Tablets for use in the treatment of Huntington's disease and method for preparing them

Abstract

This document relates to a tablet formulation of the compound 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol for use in the treatment of Huntington's disease, and methods for making same.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 113,826, filed on November 13, 2020; U.S. Provisional Patent Application No. 63 / 245,927, filed on September 19, 2021; U.S. Provisional Patent Application No. 63 / 261,467, filed on September 21, 2021; U.S. Provisional Patent Application No. 63 / 261,495, filed on September 22, 2021; and U.S. Provisional Patent Application No. 63 / 255,745, filed on October 14, 2021, the contents of which are hereby expressly incorporated by reference in their entirety.

[0002] The present invention generally relates to immediate - release pharmaceutical tablets of small - molecule compounds for use in the treatment of Huntington's disease and methods of making the same.

Background Art

[0003] Huntington's disease (HD) is a rare hereditary neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. This disorder results in behavioral, cognitive, and motor function impairments. These symptoms gradually reduce an individual's quality of life and ultimately lead to death within 15 - 25 years after the onset of clinical motor symptoms becomes apparent. Each child of a parent with a mutation in the huntingtin gene has a 50% probability of inheriting the mutation. It is estimated that approximately 1 in 10,000 people carry the mutant huntingtin gene. Current HD treatments manage the severity of symptoms, but currently, there are no approved treatments to slow disease progression.

[0004] HD is caused by a CAG repeat expansion in HTT and is characterized by a decline in motor, cognitive, mental, and functional abilities. The expansion of the CAG trinucleotide repeat results in a mutant huntingtin protein (mHTT), which is associated with neuronal dysfunction and ultimate death.

[0005] The number of CAG repeats in the HTT gene ranges from 6 to 35 in healthy individuals. Disease penetrance appears to be reduced in individuals with 36-39 CAG repeats, but individuals with 40 or more CAG repeats almost certainly develop the disease. As described in the European Journal of Neurology, 2017, pp. 24-34, the clinical diagnosis of HD is based on a confirmed family history or positive genetic testing (i.e., confirmation of CAG repeat elongation ≥ 36) and the onset of motor impairment as defined by the Unified Huntington's Disease Rating Scale (UHDRS) (using the diagnostic confidence score (DCS) of the total motor score (TMS). The DCS ranges from 0 (no motor abnormalities suggestive of HD) to 4 (motor abnormalities with ≥ 99% probability of being due to HD), with a score of 4 defining "motor-onset" or "overt" HD).

[0006] Typically, the age of onset (i.e., when DCS reaches 4) is in the range of 30 to 50 years, and the mean survival duration after clinical diagnosis is 15 to 20 years. Currently, disease staging is determined more by loss of "function" after onset (i.e., assessment of functional capacity) than by motor signs (see, e.g., Neurology, 1979, 29, pp. 1-3, or Neurology, 1981, 31, pp. 1333-1335). The Total Functional Capacity (TFC) scale (see, e.g., Movement Disorders, 1996, 11, pp. 136-142) is a component of the UHDRS, where the independence level of a person with HD ranges from 0 (completely dependent on all care) to 13 (completely independent). This scale assesses the functional status of HD patients with respect to their ability to work, manage household finances, manage household chores, perform daily living activities, and the level of care required. Based on the Total Functional Capacity (TFC) of the UHDRS, HD is divided into disease progression stages 1 through 5. The categorization of HD based on the TFC score (also known as the Shouldon and Fahn stages) can also be described as the early stage of HD (corresponding to stage 1 or 2 based on the TFC score), the moderate or mid-stage of HD (corresponding to stage 3 based on the TFC score), and the advanced or late stage of HD (corresponding to stage 4 or 5 based on the TFC score).

[0007] The international application, published as International Application No. 2020 / 005873, identifies the types of compounds that can be used in the treatment of HD, methods for preparing them, and pharmaceutical formulations thereof. This application identifies the compounds as IC 50Data also provided showing inhibition of endogenous Huntington's protein (HTT) in assays. In that application, one of the compounds disclosed as a particularly potent inhibitor of HTT, 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol, has since been found to be effective in reducing in vivo production of human HTT in a genetically modified mouse model of Huntington's disease (results have not yet been published). Currently, only symptomatic treatments are available. Therefore, to date, there are no small molecule therapies available to slow the progression of HD. Thus, there is a need for small molecule disease-modifying therapies for HD (i.e., therapeutic options that can slow disease progression). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] U.S. Provisional Patent Application No. 63 / 113,826 [Patent Document 2] U.S. Provisional Patent Application No. 63 / 245,927 [Patent Document 3] U.S. Provisional Patent Application No. 63 / 261,467 [Patent Document 4] U.S. Provisional Patent Application No. 63 / 261,495 [Patent Document 5] U.S. Provisional Patent Application No. 63 / 255,745 [Patent Document 6] International Application No. 2020 / 005873 [Non-patent literature]

[0009] [Non-Patent Document 1] European Journal of Neurology, 2017, pp. 24-34 [Non-Patent Document 2] Neurology, 1979, 29, pp. 1 - 3 [Non - Patent Document 3] Neurology, 1981, 31, pp. 1333 - 1335 [Non - Patent Document 4] Movement Disorders, 1996, 11, pp. 136 - 142 [Non - Patent Document 5] Lancet Neural., 2013, 12(7), pp. 637 - 649 [Non - Patent Document 6] Movement Disorders, 2014, 29(10), pp. 1281 - 1288 [Non - Patent Document 7] Movement Disorders, 2016, 31(10), pp. 1466 - 1478 [Non - Patent Document 8] Movement Disorders, 2015, 30(14), pp. 1954 - 1960 [Non - Patent Document 9] Neurology, 2017, 89, pp. 2495 - 2502 [Non - Patent Document 10] Movement Disorders, 2018, 33(5), pp. 742 - 749 [Non - Patent Document 11] Caron, N, Wright, G and Hayden, M; (2020a), Huntington Disease; Seattle, WA; University of Washington [Summary of the Invention] [Means for Solving the Problems]

[0010] In one embodiment, the present invention relates to a tablet containing, as an active ingredient, 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol (hereinafter referred to as Compound 1), or a pharmaceutically acceptable salt thereof (Compound 1 is present in an amount of about 1% to about 30% by mass of the total mass of the tablet), an internal excipient, and an external excipient, The granular excipients contain microcrystalline cellulose and a diluent, with a ratio of approximately 1:1 to 1:4, where microcrystalline cellulose accounts for approximately 15% to 25% of the total tablet mass, the disintegrant accounts for approximately 1% to 3% of the total tablet mass, and povidone accounts for approximately 1% to 5% of the total tablet mass. The present invention relates to tablets in which the extragranular excipients include a further amount of diluent and a further amount of disintegrant.

[0011] In one embodiment, compound 1 is present in an amount of approximately 5% to approximately 25% of the total mass of the tablet. In another embodiment, compound 1 is present in an amount of approximately 10% of the total mass of the tablet.

[0012] In one embodiment, the amount of compound 1 in the tablet is in the range of 1 mg to 200 mg.

[0013] In another embodiment, the amount of compound 1 in the tablet is in the range of 1 mg to 100 mg.

[0014] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

[0015] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0016] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0017] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0018] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg.

[0019] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0020] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg.

[0021] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, or 50 mg.

[0022] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg or 50 mg.

[0023] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg, 10 mg, 20 mg, and 30 mg.

[0024] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg, 10 mg, and 20 mg.

[0025] In one embodiment, the diluent is lactose monohydrate.

[0026] In one embodiment, the disintegrant is croscarmellose sodium.

[0027] In one embodiment, the ratio of microcrystalline cellulose to diluent in the granular excipient is approximately 1:2.

[0028] In one embodiment, at least one of the extragranular excipient and the intragranular excipient further comprises a surfactant. In such an embodiment, the surfactant is a poloxamer.

[0029] In one embodiment, the disintegrant is croscarmellose sodium.

[0030] In one embodiment, the extragranular excipient further comprises a lubricant. In such an embodiment, the lubricant is magnesium stearate.

[0031] In one embodiment, the extragranular excipient further comprises a flow promoter. In such an embodiment, the flow promoter is colloidal silicon dioxide.

[0032] In one embodiment, the total mass of the extragranular excipient is approximately 15% to 30% of the total mass of the tablet.

[0033] In one embodiment, the granular excipient is wet-granulated.

[0034] In another embodiment, the tablet contains compound 1 in an amount of about 10% by mass of the tablet, the intragranular excipients contain microcrystalline cellulose and lactose monohydrate in a ratio of about 1:2, the microcrystalline cellulose present in an amount of about 20% by mass of the tablet, the disintegrant present in an amount of 1% to about 3% by mass of the tablet, the povidone present in an amount of about 2% by mass of the tablet, and the extragranular excipients contain a further amount of lactose monohydrate in an amount of about 10% to about 25% by mass of the tablet, a further amount of disintegrant in an amount of about 1% to about 5% by mass of the tablet, and poloxamer in an amount of about 0.5% to about 2% by mass of the tablet.

[0035] In another embodiment, the tablet further contains colloidal silicon dioxide in an amount of about 0.25% to about 2% by mass of the tablet.

[0036] In another embodiment, the tablet further contains magnesium stearate in an amount of about 0.5% to about 2% by mass of the tablet.

[0037] The present invention also relates to a method for producing tablets, comprising the steps of: wet granulating an intragranular excipient; drying the resulting intragranular blend; mixing an extragranular excipient with the intragranular excipient; and compressing the resulting mixture to form a tablet.

[0038] In another embodiment, the method further includes the step of coating the tablets with a film.

[0039] In one embodiment, the present invention also relates to a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject a tablet having a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0040] In another aspect, the present invention also relates to the use of compound 1 or a pharmaceutically acceptable salt thereof in treatment for slowing the progression of Huntington's disease, wherein the effect of treatment using compound 1 or a pharmaceutically acceptable salt thereof is to slow the progression of Huntington's disease by producing an in-frame stop codon between exon 49 and exon 50 in HTT mRNA, the effect of treatment using compound 1 or a pharmaceutically acceptable salt thereof for slowing the progression of Huntington's disease is a disease-modifying treatment, the effect of treatment using compound 1 or a pharmaceutically acceptable salt thereof is to slow the decline in motor function associated with Huntington's disease, the effect of treatment using compound 1 or a pharmaceutically acceptable salt thereof is to slow the decline in cognition associated with Huntington's disease, and the effect of treatment using compound 1 or a pharmaceutically acceptable salt thereof is to slow the decline in psychiatric function associated with Huntington's disease. The effects of treatment with compound 1 or a pharmaceutically acceptable salt thereof slow down the decline in functional capacity associated with Huntington's disease, and the effects of treatment with compound 1 or a pharmaceutically acceptable salt thereof slow down the progression of the pathophysiology of Huntington's disease. [Brief explanation of the drawing]

[0041] [Figure 1] This is a time-course plot of individual plasma concentrations of compound 1 in male cynomolgus monkeys after oral administration of an oral suspension formulation of compound 1 at a dose of 30 mg in 0.5% hydroxypropyl methylcellulose (HPMC) in water (Batch 21) (Leg 1). [Figure 2] This is a time-course plot of the mean plasma concentration of compound 1 after oral administration of an oral suspension of compound 1 (batch 21) at a dose of 30 mg in 0.5% HPMC water in male cynomolgus monkeys (Leg 1). [Figure 3] This is a time-course plot of individual plasma concentrations of compound 1 after oral administration of 30 mg tablet formulation A (wet granulation batch 15) in male cynomolgus monkeys (Leg 2). [Figure 4]This is a time-course plot of the mean plasma concentration of compound 1 after oral administration of 30 mg tablet formulation A (wet granulation batch 15) in male cynomolgus monkeys (Leg 2). [Figure 5] This is a time-course plot of individual plasma concentrations of compound 1 in male cynomolgus monkeys after oral administration of 30 mg tablet formulation B (dry granulation batch 20) (Leg 3). [Figure 6] This is a time-course plot of the mean plasma concentration of compound 1 after oral administration of 30 mg tablet formulation B (dry granulation batch 20) in male cynomolgus monkeys (Leg 3). [Figure 7] This shows the dissolution profile (dissolution %) of 5 mg tablets produced from batch 23, before storage and after storage at 50°C for 2 weeks, or before storage and after storage at 40°C / 75% relative humidity for 1 month (dissolution %) of compound 1 over time. [Figure 8] This shows the dissolution profile (dissolution %) of 50 mg tablets produced from batch 23, before storage and after storage at 50°C for 2 weeks, or before storage and after storage at 40°C / 75% relative humidity for 1 month (dissolution %) of compound 1 over time. [Figure 9] Figure 9B shows the dose-dependent decrease in HTT mRNA in whole blood collected from healthy volunteers participating in single-dose escalation studies (SAD) and multi-dose escalation studies in Phase I clinical trials. Figure 9A shows the decrease in HTT mRNA in whole blood collected from healthy volunteers in the SAD cohort, where volunteers received a single dose of either placebo, 5 mg, 15 mg, 45 mg, 90 mg, or 135 mg of compound 1 once daily, and splicing was evaluated over 24 hours. Figure 9B shows the decrease in HTT mRNA in whole blood collected from healthy volunteers in the MAD cohort, who received either placebo, 15 mg, or 30 mg of compound 1 daily for 14 days. Next, on day 14, HTT splicing was evaluated by RT-PCR 6 hours after administration of compound 1. [Figure 10] This paper demonstrates how decay rates can be modeled to predict the drug-dependent decline in mRNA and protein concentrations over time. [Figure 11] The decay rates of HTT mRNA (Figure 11A) and HTT protein (Figure 11B) are modeled based on their half-lives, and a graph predicting the time to reach a steady state after treatment with a daily dose of 30 mg of compound 1 is shown. For HTT mRNA, the half-life is estimated to be approximately 24 hours. In Figure 11A, the HTT mRNA reaches a steady state after approximately 5 days. For HTT protein, the half-life is estimated to be 5-7 days, and as a result, it should take approximately 6 weeks from the start of treatment to reach a steady state level of HTT protein. [Figure 12] The decline trajectories of HTT mRNA (Figure 12A) and protein (Figure 12B) observed in multiple dose-escalation studies are compared with values ​​predicted from the HTT mRNA half-life shown in Figure 11. [Figure 13] This shows that compound 1 crosses the blood-brain barrier in non-human primates (Figure 13A) and humans (Figure 13B). [Figure 14] This is a plot of baseline percentage of HTT RNA measured over time in whole blood of human subjects administered either placebo or a single dose of 90 mg of compound 1, as described in the single dose escalation (SAD) study in Part 1 of Example 10. The results indicate that the HTT splicing effect of compound 1 is reversible and persists for 72 hours after treatment cessation. [Figure 15] This is a plot of baseline percentage of HTT RNA measured over time in whole blood of human subjects administered placebo, 15 mg, or 30 mg of Compound 1, as described in the multiple dose escalation (MAD) study described in Part 2 of Example 10. HTT splicing was monitored after the final dose on day 14 and calculated as the percentage of HTT remaining from baseline (before administration on day 0). [Figure 16]As described in Example 10, the bar graph shows huntingtin mRNA and protein levels in whole blood from MAD Cohort 2.3 (30 mg administered for 21 days, followed by a 100 mg loading dose (LD) for 2 days) 24 hours after the final dose, as a percentage of baseline, after administration of the vehicle or compound 1 to humans. The results indicate that the decrease in HTT mRNA reached a steady state. Longer administration periods were required for HTT protein levels to reach the maximum steady-state decrease. [Modes for carrying out the invention]

[0042] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure pertains. Similar or equivalent methods and materials may be used in the practice or testing of this disclosure; however, materials, methods, and examples are illustrative and not intended to be limiting. Other features of this disclosure are evident from the following detailed description and claims.

[0043] Titles or subtitles may be used herein solely for the convenience of the reader, but they are not intended to affect the scope of this disclosure or to limit any aspect of this disclosure to any subsection, subtitle, or paragraph.

[0044] 1.Definition As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless otherwise explicitly indicated by the context.

[0045] When used herein and in the claims, the phrase “at least one” referring to a list of one or more elements means at least one element selected from any one or more of the elements in the list of elements, but it should be understood that it does not necessarily have to include at least one of every element specifically enumerated in the list of elements, nor does it have to exclude any combination of elements in the list of elements. Furthermore, this definition allows for the presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether related to or unrelated to those specifically identified elements, as necessary. Therefore, as a non-restrictive example, “at least one of A and B” (or equivalently “at least one of A or B” or equivalently “at least one of A and / or B”) may, in one aspect, refer to at least one A (including elements other than B as may be) in which B is absent, and optionally two or more A's (including elements other than A as may be) may, in another aspect, refer to at least one A (including elements other than A) in which A is absent, and optionally two or more B's (including elements other than A as may be) may, in yet another aspect, refer to at least one A (including elements other than B as may be) and optionally two or more A's and at least one B (including elements other than B as may be) etc.

[0046] The term "approximately," when used with a numerical range, modifies that range by broadening the upper and lower limits of those numbers. Generally, the term "approximately" is used herein to modify a number to be above and below its stated value by a 20%, 10%, 5%, or 1% variance. In certain embodiments, the term "approximately" is used to modify a number to be above and below its stated value by a 10% variance. In certain embodiments, the term "approximately" is used to modify a number to be above and below its stated value by a 5% variance. In certain embodiments, the term "approximately" is used to modify a number to be above and below its stated value by a 1% variance.

[0047] The terms “subject” or “patient” are interchangeable to refer to individual human beings suffering from the diseases described herein (e.g., Huntington’s syndrome) that can be treated by administration of the compositions described herein.

[0048] When a range of values ​​is listed herein, it is intended to encompass each value and subrange within that range. For example, the range "1 to 5ng" or "1ng to 5ng" is intended to encompass 1ng, 2ng, 3ng, 4ng, 5ng, 1 to 2ng, 1 to 3ng, 1 to 4ng, 1 to 5ng, 2 to 3ng, 2 to 4ng, 2 to 5ng, 3 to 4ng, 3 to 5ng, and 4 to 5ng.

[0049] It will be further understood that, as used herein, the terms “comprises,” “comprising,” “includes,” and / or “including” identify the presence of the described features, integers, processes, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, processes, operations, elements, components, and / or groups thereof.

