EA045801B1 - PHARMACEUTICAL COMPOSITION OF RIMEGEPANT IN THE FORM OF FAST DISPERSING ORAL DOSAGE FORM - Google Patents

Description

Link to related applications

This application is a national phase application under 35 U.S.C. §371, International Application No. PCT/US2019/023940, filed March 25, 2019, which claims priority under U.S. Provisional Patent Application No. 62/ 647794, filed March 25, 2018, US Provisional Patent Application No. 62/664761, filed April 30, 2018, US Provisional Patent Application No. 62/774285, filed December 2, 2018, US Provisional Patent Application No. 62 /777180, filed December 9, 2018, and U.S. Provisional Patent Application No. 62/777625, filed December 10, 2018, and provides all benefits accruing therefrom under 35 U.S.C. §119, with disclosure each of these applications is incorporated herein by reference in its entirety.

Field of technology to which the invention relates

The present invention relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, the pharmaceutical composition being in the form of a molded solid, rapidly dispersing oral dosage form, for the treatment of CGRP-related disorders such as migraine.

BACKGROUND OF THE INVENTION

Migraine is a chronic and debilitating disorder characterized by recurrent attacks lasting four to 72 hours with multiple symptoms, usually including unilateral, throbbing headaches of moderate to severe pain intensity, associated with nausea or vomiting, and /or sensitivity to sounds (phonophobia) and sensitivity to light (photophobia). Migraines are often preceded by brief neurological warning symptoms known as auras, which typically include visual disturbances such as flashes of light but may also include numbness or tingling in parts of the body. Migraines are both common and disabling. The Migraine Research Foundation ranks migraine as the third most common disease in the world, and the 2015 Global Burden of Disease study ranks migraine as the seventh leading specific cause of disability worldwide. According to the Migraine Research Foundation, approximately 36 million individuals in the United States suffer from migraine attacks. Although most sufferers experience migraine attacks once or twice a month, more than 4 million people have chronic migraine, which is defined as a condition in which the patient experiences headaches on at least 15 days a month, of which at least eight occurs during migraine for more than three months. Other patients have episodic migraine, which is characterized by the patient experiencing migraine less than 15 days per month. Migraines in people with episodic migraines can progress to chronic migraines over time. Migraine attacks can last four hours or up to three days. More than 90% of individuals who suffer from migraine attacks are unable to work or perform normal activities during a migraine attack, with many having comorbid conditions such as depression, anxiety and insomnia. In addition, migraine sufferers often have associated nausea and an aversion to consuming food or liquids during an attack.

CGRP (calcitonin genetically related peptide) is a 37-amino acid neuropeptide belonging to the peptide family that includes calcitonin, adrenomedullin and amylin. There are two forms of CGRP in humans (a-CGRP and 13-CGRP) and they have similar activities. They differ in three amino acids and exhibit varying distributions. At least two CGRP receptor subtypes may also account for the differing activities. The CGRP receptor is located in pain signaling pathways, intracranial arteries, and mast cells, and its activation is thought to play a major role in the pathophysiology of migraine. For example, studies and clinical trials have shown that serum CGRP levels increase during migraine attacks, intravenous CGRP infusion causes persistent pain in migraine and non-migraine patients, and treatment with anti-migraine drugs normalizes CGRP activity.

The possible involvement of CGRP in migraine has led to the development and clinical study of a number of compounds, including, for example, olcegepant (Boehringer Ingelheim, Ridgefield, CT, USA), telcagepant (Merck Sharp & Dohme Corp., Kenilworth, NJ, USA) , ubrogepant (Allergan plc, Dublin, Ireland), rimegepant (Biohaven Pharmaceutical Holding Company Ltd., New Haven, CT, USA), galcanezumab (Eli Lilly and Company, Indianapolis, IN, USA), fremanezumab (Teva Pharmaceutical Industries, Petah -Tikva, Israel), eptinezumab (Alder Biopharmaceuticals, Inc., Bothell, WA, USA) and erenumab (Amgen Inc., Thousand Oaks, CA, USA). Another compound being studied in recent studies for the treatment of migraine is lasmiditan (Eli Lilly and Company, Indianapolis, IN, USA).

Currently, medical practitioners use a number of pharmacological agents for emergency

- 1 045801 new treatment of migraine. A study published by the American Headache Society in 2015 concluded that medications considered effective for the acute treatment of migraine fall into the following classes: triptans, ergotamine derivatives, nonsteroidal anti-inflammatory drugs drugs (NSAIDs), opioids and combination drugs. The current standard of care for acute treatment of migraine is triptans, which are serotonin 5-HT _1B/1D receptor antagonists. Triptans have been developed and approved for the acute treatment of migraine in the last two decades. The initial introduction of triptans represented a transition to drugs that more selectively target the suspected pathophysiology of migraine. Although triptans account for nearly 80% of the antimigraine therapies prescribed by primary care physicians during clinic visits, problems such as lack of response or recurrence of headaches remain important clinical limitations. Indeed, only approximately 30% of patients in clinical trials are pain-free two hours after taking triptans. In addition, triptans are contraindicated in patients with cardiovascular disease, cerebrovascular disease, or significant risk factors for any of these due to the potential for systemic and cerebrovascular vasoconstriction resulting from 5-HT1B-mediated effects. Additionally, a study published in January 2017 in the journal Headache estimated that 2.6 million migraine patients in the United States have an event, condition, or procedure that could cause cardiovascular damage and limit the potential of triptans as a means for treatment.

Accordingly, there remains a significant unmet medical need for treatments for migraine that may provide improved patient benefits compared to existing therapies. In addition, CGRP receptor antagonists may be useful pharmacological agents for disorders that include other CGRP-related disorders. In addition to migraine, such disorders may include cluster headache (Doods (2001) Curr. Opin. Invest. Drugs 2, 1261-1268; Edvinsson et al. (1994) Cephalalgia 14, 320-327); chronic tension 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 inflammation and inflammatory pain (Holzer (1988) Neuroscience 24, 739-768; Delay-Goyet et al, (1992) Acta Physiol. 1 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 mellitus (Molina et al. ( 1990) Diabetes 39, 260-265); vascular disorders; inflammation (Zhang et al. (2001) Pain 89.265); arthritis, bronchial hyperresponsiveness, 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 (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, traumatic 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 redness of the skin, pinkness and erythema of the skin; 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.

Brief Disclosure of the Invention

The present invention is directed, inter alia, to the treatment of CGRP-related disorders, such as migraine, with rimegepant and its salts. Thanks to the present invention, it is now possible to provide patients with more effective GCRP-related treatments. Patients suffering from migraine may experience an improved response in one or more categories, including, for example, fewer migraine headaches, improved freedom from pain, or freedom from the most distressing symptoms.

In accordance with one aspect of the present invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in the form of a molded solid, rapidly dispersing oral dosage form.

In accordance with one aspect of the present invention, the reduction in the number of migraine attacks per month in a specified patient is at least 30%. In accordance with one aspect of the present invention, the reduction in the number of migraine attacks per month in a specified patient is at least 40%.

In accordance with one aspect of the present invention, freedom from pain is at least about 50% greater than with placebo. In accordance with one aspect of the present invention, freedom from pain with the pharmaceutical composition is approximately 30-75% greater than with placebo. In accordance with one aspect of the present invention, freedom from pain is approximately 35-65% than with placebo.

In accordance with one aspect of the present invention, freedom from MBS is at least about 40% greater than with placebo. In accordance with one aspect of the present invention, freedom from MBS is approximately 30-50% greater than with placebo. In accordance with one aspect of the present invention, freedom from MBS is approximately 35-65% greater than with placebo.

In accordance with one aspect of the present invention, the pharmaceutical composition is administered via oral, sublingual or buccal administration.

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

In accordance with one aspect of the present invention, rimegepant is in the form of a hemisulfate salt sesquihydrate.

In accordance with one aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof to provide AUC ₀ . _t , which is approximately 80-125% of 5000 (h-ng/ml).

In accordance with one aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof to provide a Cmax of approximately 80-125% of 835 (ng/ml).

In accordance with one aspect of the present invention, the pharmaceutical composition is provided in the form of a tablet. In accordance with one aspect of the present invention, the pharmaceutical composition contains from about 50-60 wt.% rimegepant hemisulfate sesquihydrate, about 30-35 wt.% microcrystalline cellulose, about 2-7 wt.% hydroxypropylcellulose, about 3-7 wt.% croscarmellose sodium and approximately 0.1-1.0% by weight magnesium stearate. In accordance with one aspect of the present invention, the pharmaceutical composition contains about 57.1 wt.% rimegepant hemisulfate sesquihydrate, about 33.4 wt.% microcrystalline cellulose, about 4.0 wt.% hydroxypropylcellulose, about 5.0 wt.% croscarmellose sodium and approximately 0.5 wt.% magnesium stearate.

In accordance with one aspect of the present invention, the pharmaceutical composition is provided in the form of a molded solid, rapidly dispersing oral dosage form. In accordance with one aspect of the present invention, the pharmaceutical composition contains from about 70-80 wt.% rimegepant hemisulfate sesquihydrate, about 10-20 wt.% fish gelatin, about 10-20 wt.% excipient and 0.1-5.0 wt. % flavoring. In accordance with one aspect of the present invention, the excipient is mannitol.

Brief description of drawings

In fig. Figure 1 presents the probability of pain freedom as a function of time in the clinical trial entitled BHV3000-301: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) for the acute treatment of migraine (ClinicalTrials.gov, identifier: NCT03235479).

In fig. Figure 2 presents the probability of pain freedom as a function of time in the clinical trial entitled BHV3000-302: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) for the acute treatment of migraine (ClinicalTrials.gov, identifier: NCT03237845).

In fig. 3 presents the time to pain relief for up to 8 hours post-dose in a clinical trial entitled BHV3000-301: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) for the acute treatment of migraine (ClinicalTrials. gov, ID: NCT03235479).

- 3 045801

In fig. Figure 4 presents the time to pain relief for up to 8 hours post-dose in a clinical trial entitled BHV3000-302: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) for the acute treatment of migraine (ClinicalTrials. gov, ID: NCT03237845).

In fig. Figure 5 shows the Kaplan-Meier curve for pain relief over 2 hours after a single dose of rimegepant 75 mg ODT Zydis in a clinical trial entitled BHV3000303: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) in orally disintegrating tablet (ODT) for the acute treatment of migraine (ClinicalTrials.gov, identifier: NCT03461757).

In fig. Figure 6 shows freedom from pain for a period of 2 to 8 hours after a single dose of rimegepant 75 mg ODT Zydis in a clinical study entitled BHV3000-303: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant ) as an orally disintegrating tablet (ODT) for the acute treatment of migraine (ClinicalTrials.gov, identifier: NCT03461757).

Detailed Disclosure of the Invention

The following detailed description is presented to assist one skilled in the art in practicing the present invention. Modifications and changes to the embodiments described herein can be made by one skilled in the art without departing from the spirit or scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this disclosure relates. The terminology used herein is intended to describe specific embodiments only and is not intended to be limiting.

When used in this application, each of the following terms will have the meaning set forth below, except as otherwise specifically provided herein. Additional definitions are set forth throughout this application. Where a term is not specifically defined herein, the term is given the meaning accepted in the art as those skilled in the art will apply to the term when used in describing the present invention.

