COMPOSITIONS AND METHODS FOR TREATING OBSESSIVE-COMPULSIVE DISORDER

Abstract

A method for treating obsessive-compulsive disorder in a patient in need is disclosed herein by administering to the patient a dosage form that includes an effective amount of troriluzole.

Description

COMPOSITIONS AND METHODS FOR TREATING OBSESSIVE-COMPULSIVE DISORDER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 043,681 filed on June 24, 2020, and all benefits arising therefrom pursuant to 35 U.S.C. § 119, the contents of which are incorporated herein by reference in their entirety. FIELD OF INVENTION

[0001] The present invention relates to pharmaceutical compositions for treating obsessive-compulsive disorder (OCD) with riluzole prodrugs. Specifically, the present invention relates to methods for treating OCD with pharmaceutical compositions containing troriluzole. BACKGROUND OF THE INVENTION

[0002] Obsessive-compulsive disorder (OCD) is a debilitating psychiatric condition characterized by recurrent, intrusive thoughts (obsessions) and / or repetitive, stereotyped behaviors (compulsions) that last for at least one hour per day and significantly interfere with a person's normal level of functioning. Although cognitive behavioral therapy and pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) are effective treatments for some patients, a significant subgroup experiences minimal symptom relief with these standard treatments. When severe, OCD is completely disabling and has devastating consequences for patients and their families. Augmentation strategies with neuroleptic drugs may improve the effectiveness of SSRI treatment, but do not eliminate the symptoms of OCD (Saxena et al., J. Clin. Psychiatry, 1996, 57, 303-306, 1996; McDougle et al., J. CHn.Psychiatry, 1995, 56, 526-528) and are associated with adverse effects when taken chronically. The clinical observation that few patients achieve a complete response to SSRIs or dopamine antagonists suggests that other neurochemical systems are involved in the pathophysiology of OCD.

[0003] Obsessive-compulsive disorder (OCD) affects one in 40 and more than 2 million individuals in the United States, significantly impacting their quality of life. One-third of patients do not respond to current treatments. Approximately 40% to 60% of patients with OCD continue to experience significant residual symptoms despite approved treatments. Some treatment-resistant patients undergo psychosurgery (cingulotomy or deep brain stimulation) to alleviate debilitating symptoms.

[0004] There has been no mechanistically novel drug approved for OCD in over 20 years. Therefore, new treatments are urgently needed to alleviate the suffering and disability of patients with OCD. BRIEF DESCRIPTION OF THE INVENTION

[0005] The present invention relates to a pharmaceutical composition including troriluzole and methods for treating obsessive-compulsive disorder by using the composition.

[0006] In one embodiment, a method is provided for treating obsessive-compulsive disorder in a patient in need. The method includes administering to the patient a dosage form containing an effective amount of troriluzole.

[0007] In another embodiment, a dosage form is provided that includes troriluzole in an amount effective to treat obsessive-compulsive disorder in a patient who needs it. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] These and / or other aspects will become evident and be more easily appreciated from the following description of the embodiments, taken together with the accompanying drawings in which:

[0009] Figure 1 shows a phase 2 / 3 TOC study design with troriluzole; and

[0010] Figure 2 shows the mean Y-BOCS scores from the study with troriluzole at baseline and at weeks 4, 8, and 12. DETAILED DESCRIPTION OF THE INVENTION

[0011] The following detailed description is provided to assist persons of intermediate skill in implementing the embodiments of the present invention. Example embodiments are described in detail below. However, these embodiments are illustrative only, and this disclosure is not limited to them but is defined by the scope of the appended claims. Persons of intermediate skill may make modifications and variations to the embodiments described herein without departing from the spirit or scope of this disclosure.

[0012] Accordingly, the embodiments are simply described below, by reference to structures and schemes, to explain aspects of the present description. As used herein, the term and / or includes any and all combinations of one or more of the associated enumerated elements. The term or means and / or. Expressions such as at least one of, when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

[0013] It shall be understood that, when it is stated herein that an element is on another element, it may be in direct contact with the other element or there may be intervening elements. Conversely, when an element is referred to as being directly on another element, there are no intervening elements present.

