CN116635016A - Tablet for treating Huntington's disease and preparation method thereof - Google Patents

Abstract

The present application relates to tablet formulations of 2- [3- (2, 6-tetramethylpiperidin-4-yl) -3H- [1,2,3] triazolo [4,5-c ] pyridazin-6-yl ] -5- (2H-1, 2, 3-triazol-2-yl) phenol, compounds useful for the treatment of Huntington's disease and methods of making the same.

Description

Tablet for treating Huntington's disease and preparation method thereof

Cross References to Related Applications

This application claims pending U.S. Provisional Patent Application Serial No. 63/113,826 filed November 13, 2020, pending U.S. Provisional Patent Application Serial No. 63/245,927 filed September 19, 2021, 2021 Pending U.S. Provisional Patent Application Serial No. 63/261,467 filed September 21, Pending U.S. Provisional Patent Application Serial No. 63/261,495 filed September 22, 2021, and October 14, 2021 The benefit and priority of co-pending US Provisional Patent Application Serial No. 63/255,745, the contents of which are expressly incorporated by reference into this application in their entirety.

technical field

The present invention generally relates to immediate release tablets of small molecule compounds for the treatment of Huntington's disease and methods for their preparation.

Background technique

Huntington's Disease (HD) is a rare inherited neurodegenerative disorder caused by mutations in the Huntington's (HTT) gene. The disorder causes behavioral, cognitive, and movement disorders. These symptoms progressively reduce an individual's quality of life and eventually lead to death within 15 to 25 years of the onset of overt clinical motor symptoms. Each of the children of parents with a mutation in the Huntington gene has a 50 percent chance of inheriting the mutation. It is estimated that approximately one in 10,000 people carries a mutated Huntington gene. Current HD therapies can control the severity of symptoms, but there are currently no approved treatments that slow the progression of the disease.

HD is caused by a CAG repeat expansion in HTT and is characterized by decline in motor, cognitive, mental, and functional abilities. The CAG trinucleotide repeat expansion results in mutated huntingtin (mHTT) that is associated with neurological dysfunction and eventually death.

In healthy individuals, the number of CAG repeats in the HTT gene ranges from 6 to 35. Individuals with 36 to 39 CAG repeats have reduced penetrance of the disorder, but individuals with 40 or more CAG repeats are almost certain to develop the disorder. As described in European Journal of Neurology, 2017, 24-34, the clinical diagnosis of HD is based on: a confirmed family history or positive genetic testing (i.e. confirmed CAG repeat expansion ≥36); and the presence of the Huntington's Disease Unified Rating Scale (UHDRS)-defined movement disorders, Total Motor Score (TMS) Diagnostic Confidence Score (DCS), which ranges from 0 (no movement abnormalities suggestive of HD) to 4 (≥99% likely due to HD Dyskinesia), with a score of 4 defining "dyskinesia" or "symptomatic" HD.

Typically, the age of onset (ie, once DCS reaches 4) is between 30 and 50 years, and the median survival after clinical diagnosis is 15 to 20 years. Currently, it is the loss of "function" (ie assessment of functional capacity) after onset rather than motor symptoms that determines the stage of the disease (see eg Neurology, 1979, 29, 1-3; or Neurology, 1981, 31, 1333-1335). The Total Functional Capacity (TFC) Assessment Scale (see, e.g. Movement Disorders, 1996, 11, 136-142) is a component of the UHDRS, in which HD patients have levels of independence ranging from 0 (totally dependent on all care) to 13 (totally independent) . This scale assesses the functional status of HD patients in terms of ability to work, manage household finances, manage household chores, perform activities of daily living, and required level of care. HD disease progression was classified as stages 1 to 5 according to the UHDRS Total Functional Capacity Assessment (TFC). HD classification based on TFC score (also known as Shoulson stage and Fahn stage) is also described as early HD (corresponding to TFC score stage 1 or 2), intermediate HD (corresponding to TFC score stage 3), and late HD (corresponding to TFC score stage 4 or 5).

