How to Treat Spinocerebellar Ataxia

Abstract

Methods are provided for treating spinocerebellar ataxia genotype 3 in a patient in need of treatment, comprising administering to the patient a dosage form comprising an effective amount of troriluzole hydrochloride monohydrate. Also provided is a dosage form comprising an amount of troriluzole hydrochloride monohydrate effective to treat spinocerebellar ataxia genotype 3 in a patient in need of treatment.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 344,917, filed May 23, 2023, and to any and all benefits arising therefrom under 35 U.S.C. Section 119, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to a method for treating spinocerebellar ataxia. In particular, the present application relates to a method for treating spinocerebellar ataxia genotype 3. [Background technology]

[0003] Ataxia is a disorder of the central nervous system in which patients are unable to coordinate their muscles to perform voluntary movements. See, for example, Klockgether, T. “Ataxias” in Parkinsonism and Related Disorders 13, S391-S394, 2007. Typical symptoms of ataxia are impaired gait function, imbalance, impaired limb coordination, and changes in speech. In many ataxic disorders, ataxia is due to degeneration of the cerebellar cortex and its isotopic or ineffective fiber connections. Typical affected brain regions are the cerebellum, posterior columns, pyramidal tracts, and basal ganglia. Ataxia can result in a decrease in motor neuron function.

[0004] Spinocerebellar ataxias (SCAs) are a group of inherited brain disorders that affect the cerebellum, a part of the brain essential for the coordination of bodily movements, and sometimes the spinal cord. Spinocerebellar ataxias can be classified as ataxias associated with translated GAG repeat expansions (SCA types 1, 2, 3, 6, 7, and 17), ataxias associated with untranslated repeat expansions in noncoding regions (SCA types 10 and 12), and ataxias associated with point mutations (SCA types 5, 13, 14, and 27).

[0005] The most common SCAs include types 1, 2, 3, 6, 7, 8, and 10. SCA1 produces gait ataxia, limb ataxia, and akinesia, often with brainstem involvement, but few cognitive abnormalities. SCA2 is characterized by ataxia and dysarthria with slow saccadic eye movements and polyneuropathy. SCA3 (also known as Machado-Josef disease) is often associated with eyelid retraction, reduced blinking, external ophthalmoplegia, ectopia, dysphagia, and sometimes parkinsonism or peripheral neuropathy. SCA6 is relatively less severe than the other SCAs, typically progressing more slowly, limited to cerebellar involvement, and with a later age of onset. SCA7 is distinguished by retinal degeneration leading to blindness in addition to ataxia. Overall, there is significant symptom overlap between these SCAs. The common presentation of SCAs may reflect a common pathology affecting cerebellar Purkinje fibers.

[0006] Currently, there are no U.S. Food and Drug Administration (FDA) approved medications for the treatment of SCA. There remains a need for effective medications to treat the various types of SCA as well as the broader spinocerebellar ataxia population. Summary of the Invention

[0007] The present invention relates to methods of treating spinocerebellar ataxia genotype 3 and dosage forms for such treatment.

[0008] In one embodiment, a method is provided for treating spinocerebellar ataxia genotype 3 in a patient in need of treatment comprising administering to the patient a dosage form comprising an effective amount of trolilzole hydrochloride monohydrate.

[0009] In another embodiment, a dosage form is provided comprising trolilzole hydrochloride monohydrate in an amount effective to treat spinocerebellar ataxia genotype 3 in a patient in need of such treatment.

[0010] 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. [Brief description of the drawings]

[0011] [Figure 1] Figure 1 is a graph showing f-SARA change from randomization baseline to week 48 in f-SARA total score by treatment group for all SCA patients (nominal p=0.76). [Diagram 2] Figure 2 is a graph showing f-SARA change from randomization baseline to week 48 in f-SARA total score by treatment group in patients with SCA3 (baseline f-SARA ambulation item score was included as a covariate, nominal p = 0.53). [Diagram 3] Figure 3 is a graph showing f-SARA change from randomization baseline to week 48 in f-SARA total score by treatment group in SCA3 patients who were able to walk unassisted at baseline (nominal p=0.031). [Figure 4] FIG. 4 is a table showing the frequency of treatment-emergent adverse events (TEAEs) of falls among various patient groups. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The following detailed description is provided to assist those skilled in the art in practicing the present invention. Exemplary embodiments are described in detail below. However, these embodiments are merely illustrative, and the present disclosure is not limited thereto, but rather 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.

[0013] Accordingly, the embodiments are described below simply by reference to structures and schemes to illustrate aspects of the present specification. 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." A phrase such as "at least one" preceding a list of elements modifies the entire list of elements, and not each individual element of the list.

