects with acute migraine.

[0092] [Table 5]

[0093] [Table 6]

[0094] [Table 7]

[0095] Evaluation items and measurement criteria Primary outcome criteria: 1. Pain relief from rimegepant (75 mg tablets) in the acute treatment of migraine will be measured compared to placebo using the number of evaluable subjects who reported pain-free status 2 hours after administration. [Time frame: 2 hours after administration] Pain is measured using a 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe). 2. Relief from the most troublesome symptoms (MBS) with rimegepant (75 mg tablets) will be measured compared to placebo using the number of evaluable subjects who reported no MBS 2 hours after administration. [Time frame: 2 hours after administration]

[0096] MBS (Nausea, Soundphobia, or Photophobia) is measured using binary code (0 = Absence, 1 = Presence).

[0097] Secondary outcome criteria: 1. Rimegepant (75 mg tablets) was compared to placebo over a 2-24 hour period using the number of subjects who did not experience headache pain during the study period. [Time frame: 2-24 hours after administration] Relief from persistent pain, measured by a 4-point numerical rating scale (none, mild, moderate, severe). 2. Rimegepant (75 mg tablets) compared to placebo, calculated by counting the number of subjects who reported the absence of photophobia 2 hours after administration in a subset of subjects who reported the presence of photophobia at baseline for headache. [Time frame: 2 hours after administration] Freedom from photophobia 3. Rimegepant (75 mg tablet) compared to placebo, calculated by counting the number of subjects who reported the absence of phonophobia 2 hours after administration in a subset of subjects who reported the presence of phonophobia at baseline for headache. [Time frame: 2 hours after administration] Freedom from phonophobia 4. Participants reported moderate or severe pain at baseline, followed by no or mild pain, and the pain relief of remegepant was measured 2 hours after administration compared to placebo. [Time frame: 2 hours after administration] Pain relief is measured using a 4-point numerical rating scale (none, mild, moderate, severe). 5. Relief from nausea by counting the number of subjects who reported the absence of nausea 2 hours after administration in a subset of subjects who reported the presence of nausea at baseline for headache. [Time frame: 2 hours after administration] Liberation from evil thoughts

[0098] 6. The comparative measurement of the probability of requiring emergency medication with rimegepant compared to placebo will be evaluated using the number of subjects who took emergency medication within 24 hours after administration of the study drug (BHV3000 or placebo). [Time frame: up to 24 hours after administration] Emergency medicine is needed. 7. Using the number of subjects who did not experience headache pain during the study period, the effectiveness of rimegepant (75 mg tablet) in relieving persistent pain for 2 to 48 hours will be measured compared to placebo. [Time frame: 2 to 24 hours after administration] Sustained pain relief, measured using a four-level numerical rating scale (none, mild, moderate, severe). 8. Rimegepant (75 mg tablet) compared to placebo for sustained pain relief over 2 to 24 hours, using a number of subjects who did not experience moderate or severe headache pain during the period without using any emergency medication. [Time frame: 2 to 24 hours after administration] Sustained pain relief measured by a 4-point numerical rating scale (none, mild, moderate, severe) 9. Rimegepant (75 mg tablets) compared to placebo for sustained pain relief from 2 hours to 48 hours, using a number of subjects who did not use any emergency medication and did not experience moderate to severe headache pain. [Time frame: 2 hours to 48 hours after administration] Sustained pain relief measured by a 4-point numerical rating scale (none, mild, moderate, severe) 10. The proportion of subjects who were able to function normally after 2 hours, compared to placebo, using the number of subjects who self-reported "normal" on the functional impairment scale, for rimegepant (75 mg tablets). Functional impairment score 11. Rimegepant (75 mg tablets) compared to placebo in terms of pain recurrence, using the number of subjects who were painless 2 hours after administration of the study drug and subsequently experienced headache of any severity within 48 hours. [Time frame: 2 hours to 48 hours after administration] Pain recurrence (none, mild, moderate, severe) is measured using a 4-point numerical rating scale.

[0099] For details on the clinical trial, including eligibility criteria, contact information and location, and more information, please see below. www.clinicaltrials.gov This can be confirmed using the clinical trials.gov identifier: NCT03237845.

[0100] Example 4 Results of clinical trials -The results of the clinical trials described in Examples 2 and 3 are shown in Figures 1 and 2, and in Tables 2, 3, and 4.

[0101] [Table 8]

[0102] [Table 9]

[0103] [Table 10]

[0104] Example 5 bioequivalence -The bioequivalence of the oral solid-molded fast-dispersion dosage form ("ODT") prepared with a 75 mg dose of rimegepant using fish gelatin as described herein was compared to the 75 mg tablet used in the studies described in Examples 2 and 3.