The international application published as WO2020/005873 identifies a class of compounds useful in the treatment of HD, their preparation methods and their pharmaceutical formulations. It also presents data in _IC50 assays showing that these compounds inhibit endogenous huntingtin (HTT). A particularly potent HTT inhibitor disclosed in this application, 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazole And[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol was found to effectively reduce in vivo Generation of human HTT (results not yet published). Currently only symptomatic treatment is available. Therefore, so far no small molecule therapy is available to slow the progression of HD. Therefore, there is a need for small molecule disease-modifying therapies (ie, treatment options that can slow disease progression) for HD.

Contents of the invention

In one aspect, the present invention relates to a tablet comprising as active ingredient 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 (hereinafter referred to as compound 1) or its pharmaceutically acceptable Acceptable salts, intragranular excipients and extragranular excipients, wherein the content of Compound 1 accounts for about 1% by weight to about 30% by weight of the total weight of the tablet,

Wherein the intragranular excipient comprises microcrystalline cellulose and diluent, wherein the ratio of microcrystalline cellulose to diluent is about 1:1 to about 1:4, and the content of microcrystalline cellulose accounts for about 15% of the total weight of the tablet. % to about 25% by weight, the disintegrant from about 1% to about 3% of the total tablet weight, and povidone from about 1% to about 5% of the total tablet weight, and

Wherein the extragranular excipient contains an additional content of a diluent and an additional content of a disintegrant.

In one aspect, Compound 1 is present in an amount from about 5% to about 25% of the total weight of the tablet. On the other hand, Compound 1 is present in an amount of about 10% of the total weight of the tablet.

In one aspect, the content of Compound 1 in the tablet is 1 mg to 200 mg.

On the other hand, the content of Compound 1 in the tablet is 1 mg to 100 mg.

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

On the other hand, the content of compound 1 in the tablet is selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg , 120mg, 135mg and 140mg.

On the other hand, the content of compound 1 in the tablet is selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg , 135mg and 140mg.

In another aspect, the content 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.

In another aspect, the content of Compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 50 mg.

In another aspect, the content 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.

In another aspect, the content of Compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 50 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 1 mg, 5 mg or 50 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 5 mg or 50 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 5 mg, 10 mg, 20 mg and 30 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 5 mg, 10 mg and 20 mg.

In one aspect, the diluent is lactose monohydrate.

In one aspect, the disintegrant is croscarmellose sodium.

In one aspect, the ratio of microcrystalline cellulose to diluent in the intragranular excipient is about 1 to 2.

In one aspect, at least one of the extragranular excipient and the intragranular excipient further comprises a surfactant. In one such aspect, the surfactant is a poloxamer.

In one aspect, the disintegrant is croscarmellose sodium.

In one aspect, the extragranular excipient further comprises a lubricant. In one such aspect, the lubricant is magnesium stearate.

In one aspect, the extragranular excipient further comprises a glidant. In one such aspect, the glidant is colloidal silicon dioxide.

In one aspect, the total weight of extragranular excipients comprises from about 15% to about 30% of the total weight of the tablet.

In one aspect, intragranular excipients have been wet granulated.

In another aspect, the tablet contains Compound 1 in an amount of about 10% by weight of the tablet, the intragranular excipient includes microcrystalline cellulose and lactose monohydrate in a ratio of about 1:2, and the content of microcrystalline cellulose is about 10% by weight of the tablet. about 20% by weight of the tablet, the content of disintegrants accounts for 1% to about 3% by weight of the tablet, the content of povidone accounts for about 2% by weight of the tablet, and the content of extragranular excipients accounts for about 2% by weight of the tablet. Lactose monohydrate at about 10% to about 25%, disintegrant at about 1% to about 5% by weight of the tablet, and poloxamer at about 0.5% to about 2% by weight of the tablet.

In another aspect, the tablet further comprises colloidal silicon dioxide in an amount from about 0.25% to about 2% by weight of the tablet.

