Compositions and methods for treating obsessive-compulsive disorder

Abstract

Disclosed herein are methods for treating obsessive-compulsive disorder in a patient in need thereof by administering to the patient a dosage form comprising an effective amount of troriluzole.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 043,681, filed June 24, 2020, and any and all benefits arising therefrom under 35 U.S.C. § 119, the contents of which are incorporated herein by reference in their entirety. The present invention relates to a pharmaceutical composition for treating obsessive-compulsive disorder (OCD) using a riluzole prodrug. In particular, the present invention relates to a method for treating OCD with a pharmaceutical composition containing troriluzole. [Background technology]

[0002] Obsessive-Compulsive Disorder ("OCD") is a debilitating mental illness characterized by repetitive, intrusive thoughts (obsessions) and / or repetitive, stereotyped behaviors (compulsions) that persist for at least one hour per day and significantly interfere with an individual's normal level of functioning. Cognitive behavioral therapy and pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs) are effective treatments for some patients, but a substantial subset experiences minimal relief of symptoms with these standard treatments. In severe cases, OCD can have devastating consequences for patients and their families, completely robbing them of their freedom. Neuroleptic augmentation strategies can improve the effectiveness of SSRI therapy but do not eliminate OCD symptoms (Saxena et al., J. Clin. Psychiatry, 1996, 57, 303-306; McDougle et al., J. Clin. Psychiatry, 1995, 56, 526-528) and are associated with adverse effects when used chronically. The clinical observation that few patients experience a complete response to SSRIs or dopamine antagonists suggests that other neurochemical systems are involved in the pathophysiology of OCD.

[0003] OCD affects one in 40 people in the United States, or more than two million people, and significantly impacts quality of life. One-third of patients do not respond to current treatments. Approximately 40%-60% of OCD patients continue to experience significant residual symptoms despite approved therapies. Some intractable patients undergo psychosurgery (singulotomy or deep brain stimulation) to alleviate their disabling symptoms.

[0004] No mechanistically novel medications have been approved for OCD in over 20 years, and new therapies are therefore urgently needed to alleviate the suffering and disability of OCD patients. Summary of the Invention

[0005] The present invention relates to pharmaceutical compositions comprising trolilzole and methods for treating obsessive-compulsive disorder using the compositions.

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

[0007] In another embodiment, a dosage form is provided comprising an amount of trolilzole effective to treat obsessive-compulsive disorder in a patient in need thereof. [Brief explanation of the drawings]

[0008] These and / or other aspects will become apparent and more readily understood from the following description of the embodiments taken in conjunction with the accompanying drawings.

[0009] [Figure 1] FIG. 1 shows the trolilzole OCD phase 2 / 3 study design. [Figure 2] FIG. 1 shows mean Y-BOCS scores at baseline and weeks 4, 8, and 12 of the troriluzole study. DETAILED DESCRIPTION OF THE INVENTION

[0010] The following detailed description is provided to assist those skilled in the art in practicing embodiments of the present invention. Exemplary embodiments are described in detail below. However, these embodiments are merely exemplary, and the present disclosure is not limited thereto, but rather is defined by the appended claims. Those skilled in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the present disclosure.

[0011] Accordingly, embodiments are described below by reference to structures and schemes merely to illustrate aspects of the present description. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or." Phrases such as "at least one of" preceding a list of elements modify the entire list of elements, and not individual elements of the list.

[0012] When an element is referred to as being "on" another element, it will be understood that it can be in direct contact with the other element, or there may be intervening elements therebetween. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements present.

[0013] Terms such as first, second, and third may be used herein to describe various elements, components, regions, layers, and / or sections, but it should be understood that 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. Thus, a first element, component, region, layer, or section discussed below could be referred to as a second element, component, region, layer, or section without departing from the teachings of the present embodiments.