[0014] It shall be further understood that, although the terms first, second, third, etc., may be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections are not limited by these terms. These terms are used only to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Therefore, a first element, component, region, layer, or section, as discussed later, could be called a second element, component, region, layer, or section without departing from the teachings of the present embodiments.

[0015] It is understood that the term comprises and / or the expression comprising or including and / or including, when used in this descriptive memory, specifies the presence of indicated features, regions, whole numbers, stages, operations, elements and / or components, but does not exclude the presence or addition of one or more features, regions, whole numbers, stages, operations, elements, components and / or groups of these.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of average skill in the trade to which this disclosure pertains. The terminology used in the description is only to describe particular embodiments and is not intended to be exhaustive. It is further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning consistent with their meaning in the context of the relevant technique and / or this disclosure, and should not be interpreted in an idealized or overly formal sense unless expressly defined as such herein.

[0017] As used in this application, except where otherwise expressly stated herein, each of the following terms shall have the meanings set forth below. Additional definitions are provided throughout the application. In cases where LQLn / ZZnZ / E / YIAI a term is not specifically defined herein, that term receives a recognized meaning in the art from people of middle-level skill who apply that term in the context of its use when describing the embodiments of the present invention.

[0018] The articles un and una refer to one or more than one (i.e., at least one) of the article's grammatical object, unless the context clearly indicates otherwise. For example, un elemento means one or more than one item.

[0019] Additional aspects will be set out, in part, in the description below and, in part, will be evident from the description. Obsessive-Compulsive Disorder

[0020] The methods and compositions, according to embodiments of the present invention, are useful in the treatment of obsessive-compulsive disorder (OCD). In some embodiments of the invention, the treated individual is evaluated according to the claimed method by using the Yale-Brown Obsessive-Compulsive Disorder Scale (Y-BOCS). See Goodman et al., Arch. Gen. Psychiatry, 1989, 46, 1006-1011. According to this system, a person is scored using a symptom checklist by asking about specific obsessions and compulsions.These symptoms are broadly categorized as aggressive obsessions, contamination obsessions, sexual obsessions, hoarding obsessions, religious obsessions, obsessions with the need for symmetry or exactness, miscellaneous obsessions, somatic obsessions, cleaning / washing compulsions, checking compulsions, repetition rituals, counting compulsions, ordering / arranging compulsions, and miscellaneous compulsions. Each of these categories is further divided into subcategories of more specific symptoms. Individuals are scored according to their responses. Scores range from 0-7 for subclinical, 8-15 for mild, 16-23 for moderate, 24-31 for severe, and 32-40 for extreme severity. In some forms of implementation of the invention, the individual displays a Yale-Brown scale score for obsessive-compulsive disorder of at least 20 prior to treatment.In other forms of realization, the individual shows a score of at least 24, at least 26, at least 28, at least 30, at least 32, at least 34 or at least 36 before treatment.

[0021] According to the Y-BOCS system, the broad categories of symptoms can be further subdivided. Subcategories of aggressive obsessions include: fear that he may harm himself; fear that he may harm others; violent or terrifying images; fear of letting slip obscenities or insults; fear of doing something else shameful; fear that he will act on unwanted impulses (e.g., stabbing a friend); fear that he will steal things; fear that he will harm others by not being careful enough (e.g., fleeing the scene of a car accident); and fear that he will be responsible for something else terrible that may happen (e.g., fire, burglary).Subcategories of contamination obsessions include: worries or disgust about bodily secretions or waste (e.g., urine, feces, saliva); preoccupation with dirt or germs; excessive worry about environmental contaminants (e.g., asbestos, toxic radioactive waste); excessive worry about household items (e.g., cleaning solvents); excessive worry about animals (e.g., insects); annoyance with sticky substances or residues; worry that the contaminant will cause illness; worry that spreading the contaminant will make others sick (aggressive); and no concern with the consequences of contamination other than how it may feel. Subcategories of sexual obsessions include: forbidden or perverse sexual thoughts, images, or urges; content involving children or incest; content involving homosexuality; and sexual behavior toward others (aggressive).Subcategories of religious obsessions include: preoccupation with sacrilege or blasphemy; and excessive concern with right and wrong and morality. Subcategories of obsession with a need for symmetry or exactness include: accompanied by magical thinking (e.g., worry that someone else will have an accident unless things are in the right place); and not accompanied by magical thinking. Subcategories of miscellaneous obsessions include: a need to know or remember; fear of saying certain things; fear of not saying the right thing; fear of losing things; intrusive (non-violent) images; intrusive, meaningless sounds, words, or music; being bothered by certain sounds / noises; a lucky / unlucky number; colors with special significance; and three superstitious fears.