[0014] When an element is referred to as being "on" another element, it will be understood that it may 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" there are no intervening elements present.

[0015] Terms such as first, second, third, etc. may be used herein to describe various elements, components, regions, layers, and / or sections, but it will be understood that these elements, components, regions, layers, and / or sections should not be 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 may be referred to as a second element, component, region, layer, or section without departing from the teachings of the present embodiment.

[0016] As used herein, the terms "comprises" and / or "comprises", or "comprising" and / or "comprises" specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but are understood to not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. The terms used herein are only for describing specific embodiments and are not intended to be limiting. Terms such as those defined in commonly used dictionaries should be interpreted to have a meaning consistent with their meaning in the context of the relevant art and this disclosure, and it will be further understood that they will not be interpreted in an idealized or overly formal sense unless expressly defined in this specification.

[0018] As used in this application, unless expressly stated otherwise 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 is given the art-recognized meaning by those of ordinary skill in the art applying the term in the context of its use in describing the present invention.

[0019] 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 indicates otherwise. By way of example, "an element" means one element or more than one element.

[0020] Additional aspects will be described in part in, and in part apparent from, the description that follows.

[0021] Starting materials useful for making the pharmaceutical compositions of the present invention are readily available commercially or can be prepared by one of ordinary skill in the art.

[0022] In one embodiment, a method is provided for treating spinocerebellar ataxia genotype 3 in a patient in need of treatment comprising administering to the patient a dosage form comprising an effective amount of trolilzole hydrochloride monohydrate.

[0023] In one embodiment, the dosage form may be in the form of a capsule. In another embodiment, the dosage form may be in the form of a tablet. The tablet may be an orally disintegrating tablet.

[0024] Toliluzole hydrochloride monohydrate is a member of the benzothiazole chemical class and is a tripeptide prodrug conjugate of riluzole. Toliluzole hydrochloride monohydrate is chemically described as 2-amino-N-({methyl-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-carbamoyl}-methyl)-acetamide monohydrate monohydrochloride and its structural formula is:

[0025] [ka] The molecular formula of trorilzole hydrochloride monohydrate is C 15 H 16 F 3 N 5 O 4 S HCl H 2 O, representing a molecular weight of 473.85 g / mol (the molecular weight of the anhydrous free base form is 419.40 g / mol). The drug is freely soluble in water.

[0026] In one embodiment, the dosage form may contain 200 mg of trolilzole hydrochloride monohydrate and may be administered to a patient daily (QD).In another embodiment, the dosage form may contain 100 mg of trolilzole hydrochloride monohydrate and may be administered to a patient twice a day (BID).

[0027] In one embodiment, the dosage form can be administered daily for at least 48 weeks. For example, the dosage form can be administered daily for 48 weeks. When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient for 48 weeks, the patient at week 48 can show a least squares [LS] mean change difference of -0.55 compared to placebo (nominal p-value=0.053, 95% CI:-1.12, 0.01). When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient who was able to walk unaided at baseline for 48 weeks, the patient at week 48 can show a least squares [LS] mean change difference of -0.71 compared to placebo (nominal p-value=0.031, 95% CI:-1.36, -0.07).

[0028] In another embodiment, the dosage form can be administered daily for at least 4 weeks.For example, the dosage form can be administered daily for 4 weeks.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered to a patient daily for 4 weeks, the patient at week 4 can show least-squares [LS] mean change difference of at least -0.46 compared to placebo.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered to a patient, and the patient was able to walk without assistance at baseline, when administered daily for 4 weeks, the patient at week 4 can show least-squares [LS] mean change difference of at least -0.67 compared to placebo.

[0029] In another embodiment, the dosage form can be administered daily for at least 8 weeks.For example, the dosage form can be administered daily for 8 weeks.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient for 8 weeks, the patient at week 8 can show a least squares [LS] mean change difference of at least -0.12 compared to placebo.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient for 8 weeks, the patient at week 8 can show a least squares [LS] mean change difference of at least -0.33 compared to placebo.

[0030] In another embodiment, the dosage form can be administered daily for at least 12 weeks.For example, the dosage form can be administered daily for 12 weeks.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient for 12 weeks, the patient at week 12 can show a least squares [LS] mean change difference of at least -0.46 compared to placebo.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient for 12 weeks, the patient at week 12 can show a least squares [LS] mean change difference of at least -0.71 compared to placebo.