[0014] As used herein, the terms "comprises" and / or "comprising" or "includes" and / or "including" specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but are to be understood as not excluding the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in this description is intended only to describe particular embodiments and is not intended to be limiting. Furthermore, terms such as those defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the relevant technical field and in the context of this disclosure, and should not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0016] As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application. If a term is not specifically defined herein, the term will be given the art-recognized meaning by those of ordinary skill in the art applying that term in connection with its use in describing embodiments of the present invention.

[0017] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly dictates otherwise. By way of example, "an element" means one element or more than one element.

[0018] Additional aspects will be set forth in part in the description that follows, and in part will be apparent from the description.

[0019] Obsessive-compulsive disorder Methods and compositions according to embodiments of the present invention are useful for treating obsessive-compulsive disorder ("OCD"). In some embodiments of the present invention, individuals treated according to the claimed methods are assessed using the Yale Brown Obsessive Compulsive Scale ("Y-BOCS"). See Goodman et al., Arch. Gen. Psychiatry, 1989, 46, 1006-1011. According to this system, individuals are scored using a symptom checklist by asking the individual about specific obsessions and compulsions. Such symptoms are broadly categorized as aggressive obsessions, soiling obsessions, sexual obsessions, hoarding / saving obsessions, religious obsessions, obsessions with the need for symmetry or accuracy, miscellaneous obsessions, physical obsessions, cleaning / washing obsessions, checking obsessions, repetitive rituals, counting obsessions, ordering / arranging obsessions, and miscellaneous obsessions. Each of these categories is further divided into more specific symptom subcategories. Individuals are scored according to the answers provided. Scores range from 0 to 7 for asymptomatic, 8 to 15 for mild, 16 to 23 for moderate, 24 to 31 for severe, and 32 to 40 for very severe. In some embodiments of the invention, the individual exhibits a Yale Brown Obsessive Compulsive Scale score of at least 20 prior to treatment. In other embodiments, the individual exhibits 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 prior to treatment.

[0020] According to the Y-BOCS system, broad symptom categories can be further subdivided. Subcategories of aggressive obsessions include fear of harming oneself, fear of harming others, violent or frightening images, fear of uttering obscene or insulting things, fear of doing another embarrassing thing, fear of acting on an unnecessary impulse (e.g., stabbing a friend), fear of stealing something, fear of hurting others by not being careful enough (e.g., hit-and-run car accident), and fear of causing another frightening event (e.g., fire, robbery). Subcategories of contamination obsessions include concern or aversion with bodily wastes or secretions (e.g., urine, feces, saliva), concern with dirt or germs, excessive concern with environmental pollutants (e.g., asbestos, radioactive toxic waste), excessive concern with household products (e.g., cleaning agents, solvents), excessive concern with animals (e.g., insects), being bothered by sticky substances or residues, concern about becoming ill from contaminants, concern about making others ill by spreading contaminants (aggression), and lack of concern about the consequences of contamination other than sensory. 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 (aggression). Subcategories of religious obsessions include interest in worship and blasphemy, and excessive concern with right and wrong morality. Subcategories of obsessions related to the need for symmetry of precision include those with magical thinking (e.g., worrying that others will have accidents unless things are in their proper place) and those without magical thinking. Various subcategories of obsessions include the need to know or remember, fear of saying certain things, fear of not saying the right thing, fear of losing things, intrusive (nonviolent) images, intrusive nonsense sounds, words, or music, being bothered by certain sounds / noises, lucky / unlucky numbers, colors with special meanings, and three superstitious fears.