[0022] Subcategories of somatic obsessions include: preoccupation with illness; and excessive preoccupation with body parts or appearance (e.g., body dysmorphic disorder). Subcategories of cleaning / washing compulsions include: excessive or ritualized handwashing; excessive or ritualized showering, bathing, teeth brushing, or grooming; the toilet routine involves cleaning household items or other inanimate objects; and other measures to avoid or eliminate contact with contaminants. Subcategories of checking compulsions include: checking locks, stovetops, appliances; checking that others have not been / will not be hurt; checking that one has not / will not be hurt; checking that nothing terrible has / will happen; checking that no mistake has been made; and checkings linked to somatic obsessions.Subcategories of repetition rituals include: rereading or rewriting; and the need to repeat routine activities (jogging, opening / closing doors, standing up / sitting down from a chair). Subcategories of miscellaneous compulsions include: mental rituals (other than checking / counting); excessive list-making; the need to count, question, or confess; the need to touch, press, or rub; rituals involving blinking or staring; measures (not checking) to avoid: terrible consequences of harming oneself / others; ritualized eating behaviors; superstitious behaviors; trichotillomania; and other self-harming or self-mutilating behaviors. TORILUZOLE

[0023] Troriluzole (BHV-4157) is a third-generation prodrug and a novel chemical entity that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. The primary mode of action of troriluzole is to reduce synaptic glutamate levels. Troriluzole increases glutamate uptake from the synapse by increasing the expression and function of excitatory amino acid transporters (i.e., EAAT2) located on glial cells, which play a critical role in clearing glutamate from the synapse. Glutamatergic dysfunction is involved in the pathophysiology of a wide range of disorders including amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA), Alzheimer's disease (AD), generalized anxiety disorder, depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), chronic pain, and a variety of cancer types.The therapeutic potential of troriluzole is supported by clinical and translational research studies conducted with riluzole in several of these indications. Troriluzole is described, for example, in U.S. Patent No. 10,485,791. ADMINISTRATION AND DOSAGE

[0024] The methods and compositions, according to embodiments of the present invention, are used to treat a patient undergoing treatment for obsessive-compulsive disorder. As used herein, the term "treats" refers to the reduction or relief of the symptoms of a particular disorder in an individual or the improvement of a recognizable measurement associated with a particular disorder, e.g., OCD.

[0025] In one aspect, embodiments of the invention provide a pharmaceutical composition in the form of a dose comprising troriluzole in an amount effective for treating obsessive-compulsive disorder in a patient in need thereof. The amount of troriluzole in the dose form may be 200 mg or more, for example, 250 mg or more, 300 mg or more, 350 mg or more, 400 mg or more, 450 mg or more, or 500 mg or more.

[0026] The dosage form may also include a pharmaceutically acceptable excipient. As used herein, the term pharmaceutically acceptable excipient means an excipient that may be administered to a patient, together with troriluzole, and that does not destroy the pharmacological activity of troriluzole and is not toxic when administered in sufficient doses to provide a therapeutic amount of troriluzole.