[0105] The experiment is outlined below.

[0106] Main purpose : To compare the absorption rate and degree of absorption in healthy volunteers when rimegepant ODT is administered sublingually at a dose of 1 x 75 mg on an empty stomach, compared to when rimegepant tablets are administered.

[0107] Secondary purpose : The safety, tolerability, and pharmacokinetics of rimegepant tablets and ODT will be evaluated.

[0108] Exploratory objectives : This study compares the absorption rate and degree of absorption of rimegepant orally disintegrating tablets (1 x 75 mg) administered orally to healthy volunteers on an empty stomach.

[0109] Test design This is a single-center, open-label, randomized phase 1 trial conducted as follows: Part I: 4-phase, 2-sequence, full replication crossover bioequivalence study. Part II: A two-phase, two-sequence, crossover relative bioavailability study. Part II may be performed before Part I.

[0110] This trial is intended to submit applications under the regulations of the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Health Products and Foods Sector (HPFB).

[0111] Each part of this study is intended to be administered to one group. If, for any reason, any part is administered to multiple groups, all groups will be administered in the same clinical setting, and each group will follow the same protocol requirements and procedures.

[0112] Number of cases (sample size) Approximately 60 healthy adult male or female volunteers will be administered the drug. Approximately 36 subjects will be included in the Part I bioequivalence study. Based on preliminary data from previous studies, the within-subject coefficients of variation are AUC and C. maxBoth should be approximately 30%. Therefore, the expected coefficient of variation and AUC and C are as follows. max If the expected ratios are within 0.91 and 1.10, this trial should have at least 80% power to demonstrate bioequivalence in 30 subjects in a 4-phase fully replicated design, in the order of the trials.

[0113] Approximately 24 subjects will be included in Part II, the relative bioavailability portion of the study.

[0114] Restrictions and washout Part I Subjects are restricted from at least 10 hours before the first dose of the drug until after blood collection 72 hours after the fourth dose, i.e., until the morning of day 22.

[0115] There will be a washout period of 5 days or more between doses, during which subjects will be confined to the clinic. Each subject's participation in this study should last approximately 3 weeks.

[0116] Part II Subjects are restricted from at least 10 hours before the first dose of the drug until after blood collection 72 hours after the second dose, i.e., until the morning of day 8.

[0117] There will be a washout period of 4 days or more between doses, during which subjects will be confined to the clinic for the entire washout period. Participation in this study should last approximately 1.5 weeks for each subject.

[0118] Randomized and blinded In Parts I and II, each treatment will be administered to subjects according to the 4-phase 2-sequence (CBCB or BCBC) and 2-phase 2-sequence (CA or AC) block randomization schemes developed by inVentiv. The randomization codes will not be available to inVentiv's bioanalysis department until the clinical and analytical phases of the study are completed.

[0119] This study will be open-label due to the objective nature of the data.

[0120] Test reagent Part I Each subject will receive each of the following two procedures twice: Procedure C (Test): Hold 1x75 mg of rimegepant sublingual ODT under the tongue until completely dissolved, then swallow without water. Administer on an empty stomach. Treatment B (standard): Administer 1 x 75 mg rimegepant tablet with water on an empty stomach.

[0121] Part II Each subject will receive one of the following two treatments: Procedure C (Test): Hold 1x75 mg of rimegepant sublingual ODT under the tongue until completely dissolved, then swallow without water. Administer on an empty stomach. Procedure A (standard): Hold 1 x 75 mg of rimegepant ODT on the tongue until completely dissolved, then swallow without water. Administer on an empty stomach.

[0122] Part I Treatment C Clinical staff place one rimegepant ODT under each subject's tongue and instruct subjects not to swallow saliva until the ODT is completely dissolved. Subjects are instructed to give a hand sign when the ODT is completely dissolved and swallowed. Hands and mouth are checked to ensure medication intake.

[0123] The administration time is set to the time it takes for the ODT to be placed under the tongue. Water use is prohibited from 1 hour before administration until 1 hour after administration. The complete administration process should be completed within 2 minutes. If the ODT does not completely dissolve within 2 minutes, the subject should be instructed to swallow it with saliva, and this event should be recorded. The start and end times of complete administration should be recorded.

[0124] Treatment B Each subject was given one rimegepant tablet in 240 mL of water, and their hands and mouth were checked to ensure that the medication was taken.

[0125] Part II Treatment C Clinical staff place one rimegepant ODT under each subject's tongue and instruct subjects not to swallow saliva until the ODT is completely dissolved. Subjects are instructed to give a hand sign when the ODT is completely dissolved and swallowed. Hands and mouth are checked to ensure medication intake.