In another aspect, the tablet further comprises magnesium stearate in an amount from about 0.5% to about 2% by weight of the tablet.

The invention also relates to a process for the preparation of tablets comprising wet granulation of an extragranular excipient, drying the resulting intragranular mixture, mixing the extragranular excipient with the intragranular excipient, and compressing the resulting Mix to form tablets.

In another aspect, the method further includes the step of coating the tablet with a film.

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

On the other hand, the present invention also relates to the use of Compound 1 or a pharmaceutically acceptable salt thereof in the treatment of slowing down the progression of Huntington's disease; wherein the effect of using Compound 1 or a pharmaceutically acceptable salt thereof is passed through the expression of HTT mRNA An in-frame stop codon is generated between exons 49 and 50 to slow down the progression of Huntington's disease; wherein the effect of slowing down the progression of Huntington's disease with compound 1 or a pharmaceutically acceptable salt thereof is a disease-modifying therapy; wherein the compound The effect of treatment with 1 or a pharmaceutically acceptable salt thereof slows down the motor function decline associated with Huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows down the cognitive decline associated with Huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows down the mental decline associated with Huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows down the function associated with Huntington's disease Decline of capacity; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows the progression of Huntington's disease pathophysiology.

Description of drawings

Figure 1 is the individual plasma of Compound 1 after oral administration of 30 mg of Compound 1 suspension (21 batches) in 0.5% hydroxypropylmethylcellulose (HPMC) aqueous solution in male cynomolgus monkeys (Group 1 (Leg 1)) A graph of concentration versus time.

Figure 2 is the mean plasma concentration of compound 1 over time after oral administration of 30 mg compound 1 suspension (21 batches) in 0.5% hydroxypropylmethylcellulose (HPMC) aqueous solution in male cynomolgus monkeys (the first group) of the graph.

Figure 3 is a graph showing the individual plasma concentration of compound 1 over time after oral administration of tablet A (15 batches of dry granulation) containing 30 mg of compound 1 in male cynomolgus monkeys (group 2).

Figure 4 is a graph showing the mean plasma concentration of compound 1 over time after oral administration of tablet A (15 batches of dry granulation) containing 30 mg of compound 1 in male cynomolgus monkeys (group 2).

Figure 5 is a graph showing the individual plasma concentration of compound 1 over time after oral administration of tablet B (20 batches of wet granulation) containing 30 mg of compound 1 in male cynomolgus monkeys (group 3).

Fig. 6 is a graph showing the individual plasma concentration of compound 1 over time after oral administration of tablet B (20 batches of wet granulation) containing 30 mg of compound 1 in male cynomolgus monkeys (group 3).

Figure 7 is the dissolution profile (percentage of dissolved compound 1 as a function of time) of 23 batches of 5 mg tablets produced before and after storage at 75% relative humidity at 50°C for 2 weeks or at 40°C for 1 month .

Figure 8 is the dissolution profile (percentage of dissolved compound 1 as a function of time) of 50 mg tablets produced in 23 batches before and after storage at 75% relative humidity at 50°C for 2 weeks or at 40°C for 1 month.

Figure 9 shows the dose-dependent reduction of HTT mRNA in whole blood drawn from healthy volunteers participating in a single ascending dose (SAD) and multiple ascending dose study of a Phase I clinical trial.

Figure 9A shows the reduction of HTT mRNA in whole blood from healthy volunteers in the SAD cohort where splicing was assessed 124 hours after they were administered a single dose of placebo, 5 mg, 15 mg, 45 mg, 90 mg or 135 mg of compound once a day .

Figure 9B shows the reduction of HTT mRNA in whole blood of healthy volunteers in the MAD cohort taking placebo, 15 mg or 30 mg Compound 1 daily for 14 days. HTT splicing was then assessed by RT-PCR 6 hours after compound 1 administration on day 14.

Figure 10 shows how decay rates can be modeled to predict drug-dependent declines in mRNA and protein concentrations over time.