[0027] Pharmaceutically acceptable excipients that may be used in pharmaceutical compositions according to the embodiments of the present invention include, among others, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as α-tocopherol, polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial mixtures of saturated vegetable fatty acid glycerides, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphates, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose,Polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrin or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropylcyclodextrins, or other solubilized derivatives can also be used advantageously to improve the delivery of troriluzole.

[0028] Pharmaceutical compositions, according to the embodiments of the present invention, can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by means of an implanted depot. Pharmaceutical compositions, according to the embodiments of the present invention, may contain any conventional, pharmaceutically acceptable, non-toxic carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to improve the stability of the formulated troriluzole or its form of administration. As used herein, the term parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injections or infusion techniques.

[0029] The pharmaceutical compositions disclosed herein may be in the form of a sterile injectable preparation, for example, as a sterile aqueous or oily suspension for injection. This suspension may be formulated according to techniques known in the art by using suitable dispersants or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile solution or suspension for injection in a pharmaceutically acceptable, non-toxic diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be employed include mannitol, water, Ringer's solution, and LQLn / ZZnZ / E / YIAI isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspension medium. For this purpose, any tasteless fixed oil, including synthetic monoglycerides or diglycerides, may be employed. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable products, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as those described in the Swiss Pharmacopoeia or a similar alcohol, or carboxymethylcellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, such as emulsions and / or suspensions.Other commonly used surfactants, such as Tweens or Spans, and / or other similar emulsifying agents or bioavailability enhancers that are generally used in the preparation of solid, liquid, or other pharmaceutically acceptable dosage forms may also be used for formulation purposes.

[0030] The pharmaceutical compositions, according to the embodiments of the present invention, can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, the carriers generally used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also commonly added. For oral administration in tablet form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavorings, and / or coloring agents may be added.

[0031] The pharmaceutical compositions disclosed herein may also be administered in the form of suppositories for rectal administration. These compositions may be prepared by mixing troriluzole with a suitable non-limiting excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0032] Topical administration of pharmaceutical compositions, according to the embodiments of the present invention, is especially useful when the desired treatment involves areas or organs that can be easily accessed by topical administration. For topical application to the skin, the pharmaceutical composition should be formulated as a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for the topical administration of troriluzole include, but are not limited to, mineral oil, LQLn / ZZnZ / E / YIAI liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing troriluzole suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions, according to the embodiments of the present invention, may also be applied topically to the lower intestinal tract by means of a rectal suppository formulation or in a suitable enema formulation. Transdermal patches are also included in the present invention.

[0033] The pharmaceutical compositions, according to the embodiments of the present invention, can be administered by nasal spray or inhalation. Such compositions are prepared according to well-known techniques in the art of pharmaceutical formulation and can be prepared as saline solutions, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0034] Pharmaceutical compositions, according to the embodiments of the present invention, can be conveniently presented in unit-dose form and can be prepared by any method known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single-dose form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single-dose form will generally be the amount of troriluzole that produces a therapeutic effect.In general, out of one hundred percent, this amount will vary in some embodiments from about 1 percent to about ninety-nine percent of the active ingredient, in some embodiments from about 5 percent to about 70 percent, and in some embodiments from about 10 percent to about 30 percent.

[0035] The selected dose level will depend on a variety of factors, including the activity of troriluzole or its ester, salt, or amide, the route of administration, the time of administration, the rate of excretion of troriluzole, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and similar factors known in medical practice.

[0036] A mid-level physician can easily determine and prescribe the effective amount of the necessary pharmaceutical composition. For example, the physician could begin LQLn / ZZnZ / E / YIAI the doses of troriluzole used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0037] In general, an appropriate daily dose of troriluzole will be the amount that is the lowest effective dose to produce a therapeutic effect. This effective dose will generally depend on the factors described above.

[0038] If desired, the effective daily dose of troriluzole may be administered as one, two, three, four, five, six, or more subdoses administered separately at suitable intervals during the day, optionally in unit-dose forms. In certain embodiments of the present invention, troriluzole may be administered two or three times a day. In some embodiments, troriluzole will be administered once a day.