[0050] The terms “treat,” “treatment,” and “treating” refer to therapeutic actions whose purpose is to reverse, reduce, improve, inhibit, slow, or halt the progression or severity of a disorder. The term “treating” also includes, as an alternative, the term “improving,” which refers to reducing or mitigating at least one adverse effect or symptom of a condition, disease, or disorder. A treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, a treatment is “effective” if the progression of a disorder is slowed, reduced, or halted. That is, “treatment” includes not only improvement of symptoms or markers but also cessation, or at least slowing, of the progression or worsening of symptoms compared to what would be expected without treatment. Beneficial or desired clinical outcomes include, but are not limited to, the reduction of one or more symptoms, whether detectable or undetectable; a reduction in the severity of the disease; stabilization of the disease (i.e., no worsening); delay or slowing of disease progression; relief or reduction of the disease; remission (whether partial or complete); and / or a reduction in mortality. Furthermore, the term “treatment” of the disease includes providing relief from the symptoms or side effects of the disease (including symptomatic treatment).

[0051] As used herein, the term “excipient” means any substance that is not a therapeutic agent itself, which is added to a pharmaceutical composition to be used as a carrier or vehicle for delivering a therapeutic agent to a target, or to improve the handling or storage properties of the pharmaceutical composition, or to enable or facilitate the formation of dose units of the composition into separate things, such as capsules or tablets suitable for oral administration. Excipients include, but are not limited to, diluents, disintegrants, binders, adhesives, surfactants, lubricants, flow enhancers, surface modifiers, substances added to mask or counteract unpleasant tastes or odors, flavors, dyes, fragrances, and substances added to improve the appearance of a composition.

[0052] The terms "HD" or "Huntington's disease," as used herein, refer to a neurodegenerative disorder characterized by impaired motor, cognitive, psychiatric, and functional abilities, caused by elongation of the CAG repeat in the huntingtin gene.

[0053] As used herein, the term "intragranular" refers to a component that is incorporated into the formulation before granulation, i.e., a component located inside or in part of the granular structure.

[0054] As used herein, the term "extragranular" refers to components that are incorporated into the formulation after granulation, i.e., components located outside the granular structure.

[0055] As used herein, the terms "administer" or "dose" refer to the act of physically delivering a substance that is present outside the body to a subject.

[0056] The terms “overt HD” or “overt Huntington’s disease” as used herein refer to a clinically established diagnosis of HD (e.g., based on a confirmed family history or positive genetic testing (confirmation of CAG repeat extension ≥ 36)) and the onset of motor impairment (e.g., a diagnostic confidence score (DCS) of 4 as defined by the Total Motor Score (TMS) of the Unified Rating Scale for Huntington’s Disease (UHDRS)). In one embodiment, the terms “overt HD” or “overt Huntington’s disease” as used herein refer to a patient having a clinically established diagnosis of HD (e.g., based on a confirmed family history or positive genetic testing (confirmation of CAG repeat extension ≥ 36)) and the onset of motor impairment (e.g., a diagnostic confidence score (DCS) of 4 as defined by the Total Motor Score (TMS) of the Unified Rating Scale for Huntington’s Disease (UHDRS)).

[0057] The terms “pre-manifest HD” or “pre-manifest Huntington’s disease” as used herein refer to a patient who has a genetic diagnosis of HD [e.g., based on positive gene testing (confirmation of CAG repeat extension ≥ 40)], without the onset of clinically established motor impairment, as assessed according to a standard scale, e.g., a clinical scale [e.g., based on a diagnostic confidence score (DCS) < 4 as defined by the total motor score (TMS) of the Unified Rating Scale for Huntington’s Disease (UHDRS)]. In one embodiment, the terms “pre-manifest HD” or “pre-manifest Huntington’s disease” as used herein refer to a patient who has a genetic diagnosis of HD [e.g., based on positive gene testing (confirmation of CAG repeat extension ≥ 40)], without the onset of clinically established motor impairment, as assessed according to a standard scale, e.g., a clinical scale [e.g., based on a diagnostic confidence score (DCS) < 4 as defined by the total motor score (TMS) of the Unified Rating Scale for Huntington’s Disease (UHDRS)].

[0058] The terms “slowing the progression of HD,” “slowing the progression of Huntington’s disease,” “for slowing the progression of HD,” or “for slowing the progression of Huntington’s disease,” as used herein, refer to one or more treatment effects selected from reducing the rate of progression of Huntington’s disease (e.g., reducing the rate of progression between stages of Huntington’s disease), delaying the onset of Huntington’s disease, delaying the onset of symptoms associated with Huntington’s disease, reducing the rate of progression of symptoms associated with Huntington’s disease (e.g., one or more symptoms) (e.g., reducing the rate of decline per year), or reducing the rate of progression of the pathophysiology of Huntington’s disease (e.g., treatment effects measured according to the above or below standard scales, e.g., clinical scales, or neuroimaging criteria, e.g., compared to placebo or a natural history control group).

[0059] When used herein, the term “rate of progression” refers to, for example, the annual rate of change (e.g., decline) or the rate of change (e.g., decline) per year, as assessed according to, for example, a standard scale, such as a clinical scale, or according to neuroimaging criteria.

[0060] As used herein, the term "reduce" refers, for example, to a reduction of 5%, 10%, 20%, 30%, 40%, 50%, 60%, or 70% per year of treatment.

[0061] The term “to delay” as used herein means, for example, to delay by at least 0.5 years, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 11 years, at least 12 years, at least 13 years, at least 14 years, or at least 15 years.

[0062] The terms “to slow the progression of HD,” “to slow the progression of Huntington’s disease,” “for the purpose of slowing the progression of HD,” or “for the purpose of slowing the progression of Huntington’s disease,” as used herein, mean delaying the onset of Huntington’s disease, for example, increasing the time it takes to develop Huntington’s disease, as defined herein. In other embodiments, the terms mean reducing the rate of progression between stages of Huntington’s disease, for example, compared to placebo, as assessed according to a standard scale, for example, a clinical scale [for example, according to the Total Functional Capacity (TFC) scale of the UHDRS, Neurology, 1979, pp. 29, pp. 1-3], for example, reducing the rate of progression from an early stage of HD to a more advanced stage of HD. In other embodiments, the terms mean reducing the rate of progression from stage 1 of HD to stage 2 of HD (for example, compared to placebo). In other embodiments, the terms mean reducing the rate of progression from stage 2 of HD to stage 3 of HD (for example, compared to placebo). In other embodiments, this term refers to reducing the rate of progression from Stage 3 of HD to Stage 4 of HD (e.g., compared to placebo). In other embodiments, this term refers to reducing the rate of progression from Stage 4 of HD to Stage 5 of HD (e.g., compared to placebo). In other embodiments, this term refers to reducing the rate of progression from early-stage HD to intermediate-stage HD (e.g., compared to placebo). In other embodiments, this term refers to reducing the rate of progression from intermediate-stage HD to advanced-stage HD (e.g., compared to placebo).

[0063] As used herein, the term "reducing the rate of progression" refers, for example, to increasing the time it takes for the HD stages to progress (e.g., compared to a placebo).

[0064] The terms “to slow the progression of HD,” “to slow the progression of Huntington’s disease,” “in order to slow the progression of HD,” or “in order to slow the progression of Huntington’s disease,” as used herein, mean delaying the onset of Huntington’s disease by at least 25% (e.g., 25% or more, e.g., 25% to 50%) (e.g., increasing the time it takes for Huntington’s disease to develop, as defined herein).

[0065] When used herein, the term “onset of Huntington’s disease” refers to the generally established clinical diagnosis of HD [for example, the onset of motor impairment based on a diagnostic confidence score (DCS) of 4 as defined by the Total Motor Score (TMS) of the Unified Rating Scale for Huntington’s Disease (UHDRS)].

[0066] The terms “slowing the progression of HD,” “slowing the progression of Huntington’s disease,” “for slowing the progression of HD,” or “for slowing the progression of Huntington’s disease,” as used herein, mean delaying the onset of symptoms associated with Huntington’s disease, for example, increasing the time to the onset of one or more symptoms associated with Huntington’s disease, selected from Huntington’s disease-related motor function decline, Huntington’s disease-related cognitive decline, Huntington’s disease-related psychiatric decline, and Huntington’s disease-related functional impairment. In another embodiment, the terms mean reducing the rate of progression of one or more symptoms associated with Huntington’s disease, selected from Huntington’s disease-related motor function decline, Huntington’s disease-related cognitive decline, Huntington’s disease-related psychiatric decline, and Huntington’s disease-related functional impairment, as defined herein. The term “reducing the rate of progression,” as used herein, means, for example, increasing the time to onset or increasing the time to severity (e.g., compared to placebo). In other embodiments, the terms “slowing the progression of HD,” “slowing the progression of Huntington’s disease,” “for slowing the progression of HD,” or “for slowing the progression of Huntington’s disease,” as used herein, mean reducing the rate of progression from asymptomatic HD to overt HD [i.e., delaying the onset of overt HD compared to placebo, for example, as assessed by a diagnostic confidence score (DCS) of 4 as defined by the total motor score (TMS) of the Unified Rating Scale for Huntington’s Disease (UHDRS)].

[0067] The terms “slowing the progression of HD,” “slowing the progression of Huntington’s disease,” “in order to slow the progression of HD,” or “in order to slow the progression of Huntington’s disease,” as used herein, refer to slowing the pathophysiological progression of Huntington’s disease.

[0068] The term “slowing the progression of the pathophysiology of Huntington’s disease,” as used herein, refers to reducing the rate of progression of the pathophysiology of Huntington’s disease, as assessed, for example, by magnetic resonance imaging (MRI) [e.g., by neuroimaging evaluation criteria in Lancet Neural. 2013, 12(7), pp. 637-649, etc.]. For example, this term refers to reducing the rate of volume loss (e.g., %) of the brain (e.g., whole brain, caudate nucleus, striatum, or cortex) associated with Huntington’s disease (e.g., as assessed by MRI) (e.g., reducing the rate per year, for example, compared to placebo).

[0069] When used herein, the term “motor function” refers to the motor features of HD, including, for example, one or more selected from the group consisting of ophthalmomotor function, dysarthria, chorea, postural stability, and gait.

[0070] As used herein, the term "decreased motor function" refers to a decline in motor function (e.g., from normal motor function or from a previous clinic visit). Decreased motor function may be assessed according to, for example, standard scales, such as clinical scales (e.g., the UHDRS Motor Assessment Scale, measured by the total motor score of the UHDRS, as described in Movement Disorders, 1996, 11, pp. 136-142).

[0071] When used herein, the terms “slowing the decline of motor function” or “for the purpose of slowing the decline of motor function” mean reducing the rate of decline of motor function (for example, reducing the annual rate of decline of motor function, for example, compared to placebo, for example, as assessed by the total motor score of UHDRS).

[0072] As used herein, the term "reducing the rate" means increasing the time to onset or increasing the time to severity (for example, reducing the rate of decline per year compared to placebo, for example, compared to placebo).

[0073] As used herein, the term “cognitive decline” refers to a decline in cognitive ability (e.g., from normal cognitive function or from a previous clinic visit). In one aspect, the term refers to a decline in one or more cognitive functions selected from the group consisting of attention, processing speed, visuospatial processing, timing, affect processing, memory, speech fluency, psychomotor functioning, and executive functioning. Cognitive decline can be assessed, for example, according to standardized scales, such as clinical scales [as assessed by, for example, the Symbol-Nuclear Modality Test, the Stroop Word Reading Test, the Montreal Cognitive Assessment, or the HD Cognitive Assessment Battery (including the Symbol-Nuclear Modality Test, Trail Making Test B, One Touch Stockings, Paced Tapping, Affect Recognition Test, and Hopkins Language Learning Test)].

[0074] The terms “slowing cognitive decline” or “for slowing cognitive decline” as used herein mean reducing the rate of cognitive decline (for example, reducing the annual rate of cognitive decline compared to placebo, as assessed by the Symbol-Number Modality Test, the Stroop Word Reading Test, the Montreal Cognitive Assessment, or the HD Cognitive Assessment Battery). The term “reducing rate” as used herein means increasing the time to onset or increasing the severity (for example, reducing the annual rate of decline compared to placebo, as assessed by the Symbol-Number Modality Test, the Stroop Word Reading Test, the Montreal Cognitive Assessment, or the HD Cognitive Assessment Battery).

[0075] As used herein, the term “psychiatric decline” refers to a decline in psychiatric function (e.g., from normal psychiatric function or from past clinic visits). In one aspect, the term refers to one or more psychiatric functions selected from the group consisting of, for example, affective blunting, anxiety, depression, obsessive-compulsive behavior, suicidal ideation, irritability, and agitation. Psychiatric decline may be assessed, for example, according to standard scales, such as clinical scales (e.g., as assessed by, for example, the Affective Blunting Rating Scale or the Hospital Anxiety and Depression Scale, as found in Movement Disorders, 2016, 31(10), pp. 1466–1478 and Movement Disorders, 2015, 30(14), pp. 1954–1960).

[0076] The terms “slowing psychiatric decline” or “for slowing psychiatric decline” as used herein mean reducing the rate of psychiatric decline (for example, reducing the rate of annual psychiatric decline compared to placebo, as assessed by the Affective Blurring Rating Scale or the Hospital Anxiety and Depression Scale). The term “reducing rate” as used herein means increasing the time to onset or increasing the severity (for example, reducing the rate of annual decline compared to placebo, as opposed to placebo).

[0077] As used herein, the term “functional capacity” refers, for example, to the ability to work, manage household finances, manage household chores, perform daily living activities, and the level of care required. Functional capacity includes, for example, one or more selected from the group consisting of the ability to work, manage household finances, manage household chores, perform daily living activities, and the level of care required.

[0078] As used herein, the term "decreased functional capacity" refers to a decrease in functional capacity (e.g., from normal functional capacity or from past clinic visits). Decreased functional capacity may be assessed, for example, according to standard scales, such as clinical scales (e.g., the UHDRS functional assessment scales and independent scales, and the UHDRS overall functional capacity scale, as found in Movement Disorders, 1996, 11, pp. 136-142).

[0079] The terms “slowing the decline in functional ability” or “for slowing the decline in functional ability” as used herein mean reducing the rate of decline in functional ability (for example, reducing the annual rate of decline in functional ability as assessed by the UHDRS Functional Assessment Scale and Independent Scale, or by the UHDRS Total Functional Ability Scale, for example, compared to placebo, for example, compared to placebo). The terms “reducing the rate” as used herein mean increasing the time to onset or increasing the severity (for example, reducing the annual rate of decline as assessed by placebo, for example, compared to placebo, for example, compared to placebo).

[0080] As used herein, the term "decline" refers to, for example, the deterioration over time (e.g., annually or per year) of a condition or a particular feature of a condition, as assessed according to a standard scale, such as a clinical scale.

[0081] When used herein, the terms “Huntington’s Disease Unified Rating Scale” or “UHDRS” refer to the clinical rating scale developed by the Huntington Research Group (e.g., in Movement Disorders, 1996, 11, pp. 136–142, which is fully incorporated herein by reference) that assesses the clinical outcomes and areas of ability of individuals with HD. The UHDRS includes rating scales for motor function, cognitive function, and functional ability. The UHDRS yields scores that assess the key features of HD (e.g., motor and cognitive) and the overall functional impact of these features.

[0082] The term "cHDRS" refers to the Combined Huntington's Disease Unified Rating Scale (e.g., Neurology, 2017, 89, pp. 2495-2502), which provides a combined assessment of motor, cognitive, and general functional abilities.

[0083] The terms “HD Stage 1,” “HD Stage I,” “Huntington’s Disease Stage 1,” “Huntington’s Disease Stage I,” “Huntington’s Disease Stage 1,” or “Huntington’s Disease Stage I,” as used herein, refer to the clinically established stage of HD [e.g., assessed according to a standard scale, e.g., a clinical scale, e.g., based on the Total Functional Capacity (TFC) scale of the UHDRS, e.g., where the TFC score is 11–13]. In HD Stage 1, the patient typically has a clinical diagnosis of HD, is fully functional at home and in the workplace, maintains independence with respect to functional capacity, and is typically 0–8 years old since the onset of Huntington’s disease.

[0084] The terms “HD Stage 2,” “HD Stage II,” “Huntington’s Disease Stage 2,” “Huntington’s Disease Stage II,” “Huntington’s Disease Stage 2,” or “Huntington’s Disease Stage II,” as used herein, refer to the clinically established stage of HD [e.g., assessed according to standard scales, e.g., clinical scales, e.g., based on the Total Functional Capacity (TFC) scale of the UHDRS, e.g., where the TFC score is 7–10]. In HD Stage 2, typically, the patient is still functioning in the workplace but is less capable and has some impairment, yet is able to perform most daily activities, usually requiring only minimal assistance, and is typically 3–13 years old since the onset of Huntington’s disease.

[0085] The terms “HD Stage 3,” “HD Stage III,” “Huntington’s Disease Stage 3,” “Huntington’s Disease Stage III,” “Huntington’s Disease Stage 3,” or “Huntington’s Disease Stage III,” as used herein, refer to the clinically established stages of HD [e.g., assessed according to standard scales, e.g., clinical scales, e.g., based on the Total Functional Capacity (TFC) scale of the UHDRS, e.g., where the TFC score is 4–6]. In HD Stage 3, typically, the patient is no longer able to work or manage household chores and requires substantial assistance with daily household finances, household chores, and daily living activities, and typically 5–16 years have passed since the onset of Huntington’s disease.

[0086] The terms “HD Stage 4,” “HD Stage IV,” “Huntington’s Disease Stage 4,” “Huntington’s Disease Stage IV,” “Huntington’s Disease Stage 4,” or “Huntington’s Disease Stage IV,” as used herein, refer to the clinically established stages of HD [e.g., assessed according to standard scales, e.g., clinical scales, e.g., based on the Total Functional Capacity (TFC) scale of the UHDRS, e.g., where the TFC score is 1–3]. In HD Stage 4, the patient is typically able to live at home, but not independently, with the help of either family or a professional. However, they require substantial assistance with household finances, household chores, and most daily living activities, and typically 9–21 years have passed since the onset of Huntington’s disease.

[0087] The terms “HD Stage 5,” “HD Stage V,” “Huntington’s Disease Stage 5,” “Huntington’s Disease Stage V,” “Huntington’s Disease Stage 5,” or “Huntington’s Disease Stage V,” as used herein, refer to the clinically established stage of HD [e.g., assessed according to standard scales, e.g., clinical scales, e.g., based on the Total Functional Capacity (TFC) scale of the UHDRS, e.g., where the TFC score is 0]. In HD Stage 5, patients typically require full support for daily activities through professional care and are typically 11 to 26 years post-onset Huntington’s disease.