[0126] The administration time should be set to the time it takes for the ODT to be placed under the tongue. Water use is prohibited from one hour before administration until one hour after administration. The complete administration process should be completed within two minutes. If the ODT does not dissolve completely within two minutes, the subject should be instructed to swallow it with saliva, and this event should be recorded. The start and end times of complete administration should be recorded.

[0127] Procedure A Clinical staff place one rimegepant ODT on each subject's tongue and instruct subjects not to swallow saliva until the ODT is completely dissolved. Subjects are instructed to give a hand sign when the ODT has completely dissolved and been swallowed. Hands and mouth are checked to ensure medication intake.

[0128] The administration time is set to the time it takes for the ODT to be placed on the tongue. Water use is prohibited from 1 hour before administration until 1 hour after administration. The complete administration process should be completed within 2 minutes. If the ODT does not completely dissolve within 2 minutes, the subject should be instructed to swallow it with saliva, and this event should be recorded. The start and end times of complete administration should be recorded.

[0129] Sample collection and processing During each period, a total of 17 blood samples will be collected from each subject for pharmacokinetic analysis. Blood samples will be collected before drug administration and at 0.083, 0.167, 0.333, 0.5, 0.667, 0.833, 1, 1.5, 2, 2.5, 5, 8, 12, 24, 48, and 72 hours after administration (3 mL per sampling time). The time tolerance for blood sample collection is ±29 seconds for all post-administration samples collected during the containment period. Sample collection performed outside the predefined time frame will not be considered a protocol deviation, as the actual post-administration collection time will be used for pharmacokinetic and statistical analysis. Unless otherwise specified, or for the safety of the subject, blood collection will take precedence if it overlaps with other procedures. Where appropriate, a dead-volume intravenous catheter will be used for blood collection to avoid multiple skin punctures. Otherwise, blood samples are collected by direct venipuncture.

[0130] The total blood volume, including blood collected for eligibility, genotyping, and safety purposes, must not exceed 308 mL in Part I and 185 mL in Part II.

[0131] A plasma sample is collected and processed.

[0132] Pharmacokinetics and statistical analysis PK analysis will be performed using Phoenix® WinNonlin®, which is effective for bioequivalence / bioavailability testing. Inferential statistical analysis will be performed using SAS® in accordance with FDA, EMA, and HPFB guidelines.

[0133] Before commencing pharmacokinetic and statistical analyses, all samples must be subjected to complete bioanalysis.

[0134] Pharmacokinetics In the limegepant, the following PK parameters are calculated using the standard non-compartmental method: AUC 0-tArea under the concentration-time curve from 0 to the last non-0 time point AUC 0-inf Area under the concentration-time curve from 0 to infinity (estimated value) ·C max : Highest concentration measured ·Remaining area: 100*(1-AUC 0-t / AUC 0-inf ) is calculated ·T max : Measured C max time ·T 1 / 2 el: Emission half-life ·Kel: Discharge rate constant

[0135] Additional PK analysis may be performed.

[0136] Safety Population (the population targeted for safety analysis) The population included in the safety analysis is defined as all subjects who received at least one dose of the investigational drug.

[0137] Pharmacokinetic population In Part I, the pharmacokinetic population includes all subjects who have completed at least two periods, including Treatment C and Treatment B, and whose pharmacokinetic profiles can be adequately characterized.

[0138] In Part II, the pharmacokinetic population includes all subjects who complete the study and whose pharmacokinetic profiles can be adequately characterized.

[0139] In subjects with pre-administration concentrations, the pre-administration concentration was measured at C max If the value exceeds 5%, it will be recorded in the concentration table and PK table, but will be excluded from the descriptive statistical analysis and inferential analysis (for the relevant period in Part I).

[0140] Data from subjects who experienced vomiting during the sampling interval and did not withdraw their reports may be evaluated after the completion of the PK analysis. The median T of the remegepant is... maxParticipants who experienced vomiting within twice the specified period will be excluded from statistical analysis (i.e., descriptive statistical analysis and inferential analysis). Similarly, participants who withdrew due to AE or vomiting episodes will be included in the data list but excluded from the statistical analysis table (for the relevant period in Part I).

[0141] statistical analysis The statistical analysis plan (SAP) is created after the final protocol is completed and decided before the database lock is executed.

[0142] Demographic parameters will be summarized descriptively. Triadically adverse events (TEAEs) occurring during treatment will be summarized descriptively for each treatment, covering all subjects who received the treatment (the safety analysis population). Inferential statistical analysis of safety data is not planned.

[0143] Individual and mean plasma concentration-versus-time curves are shown on both linear and semi-logarithmic scales. Descriptive statistics for plasma concentration and PK parameters (arithmetic and geometric mean, standard deviation [SD], coefficient of variation [CV%], minimum [Min], maximum [Max], median) are shown.