[0039] In another aspect of the invention, troriluzole is administered alone or in conjunction with another therapeutic agent. As used herein, the phrase "conjunct administration" refers to any form of administration of two or more different therapeutic compounds so as to achieve the desired effect. For example, the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). The different therapeutic compounds may be administered in the same formulation or in a separate formulation, either concomitantly or sequentially. Therefore, an individual receiving such treatment may benefit from a combined effect of different therapeutic compounds. Conjunct administration includes the simultaneous or sequential administration of two or more compounds.

[0040] In certain embodiments, troriluzole is administered in conjunction with a serotonin reuptake inhibitor. The serotonin reuptake inhibitor is, for example, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, or combinations with other psychotropic medications, including an antipsychotic, an anticonvulsant, a tricyclic antidepressant, a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor, a selective serotonin-norepinephrine reuptake inhibitor, a dopamine-norepinephrine reuptake inhibitor, a serotonin-2 reuptake inhibitor and antagonist, a benzodiazepine, a wakefulness-promoting agent, an antimanic agent, or a combination of one or more of the foregoing.

[0041] In another embodiment, a method is provided for treating obsessive-compulsive disorder in a patient in need. The method includes administering to the patient a dosage form that includes an effective amount of troriluzole.

[0042] The dosage form can be administered daily for four weeks LQLn / ZZnZ / E / YIAI or more, and the patient at week 4 may have a change in mean total Y-BOCS score of at least -3.4 points from baseline. The dosage form may be administered daily for four weeks or more, and the patient at week 4 may have a change in mean total Y-BOCS score of at least 0.5 points compared to placebo.

[0043] The dosage form can be administered daily for eight weeks or more, and the patient at week 8 may have a change in mean total Y-BOCS score of at least -5.1 points from baseline. The dosage form can be administered daily for eight weeks or more, and the patient at week 8 may have a change in mean total Y-BOCS score of at least 1.5 points compared to placebo.

[0044] The dosage form can be administered daily for twelve weeks or more, and the patient at week 12 may have a change in mean total Y-BOCS score of -5.9 points from baseline. The dosage form can be administered daily for twelve weeks or more, and the patient at week 12 may have a change in mean total Y-BOCS score of 1.0 point compared to placebo.

[0045] The patient has a median Y-BOCS score of 26 or higher. The dosage form can be administered daily for four weeks or more, and the patient at week 4 may have a change in mean total Y-BOCS score of at least -4.1 points from baseline. The dosage form can be administered daily for four weeks or more, and the patient at week 4 may have a change in mean total Y-BOCS score of at least 0.6 points compared to placebo.

[0046] The dosage form can be administered daily for eight weeks or more, and the patient at week 8 may have a change in mean Y-BOCS total score of at least -6.0 points from baseline. The dosage form can be administered daily for eight weeks or more, and the patient at week 8 may have a change in mean Y-BOCS total score of at least 2.9 points compared to placebo.

[0047] The dosage form can be administered daily for twelve weeks or more, and the patient at week 12 may have a change in mean total Y-BOCS score of -7.0 points from baseline. The dosage form is administered daily for twelve weeks or more, and the patient at week 12 may have a change in mean total Y-BOCS score of 2.4 points compared to placebo.

[0048] The invention is further illustrated by the following non-limiting examples. EXAMPLE: TRORILUZOLE TEST-OF-CONCEPT STUDY FOR THE LQLn / ZZnZ / E / YIAI Obsessive-Compulsive Disorder (OCD) STUDIO DESIGN

[0049] The study design is shown schematically in Figure 1. Subjects take the maximum tolerated dose of a selective serotonin reuptake inhibitor (SSRI) or clomipramine for at least 10 weeks at baseline*. Subjects receive a dose of 140 mg once daily (QD) for the first four (4) weeks, and then the dose is increased to 200 mg QD for the duration of the study. Downward titration is permitted only to address tolerability issues**. Suitable subjects include those who benefited in the early phases or those for whom the principal investigator (PI) believes extended treatment with BHV-4157 could offer an acceptable risk-benefit profile***. Subjects begin the dose extension phase from the dose they were taking at the end of the randomization phase.Subjects receiving placebo during the randomization phase are switched in blinded fashion to a dose of 140 mg once daily (QD) for the first 4 weeks, and then the dose is increased to 200 mg QD (at week 4 visits). Downward titration is permitted only to address tolerability issues. All visits after week 4 are open-label.