[0088] The terms “early HD,” “early Huntington’s disease,” “early stage HD,” or “early stage Huntington’s disease,” as used herein, refer to a stage of HD in which a patient is mostly functional and able to continue working and living independently, despite having one or more of the following conditions selected from the group consisting of, for example, minor involuntary movements, slight ataxia of coordination, and difficulty thinking about complex problems. In other embodiments, the terms “early HD,” “early Huntington’s disease,” “early stage HD,” or “early stage Huntington’s disease” refer to “HD Stage 2” as defined herein.

[0089] The terms “moderate HD,” “moderate Huntington’s disease,” “moderate stage HD,” “moderate stage Huntington’s disease,” “mid-stage HD,” “mid-stage Huntington’s disease,” or “mid-stage HD,” as used herein, refer to a stage of HD in which the patient is unable to work, manage household finances, or perform household chores, but is able to eat, dress, and maintain personal hygiene with assistance. Typically, at this stage, chorea may be prominent, and there may be difficulties with swallowing, maintaining balance, falling, weight loss, and problem-solving. In other embodiments, the terms “moderate HD,” “moderate Huntington’s disease,” “moderate stage HD,” “moderate stage Huntington’s disease,” “mid-stage HD,” or “mid-stage HD,” refer to “HD Stage 3” as defined herein.

[0090] The terms “advanced HD,” “advanced Huntington’s disease,” “advanced stage HD,” “advanced stage Huntington’s disease,” “late HD,” or “late Huntington’s disease,” “late stage HD,” or “late stage Huntington’s disease,” as used herein, refer to the stage of HD in which the patient requires assistance in all daily living activities. Typically, at this stage, chorea, for example, may be severe, but is more often replaced by rigidity, dystonia, and bradykinesia. In other embodiments, the terms “advanced HD,” “advanced stage HD,” “advanced stage Huntington’s disease,” “late HD,” or “late stage Huntington’s disease,” “late stage HD,” or “late stage Huntington’s disease,” refer to “HD stage 4” or “HD stage 5” as defined herein.

[0091] When used herein, the terms “juvenile HD” or “juvenile Huntington’s disease” refer to a clinically established diagnosis of HD {for example, based on a confirmed family history or a positive genetic test (i.e., confirmation of CAG repeat extension 2:36 (SEQ ID NO: 22)) and onset of symptoms by age 21}.

[0092] When used herein, the terms “juvenile HD” or “juvenile Huntington’s disease” refer to patients who are affected by HD {for example, based on a confirmed family history or a positive genetic test (i.e., confirmation of CAG repeat extension 2:36 (SEQ ID NO: 22))} and who have developed symptoms by age 21.

[0093] When used herein, the terms “childhood HD” or “childhood Huntington’s disease” refer to a patient who is affected by HD {for example, based on a confirmed family history or positive genetic test (i.e., confirmation of CAG repeat extension 2:36 (SEQ ID NO: 22)) and a clinical diagnosis}, and who is <18 years of age.

[0094] The terms “HD patient,” “Huntington’s disease patient,” “Patient with Huntington’s disease,” or “Patient with HD” refer to patients with HD as defined herein.

[0095] The terms “to treat,” “to treat,” “treatment,” or “therapy,” as used herein, refer to obtaining a beneficial or desired outcome, such as a clinical outcome. Beneficial or desired outcomes may include, but are not limited to, stabilization or improvement of the progression of the stage of hemorrhagic disease (e.g., compared to a placebo). One aspect of a treatment is, for example, that the treatment should have minimal adverse effects on the patient, and that the drugs used should have a high level of safety, for example, without causing adverse side effects. In another aspect, the term “method for treatment,” as used herein, refers to “method for treatment.”

[0096] The terms “intermittent dosing regimen” or “intermittent dosing schedule,” as used herein, mean a dosing regimen comprising administering Compound 1, followed by a rest period. For example, Compound 1 is administered according to an intermittent dosing schedule of at least two cycles, each cycle comprising (a) a dosing period, followed by (b) a rest period.

[0097] As used herein, the term “drug-free period” specifically refers to a period during which a patient is not administered compound 1 (i.e., a period during which treatment with compound 1 is withheld). For example, if compound 1 is administered on a daily basis, a drug-free period may exist if the daily administration is interrupted for a period, e.g., several days, or if the plasma concentration of compound 1 is maintained at a level below the therapeutic dose for a period, e.g., several days. The duration and / or dose of compound 1 administration may be the same or different between cycles. The total treatment period (i.e., the number of cycles for treatment) may also vary from patient to patient, for example, based on the specific patient being treated (e.g., a stage I HD patient).

[0098] In another embodiment, the intermittent dosing schedule comprises at least two cycles, each cycle comprising (a) a dosing period in which a therapeutically effective amount of compound 1 is administered to the patient, and thereafter (b) a rest period. The terms “intermittent dosing regimen” or “intermittent dosing schedule,” as used herein, refer to both dosing regimens for compound 1 alone (i.e., monotherapy) or dosing regimens for administering compound 1 in combination with at least one further active ingredient (i.e., combination therapy). In another embodiment, the terms “intermittent dosing regimen” or “intermittent dosing schedule” refer to a treatment that is repeatedly switched on and off, in which compound 1 is administered periodically at regular intervals, for example, once daily, every two days, every three days, every four days, once a week, or twice a week.

[0099] In the context of administering a drug, the terms “once daily,” “once every day,” or “QD” mean, as used herein, that one dose of the drug is administered once each day, for example, at the same time each day.

[0100] In one embodiment, the terms “administer” or “administer compound 1 once daily” refer, as used herein, to an amount of compound 1 in a tablet ranging from 1 mg to 100 mg administered once daily.

[0101] In another embodiment, the amount of compound 1 in the tablet is in the range of 1 mg to 200 mg administered once daily.

[0102] In another embodiment, the amount of compound 1 in the tablet is in the range of 1 mg to 100 mg administered once daily.

[0103] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg, administered once daily.

[0104] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once daily.

[0105] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once daily.

[0106] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once daily.

[0107] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg administered once daily.

[0108] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once daily.

[0109] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, or 50 mg administered once daily.

[0110] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg or 50 mg administered once daily.

[0111] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg, 10 mg, 20 mg, and 30 mg administered once daily.

[0112] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg, 10 mg, and 20 mg administered once daily.

[0113] In the context of administering compound 1, the terms “once a week,” “once a week,” or “QW” mean, as used herein, that one dose of compound 1 is administered once each week, for example, on the same day of the week each week.

[0114] In one embodiment, the terms “administer” or “administer compound 1 once a week” mean, as used herein, compound 1 administered in amounts selected from 25 mg to 100 mg once a week, 25 mg to 200 mg once a week, and 50 mg to 200 mg once a week.

[0115] In another embodiment, compound 1 is administered in amounts selected from 35 mg once weekly, 70 mg once weekly, and 140 mg once weekly.

[0116] In the context of administering Compound 1, the terms “twice a week,” “twice a week,” or “BIW” mean, as used herein, that one dose of Compound 1 is administered twice each week, with each dose administered on separate days each week at regular intervals ranging from 48 to 72 hours.

[0117] In one embodiment, the terms “administer” or “administer compound 1 twice a week” as used herein refer to compound 1 administered in amounts selected from 10 mg to 100 mg twice a week, 10 mg to 200 mg twice a week, and 25 mg to 100 mg twice a week.

[0118] In another embodiment, compound 1 is administered in amounts selected from 10 mg to 20 mg twice a week, for example, about 15 mg twice a week; 30 mg to 40 mg twice a week, for example, 35 mg twice a week; and 50 mg to 90 mg twice a week, for example, 70 mg twice a week.

[0119] The term "approximately" in relation to a numerical value X means, for example, X ± 15% (including all values ​​within this range).

[0120] When used herein, the terms “disease-modifying treatment” or “disease-modifying procedure” refer to a drug (i.e., a disease-modifying drug) that can modify or alter the course of a condition, disorder, or disease, such as HD, as defined herein.

[0121] As used herein, the term "subject" refers to a mammalian organism, preferably a human (male or female).

[0122] As used herein, the term "patient" refers to an individual who is in a diseased state and who can benefit from treatment.

[0123] As used herein, the term "in need" refers to a procedure from which such a person (patient) can benefit biologically, medically, or in terms of quality of life.

[0124] The terms “therapeutic effective dose” or “effective dose” of Compound 1, as used herein, refer to the amount of Compound 1 that elicits a biological or medical response in a subject. In another embodiment, the terms refer to the amount of Compound 1 that, when administered to a subject, is effective in at least partially improving a condition, disorder, or disease.

[0125] The term "one or more" refers to either one or a number greater than one (for example, two, three, four, five, etc.).

[0126] 2.Compound The active ingredient of the tablet compositions disclosed herein is 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol (compound 1) or a pharmaceutically acceptable salt thereof. Compound 1 and suitable methods for preparing it are disclosed in International Application No. 2020 / 005873 (compound 163 in that publication).

[0127] In one embodiment, the amount of compound 1 in the tablet, based on the total mass of the tablet, is selected from 5% to 30%, 5% to 25%, 10% to 20%, and 10%.

[0128] In one embodiment, the amount of compound 1 in the tablet is in the range of 1 mg to 200 mg.

[0129] In another embodiment, the amount of compound 1 in the tablet is in the range of 1 mg to 100 mg.

[0130] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

[0131] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0132] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0133] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0134] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg.

[0135] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0136] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg.

[0137] In another embodiment, the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, or 50 mg.

[0138] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg or 50 mg.

[0139] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg, 10 mg, 20 mg, and 30 mg.

[0140] In another embodiment, the amount of compound 1 in the tablet is selected from 5 mg, 10 mg, and 20 mg.

[0141] Tablets of compound 1 can be produced by direct compression, by mixing compound 1 with an excipient and compressing them to form a tablet. Tablets of compound 1 can also be produced by other methods, including wet granulation or dry granulation. When granulation is used, compound 1 may be an intragranular and / or extragranular component of the tablet. In one aspect of the present invention, compound 1 is an intragranular component of the tablet. Compound 1 can be mixed with at least one intragranular excipient and wet or dry granulated to form an intragranular blend used in the production of a tablet. In one aspect of the present invention, a tablet is produced by a method comprising the steps of: mixing compound 1 with at least one intragranular excipient; wet granulating the mixture to form an intragranular blend; mixing the intragranular blend with at least one extragranular excipient; and compressing the resulting mixture to form a tablet.

[0142] 3. Excipients In one embodiment, the tablets provided herein include an excipient selected from the group consisting of diluents, binders, surfactants, disintegrants, flow enhancers, and lubricants. In the embodiments of the tablets provided herein, some excipients are either intragranular or extragranular excipients only, while other excipients are both intragranular and extragranular excipients.

[0143] a. Diluent Diluents are excipients used to dilute the components of a formulation, such as the active ingredient, to adjust them to a suitable amount for the formulation, and, in some cases, to impart stability or improved moldability. Examples of diluents include sugars, such as lactose or glucose; sugar alcohols, such as mannitol, xylitol, maltitol, sorbitol, isomalt, and crystalline cellulose, lactose, glucose, sucrose, fructose, maltose, and trehalose. Microcrystalline cellulose can also act as a diluent in tablet formulations and is included as an intragranular excipient in the tablets of the present invention. However, as used herein, the term “diluent” refers to diluents other than microcrystalline cellulose.

[0144] In one embodiment, the amount of microcrystalline cellulose contained as an internal excipient in the tablet of the present invention is selected from the group consisting of about 15% to about 25% by mass and about 15% to about 20% by mass of the total mass of the tablet. In another embodiment, the amount of microcrystalline cellulose contained as an internal excipient in the tablet of the present invention is about 20% by mass of the total mass of the tablet. In one embodiment, the diluent contained as an internal excipient is present in a ratio of microcrystalline cellulose to diluent selected from the group consisting of a ratio of about 1:1 to about 1:4 and about 1:1 to about 1:2. In another embodiment, the diluent contained as an internal excipient is present in a ratio of about 1:2. In one embodiment, the amount of diluent contained as an internal excipient is selected from the group consisting of about 15% to about 40% by mass and about 20% to about 40% by mass of the total mass of the tablet. In another embodiment, the amount of diluent contained as an internal excipient is about 40% by mass of the total mass of the tablet. When the diluent is included as an external excipient, in one embodiment, the diluent is present in an amount selected from the group consisting of about 5% to about 25% by mass and about 10% to about 25% by mass of the total mass of the tablet. When the diluent is included as an external excipient, in another embodiment, the diluent is present in an amount of about 20% by mass of the total mass of the tablet.

[0145] In one embodiment, the diluent is lactose, preferably lactose monohydrate.

[0146] b. Binder Binders are classified as excipients that impart tackiness to maintain the quality of the tablet after it has been formed. The amount of binder in the tablets provided herein varies, for example, based on the type of binder (properties such as molecular weight, solubility, and viscosity), the type and amount of other excipients, the type and amount of composite materials, and the dosage form in the formulation process (granulation method and tableting method).

[0147] Examples of binders that can be used include hydroxypropylcellulose, hypromellose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, corn starch, pea starch, pregelatinized starch, acacia, tragacanth, modified gum, gelatin, and povidone.

[0148] In one embodiment, povidone is included as an internal excipient in the tablets of the present invention, present in an amount of 1% to about 5% by mass, or 1.5% to about 4% by mass, or about 2% to about 3% by mass, or about 2% by mass of the total mass of the tablets.

[0149] c. Disintegrant A disintegrant is an excipient that functions to disintegrate the tablet by absorbing water and swelling after administration, thereby promoting the release of the active ingredient. In one embodiment of the tablet of the present invention, the disintegrant is included as both an intragranular and extragranular excipient. In one embodiment, the amount of the disintegrant is selected from the group consisting of about 1% to about 5% by mass, about 1% to about 3% by mass, and about 1.5% to about 2.5% by mass of the total mass of the tablet, in both the intragranular and extragranular portions of the tablet, respectively. In another embodiment, the amount of the disintegrant is about 2.5% by mass of the total mass of the tablet, in both the intragranular and extragranular portions of the tablet, respectively.

[0150] Examples of suitable disintegrants include sodium starch glycolate, crospovidone, cross-linked alginate, cross-linked starch, cross-linked sodium alginate, carmellose, carmellose calcium, croscarmellose sodium, glycerol fatty acid esters, low-substituted sodium carboxymethyl starch, and partially gelatinized starch. In one embodiment, the disintegrant is carmellose sodium.

[0151] d. Surfactants Surfactants are excipients used to improve the solubilization of surfactants. Surfactants may be included as intragranular excipients and / or extragranular excipients. In one embodiment, the surfactant is included as an intragranular excipient, and in another embodiment, it is included as an extragranular excipient.

[0152] Non-limiting examples of surfactants that can be used include quaternary ammonium compounds, e.g., dioctyl sodium sulfosuccinate; polyoxyethylene alkylphenyl (alklphenyl) ethers, e.g., nonoxynol 9, nonoxynol 10 and octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block copolymers, e.g., poloxamer 407); polyoxyethylene fatty acid glycers and oils, e.g., polyoxyethylene (8), caprylic / capric acid mono- and diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyethylene alkyl ethers, e.g., polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid esters, e.g., polyoxyethylene (40) stearate; polyoxyethylene sorbitan esters, e.g., polysorbate 20 and polysorbate 80 (e.g., Tween 80) Examples include propylene glycol fatty esters, such as propylene glycol laurate, sodium lauryl sulfate, fatty acids and their salts, such as oleic acid, sodium oleate and triethanolamine oleate, glyceryl fatty acid esters, such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate, tyloxapol, and mixtures thereof.

[0153] In one embodiment, the amount of surfactant contained in the tablet is appropriately selected from the group consisting of a range of about 0.5% to about 2% and about 0.5% to about 1.5%. In another embodiment, the amount of surfactant contained in the tablet is preferably about 1%.

[0154] The surfactant contained in the tablets of the present invention is poloxamer, preferably poloxamer 407.

[0155] e. Lubricants Lubricants are excipients that can be used to reduce friction between the apparatus and the granulated mixture during compression for tablet formation. Examples of suitable lubricants include glyceryl behenate, glyceryl behaptate; sodium stearyl fumarate, stearic acid, and their salts including magnesium stearate, calcium stearate, and sodium stearate; hydrogenated vegetable oil; colloidal silica; talc; wax; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycol; sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate, individually or in combination. When a lubricant is used in the tablets of the present invention, the lubricant is preferably magnesium stearate.

[0156] In one embodiment, the lubricant is included as an excipient in proportion to the total mass of the tablet. In another embodiment, the amount of lubricant included as an excipient is selected from the group consisting of 0.5% to about 3% and about 1% to about 2% by mass of the total mass of the tablet. In yet another embodiment, the amount of lubricant included as an excipient is about 1.5% by mass of the total mass of the tablet. The lubricant is preferably magnesium stearate.

[0157] f. Flow promoter Flow promoters are excipients used as anti-adhesion agents. Examples of flow promoters include colloidal silicon dioxide, hydrated sodium sulfoaluminate, and talc. In one embodiment of the tablet of the present invention, the flow promoter is included as an extragranular excipient. When a flow promoter is present, it is present in an amount selected from the group consisting of about 0.25% to about 2% by mass and about 0.25% to about 1% by mass of the total mass of the tablet. When a flow promoter is present, it is present in an amount of about 0.5% by mass of the total mass of the tablet.

[0158] g. Other excipients The tablets provided herein may contain a variety of excipients other than those described herein. Examples of other excipients include, but are not limited to, solubility enhancers, stabilizers, pH adjusters, coatings, and pigments.

[0159] 4. Coating The tablets of the present invention are coated with a film suitable for immediate-release tablets, such as a film coating containing polyvinyl alcohol and hydroxypropyl methylcellulose, as needed.

[0160] 5. How to make tablets In one embodiment, the present invention is a method for producing tablets of the present invention using wet granulation. This method is appropriately carried out in three steps according to the following steps.

[0161] Stage 1 (Intragranular Stage) (a) Dissolve povidone in water, (b) The remaining grain components are sieved, for example, through a 30-gauge mesh, (c) Blend the sieved components to form granular material, (d) Wet the granules with povidone solution and blend until the optimal granules are obtained. (e) Dry the optimal granules until a moisture content of approximately 2% is achieved. (f) The dried granules are passed through a sieve of a specific size, for example, a 20-mesh sieve.