Singular forms refer to one or more than one (i.e., at least one) grammatical entity in a given document, unless the context clearly suggests otherwise. By way of example, an element means one element or more than one element.

The term approximately refers to a value or composition that is within the acceptable range of error for a particular value or composition as determined by one skilled in the art, which will depend in part on how the value or composition is measured or determined, i.e. from the limitations of the measuring system. For example, approximately may mean being within 1 or more than 1 standard deviation in accordance with the practice used in the art. Alternatively, approximately may mean a range of up to 1%, 5%, 10% or 20% (ie ±10% or ±20%) depending on application conditions. For example, approximately 3 mg may include any value 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%). Moreover, particularly when applied to biological systems or processes, the terms can mean a range of up to a value on the order of the measured value or up to 5 times the measured value. Where specific meanings or compositions are presented in the application and claims, unless otherwise stated, the meaning of the term should be assumed to be approximately within the acceptable error range for that particular meaning or composition.

The term administration refers to the physical administration to a subject of a composition containing a therapeutic agent using any of the various delivery methods and systems known to those skilled in the art. Administration may also be carried out, for example, once, several times and/or over one or more extended periods, and the dose administered may be a therapeutically effective dose or a subtherapeutic dose.

The term AUC (area under the curve) refers to the total amount of drug absorbed or exposed to a subject. Typically, the AUC can be obtained using a mathematical method based on a graph of the change in drug concentration over time until the concentration becomes negligible. The term AUC can also refer to partial AUC at specific time intervals.

The term Cmax refers to the maximum concentration of a drug in the blood, serum, specific compartment, or area of interest of a subject between the administration of the first dose and the administration of the second dose. The term Cmax may also refer to dose-normalized ratios, if mentioned.

The term dosing interval refers to the amount of time that elapses between

- 4 045801 administering multiple doses of a composition disclosed herein to a subject. Therefore, the interval between doses can be specified in the form of ranges.

The term dosing frequency refers to the frequency of dosing of a composition disclosed herein at a given time. Dosing frequency may be specified as the number of doses over a given period of time, for example, once a week or once every two weeks.

The terms in combination with and in combination with refer to the administration of one treatment modality in addition to another treatment modality. In this regard, in combination with or in combination with refers to the administration of one treatment method to a subject before, during, or after the administration of another treatment method.

The term pharmaceutically acceptable salt refers to a salt form of one or more of the compounds described herein, which is typically present to increase the solubility of the compound in gastric or intestinal juices in the gastrointestinal tract of a patient in order to promote dissolution and bioavailability of the compounds . Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, as appropriate. Suitable salts include, for example, salts derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium, and ammonium salts, in addition to numerous other acids and bases known in the pharmaceutical field.

The terms subject and patient refer to any human or non-human animal. The term non-human animal includes, without limitation, vertebrates such as non-human primates, sheep, dogs and rodents such as mice, rats and guinea pigs. In accordance with some embodiments, the subject is a human. The terms subject and patient are used interchangeably throughout this document.

The terms effective amount, therapeutically effective amount, therapeutically effective dosage, and therapeutically effective dose of an agent (also sometimes referred to herein as a drug) refer to any amount of an agent that, when administered alone or in combination with another agent, protects a subject from the onset of a disease or promotes the treatment development of the disease, as evidenced by a decrease in the severity of symptoms of the disease, an increase in the frequency and duration of asymptomatic periods, or an alleviation of impairment or inability to perform functions due to the disease. The therapeutically effective amount of an agent can be assessed using a variety of methods known to one skilled in the art, such as through clinical trials in human subjects, in animal model systems predictive of efficacy in humans, or by in vitro activity assays of the agent. analyses.

The term Tmax refers to the time or period after drug administration at which the maximum concentration (Cmax) is reached in the blood, serum, specific compartment, or area of interest of a subject.

The term treatment refers to any treatment of a condition or disease in a subject and may include: (i) preventing the occurrence of a disease or condition in a subject who may be predisposed to the disease but has not yet been diagnosed with it; (ii) inhibiting a disease or condition, i.e. delay in its development; relief of a disease or condition, i.e. causes a reversal of the development of the condition; or (iii) weakening or alleviating conditions caused by the disease, i.e. symptoms of the disease. Treatment can be used in combination with other standard therapies or alone. Treatment or therapy in a subject also includes any type of intervention or process performed on a subject, or administration of an agent to a subject, for the purpose of reversing the development, alleviation, attenuation, inhibition, retardation, or prevention of the onset, progression, development, severity, or recurrence of a symptom. , complications or conditions or biochemical features associated with the disease.

In the context of headache, treatment is an approach to obtaining favorable or desired results for the subject. In the context of the present invention, beneficial or desired clinical outcomes include, without limitation, one or more of the following: improvement in any aspect of the headache, including reduction in severity, reduction in pain intensity and other associated symptoms, reduction in recurrence rate, improvement in quality of life patients suffering from headaches, reduce the dose of other medications required to treat headaches, and reduce the number of headache days per month. In the case of migraine, other associated symptoms include, but are not limited to, nausea, vomiting and sensitivity to light, sound and/or movement. In the case of a cluster headache, other associated symptoms include, but are not limited to, swelling under or around the eyes, excessive tearing, red eyes, rhinorrhea or nasal congestion, and redness of the skin on the face.

For the purposes of this disclosure, reference is made to the U.S. Food and Drug Administration (FDA), Guidance for

- 5 045801

Industry, Migraine: Developing Drugs for Acute Treatment, February 2018, available at https://www.fda.gov/downloads/drugs/guidances/ucm419465.pdf. Terms used in the Examples section, such as most distressing symptoms (MBS) and freedom from pain, are described in the guide

FDA.

Starting materials suitable for preparing the pharmaceutical compositions of the present invention are readily available from commercial suppliers or can be obtained by those skilled in the art.

Rimegepant has the chemical formula, C ₂₈ H ₂₈ F ₂ N ₆ Q ₃ and the IUPAC name [(5S,6S,9R)-5amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro- 5H-cyclohepta[b]pyridin-9-yl] 4-(2-oxo-3H-imilazo[4,5-b]pyridin-1-yl)piperidin-1-carboxylate. Rimegepant is also referred to as BHV-3000 in this document.

The structure of rimegepant is

Rimegepant is described, for example, in international application WO 2011/046997, published April 21, 2011.

In accordance with a preferred aspect of the present invention, rimegepant is in the form of a hemisulfate salt sesquihydrate. This preferred salt form is described in international application WO 2013/130402, published September 6, 2013.

The chemical formula of the salt form is C ₂₈ H ₂₈ F ₂ N ₆ Q ₃ -0.5 H ₂ SQ ₄ -1.5 H ₂ O, and its structure is as follows:

The pharmaceutical compositions of the present invention can be prepared in any suitable dosage form, including, for example, tablets, capsules, nasal sprays, powders, granules, ointments, solutions, suppositories, injections, inhalations, gels, microspheres and aerosols. .

Pharmaceutical compositions of the present invention containing rimegepant generally also include other pharmaceutically acceptable carriers (also referred to as excipients), such as, for example, binders, lubricants, diluents, coating agents, disintegrants, barrier layer components, agents, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, cofactors, emulsifiers, solubilizing agents, suspending agents, flavorings, preservatives and mixtures thereof. The choice of excipients depends on the desired characteristics of the compositions and on the nature of other pharmacologically active compounds in the composition. Suitable excipients are known to those skilled in the art (see Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., McGraw Hill).

Examples of pharmaceutically acceptable carriers that can be used in the preparation of the pharmaceutical compositions of the present invention may include, without limitation, excipients such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate-buffered solutions, emulsifiers, isotonic saline solution, pyrogen-free water and combinations thereof. If necessary, can also be combined and

- 6 045801 disintegrants, and exemplary disintegrants may be, without limitation, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In accordance with an aspect of the present invention, the flavor is selected from mint, peppermint, berry, cherry, menthol and sodium chloride flavors and combinations thereof. In accordance with an aspect of the present invention, the sweetener is selected from sugar, sucralose, aspartame, acesulfame, neotame, and combinations thereof.

In general, the pharmaceutical compositions of the present invention can be produced by conventional methods known in the art, for example, through conventional mixing, dissolution, granulation, dragee processes, elutriation, emulsification, encapsulation, entrapment, lyophilization, and the like.

In accordance with one aspect of the present invention, the pharmaceutical compositions are provided in the form of a molded solid, rapidly dispersing oral dosage form, such as those described in US Pat. No. 9,192,580, issued November 24, 2015.

The phrase rapidly dispersing dosage form refers to compositions that disintegrate or disperse within 1-60 seconds, preferably 1-30 seconds, more preferably 1-10 seconds, and especially 2-8 seconds after being placed in contact with a liquid. Preferably, the liquid is that which is found in the oral cavity, i.e. saliva, as is the case with oral administration.

According to a preferred embodiment, the compositions of the present invention are solid, rapidly dispersing dosage forms comprising a solid network structure of the active ingredient, rimegepant, and a water-soluble or water-dispersible carrier containing fish gelatin. Accordingly, the carrier is inert with respect to the active ingredient. The network structure is obtained by sublimation of the solvent from the composition into a solid state, the composition containing the active ingredient and a solution of the carrier in the solvent. Dosage forms according to the present invention can be prepared in accordance with the method disclosed by Gregory et al. in UK Patent No. 1548022, using fish gelatin as a carrier. Accordingly, an initial composition (or mixture) containing the active ingredient and a solution of the fish gelatin carrier in a solvent is prepared, followed by sublimation. Sublimation is preferably carried out by lyophilizing the composition. The composition may be contained in a form during a lyophilization process to obtain a solid form having any desired shape. The mold can be cooled using liquid nitrogen or solid carbon dioxide as a preparatory step before the composition is placed into it. After freezing the form and composition, they are then subjected to reduced pressure and, if necessary, controlled application of heat to promote sublimation of the solvent. The reduced pressure used in the process may be below approximately 4 mmHg. Art., preferably below about 0.3 mm Hg. Art. The lyophilized compositions can then be removed from the mold, if necessary, or stored therein until further use.

If the process uses the active ingredients and fish gelatin as a carrier, a solid, rapidly dispersing dosage form is obtained having the advantages associated with the use of fish gelatin described herein. Typically, fish gelatin is classified according to whether it comes from cold-water or warm-water fish, and whether it is a gelling or non-gelling variety. The non-gelling variety of fish gelatin, compared to gelling fish gelatin and bovine gelatin, has a lower content of proline and hydroxyproline amino acids, which are known to be associated with cross-linking properties and gelling ability. Non-gelling fish gelatin can remain in solution in concentrations up to approximately 40% and at temperatures up to 20°C. In accordance with one aspect of the present invention, the fish gelatin used according to the present invention is preferably obtained from cold-water fish sources and is a non-gel-forming type of fish gelatin. More preferably, in accordance with one aspect of the present invention, a non-hydrolyzed form of non-gelling fish gelatin is used. In an alternative embodiment, spray-dried, non-hydrolyzed, non-gelling fish gelatin can be used. Fish gelatins suitable for use in the present invention are commercially available.