[0021] Subcategories of body obsessions include concerns about illness or disease and excessive concern with body parts or aspects of appearance (e.g., dysmorphophobia). Subcategories of cleaning / washing obsessions include excessive or ritualized handwashing, excessive or ritualized showering, bathing, toothbrushing, grooming, or toileting habits, cleaning household utensils or other inanimate objects, and other measures to prevent or remove contact with contaminants. Subcategories of checking obsessions include checking locks, stoves, appliances, etc., making sure they haven't / will not hurt others, making sure they haven't / will not hurt themselves, making sure nothing frightening has / will happen, making sure they're not wrong, and checking associated with body obsessions. Subcategories of repetitive rituals include rereading or rewriting and the need to repeat daily activities (jogging, indoors / outdoors, climbing up and down from a chair). Various obsession subcategories include mental rituals (excluding checking / counting), excessive listing, the need to tell, ask, or confess, the need to touch, tap, or rub, rituals involving blinking or staring, preventative measures (not checking), acts of harming others or self, fearful consequences, ritualized eating behaviors, superstitious behaviors, trichotillomania, and other acts of self-harm or self-mutilation.

[0022] Troriluzole 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. Troriluzole's primary mode of action is to reduce synaptic levels of glutamate. Troriluzole increases synaptic glutamate uptake by enhancing the expression and function of excitatory amino acid transporters (EAAT2) located on glial cells, which play a key role in removing glutamate from synapses. Glutamate dysfunction is implicated 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 various cancers. The therapeutic potential of troriluzole is supported by clinical and translational studies conducted with riluzole in a variety of these indications. Troriluzole is described, for example, in US Pat. No. 10,485,791.

[0023] Administration and Dosage Methods and compositions according to embodiments of the present invention are used to treat patients with obsessive-compulsive disorder. As used herein, the term "treating" refers to the reduction or alleviation of symptoms of a particular disorder in an individual, or the improvement of an identifiable measure associated with a particular disorder, such as OCD.

[0024] In one aspect, an embodiment of the present invention provides a pharmaceutical composition in the form of a dosage form comprising an amount of troriluzole effective to treat obsessive-compulsive disorder in a patient in need thereof. The amount of troriluzole in the dosage form can be 200 mg or more, e.g., 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.

[0025] The dosage form may further comprise a pharmaceutically acceptable excipient. As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that may be administered to a patient together with troriluzole, that does not destroy the pharmacological activity of troriluzole, and that is non-toxic when administered in dosages sufficient to deliver a therapeutic amount of troriluzole.

[0026] Pharmaceutically acceptable excipients that may be used in pharmaceutical compositions, according to embodiments of the present invention, include, but are not limited to, 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 Tween or other similar polymeric delivery matrices, serum proteins, such as serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, may also be advantageously used to enhance delivery of trolilzole.

[0027] According to embodiments of the present invention, pharmaceutical compositions can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. According to embodiments of the present invention, pharmaceutical compositions can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated troriluzole or its delivery form. The term parenteral, as used herein, includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0028] The pharmaceutical compositions disclosed herein may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are mannitol, water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions may contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica or similar alcohols, or carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. For formulation purposes, other commonly used surfactants such as Tween or Span, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used.

[0029] The pharmaceutical composition according to the embodiment of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.For aqueous suspensions administered orally, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners and / or flavorings and / or colorings may be added.

[0030] The pharmaceutical compositions disclosed herein may be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing trolilzole with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the active ingredient.Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0031] According to embodiments of the present invention, topical administration of pharmaceutical compositions is particularly useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of troriluzole include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutical composition can 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 esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. According to embodiments of the present invention, the pharmaceutical composition may be topically applied to the lower intestinal tract via a rectal suppository formulation or in a suitable enema formulation. Topically transdermal patches are also included in the present invention.

[0032] Pharmaceutical compositions, according to embodiments of the present invention, may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art.

[0033] Pharmaceutical compositions, according to embodiments of the present invention, can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage 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 dosage form will generally be that amount of trolilzole that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about 99 percent of the active ingredient in some embodiments, from about 5 percent to about 70 percent in some embodiments, and from about 10 percent to about 30 percent in some embodiments.