[0050] Subjects remaining on standard of care (SOC) who have an inadequate response to SOC are randomized to receive either placebo (QD) or troriluzole for 12 weeks (200 mg QD, followed by four weeks of 140 mg QD). Subjects who complete the randomization phase are offered approximately 48 weeks of open-label treatment. The study was conducted from December 2017 to June 2020 with 242 randomized subjects at more than 56 sites. Full study details are available at https: / / clinicaltrials.gov / ct2 / show / study / NCT03299166?term=biohaven&cond=ObsessiveCompulsive+Disorder&draw=2&rank=l. KEY INCLUSION CRITERIA

[0051] The study involves subjects with a primary diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, as confirmed by MINI in screening.

[0052] The duration of the subject's illness must be equal to or greater than 1 year.

[0053] Subjects must not currently be experiencing a response or must have an inadequate response to their current standard of care (SOC) medication, defined as: (1) the subjects' total Y-BOCS score must be equal to or greater than 19 at screening and baseline, reflecting moderate or severe symptoms of OCD; and (2) the subjects must currently be on monotherapy with a selective serotonin reuptake inhibitor (SSRI) or clomipramine, venlafaxine, or desvenlafaxine for an adequate duration (at LQLn / ZZnZ / E / YIAI less than 8 weeks at screening and 10 weeks at baseline) and with an adequate dose.

[0054] The Clinical Global Impression Rating Scale (CGI-S) must be equal to or greater than 4 at screening or at baseline. FUNDAMENTAL EXCLUSION CRITERIA

[0055] Subjects with a history of more than two (2) previous failed treatment trials of SSRIs, clomipramine, venlafaxine, or desvenlafaxine (not including the current SSRI trial) administered for an adequate period at an adequate dose, as defined by MGH-TRQ-TOC, are excluded.

[0056] Subjects are excluded if they have a history of suicide attempts or serious suicidal tendencies or self-harming behavior in the past 12 months.

[0057] Subjects are excluded if they have a Brown Belief Assessment Score (BABS) greater than 17 at screening and at baseline.

[0058] The use of a stimulant, a neuroleptic (antipsychotic), a mood stabilizer and a glutamate agent (e.g. topiramate, lamotrigine, N-acetylcysteine, ketamine, memantine, sodium valproate) is prohibited within 4 weeks prior to screening and during the study.

[0059] The daily use of anxiolytics or benzodiazepines is currently prohibited. STUDY RESULTS

[0060] The results of the primary assessment criterion analysis are listed in Tables 1 to 5 below: LQLn / zznz / E / YiAi Table 1 Final unblinded analysis of BHV4157-202 Total YBOCS change from baseline per week Mean LS and SE from MMRM model MITT dataset Placebo Troriluzole Troriluzole vs. placebo Difference Week N Mean LS N Mean LS 95% Cl estimate p-value 4 115 -2.9 111 -3.4 -0.5 (-1.67, 0.75) 0.451 8 108 -3.6 96 -5.1 -1.5 (-3.02, -0.06) 0.041 12 102 -4.9 99 -5.9 -1.0 (-2.59, 0.60) 0.220