Figure 11 shows the modeling of HTT mRNA (Figure 11A) and HTT protein (Figure 11B) decay rates based on their half-lives and then predicting the time to reach steady state following treatment with Compound 1 at a daily dose of 30 mg. For HTT mRNA, the estimated half-life is approximately 24 hours. HTT mRNA in Figure 11A reached a steady state after about 5 days. For HTT protein, the half-life is estimated to be 5-7 days, so the steady-state level of HTT protein takes about 6 weeks from the start of treatment.

FIG. 12 compares the trajectories of HTT mRNA ( FIG. 12A ) and protein ( FIG. 12B ) reduction seen in multiple ascending dose studies with those predicted for the half-lives of HTT mRNA and protein shown in FIG. 11 .

Figure 13 shows that Compound 1 crosses the blood brain barrier in non-human primates (Figure 13A) and humans (Figure 13B).

Figure 14 is a graph of HTT RNA as a percentage of baseline measured over time in whole blood of human subjects administered placebo or a single dose of 90 mg of Compound 1, as in Single Ascending Dose (SAD) in Example 10, Part 1 described in the study. The results showed that the HTT splicing effect of compound 1 was reversible and persisted for 72 hours after cessation of treatment.

Figure 15 is a graph of HTT RNA as a percentage of baseline measured over time in whole blood of human subjects administered placebo or 15 or 30 mg of Compound 1, as in the multiple ascending dose (MAD) study of Example 10, part 2 described in . HTT splicing was monitored after the last dose on Day 14 as a percentage of remaining HTT from baseline (Day 0 pre-dose).

Figure 16 is a bar graph showing huntingtin mRNA and protein levels in whole blood from MAD cohort 2.3 (100 mg loading dose (LD) for 2 days, 30 mg for 21 days), as described in Example 10, with As a percentage of baseline, following administration of vehicle or Compound 1 to humans, 24 hours after the last dose. The results showed that HTT mRNA reduction reached a steady state. HTT protein levels required longer dosing to achieve maximal steady-state reduction.

Detailed ways

Unless otherwise specified, the meanings of all words (including technical terms and scientific terms) used in this invention are the same as those commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, these materials, methods, and examples are illustrative only and not restrictive. Other features of the invention will be apparent from the following detailed description and claims.

The use of headings or subheadings in the specification is for the convenience of the reader only and is not intended to affect the scope of the invention or limit any aspect of the invention to any subsection, subheading or paragraph.

1. Definition

In the present invention, the singular forms "one (a)", "one (an)" and "the" also include plural forms unless the context clearly indicates otherwise.

As used herein and in the claims, the phrase "at least one" referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including the list of elements. At least one of each element explicitly listed, and any combination of elements in the list of elements is not excluded. This definition also allows that elements may optionally be present other than the elements specifically listed on the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically listed. Thus, by way of non-limiting 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")— An aspect may refer to at least one, optionally including more than one A, the absence of B (and optionally including elements other than B); another aspect refers to at least one, optionally including more than one B, the absence of A (and optionally including elements other than B); includes elements other than A); on the other hand, refers to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements), and the like.

When the term "about" is used in conjunction with a numerical range, it modifies the numerical range by extending the boundaries above and below those values. Generally, the term "about" is used herein to modify a numerical value by 20%, 10%, 5%, or 1% above and below the stated value. In certain aspects, the term "about" is used herein to modify a numerical value by 10% above and below the stated value. In certain aspects, the term "about" is used herein to modify a numerical value by 5% above and below the stated value. In certain aspects, the term "about" is used herein to modify a numerical value by 1% above and below the stated value.

The terms "subject" or "patient" are used interchangeably and refer to a human individual suffering from a disease described herein (eg, Huntington's syndrome) that can be treated by administering a composition described herein.

When numerical ranges are recited herein, every value and subrange within that range is intended to be encompassed. For example, "1-5ng" or "1ng to 5ng" is intended to include 1ng, 2ng, 3ng, 4ng, 5ng, 1-2ng, 1-3ng, 1-4ng, 1-5ng, 2-3ng, 2-4ng, 2-5ng, 3-4ng, 3-5ng and 4-5ng.