[0034] 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 used, the age, sex, weight, condition, general health, and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0035] A physician of ordinary skill can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician can start the dosage of troriluzole used in the pharmaceutical composition at a lower level than needed to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0036] Generally, a suitable daily dose of troliluzole will be that amount that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0037] If desired, the effective daily dose of troriluzole can be administered as one, two, three, four, five, six, or more subdoses at appropriate intervals throughout the day, optionally in unit dosage forms. In certain embodiments of the invention, troriluzole can be administered two or three times daily. In some embodiments, troriluzole is administered once daily.

[0038] In another aspect of the present invention, troriluzole is administered alone or simultaneously with another therapeutic agent. As used herein, the phrase "co-administration" refers to any form of administration of two or more different therapeutic compounds to achieve a desired effect. For example, a second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are effective in the patient simultaneously, which may include a synergistic effect of the two compounds). Different therapeutic compounds can be administered in combination or sequentially, either in the same formulation or in separate formulations. Thus, individuals receiving such treatment can benefit from the combined effects of the different therapeutic compounds. Co-administration includes simultaneous or sequential administration of two or more compounds.

[0039] In certain embodiments, trolilzole is administered simultaneously with a serotonin reuptake inhibitor, such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine, mirtazepine, clomipramine, or other psychotropic medications, including antipsychotics, anticonvulsants, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, selective serotonin-norepinephrine reuptake inhibitors, norepinephrine dopamine reuptake inhibitors, serotonin-2 antagonist reuptake inhibitors, benzodiazepines, wake-promoting agents, antimanic agents, or combinations of one or more of the foregoing.

[0040] In another embodiment, a method for treating obsessive-compulsive disorder in a patient in need thereof is provided, the method comprising administering to the patient a dosage form comprising an effective amount of troriluzole.

[0041] The dosage form may be administered daily for four or more weeks, and at week 4, patients may have a mean Y-BOCS total scale change from baseline of at least -3.4 points. The dosage form may be administered daily for four or more weeks, and at week 4, patients may have a mean Y-BOCS total scale change of at least 0.5 points compared to placebo.

[0042] The dosage form may be administered daily for 8 weeks or more, and at week 8, patients may have a mean Y-BOCS total scale change from baseline of at least -5.1 points. The dosage form may be administered daily for 8 weeks or more, and at week 8, patients may have a mean Y-BOCS total scale change of at least 1.5 points compared to placebo.

[0043] The dosage form may be administered daily for 12 or more weeks, and at week 12, patients may have a mean Y-BOCS total scale change of -5.9 points from baseline. The dosage form may be administered daily for 12 or more weeks, and at week 12, patients may have a mean Y-BOCS total scale change of 1.0 points compared to placebo.

[0044] Patients have a median Y-BOCS score of 26 or greater. The dosage form can be administered daily for four or more weeks, and at week four, patients can have a mean Y-BOCS total scale change of at least -4.1 points from baseline. The dosage form can be administered daily for four or more weeks, and at week four, patients can have a mean Y-BOCS total scale change of at least 0.6 points compared to placebo.

[0045] The dosage form may be administered daily for 8 weeks or more, and at week 8, patients may have a mean Y-BOCS total scale change from baseline of at least -6.0 points. The dosage form may be administered daily for 8 weeks or more, and at week 8, patients may have a mean Y-BOCS total scale change of at least 2.9 points compared to placebo.

[0046] The dosage form may be administered daily for 12 weeks or more, and at week 12, patients may have a mean Y-BOCS total scale change of -7.0 points from baseline. The dosage form may be administered daily for 12 weeks or more, and at week 12, patients may have a mean Y-BOCS total scale change of 2.4 points compared to placebo. [Example]

[0047] The present invention is further illustrated by the following non-limiting examples. Example: Troriluzole Proof-of-Concept Obsessive-Compulsive Disorder (OCD) Study