[0061] Table 1 shows the change in the mean total score of the Yale-Brown scale for obsessive-compulsive disorder (Y-BOCS) over time. Subjects treated with troriluzole had a mean Y-BOCS improvement of -5.1 points from baseline compared to -3.6 for placebo-treated patients [difference of -1.5, p-value = 0.041, 95% CI: 3.02, -0.06] at week 8, and -5.9 points compared to -4.9 for placebo-treated subjects [difference of -1.0, p-value = 0.220, 95% CI: -2.59, 0.60] at week 12. Although the p-value in this proof-of-concept study did not reach statistical significance for the primary Y-BOCS endpoint at week 12, the results reveal a consistent benefit of troriluzole treatment over time and provide adequate data to inform future studies. The results are represented in Figure 1. Table 2 LQLn / ZZnZ / E / YIAI Final unblinded analysis of BHV4157-202 YBOCS obsessions subscale change from baseline per week Mean LS and SE from MMRM model MITT dataset Placebo Troriluzole Troriluzole vs. placebo Difference Week N Mean LS N Mean LS 95% CI estimate p-value 4 115 -1.65 111 -1.67 -0.02 (-0.70, 0.66) 0.952 8 108 -2.15 96 -2.50 -0.36 (-1.23, 0.51) 0.419 12 102 -2.55 99 -2.91 -0.36 (-1.24, 0.52) 0.422 Table 3 Final unblinded analysis of BHV4157-202 YBOCS compulsion subscale change from baseline per week Mean LS and SE from MMRM model MITT dataset Placebo Troriluzole Troriluzole vs. placebo Difference Week N Mean LS N Mean LS 95% CI estimate p-value 4 115 -1.28 111 -1.72 -0.44 (-1.09, 0.22) 0.194 8 108 -1.41 96 -2.61 -1.20 (-1.98, -0.43) 0.003 12 102 -2.37 99 -3.01 -0.64 (-1.50, 0.22) 0.143 Table 4 Final unblinded analysis of BHV4157-202 Total YBOCS change from baseline per week Mean LS and SE from MMRM model MITT dataset Subjects only > baseline YBOCS = 26 (median) Placebo Troriluzole Troriluzole vs. placebo Difference Week N Mean LS N Mean LS 95% CI estimate p-value 4 47 -3.5 49 -4.1 -0.6 (-2.80, 1.58) 0.584 8 45 -3.1 42 -6.0 -2.9 (-5.49, -0.21) 0.035 12 43 -4.6 44 -7.0 -2.4 (-5.18, 0.33) 0.084

[0062] The troriluzole treatment differences compared with placebo were greater in patients who had more severe illness at baseline (i.e., total Y-BOCS scores greater than the median score of 26, representing severe OCD symptoms), see Table 2. Subjects treated with troriluzole (n=42) had a mean YBOCS change from baseline of -6.0 points compared with -3.1 for placebo-treated subjects (n=45) [difference of -2.9, p=0.035, 95% CI: -5.49, -0.21] at week 8, and -7.0 points (n=44) compared with -4.6 for placebo-treated subjects (n=43) [treatment difference of -2.4, p=0.084, 95% CI: -5.18, 0.33] at week 12. Table 5 LQLn / ZZnZ / E / YIAI Final unblinded analysis of BHV4157-202 (not validated) Change in total YBOCS score from baseline per week Mean LS and SE from MMRM model MITT dataset Subjects only <= Median total baseline YBOCS = 26 Placebo Troriluzole Week N Mean LS N Mean LS p-value 4 68 -2.6 62 -2.8 0.783 8 63 -4.0 54 -4.4 0.617 12 59 -5.2 55 -5.0 0.877 COMPENDIUM OF SUPERIOR RESULTS

[0063] Administering 200 mg of troriluzole once daily as add-on therapy to OCD patients with an inadequate response to standard treatment showed a consistent numerical improvement over placebo on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) at all study time points (weeks 4 to 12), but did not reach the primary outcome measure at week 12 (p < 0.05 at week 8 and p = 0.22 at week 12). A strong signal was observed for compulsive behaviors and in patients with severe illness, as evidenced by changes in the Y-BOCS compulsions subscale. The safety profile of troriluzole is safe and well-tolerated, and appears to be consistent with other trials of troriluzole. This trial is considered a proof-of-concept study for troriluzole as add-on therapy for OCD patients with an inadequate response to standard treatment.