[0162] Stage 2 (External stage) (a) All extragranular excipients except lubricants (e.g., magnesium stearate) are passed through a sieve, for example, a 20-mesh sieve. (b) Add the sieved excipient to the granules milled from step 1 and blend them together. (c) Sift the lubricant using, for example, a No. 30 mesh sieve, add it to the blend, and blend again.

[0163] Stage 3 (tablet compression) The blend from the final step of stage 2 above is compressed into tablets using a tablet compressor, and each tablet is coated with a film coating as needed.

[0164] 6. Characteristics of the tablets Tablets of compound 1 of the present invention preferably have all of the following characteristics. - When dissolved in 0.01N HCl, it disintegrates rapidly. - When administered to the target, the bioavailability of compound 1 is good. - Physical integrity of the tablet, e.g., good crushability and strength, - Stability of compound 1 in tablets.

[0165] 7. Use of Compound 1 The tablets of compound 1 provided herein are useful for treating or improving Huntington's disease.

[0166] In one embodiment, treating or improving Huntington's disease with compound 1, or a pharmaceutically acceptable salt thereof, as a disease-modifying treatment results in the production of an in-frame stop codon between exon 49 and exon 50 in the HTT mRNA transcript, and the resulting reduction in mRNA and wild-type and mutant HTT proteins has one or more of the following effects:

[0167] (i) Slowing of the rate of decline of motor function loss associated with Huntington's disease. Here, slowing of the rate of decline of motor function associated with Huntington's disease after treatment with compound 1 is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins, or by comparison with placebo, and motor function is selected from a group consisting of ocular motor function, dysarthria, dystonia, chorea, postural stability and gait, and is assessed using a standard clinical scale, e.g., the UHDRS Motor Assessment Scale (e.g., Movement Disorders, 1996, 11, pp. 136-142).

[0168] (ii) Slowing of the rate of cognitive decline associated with Huntington's disease. Here, slowing of the rate of cognitive decline associated with Huntington's disease after treatment with compound 1 is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins, or by comparison with placebo, and cognitive function is assessed by using standard clinical scales, e.g., the Symbol-Number Modality Test, the Stroop Word Reading Test, the Montreal Cognitive Assessment, or the HD Cognitive Assessment Battery (e.g., the Symbol-Number Modality Test, Trail Making Test B, One-Touch Stocking, Pace Tapping, Affect Recognition Test, and Hopkins Language Learning Test, as described in Movement Disorders, 2014, 29(10), pp. 1281-1288).

[0169] (iii) Slowing of the rate of psychiatric decline associated with Huntington's disease. Here, slowing of the rate of psychiatric decline associated with Huntington's disease after treatment with compound 1 is indicated by a decrease in mRNA and wild-type and mutant HTT proteins, or by comparison with placebo, and psychiatric decline is selected from a group consisting of affective blunting, anxiety, depression, obsessive-compulsive behavior, suicidal ideation, irritability and agitation, and is assessed by using standard clinical scales, e.g., the Affective Blunting Rating Scale, as in Movement Disorders, 2016, 31(10), pp. 1466-1478, Movement Disorders, 2015, 30(14), pp. 1954-1960, or by the Hospital Anxiety and Depression Scale.

[0170] (iv) Slowing of the rate of decline in functional abilities associated with Huntington's disease. Here, the slowing of the rate of decline in functional abilities associated with Huntington's disease after treatment with compound 1 is demonstrated by a decrease in mRNA and wild-type and mutant HTT proteins, or by comparison with placebo, and functional abilities are selected from a group consisting of the ability to work, the ability to manage household finances, the ability to manage household chores, the ability to perform daily living activities, and the level of care required, and are assessed using standard clinical scales, e.g., UHDRS Total Functional Ability, Functional Assessment and Independent Scales (e.g., Movement Disorders, 1996, 11, pp. 136-142).

[0171] (v) Slowing of the pathophysiological progression of Huntington's disease. Here, the slowing of the pathophysiological progression of Huntington's disease associated with treatment with compound 1 [e.g., a reduction in the rate of brain volume loss (e.g., %) from baseline volume] is indicated by a decrease in mRNA and wild-type and mutant HTT proteins, or by comparison with placebo, and is assessed using standard techniques, e.g., MRI (e.g., by neuroimaging criteria) (see, e.g., Lancet Neural. 2013, 12(7), pp. 637-649).

[0172] (vi) Slowing of the onset of Huntington's disease or symptoms associated with Huntington's disease. Here, the slowing of the onset of Huntington's disease or symptoms associated with Huntington's disease after treatment with compound 1 is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins, or by comparison with placebo, and is assessed using standard clinical scales, e.g., the Huntington's Disease Health-Related Quality of Life Questionnaire (HDQoL) (e.g., Movement Disorders, 2018, 33(5), pp. 742-749). Alternatively,

[0173] (vii) Reduction of the decline in quality of life associated with Huntington's disease. Here, the slowing of the onset of Huntington's disease or Huntington's disease-related symptoms after treatment with compound 1 is indicated by a decrease in mRNA and wild-type and mutant HTT proteins, or by comparison with placebo, and is assessed using standard clinical scales, e.g., the Huntington's Disease Health-Related Quality of Life Questionnaire (HDQoL) (e.g., Movement Disorders, 2018, 33(5), pp. 742-749).

[0174] In another embodiment, treating or improving Huntington's disease with compound 1 or a pharmaceutically acceptable salt thereof has one or more of the following effects: (i) a preferred therapeutic profile, e.g., a preferred safety profile or metabolic profile; or (ii) a preferred off-target effect profile, e.g., a preferred psychiatric adverse event profile, a preferred toxicity (e.g., genotoxicity) or cardiovascular adverse event (e.g., blood pressure, heart rate, electrocardiogram parameters) profile.

[0175] In one embodiment, a patient requiring such treatment is orally administered a tablet of the present invention containing a therapeutically effective amount of compound 1.

[0176] In another embodiment, the tablet contains a therapeutically effective amount of compound 1 ranging from 1 mg to 200 mg.

[0177] In another embodiment, the tablet contains a therapeutically effective amount of compound 1 in the range of 1 mg to 100 mg.

[0178] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

[0179] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0180] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0181] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0182] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg.

[0183] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0184] In another embodiment, the tablet contains a therapeutically effective dose selected from 1 mg, 5 mg, or 50 mg.

[0185] In another embodiment, the tablet contains a therapeutically effective dose selected from 5 mg or 50 mg.

[0186] In another embodiment, the tablet contains a therapeutically effective dose selected from 5 mg, 10 mg, 20 mg, and 30 mg.

[0187] In another embodiment, the tablet contains a therapeutically effective dose selected from 5 mg, 10 mg, and 20 mg.

[0188] In one embodiment, a patient requiring such treatment is orally administered a tablet of the present invention containing a therapeutically effective amount of compound 1, which is administered once daily.

[0189] In another embodiment, the tablet contains a therapeutically effective amount of compound 1 ranging from 1 mg to 200 mg, administered once daily.

[0190] In another embodiment, the tablet contains a therapeutically effective amount of compound 1 ranging from 1 mg to 100 mg, administered once daily.

[0191] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg, administered once daily.

[0192] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once daily.

[0193] In another embodiment, the tablets contain a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once daily.

[0194] In another embodiment, the tablet contains a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once daily.

[0195] In another embodiment, the tablet contains a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg, administered once daily.

[0196] In another embodiment, the tablet contains a therapeutically effective dose selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once daily.

[0197] In another embodiment, the tablet contains a therapeutically effective dose selected from 1 mg, 5 mg, or 50 mg, administered once daily.

[0198] In another embodiment, the tablet contains a therapeutically effective dose selected from 5 mg or 50 mg, administered once daily.

[0199] In another embodiment, the tablet contains a therapeutically effective dose selected from 5 mg, 10 mg, 20 mg, and 30 mg, administered once daily.

[0200] In another embodiment, the tablet contains a therapeutically effective dose selected from 5 mg, 10 mg, and 20 mg, administered once daily.

[0201] In another embodiment, the tablet contains 1 mg of a therapeutically effective dose of compound 1.

[0202] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 5 mg.

[0203] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 10 mg.

[0204] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 15 mg.

[0205] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 20 mg.

[0206] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 25 mg.

[0207] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 30 mg.

[0208] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 35 mg.

[0209] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 40 mg.

[0210] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 45 mg.

[0211] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 50 mg.

[0212] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 55 mg.

[0213] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 60 mg.

[0214] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 65 mg.

[0215] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 70 mg.

[0216] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 75 mg.

[0217] In another embodiment, the tablet contains 80 mg of a therapeutically effective dose of compound 1.

[0218] In another embodiment, the tablet contains 85 mg of a therapeutically effective dose of compound 1.

[0219] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 of 90 mg.

[0220] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 95 mg.

[0221] In another aspect, the tablet contains a therapeutically effective amount of 100 mg of Compound 1.

[0222] In another aspect, the tablet contains a therapeutically effective amount of 105 mg of Compound 1.

[0223] In another aspect, the tablet contains a therapeutically effective amount of 110 mg of Compound 1.

[0224] In another aspect, the tablet contains a therapeutically effective amount of 115 mg of Compound 1.

[0225] In another aspect, the tablet contains a therapeutically effective amount of 120 mg of Compound 1.

[0226] In another aspect, the tablet contains a therapeutically effective amount of 125 mg of Compound 1.

[0227] In another aspect, the tablet contains a therapeutically effective amount of 130 mg of Compound 1. [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​

[0235] In another aspect, the tablet contains a therapeutically effective amount of 170 mg of Compound 1.

[0236] In another aspect, the tablet contains a therapeutically effective amount of 175 mg of Compound 1.

[0237] In another aspect, the tablet contains a therapeutically effective amount of 180 mg of Compound 1.

[0238] In another aspect, the tablet contains a therapeutically effective amount of 185 mg of Compound 1.

[0239] In another aspect, the tablet contains a therapeutically effective amount of 190 mg of Compound 1.

[0240] <000092​​​​​​​​​​​​​​​​​​​​​​​​​​​​In one embodiment, the use of a tablet containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof as a disease-modifying therapy for treating or improving Huntington's disease includes Huntington's diseases selected from the group consisting of Huntington's diseases genetically characterized by 36-39 CAG repeat extensions in the HTT gene on chromosome 4, and Huntington's diseases genetically characterized by more than 39 CAG repeat extensions in the HTT gene on chromosome 4.

[0248] In one embodiment, the use of a tablet containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof as a disease-modifying therapy for treating or improving Huntington's disease includes Huntington's diseases selected from the group consisting of overt Huntington's disease, juvenile Huntington's disease, childhood Huntington's disease, early-stage Huntington's disease, mid-stage Huntington's disease, advanced-stage Huntington's disease, stage I Huntington's disease, stage II Huntington's disease, stage III Huntington's disease, stage IV Huntington's disease, stage V Huntington's disease, and asymptomatic Huntington's disease.

[0249] In one embodiment, a tablet containing a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, is administered according to an intermittent dosing schedule.

[0250] In another embodiment, a tablet containing a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, is administered once or twice a week.

[0251] In another embodiment, a tablet containing a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0252] In another embodiment, a tablet containing a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, is provided in the form of a pharmaceutical composition.

[0253] In another aspect, tablets containing a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, are provided in the form of a medical combination.

[0254] In another aspect, tablets containing a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, are administered after gene therapy or treatment using an antisense compound.

[0255] In one aspect, a method of treating for slowing the progression of Huntington's disease in a subject in need thereof, the method comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1.

[0256] In another aspect, a method of treating for slowing the decline in motor function associated with Huntington's disease in a subject in need thereof, the method comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1.

[0257] In another aspect, a method of treating for slowing the decline in cognition associated with Huntington's disease in a subject in need thereof, the method comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1.

[0258] In another aspect, a method of treating for slowing the psychiatric decline associated with Huntington's disease in a subject in need thereof, the method comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1.

[0259] In another aspect, a method of treating for slowing the decline in functional ability associated with Huntington's disease in a subject in need thereof, the method comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1.

[0260] In another embodiment, a method for treatment to slow the progression of Huntington's disease-related pathophysiology in a subject in need [e.g., reducing the rate of brain volume loss (e.g., %) from baseline volume] (e.g., as assessed by MRI), the method comprising administering to the subject one or more tablets containing a therapeutically effective amount of compound 1.

[0261] In another embodiment, a method for treating a decline in motor function associated with Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1, wherein the motor function is selected from the group consisting of ocular movement, dysarthria, dystonia, chorea, postural stability, and gait.

[0262] In another embodiment, a method for treating cognitive decline associated with Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1, wherein the cognitive decline is selected from the group consisting of attention, processing speed, visuospatial processing, timing, emotional processing, memory, speech fluency, psychomotor function, and executive function.

[0263] In another embodiment, a method for treating a psychiatric decline associated with Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1, wherein the psychiatric decline is selected from the group consisting of emotional blunting, anxiety, depression, obsessive-compulsive behavior, suicidal ideation, irritability and agitation.

[0264] In another embodiment, a method for slowing the decline in functional capacity associated with Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1, wherein the functional capacity includes one or more selected from the group consisting of the ability to work, the ability to manage household finances, the ability to manage household chores, the ability to perform daily living activities, and the level of care required.

[0265] In another embodiment, a method for treatment to slow the progression of Huntington's disease-related pathophysiology in a subject in need [e.g., reducing the rate of brain volume loss (e.g., %) from baseline volume] (e.g., as assessed by MRI), the method comprising administering to the subject one or more tablets containing a therapeutically effective amount of compound 1.

[0266] In one embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains a therapeutically effective amount of compound 1 in the range of 1 to 200 mg.

[0267] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains a therapeutically effective amount of compound 1 ranging from 1 to 100 mg.

[0268] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 1 mg of a therapeutically effective amount of compound 1.

[0269] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 5 mg of a therapeutically effective amount of compound 1.

[0270] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 10 mg of a therapeutically effective amount of compound 1.

[0271] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 15 mg of a therapeutically effective amount of compound 1.

[0272] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 20 mg of a therapeutically effective amount of compound 1.

[0273] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 25 mg of a therapeutically effective amount of compound 1.

[0274] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 30 mg of a therapeutically effective amount of compound 1.

[0275] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 35 mg of a therapeutically effective amount of compound 1.

[0276] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 40 mg of a therapeutically effective amount of compound 1.

[0277] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 45 mg of a therapeutically effective amount of compound 1.

[0278] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 50 mg of a therapeutically effective amount of compound 1.

[0279] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 55 mg of a therapeutically effective amount of compound 1.

[0280] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 60 mg of a therapeutically effective amount of compound 1.

[0281] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 65 mg of a therapeutically effective amount of compound 1.

[0282] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 70 mg of a therapeutically effective amount of compound 1.

[0283] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 75 mg of a therapeutically effective amount of compound 1.

[0284] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 80 mg of a therapeutically effective amount of compound 1.

[0285] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 85 mg of a therapeutically effective amount of compound 1.

[0286] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 90 mg of a therapeutically effective amount of compound 1.

[0287] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 95 mg of a therapeutically effective amount of compound 1.

[0288] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 100 mg of a therapeutically effective amount of compound 1.

[0289] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 105 mg of a therapeutically effective amount of compound 1.

[0290] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 110 mg of a therapeutically effective amount of compound 1.

[0291] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 115 mg of a therapeutically effective amount of compound 1.

[0292] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 120 mg of a therapeutically effective amount of compound 1.

[0293] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 125 mg of a therapeutically effective amount of compound 1.

[0294] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 130 mg of a therapeutically effective amount of compound 1.

[0295] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 135 mg of a therapeutically effective amount of compound 1.

[0296] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 140 mg of a therapeutically effective amount of compound 1.

[0297] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 145 mg of a therapeutically effective amount of compound 1.

[0298] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 150 mg of a therapeutically effective amount of compound 1.

[0299] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 155 mg of a therapeutically effective amount of compound 1.

[0300] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 160 mg of a therapeutically effective amount of compound 1.

[0301] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 165 mg of a therapeutically effective amount of compound 1.

[0302] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 170 mg of a therapeutically effective amount of compound 1.

[0303] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 175 mg of a therapeutically effective amount of compound 1.

[0304] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 180 mg of a therapeutically effective amount of compound 1.

[0305] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 185 mg of a therapeutically effective amount of compound 1.

[0306] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 190 mg of a therapeutically effective amount of compound 1.

[0307] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 195 mg of a therapeutically effective amount of compound 1.

[0308] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein each tablet contains 200 mg of a therapeutically effective amount of compound 1.

[0309] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it comprises administering to the subject once daily one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0310] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it comprises administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof twice daily.

[0311] In another embodiment, a method for treating or improving Huntington's disease in a subject in need thereof comprises administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof three times a day.

[0312] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it comprises administering to the subject once a week one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0313] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it comprises administering to the subject once every two weeks one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0314] In one embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment comprises administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein Huntington's disease is selected from the group consisting of Huntington's disease genetically characterized by 36-39 CAG repeat extensions in the HTT gene on chromosome 4, and Huntington's disease genetically characterized by more than 39 CAG repeat extensions in the HTT gene on chromosome 4.

[0315] In one embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment comprises the step of administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein Huntington's disease is selected from the group consisting of overt Huntington's disease, juvenile Huntington's disease, childhood Huntington's disease, early-stage Huntington's disease, mid-stage Huntington's disease, advanced-stage Huntington's disease, stage I Huntington's disease, stage II Huntington's disease, stage III Huntington's disease, stage IV Huntington's disease, stage V Huntington's disease, and asymptomatic Huntington's disease.

[0316] In one embodiment, a method for treating or improving Huntington's disease in a subject requiring it includes administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, according to an intermittent dosing schedule.

[0317] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment comprises administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof once daily, once weekly, or twice weekly.

[0318] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it comprises the step of orally administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0319] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it includes administering to the subject one or more tablets in the form of a pharmaceutical composition containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0320] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it includes administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof in the form of a medical combination.

[0321] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring it includes administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, after gene therapy or treatment with an antisense compound.

[0322] In another embodiment, a method for treating or improving Huntington's disease in a subject requiring such treatment comprises administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof to produce an in-frame stop codon between exon 49 and exon 50 in HTT mRNA.

[0323] In another embodiment, a method for slowing the progression of Huntington's disease in a subject requiring it comprises administering to the subject one or more tablets containing a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof to produce an in-frame stop codon between exon 49 and exon 50 in HTT mRNA. [Examples]

[0324] The following examples include illustrative embodiments of the present invention. These examples should not be construed as limiting.