[0031] In another embodiment, the dosage form may be administered daily for at least 24 weeks.For example, the dosage form may be administered daily for 24 weeks.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered to a patient daily for 24 weeks, the patient at week 24 may show a least squares [LS] mean change difference of at least -0.17 compared to placebo.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered to a patient daily for 24 weeks, the patient at week 24 may show a least squares [LS] mean change difference of at least -0.40 compared to placebo.

[0032] In another embodiment, the dosage form can be administered daily for at least 36 weeks.For example, the dosage form can be administered daily for 36 weeks.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient for 36 weeks, the patient at week 36 can show a least squares [LS] mean change difference of at least -0.72 compared to placebo.When a dosage form containing 200mg of troriluzole hydrochloride monohydrate is administered daily to a patient for 36 weeks, the patient at week 36 can show a least squares [LS] mean change difference of at least -0.55 compared to placebo.

[0033] In another embodiment, the dosage form may be administered daily for 48 weeks and then again daily for an additional 48 weeks.

[0034] In another embodiment, a dosage form is provided that comprises an amount of trolilzole hydrochloride monohydrate effective for treating spinocerebellar ataxia genotype 3 in a patient in need of such treatment. In one aspect, the dosage form may comprise trolilzole hydrochloride monohydrate in an amount of 100 mg or more. In another aspect, the dosage form may comprise trolilzole hydrochloride monohydrate in an amount of 140 mg or more. In yet another aspect, the dosage form may comprise trolilzole hydrochloride monohydrate in an amount of 200 mg or more. The present invention is further illustrated by the following non-limiting examples. EXAMPLES

[0035] Phase III clinical trial of toriluzole in adult subjects with spinocerebellar ataxia Short summary: The objective of this study is to compare the efficacy of trolilzole (200 mg once daily) with placebo after 48 weeks of treatment in subjects with spinocerebellar ataxia (SCA).

[0036] Condition or Disease: Spinocerebellar ataxia Spinocerebellar ataxia type 1 Spinocerebellar ataxia type 2 Spinocerebellar ataxia type 3 Spinocerebellar ataxia type 6 Spinocerebellar ataxia type 7 Spinocerebellar ataxia type 8 Spinocerebellar ataxia type 10

[0037] Intervention / Treatment: Troriluzole placebo

[0038] Study design: Study type: Intervention (clinical trial) Actual registration: 218 participants Allocation: Randomized Intervention model: Parallel allocation Masking: Triple (participant, caregiver, investigator) Primary purpose: Treatment Official title: Phase III, long-term, randomized, double-blind, placebo-controlled study of toriluzole in adult subjects with spinocerebellar ataxia.

[0039] Treatment Groups and Interventions: treatment group Experiment: Group 1: BHV-4157 Oral trorilzole 200mg Placebo control: Group 2: Placebo Placebo 200mg orally Intervention / Treatment Drug: Troriluzole 200 mg orally Drug: Placebo 200 mg orally

[0040] Evaluation items Primary endpoint 1. Change from baseline in the Modified Functional Scale for Assessment and Evaluation of Ataxia (f-SARA) total score after 48 weeks of treatment. (Time frame: baseline to week 48) An increase in the total score indicates worsening of symptoms.

[0041] Secondary endpoints 1. Change from baseline in Patient Impression of Functioning and Daily Living Scale (PIFAS) scores at week 48 after randomization. (Time frame: baseline to week 48) An increase in the total score indicates worsening of symptoms. 2. Change from baseline in the Friedreich Ataxia Rating Scale-Activities of Daily Living (FARS-ADL) at 48 weeks after randomization. (Time frame: baseline to week 48) An increase in the total score indicates worsening of symptoms. 3. Change from baseline in functional grade of ataxia from the Friedreich Ataxia Rating Scale (FARS-FUNC) at 48 weeks after randomization. (Time frame: baseline to week 48) An increase in the total score indicates worsening of symptoms. 4. Frequency of subjects with the following adverse events (AEs) identified from case report forms: AEs (by severity, by relationship to study drug, and overall), SAEs, and AEs leading to treatment discontinuation. (Time frame: from baseline to Week 48)