The compositions according to the present invention, in addition to the active ingredient and the fish gelatin carrier, may also contain other matrix-forming agents and secondary components. Matrix-forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as other gelatins, dextrins and soybean, wheat and psyllium seed proteins; gums such as acacia gum, guar gum, agar and xanthan gum; polysaccharides; alginates; carboxymethylcellulose; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-gum acacia complexes.

Other materials that may also be included in instant compositions according to

- 7 045801 but the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms, such as 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 included in the solution or suspension prior to solidification (freezing). The matrix-forming agent may be present in addition to the surfactant or instead of the surfactant. In addition to forming a matrix, the matrix-forming agent can help maintain the dispersion of any active ingredient in solution in a suspension. This is particularly useful in the case of active agents which are not sufficiently soluble in water and therefore must be suspended rather than dissolved. Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, coloring agents, flavors, pH modifiers, sweeteners or flavoring agents may also be included in instant compositions. Suitable colorants include red, black and yellow iron oxides and FD&C dyes such as FD&C Blue No. 2 (blue) and FD&C Red No. 40 (red), available from Ellis & Everard. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations thereof. Suitable pH modifiers include edible acids and bases such as citric acid, tartaric acid, phosphoric acid, hydrochloric acid, malic acid and sodium hydroxide. Suitable sweeteners include, for example, sucralose, aspartame, acesulfame K and thaumatin. Suitable taste-correcting agents include, for example, sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbed substances or microencapsulated active agents.

Typical routes of administration of the pharmaceutical compositions of the present invention include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions in accordance with certain embodiments of the present invention are formulated to allow the active ingredients contained therein to remain bioavailable after administration of the composition to a patient. The compositions to be administered to a subject or patient may take the form of one or more dosage units. Current methods for preparing such dosage forms are known or will be obvious to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).

Solid compositions are typically formulated in dosage units providing from about 1 to about 1000 mg of active ingredient per dose. Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 37.5 mg, 75 mg, 100 mg, 150 mg, 300 mg, 500 mg, 600 mg, and 1000 mg. Typical dosage ranges in accordance with the present invention include from about 10-600 mg, 25-300 mg, 25-150 mg, 50-100 mg, 60-90 mg and 70-80 mg. Liquid compositions typically have a unit dose range of 1-100 mg/ml. Some examples of liquid dosage units are 0.1 mg/ml, 1 mg/ml, 10 mg/ml, 25 mg/ml, 50 mg/ml and 100 mg/ml.

In accordance with some embodiments, the method may include administering to the subject one or more additional agents simultaneously or sequentially with rimegepant. In some embodiments, the additional agent may be a headache drug, such as an exemplary headache drug (eg, 5-HT1 agonists, triptans, ergot alkaloids, opiates, adrenergic receptor antagonists, NSAIDs, or antibodies) known in the state of the art. In some embodiments, the therapeutic effect may be greater than that of rimegepant or one or more additional agents alone. Accordingly, a synergistic effect of rimegepant and one or more additional agents may be achieved. In accordance with some embodiments, the subject may take one or more additional agents for prophylactic purposes.

In addition to migraine, other CGRP-related disorders that can be treated using the pharmaceutical compositions and methods of the present invention include, for example, cluster headache; chronic tension headache; chronic pain; neurogenic inflammation and inflammatory pain; Pain in the eyes; toothache; non-insulin-dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity; asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; psoriasis; encephalitis, traumatic brain injury, ischemia, stroke, epilepsy and neurodegenerative diseases; skin diseases; neurogenic redness of the skin, pinkness and erythema of the skin; tinnitus; obesity; inflammatory bowel disease; irritable bowel syndrome and cystitis.

In accordance with one aspect, the present invention also provides kits for use in these methods. The kits may include one or more containers containing a pharmaceutical composition described herein and instructions for use in accordance with any of the methods described herein. Typically, these instructions will describe the administration of a pharmaceutical composition for the treatment, relief or prevention of headache (such as migraine) or other CRGP disorder in accordance with any of the methods described herein. For example, the set may contain a description of selecting an individual eligible for treatment based on identifying whether the individual has a headache, or whether the individual is at risk for headaches. The instructions are typically provided in the form of a package insert or label as required by the regulatory authority in the jurisdiction where the pharmaceutical composition is to be provided to patients.

In accordance with the present invention, administration of pharmaceutical compositions containing rimegepant to a subject may help reduce severity (which may include reducing the need for other drugs and/or therapies and/or reducing the amount (e.g., exposure) of other drugs and/or therapies commonly used for the condition, including, for example, ergotamine, dihydroergotamine, or triptans in the case of migraine), duration and/or frequency (including, for example, a delay or increase in time until the individual's next episodic attack).

In addition, administration to a subject of pharmaceutical compositions containing rimegepant may reduce or improve one or more headache symptoms or reduce the duration of the symptom compared to no administration of the treatment.

In addition, administration to a subject of pharmaceutical compositions containing rimegepant may help reduce the frequency of headache attacks in the subject (compared to pre-treatment levels) over a period of time, such as a month. For example, an individual's seizure frequency may be reduced by at least about any amount of 10%, 20%, 30%, 40%, 50%, 60%, or 70% compared to pre-treatment levels.

In addition, administration to a subject of pharmaceutical compositions containing rimegepant may help delay the development of headaches, i.e. postpones, complicates, slows down, inhibits, stabilizes and/or delays the progression of the disease. This delay may be for variable periods of time depending on the history and/or individuals receiving treatment.

In addition, administration to a subject of pharmaceutical compositions containing rimegepant may delay the development or progression of headache, i.e. delays the initial manifestations and/or subsequent progression of the disorder. The development of headache can be detected and assessed using standard clinical techniques that are well known in the art. However, development also refers to progression that may not be detectable.

Examples

The following examples illustrate the present invention and are not intended to limit the scope of the present invention.

Example 1.

Tablet production: A batch for the production of tablets containing a 75 mg dose of rimegepant is prepared as follows. The composition in the batch is outlined below in the table. 1. Tablets are obtained from the batch as indicated.

- 9 045801

Table 1

Ingredient Percentage content per tablet Amount per tablet (mg) Quantity per batch of 100,000 tablets (g) Intragranular Rimegepant (as hemisulfate sesquihydrate, equivalent to 75 mg rimegepant base) 57.11 85.67 8575.5 Microcrystalline cellulose, NF 13.39 20.09 2011.0 Hydroxypropyl cellulose), USP/NF (Klucel EXF PHARM) 4.00 6.00 600.6 Croscarmellose sodium, NF 2.50 3.75 375.4 Purified Water, USP Sufficient quantity No data 0' Intragranular distributed solids 11562 Extragranular Microcrystalline cellulose, NF 20.00 30.00 3003.0 Croscarmellose sodium, NF 2.50 3.75 375.4 Magnesium stearate, NF 0.50 0.75 75.08 Total in tablet core 100.0 150 15015

¹ Purified water is removed during the process. Excessive dosage. The consumed part is documented. The intragranular distributed solids do not include water.

1. Weigh out rimegepant hemisulfate sesquihydrate and all excipients.

2. Sift rimegepant hemisulfate sesquihydrate, microcrystalline cellulose (intragranular portion), hydroxypropyl cellulose, and croscarmellose sodium (intragranular portion) through a 20 mesh sieve.

3. Load the inoculated mixture from stage 2 into a suitable granulator equipped with an appropriately sized bowl and dry mix for 10 minutes. Set the impeller speed to low and turn off the chopper.

4. During mixing, equip the granulator with a spray tip and add purified water until the expected result is achieved.

5. Mix the wet mixture for 30 seconds with the impeller set to low speed and the chopper set to low speed.

6. Discharge the wet mass into the expansion chamber in the fluid bed dryer. Dry to target LOD <2%.

7. Grind the dried granules using a Comil mill with an appropriate sieve (0.075R) and spacer (0.050). Analyzes of bulk density before and after compaction and particle size distribution are carried out. Record the results. The Carr index and the average Carr index for the two samples are calculated.

8. Calculate the relative yield. The extragranular quantities are recalculated.

9. Sift the microcrystalline cellulose and croscarmellose through a 20 mesh sieve.

10. Combine the ground granulate with recalculated amounts of microcrystalline cellulose (extragranular portion), croscarmellose sodium (extragranular portion) into a 2-cubic-foot transport container and mix through 150 inversions.

11. Sift the magnesium stearate through a 30 mesh sieve.

12. Add the sifted magnesium stearate to the contents of the 2 cubic foot transport container and mix through 75 inversions.

13. Collect samples to determine mixture homogeneity as planned.

14. Bulk density analyzes before and after compaction and particle size analysis are carried out and the Carr index is calculated.

15. Unload into a suitable container and weigh.

16. Install a rotary tablet press with 716 pressing units with 7 mm round concave smooth equipment. Adjust the required number of nodes.

17. Adjust the press to achieve the following characteristics for tablets: attrition loss <0.3%; hardness 10-14 kPa; thickness 3.60-4.10 mm; and disintegration >2:30 min.

18. Carry out the following tests during the process.

Abrasion and disintegration of the tablet at the beginning, during and at the end of work.

- 10 045801

Tablet hardness, tablet thickness, individual tablet weights, average tablet weights, and appearance at 15-minute intervals.

19. Pass the tablets through a dust remover and a metal detector.

20. Pack the tablets in double polyethylene bags in a suitable container.

Example 2: Clinical Trial - BHV3000-301: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) for the acute treatment of migraine (ClinicalTrials.gov, Identifier: NCT03235479).

The phase 3 clinical trial was conducted as follows with 1490 participants.

Description of the study.

The purpose of this study was to compare the effectiveness of BHV-3000 (rimegepant) versus placebo in subjects with acute migraine.

Condition or disease Intervention/treatment

Migraine Medicine: BHV| 3000 j

Acute migraine

Phonophobia Medication: Oral placebo tablet Photophobia Research plan. Study type: interventional (clinical trial)

Actual number of participants: 1490 participants

Allocation: randomized

Intervention model: concurrent assignment

Description of the intervention model: Sponsor, Investigator and Subject, Double-Blind, Randomized Controlled Trial

Masking: Triple (participant, healthcare worker, researcher)

Description of blinding: double-blind for sponsor, investigator and subject

Main goal: treatment

Official title: BHV3000-301: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV3000 (rimegepant) for the acute treatment of migraine

Groups and interventions.

Group Intervention/Treatment

Experimental: BHV-3000 Drug: BHV-3000 75 mg tablet QD

Placebo comparison: Drug: oral placebo tablet equivalent to 75 mg QD tablet _;

Outcome indicators.

Key outcome indicators.

1. Freedom from pain with rimegepant (75 mg tablet) compared with placebo in the acute treatment of migraine will be measured using the number of evaluable subjects who report freedom from pain 2 hours after dosing. [Time frame: two hours after dosing.]

Pain will be measured on a 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe).

- 11 045801

2. Freedom from most distressing symptom (MBS) with rimegepant (75 mg tablet) compared with placebo will be measured using the number of evaluable subjects who report no MBS at 2 hours post-dose. [Time frame: two hours after dosing.]

MBS (nausea, phonophobia, or photophobia) will be measured using a binary scale (0=absent, 1=present).