[0325] (Example 1) Six development batches (1-6) of Compound 1 tablets were prepared using direct compression by weighing the components, sieving them through a 35-mesh sieve, then mixing them under low shear and compressing them into tablets. However, the flow was not adequate, and sticking to the tablet punch was observed during tableting. Two batches (7 and 8) of placebo tablets were prepared in the same manner without Compound 1. The batch compositions are shown in TABLE 1 below.

[0326] [Table 1]

[0327] (Example 2) To address the flow resistance and sticking issues associated with direct compression found in the batch of Example 1, dry granulation using roller compression was introduced. Three additional batches (9, 10, and 11) were prepared by weighing the components, sieving them through a 35-mesh container, mixing them using a Turbula mixer, and then roller compressing them. Subsequently, the ribbons were crushed, passed through a 20-mesh container, mixed with extra-granular components using a Turbula mixer, and then compressed using a tablet press. Good blend uniformity was achieved. The composition of all three batches was the same and similar to batch 6 described above, except that they contained equal mass percent lactose monohydrate and mcc (41.5% each). However, different roller compression parameters (rotation speed, screw speed, and pressure) were used for each batch. Batch 9 produced the best ribbons during roller compression. Batch 11 stuck to the rolls and the ribbons were brittle, while batch 12 produced discontinuous ribbons.

[0328] The dissolution test was conducted using batch 9 of dry granulation, but due to wetting issues associated with compound 1, granules were suspended on the surface of the dissolution medium.

[0329] (Example 3) To mitigate the wetting problem observed in Example 2, it was decided to introduce a surfactant into the formulation. Direct compression batches 13 and 14 were prepared using 50 mg of compound 1 with 5 w / w% sodium lauryl sulfate (SLS) and 1% poloxamer 188, respectively. Batch 13, containing SLS, showed even more undissolved granules of compound 1 suspended around it than batch 9 tested in Example 2, and drug release was minimal. Batch 14, containing 1% poloxamer 188, showed better dissolution performance with no granules suspended on the surface of the dissolution medium. Therefore, it appeared that the inclusion of poloxamer reduced the wetting of compound 1 granules. However, during dissolution experiments at 50 revolutions per minute, a mounding phenomenon was observed, and complete drug release was only observed when the paddle speed increased to 150 rpm at 75 minutes.

[0330] Furthermore, a direct compression batch 17 was prepared in a similar manner using a low concentration of microcrystalline cellulose and poloxamer 407 as a surfactant. This batch had the problem of poor processability.

[0331] The compositions of batches 13, 14, and 17 are summarized in Table 2 below.

[0332] [Table 2]

[0333] (Example 4) To minimize the bulging phenomenon in the dissolution container, wet granulation batches 15 and 16 were prepared using smaller amounts of Avicel PH102, and 0.5 w / w% and 2.5 w / w% polyvinylpyrrolidone (PVP) K30, and 1% poloxamer 407, respectively. Wet granulation was performed using a mortar and pestle. The granular components were passed through a No. 20 mesh sieve and blended. Povidone K30 was dissolved in water to obtain a granulation fluid. Next, the pre-blend was wet-granulated with the povidone K30 solution using a mortar and pestle to obtain optimal granules. The wet mass was dried in a tray oven at 60°C until a moisture content of approximately 2% was achieved. The dried granules were passed through a No. 20 sieve and blended with the granular excipients sieved through a No. 20 mesh. The unlubricated blend was mixed with magnesium stearate sieved through a 35-mesh sieve to obtain the final blend.

[0334] Batch 15 was found to be the optimal formulation, exhibiting minimal buildup during dissolution at 50 rpm. Batch 16, containing 2.5 w / w% PVP K30, was found to have inferior dissolution performance compared to batch 15, most likely due to greater granular compression resulting from a higher level of PVP K30 binder.

[0335] Furthermore, a wet granulation batch 18 was prepared using a smaller amount of Avicel PH102 (10 w / w%) in the same manner as described above, and tested to see if the buildup during dissolution could be further reduced. However, during the dissolution test, that batch did not release any compound 1 at all.

[0336] Furthermore, a wet granulation batch 19 was prepared in a similar manner to that described above, except that 30% mcc was used for both the intragranular and extragranular blends. This batch also had problems with bulging and low integrity.

[0337] (Example 5) Further dry granulation batches 20 were prepared using 41% microcrystalline cellulose (mcc) and lactose monohydrate in the granular blend, but without using mcc or lactose monohydrate in the extragranular components.

[0338] The compositions of batches 15, 16, 18, 19, and 20 are shown in Table 3 below.

[0339] [Table 3]

[0340] (Example 6) The solubility of batches 9, 14, 15, 16, 17, 18, and 20 was tested in 500 ml of 0.01 N HCl, stirring with a paddle at 50 rpm up to 60 minutes, increasing to 75 rpm up to 75 minutes, and increasing to 150 rpm up to 90 minutes, while removing 5 ml at 5, 10, 15, 20, 30, 45, 60, 75, and 90 minutes.

[0341] Furthermore, batches 15, 16, and 17 were stored at 80°C and 5% relative humidity, and at 80°C and 75% relative humidity, and then tested for decomposition on days 7 and 14. No decomposition was observed in any of the samples at lower humidity levels, and decomposition was minimal and comparable in all three batches tested at higher humidity levels.

[0342] The solubility stability of batch 15 was tested at various paddle speeds (50, 65, and 75 revolutions per minute) and accelerated temperature conditions. The percentage of drug released at each time point was higher with increasing speed, with 81%, 88%, and 95% of the initial release occurring within the first 5 minutes at each speed, respectively. When tested in 0.01 N HCl at a paddle speed of 75 rpm at room temperature, 40°C, or 65°C, the release rate was even faster, with initial release percentages of 95.4%, 92.6%, and 96.4%, respectively.

[0343] Based on the above results, batches 15 (wet granulation) and 20 (dry granulation) were selected for further studies involving pharmacokinetics.

[0344] (Example 7) A study to evaluate the exposure to compound 1 after oral (PO) administration of three formulations of the compound to fasted male cynomolgus monkeys was conducted as follows. One of the formulations (batch 21) was a suspension of 6 w / w% compound 1 in 0.5 w / w% hydroxypropyl methylcellulose (HPMC). The other two formulations tested were tablets from wet granulation batch 15 and dry granulation batch 20 prepared as described in Example 4 above.

[0345] The monkeys were divided into three groups of four animals each. The monkeys were fed in the afternoon the day before administration, and any remaining food was removed at 7 p.m. The food was returned 4 hours after administration. Each monkey received a 30 mg oral dose of Compound 1 (5 ml of 6 mg / ml Compound 1 in suspension batch 21, or two tablets of 15 mg each from wet granulation batch 15 or dry granulation batch 20 per animal) via a rubber oral gastric tube or tablets, and each dose was followed by flushing with 3 ml of deionized water. Blood samples were collected from each monkey at the following time points: before administration (0), 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, and 48 hours. Each sample was centrifuged at 3,000 × g for 5 minutes at temperatures up to 8°C to collect plasma, and the samples were frozen on dry ice until testing. Plasma concentrations were determined by LC-MS / MS. Pharmacokinetic parameters were also determined.

[0346] Plots of individual plasma concentrations of compound 1 after oral administration of an oral suspension formulation of compound 1 (batch 21) at a dose of 30 mg in 0.5% HPMC water in male cynomolgus monkeys (Leg 1) are provided in Figure 1. The four monkeys in the study are identified as "Mky 15-218," "Mky 15-172," "Mky 16-108," and "Mky 170004" in Figure 1 and other figures below. Plots of mean plasma concentrations at each time point for Leg 1 are provided in Figure 2. The results are summarized in Table 4 below.

[0347] [Table 4]

[0348] As shown in TABLE 4, the maximum plasma concentration (mean 111 ± 47.6 ng / mL) was observed 6–12 hours after oral administration (Leg 1) of the suspension formulation (batch 21) at a dose of 30 mg / animal. The mean half-life after oral administration was 20.7 hours. The overall mean exposure to compound 1 at 30 mg / animal (Leg 1) was 2515 ± 788 hours* ng / mL, and the dose-normalized AUC was also observed. last Based on this, the result was 369 ± 138 hours * kg * ng / mL / mg.

[0349] Plots of individual plasma concentrations obtained from each monkey after oral administration of 30 mg / animal of tablet formulation A (wet granulation batch 15) are provided in Figure 3 (Leg 2). Plots of mean plasma concentrations at each time point are provided in Figure 4. The results for Leg 2 of the study are summarized in Table 5.

[0350] [Table 5]

[0351] As shown in TABLE 5, the maximum plasma concentration (mean 124 ± 58.8 ng / mL) of tablet formulation A (wet granulation batch 15) in 30 mg / animals was observed 6–8 hours after administration (Leg 2). The mean half-life after oral administration was 28.0 ± 10.3 hours. The overall mean exposure to compound 1 in 30 mg / animals (Leg 2) was 3110 ± 997 hours* ng / mL, and the dose-normalized AUC was 3110 ± 997 hours*. last Based on this, the result was 455 ± 151 hours * kg * ng / mL / mg.

[0352] Plots of individual plasma concentrations obtained from each monkey after oral administration of 30 mg / animal of tablet formulation B (dry granulation batch 20) are provided in Figure 5 (Leg 3). Plots of mean plasma concentrations at each time point are provided in Figure 6. The results for Leg 3 of the study are summarized in Table 6, where * indicates the AUC from the suspension formulation. last This shows p<0.05 when compared to [another value].

[0353] [Table 6]

[0354] As can be seen from TABLE 6, the maximum plasma concentration (mean 73.5 ± 37.2 ng / mL) of tablet formulation B (dry granulation batch 20) in animals at 30 mg was observed 6 hours after administration (Leg 3). The mean half-life after oral administration was 26.4 ± 4.20 hours. The overall mean exposure to compound 1 in animals at 30 mg (Leg 3) was 1524 ± 562 hours* ng / mL, and the dose-normalized AUC was last Based on this, the result was 237 ± 102 hours * kg * ng / mL / mg.

[0355] Average dose normalized AUC lastBased on the values, tablet formulation A (wet granulation batch 15) had an exposure of 455 hours*kg*ng / mL / mg, which is 124±23% of the exposure from the suspension formulation (369 hours*kg*ng / mL / mg). Tablet formulation B (dry granulation batch 20) had an exposure of 237 hours*kg*ng / mL / mg, which is 58±10% of the exposure from the suspension formulation. Therefore, the AUC from solid formulation A was found to be quite comparable to the AUC from the suspension formulation. However, the AUC from solid formulation B was significantly lower compared to the value from the suspension formulation (P<0.05). In other words, these studies indicate that compound 1 had significantly higher bioavailability in tablets produced by wet granulation (formulation batch 15) than in suspension formulations or tablets produced by dry granulation (formulation batch 20).

[0356] (Example 8) To identify excipients that can be scaled up during the tableting process, are easily processed, and possess excellent physical characteristics, including rapid dissolution, as well as the concentrations of each excipient, further research was conducted using tablets from wet granulation batch 15 as a starting point. Multiple grades of lactose and cellulose particularly suitable for wet granulation were selected, and the total amount of intragranular excipients was increased. The concentration of povidone was increased from 1%-2% to 5% in three different batches. In addition, the total amount of lactose monohydrate used in the formulation was increased, and the ratio of mcc to lactose monohydrate was reduced. Examples of the three formulations prepared and tested are provided in TABLE 7 below. For each of the formulations below, a 500-gram batch of compound 1 was prepared, with 50 g per batch.

[0357] [Table 7]

[0358] Tablets produced by wet granulation using the aforementioned composition were coated, but the coating did not affect the disintegration time. Table 8 below shows the results obtained from testing tablet cores produced from batches 23-25, some containing 5 mg of compound 1(A) and others containing 50 mg of compound 1(B).

[0359] [Table 8]

[0360] Batch 22, with a PVP level of 1%, exhibited sticking, and when the formulation was scaled up to 500g, it showed a large amount of fine particles. Due to these problems, compression of this lot was abandoned.

[0361] Batch 23, which had a PVP level of 2%, was found to compress into tablets without sticking issues.

[0362] For batch 24, which had a PVP level of 5%, the disintegration time of the resulting tablets increased significantly to 17 minutes. Furthermore, the final blend of batch 24 showed separation of granular and powdered excipients.

[0363] Batch 25, which has a PVP level of 3%, showed a decay time between that of batch 23 and batch 24, indicating the role of PVP as a binder.

[0364] (Example 9) As described above, tablets produced from batch 23 (containing 2% PVP) containing 5 mg and 50 mg of compound 1, respectively, were tested for stability after being stored at 50°C for 2 weeks and at 40°C / 75% relative humidity for 1 month. Dissolution was performed in apparatus II in 500 ml of 0.01 N HCl, stirred at 75 revolutions per minute. The tablets showed chemical stability, as there was no observed increase in the related substance. The resulting dissolution profiles are shown in Figure 8 (5 mg tablet) and Figure 9 (50 mg tablet). The dissolution profiles show immediate release of compound 1 from each tablet and maintain a profile comparable to the initial one even after storage at higher temperatures and humidity.

[0365] (Example 10) Phase 1 Clinical Study Protocol A Phase 1 dose-escalation study was initiated in healthy subjects to assess the safety and pharmacokinetics of oral tablets (5 mg and 50 mg) of compound 1 compared to placebo.

[0366] Main research objective (i) Characterize the safety and tolerability of a single dose escalating of compound 1 in healthy subjects; (ii) Characterize the safety and tolerability of compound 1 administered to healthy subjects for 14 or up to 21 days; (iii) Characterize the pharmacokinetics in plasma and cerebrospinal fluid (CSF) after 7 days of administration of compound 1 in healthy subjects; (iv) Characterize the food effect on the plasma pharmacokinetics (PK) of compound 1 after administration of a single dose of compound 1 in healthy subjects; and (v) Characterize the safety and tolerability of compound 1 administered to healthy subjects for up to 28 days.

[0367] Secondary research objectives (i) Characterize the pharmacokinetics of a single dose of compound 1 in healthy subjects; (ii) Characterize the pharmacokinetics of compound 1 administered to healthy subjects for 14 or up to 21 days; (iii) Assess the QTc and drug concentration effect of compound 1 after repeated dose escalations; (iv) Assess the safety and tolerability of compound 1 after 7 days of administration in healthy subjects; (v) Characterize the safety and tolerability of a single dose of compound 1 administered to healthy subjects in a fed state; and (vi) Characterize the pharmacokinetics of compound 1 administered to healthy subjects for up to 28 days.

[0368] Exploratory research purpose (i) Explore the effect of a single dose of compound 1 administered to healthy subjects on huntingtin (HTT) premRNA splicing in the blood; (ii) Explore the effect of a single dose of compound 1 administered to healthy subjects on HTT premRNA splicing and HTT protein levels in the blood for up to 14 or 21 days; (iii) Explore the effect of a single dose of compound 1 administered (with food) on HTT premRNA splicing in the blood of healthy subjects; and (iii) Explore the effect of a single dose of compound 1 administered to healthy subjects on HTT premRNA splicing and HTT protein levels in the blood for up to 28 days.

[0369] research design The Phase 1 study was conducted in the following five parts: single dose escalation (SAD) (Part 1), multiple dose escalation (MAD) (Part 2), CSF and blood sampling after 7 days of compound 1 administration (Part 3), food effects (Part 4), and multiple doses up to 28 days (Part 5). Parts 1, 2, and 5 were double-blind, while Parts 3 and 4 were open-label. Note that Parts 3, 4, and 5 may be conducted concurrently.

[0370] Research method The study was monitored by a Safety Review Committee (SRC). The SRC's intent was to ensure that the treatment did not impose an undue risk on the subjects. Safety and tolerability were assessed by the SRC across each cohort before dose escalations from one dose level to the next higher dose level in Part 1 (Single Elevation Dose [SAD]) and Part 2 (Multiple Elevation Dose [MAD]), as well as before initiating Part 3 (CSF), Part 4 (FE), and Part 5.

[0371] The SRC consisted of the following personnel: the principal investigator or their representative (the representative only if the principal investigator is unavailable), and the sponsor's medical monitor or representative (who must be a physician). Other internal or external experts may be invited to participate in the review or to be consulted.

[0372] Multiple parts of the study were not necessarily conducted in numerical order and may be conducted simultaneously. The SRC met before the start of Part 5 of the study to determine the doses to be used in that part. The doses (which may include loading and maintenance doses) were selected based on available SAD and MAD data before the start of Part 5. The SRC did not plan any inter-cohort meetings within Part 5.

[0373] Part 1 (SAD) The single-dose escalation (SAD) portion of the study was randomized, double-blind, and included placebo control in healthy male and female subjects.

[0374] The plan was to test five dose levels in five cohorts (cohorts 1.1–1.5), each with eight participants. However, the sponsor may select additional cohorts to evaluate.

[0375] The initial dose in the first cohort was ≤1 / 10 of the human equivalent dose (HED), estimated from the NOAEL (No Observed Adverse Effect Level) in the most susceptible species, male rats, in accordance with FDA and EMA guidance on the recommended maximum starting dose (MRSD). The rat NOAEL is 6 mg / kg. This value was determined by observation of germ cell detachment in the epididymis and testes in male rats. The HED was calculated to be 0.97 mg / kg, which was estimated to be 68 mg in a 70 kg human. Adjusting this dose by 1 / 10 resulted in a dose of 6.8 mg for the first cohort, but the actual dose administered would be 5 mg.

[0376] In Cohort 1.1, sentinel therapy was administered to two subjects (one received compound 1 and the other received a placebo). If no clinically significant safety issues were observed, the remaining subjects in this cohort were administered at least 24 hours later. The remaining six subjects (five received compound 1 and one received a placebo) could be administered as a single group. Cohort 1.1 was the only cohort in which sentinel therapy was administered. In subsequent cohorts, all eight subjects could be administered as a single group.

[0377] After administration to each cohort was completed, a meeting regarding dose escalation had to be held. The dose level for the next cohort could be determined based on PK and safety from the previous cohort. Dose escalation was determined by the relationship between the mean exposure in the cohort and the mean exposure at NOAEL.

[0378] If the area under the mean curve (AUC) is <1 / 10 of that at NOAEL, the dose can be increased by up to 200%. That is, subsequent doses can be up to three times the previous dose.

[0379] If the mean AUC is ≥1 / 10 to <1 / 5 of the AUC at NOAEL, the dose can be increased up to 100%. That is, the subsequent dose can be up to twice the previous dose.

[0380] If the mean AUC is ≥1 / 5 to <1 / 2 of the AUC at NOAEL, the dose can be increased by up to 50%. That is, subsequent doses can be up to 1.5 times the previous dose.