[0042] Eligibility Criteria Inclusion criteria 1. Subjects with known or suspected specific genetic ataxias: SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA10; currently only enrolling SCA1, SCA2, SCA3, SCA7, and SCA10 (cap has been met for SCA6 and SCA8 (May 31, 2019)); a. The subject must have had a confirmed genotypic diagnosis from a CLIA-certified laboratory (capable of generating test results); or b. Subjects who have family members with a confirmed genotype diagnosis (test results available) from a CLIA-certified laboratory and who are willing to undergo genetic testing to provide the basis for a diagnosis of SCA; or c. Subjects who have a confirmed genotypic diagnosis from a non-CLIA certified laboratory and are willing to undergo genetic testing to confirm the underlying SCA diagnosis; or d. Subject must have clinical evidence supporting a diagnosis of any of the aforementioned SCA genotypes, but have no family or personal productive test results from a CLIA-certified laboratory, and be willing to undergo such testing to confirm the SCA diagnosis (in this case the site must await the genotype test results prior to randomization). 2. Ability to walk 8 metres unassisted (canes and other devices are acceptable). 3. Screening f-SARA total score ≥ 3. 4. f-SARA gait subscore ≥1. 5. Medically stable at baseline / randomization as determined by the investigator based on medical history, physical examination, laboratory tests, and electrocardiogram.

[0043] Exclusion criteria 1. A difference of ≥ 2 points in modified functional SARA score between screening and baseline. 2. MMSE score < 24. 3. Any medical condition, other than one of the hereditary ataxias specified in the inclusion criteria, that may primarily explain or significantly contribute to the subject's symptoms of ataxia. 4. Significant extension or dystonia that, in the investigator's opinion, impairs the ability of the SARA instrument to assess the severity of the underlying ataxia. 5. 4 points for any of the individual items of the f-SARA (items 1–4). 6. Subjects should be excluded at screening or baseline if they develop or experience a change in medical condition that would confound the ability of SARA to accurately reflect changes in ataxia severity. 7. History of active liver disease or hepatic intolerance to any medication that is deemed medically significant in the investigator's judgment.

[0044] result The primary endpoint, change from baseline to week 48 in the modified Functional Scale for Assessment and Evaluation of Ataxia (f-SARA), did not reach statistical significance in the overall SCA population due to less than expected disease progression over the course of the study. In the full study population (N=213), the trolilzole and placebo groups each had a mean baseline score of 4.9 points on the f-SARA, and at the 48-week endpoint, both groups showed minimal change with f-SARA scores of 5.1 and 5.2 points, respectively (p=0.76). The results are shown in Figure 1.

[0045] Post-hoc analysis of efficacy outcomes by genotype suggests a treatment effect in patients with the SCA3 genotype, which represents the most common form of SCA. In the SCA3 subgroup (Figure 2), troriluzole demonstrated a numerical treatment benefit compared with placebo in the change from baseline to week 48 in f-SARA score (least squares [LS] mean change difference -0.55, nominal p-value = 0.053, 95% CI: -1.12, 0.01). Furthermore, in patients in the SCA3 subgroup who were able to walk unaided at baseline (i.e., f-SARA ambulation item score = 1) (Figure 3), troriluzole demonstrated a greater numerical treatment benefit compared with placebo in the change from baseline to week 48 in f-SARA score (LS mean change difference -0.71, nominal p-value = 0.031, 95% CI: -1.36, -0.07). Of note, f-SARA used a novel 16-point rating scale, developed in collaboration with the FDA, as the primary endpoint of the study, which was designed to limit subjective measures and focus on the functional aspects of the disease, with significant changes being considered clinically meaningful.

[0046] SCA3 genotype analysis also demonstrated a reduced relative risk of falls in troriluzole-treated patients compared with placebo (nominal p=0.04). As measured by adverse events, patient-reported falls, there was an approximately 50% reduction in risk of falls in the troriluzole group (16% vs. 32% AE incidence of falls in the troriluzole and placebo groups, respectively).

[0047] Across all genotypes, the relative risk of falls in troriluzole-treated patients was reduced compared to placebo in patients who were ambulatory at baseline (i.e., f-SARA ambulation score = 1). Patient-reported falls, as measured by adverse events, reduced the risk of falls by approximately 59% in the troriluzole group (10% vs. 23% AE incidence of falls in the troriluzole and placebo groups, respectively, nominal p = 0.043). Overall, troriluzole demonstrated a favorable safety and tolerability profile, consistent with previous clinical trial experience.

[0048] 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 herein by reference in their entireties 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.

[0049] 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 the present invention and are encompassed by the following claims. For example, pharma- ceutically acceptable salts other than those specifically disclosed in the description and examples herein can be used. Furthermore, it is contemplated that any particular item in a list of items, or any subset group of items within a larger group of items, can be combined with any other particular item, subset group of items, or larger group of items, regardless of whether there is a specific disclosure herein identifying such combination.

Claims

1. A pharmaceutical agent for treating spinocerebellar ataxia genotype 3 in a patient requiring treatment for spinocerebellar ataxia genotype 3, comprising troriluzole hydrochloride monohydrate.