[0144] The results of the bioequivalence experiment are shown in Tables 5, 6, and 7.

[0145] [Table 11]

[0146] [Table 12]

[0147] [Table 13]

[0148] Example 6 Effectiveness of Rimegepant -Clinical trial results and analysis- BHV3000-301 as described in Example 2.

[0149] the purpose To compare the efficacy, safety, and tolerability of rimegepant 75 mg oral tablets with placebo in the acute treatment of migraine in adults.

[0150] method In a double-blind, randomized, placebo-controlled, multicenter trial (Trial 301, NCT03235479), eligible participants were adults ≥18 years of age with at least one year of history of ICHD3-β migraine. After a 3–28 day screening period, participants were randomized to receive either rimegepant 75 mg or a matching placebo, and were instructed to treat one dose of the blinded study drug (rimegepant or placebo) per migraine attack when headache pain reached moderate or severe intensity. The coprimary endpoints were pain relief 2 hours post-administration and relief from the most troublesome symptom (MBS) 2 hours post-administration. Safety assessments included routine clinical examinations, including adverse events (AEs), ECG, vital signs, physical measurements, and liver function assessments. Unless otherwise noted, values ​​shown are mean ± SD.

[0151] result A total of 1162 subjects were randomized to receive either rimegepant (n=582) or placebo (n=580), and efficacy was evaluated in 1084 subjects (rimegepant n=543, placebo n=541). The subjects had a mean age of 41.6 ± 12.2 years, 85.5% were female, and had a history of 4.7 ± 1.8 seizures per month. Two hours after administration, rimegepant-treated patients showed a higher rate of painlessness (19.2% vs. 14.2%, P=0.0298), a higher likelihood of being free from MBS (36.6% vs. 27.7%, P=0.0016), and a higher rate of pain relief (56.0% vs. 45.7%, P=0.0006) than placebo-treated patients. A single dose of rimegepant without the use of emergency medication demonstrated superiority over placebo in terms of relief from persistent pain and pain relief from 2 to 48 hours post-administration (P=.013 and P=.0003, respectively). In measuring functional impairment, the majority of patients treated with rimegepant achieved normal function within 2 hours (P<.0001).

[0152] The safety and tolerability profile of rimegepant was comparable to that of placebo. The most common adverse events were nausea (0.9%, 5 / 546 vs. 1.1%, 6 / 549) and dizziness (0.7%, 4 / 546 vs. 0.4%, 2 / 549). Serum ALT or AST levels exceeding the upper limit of normal (ULN) were observed in 2.0% (11 / 546) and 3.6% (20 / 549) of subjects treated with rimegepant and placebo, respectively. One subject (0.2%) in the rimegepant group and one subject (0.2%) in the placebo group had transaminases levels greater than 3 times the ULN, while no subjects in either group had levels greater than 5 times the ULN. No bilirubin elevations greater than 2 times the ULN were observed. Serious adverse events (SAEs) occurred in 0.4% (n=2) of subjects in the rimegepant group and 0.2% (n=1) of subjects in the placebo group. No SAEs were determined to be related to the study drug. Neither of the subjects in the rimegepant group who experienced SAEs had received the drug prior to the onset of the SAEs.

[0153] conclusion A single dose of rimegepant demonstrated significant and sustained clinical effects across multiple endpoints, including pain relief, MBS relief, pain reduction, and restoration of normal function. Rimegepant 75 mg oral tablets showed good tolerability and safety, including a liver safety profile comparable to placebo. These clinically meaningful results complement the benefits observed in the same Phase 3 trial (Trial 302) and previous Phase 2b trials. Ultimately, rimegepant may offer patients a novel approach for the acute treatment of migraine.

[0154] [Table 14]

[0155] Example 7 Effectiveness of Rimegepant -Results and analysis of the clinical trial BHV3000-302 described in Example 3.

[0156] the purpose To compare the efficacy, safety, and tolerability of rimegepant 75 mg oral tablets with placebo in the acute treatment of migraine in adults.

[0157] method In a double-blind, randomized, placebo-controlled, multicenter trial (Trial 302, NCT03237845), eligible participants were adults ≥18 years of age with at least one year of history of ICHD3-β migraine. After a 3–28 day screening period, participants were randomized to receive either rimegepant 75 mg or a matching placebo, and were instructed to treat one dose of the blinded study drug (rimegepant or placebo) per migraine attack when headache pain reached moderate or severe intensity. The coprimary endpoints were pain relief 2 hours post-administration and relief from the most troublesome symptom (MBS) 2 hours post-administration. Safety assessments included routine clinical examinations, including adverse events (AEs), ECG, vital signs, physical measurements, and liver function assessments. Unless otherwise noted, values ​​shown are mean ± SD.