Secondary outcome measures.

1. Measure the difference between rimegepant (75 mg tablet) versus placebo over the 2 to 24 hour period using the number of subjects who do not experience any headache during the time period of interest. [Time frame: 2 hours -24 hours after dosing.]

Long-term freedom from pain, measured on a 4-point numeric rating scale (none, mild, moderate, severe).

2. Difference between rimegepant (75 mg tablet) versus placebo based on tabulated absence of photophobia at 2 hours post-dose in the subgroup of subjects who reported photophobia for headache at inclusion. [Time frame: 2 hours after dose.]

Photophobia.

3. Evaluation of rimegepant (75 mg tablet) versus placebo based on the tabulated number of subjects who reported no phonophobia 2 hours after dosing, in the subgroup of subjects who reported phonophobia for headache at inclusion. [Time frame: 2 hours after dose.]

Phonophobia.

4. Measurement of the difference between rimegepant (75 mg tablet) versus placebo in pain relief at 2 hours post-dose for those subjects who reported moderate to severe pain at enrollment and then reported no or no pain. its weak level. [Time frame: 2 hours after dose.]

Pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

5. Freedom from nausea based on inclusion in the table of the number of subjects who reported no nausea 2 hours after dosing, in the subgroup of subjects who reported nausea with headache at inclusion. [Time frame: 2 hours after dose.]

Freedom from nausea.

6. Difference between rimegepant (75 mg tablet) versus placebo in the likelihood of requiring a rescue drug based on the number of subjects who received a rescue drug within 24 hours of study drug administration (BHV3000 or placebo). [Time frame: up to 24 hours after dosing.]

The need for a reserve therapy drug.

7. Measurement of the difference between rimegepant (75 mg tablet) compared with placebo in long-term freedom from pain over the period 2 to 48 hours using the number of subjects who do not experience any headache during the time period of interest. [Time frame: 2 hours - 24 hours after dosing.]

Long lasting freedom from pain.

8. Rimegepant (75 mg tablet) compared with placebo for pain relief over a period of 2 to 24 hours using the number of subjects who do not use any rescue therapy and do not experience any moderate or severe headache during this period . [Time frame: 2 hours - 24 hours after dosing.]

Long-term pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

9. Measurement of the difference between rimegepant (75 mg tablet) versus placebo in long-term pain relief over the 2 to 48 hour period using the number of subjects not using any salvage medications and not experiencing moderate-to-severe headache. [Time frame: 2 hours - 48 hours after dosing.]

Long-term pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

10. Measure the difference between rimegepant (75 mg tablet) and placebo in the proportion of subjects who were able to function normally at 2 hours, using the number of subjects who report themselves as normal on a functional disability scale. [Time frame: 2 hours after dose.]

Functional assessment of disability.

11. Measuring the difference between rimegepant (75 mg tablet) versus placebo in pain return using the number of subjects who are pain-free 2 hours after dosing and then have headache of any severity over a period of 48 hours after dosing study drug. [Time frame: 2 hours - 48 hours after dosing.]

Return of pain measured on a 4-point numeric rating scale (none, mild, moderate, severe).

- 12 045801

Additional details related to the clinical trial, including eligibility criteria, contacts and locations, and more information can be found at www.dinicaltrials.gov under ClinicalTrials.gov identifier NCT03235479.

Example 3 Clinical Trial - BHV3000-302: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) for the acute treatment of migraine (ClinicalTrials.gov, ID: NCT03237845).

The phase 3 clinical trial was conducted as follows with 1503 participants.

Description of the study.

Short description.

The purpose of this study is to compare the effectiveness of BHV-3000 (rimegepant) versus placebo in subjects with acute migraine.

State or _,

Intervention/treatment of disease

Migraine Drug: BHV3000

Acute migraine

Medicine:

Phonophobia oral placebo tablet

Photophobia

Research plan. Study type: interventional (clinical trial) Actual number included: 1503 participants Distribution: randomized Intervention model: parallel assignment Description of the intervention model: double blind for sponsor, investigator and subject Disguise: triple (participant, health worker, researcher) Description of disguise: double blind for sponsor, investigator and subject Primary goal: treatment Official name: BHV3000-302: phase 3: double-blind randomized placebo controlled trial safety and effectiveness of BHV3000 (rimegepant) for the acute treatment of migraine Date of actual start of the study: July 26, 2017 Completion date for the assessment of key indicators: January 25, 2018 Study completion date: January 31, 2018

Groups and interventions.

Group Intervention/treatment

Experimental: BHV-3000 rimegepant 75 mg tablet QD Drug: rimegepant active drug Comparative with placebo: placebo Corresponding 75 mg QD placebo tablet Drug: placebo placebo

- 13 045801

Outcome indicators.

Key outcome indicators.

1. Freedom from pain with rimegepant (75 mg tablet) compared with placebo in the acute treatment of migraine will be measured using the number of evaluable subjects who report freedom from pain 2 hours after dosing. [Time frame: two hours after dosing.]

Pain will be measured on a 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe).

2. Freedom from most distressing symptom (MBS) with rimegepant (75 mg tablet) compared with placebo will be measured using the number of evaluable subjects who report no MBS at 2 hours post-dose. [Time frame: two hours after dosing.]

MBS (nausea, phonophobia, or photophobia) will be measured using a binary scale (0=absent, 1=present).

Secondary outcome measures.

1. Rimegepant (75 mg tablet) compared with placebo over the period 2 to 24 hours using the number of subjects who do not experience any headache during the time period of interest. [Time frame: 2 hours -24 hours after dosing.]

Long-term freedom from pain, measured on a 4-point numeric rating scale (none, mild, moderate, severe).

2. Rimegepant (75 mg tablet) versus placebo based on the tabulated number of subjects who reported no photophobia 2 hours after dosing, in the subgroup of subjects who reported photophobia for headache at inclusion. [Time frame: 2 hours after dose.]

Freedom from photophobia.

3. Rimegepant (75 mg tablet) versus placebo based on the tabulated number of subjects who reported no phonophobia 2 hours after dosing, in the subgroup of subjects who reported phonophobia for headache at inclusion. [Time frame: 2 hours after dose.]

Freedom from phonophobia.

4. Measurement of rimegepant (75 mg tablet) compared with placebo for pain relief at 2 hours post-dose in cases that reported moderate to severe pain at enrollment and then reported no or no pain. about its weak level. [Time frame: 2 hours after dose.]

Pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

5. Freedom from nausea will be determined by tabulating the number of subjects who report no nausea 2 hours after dosing in the subset of subjects who reported nausea with headache at enrollment. [Time frame: 2 hours after dose.]

Freedom from nausea.

6. Rimegepant (75 mg tablet) versus placebo for the likelihood of requiring a rescue drug will be assessed based on the number of subjects who received a rescue drug within 24 hours of study drug administration (BHV3000 or placebo). [Time frame: up to 24 hours after dosing.]

The need for a reserve therapy drug.

7. Performance for rimegepant (75 mg tablet) versus placebo for long-term pain freedom over the 2 to 48 hour period will be measured using the number of subjects who do not experience any headache during the time period of interest. [Time frame: 2 hours - 48 hours after dosing.]

Long-term freedom from pain, measured on a 4-point numeric rating scale (none, mild, moderate, severe).

8. Rimegepant (75 mg tablet) compared with placebo for pain relief over a period of 2 to 24 hours using the number of subjects who do not use any rescue therapy and do not experience any moderate or severe headache during this period . [Time frame: 2 hours - 24 hours after dosing.]

Long-term pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

9. Rimegepant (75 mg tablet) compared with placebo for long-term pain relief over a period of 2 to 48 hours using the number of subjects not using any rescue medication and not experiencing moderate-to-severe headache. [Time frame: 2 hours 48 hours after dosing.]

Long-term pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

10. Rimegepant (75 mg tablet) compared with placebo in the proportion of subjects who

- 14 045801 were able to function normally after 2 hours, using the number of subjects who report their condition as normal on the functional disability scale. [Time frame: 2 hours after dose.]

Functional assessment of disability.

11. Rimegepant (75 mg tablet) versus placebo for pain return will be measured using the number of subjects who are pain-free 2 hours after dosing and then have headache of any severity over a period of 48 hours after dosing. drug. [Time frame: 2 hours - 48 hours after dosing.]

Return of pain measured on a 4-point numeric rating scale (none, mild, moderate, severe).

Additional details related to the clinical trial, including eligibility criteria, contacts and locations, and more information can be found at www.clinicaltrials.gov under ClinicalTrials.gov ID: NCT03237845.

Example 4.

Clinical Trial Results: The research results based on the clinical studies described in Example 2 and Example 3 are shown in FIG. 1, 2 and in table. 2, 3 and 4.

table 2

14.2%

27.7% ¹ most distressing symptom, including photophobia, phonophobia and nausea

Freedom from pain

Freedom from MBS ¹

Freedom from pain 19.6% 12.0% <0.001 Freedom from MBS ¹ 37.6% 25.2% <0.0001

19.2%

Table 3

Rome! eiant p-537

Placebo n=535

Data are Kaplan-Meier estimates for freedom from pain; censored (did not include) subjects who were taking a rescue drug or were not present for follow-up within a specified period

- 15 045801

Table 4

Liver function test (LET) profile: rnme epan ι was similar to placebo in both studies Complete data set of LFT results from Study 301 and Study 302 Rimeyupash |m IVINVIVVV pnNTsM 22(2.0%)) 24(2 2%)) 3 11 X 1 (about |%,) 1 (About 1%) > and \ 0 ABOUT 0 0 2o UX 0 ABOUT A.S.I. Phmci ei iani IENIVI 12(1 1%>) Placebo IIN| 1<Х1>%,) 3 1 1 X 1 (<>1%,) ABOUT MiligliiiBMiM 0 0 0 0 2о 1 1 X 0 O *No increases in bilirubin levels >2xULN in both studies *All cases resolved 301 and 302

Example 5.

Bioequivalence: The bioequivalence of the molded solid, rapidly dispersing oral dosage form prepared with fish gelatin described herein (ODT) at a dose of 75 mg of rimegepant was compared with the 75 mg tablets used in the studies described in Examples 2 and 3.

A summary of the experiment is presented below.

Primary goal.

To compare the rate and extent of absorption of ODT rimegepant administered sublingually versus rimegepant tablet administered as 1x75 mg in fasted healthy volunteers.

Secondary Objective: To evaluate the safety, tolerability and PK of rimegepant tablet and ODT.

Research purpose.

To compare the rate and extent of absorption of ODT rimegepant administered on the upper tongue versus rimegepant tablet administered as 1x75 mg in fasted healthy volunteers.

Research plan.

This study is a single-center, open-label, randomized, phase 1 trial designed to be conducted as follows:

Part I: 4-period, 2-sequential, crossover bioequivalence study with a fully replicated design.

Part II: A 2-period, 2-consecutive, crossover study of relative bioavailability. Part II can be done before Part I.

This study is intended to be submitted under the regulations of the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Health Canada. (Health Product and Food Branch) (HPFB).

Each part of the study involves dosing in one group; If for any reason more than one arm is dosed in one part of the study, all arms will receive the dose at the same clinical site and the same protocol requirements and procedures will be followed within each arm.