[0381] The highest dose level was associated with an average exposure not exceeding half of the AUC in the NOAEL, and no further dose escalation was performed. Dose escalation was continued unless the criteria for stopping dose escalation were met.

[0382] Eligibility was to be assessed during a screening period of up to 28 days. Participants were to visit the clinic the day before administration (-1 day). On the morning of 1 day, after fasting for at least 10 hours overnight, participants received oral administration of compound 1 or placebo. Participants were discharged from the clinic on 8 day, if medically appropriate, after all necessary research procedures had been completed. A follow-up telephone call regarding safety was to be made 4 weeks (±1 week) after discharge on 8 day.

[0383] Part 2 (MAD) The multiple dose escalation (MAD) part of the study was randomized, double-blind, and included a placebo control in healthy male and female subjects. Up to five regimens were planned to be tested in up to five cohorts (cohorts 2.1–2.5), each containing eight subjects. Six subjects in each cohort received compound 1, and two subjects received placebo. Subjects in cohorts 2.1 and 2.2 received the compound for 14 days, while subjects in cohorts 2.3–2.5 received it for up to 21 days.

[0384] Part 2 can be initiated after at least two cohorts from Part 1 have been administered, safety parameters have been reviewed, the respective SAD PK parameters have been calculated, and MAD dosing simulations for the corresponding SAD doses have been performed. The selection of specific multiple dose levels was guided by available SAD PK data, simulations, and general safety observed in Part 1. After dose levels were evaluated in individual form, pharmacokinetic simulations were performed to determine variations within the dosing interval. In cohort 2.3, the dosing on days 1 and 2 was to be a loading dose higher than the dose selected for the remainder of the scheduled dosing. For cohorts 2.4 and 2.5, similar dosing schedules may be selected. Alternative dosing schedules may be considered for all cohorts in Part 2 if supported by data collected and analyzed during the study.

[0385] Eligibility was to be assessed during a screening period of up to 28 days. Participants were to be checked at the clinic the day before administration (-1 day). Compound 1 or placebo was to be administered orally each morning during the scheduled administration period (i.e., from day 1 to day 21) after fasting for at least 10 hours overnight. Participants were to be discharged 7 days after the final dose (i.e., up to day 21 or 28), if medically appropriate, after all necessary research procedures had been completed. Participants were to return to the clinic as an outpatient 7 days after discharge (i.e., up to day 28 or 35) for collection of PK and PD (mRNA and HTT protein) samples. A telephone call or outpatient visit for safety follow-up was to be conducted on day 49 (±7 days).

[0386] Part 3 (CSF) The concentrations of compound 1 in plasma and CSF were to be assessed in healthy male and female subjects using an open-label design. A single dose of compound 1 was administered daily for 7 days to one cohort of 6 subjects (cohort 3.1). The dose level for Part 3 was to be determined based on the review of safety, tolerability, and PK data from Parts 1 and 2 of the study. If the MAD dose needed to be further determined in development, that dose and schedule were to be applied to this part of the study.

[0387] Eligibility was to be assessed during a screening period of up to 28 days. Participants were to be checked at the clinic the day before administration (-1 day). Compound 1 was to be administered orally in the mornings of days 1 to 7, after fasting for at least 10 hours each day. Continuous sampling of CSF for drug concentration and plasma sampling were to be performed on day 7. The exact timing of CSF and blood sampling (samples) was to be determined based on the results of Parts 1 and 2. Participants were to be discharged from the clinic on day 9, if medically appropriate, after all necessary research procedures had been completed. A telephone follow-up for safety was to be conducted 4 weeks (±1 week) after discharge on day 9.

[0388] Part 4 (FE) The Food Effects (FE) part was a parallel, open-label part involving healthy men and women in up to three cohorts, each with six subjects. Compound 1 was administered at up to three dose levels 30 minutes after the initiation of a high-fat, high-calorie breakfast. Part 4 may be initiated if sufficient data from Part 1 is available. The dose levels for this part were to be selected based on a review of the available safety, tolerability, and PK data determined in Parts 1 and 2.

[0389] Eligibility was to be assessed during a screening period of up to 28 days. Participants were to be checked at the clinic the day before administration (-1 day). Compound 1 was to be administered orally at breakfast on 1 day, after consuming a standardized high-fat, high-calorie breakfast. Participants were to be discharged from the clinic on 8 day, if medically appropriate, after all necessary research procedures had been completed. Follow-up telephone calls regarding safety were to be made 4 weeks (±1 week) after discharge on 8 day.

[0390] Part 5 (Multiple doses over up to 28 days [MD28D]) Part 5 was a randomized, double-blind, placebo-controlled assessment of multiple doses over up to 28 days in healthy male and female subjects. Up to three cohorts of eight subjects each were planned. Prior to the commencement of Part 5, the SRC was to meet to select the dose (may include loading and maintenance doses), administration regimen (including fed or fasted status), and duration (up to 28 days) for this part of the study, based on data available from the completed cohorts of Parts 1 and 2. Six subjects in each cohort were to receive Compound 1 and two subjects were to receive placebo. The total dose on any given day was not to exceed the dose established as well-tolerated (SAD) in Part 1.

[0391] Eligibility was to be assessed during a screening period of up to 28 days. Participants were to be checked at the clinic the day before administration (-1 day). On each administration day, compound 1 or placebo was to be administered orally either the morning after an overnight fast or after a standard high-fat breakfast, according to the regimen determined by the SRC for the given cohort. Participants were to be discharged from the clinic 7 days after the last dose, if medically appropriate, after all necessary research procedures had been completed. Seven days after discharge, participants were to return to the clinic on an outpatient basis for PK and PD (mRNA and HTT protein) sample collection and safety assessment. On 1 day and the day of expected maximum exposure (i.e., 2 days, or 29 days if a loading dose was not used), patients were to be monitored using a 24-hour Holter monitoring device.

[0392] research group Part 1: Targeting up to 48 men and women aged 18-65 (including both extremes).

[0393] Part 2: Targeting up to 40 men and women aged 18-65 (including both ends of the age range).

[0394] Part 3: Six men and women aged 50-65 (including both ends of the age range).

[0395] Part 4: Target group consists of up to 18 men and women aged 18-65 (including both ends of the age range).

[0396] Part 5: Target group consists of up to 24 men and women aged 18-65 (including both ends of the age range).

[0397] Inclusion Criteria The following criteria must be met by all individuals whose participation in the study should be considered.

[0398] For Parts 1, 2, 4, and 5, healthy male or female subjects were aged 18–65 years at the time of screening, including both ends of the age range. For Part 3, healthy male or female subjects were aged 50–65 years at the time of screening, including both ends of the age range.

[0399] Participants must understand the nature of the research and provide signed, dated, written informed consent before any research-related procedures are carried out.

[0400] At the time of screening, the body mass index (BMI) was ≥ 18.5 kg / m². 2 Furthermore, ≤30.0 kg / m 2 For male subjects, the weight must be ≥ 50.0 kg, and for female subjects, the weight must be ≥ 45.0 kg.

[0401] The patient must be determined to be healthy by the clinical trial researcher based on a medical assessment including medical history, physical examination, laboratory test results, ECG recording (e.g., QTcF ≤ 450 ms for males and QTcF ≤ 470 ms for females) and vital signs. Values ​​outside the range may be repeated.

[0402] Male subjects and women of childbearing age must willingly use two methods of contraception throughout the duration of the study and for 30 days after the last dose.

[0403] Postmenopausal women must have experienced spontaneous amenorrhea for ≥12 months (follicle-stimulating hormone (FSH) ≥30 mIU / mL at the time of screening). Women who have undergone sterilization surgery are defined as those who have had a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation within ≥6 months prior to screening.

[0404] All women of childbearing age must have a negative result on a serum pregnancy test at the time of screening and a negative result on a urine pregnancy test on day -1.

[0405] Male participants must not consent to sperm donation during the duration of the study and for at least three months after the final dose.

[0406] Part 3 only: Participants must willingly undergo a lumbar puncture for CSF sampling.

[0407] Part 4 only: Participants must willingly consume and be able to consume all high-fat breakfast items within the specified time frame.

[0408] Exclusion criteria Those who meet any of the following criteria will be excluded.

[0409] Participants who have participated in a clinical study of any drug or device within 60 days prior to screening, or who are expected to participate in a clinical study of any drug or device during the duration of this study.

[0410] Past or ongoing medical conditions (e.g., comorbidities, psychiatric conditions), medical history, or physical findings that, in the opinion of the clinical trial investigator, may have adverse effects on the safety of the subject or may impair the assessment of the study results.

[0411] Abnormalities in general neurological test results.

[0412] The presence of any clinically significant abnormality during screening.

[0413] Any psychological or emotional problem, any disorder, or any treatment resulting therefrom that would likely invalidate informed consent or limit the subject's ability to comply with protocol requirements.

[0414] During screening, the patient tested positive for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) antibody.

[0415] Plasma donation within 7 days prior to administration. Blood donation or loss (excluding the volume collected at screening or menstruation) of 50 mL to 499 mL of blood within 30 days prior to administration, or more than 499 mL of blood within 56 days prior to administration.

[0416] Excessive alcohol consumption within the six months prior to screening (regular alcohol consumption is defined as ≥21 units per week for men and ≥14 units per week for women). One unit (8g) is equivalent to ½ pint (280mL) of beer, 1 mark (25mL) of spirits, or ½ small glass (125mL) of wine.

[0417] The subject is either a smoker or uses other nicotine-containing products. Ex-smokers must have abstained from smoking for >3 months prior to screening.

[0418] Positive results from urine drug screening, cotinine screening, or alcohol breath test at the time of screening or on the first day of each treatment period.

[0419] Pregnant or breastfeeding women.

[0420] The subject has already received compound 1.

[0421] Part 3 only: Contraindications for lumbar puncture, e.g., hypothrombocytopenia, abnormal prothrombin time international normalized ratio (PT-INR), spinal cord malformations, or other spinal cord conditions in which lumbar puncture may be ruled out at the discretion of the investigator.

[0422] Duration of treatment Part 1: 1 day, Part 2: 14 days (Cohorts 2.1 and 2.2) or up to 21 days (Cohorts 2.3-2.5), Part 3: 7 days, Part 4: 1 day, Part 5: up to 28 days

[0423] Evaluation Criteria Effectiveness The following PK parameters were assessed for PK on Day 1 (single dose) of the part, wherever it would be feasible [Part 1 (SAD), Part 2 (MAD, Day 1), Part 4 (FE), and Part 5 (MD28D, Day 1)]: C max ; Observed maximum plasma concentration, C max / D; Dose-normalized C max (for Part 1 only), T max ; C max Time to reach, AUC 0-24 (area under the concentration-time curve from 0 to 24 hours), AUC 0-72 (area under the concentration-time curve from 0 to 72 hours), AUC 0-tau (for Part 2 only, area under the concentration-time curve within the dosing interval calculated by the linear (up) / logarithmic (down) trapezoidal method), AUC 0-t (area under the concentration-time curve from zero time to time t calculated by the linear (up) / logarithmic (down) trapezoidal method, where t is the time of the measured (or measurable) final concentration (C t ) (for Parts 1 and 4 only), AUC 0-t / D (dose-normalized AUC from zero time to the quantifiable final concentration, for Part 1 only), AUC 0-inf (area under the concentration-time curve from zero time to infinity calculated by the linear (up) / logarithmic (down) trapezoidal method, AUC 0-inf = AUC 0-t + C<00​​​​​​​​​​​​​​​z / F(dose / (λ z *AUC 0-inf (The apparent volume of distribution calculated as...).

[0424] The following PK parameters were assessed for PK on day 14, day 21, or day 28 (multiple doses), determining where feasible [Part 2 (MAD) cohorts 2.1 and 2.2 (day 14), cohorts 2.3-2.5 (day 21), and Part 5 (MAD) cohorts 5.1-5.3 (day 28)]:C max (Maximum plasma concentration observed over the dosing interval), T max (C over the administration interval) max (Time until it reaches), C min (Minimum concentration over the dosing interval), C avg (Average concentration over the dosing interval), AUC 0-tau (Area under the concentration-time curve within the dosing interval, calculated by the linear (top) / logarithmic (bottom) trapezoidal method), AUC 0-tau / D(dose standardized AUC 0-tau ), λ z (The apparent terminal phase disappearance rate constant, calculated by linear regression of the terminal linear portion of the logarithmic concentration-time curve), t 1 / 2 (ln(2) / λ z (Apparent terminal phase half-life calculated as), CL / F (dose / AUC) 0-tau (Calculated as the whole body clearance), V z / F(dose / (λ z *AUC 0-tau (Apparent volume of distribution calculated as AUCR) auc (AUC 0-tau Accumulation ratio based on: AUC at the final dose 0-tau AUC on day 1 0-tau ), and AUCR cmax (C max Accumulation ratio based on: C at the final dose max Day 1 C max ).

[0425] The following PK parameters were measured for the final dose on day 14 of Part 2 (Cohorts 2.1 and 2.2) or day 21 of Part 2 (Cohorts 2.3-2.5) or day 28 of Part 5 (Cohorts 5.1-5.3), and for PK:C on day 7 (multiple doses) [Part 3 (Day 7)]. max (Maximum observed plasma concentration), T max (C max (Time to reach), AUC 0.5~12 We assessed where feasible the calculations for the area under the concentration-time curve from 0.5 to 12 hours (calculated using a linear (top) / logarithmic (bottom) trapezoidal method) and the CSF / plasma ratio (the ratio of CSF concentration to plasma concentration (Part 3 only)).

[0426] safety The following parameters were defined as parameters related to safety and acceptability.

[0427] Changes in vital signs from baseline to each scheduled time point and from those time points to end-of-situation (EOS); changes in ECG parameters from baseline to each scheduled time point and from those time points to EOS; changes in laboratory values ​​from baseline to each scheduled time point and from those time points to EOS; changes in C-SSRS scores from baseline (Parts 2, 3, and 5 only); adverse events (AEs) occurring during treatment up to EOS; adverse events occurring during treatment resulting in premature discontinuation of the study drug; serious adverse events (SAEs) occurring during treatment up to EOS; and abnormal physical examination values.

[0428] statistical methods Pharmacokinetics A list of individual subjects was provided. The mean individual plasma concentration-time profiles for compound 1 were presented in charts and graphs for each group.

[0429] PK variables were summarized using the arithmetic mean, standard deviation, geometric mean, median, minimum, maximum, and CV%.

[0430] The attainment of a steady state was determined by visual inspection of trough plasma concentration.

[0431] To assess the effects of the food, the PK parameters of compound 1 under fasting (Part 1) and feeding (Part 4) conditions were presented in charts and graphs, and descriptive statistics were prepared. Statistical analysis per dose level was performed on six subjects using compound 1, with the feeding treatment (Part 4) as the test and the same dose treatment under fasting conditions (Part 1) as the reference.

[0432] The main PK parameter is C max AUC 0-t , and AUC 0-inf It was assumed that this was the case. First, C max AUC 0-t , and AUC 0-inf The PK parameters were naturally logarithmically transformed, and the mean of these logarithmically transformed parameters was estimated using a linear model with treatment (compound 1 administered under a fed state versus a linear model of compound 1 administered under a fasting state) as the only fixed factor. The difference between these means (logarithmic scale) and its 90% confidence interval (CI) were raised to power to form the ratio of the geometric mean and the corresponding CI. max AUC 0-t , and AUC 0-inf If all 90% CI results for GMR fall within the 80.00% to 125.00% range, it was concluded that there was no food effect.

[0433] safety All safety parameters were summarized by dose level in Parts 1 through 5.

[0434] For continuous demographic variables (e.g., age, height, and weight), summary statistics (mean, median, standard deviation, minimum, maximum, and number of available findings) are provided. A list of individual subjects in the demographic data is also provided.

[0435] Qualitative demographic characteristics (sex, race) were summarized using quantitative and percentage figures. Only other baseline characteristics (e.g., medical history, clinical findings from physical examination, medication history, and inclusion / exclusion checklists) were listed.

[0436] ECG variables, vital sign measurements, and laboratory measurements were summarized at each time point using the mean, median, standard deviation, minimum, maximum, number of available findings, and change from baseline. C-SSRS parameters were analyzed using descriptive statistics where appropriate. A list of individual subjects for ECG data, vital sign data, laboratory measurements, and C-SSRS (Parts 2, 3, and 5 only) is provided.

[0437] The distributions of these parameters were compared descriptively only between the treatment groups (fasting or feeding). Statistical inference was performed.

[0438] Holter analysis / plasma concentration-QTc effect of compound 1 can be performed, and the results will be provided in a separate report.

[0439] Results of Phase 1 research A key objective of the Phase 1 trial involving healthy volunteers was to establish a target dose range for compound 1 to reduce HTT mRNA and protein. The trial consisted of single-dose escalation (SAD) and multi-dose escalation (MAD) cohorts. Administration in all cohorts was well-tolerated, with no safety-related findings, and demonstrated dose-dependent splicing of HTT mRNA. The MAD cohort had a longer study duration, allowing for longer-term evaluation of HTT mRNA splicing and HTT protein reduction. In the MAD cohort, compound 1 demonstrated a long drug half-life, with splicing maintained up to 72 hours after the final dose.

[0440] CSF sampling enabled the evaluation of the pharmacokinetics of compound 1 in CSF, comparing the level of compound 1 in CSF with the level in plasma. Results from a Phase 1 study demonstrated that the level of compound 1 in CSF was equal to or higher than the level observed in plasma. The food effect portion allowed for the evaluation of the pharmacokinetics of compound 1 in plasma after administration of a single dose of compound 1 in healthy subjects.

[0441] As shown in Figure 9A, the SAD cohort showed a dose-dependent decrease in HTT mRNA in whole blood samples taken from healthy volunteers 24 hours after administration of either placebo or compound 1 at 5 mg, 15 mg, 45 mg, 90 mg, or 135 mg doses.

[0442] Similarly, the MAD cohort (Figure 9B) also showed a dose-dependent decrease in HTT mRNA in whole blood collected from healthy volunteers who received either placebo, 15 mg, or 30 mg of compound 1 for 14 days. Next, on day 14, the amount of HTT mRNA was assessed by RT-PCR 6 hours after administration of compound 1.