[0158] result A total of 1186 subjects were randomized to receive either remegepant (n=594) or placebo (n=592), and efficacy was evaluated in 1072 subjects (rimegepant n=537, placebo n=535). The subjects had a mean age of 40.6 ± 12.0 years, 88.7% were female, and had a history of 4.6 ± 1.8 seizures per month. Two hours after administration, remegepant-treated patients showed a higher rate of painlessness (19.6% vs. 12.0%, P=.0006), a higher likelihood of MBS-free (37.6% vs. 25.2%, P<.0001), and a higher rate of pain relief (58.1% vs. 42.8%, P<.0001) than placebo-treated patients. A single dose of rimegepant without the use of emergency medication demonstrated superiority over placebo in terms of relief from persistent pain and pain relief from 2 to 48 hours post-administration (P=.0181 and P<.0001, respectively). In measuring functional impairment, the majority of patients treated with rimegepant achieved normal function within 2 hours (P<.0001).

[0159] The safety and tolerability profile of rimegepant was comparable to that of placebo. The most common adverse events (AEs) were nausea (1.8%, 10 / 543 vs. 1.1%, 6 / 543) and urinary tract infection (1.5%, 8 / 543 vs. 1.1%, 6 / 543). Serum ALT or AST levels exceeding the upper limit of normal (ULN) were observed in 2.4% (13 / 543) and 2.2% (12 / 543) of subjects treated with rimegepant and placebo, respectively. No subjects in either treatment group had transaminase levels exceeding 3 times the ULN, and no bilirubin elevations exceeding 2 times the ULN. One serious adverse event (SAE) (low back pain) was observed in the rimegepant group, and two in the placebo group. No SAEs were judged to be related to the study drug.

[0160] conclusion A single dose of rimegepant demonstrated significant and sustained clinical effects across multiple endpoints, including pain relief, MBS relief, pain reduction, and restoration of normal function. Rimegepant 75 mg oral tablets showed good tolerability and safety, including a liver safety profile comparable to placebo. These clinically meaningful results complement the benefits observed in Trial 301. Ultimately, rimegepant may offer patients a novel approach to the acute treatment of migraine.

[0161] [Table 15]

[0162] Example 8 Clinical trials - BHV3000-303: Phase 3: A double-blind, randomized, placebo-controlled safety and efficacy study of BHV-3000 (rimegepant) orally disintegrating tablets (ODT) in the acute treatment of migraine (clinicals.gov identifier: NCT03461757)

[0163] A Phase 3 clinical trial was conducted with 1812 participants, as described below.

[0164] Exam Description overview: The purpose of this study was to compare the efficacy of BHV-3000 (rimegepant ODT) with placebo in subjects with acute migraine.

[0165] [Table 16]

[0166] [Table 17]

[0167] [Table 18]

[0168] Evaluation items and measurement criteria Primary outcome criteria: 1. Pain relief from rimegepant in the acute treatment of migraine will be measured compared to placebo using the number of evaluable subjects who reported pain-free 2 hours after administration. [Time frame: 2 hours after administration] Pain relief is assessed using a 4-point numerical scale (0=none, 1=mild, 2=moderate, 3=severe). It is measured by [method]. 2. Relief from the most troublesome symptoms (MBS) of remegepant will be measured compared to placebo using the number of evaluable subjects who reported no MBS 2 hours after administration. [Time frame: 2 hours after administration] MBS (Nausea, Soundphobia, or Photophobia) is measured using binary code (0 = Absence, 1 = Presence).