Sample size.

A total of approximately 60 healthy adult male or female volunteers will receive doses. Approximately 36 subjects will be included in Part I of the study, which examines bioequivalence. Based on preliminary data from previous studies, the intraindividual coefficient of variation should be approximately 30% for both AUC and Cmax. Thus, with this expected coefficient of variation and the expected AUC to Cmax ratio of 0.91 and 1.10, the study should have at least 80% power to

- 16 045801 show bioequivalence with 30 subjects in a 4-period study with a fully replicated design. By way of research.

Approximately 24 subjects will be included in Part II of the study, which examines relative bioavailability.

Holding periods and washout periods.

Part I

Subjects will be retained for a period from at least 10 hours before drug administration in period 1 until blood is drawn 72 hours after dosing in period 4, i.e. until the morning of Day 22.

There will be a washout period of 5 days or more between doses; subjects will continue to be retained in the clinic during washout periods. Each subject's participation in the study should last approximately 3 weeks.

Part II.

Subjects will be retained for a period from at least 10 hours before drug administration in period 1 until blood is drawn 72 hours after dosing in period 2, i.e. until the morning of Day 8.

There will be a washout period of 4 days or more between doses; subjects will continue to be retained in the clinic during washout periods. Each subject's participation in the study should last approximately 1.5 weeks.

Randomization and masking.

Subjects will be assigned to each treatment according to a 4-period, 2-sequential (CBCB or BCBC) and 2-period, 2-sequential (CA or AC) block randomization design generated using inVentiv for Part I and Part II, respectively. . The randomization code will not be made available to inVentiv's Bioanalytical Department until the clinical and analytical phases of the study are completed.

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

Study drug.

Part I

Each subject will receive each of the following 2 treatments twice.

Treatment C (study): 1x75 mg sublingual rimegepant ODT should be held under the tongue until completely dissolved and then swallowed without water, administered on an empty stomach.

Treatment B (comparative): 1x75 mg rimegepant tablet swallowed with water, administered on an empty stomach.

Part II.

Each subject will receive each of the following 2 treatments once.

Treatment C (study): 1x75 mg sublingual rimegepant ODT should be held under the tongue until completely dissolved and then swallowed without water, administered on an empty stomach.

Treatment A (comparative): 1x75 mg ODT rimegepant should be held on the top of the tongue until completely dissolved and then swallowed without water, administered on an empty stomach.

Part I

Processing C.

One ODT of rimegepant will be placed under each subject's tongue by health care facility personnel, and the subject will be instructed not to swallow saliva until the ODT is completely dissolved. The subject will be instructed to make a hand sign after the ODT is completely dissolved and swallowed. The hand and mouth will be checked to ensure medication consumption.

The dosing time will be the time the ODT is placed under the tongue. Drinking water will be prohibited from 1 hour before dosing until 1 hour after dosing. The complete dosing procedure should be completed within 2 minutes. If the ODT has not completely dissolved within 2 min, the subject will be asked to swallow the saliva and this will be documented. The start and end times of the full dose will be recorded.

Processing B.

One tablet of rimegepant will be administered to each subject with 240 ml of water, and hand and mouth checks will be performed to ensure drug consumption.

Part II.

Processing C.

One ODT of rimegepant will be placed under each subject's tongue by health care facility personnel, and the subject will be instructed not to swallow saliva until the ODT is completely dissolved. The subject will be instructed to make a hand sign after the ODT is completely dissolved and swallowed. The hand and mouth will be checked to ensure medication consumption.

- 17 045801

The dosing time will be the time the ODT is placed under the tongue. Drinking water will be prohibited from 1 hour before dosing until 1 hour after dosing. The complete dosing procedure should be completed within 2 minutes. If the ODT has not completely dissolved within 2 min, the subject will be asked to swallow saliva and this will be recorded. The start and end times of the full dose will be recorded.

Processing A.

One rimegepant ODT will be placed on the top of each subject's tongue by health care facility personnel, and the subject will be instructed not to swallow saliva until the ODT has completely dissolved. The subject will be instructed to make a hand sign after the ODT is completely dissolved and swallowed. The hand and mouth will be checked to ensure medication consumption.

The dosing time will be the time the ODT is placed on the tongue. Drinking water will be prohibited from 1 hour before dosing until 1 hour after dosing. The complete dosing procedure should be completed within 2 minutes. If the ODT has not completely dissolved within 2 min, the subject will be asked to swallow the saliva and this will be documented. The start and end times of the full dose will be recorded.

Sample collection and processing.

In each period, a total of 17 blood samples will be collected from each subject for pharmacokinetic analyses. 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 dosing dose (3 ml for each sampling time). The time tolerance for blood sample collection will be ±29 s for all post-dose samples collected during the retention period. Sample collections performed outside of the predetermined time intervals will be considered protocol deviations as the actual post-dose sample collection times will be used for pharmacokinetic and statistical analyses. Unless otherwise specified, or for reasons of subject safety, when blood sampling and other procedures overlap, blood sampling will be performed first. A dead volume intravenous catheter will be used to draw blood to avoid multiple skin punctures when appropriate. In other cases, blood samples will be collected through direct venipuncture.

The total blood volume, including samples collected for eligibility, genotyping and safety purposes, should not exceed 308 ml for Part I and 185 ml for Part II.

Blood plasma samples will be collected and processed.

Pharmacokinetic and statistical analyses.

PK analysis will be carried out using Phoenix!!! WinNonlin!!!, which is validated for bioequivalence/bioavailability studies. Inductive statistical analyzes will be performed using SAS!!! in accordance with FDA, EMA and HPFB guidelines.

Biological analysis of all samples must be completed before pharmacokinetic and statistical analyses.

Pharmacokinetic parameters.

The following PK parameters will be calculated using standard non-compartmental methods for rimegepant:

AUC0-t: area under the concentration-time curve from time zero to the last non-zero concentration;

AUC0-inf: area under the concentration-time curve from time zero to infinity (extrapolated);

Cmax: maximum observed concentration;

Residual area: calculated as 100-(1-AUC0-t/AUC0-inf);

Tmax: point in time when Cmax is observed;

T ^1/2 _el : half-life;

Kel: elimination rate constant;

Additional PK analysis can be performed.

Safety analysis population.

The safety study population was defined as all subjects who received at least one dose of the study drug.

Population for pharmacokinetic analysis.

For Part I, the pharmacokinetic analysis population will include all subjects who completed at least 2 periods, including treatment C and treatment B, and for whom the pharmacokinetic profile can be sufficiently characterized.

For Part II, the pharmacokinetic analysis population will include all subjects who completed the study and for whom the pharmacokinetic profile can be sufficiently characterized.

- 18 045801

Any subject with pre-dose concentrations will be presented in the concentration tables and

PK tables, but will be excluded from descriptive statistics and inductive analyzes (for the period considered in Part I) if the predose concentration is more than 5% of the Cmax measured for that subject.

Data from subjects who vomit during the sampling interval and who were not excluded from the study can be assessed after completion of the PK analysis. Any subject who experienced vomiting during a period equal to 2 times the median Tmax for rimegepant will be excluded from the statistical analyzes (i.e., descriptive statistics and inductive analyses). Similarly, subjects excluded from the study due to AEs (adverse events) or episodes of vomiting will be presented in the data lists, but excluded from the tables for statistical analysis (for the period of interest in Part I).

Statistical analyses.

A statistical analysis plan (SAP) will be prepared upon completion of the final protocol and finalized prior to database locking.

Demographic parameters will be briefly described descriptively. Treatment-emergent adverse events (TEAEs) will be summarized descriptively in relation to treatment for all subjects who received doses (safety analysis population). No inductive statistical analysis of the safety data was planned.

Plasma concentration-time curves for individual and average values will be presented on both linear and semi-logarithmic scales. Descriptive statistics (arithmetic and geometric means, standard deviation [SD], coefficient of variation [CV%], minimum [Min], maximum [Max], and median) for plasma concentrations and PK parameters will be presented.

The results of the experiment to determine bioequivalence are presented in table. 5, 6 and 7.

Table 5

Summary of descriptive statistics measures in BHV3000 for

( Analyst ) armakokinetic pa parameters in relation to processing and introduction ) - part I Introduction Treatment Subsequence AUC015 min. (hour*ng/ml) AUC030 min. (hour*ng/ml) AUC0-1 hour (hour*ng/ml) AUC0-2 hours (hour*ng/ml) AUCo-t (hour*ng/ml) AUCo-mf (hour*ng/ml) Residual area (%) (ng/ml) T _tah (hour) To _/O (hour) K _d (1/hour) BHV300 0 BHV300 0 1 2 Rimegepant OPT (investigational) Rimegepant ODT (investigational) N Average value SD cv% Minimum Median Maximum Geometric mean N Average value SD cv% 34 3.33 5.25 157.92 0.00 0.95 24.49 NC 33 3.37 4.44 131.57 34 48.61 54.43 111.96 0.00 25.58 179.44 NC 33 51.96 55.31 106.44 34 316.30 251.82 79.61 1.28 280.40 911.21 181.16 33 320.86 242.39 75.54 34 1049.14 500.98 47.75 301.45 1041.73 2171.04 927.52 33 1030.22 532.43 51.68 34 4973.13 1429.06 28.74 2707.35 4539.82 8132.62 4773.19 33 5339.16 1512.51 28.33 34 4986.40 1429.42 28.67 2717.72 4547.99 8147.14 4787.03 33 5354.99 1514.60 28.28 34 0.29 0.18 63.45 0.09 0.22 1.06 0.25 33 0.31 0.16 52.24 34 904.02 319.43 35.34 292.92 916.06 1855.8 4 849.54 33 915.87 308.35 33.67 34 1.47 0.64 43.30 0.67 1.50 2.50 1.34 33 1.54 0.70 45.10 34 7.84 1.56 19.93 5.75 8.11 10.44 7.68 33 8.69 1.83 21.04 34 0.0921 0.0190 20,607 6 0.0664 0.0855 0.1205 0.0902 33 0.0835 0.0189 22,646 9 Minimum 0.01 0.50 3.30 103.79 2344.91 2356.32 0.12 377.61 0.67 5.73 0.0540 Median 1.38 29.25 255.77 1082.04 5408.31 5421.88 0.25 920.80 1.50 8.54 0.0812 Maximum 18.95 210.33 753.99 2029.77 8855.17 8866.97 0.64 1529.9 1 2.50 12.84 0.1210