[0048] Test Design The study design is shown schematically in Figure 1. Subjects received a maximum tolerated dose of selective serotonin reuptake inhibitors (SSRIs) or clomipramine at baseline. * Subjects will receive a 140 mg QD dose for the first 4 weeks, then the dose will be increased to 200 mg QD for the duration of the study. Down-titration will be permitted only to address tolerability issues. ** Eligible subjects include those who have benefited from previous phases or for whom the principal investigator (PI) believes long-term treatment with BHV-4157 offers an acceptable risk-benefit profile. *** Subjects will begin the extension phase on the dose they were taking at the end of the randomized phase. Subjects receiving placebo in the randomized phase will be blindly switched to a 140 mg dose QD for the first 4 weeks, and then the dose will be increased to 200 mg QD (at the week 4 visit). Down-titration will be permitted only to address tolerability issues. All visits after week 4 will be open-label. **** is.

[0049] Subjects who are stable on standard of care (SOC) medication and have an inadequate response to SOC will receive placebo (QD) or troriluzole for 12 weeks ( After 4 weeks of 140 mg QD, 200mg Q D)Subjects will be randomized to receive additional treatment. Subjects who complete the randomization phase will be offered approximately 48 weeks of open-label treatment. The trial ran from December 2017 to June 2020, with 242 subjects randomized at over 56 sites. Full trial details are available online at https: / / clinicaltrials.gov / ct2 / show / study / NCT03299166?term=biohaven&cond=Obsessive-Compulsive+Disorder&draw=2&rank=1.

[0050] Main inclusion criteria The study will involve subjects with a primary diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, as confirmed by MINI at screening.

[0051] The duration of the illness must be at least one year.

[0052] Subjects must currently be experiencing no or inadequate response to current standard of care (SOC) medications, defined as follows: (1) the subject's Y-BOCS total score must be ≥ 19 at screening and baseline, reflecting moderate or severe OCD symptoms; and (2) the subject must currently be receiving selective serotonin reuptake inhibitor (SSRI) or clomipramine, venlafaxine, or desvenlafaxine monotherapy treatment for an appropriate duration (at least 8 weeks at screening and 10 weeks at baseline) and in an appropriate dosage.

[0053] The Clinical Global Impression score (CGI-S) at screening and baseline must be 4 or greater.

[0054] Main exclusion criteria Subjects with a history of more than two previous failed therapeutic clinical trials (not including current SSRI clinical trials) of SSRIs, clomipramine, venlafaxine, or desvenlafaxine given at appropriate dosages for an appropriate duration as defined by the MGH-TRQ-OCD will be excluded.

[0055] Subjects will be excluded if they exhibit acute suicidality or suicide attempts or self-harm behaviors within the past 12 months.

[0056] Subjects will be excluded if they have a Brown Assessment of Beliefs (BABS) score greater than 17 at screening and baseline.

[0057] Use of stimulants, neuroleptics (antipsychotics), mood stabilizers, and glutamate medications (e.g., topiramate, lamotrigine, N-acetylcysteine, ketamine, memantine, sodium valproate) is prohibited within 4 weeks prior to screening and throughout the study.

[0058] Daily use of anti-anxiety medications or benzodiazepines is currently prohibited.

[0059] Test results The results of the primary endpoint analysis are listed in Tables 1-5 below. [Table 1]

[0060] Table 1 shows the mean change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score over time. Troriluzole-treated subjects had a mean Y-BOCS improvement from baseline of -5.1 points compared with -3.6 for placebo-treated subjects at week 8 (difference -1.5, p = 0.041, 95% CI: -3.02, -0.06) and a -5.9 point improvement compared with -4.9 for placebo subjects at week 12 (difference -1.0, p = 0.220, 95% CI: -2.59, 0.60). 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 demonstrate a consistent therapeutic benefit of troriluzole over time and provide appropriate data to drive future trials. The plotted results are shown in Figure 1. [Table 2] [Table 3] [Table 4]

