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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/06—Tripeptides

Definitions

• the present invention relates to methods of treating spinocerebellar ataxias.
• this application relates to methods of treating spinocerebellar ataxia genotype type 3.
• Ataxia is a disorder of the central nervous system, wherein the patient is unable to coordinate muscles for the execution of voluntary movement, see, e.g., Klockgether, T. "Ataxias" in Parkinsonism and Related Disorders 13, S391-S394, 2007.
• Typical symptoms of ataxia are gait dysfunctions, imbalance, impaired limb coordination and altered speech.
• the ataxia is due to degeneration of the cerebellar cortex and its afferent or efferent fiber connections.
• Typical affected brain regions are cerebellum, posterior column, pyramidal tracts and basal ganglia. Ataxia may lead to a decreased motoneuron function.
• SCA Spinocerebellar ataxia
• SCA1 often produces gait ataxia, limb ataxia, and dysarthria, with brainstem involvement but little cognitive abnormality.
• SCA2 is notable for the association of ataxia and dysarthria with slow saccadic eye movements and polyneuropathy.
• SCA3 also known as Machado-Joseph disease
• SCA6 is comparatively less severe, typically progresses more slowly, is more limited to cerebellar involvement than other SCAs, and has a later age of onset.
• SCA7 is distinguished by retinal degeneration leading to blindness, in addition to ataxia. Overall, there is significant symptom overlap among these SCAs.
• the shared symptomatic manifestations of the SCAs may reflect common pathology affecting cerebellar purkinje cell fibers.
• FDA United States Food and Drug Administration
• the present invention is directed to methods of treating spinocerebellar ataxia genotype type 3 and dosage forms for such treatment.
• a method for treating spinocerebellar ataxia genotype type 3 in a patient in need thereof including administering to the patient a dosage form comprising an effective amount of troriluzole hydrochloride monohydrate.
• a dosage form including troriluzole hydrochloride monohydrate in an amount effective to treat spinocerebellar ataxia genotype type 3 in a patient in need thereof.
• FIG. 4 is a table showing frequency of treatment-emerging adverse events (TEAE) of fall among various patient groups.
• the term “and/or” includes any and all combinations of one or more of the associated listed items.
• 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.
• 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 should not be limited by these terms. These terms are only used 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 termed a second element, component, region, layer, or section without departing from the teachings of the present embodiments.
• a method for treating spinocerebellar ataxia genotype type 3 in a patient in need thereof including administering to the patient a dosage form comprising an effective amount of troriluzole hydrochloride monohydrate.
• the dosage form may be in the form of a capsule. In another aspect, the dosage form may be in the form of a tablet.
• the tablet may be an orally disintegrating tablet.
• Troriluzole hydrochloride monohydrate is a member of the benzothiazole chemical class and is a tripeptide prodrug conjugate of riluzole.
• Troriluzole hydrochloride monohydrate is described chemically as 2-amino-N-( ⁇ methyl-[(6-trifluoromethoxy-benzothiazol-2-ylcarbamoyl)-methyl]-carbamoyl ⁇ -methyl)- acetamide monohydrate monohydrochloride and its structural formula is:
• the molecular formula of troriluzole hydrochloride monohydrate is C15H16F3N5O4S • HCI • H2O, representing a molecular weight of 473.85 g/mol (anhydrous free base form molecular weight is 419.40 g/mol).
• the drug substance is freely soluble in water.
• the dosage form may include 200 mg of troriluzole hydrochloride monohydrate, and may be administered to the patient daily (QD). In another aspect, the dosage form may include 100 mg of troriluzole hydrochloride monohydrate, and may be administered to the patient twice a day (BID).
• the dosage form may be administered daily for at least forty-eight weeks.
• the dosage form may be administered daily for forty-eight weeks.
• the dosage form may be administered daily for at least four weeks.
• the dosage form may be administered daily for four weeks.
• the patient at week 4 may show a least squares [LS] mean change difference of at least -0.46 compared to placebo.
• the dosage form including 200 mg of troriluzole hydrochloride monohydrate is administered to the patient, who was able to walk without assistance at baseline, daily for four weeks, the patient at week 4 may show a least squares [LS] mean change difference of at least -0.67 compared to placebo.
• the dosage form may be administered daily for at least eight weeks.
• the dosage form may be administered daily for eight weeks.
• the patient at week 8 may show a least squares [LS] mean change difference of at least -0.12 compared to placebo.