[0064] Throughout this application, various publications are referenced by author and date, or by patent number or patent publication number. The disclosures in these publications are incorporated by reference in their entirety into this application for the purpose of more fully describing the prior art as known to persons of a middling skill at the date of the invention described and claimed herein. However, the citation of a reference herein shall not be construed as an acknowledgment that such reference belongs to the prior art of the present invention.

[0065] Persons of average skill will recognize or be able to recognize various equivalents of the specific procedures described herein through routine experimentation only. Such equivalents are deemed to be within the scope of this invention, and the following claims encompass them. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and examples herein may be employed. Furthermore, it is intended that specific elements within lists of elements, or subgroups of elements within larger groups of elements, may be combined with other specific elements, subgroups, or larger groups of elements, whether or not a specific disclosure herein identifies such a combination.

Claims

1. A method for treating obsessive-compulsive disorder in a patient in need, comprising administering to the patient a dosage form comprising an effective amount of troriluzole.

2. The method according to claim 1, wherein the dosage form is administered daily for four weeks or more and wherein the patient at week 4 has a change in mean total Y-BOCS score of at least -3.4 points from baseline.

3. The method according to claim 1, wherein the dosage form is administered daily for four weeks or more and wherein the patient at week 4 has a change in mean total Y-BOCS score of at least 0.5 points compared to placebo.

4. The method according to claim 1, wherein the dosage form is administered daily for eight weeks or more and wherein the patient at week 8 has a change in mean total Y-BOCS score of at least -5.1 points from baseline.

5. The method according to claim 1, wherein the dosage form is administered daily for eight weeks or more and wherein the patient at week 8 has a change in mean total Y-BOCS score of at least 1.5 points compared to placebo.

6. The method according to claim 1, wherein the dosage form is administered daily for twelve weeks or more and wherein the patient at week 12 has a change in mean total Y-BOCS score of -5.9 points from baseline.

7. The method according to claim 1, wherein the dosage form is administered daily for twelve weeks or more and wherein the patient at week 12 has a change in mean total Y-BOCS score of 1.0 points compared to placebo.

8. The method according to claim 1, wherein the patient has a median Y-BOCS score of 26 or more.

9. The method according to claim 8, wherein the dosage form is administered daily for four weeks or more and wherein the patient at week 4 has a change in mean total Y-BOCS score of at least -4.1 points from baseline.

10. The method according to claim 8, wherein the dosage form is administered daily for four weeks or more and wherein the patient at week 4 has a change in mean total Y-BOCS score of at least 0.6 points compared to placebo. LQLn / ZZnZ / E / YIAI 11. The method according to claim 8, wherein the dosage form is administered daily for eight weeks or more and wherein the patient at week 8 has a change in mean total Y-BOCS score of at least -6.0 points from baseline.

12. The method according to claim 8, wherein the dosage form is administered daily for eight weeks or more and wherein the patient at week 8 has a change in mean total Y-BOCS score of at least 2.9 points compared to placebo.

13. The method according to claim 8, wherein the dosage form is administered daily for twelve weeks or more and wherein the patient at week 12 has a change in mean total Y-BOCS score of -7.0 points from baseline.

14. The method according to claim 8, wherein the dosage form is administered daily for twelve weeks or more and wherein the patient at week 12 has a change in mean total Y-BOCS score of 2.4 points compared to placebo.

15. A dosage form comprising troriluzole in an amount effective for treating obsessive-compulsive disorder in a patient in need thereof.

16. The dosage form according to claim 15, comprising troriluzole in an amount of 200 mg or more.

17. The dosage form according to claim 15, comprising troriluzole in an amount of 250 mg or more.

18. The dosage form according to claim 15, comprising troriluzole in an amount of 300 mg or more.

19. The dosage form according to claim 15, comprising troriluzole in an amount of 350 mg or more.

20. The dosage form according to claim 15, comprising troriluzole in an amount of 400 mg or more.

21. The dosage form according to claim 15, comprising troriluzole in an amount of 450 mg or more.

22. The dosage form according to claim 15, comprising troriluzole in an amount of 500 mg or more.