- 19 045801

Geometric mean 0.98 20.27 197.12 847.73 5125.96 5141.76 0.27 861.48 1.38 8.50 0.0816 BHV300 0 1 Rimegepant tablet (comparative) N 34 34 34 34 34 34 34 34 34 34 34 Average value 0.68 19.87 232.43 924.82 5201.88 5215.35 0.28 907.50 2.04 7.98 0.0910 SD 0.88 19.95 186.00 514.82 1552.87 1552.78 0.16 366.37 1.24 1.73 0.0199 cv% 128.78 100.37 80.03 55.65 29.85 29.77 57.73 40.37 60.80 21.74 21,843 4 Minimum 0.00 0.05 4.19 75.32 2635.48 2649.68 0.09 338.78 0.67 5.51 0.0603 Median 0.43 14.61 184.61 966.91 4838.68 4863.29 0.22 910.77 2.00 8.06 0.0860 Maximum 3.91 98.96 608.73 1957.51 9551.84 9565.90 0.86 2204.0 5 5.00 11.50 0.1257 Geometric mean NC 9.51 139.80 743.54 4992.61 5006.58 0.24 841.03 1.75 7.79 0.0889 BHV300 0 2 Rimegepant tablet (comparative) N 33 33 33 33 33 33 33 33 JJ JJ 33 Average value 1.13 25.37 259.64 950.90 5493.72 5509.22 0.29 834.10 1.83 8.60 0.0833 SD 1.74 30.78 181.00 459.51 1670.65 1674.11 0.15 289.63 0.88 1.50 0.0164 cv% 154.86 121.33 69.71 48.32 30.41 30.39 50.78 34.72 48.30 17.39 19,637 Minimum 0.00 0.29 5.44 84.31 2916.65 2936.35 0.12 386.15 0.67 5.89 0.0624 Median 0.31 11.41 226.97 889.26 5272.46 5293.49 0.28 798.82 1.50 8.49 0.0817 Maximum 6.89 121.36 732.48 2008.09 9819.52 9864.26 0.71 1671.5 5 5.00 11.10 0.1176 Geometric mean NC 11.38 186.64 811.29 5258.65 5274.04 0.26 786.69 1.64 8.46 0.0819

Table 6

Summary of Descriptive Statistics in BHV3000 for Pharmacokinetic Parameters in Relation to Treatment - Part I

An alit Treatment AUC015 min. (hour*ng/ml) AUC030 min. (hour*ng/ml) AUC0-1 hour (hour*ng/ml) AUC0-2 hours (hour*ng/ml) AUCo-t (hour*ng/ml) AUCo-mf (hour*ng/ml) Residual area (%) (ng/ml) t _tah (hour) To/, (hour) Ka(1/hour) BHV300 0 Sublingual ODT of rimegepant (investigational) N 67 67 67 67 67 67 67 67 67 67 67 Average value 3.35 50.26 318.55 1039.82 5153.41 5167.94 0.30 909.86 1.50 8.26 0.0879 SD 4.83 54.47 245.35 512.86 1471.15 1472.53 0.17 311.69 0.66 1.74 0.0193 CV% 144.27 108.38 77.02 49.32 28.55 28.49 57.53 34.26 44.00 21.07 21.9579 Minimum 0.00 0.00 1.28 103.79 2344.91 2356.32 0.09 292 92 0.67 5.73 0.0540 Median 1.26 29.16 267.11 1082.04 4956.26 4963.67 0.24 920.80 1.50 8.39 0.0827 Maximum 24.49 210.33 911.21 2171.04 8855.17 8866.97 1.06 1855.84 2.50 12.84 0.1210 Geometric mean NC NC 188.85 887.32 4943.80 4958.58 0.26 855.40 1.36 8,078 0.0859 BHV300 0 Rimegepant tablet (comparative) N 67 67 67 67 67 67 67 67 67 67 67 Average value 0.90 22.58 245.83 937.67 5345.62 5360.09 0.29 871.35 1.94 8.28 0.0872 SD 1.38 25.81 182.68 484.74 1606.41 1608.21 0.15 330.38 1.08 1.64 0.0185 cv% 153.46 114.29 74.31 51.70 30.05 30.00 53.91 37.92 55.60 19.78 21.2192 Minimum 0.00 0.05 4.19 75.32 2635.48 2649.27 0.09 338.78 0.67 5.51 0.0603 Median 0.34 14.03 218.33 899.23 5093.43 5104.27 0.25 851.12 2.00 8.40 0.0825 Maximum 6.89 121.36 732.48 2008.09 9819.52 9864.26 0.86 2204.05 5.00 11.50 0.1257 Geometric mean 10.39 161.18 776.17 5121.92 5136.57 0.25 813.81 1.69 8.12 0.0854

Table 7

Ratios, 90% geometric confidence intervals, CV _WR (FDA method)______

RK parameter Ratio ¹ (%) 90% lower CL ² (%) 90% upper CI ² (%) 95% upper confidence limits ³ (%) CVwr(%) Ln(AUCo-t) 96.79 92.63 101.15 - 15.70 Ln(AUCo- _mf ) 96.81 92.66 101.14 - 15.68 Ln(Cmax) 104.65 97.04 112.84 - 23.74

Calculated using the mean values obtained by the least squares method according to the formula: _e (DIFFER _E NCE) _xl00 .

² 90% geometric confidence interval using ln-transformed data.

³ ABE approach with edge scaling.

-20045801

Example 6: Efficacy of rimegepant; results and analysis from the BHV3000301 clinical trial described in Example 2.

Goals.

To compare the efficacy, safety and tolerability of rimegepant 75 mg oral tablet with placebo for the acute treatment of migraine in adults.

Methods.

The double-blind, randomized, placebo-controlled, multicenter study (Study 301, NCT03235479) was eligible to enroll adults aged >18 years with at least 1 year of migraine according to ICHD 3-beta anamnesis criteria. After a 3- to 28-day screening period, subjects were randomized to receive rimegepant 75 mg or matched placebo and instructed to treat one migraine attack with 1 dose of masked study drug (rimegepant or placebo) when the headache was of moderate to severe intensity. The composite primary endpoints were freedom from pain at 2 hours post-dose and freedom from most distressing symptom (MBS) at 2 hours post-dose. Safety assessments included adverse events (AEs), ECG, vital signs, physical performance measurements, and standard laboratory tests, including liver function assessment. Unless otherwise stated, values are presented as mean ±SD.

Results.

A total of 1162 subjects were randomized to receive rimegepant (n=582) or placebo (n=580), and 1084 were assessed for efficacy (rimegepant n=543, placebo n=541). Subjects had a mean age of 41.6 ± 12.2 years, 85.5% were female, and had a history of 4.7 ± 1.8 attacks per month. At 2 hours post-dose, rimegepant-treated patients had higher pain freedom scores than placebo-treated patients (19.2% vs. 14.2%, P=0.0298) and were more likely to be free of MBS (36.6% vs. 27.7%, P=0.0016); and had higher rates of pain relief (56.0% vs. 45.7%, P=0.0006). A single dose of rimegepant without rescue drug was superior to placebo for long-term pain freedom and pain relief from 2 to 48 hours after dosing (P=0.013 and P=0.0003, respectively). When measuring functional disability, a higher proportion of rimegepant-treated patients achieved normal functioning at 2 hours (P<0.0001).

The safety and tolerability profiles of rimegepant were similar to placebo. The most common AEs 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 above the upper limit of normal (ULN) were observed in 2.0% (11/546) and 3.6% (20/549) of rimegepant- and placebo-treated subjects, respectively. One subject in the rimegepant group (0.2%) and 1 subject in the placebo group (0.2%) had a transaminase level 3 times the ULN, and no subjects in either group had a level 5 times the ULN . No increases in bilirubin levels greater than 2 times ULN were observed. Serious AEs (SAEs) were observed in 0.4% (n=2) of subjects in the rimegepant group and 0.2% (n=1) in the placebo group. It was determined that no SAEs were associated with the study drug. Both subjects with SAE in the rimegepant group were not dosed prior to the onset of SAE.

Conclusions.

Significant and durable clinical effects were observed with a single dose of rimegepant on several outcome measures, including freedom from pain, freedom from MBS, pain relief, and return to normal function. The rimegepant 75 mg oral tablet demonstrated favorable tolerability and safety, including a liver safety profile similar to placebo. These clinically significant results complement the beneficial effects observed in an identical phase 3 study (Study 302) and a prior phase 2b study. Rimegepant may potentially offer patients a new approach to the acute treatment of migraine.

Endpoints । Rimegepant, 75 mg Placebo P-value ^£ Compound main Freedom from pain in 2 hours I 19.2% [104/543] 14.2% [77/541] 0 0298 Freedom from MBS in 2 hours ! 36.6% [199/543] 27.7% [150/541] 0.0016 Selected secondary Freedom from photophobia in 2 hours 1 34.9% [164/470] 24.8% [120/483] 0.0005

- 21 045801

Freedom from phonophobia in 2 hours 38.6% [133/345] 30.9% [1 13/366] 0.0299 Pain relief in 2 hours 56.0% [304/543] 45.7% [247/541] 0.0006 Freedom from nausea in 2 hours 46.9% 1149/318| 41.6% 1134/3221 0.1815 Long lasting pain relief, 2-24 hours 38.9% [211/543] 27.9% [151/541] 0.0001

MBS is the most distressing symptom.

^a Endpoints were tested hierarchically in the order shown at P=0.05.

The results from Example 6 are also shown in FIG. 3.

Example 7 Efficacy of rimegepant: results and analysis from the clinical trial BHV3000302 described in Example 3.

Goals.

To compare the efficacy, safety and tolerability of rimegepant 75 mg oral tablet with placebo for the acute treatment of migraine in adults.

Methods.

The double-blind, randomized, placebo-controlled, multicenter study (Study 302, NCT03237845) was eligible to enroll adults aged >18 years with at least 1 year of migraine according to ICHD 3-beta anamnesis criteria. After a 3- to 28-day screening period, subjects were randomized to receive rimegepant 75 mg or matched placebo and instructed to treat one migraine attack with 1 dose of masked study drug (rimegepant or placebo) when the headache was of moderate to severe intensity. The composite primary endpoints were freedom from pain at 2 hours post-dose and freedom from most distressing symptom (MBS) at 2 hours post-dose. Safety assessments included adverse events (AEs), ECG, vital signs, physical performance measurements, and standard laboratory tests, including liver function assessment. Unless otherwise stated, values are presented as mean ±SD.

Results.

A total of 1186 subjects were randomized to receive rimegepant (n=594) or placebo (n=592), and 1072 were assessed for efficacy (rimegepant n=537, placebo n=535). Subjects had a mean age of 40.6 ± 12.0 years, 88.7% were female, and had a history of 4.6 ± 1.8 attacks per month. At 2 hours post-dose, rimegepant-treated patients had higher pain freedom scores than placebo-treated patients (19.6% vs. 12.0%, P=0.0006) and were more likely to be free of MBS (37.6% vs. 25.2%, P<0.0001); and had higher rates of pain relief (58.1% vs. 42.8%, P<0.0001). A single dose of rimegepant without rescue drug was superior to placebo for long-term pain freedom and pain relief from 2 to 48 hours after dosing (P=0.0181 and P<0.0001, respectively). When measuring functional disability, a higher proportion of rimegepant-treated patients achieved normal functioning at 2 hours (P<0.0001).

The safety and tolerability profiles of rimegepant were similar to placebo. The most common 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 above the upper limit of normal (ULN) were observed in 2.4% (13/543) and 2.2% (12/543) of rimegepant- and placebo-treated subjects, respectively. No subjects in any of the treatment groups had transaminase levels greater than 3 times the ULN or observed bilirubin levels greater than 2 times the ULN. Serious AEs (SAEs) were observed in 1 subject in the rimegepant group (back pain) and 2 subjects in the placebo group. It was determined that no SAEs were associated with the study drug.

Conclusions.