2. The pharmacopoeia according to claim 1, comprising (i) 200 mg of troliruzole hydrochloride monohydrate, administered daily to the patient for 48 weeks, wherein at 48 weeks the patient exhibits a least squares [LS] mean difference of -0.55 compared to placebo (nominal p-value = 0.053, 95% CI: -1.12, 0.01), or (ii) 200 mg of troliruzole hydrochloride monohydrate, administered daily for 48 weeks to the patient who was able to walk without assistance at baseline, wherein at 48 weeks the patient exhibits a least squares [LS] mean difference of -0.71 compared to placebo (nominal p-value = 0.031, 95% CI: -1.36, -0.07).

3. The pharmaceutical product according to claim 1, in the form of a capsule or a tablet.

4. The pharmaceutical product according to claim 1, in the form of an orally disintegrating tablet.

5. The pharmaceutical product according to claim 1, comprising 200 mg of troriluzole hydrochloride monohydrate, which is administered to the patient daily.

6. The pharmaceutical product according to claim 1, comprising 100 mg of troriluzole hydrochloride monohydrate, which is administered to the patient twice a day.

7. The pharmaceutical product according to any one of claims 1 to 6, which is administered daily for at least four weeks.

8. (i) comprising 200 mg of troliruzole hydrochloride monohydrate, administered to the patient daily for 4 weeks, wherein at 4 weeks the patient exhibits a least squares [LS] mean difference of at least -0.46 compared to placebo, or (ii) comprising 200 mg of troliruzole hydrochloride monohydrate, administered daily for 4 weeks to the patient who was able to walk without assistance at baseline, wherein at 4 weeks the patient exhibits a least squares [LS] mean difference of at least -0.67 compared to placebo, according to claim 7.

9. The pharmaceutical product according to any one of claims 1 to 6, which is administered daily for at least eight weeks.

10. (i) comprising 200 mg of troliruzole hydrochloride monohydrate, administered to the patient daily for 8 weeks, wherein at 8 weeks the patient exhibits a least squares [LS] mean difference of at least -0.12 compared to placebo, or (ii) comprising 200 mg of troliruzole hydrochloride monohydrate, administered to the patient daily for 8 weeks, wherein at 8 weeks the patient exhibits a least squares [LS] mean difference of at least -0.33 compared to placebo, according to claim 9.

11. The pharmaceutical product according to any one of claims 1 to 6, which is administered daily for at least 12 weeks.

12. (i) comprising 200 mg of troriruzole hydrochloride monohydrate, administered to the patient daily for 12 weeks, wherein at 12 weeks the patient exhibits a least squares [LS] mean difference of at least -0.46 compared to placebo, or (ii) comprising 200 mg of troriruzole hydrochloride monohydrate, administered to the patient daily for 12 weeks, wherein at 12 weeks the patient exhibits a least squares [LS] mean difference of at least -0.71 compared to placebo, according to claim 11.

13. The pharmaceutical product according to any one of claims 1 to 6, which is administered daily for at least 24 weeks.

14. (i) comprising 200 mg of troliruzole hydrochloride monohydrate, administered to the patient daily for 24 weeks, wherein at 24 weeks the patient exhibits a least squares [LS] mean difference of at least -0.17 compared to placebo, or (ii) comprising 200 mg of troliruzole hydrochloride monohydrate, administered to the patient daily for 24 weeks, wherein at 24 weeks the patient exhibits a least squares [LS] mean difference of at least -0.40 compared to placebo, according to claim 13.

15. The pharmaceutical product according to any one of claims 1 to 6, which is administered daily for at least 36 weeks.

16. (i) comprising 200 mg of troliruzole hydrochloride monohydrate, administered to the patient daily for 36 weeks, wherein at 36 weeks the patient exhibits a least squares [LS] mean difference of at least -0.72 compared to placebo, or (ii) comprising 200 mg of troliruzole hydrochloride monohydrate, administered to the patient daily for 36 weeks, wherein at 36 weeks the patient exhibits a least squares [LS] mean difference of at least -0.55 compared to placebo, according to claim 15.

17. The pharmaceutical product according to any one of claims 1 to 6, which is administered daily for at least 48 weeks.

18. The pharmaceutical product according to claim 17, further administered daily for 48 weeks.

19. The pharmaceutical product according to claim 1, comprising 100 mg or more of troriluzole hydrochloride monohydrate.

20. The pharmaceutical product according to claim 1, comprising 140 mg or more of troriluzole hydrochloride monohydrate.

21. The pharmaceutical product according to claim 1, comprising 200 mg or more of troriluzole hydrochloride monohydrate.

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