[0443] In both the SAD and MAD cohorts, the lowest doses tested achieved a target reduction level of 30–50%. The half-life of HTT mRNA was estimated to be approximately 24 hours. Therefore, if no HTT mRNA was synthesized the following day, the total amount of HTT mRNA could be predicted to be approximately 50% of the baseline. Administration of compound 1 in the SAD cohort essentially inhibited all HTT mRNA de novo synthesis. Therefore, even with higher concentrations of compound 1, the total amount of HTT mRNA remained at approximately 50% of the baseline, corresponding to the amount of HTT mRNA synthesized before the administration of compound 1.

[0444] The results of measuring HTT mRNA in the whole blood of subjects in the SAD cohort are shown in Figure 14. These results also indicate that the HTT splicing effect of compound 1 is reversible and lasts for 72 hours after treatment discontinuation.

[0445] As described in the multi-stage dose escalation (MAD) studies above, the results of measuring HTT RNA in whole blood of human subjects administered placebo, 15 mg, or 30 mg of compound 1 are shown in Figure 15. HTT splicing was monitored after the final dose on day 14 and calculated as the percentage of HTT remaining from baseline (before administration on day 0).

[0446] Figure 10 is an illustrative diagram of the degradation dynamics of HTT mRNA and protein, which result in steady-state levels of RNA and protein.

[0447] In untreated cells, the amount of mRNA or protein being synthesized is equal to the amount being degraded, and therefore mRNA and protein levels remain constant over time, indicating that they are at steady-state levels. The addition of compound 1 triggers the inclusion of HTT pseudoexons into the transcript, thereby resulting in a rapid decay of HTT mRNA and a decrease of approximately 50% of the baseline level. The half-life of HTT mRNA is approximately 24 hours. Therefore, the amount of HTT mRNA present the day after drug treatment is controlled by the administration of compound 1. In this example, approximately 50% of newly synthesized mRNA was inhibited. Of the HTT mRNA synthesized before treatment, approximately 50% was degraded after 24 hours. HTT protein levels vary depending on how much mRNA is produced. Therefore, a 50% decrease should result in a 50% decrease in HTT protein. However, since HTT protein has a half-life of approximately 5-7 days, it takes longer than that to reach a new steady-state level. Finally, a new steady state is reached when 50% of the mRNA is present and the new protein level has decreased to 50% of the original amount. Changes in HTT protein levels were assessed over a longer period in the MAD cohort. Therefore, after treating healthy subjects for 21 days, the amounts of HTT mRNA and protein were measured in blood samples collected from each subject.

[0448] Figure 16 shows huntingtin mRNA and protein levels measured in whole blood from MAD cohort 2.3 (30 mg administered for 21 days, followed by 100 mg LD administered for 2 days) 24 hours after the final dose, as described above, as a percentage of baseline. The results indicate that the decrease in HTT mRNA reached a steady state. Longer administration was required for the HTT protein level to reach its maximum steady state decrease. The changes in HTT mRNA observed in the blood suggest that if a steady state decrease in HTT is achieved over time with continuous treatment using compound 1, a similar decrease in HTT protein levels is expected in Huntington's disease patients.

[0449] Figure 11 shows a graph predicting the time to reach a steady state after treatment with a daily dose of 30 mg of compound 1, modeling the decay rates of HTT mRNA (Figure 11A) and HTT protein (Figure 11B) based on their half-lives. For HTT mRNA, the half-life was estimated to be approximately 24 hours. HTT mRNA reached a steady state after approximately 5 days. For HTT protein, the half-life was estimated to be 5-7 days, and as a result, a steady state level of HTT protein was first achieved approximately 6 weeks after the start of treatment.

[0450] Figure 12 compares the decline trajectories of HTT mRNA (Figure 12A) and protein (Figure 12B) observed in multiple dose-escalation studies with values ​​predicted from the half-lives of HTT mRNA and protein shown in Figure 11. The results show that HTT mRNA levels declined rapidly, reaching a steady state around 4-5 days after treatment. As predicted, the rate of decline of protein was considerably slower, but after 21 days of treatment, the amount of HTT protein decreased by approximately 40%. Therefore, comparable steady-state levels of HTT mRNA and protein could be reached approximately 4-5 weeks after the start of treatment.

[0451] As shown in Figure 13, the level of compound 1 in cerebrospinal fluid (CSF) demonstrated that compound 1 crossed the blood-brain barrier and was directly correlated with the level of compound 1 in free plasma in both humans (Figure 13A) and non-human primates (Figure 13B). Two subjects in this cohort received a daily dose of 30 mg. Therefore, compound 1 crossed the blood-brain barrier. The level of compound 1 found in CSF was at least equivalent to, or greater than, the level observed in plasma, thus demonstrating in humans that compound 1 was present and not excreted.

[0452] In the food effects cohort, compound 1 showed similar exposure regardless of whether the subjects were fasting or consuming food.

[0453] In conclusion, the Phase I study demonstrated that compound 1 crossed the blood-brain barrier and selectively and dose-dependently reduced HTT mRNA and protein in both the CNS and periphery. These results confirm that exposure to compound 1 in human patients results in a demonstrable reduction of both HTT mRNA and HTT protein.

[0454] (Example 11) Phase 2 Clinical Study Protocol A randomized, placebo-controlled 12-week Phase 2 dose-finding study to evaluate the safety and efficacy of compound 1 in subjects with Huntington's disease.

[0455] Prior to the development of this Phase 2 study, compound 1 was extensively evaluated in in vivo and in vitro preclinical pharmacological models, in a comprehensive toxicology program, and in an ongoing Phase 1 study with healthy volunteers. Overall, the resulting data confirm that treatment with compound 1 results in a dose-dependent reduction of premRNA splicing and protein transcription, and that treatment with compound 1, including a single dose of as high as 135 mg and multiple doses of as high as 30 mg over 21 days, is safe and well-tolerated in a clinical setting.

[0456] A 12-week double-blind study of the present invention will enable the quantification of the effect of compound 1 on the reduction of total HTT (tHTT) protein in subjects with HD, and the evaluation of the safety of two doses of compound 1 over a 12-week treatment period.

[0457] The parallel-group design was chosen because it allows for the recruitment of patients from all treatment arms within the same timeframe. Time-course data on blood HTT protein, mRNA, and other indicators of drug response in untreated patients are unavailable. The use of a parallel-arm design with a placebo control simultaneously enables direct assessment comparisons to determine the effect of aggressive treatment.

[0458] The patient population was selected to reduce variability in an otherwise heterogeneous disease population by identifying subjects with active disease who have not yet experienced functional decline. Therefore, in this study, subjects will be enrolled in the trial at randomization based on baseline measurements of CAG repeat length, as well as symbol-number modality tests (SDMT), total motor score (TMS), independence scale (IS), and total functional capacity (TFC). These factors will be used to identify and enroll subjects with active disease who have not yet experienced functional decline (and may indicate disease progression that would allow them to accept intervention). Huntington's Disease Prognostic Index (PI) HD ) or a prognostic index (PIN) defined by its norm HDThe score can be used to predict the likelihood of HD progression. The PIN score is calculated at baseline to identify eligible subjects for study participation.

[0459] Based on the dynamics of compound 1-mediated HTT reduction in humans, the maximum reduction in tHTT protein in HD patients is expected to be achieved within 4–6 weeks. A 12-week dosing regimen may further demonstrate that steady-state reduction in tHTT is maintained over time with continued treatment with compound 1 in a Phase 2 study, followed by a one-year open-label extension study. The Phase 2 study will include exploratory clinical outcome endpoints to assess the effects of compound 1 on cognitive and motor function in subjects, as measured by the Huntington's Disease Unified Rating Scale (UHDRS), in addition to primary endpoints of tHTT protein change from baseline and safety. The UHDRS has been extensively studied and developed to assess disease progression across multiple domains. Cognitive impairment, motor loss, and accelerated loss of caudate nucleus and putamen volume are key features of this disorder and have a significant impact on quality of life. More sensitive assessment of early motor changes using wearable devices will also be included in the Phase 2 study as an exploratory endpoint. These 12-week endpoint studies provide insights into the rate of change in earlier stages of the disease and identify crucial measures that could serve as early indicators of HD progression.

[0460] Risk / Benefit Assessment As described, Huntington Disease (HD) is a relentlessly progressive neurodegenerative disorder. In the early stages of the disease, patients exhibit only mild symptoms. As the disease progresses, writhing involuntary movements become more pronounced, voluntary motor function declines, speech and swallowing gradually deteriorate, and aggressive disinhibited behaviors become more frequent. The final stage of the disease is characterized by severe inability to walk, speak, swallow, or care for oneself, ultimately requiring full-time care and ultimately leading to death, typically 15 to 18 years after the onset of symptoms (see Caron, N, Wright, G and Hayden, M; (2020a), Huntington Disease; Seattle, WA; University of Washington).

[0461] Currently, there are no disease-modifying interventions approved for use in hemodialysis (HD), and without intervention, the patient population included in this trial will face ongoing disease progression, functional loss, and inevitably death. Inevitable disease progression and inevitable disease mortality indicate a specific medical need that is not being met in HD. Reduction of mHTT has been identified as an important therapeutic target.

[0462] As previously mentioned, in the Phase 1 study, multiple doses of compound 1 were associated with a significant decrease in HTT mRNA and protein. Pharmacokinetic-pharmacodynamic (PKPD) modeling based on interim data from the Phase 1 study determined that exposure to 10 mg and 20 mg QD doses was associated with a decrease in full-length HTT mRNA levels that precisely encompassed the established mean target range of 30%–50% for HTT protein reduction. Therefore, the 10 mg and 20 mg QD doses are expected to be associated with therapeutic benefits and a final slowing of disease progression in this Phase 2 study.

[0463] The results of the Phase 1 study provided evidence of the stability and tolerability of Compound 1 in single doses ranging from 5 mg to 135 mg, as well as in multiple doses of 15 mg and 30 mg with durations of up to 21 days. In this study, Compound 1 was safe and generally well-tolerated. In both the single-dose escalation (SAD) and multi-dose escalation (MAD) portions of the Phase 1 study, the overall incidence of adverse events (AEs) was similar between the placebo-receiving and Compound 1-receiving groups. No events were considered dose-limiting toxicities, and all adverse events (AEs) had resolved by the interim analysis deadline. Furthermore, no clinically significant study abnormalities or electrocardiogram (ECG) findings were observed at any dose in any portion of the study.

[0464] Phase 1 studies include a Data and Safety Monitoring Committee (DSMB) to carefully monitor the stability of the subjects. Based on preclinical and clinical data to date, compound 1 has a favorable risk / benefit profile in subjects with hemodialysis (HD).

[0465] Main research objective The safety and pharmacodynamic efficacy of two treatment regimens, compound 1 and placebo, in subjects with Huntington's disease (HD) will be evaluated as assessed by (i) the frequency of adverse events (TEAEs) occurring under treatment, and abnormalities in clinical laboratory values, electrocardiogram (ECG), vital signs, slit-lamp eye examination, and physical examination, and (ii) a decrease in total huntingtin protein (HTT) levels in the blood. This aspect is intended to demonstrate the safety, tolerability, and pharmacology of compound 1, as well as the reduction of HTT mRNA and HTT protein in HD patients.

[0466] Secondary research objectives (i) the effect of compound 1 on HTT mRNA in the blood and mHTT protein in cerebrospinal fluid (CSF), and (ii) the reduction of blood mutant huntingtin protein (mHTT) levels. This aspect is intended to demonstrate the effect of compound 1 on blood-based biomarkers, CSF-based biomarkers, and radioactive biomarkers of Huntington's disease.

[0467] Exploratory research purpose (i) assess the effects of compound 1 on changes in whole brain, caudate nucleus, and putamen volume via volumetric magnetic resonance imaging (vMRI); (ii) assess the effects of compound 1 on changes in ventricular volume via vMRI; (iii) assess the effects of compound 1 on neurofilament light chain (NfL) protein concentrations in plasma and CSF; (iv) after 12 weeks of treatment, assess changes in relevant scales, including (a) the Unified Huntington's Disease Rating Scale (UHDRS) and its subcomponents, including (a) the Significant Numerical Modality Test (SDMT), (b) the Transmuscular Mass Score (TMS), (c) the Independent Scale, (d) Total Functional Capacity (TFC), (e) gait and motor assessment using a wearable accelerometer, (f) the Clinical Global Impression of Change (CGI-C), and (g) the Quality of Life Questionnaire for Huntington's Disease (HDQoL).

[0468] Objectives related to pharmacokinetics Evaluate the concentration of compound 1 in subjects exhibiting HD.

[0469] Clinical endpoints Key safety endpoints The safety profile is evaluated, characterized by TEAE, abnormal laboratory values, ECG, vital signs, slit-lamp eye examination, and physical examination.

[0470] Primary efficacy endpoint Change from baseline in total blood HTT protein at the fifth visit.

[0471] Biomarker endpoints (i) Percentage decrease in HTT protein in CSF, (ii) changes in neurofilament light chains (NfL) in plasma and CSF, and (iii) changes in caudate nucleus, putamen, and ventricular volume on volumetric MRI imaging.

[0472] Secondary endpoints (i) Changes from baseline in serum HTT mRNA at the 3rd, 4th, and 5th visits, (ii) Changes from baseline in mHTT in CSF at the 5th visit, and (iii) Changes from baseline in serum mHTT protein at the 5th visit.

[0473] exploratory endpoints (i) Changes from baseline in whole brain, caudate nucleus, putamen, and ventricular volume (as assessed by vMRI), (ii) Changes from baseline in plasma and CSF NfL protein concentrations, (iii) Changes from baseline in UHDRS scores for each subscale, including SDMT, TMS, independent scales, and TFC, (iv) Changes from baseline in overall UHDRS, (v) Changes from baseline in assessment of gait and motor function using wearable accelerometers, (vi) Assessment of changes using CGI-C, and (vii) Changes from baseline in the HDQoL questionnaire.

[0474] Pharmacokinetic endpoints (i) Plasma trough concentration of compound 1 at the 3rd, 4th, and 5th visits (C trough ) and plasma accumulation ratio, and (i) CSF accumulation ratio of compound 1 at the 5th visit.

[0475] Biomarker endpoints (i) Percentage decrease in HTT protein in CSF, (ii) changes in neurofilament light chains (NfL) in plasma and CSF, and (iii) changes in caudate nucleus, putamen, and ventricular volume on volumetric MRI imaging.

[0476] Research design / method The Phase 2 study is a randomized, placebo-controlled, parallel-arm dose-finding study to evaluate the safety and efficacy of 10 mg and 20 mg of Compound 1 after 12 weeks of treatment in subjects with HD, and to determine the HTT protein-reducing effect of these doses.

[0477] Individuals who have signed informed consent will be enrolled in a screening process to determine their eligibility for the study. During screening, potential subjects will undergo further evaluation to confirm that their genetic mutation status is verified by the clinical trial investigator (either through historical gene sequencing or in-study gene sequencing assessment) and that they meet the enrollment criteria. Subjects who meet all enrollment criteria at screening will undergo a baseline assessment and be randomized in a 1:1:1 ratio to receive either 10 mg or 20 mg of the study drug or placebo for a total of 12 weeks of treatment (plus or minus clinic visits). Once assigned to treatment, subjects will take the assigned dose of the study drug once daily, in the morning, at least two hours before their first meal. Subjects will be asked to return to the clinic or, instead of visiting the clinic themselves, receive home care services for a study assessment every 28 days after randomization (approximately on days 29, 57, and 85). On day 85, participants receive their final dose of the investigational drug and complete the research assessment. On day 113, a follow-up safety visit is conducted via telephone / telemedicine to collect adverse events (AEs).

[0478] Justification of sample size Sample size is calculated based on the mean change from baseline in total serum HTT protein at the fifth visit (the primary endpoint). Using an effect size of 0.85 (i.e., the magnitude of the treatment difference is 85% of one standard deviation), 31 subjects should be needed to achieve 90% power at a two-sided alpha level of 0.05. Assuming a 10% dropout rate, approximately 35 subjects will be randomized to each dose.

[0479] Planned number of patients Approximately 200 adult men and women will be registered.

[0480] Inclusion Criteria Individuals eligible to participate in this study include those who meet all of the following inclusion criteria: (i) male or female outpatients aged 25 years or older (inclusive), (ii) subjects (or legally recognized representatives) willingly provide informed consent and willingly comply with and be able to comply with all protocol requirements, (iii) a genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length of 42-50 including both ends, (iv) a UHDRS-Independent Scale score of 100, (v) a TFC score of 13, (vi) a norm-defined prognostic index for the HD score between 0.18 and 4.93 including both ends, and (vii) women of childbearing age (WOCBP): must agree to use highly effective contraception during administration and for 6 months after discontinuation of the study drug.

[0481] WOCBP is defined as a woman who is capable of becoming pregnant after menarche and after menopause, unless she is permanently infertile. Permanent infertility includes hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without another medical cause. High follicle-stimulating hormone (FSH) levels in the postmenopausal range may be used to confirm postmenopausal status in women who are not using hormonal contraceptives or hormone replacement therapy. However, a single FSH measurement is insufficient if there has been no amenorrhea for 12 months. Highly effective contraception is defined as contraception that, when used consistently and accurately, can achieve a failure rate of less than 1% per year, and includes (a) hormonal contraceptives (containing estrogen and progestogen) in combination with ovulation inhibition, including oral (WOCBPs using oral contraceptives must be stable on the same pill for at least three months prior to screening), vaginal, or transdermal administration; (b) hormonal contraceptives containing only progestogens associated with ovulation inhibition, including oral (WOCBPs using oral contraceptives must be stable on the same pill for at least three months prior to screening), injectable, implantable, intrauterine device, or intrauterine hormone-releasing system administration; or (c) contraception in combination with bilateral fallopian tube occlusion, a vasectomy partner, or abstinence.

[0482] (viii) Sexually active, fertile men must use condoms during sexual intercourse while taking the study drug and for six months after discontinuing the study drug, and must not conceive children or donate sperm during this period. Condom use is also required by men who have undergone vasectomy to prevent potential drug delivery through semen.