It should be further understood that when used herein, the words "comprising" and/or "comprising" refer to the presence of specified features, integers, steps, operations, elements and/or components, but do not exclude the presence or addition of one or Multiple other features, integers, steps, operations, elements, components and/or combinations thereof.

The term "treatment" refers to therapeutic treatment, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a disease. Alternatively, the term "treating" includes the term "improving", which refers to reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder. Treatment is generally "effective" if one or more symptoms or clinical markers decrease. Alternatively, treatment is "effective" if the progression of the disease is slowed, reduced or stopped. That is, "treating" includes not only improving symptoms or markers compared to what would be expected without treatment, but also stopping or at least slowing down the progression or worsening of symptoms. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of one or more symptoms, lessening of disease extent, stabilization (i.e., not worsening) of disease state, delay or slowing of disease progression, amelioration or palliation of disease state, remission (whether partial or all) and/or reduce mortality, whether detectable or undetectable. The term "treatment" of a disease also includes alleviation of symptoms or side effects of a disease (including palliative care).

As used herein, the term "excipient" refers to any substance that is not a therapeutic agent itself, but is used as a carrier or vehicle, which is used to deliver a therapeutic agent to a subject or added to a pharmaceutical composition to improve a pharmaceutical composition The handling or storage characteristics may permit or facilitate the formation of dosage units of the composition into dispersible preparations, such as capsules or tablets suitable for oral administration. Excipients include, but are not limited to, diluents, disintegrants, binders, adhesives, surfactants, lubricants, glidants, surface modifiers, substances added to mask or eliminate unpleasant tastes or odors , flavorings, dyes, fragrances and substances added to improve the appearance of the composition.

The term "HD" or "Huntington's disease" as used herein refers to a neurodegenerative disease caused by a CAG repeat expansion in the Huntington gene and characterized by decreased motor, cognitive, mental and functional abilities.

As used herein, the term "intragranular" refers to ingredients that are incorporated into the formulation prior to granulation, ie, ingredients that are internal to or part of the granule structure.

As used herein, the term "extragranular" refers to ingredients that are incorporated into the formulation after granulation, ie ingredients that are located outside the granule structure.

As used herein, the term "administering" refers to the act of physically delivering a substance that exists outside the body into the body of a subject.

As used herein, the term "symptomatic HD" or "symptomatic Huntington's disease" refers to clinically confirmed HD (eg, based on: confirmed family history or positive genetic testing (confirmed CAG repeat expansion ≥ 36); and Dyskinesia present [Diagnostic Confidence Score (DCS) as defined by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) is 4]. In one aspect, as used herein, the term "symptomatic HD" or "Symptomatic Huntington's disease" refers to patients with clinically confirmed HD (eg, based on: confirmed family history or positive genetic testing (confirmed CAG repeat expansion ≥36); and presenting with dyskinesias [based on: The Diagnostic Confidence Score (DCS) defined by the Total Motor Score (TMS) of the Rating Scale (UHDRS) is 4].

As used herein, the term "presymptomatic HD" or "presymptomatic Huntington's disease" refers to genetically confirmed HD [eg based on: positive genetic testing (confirmed CAG repeat expansion ≥ 40) in the absence of clinically definite movement disorders eg , assessed according to standard scales, such as clinical scales [eg, as defined by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) with a Diagnostic Confidence Score (DCS) <4]. In one aspect, the term "presymptomatic HD" or "presymptomatic Huntington's disease" refers to a patient with a genetically confirmed HD [eg based on: a positive genetic test (confirming a CAG repeat expansion ≥40) without clinically definite movement disorders, eg , assessed according to standard scales, such as clinical scales [eg, as defined by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) with a Diagnostic Confidence Score (DCS) <4].