Significant and durable clinical effects were observed with a single dose of rimegepant on several outcome measures, including freedom from pain, freedom from MBS, pain relief, and return to normal function. The rimegepant 75 mg oral tablet demonstrated favorable tolerability and safety, including a liver safety profile similar to placebo. These clinically significant results complement the beneficial effects observed in Study 301. Rimegepant may potentially offer patients a new approach to the acute treatment of migraine.

- 22 045801

Endpoints । Rimegepant, 75 mg Placebo P-value ^a

Compound main

Freedom from pain in 2 hours Freedom from MBS in 2 hours Selected secondary Freedom from photophobia in 2 hours Freedom from fopophobia in 2 hours Pain relief in 2 hours Freedom from nausea in 2 hours Long lasting pain relief, 2-24 1 19.6% [105/537] 12.0% [64/535] 0.0006 1 37.6% 1202/5371 25.2% | 135/5351 <0.0001 1 37.4% [183/489] 22.3% [106/477] <0.0001 i 36.7% [ 133/362] 26.8% [ 100/374] 0.0039 58.1% [3 12/537] 42.8% [229/535] <0.0001 ! 48.1% [171/355] 43.3% [145/336] 0.2084 hours 1 42.6% [229/537] 26.5% [142/535] <0.0001

MBS is the most distressing symptom.

^a Endpoints were tested hierarchically in the order shown at P = 0.05.

The results from Example 7 are also shown in FIG. 4.

Example 8 Clinical Trial - BHV3000-303: Phase 3: Double-blind, randomized, placebo-controlled trial of the safety and efficacy of BHV-3000 (rimegepant) Orally Disintegrating Tablet (ODT) for the acute treatment of migraine (ClinicalTrials.gov, ID: NCT03461757).

The phase 3 clinical trial was conducted as follows with 1812 participants.

Description of the study.

Short description.

The purpose of this study is to compare the effectiveness of BHV-3000 (rimegepant ODT) versus placebo in subjects with acute migraine.

Condition or

disease Intervention/Treatment Phase

Migraine Drug: Rimegepant Phase 3

Drug: placebo

Research plan. Study type: interventional (clinical trial)

Actual number of participants: 1812 participants

Distribution: Intervention model: randomized parallel assignment Disguise: triple (participant, medical worker, researcher) Primary goal: treatment Official name: BHV3000-303: phase 3, double-blind, randomized placebo controlled trial safety and effectiveness of BHV3000 (rimegepant) as an orally disintegrating tablet (ODT) for the acute treatment of migraine

Date of actual start of the study: February 27, 2018

The date of actual completion of the assessment is October 8, 2018 of the main indicators:

Date of actual completion October 15, 2018 of the study:

-23 045801

Groups and interventions.

Group Intervention/Treatment

Experimental: Group I: BHV-3000 Drug:

(active agent) rimegepant

BHV-3000 (rimegepant) 75 mg (ODT)

Comparison with placebo: group 2: Drug:

comparative drug placebo placebo mg corresponding ODT placebo

Outcome indicators.

Key outcome indicators.

1. Freedom from pain with rimegepant versus placebo in the acute treatment of migraine will be measured using the number of evaluable subjects who report freedom from pain 2 hours after dosing. [Time frame: two hours after dosing.]

Pain will be measured on a 4-point Likert scale (0=none, 1=mild, 2=moderate, 3=severe).

2. Freedom from most distressing symptom (MBS) with rimegepant versus placebo will be measured using the number of evaluable subjects who report no MBS at 2 hours post-dose. [Time frame: two hours after dosing.]

MBS (nausea, phonophobia, or photophobia) will be measured using a binary scale (0=absent, 1=present).

Secondary outcome measures.

1. Measure rimegepant versus placebo for pain relief at 2 hours post-dose for those who reported moderate to severe pain at enrollment and then reported no or mild pain. [Time frame: 2 hours after dose.]

Pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

2. Functional disability scale. [Time frame: 2 hours after dose.]

Subjects report themselves as normal on a functional disability scale

3. Rimegepant compared with placebo for pain relief over the period 2 to 24 hours, using the number of subjects who do not use any salvage drugs and do not experience any moderate or severe headache during this period. [Time frame: 2 hours - 24 hours after dosing.]

Long-term pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

4. Long-term freedom from the most distressing symptom over a period of 2 to 24 hours, assessed using the number of subjects who do not experience their most distressing symptom during the specified time period. [Time frame: 2 -24 hours after dosing.]

The most painful symptom.

5. The outcome for rimegepant versus placebo for the likelihood of requiring a rescue drug will be assessed based on the number of subjects who received a rescue drug within 24 hours of administration of the study drug (BHV3000 or placebo). [Time frame: up to 24 hours after dosing.]

The need for a reserve therapy drug.

6. Long-term ability to function at a normal level, as measured by a functional disability scale. [Time frame: 2-24 hours after dosing.]

Subjects report their condition as normal on a functional disability scale.

7. Rimegepant versus placebo for long-term pain relief over 2 to 48 hours using the number of subjects not using any salvage medications and not experiencing moderate-to-severe headache. [Time frame: 2 hours - 48 hours after dosing.]

Long-term pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

- 24 045801

8. Rimegepant compared with placebo for freedom from pain, the most distressing symptom within 2 to 48 hours after dosing. [Time frame: 2-48 hours after dosing.]

The most painful symptom.

9. Long-term ability to function at a normal level, as measured by a functional disability scale. [Time frame: 2-48 hours after dosing.]

Subjects report their condition as normal on a functional disability scale.

10. Rimegepant versus placebo based on the tabulated number of subjects who reported no photophobia at 2 hours post-dose, in the subgroup of subjects who reported photophobia for headache at inclusion. [Time frame: 2 hours after dose.]

Freedom from photophobia.

11. Functional disability scale. [Time frame: 90 minutes after dose.]

Subjects report their condition as normal on a functional disability scale.

12. Rimegepant versus placebo for long-term pain relief at 90 minutes using the number of subjects not using any salvage medications and not experiencing moderate-to-severe headache. [Time frame: 90 minutes after dose.]

Pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

13. Rimegepant versus placebo over the 2 to 24 hour period using the number of subjects who do not experience any headache during the time period of interest. [Time frame: 2 hours -24 hours after dosing.]

Long-term freedom from pain, measured on a 4-point numeric rating scale (none, mild, moderate, severe).

14. Long-term freedom from the most distressing symptom at 90 minutes, assessed using the number of subjects who do not experience their most distressing symptom during the specified time period. [Time frame: 90 minutes after dose.]

The most painful symptom.

15. Performance for rimegepant versus placebo for long-term pain freedom at 90 minutes post-dose will be measured using the number of subjects who do not experience any headache during the time period of interest. [Time frame: 90 minutes after dose.]

Long-term freedom from pain, measured according to a 4-point numeric rating scale.

16. Rimegepant versus placebo based on the tabulated number of subjects who reported no phonophobia at 2 hours post-dose, in the subgroup of subjects who reported phonophobia for headache at inclusion. [Time frame: 2 hours after dose.]

Freedom from phonophobia.

17. Rimegepant versus placebo for long-term pain freedom over the period 2 to 48 hours will be measured using the number of subjects who do not experience any headache during the time period of interest. [Time frame: 2 hours - 48 hours after dosing.]

Long-term freedom from pain, measured on a 4-point numeric rating scale (none, mild, moderate, severe).

18. Measure rimegepant versus placebo for pain relief at 60 minutes post-dose in cases that reported moderate to severe pain at enrollment and then reported no or mild pain. [Time frame: 60 minutes after dose.]

Long-term pain relief measured on a 4-point numeric rating scale (none, mild, moderate, severe).

19. Functional disability scale. [Time frame: 60 minutes after dose.]

Subjects report their condition as normal on a functional disability scale.

20. Freedom from nausea will be determined by tabulating the number of subjects who report no nausea 2 hours after dosing in the subset of subjects who reported nausea with headache at enrollment. [Time frame: 2 hours after dose.]

Freedom from nausea.

21. Assess the number of subjects who are pain-free 2 hours after dosing and then have headache of any severity (response 1, 2, or 3 on a 4-point scale) within 48 hours after administration of study drug, rimegepant, or placebo. [Time frame: 2 hours - 48 hours after dosing.]

- 25 045801

Return of pain.

Additional details related to the clinical trial, including eligibility criteria, contacts and locations, and more information can be found at www.clinicaltrials.gov for ClinicalTrials.gov Identifier: NCT03461757.

Example 9 The results of the clinical trial described in Example 8 are summarized below.

Study 303 met its composite primary endpoints of freedom from pain and freedom from most distressing symptom (MBS) at 2 hours using a single dose (Table 8). Importantly, patients treated with the ODT formulation of Zydis rimegepant according to the present invention were quantitatively different from placebo in terms of pain relief after 15 minutes and demonstrated statistical significance at 60 minutes (p<0.0001) (see FIG. 5 ). In fig. Figure 5 shows the percentage of patients experiencing pain relief 0 to 2 hours post-dose for patients who received a single 75 mg dose of rimegepant ODT Zydis or placebo. Data are Kaplan-Meier exploratory estimates, with pain relief defined as patients who have either mild pain or no pain for a specified interval. Subjects were censored if they were taking a salvage drug or did not show up for a follow-up appointment within a specified interval. In addition, a significantly greater percentage of patients treated with ODT Zydis rimegepant returned to normal function within 60 minutes compared with placebo (p<0.002). Long-term clinical benefit was observed over 48 hours for pain relief (p<0.001), freedom from pain (p<0.001), most distressing symptom (p<0.001), functional disability (p<0.003) and several other secondary endpoints after a single dose of rimegepant compared with placebo. The vast majority of patients treated with ODT Zydis rimegepant (85%) did not use any salvage therapy.

Table 8

Study 303: Freedom from Pain and Freedom from Your Worst Symptom

End point in 2 hours Rimegepant (N=669) Placebo (N=682) Difference Adjusted p-value Freedom from pain 21.2% 10.9% 10.3% <0.0001 Freedom from MBS ¹ 35.1% 26.8% 8.3% 0.0009

In Study 303, the Zydis ODT rimegepant was statistically different from placebo for the two composite primary endpoints, and the first 21 consecutive secondary outcome measures were prespecified in a hierarchical test (p-values <0.05). These secondary outcome measures and additional study outcome measures in this study are expected to be presented at upcoming scientific conferences in 2019.

The safety and tolerability of rimegepant in Study 303 was consistent with the profile previously observed in Study 301 (Example 2) and 302 (Example 3). In table Figure 9 shows the pooled safety data from all three trials. No adverse events (AEs) occurred in the rimegepant group with an incidence greater than 1.6%, and cumulative AE rates were similar to placebo. Regarding liver function tests, one placebo-treated patient and one rimegepant-treated patient demonstrated LFT >3xULN in Study 303. Pooled liver function test results from the three pivotal clinical trials (n=3556) conducted to date , demonstrated that rimegepant was similar to placebo in terms of aminotransferase (ALT or AST) levels above the upper limit of normal (ULN) and the absence of patients having increases in bilirubin levels 2 times the ULN (Table 10).

- 26 045801

Table 9

Pooled safety and adverse event (AE) data.