[0483] Main exclusion criteria An individual is ineligible to participate in this study if they meet or will meet any of the following exclusion criteria: (i) are unable to swallow or will not attempt to swallow oral tablets; (ii) have received an experimental drug, including an RNA or DNA-targeted HD-specific investigational drug, such as an antisense oligonucleotide, cell transplant, or any other experimental brain surgery, within 90 days prior to screening or within 5 half-lives, or at any time during the duration of this study; (iii) have a history of exposure to any gene therapy for the treatment of HD; or (iv) have been in a research clinical trial or research program within 90 days prior to screening or at any time during the duration of this study. (v) participation in a ladigm (e.g., exercise / physical activity, cognitive therapy, brain stimulation, etc.), (vi) presence of an implanted deep brain stimulation device, (vi) family history of early-onset cataracts, or presence of cataracts at baseline using a cataract scoring system (lens opacity classification system III), (vii) brain or spinal cord pathology that may interfere with CSF homeostasis and circulation, elevated intracranial pressure (including the presence of a shunt or implanted CNS catheter for CSF drainage), malformations, and / or tumors, (viii) 12 weeks of screening (ix) hospitalization for any major medical or surgical procedure involving general anesthesia, planned during or after the study; (x) significant suicide risk with a moderate or higher risk rating as measured by the Columbia Suicide Severity Rating Scale (C-SSRS); (x) risk of major depressive episode, psychosis, confusional state, or violent behavior as assessed by the investigator; (xi) any history of brain or spinal cord disease that may interfere with the lumbar puncture procedure or safety assessment; (xii) evidence of local recurrence or metastasis. (xiii) any medical history or condition that may interfere with the ability to complete protocol-specific assessments (e.g., implanted shunts, conditions that interfere with MRI procedures), (xiv) use of antidepressants or benzodiazepines with a dosage regimen that is not expected to change during the study, unless a stable dose has been received for at least six weeks prior to screening.(xvi) A lifetime history of drug or alcohol use in a high-risk category, as assessed by the investigator for a duration of more than one month, according to the World Health Organization; (xvii) A clinically significant medical condition, in the opinion of the investigator, that may have adverse effects on the safety of the subject or impair the assessment of the study results; (xviii) Current significant renal impairment, defined as an estimated glomerular filtration rate of <60 mL / min at screening; (xvix) A renal impairment elevated to three times the upper limit of normal at screening. (xx) Present liver dysfunction resulting in elevated liver function test values ​​(aspartate transaminase, alanine transaminase, alanine phosphatase), (xx) Pregnant, planning to become pregnant during the clinical trial, or currently breastfeeding, (xxi) Use of a moderate or potent CYP3A4 inhibitor within one week of screening, or use of a moderate or potent CYP3A4 inhibitor within two weeks of screening, or planning to use a moderate or potent CYP3A4 inhibitor or inducer during the study period.

[0484] Investigational products and reference products, dosage, and method of administration The tablet of compound 1 is administered orally via QD. The two investigational product administration arms are 10 mg for 12 weeks and 20 mg for 12 weeks.

[0485] Tablets of the active investigational product of Compound 1 and a matching placebo reference product are administered orally in QD form. The investigational drug product of Compound 1 is in the form of film-coated tablets for oral administration. White to off-white coated round tablets are provided in two dose strengths, 10 mg and 20 mg, each containing the drug substance of Compound 1, as well as an excipient selected from microcrystalline cellulose, lactose monohydrate, povidone K30, croscarmellose sodium, poloxamer 407, and magnesium stearate. The 10 mg and 20 mg tablets are provided in two different sizes. Placebo tablets contain the same official excipients and are manufactured in the same tablet size with the same appearance to match the 10 mg and 20 mg tablets of Compound 1.

[0486] Evidence regarding the safety of the selected doses is provided by the results of the ongoing Phase 1 study and the comprehensive preclinical toxicology program to date. In the Phase 1 study, single doses ranging from 5 mg to 135 mg, as well as multiple doses of 15 mg and 30 mg over 14 days, were safe and generally well-tolerated.

[0487] A 30%–50% reduction in targeted mHTT is within the range associated with reduced patient pathology and expected therapeutic benefit. In a Phase 1 study, compound 1-mediated HTT premRNA splicing was dose-dependent across all cohorts in both the SAD and MAD portions of the study. After 14-day treatment with 15 mg and 30 mg of compound 1, mean reductions of 40% and 60%, respectively, in full-length HTT mRNA levels were observed. Based on these clinical data, a PK-PD compartment model was used to simulate the percentage of mRNA reduction (and therefore the expected magnitude of HTT protein reduction) at further potentially possible clinical doses.

[0488] The predicted percentage reduction in full-length HTT mRNA at the selected 10 mg and 20 mg QD doses is within the target range of 30–50% from baseline. In preclinical data from a bacterial artificial chromosome gene transgenic mouse model of HD, mice showed a strong correlation between the level of HTT premRNA splicing and the degree of protein reduction after administration of compound 1. Therefore, the observed preclinical changes in HTT mRNA are expected to result in similar reductions in HTT protein levels in HD patients. Accordingly, based on the clinical and preclinical safety data to date, as well as the expected reductions in HTT mRNA and protein derived from clinical data and pharmacokinetic-pharmacodynamic models, the 10 mg and 20 mg doses are expected to be safe, well-tolerated, and beneficial for subjects with HD.

[0489] Reference product, dosage, and method of administration The matching placebo tablet is administered orally via QD.

[0490] safety standards Safety assessment includes observation of TEAEs, clinical tests, vital signs, ECG, C-SSRS, slit-lamp eye examination, and physical examination.

[0491] Effectiveness Criteria The assessment of effectiveness includes (i) blood HTT protein and NfL in CSF, (ii) UHDRS, (iii) CGI-C, (iv) wearable accelerometer for motor function, and (v) neuroimaging (vMRI) analysis.

[0492] Enrichment Criteria Enrichment is defined as the positive use of any patient, characterized by selecting a research population in which the drug effect (if any) is more likely to be detected than in a randomly selected population. Due to the highly variable population of patients with HD, the enrichment strategy for this Phase 2 study is intended to select subjects who have preserved abilities for daily living activities, work, finance, and self-care, but who perform poorly on motor and cognitive tests and are predicted to experience functional impacts on daily living activities within three years. The TMS and SDMT of the UHDRS will be assessed at screening (along with CAG repeat length and age) and used to identify this population by the HD prognostic index confirmed for asymptomatic HD patients.

[0493] Huntington's disease prognosis index (PI) HD ) or a prognostic index (PIN) defined by its norm HD Using this, the likelihood of HD progression can be predicted, with higher scores indicating a higher risk of functional decline. PI HD The natural course survival curve created using a specific PI HD This shows the disease trajectory in patients with a score. PIN HD The score allows researchers to predict disease progression in the studied population with high certainty. Historically, disease progression has generally been indexed by the CAG-Age Product (CAP), which is a kind of loading score of age and CAG elongation, which has several variants. Supplementing the CAP with TMS and SDMT of the UHDRS increases the predictability of HD progression. Using these enrichment criteria, a group of subjects with HD and no functional decline (measured by TFC and IS) can be identified, and changes in serum HTT levels after treatment can be measured. This group is likely to experience decline without HTT-reducing treatment, as early-stage HD has been found to be characterized by elevated mHTT levels in CSF compared to controls.

[0494] At baseline in this study, cognitive and motor function of participants was assessed using SDMT and TMS scores, respectively. Enrolled participants were in a state of no functional impairment, as assessed by TFC and IS. Participants were assigned PINs calculated by IRT before randomization. HD Based on the calculated score, it will be included in the study. Baseline PINs from 0.18 to 4.93, including both ends. HD Subjects with a score are eligible to enroll in the clinical trial. The following formula is PIN HD It is used to calculate the score. PI HD = 51 × (TMS) + (-34) × SDMT + 7 × (age) × (CAG - 34)

[0495] PI HD The score is converted to a standardized score using the following transformation. PIN HD =( PI HD -883) / 1044

[0496] Using the registered HD database (periodic data updates 5), PINs in the range of 0.18 to 4.93 are included in the study. HD The score was identified.

[0497] Pharmacokinetics Pharmacokinetic assessment involves plasma C trough (Including the 3rd, 4th, and 5th visits). Calculate and report the accumulation ratio in plasma (3rd, 4th, and 5th visits) and CSF (5th visit).

[0498] statistical methods A repeated measures analysis model (repeated at visits) is used to compare each dose to placebo for total blood HTT protein. This model includes administration, visits, administration-visit interactions, and baseline. Nominal p-values ​​and 95% confidence intervals (active agent vs. placebo) are provided for each pairwise comparison at the fifth visit. The model uses PIN as a stratification factor. HDThis includes: using the same analysis for serum HTT mRNA as used for serum HTT protein; exploring dose-response relationships; descriptively summarizing demographic and baseline characteristics, pharmacokinetics, safety, and efficacy endpoints by treatment group; and applying statistical models to understand the relationship between UHDRS and its components to blood and CSF assessments.

[0499] Results of Phase 2 Study The primary objective of a randomized, placebo-controlled, 12-week Phase 2a dose-finding study is to evaluate the safety and pharmacodynamic efficacy of two treatment regimens, Compound 1 and placebo, in subjects with Huntington's disease. To achieve this primary objective, the incidence of targeted adverse events (TEAEs) occurring under treatment; abnormalities in clinical laboratory values, electrocardiogram (ECG), vital signs, slit-lamp eye examination, and physical examination values; and reductions in serum total huntingtin protein (HTT) levels will be assessed.

[0500] A secondary objective of this study is to determine the effects of compound 1 on HTT mRNA in the blood and mHTT protein in cerebrospinal fluid (CSF), as well as the reduction of mutant huntingtin protein (mHTT) levels in the blood.

[0501] For the exploratory purposes of this study, the effects of Compound 1 on changes in whole brain, caudate nucleus, and putamen volume will be assessed via volumetric magnetic resonance imaging (vMRI), the effects on changes in ventricular volume will be assessed via vMRI, the effects of Compound 1 on neurofilament light chain (NfL) protein concentrations in plasma and CSF will be assessed, and changes in relevant scales will be assessed after 12 weeks of treatment, including assessments using the Unified Huntington's Disease Rating Scale (UHDRS) and its subcomponents. The UHDRS subcomponents will be used to assess qualitative effectiveness, including (a) Significant Numerical Modality Test (SDMT), (b) Total Motor Score (TMS), (c) Independent Scales, (d) Total Functional Capacity (TFC), (e) Gait and Motor Assessment using Wearable Accelerometer, (f) Clinical Global Impression of Change (CGI-C), and (g) Quality of Life Questionnaire for Huntington's Disease (HDQoL).

[0502] For the pharmacokinetic objectives of this study, the concentration of compound 1 in subjects with hemodialysis (HD) will be evaluated. The invention described in the original claims of this application is listed below. [1] A tablet containing, as an active ingredient, 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol (hereinafter referred to as Compound 1), or a pharmaceutically acceptable salt thereof (Compound 1 is present in an amount of about 5% to about 30% by mass of the total mass of the tablet), an internal excipient, and an external excipient, wherein the internal excipient A tablet comprising a binder containing microcrystalline cellulose and a diluent, with a ratio of microcrystalline cellulose to diluent of approximately 1:1 to approximately 1:4, where microcrystalline cellulose is present in an amount of approximately 15% to approximately 25% of the total mass of the tablet, a disintegrant is present in an amount of approximately 1% to approximately 3% of the total mass of the tablet, povidone is present in an amount of 1% to approximately 5% of the total mass of the tablet, and an extragranular excipient containing further amounts of diluent and further amounts of disintegrant. [2] The tablet according to [1], wherein compound 1 is present in an amount of approximately 5% to approximately 25% of the total mass of the tablet. [3] The tablet according to [2], wherein compound 1 constitutes about 10% of the total mass of the tablet. [4] The tablet according to [1], wherein the amount of compound 1 in the tablet is approximately 1 mg to 200 mg. [5] The tablet according to [4], wherein the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg. [6] The tablet according to [1], wherein the amount of compound 1 in the tablet is approximately 1 mg to 100 mg. [7] The tablet according to [6], wherein the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg. [8] The tablet according to [1], wherein the diluent is lactose monohydrate. [9] The tablet according to [1], wherein the ratio of microcrystalline cellulose to diluent in the granular excipient is approximately 1:2.

[10] The tablet described in [1], wherein the extragranular diluent is present in an amount of approximately 15% to approximately 30% of the total mass of the tablet.

[11] The tablet according to [1], wherein at least one of the extragranular excipient and the intragranular excipient further comprises a surfactant.

[12] The tablet according to

[11] , wherein the surfactant is poloxamer.

[13] The tablet according to [1], wherein the disintegrant is croscarmellose sodium.

[14] The tablet according to [1], wherein the extragranular excipient further comprises a lubricant.

[15] The tablet according to

[14] , wherein the lubricant is magnesium stearate.

[16] The tablet according to [1], wherein the extragranular excipient further comprises a flow promoter.

[17] The tablet according to

[16] , wherein the flow promoter is colloidal silicon dioxide.

[18] The tablet according to [1], wherein the mass of the extragranular excipient is approximately 15% to approximately 30% by mass of the total mass of the tablet.

[19] The tablet according to [1], wherein the granular excipient is wet-granulated.

[20] The tablet according to [1], wherein compound 1 is present in an amount of 10% by mass of the tablet, the intragranular excipients include microcrystalline cellulose and lactose monohydrate in a ratio of about 1:2, the microcrystalline cellulose is present in an amount of about 20% by mass of the tablet, the disintegrant is present in an amount of about 1% to about 3% by mass of the tablet, povidone is present in an amount of about 2% by mass of the tablet, and the extragranular excipients include lactose monohydrate in an amount of about 10% to about 25% by mass of the tablet, the disintegrant in an amount of about 1% to about 5% by mass of the tablet, and poloxamer in an amount of about 0.5% to about 2% by mass of the tablet.

[21] The tablet according to

[20] , wherein the extragranular excipient further contains colloidal silicon dioxide in an amount of about 0.25% to about 1% by mass of the tablet.

[22] The tablet according to

[20] , wherein the extragranular excipient further contains magnesium stearate in an amount of about 0.5% to about 2% by mass of the tablet.

[23] A method for producing the tablets described in [1], comprising the steps of wet granulation of an external excipient, drying the resulting intragranular blend, mixing the external excipient with the intragranular excipient, and compressing the resulting mixture to form a tablet.

[24] The method according to

[23] , further comprising the step of coating the resulting compressed tablets with a film.

[25] A method for treating or improving Huntington's disease in a subject in need thereof, comprising the step of orally administering to the subject a tablet according to [1] having a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[26] The method according to

[25] , wherein the tablet contains a therapeutically effective amount of compound 1 in the range of 1 mg to 200 mg.

[27] The method according to

[26] , wherein the therapeutically effective dose of compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

[28] The method according to

[25] , wherein the tablet contains 1 to 100 mg of compound 1.

[29] The method according to

[28] , wherein the tablets contain 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg of compound 1.

[30] The method according to

[25] , wherein the tablet is administered once daily.

Claims

1. The tablet contains, as an active ingredient, 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol (hereinafter referred to as Compound 1), or a pharmaceutically acceptable salt thereof (Compound 1 is present in an amount of 5% to 30% by mass of the total mass of the tablet), an internal excipient, and an external excipient. A tablet wherein the internal excipients include microcrystalline cellulose and a diluent, with a ratio of microcrystalline cellulose to diluent of 1:1 to 1:4, the microcrystalline cellulose is present in an amount of 15% to 25% of the total mass of the tablet, the disintegrant is present in an amount of 1% to 3% of the total mass of the tablet, and povidone is present in an amount of 2% of the total mass of the tablet, and the external excipients include a further amount of diluent and a further amount of disintegrant.

2. The tablet according to claim 1, wherein compound 1 is present in an amount of 5% to 25% of the total mass of the tablet.

3. The tablet according to claim 2, wherein compound 1 constitutes 10% of the total mass of the tablet.

4. The tablet according to claim 1, wherein the amount of compound 1 in the tablet is 1 mg to 200 mg.

5. The tablet according to claim 4, wherein the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

6. The tablet according to claim 1, wherein the amount of compound 1 in the tablet is 1 mg to 100 mg.

7. The tablet according to claim 6, wherein the amount of compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg.

8. The tablet according to claim 1, wherein the diluent is lactose monohydrate.

9. The tablet according to claim 1, wherein the ratio of microcrystalline cellulose to diluent in the granular excipient is 1:

2.

10. The tablet according to claim 1, wherein the extragranular diluent is present in an amount of 15% to 30% of the total mass of the tablet.

11. The tablet according to claim 1, wherein at least one of the extragranular excipient and the intragranular excipient further contains a surfactant.

12. The tablet according to claim 11, wherein the surfactant is poloxamer.

13. The tablet according to claim 1, wherein the disintegrant is croscarmellose sodium.

14. The tablet according to claim 1, wherein the extragranular excipient further comprises a lubricant.

15. The tablet according to claim 14, wherein the lubricant is magnesium stearate.

16. The tablet according to claim 1, wherein the extragranular excipient further comprises a flow promoter.

17. The tablet according to claim 16, wherein the flow promoter is colloidal silicon dioxide.

18. The tablet according to claim 1, wherein the mass of the extragranular excipient is 15% to 30% by mass of the total mass of the tablet.

19. The tablet according to claim 1, wherein the internal excipient is wet-granulated.

20. The tablet according to claim 1, wherein compound 1 is present in an amount of 10% by mass of the tablet, the intragranular excipients include microcrystalline cellulose and lactose monohydrate in a ratio of 1:2, the microcrystalline cellulose is present in an amount of 20% by mass of the tablet, the disintegrant is present in an amount of 1% to 3% by mass of the tablet, povidone is present in an amount of 2% by mass of the tablet, and the extragranular excipients include lactose monohydrate in an amount of 10% to 25% by mass of the tablet, a disintegrant in an amount of 1% to 5% by mass of the tablet, and poloxamer in an amount of 0.5% to 2% by mass of the tablet.

21. The tablet according to claim 20, wherein the extragranular excipient further comprises colloidal silicon dioxide in an amount of 0.25% to 1% by mass of the tablet.

22. The tablet according to claim 20, wherein the extragranular excipient further comprises magnesium stearate in an amount of 0.5% to 2% by mass of the tablet.

23. A method for producing a tablet according to claim 1, comprising the steps of: wet granulating an external excipient; drying the resulting internal blend; mixing the external excipient with the internal excipient; and compressing the resulting mixture to form a tablet.

24. The method according to claim 23, further comprising the step of coating the resulting compressed tablet with a film.

25. A tablet according to claim 1 for treating or improving Huntington's disease in a person requiring it.

26. The tablet according to claim 25, wherein the tablet contains a therapeutically effective amount of compound 1 in the range of 1 mg to 200 mg.

27. The tablet according to claim 26, wherein the therapeutically effective dose of compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

28. The tablet according to claim 25, wherein the tablet contains 1 to 100 mg of compound 1.

29. The tablet according to claim 28, wherein the tablet contains 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg of compound 1.

30. The tablet according to claim 25, wherein the tablet is administered once a day.

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