As used herein, the terms "slowing the progression of HD", "slowing the progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease" refer to one or more treatments selected from Effects: Reduces the rate of progression of Huntington's disease (e.g., reduces the rate of progression between stages of Huntington's disease); delays the onset of Huntington's disease; delays the onset of symptoms associated with Huntington's disease; reduces symptoms associated with Huntington's disease (e.g., a reduction in the annual rate of decline); or reduction in the rate of progression of Huntington's disease pathophysiology (e.g., treatment effect compared to placebo or compared to a natural history control group; For example, according to a standard scale as described above or below, such as a clinical scale, or according to neuroimaging measurements).

As used herein, the term "rate of progression" refers to the annual rate of change (eg, decline) or annual rate of change (eg, decline), eg, as assessed according to a standard scale, such as a clinical scale, or according to neuroimaging measurements.

The term "decrease" as used herein means, for example, a reduction in treatment by 5%, 10%, 20%, 30%, 40%, 50%, 60% or 70% per year.

As used herein, the term "delay" means a delay of at least, eg, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 years.

As used herein, the terms "slowing the progression of HD", "slowing the progression of Huntington's disease", "to slow the progression of HD" or "slowing the progression of Huntington's disease" refer to delaying the onset of Huntington's disease, e.g., adding Time to defined Huntington's disease onset. In another aspect, the term refers to a reduction in the rate of progression between the stages of Huntington's disease, e.g. from early HD to more advanced HD, e.g. compared to placebo, on a standard scale, e.g. a clinical scale [ Assessment is performed eg according to the UHDRS Total Functional Capacity Assessment (TFC) scale, eg as described in Neurology, 1979, 29, 1-3]. In another aspect, the term refers to a reduction in the rate of progression from HD stage 1 to HD stage 2 (eg, compared to placebo). In another aspect, the term refers to a reduction in the rate of progression from HD stage 2 to HD stage 3 (eg, compared to placebo). In another aspect, the term refers to a reduction in the rate of progression from HD stage 3 to HD stage 4 (eg, compared to placebo). In another aspect, the term refers to a reduction in the rate of progression from HD stage 4 to HD stage 5 (eg, compared to placebo). In another aspect, the term refers to a reduction in the rate of progression from early HD to intermediate HD (eg, compared to placebo). In another aspect, the term refers to a reduction in the rate of progression from intermediate HD to advanced HD (eg, compared to placebo).

As used herein, the term "reducing the rate of progression" means, for example, increasing the time to progression of HD stages (eg, compared to placebo).

As used herein, the terms "slowing the progression of HD", "slowing the progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease" refer to delaying the onset of Huntington's disease (e.g., Increases the time to onset of Huntington's disease as defined herein) by at least 25% (eg 25% or more, eg 25% to 50%).

As used herein, the term "onset of Huntington's disease" refers to a commonly established clinical diagnosis of HD [eg, as defined by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS), Diagnostic Confidence Score (DCS ) is a dyskinesia episode of 4].

As used herein, the term "slowing the progression of HD", "slowing the progression of Huntington's disease", "to slow the progression of HD", or "to slow the progression of Huntington's disease" means delaying the onset of symptoms associated with Huntington's disease, For example, increased time to onset of one or more symptoms associated with Huntington's disease selected from motor decline associated with Huntington's disease, cognitive decline associated with Huntington's disease, Mental decline and functional decline associated with Huntington's disease. In another aspect, the term means reducing the rate of progression of one or more symptoms associated with Huntington's disease selected from the group consisting of motor decline associated with Huntington's disease, cognitive impairment associated with Huntington's disease, as defined herein decline, mental decline associated with Huntington's disease, and functional decline associated with Huntington's disease. As used herein, the term "reduced rate" refers to, for example, prolonging the time to onset of onset or increasing the time to severity (eg, compared to placebo). On the other hand, the terms "slowing the progression of HD", "slowing the progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease" as used herein refer to presymptomatic HD progression to symptomatic Speed of HD [i.e. delayed onset of symptomatic HD; e.g. compared to placebo; as defined by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) with a Diagnostic Confidence Score (DCS) of 4] .