[0061] The difference in troriluzole treatment compared with placebo was greater in patients who were more severely ill at baseline (i.e., Y-BOCS total score greater than the median score of 26, representing severe OCD symptoms). See Table 2. Troriluzole-treated subjects (n=42) had a mean Y-BOCS change from baseline of -6.0 points compared with -3.1 for placebo (n=45) subjects at week 8 [difference -2.9, p=0.035, 95% CI: -5.49, -0.21], and a change of -7.0 points (n=44) compared with -4.6 for placebo (n=43) subjects at week 12 [treatment difference -2.4, p=0.084, 95% CI: -5.18, 0.33]. [Table 5]

[0062] Summary of best results Troriluzole 200 mg administered once daily as adjunctive therapy in patients with OCD who have an inadequate response to standard treatment demonstrated consistent numerical improvements compared with placebo on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at all study time points (Weeks 4 through 12), but did not meet the primary efficacy endpoint at Week 12: p<0.05 at Week 8 and p=0.22 at Week 12. A stronger signal was observed in patients with obsessive-compulsive behaviors and severe illness, as evidenced by changes in the Y-BOCS obsession subscale. The safety profile of troriluzole appears to be safe, well-tolerated, and consistent with other troriluzole clinical trials. This clinical trial is considered a proof-of-concept study of troriluzole as adjunctive therapy in patients with OCD who have an inadequate response to standard treatment.

[0063] Throughout this application, various publications are referenced by author name and date, or patent or patent publication number. The disclosures of these publications are incorporated by reference in their entireties into this application in order 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 a reference herein should not be construed as an admission that such reference is prior art to the present invention.

[0064] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the detailed description and examples herein may be used. Furthermore, it is contemplated that particular items within the list of items, or subsets of items within larger groups of items, may be combined with other particular items, subsets of items, or larger groups of items, regardless of the presence or absence of specific disclosure herein identifying such combinations. The present application also includes the following aspects. [Aspect 1] 1. A method for treating obsessive-compulsive disorder in a patient in need thereof, comprising administering to said patient a dosage form comprising an effective amount of troriluzole. [Aspect 2] The method of embodiment 1, wherein said dosage form is administered daily for four or more weeks and wherein at week four said patient has a mean Y-BOCS total scale change from baseline of at least −3.4 points. [Aspect 3] The method of embodiment 1, wherein said dosage form is administered daily for four or more weeks and wherein at week four said patient has a mean Y-BOCS total scale change compared to placebo of at least 0.5 points. [Aspect 4] The method of embodiment 1, wherein said dosage form is administered daily for eight or more weeks, and wherein at week 8 said patient has a mean Y-BOCS total scale change from baseline of at least −5.1 points. [Aspect 5] The method of embodiment 1, wherein said dosage form is administered daily for eight or more weeks, and at week 8 said patient has a mean Y-BOCS total scale change of at least 1.5 points compared to placebo. [Aspect 6] The method of embodiment 1, wherein the dosage form is administered daily for 12 weeks or more, and wherein at week 12 the patient has a mean Y-BOCS total scale change from baseline of -5.9 points. [Aspect 7] The method of embodiment 1, wherein said dosage form is administered daily for 12 weeks or more, and at week 12 said patients have a mean Y-BOCS total scale change of 1.0 point compared to placebo. [Aspect 8] 2. The method of embodiment 1, wherein said patient has a median Y-BOCS score of 26 or greater. [Aspect 9] The method of embodiment 8, wherein the dosage form is administered daily for four or more weeks and wherein at week four the patient has a mean Y-BOCS total scale change from baseline of at least −4.1 points. [Aspect 10] The method of embodiment 8, wherein said dosage form is administered daily for four or more weeks and wherein at week four said patient has a mean Y-BOCS total scale change of at least 0.6 points compared to placebo. [Aspect 11] The method of embodiment 8, wherein the dosage form is administered daily for eight or more weeks and wherein at week 8 the patient has a mean Y-BOCS total scale change from baseline of at least −6.0 points. [Aspect 12] The method of embodiment 8, wherein said dosage form is administered daily for eight or more weeks, and at week 8 said patient has a mean Y-BOCS total scale change of at least 2.9 points compared to placebo. [Aspect 13] The method of embodiment 8, wherein the dosage form is administered daily for 12 weeks or more, and wherein at week 12 the patient has a mean Y-BOCS total scale change from baseline of -7.0 points. [Aspect 14] The method of embodiment 8, wherein the dosage form is administered daily for 12 weeks or more, and at week 12, the patient has a mean Y-BOCS total scale change of 2.4 points compared to placebo. [Aspect 15] A dosage form comprising an amount of trolilzole effective to treat obsessive-compulsive disorder in a patient in need of such treatment. [Aspect 16] 16. The dosage form of embodiment 15, comprising trolilzole in an amount of 200 mg or more. [Aspect 17] 16. The dosage form of embodiment 15, comprising trolilzole in an amount of 250 mg or more. [Aspect 18] 16. The dosage form of embodiment 15, comprising trolilzole in an amount of 300 mg or more. [Aspect 19] 16. The dosage form of embodiment 15, comprising trolilzole in an amount of 350 mg or greater. [Aspect 20] 16. The dosage form of embodiment 15, comprising trolilzole in an amount of 400 mg or more. [Aspect 21] 16. The dosage form of embodiment 15, comprising trolilzole in an amount of 450 mg or more. [Aspect 22] 16. The dosage form of embodiment 15, comprising trolilzole in an amount of 500 mg or more.