[0169] Secondary outcome criteria: 1. Remegepant pain relief at 2 hours post-administration was measured compared to placebo, with participants reporting moderate or severe pain levels at baseline, followed by no or mild pain levels. [Time frame: 2 hours post-administration] Pain relief is measured using a 4-point numerical rating scale (none, mild, moderate, severe). 2. Disability scale [Time frame: 2 hours after administration] In the disability scale, the subjects self-reported that they were "normal." 3. Rimegepant compared to placebo for sustained pain relief over 2 to 24 hours, using a number of subjects who did not use any emergency medication and did not experience moderate or severe headache pain during that period. [Time frame: 2 to 24 hours after administration] Sustained pain relief measured by a 4-point numerical rating scale (none, mild, moderate, severe) 4. Evaluate sustained relief from the most troublesome symptoms during the 2-24 hour period, using the number of subjects who did not experience the most troublesome symptoms during the following timeframe: [Time frame: 2 hours to 24 hours after administration] The most troublesome symptoms 5. The comparative measurement of the probability of requiring emergency medication with rimegepant compared to placebo will be evaluated using the number of subjects who took emergency medication within 24 hours after administration of the study drug (BHV3000 or placebo). [Time frame: up to 24 hours after administration] Emergency medicine is needed. 6. Sustained ability to function at a normal level, as measured by the disability scale. [Time frame: 2 to 24 hours after administration] In the disability scale, the subject self-reports as "normal". 7. Rimegepant compared to placebo for sustained pain relief over 2 to 48 hours in subjects who did not use any emergency medication and did not experience moderate to severe headache pain. [Time frame: 2 to 48 hours post-administration] Sustained pain relief, measured using a four-level numerical rating scale (none, mild, moderate, severe). 8. Rimegepant compared to placebo in relief from the most troublesome symptoms 2 to 48 hours after administration. [Time frame: 2 to 48 hours after administration] The most troublesome symptoms 9. Sustained ability to function at a normal level, as measured by the disability scale. [Time frame: 2 to 24 hours after administration] In the disability scale, the subject self-reports as "normal". 10. Rimegepant compared to placebo, calculated by counting the number of subjects who reported the absence of photophobia at 2 hours post-administration in a subset of subjects who reported the presence of photophobia at baseline for headache. [Time frame: 2 hours post-administration] Freedom from photophobia

[0170] 11. Disability Scale [Time frame: 90 minutes after administration] In the disability scale, the subjects self-reported that they were "normal." 12. Rimegepant compared to placebo for sustained pain relief over 90 minutes in subjects who did not use any emergency medication and did not experience moderate to severe headache pain. [Time frame: 90 minutes after administration] Sustained pain relief, measured using a four-level numerical rating scale (none, mild, moderate, severe). 13. Rimegepant compared to placebo over a 2-24 hour period, using the number of subjects who did not experience headache pain during the study period. [Time frame: 2-24 hours after administration] Relief from persistent pain, measured by a 4-point numerical rating scale (none, mild, moderate, severe). 14. Sustained relief from the most troublesome symptom at 90 minutes, assessed using the number of subjects who did not experience the most troublesome symptom during the following period. [Time frame: 90 minutes after administration] The most troublesome symptoms 15. Relief from persistent pain 90 minutes after administration of rimegepant will be observed using the number of subjects who did not experience headache pain during the study period. [Time frame: 90 minutes after administration] Relief from persistent pain, measured by a 4-point numerical rating scale. 16. Rimegepant compared to placebo, calculated by counting the number of subjects who reported the absence of phonophobia 2 hours after administration in a subset of subjects who reported the presence of phonophobia at baseline for headache. [Time frame: 2 hours after administration] Freedom from phonophobia 17. Relief from persistent pain for 2 to 48 hours using rimegepant compared to placebo will be observed using the number of subjects who did not experience headache pain during the control period. [Time frame: 2 to 48 hours after administration] Relief from persistent pain, measured by a 4-point numerical rating scale (none, mild, moderate, severe). 18. For pain relief, rimegepant should be observed compared to placebo in patients who reported moderate or severe pain at baseline 60 minutes after administration, and subsequently reported no or mild pain. [Time frame: 60 minutes after administration] Sustained pain relief measured by a 4-point numerical rating scale (none, mild, moderate, severe) 19. Functional impairment scale [Time frame: 60 minutes after administration] In the disability scale, the subjects self-reported that they were "normal." 20. Relief from nausea was assessed by counting the number of subjects who reported the absence of nausea 2 hours after administration in a subset of subjects who reported the presence of phonophobia at baseline for headache. [Time frame: 2 hours after administration] Liberation from evil thoughts 21. Evaluate the number of subjects who were painless 2 hours after administration of the study drug, rimegepant, or placebo, and who subsequently experienced headache of any severity (response 1, 2, or 3 on a 4-point scale) within 48 hours. [Time frame: 2 hours to 48 hours after administration] Pain recurrence

[0171] For details on the clinical trial, including eligibility criteria, contact information and location, and more information, please see below. www.clinicaltrials.gov This can be confirmed using the clinical trials.gov identifier: NCT03461757.

[0172] Example 9 The results of the clinical trial described in Example 8 are summarized as follows. In the 303 trial, the co-primary registration endpoints of pain relief and relief from the most bothersome symptoms (MBS) were achieved within 2 hours by single-dose administration (Table 8). Importantly, patients treated with the rimegepant Zydis ODT formulation according to the present invention began to numerically separate from the placebo with respect to pain relief as early as 15 minutes and showed statistical significance by 60 minutes (p<0.0001) (see Figure 5). Figure 5 shows the percentage of patients who experienced pain relief between 0 and 2 hours after administration for patients administered a single dose of rimegepant Zydis ODT 75mg or placebo. The data are Kaplan-Meier exploratory estimates that include pain relief defined as patients having mild pain or no pain during a specific interval. Subjects who took rescue medication during a specific interval or who failed follow-up were censored. Also, compared to placebo, patients treated with rimegepant Zydis ODT returned to normal function at a significantly higher rate within 60 minutes (p<0.002). Compared to placebo, persistent clinical utility was observed in pain relief (p<0.001), relief from pain (p<0.001), the most bothersome symptoms (p<0.001), dysfunction (p<0.003) and several other secondary endpoints during the 48 hours after a single dose of rimegepant. The majority (85%) of patients treated with rimegepant Zydis ODT did not use any rescue medication.