Full set of AE data from studies 301, 302 and 303 from patients reporting AE within 48 hours of dosing with an incidence >1% Adverse event Rimegepant (n=1771) Placebo (n=1785) >1 AE per period research* 252 (14.2%) 209 (13.2%) Nausea 26 (1.5%) 15 (0.8%) in 21 (1.2%) 12 (0.7%) SAE** 3 (0.2%) 3 (0.2%) *Without other individual AEs >1% in rimegepant-treated subjects other than those listed in the table. Includes all AEs without determination of drug relatedness. **No drug-related serious adverse events (SAEs). 2 of the subjects with SAE in the rimegepant group and 1 in the placebo group were not dosed before the SAE occurred. Table 10 Pooled Liver Function Test (LFT) profile: complete set of LFT data from studies 301,302 and 03* ALT or AST Rimegepant (n=1771) Placebo (n=1785) >ULN ¹ 48 (2.7%) 52 (2.9%) >3xULN 2(0.1%) 2(0.1%) >5x ULN 1 (0.06%) ² 0 > Yuh ULN 0 0 > 20χ ULN 0 0

Upper limit of normal; ALT - alanine aminotransferase; AST - aspartate aminotransferase.

² Non-drug-related elevation in AST according to investigator: Subject has recently begun weightlifting with laboratory findings consistent with muscle damage.

*AST/ALT categories are not mutually exclusive; no increases in bilirubin levels >2xUTN in studies 301, 302 and 303.

Additional results from the clinical trial described in Example 8 (Study 303) are presented in Table 1. 11, 12 and fig. 6.

-27045801

Table 11

ORDER Primary Endpoints Rimegepant Placebo P-value Home, 1 Pain after 2 hours 21.2% 10.9% <0.0001 Home, 2 MBS in 2 hours 35.1% 26.8% 0.0009 ORDER SECONDARY Secondary endpoints BHV RVO P-value 1 Pain relief through 2 hours 59.3% 43.3% <0.0001 2 Functional disability after 2 hours 38.1% 25.8% <0.0001 3 Long lasting pain relief within 2-24 hours 47.8% 27.7% <0.0001 4 MBS 2-24 27.1% 17.7% <0.0001 Probability of acceptance 5 backup therapy drugs 24 hours in advance 14.2% 29.2% <0.0001 6 Functional disability 2-24 29.6% 16.9% <0.0001 7 Long lasting pain relief for 2-48 hours 42.2% 25.2% <0.0001 8 MBS 2-48 23.2% 16.4% 0.0018 9 Functional disability 2-48 26.0% 15.4% <0.0001 10 Photophobia after 2 hours 33.4% 24.5% 0.0007 eleven Functional disability after 90 minutes 30.2% 21.3% 0.0002 12 Pain relief in 90 minutes 49.6% 37.2% <0.0001 13 Long lasting freedom from pain for 2-24 hours 15.7% 5.6% <0.0001 14 Freedom from MBS in 90 minutes 27.4% 21.5% 0.0128 15 Freedom from pain in 90 minutes 15.1% 7.3% <0.0001 16 Phonophobia after 2 hours 41.7% 30.2% 0.0003 17 Long lasting freedom from pain for 2-48 hours 13.5% 5.4% <0.0001 18 Pain relief after 60 minutes 36.8% 31.2% 0.0314 19 Functional disability after 60 minutes 22.3% 15.8% 0.0025 20 Nausea after 2 hours 51.0% 45.2% 0.0898 21 Return of pain 2-48 36.6% 50.0% 0.0577

-28045801

Table 12

Phase 3 Study of Rimegepant (BHV-3000) - Study 303 Long-lasting Pain Relief ¹ 2, 3, and 4 to 24 or 48 hours Long lasting pain relief Rimegepant n=669 Placebo n=682 p-value 24 hours 2-24 hours 47.8% 27.7% <0.0001 3-24 hours 56.4% 33.1% <0.0001 4-24 hours 61.7% 36.8% <0.0001 48 hours 2-48 hours 42.2% 25.2% <0.0001 3-48 hours 49.9% 29.8% <0.0001 4-48 hours 54.7% 33.0% <0.0001 ¹ Long-term pain relief is defined as patients who either have mild pain or are pain-free for a specified interval without the use of a rescue drug. Analyzes 3-24, 4-24, 3-48 and 4-48 are exploratory

Example 10: Clinical Trial - BHV3000-201: Open-label Safety Study in the Acute Treatment of Migraine (ClinicalTrials.gov, Identifier: NCT 03266588).

The Phase 2/3 clinical trial is conducted as follows with approximately 2000 participants.

Description of the study.

Short description.

The purpose of this study is to evaluate the safety and tolerability of BHV3000 (rimegepant).

Condition or disease Intervention/treatment Phase migraine drug: rimegepant phase 2, phase 3

Research plan. Study type: interventional (clinical trial) Estimated number included: 2000 participants Intervention model: assignment of one group Disguise: no (open) Primary goal: treatment Official name: multicenter, open-label, long-term study of the safety of BHV3000 in the acute treatment of migraine Date of actual start of the study: August 30, 2017

Estimated completion date for the assessment of key outcome measures July 2019:

Estimated completion date of the study: July 2019

Groups and interventions.

Group : Intervention/treatment

Experimental: rimegepant Medicine: rimegepant 75 mg oral tablet Other name: BHV3000

- 29 045801

Key outcome indicators.

1. Assess the safety and tolerability of rimegepant (BHV-3000) by measuring the incidence and severity of adverse events and early study discontinuations due to adverse events. [Time frame: 52 weeks.] Number of subjects with treatment-emergent adverse events assessed by laboratory tests, ECG, physical examination (safety and tolerability).

Secondary outcome measures.

1. ALT or AST >3xULN with increased total bilirubin >2xULN. [Time frame: 52 weeks] in liver function tests.

2. liver-related adverse events and liver-related adverse events that lead to early termination of study participation. [Time frame: 52 weeks] liver-related adverse events.

Additional details related to the clinical trial, including eligibility criteria, contacts and locations, and more information can be found at www.clinicaltrials.gov under ClinicalTrials.gov ID: NCT03266588.

Example 11 The results of the clinical trial described in Example 10 are summarized below.

The BHV3000-201 study showed initial positive results. The interim analysis (database lock dated November 21, 2018) demonstrated that the safety and tolerability of long-term dosing of rimegepant in patients with migraine is consistent with the profile observed in phase 1-3 studies to date. Patients were allowed to treat migraine attacks of all degrees of severity (from mild to severe) up to once a day throughout the year. Initial results for the liver safety and tolerability of 75 mg rimegepant in study participants are based on both adverse event analyzes and routinely scheduled liver function tests. Interim liver data were reviewed by a third-party and independent panel of liver experts. There were no cases of liver injury assessed as likely to be related to the study drug, and no cases of Hay's law were identified. The panel concluded that no signal of liver hazard was identified at this time, including in the subgroup of patients with near-daily dosing (>15 doses/month). Overall, it was noted that, compared with trials of migraine treatment with drugs other than rimegepant, there was a very low incidence of overall liver function test abnormalities in patients treated with rimegepant (1.0% incidence of serum ALT or AST at the level >3xULN). Subjects will continue to participate in Study 201, with additional data analyzes being sent to

NDA, as well as required security updates over a 120-day period.

In addition to the interim safety analysis, data from subjects were assessed to determine reductions in headache days per month. The data presented in the table demonstrate that patients experienced headache on fewer days per month while taking rimegant during their treatment phase compared to their observation phase of the study. For example, of 1731 subjects, 683 (39.5%) had at least a 20% reduction in headache days per month, and 602 (34.8%) had at least a 25% reduction in headache days per month. , 523 (30.2%) had a decrease in headache days per month of at least

30%, 442 (25.5%) had at least a decrease in headache days per month

35%, 362 (20.9%) had at least a decrease in headache days per month

40%, 287 (16.6%) had at least a decrease in headache days per month

45%, 226 (13.1%) had at least a decrease in headache days per month

50%. This result was surprising and unexpected and indicates that rimegepant may function as a prophylactic treatment for migraine as well as an acute treatment. Reductions in the average number of days with headache per month were observed starting from the first month, and they continued in subsequent months of therapy.

Accordingly, according to the present invention, it is possible to treat patients who suffer from migraine headaches by administering rimegepant to the patient at a dose of, for example, 75 mg, and at a frequency of, for example, once a month, twice a month, three times a month , four times a month, five or more times a month, ten or more times a month, fifteen or more times a month, effective in reducing the number of headaches per month, for example, a 20% or greater reduction in the number.

-

Claims (6)

BHV-3000-201: percentage reduction in the number of migraine attacks in g Table 13 and month Group included in Group included in Group included in Total research (2-8) research (9-14) research (4-14) Overall percentage decline 1004 458 269 1731 >= 20.0% decrease 353 (35.2) 171 (37.3) 159(59.1) 683 (39.5) >= 25.0% decrease 308 (30.7) 150 (32.8) 144 (53.5) 602 (34.8) >= 30.0% decrease 268 (26.7) 125 (27.3) 130(48.3) 523 (30.2) >= 35.0% decrease 224 (22.3) 101 (22.1) 117(43.5) 442 (25.5) >= 40.0% decrease 181 (18.0) 81 (17.7) 100 (37.2) 362 (20.9) >= 45.0% decrease 144(14.3) 60(13.1) 83 (30.9) 287(16.6) >= 50.0% decrease 113 (11.3) 46 (10.0) 67 (24.9) 226(13.1) In this application, various publications are referred to by reference to the author's name and date, or to the patent number or patent publication number. The disclosures of these publications are thus incorporated herein by reference in their entirety to more fully describe the state of the art known to those skilled in the art as of the date of the invention described and claimed herein. However, the citation of references herein should not be construed as an endorsement that such reference is prior art of the present invention. Those skilled in the art will understand or be able to determine numerous equivalents to the specific procedures described herein using no more than routine experimentation. Such equivalents are considered to be within the scope of the present invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the specification and examples herein may be used. Moreover, it is contemplated that specific elements within lists of elements, or subsets of elements within larger groups of elements, may be combined with other specific elements, subsets of elements, or larger groups of elements, whether or not there is specific disclosure herein identifying such combination . CLAIM 1. A pharmaceutical composition containing a pharmaceutically acceptable carrier and a therapeutically effective amount of rimegepant or a pharmaceutically acceptable salt thereof; and wherein the pharmaceutical composition is in the form of a molded solid, rapidly dispersing oral dosage form. 2. The pharmaceutical composition according to claim 1, wherein the molded solid, rapidly dispersing oral dosage form contains 75 mg of rimegepant or a pharmaceutically acceptable salt thereof equivalent to 75 mg of rimegepant base. 3. The pharmaceutical composition according to claim 2, wherein rimegepant is in the form of a hemisulfate salt sesquihydrate. 4. Pharmaceutical composition according to claim 2 in the form of an oral tablet. 5. Pharmaceutical composition according to claim 1, containing from 70-80 wt.% rimegepant hemisulfate sesquihydrate, 10-20 wt.% fish gelatin, 10-20 wt.% filler and 0.1-5.0 wt.% flavoring. 6. Pharmaceutical composition according to claim 5, wherein the excipient is mannitol. -