Claims

1. A pharmaceutical composition for treating obsessive-compulsive disorder in a patient in need thereof, comprising troriluzole, the pharmaceutical composition comprising trolilzole in an amount of 200 mg or more; the patient has a median Y-BOCS score of 26 or greater; The pharmaceutical composition.

2. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for four or more weeks, and at week four the patient has a mean Y-BOCS total scale change from baseline of at least -3.4 points.

3. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for four or more weeks, and at week four the patient has a mean Y-BOCS total scale change of at least 0.5 points compared to placebo.

4. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for eight weeks or more, and at week eight the patient has a mean Y-BOCS total scale change from baseline of at least -5.1 points.

5. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for eight weeks or more, and at week eight the patient has a mean Y-BOCS total scale change of at least 1.5 points compared to placebo.

6. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for 12 weeks or more, and at week 12, the patient has a mean Y-BOCS total scale change from baseline of -5.9 points.

7. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for 12 weeks or more, and at week 12, the patient has a mean Y-BOCS total scale change of 1.0 point compared to placebo.

8. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for four or more weeks, and at week four the patient has a mean Y-BOCS total scale change from baseline of at least -4.1 points.

9. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for four or more weeks and at week four the patient has a mean Y-BOCS total scale change of at least 0.6 points compared to placebo.

10. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for eight weeks or more, and at week eight the patient has a mean Y-BOCS total scale change from baseline of at least -6.0 points.

11. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for eight weeks or more, and at week eight the patient has a mean Y-BOCS total scale change of at least 2.9 points compared to placebo.

12. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for 12 weeks or more, and at week 12, the patient has a mean Y-BOCS total scale change from baseline of -7.0 points.

13. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered daily for 12 weeks or more, and at week 12, the patient has a mean Y-BOCS total scale change of 2.4 points compared to placebo.

14. A pharmaceutical composition according to any one of claims 1 to 13, comprising trolilzole in an amount of 250 mg or more.

15. A pharmaceutical composition according to any one of claims 1 to 13, comprising trolilzole in an amount of 300 mg or more.

16. A pharmaceutical composition according to any one of claims 1 to 13, comprising trolilzole in an amount of 350 mg or more.

17. A pharmaceutical composition according to any one of claims 1 to 13, comprising trolilzole in an amount of 400 mg or more.

18. A pharmaceutical composition according to any one of claims 1 to 13, comprising trolilzole in an amount of 450 mg or more.

19. A pharmaceutical composition according to any one of claims 1 to 13, comprising trolilzole in an amount of 500 mg or more.

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