[0173]

Table 19

[0174] In Study 303, rimegepant Zydis ODT, which was statistically distinguishable from placebo on two primary measures, and the first 21 consecutive secondary measure criteria were pre-specified in a hierarchical test (p-value<0.05). These secondary measure criteria and additional exploratory measure criteria for this study are scheduled to be presented at scientific meetings scheduled for 2019.

[0175] The safety and tolerability of rimegepant in Study 303 were consistent with the profiles previously observed in Study 301 (Example 2) and Study 302 (Example 3). Table 9 shows pooled safety data across all three studies. No single adverse event (AE) occurred in the rimegepant group with an incidence rate exceeding 1.6%, and the overall incidence rate of AEs was similar to that of placebo. Regarding liver function tests, in Study 303, one patient treated with placebo and one patient treated with rimegepant showed LFT > 3x ULN. The results of pooled liver function tests across three important studies (n = 3,556) conducted to date show that rimegepant is similar to placebo with respect to aminotransferase (ALT or AST) levels exceeding the upper limit of normal (ULN), and no patient experienced an increase in bilirubin > 2x ULN (Table 10).

[0176]

Table 20

[0177]

Table 21

[0178] Further results of the clinical study (Study 303) described in Example 8 are shown in Tables 11, 12, and Figure 6.

[0179]

Table 22

[0180]

Table 23

[0181] Example 10 Clinical trials - BHV3000-201: Open-Label Safety Study in the Acute Treatment of Migraine (ClinicalTrials.gov Identifier: NCT03266588)

[0182] A Phase 2 / 3 clinical trial as described below will be conducted on approximately 2,000 participants.

[0183] Description of the Trial Summary: The purpose of this trial is to evaluate the safety and tolerability of BHV3000 (rimezepant).

[0184] [Table 24]

[0185] [Table 25]

[0186] [Table 26]

[0187] Evaluation Item Measurement Criteria Primary Evaluation Item Measurement Criteria: 1. Evaluate the safety and tolerability of rimezepant (BHV-3000) by measuring the frequency and severity of adverse events and the presence or absence of discontinuation due to adverse events [Time Frame: 52 weeks] Number of subjects in whom adverse events occurred during treatment, evaluated by clinical examinations, ECG, and physical examination findings (safety and tolerability).

[0188] Secondary Evaluation Item Measurement Criteria: 1. High values in liver function tests: ALT or AST > 3x ULN, total bilirubin > 2x ULN [Time Frame: 52 weeks] 2. Liver-related adverse events and liver-related adverse events that caused discontinuation [Time Frame: 52 weeks] Liver-related adverse events

[0189] Details regarding the clinical trial, including inclusion criteria, contact information and location, and more information, can be www.clinicaltrials.gov found at the clinicaltrials.gov identifier: NCT03266588.

[0190] Example 11 The results of the clinical trial described in Example 10 are summarized below. Trial BHV3000-201 showed the first positive results. An interim analysis (database cutoff November 21, 2018) showed that the safety and tolerability of long-term administration of rimegepant in migraine patients were consistent with the profile observed in previous Phase 1-3 trials. Patients were allowed to treat migraine attacks of all severity levels (mild to severe) up to once daily for one year. Initial hepatic safety and tolerability results for rimegepant 75 mg in trial participants are based on both adverse events and regularly scheduled liver function tests. Interim liver data were reviewed by an external, independent liver specialist panel. No liver cases were assessed as potentially related to the study drug, and no Hy's Law cases were identified. The panel concluded that no liver safety signals have been detected to date, including in a subset of patients receiving nearly daily administration (15 times / month). Overall, it was noted that the incidence of overall elevation in liver function test abnormalities was very low in patients treated with rimegepant compared to migraine trials using drugs other than rimegepant (incidence of serum ALT or AST > 3xULN: 1.0%). Participants will continue to participate in trial 201, submit additional data analysis to the NDA, and require a 120-day safety update.