• the dosage form including 200 mg of troriluzole hydrochloride monohydrate is administered to the patient daily for eight weeks, the patient at week 8 may show a least squares [LS] mean change difference of at least -0.33 compared to placebo.
• the dosage form may be administered daily for at least twelve weeks.
• the dosage form may be administered daily for twelve weeks.
• the dosage form including 200 mg of troriluzole hydrochloride monohydrate is administered to the patient daily for twelve weeks, the patient at week 12 may show a least squares [LS] mean change difference of at least - 0.46 compared to placebo.
• the dosage form including 200 mg of troriluzole hydrochloride monohydrate is administered to the patient daily for twelve weeks, the patient at week 12 may show a least squares [LS] mean change difference of at least -0.71 compared to placebo.
• the dosage form may be administered daily for at least twenty-four weeks.
• the dosage form may be administered daily for twenty-four weeks.
• the patient at week 24 may show a least squares [LS] mean change difference of at least -0.17 compared to placebo.
• the dosage form including 200 mg of troriluzole hydrochloride monohydrate is administered to the patient daily for twenty-four weeks, the patient at week 24 may show a least squares [LS] mean change difference of at least -0.40 compared to placebo.
• the dosage form may be administered daily for at least thirty-six weeks.
• the dosage form may be administered daily for thirty-six weeks.
• the patient at week 36 may show a least squares [LS] mean change difference of at least -0.72 compared to placebo.
• the dosage form including 200 mg of troriluzole hydrochloride monohydrate is administered to the patient daily for thirty-six weeks, the patient at week 36 may show a least squares [LS] mean change difference of at least -0.55 compared to placebo.
• the dosage form may be administered daily for forty-eight weeks, and then administered daily again for an additional forty-eight weeks.
• a dosage form including troriluzole hydrochloride monohydrate in an amount effective to treat spinocerebellar ataxia genotype type 3 in a patient in need thereof.
• the dosage form may include troriluzole hydrochloride monohydrate in an amount of 100 mg or greater.
• the dosage form may include troriluzole hydrochloride monohydrate in an amount of 140 mg or greater.
• the dosage form may include troriluzole hydrochloride monohydrate in an amount of 200 mg or greater.
• the purpose of this study is to compare the efficacy of Troriluzole (200mg once daily) versus placebo after 48 weeks of treatment in subjects with spinocerebellar ataxia (SCA).
• Subjects with a known or suspected diagnosis of the following specific hereditary ataxias SCA1, SCA2, SCAB, SCA6, SCA7, SCA8 and SCA10; currently only enrolling SCA 1, SCA2, SCA3, SCA7, and SCA10 (the cap has been met for SCA6 and SCA8 (on May 31, 2019)); a.
• a subject should have a confirmed genotypic diagnosis from a CLIA certified lab (can produce test results); or b.
• a subject has a family member that has a confirmed genotypic diagnosis from a CLIA certified lab (can produce test results) and must be willing to undergo genetic testing to confirm underlying SCA diagnosis; or c.
• a subject has a confirmed genotypic diagnosis from a lab that is not CLIA certified and must be willing to undergo genetic testing to confirm underlying SCA diagnosis; or d.
• a subject has clinical evidence that supports diagnosis of one of the aforementioned SCA genotypes but does not have producible test results from a CLIA certified lab from either a family member or for his or herself and the subject must be willing to undergo such testing to confirm the SCA diagnosis (in this case, site must wait for results of genotypic testing prior to randomization).
• Subjects should be excluded at screening or baseline if medical conditions have arisen or there is a change in disease status that could confound the ability of the SARA to accurately reflect changes in ataxia severity.
• the results are shown in FIG. 1.
• the f-SARA is a novel, 16-point scale developed in collaboration with FDA as the primary outcome measure for this trial; the scale was designed to limit subjective scale and focus on functional aspects of the disease so that significant changes would be considered clinically meaningful.
• Patient reported falls, as measured by adverse events reveal an approximately 50% reduction of fall risk in the troriluzole group (16% versus 32% AE incidence of falls in the troriluzole and placebo groups, respectively).
• troriluzole demonstrated a favorable safety and tolerability profile, consistent with past clinical trial experience.

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• 2023
  • 2023-05-23 WO PCT/US2023/067326 patent/WO2023230451A2/en not_active Ceased
  • 2023-05-23 KR KR1020247038718A patent/KR20250020409A/ko active Pending
  • 2023-05-23 JP JP2024569498A patent/JP2025517509A/ja active Pending
  • 2023-05-23 EP EP23812702.1A patent/EP4529485A2/en active Pending
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