[0191] In addition to the interim safety analysis, the subjects' data were evaluated to confirm the reduction in headache days per month. The data shown in the table indicate that patients experienced fewer headache days per month while taking rimegepant during the treatment phase compared to the observation phase of the study. For example, of 1731 subjects, 683 (39.5%) experienced at least a 20% reduction in headache days per month, 602 (34.8%) experienced at least a 25% reduction, 523 (30.2%) experienced at least a 30% reduction, 442 (25.5%) experienced at least a 35% reduction, 362 (20.9%) experienced at least a 40% reduction, 287 (16.6%) experienced at least a 45% reduction, and 226 (13.1%) experienced at least a 50% reduction. These results were surprising and unexpected, suggesting that remegepant can function as both a preventative and acute treatment for migraines. A reduction in the average number of headache days per month was observed as early as the first month and continued throughout the following months of treatment.

[0192] Accordingly, in the present invention, patients suffering from migraines may be treated by administering rimegepant, for example, at a dose of 75 mg, at a frequency of, for example, once, twice, three, four, five or more times a month, ten or more times a month, or fifteen or more times a month, to reduce the number of headaches per month, for example, by 20% or more.

[0193] [Table 27]

[0194] In this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are incorporated into this application by whole reference to more fully illustrate the latest art known to those skilled in the art as of the date of the inventions described herein and claimed herein. However, the citation of references herein should not be construed as an admission that such references are prior art of the present invention.

[0195] Those skilled in the art will recognize or confirm, through ordinary experimentation, that there are numerous equivalents to the specific operations described herein. Such equivalents are considered to fall within the scope of the present invention and are encompassed within the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed herein may be used. Furthermore, specific items within the list of items, or subsets of items within larger groups of items, are intended to be combined with other specific items, subsets of items, or larger groups of items, regardless of whether specific disclosures identifying such combinations are present herein.

Claims

1. A method for treating migraine in a patient requiring treatment, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, such that the number of migraine episodes per month in the patient is reduced by at least 20%.

2. The method according to claim 1, which reduces the number of migraine episodes per month in a patient by at least 30%.

3. The method according to claim 1, which reduces the number of migraine episodes per month in a patient by at least 40%.

4. A method for treating migraine in a patient requiring treatment, wherein the patient is administered a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, thereby enabling the pharmaceutical composition to provide approximately 30% higher pain relief than a placebo.

5. The method according to claim 1, wherein the pain relief of the pharmaceutical composition is at least about 50% higher than that of a placebo.

6. The method according to claim 4, wherein the relief from pain of the pharmaceutical composition is approximately 30-75% higher than that of a placebo.

7. The method according to claim 6, wherein the pain relief of the pharmaceutical composition is approximately 35-65% higher than that of a placebo.

8. A method for treating migraine in a patient requiring treatment, wherein the patient is administered a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, thereby enabling the pharmaceutical composition to provide approximately 30% higher relief from MBS than a placebo.

9. The method according to claim 8, wherein the liberation of the pharmaceutical composition from MBS is approximately 40% higher than that of a placebo.

10. The method according to claim 8, wherein the liberation of the pharmaceutical composition from MBS is approximately 30-50% higher than that of a placebo.

11. AUC of approximately 80-125% of 5000 (hr*ng / mL) 0-t The method according to claim 4, which provides...

12. Approximately 80-125% of 835 (ng / mL) C max The method according to claim 4, which provides...

13. AUC of approximately 80-125% of 5000 (hr*ng / mL) 0-t A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, which provides a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, comprising approximately 75 mg of rimegepant or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 13, wherein rimegepant is in the form of a hemisulfate sesquihydrate salt.

16. The pharmaceutical composition according to claim 13, in the form of a tablet.

17. The pharmaceutical composition according to claim 16, comprising approximately 50-60 wt% rimegepanthemisulfate sesquihydrate, approximately 30-35 wt% microcrystalline cellulose, approximately 2-7 wt% hydroxypropyl cellulose, approximately 3-7 wt% croscarmellose sodium, and approximately 0.1-1.0 wt% magnesium stearate.

18. The pharmaceutical composition according to claim 17, comprising approximately 57.1 wt% rimegepanthemisulfate sesquihydrate, approximately 33.4 wt% microcrystalline cellulose, approximately 4.0 wt% hydroxypropyl cellulose, approximately 5.0 wt% croscarmellose sodium, and approximately 0.5 wt% magnesium stearate.

19. The pharmaceutical composition according to claim 13, in the form of a high-speed dispersible dosage form for oral solid molding.

20. The pharmaceutical composition according to claim 19, comprising approximately 70-80 wt% rimegepanthemisulfate sesquihydrate, approximately 10-20 wt% fish gelatin, approximately 10-20 wt% bulking agent, and 0.1-5.0 wt% flavoring agent.

21. The pharmaceutical composition according to claim 20, wherein the volume-enhancing agent is mannitol.

Images