As used herein, the terms "slowing the progression of HD", "slowing the progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease" refer to slowing the progression of Huntington's disease pathophysiology.

As used herein, the term "slowing the progression of Huntington's disease pathophysiology" refers to reducing the rate of progression of Huntington's disease pathophysiology, for example, as assessed by magnetic resonance imaging (MRI) [for example by neuroimaging measures, such as Lancet Neural .2013, 12(7), 637-649 were evaluated]. For example, it refers to a reduction in the rate (e.g., percentage of volume loss relative to baseline) of brain (e.g., whole brain, caudate, striatum, or cortex) volume loss associated with Huntington's disease (e.g., as assessed by MRI) (e.g., Reduced annualized loss compared to placebo).

The term "motor function" as used herein refers to the motor characteristics of HD, including, for example, one or more selected from oculomotor function, dysarthria, chorea, postural stability, and gait.

As used herein, the term "motor decline" refers to a decline in motor function (eg, compared to normal motor function or a previous medical visit). For example, motor function can be assessed according to standard scales, such as clinical scales (measured according to a UHDRS rating scale, such as the UHDRS Total Motor Score (TMS); e.g., as described in Movement Disorders, 1996, 11, 136-142). decline.

As used herein, the term "slowing the decline of motor function" refers to reducing the rate of decline of motor function (e.g., compared to placebo; e.g., reducing the annual rate of decline of motor function, e.g., relative to placebo; e.g., as UHDRS total motor function scoring evaluation).

As used herein, the term "reduced rate" refers to prolonging the time to onset of onset or increasing the time to severity (eg, compared to placebo; eg, reducing the rate of annual decline, eg, compared to placebo).

As used herein, the term "cognitive decline" refers to a decline in cognitive ability (eg, compared to normal cognitive function or previous medical visits). In one aspect, the term refers to, for example, a decline in one or more cognitive functions selected from the group consisting of attention, processing speed, visuospatial processing, timing, emotional processing, memory, verbal fluency, psychomotor function, and executive function . For example, assessments can be based on standard scales, such as clinical scales [e.g., composed of the Signed Numeric Patterns Test, the Stroop Word Reading Test, the Montreal Cognitive Assessment, or the HD Cognitive Assessment Combo (including the Signed Numeric Patterns Test). , Wired Test B, One Touch Stocking, Rhythm Tapping, Emotion Recognition Test, Hopkins Word Learning Test); for example as described in Movement Disorders, 2014, 29(10), 1281-1288 evaluation of).

The term "slowing cognitive decline" as used herein refers to reducing the rate of cognitive decline (e.g. compared to a placebo; e.g. a reduction in the annual rate of cognitive decline compared to a placebo; e.g. Tru word reading test, Montreal Cognitive Assessment or HD Cognitive Assessment Combination). As used herein, the term "reduced rate" refers to prolonging the time to onset of onset or increasing the time to severity (eg, compared to placebo; eg, reducing the rate of annual decline, eg, compared to placebo).

As used herein, the term "mental decline" refers to a decline in mental function (eg, compared to normal mental function or a previous medical visit). In one aspect, the term refers to, for example, one or more mental functions selected from apathy, anxiety, depression, compulsive behavior, suicidal thoughts, irritability and agitation. For example, mental decline can be assessed according to standard scales (e.g. clinical scales) (e.g. via the Apathy Assessment Scale or the Hospital Anxiety and Depression Scale; e.g. as in Movement Disorders, 2016, 31(10), 1466-1478, Movement Disorders, 2015 , 30(14), 1954-1960 as described).

As used herein, the term "reducing mental decline" refers to reducing the rate of mental decline (e.g., compared to placebo; e.g., a reduction in the annual rate of mental decline compared to placebo; e.g. evaluated). As used herein, the term "reduced rate" refers to prolonging the time to onset of onset or increasing the time to severity (eg, compared to placebo; eg, reducing the rate of annual decline, eg, compared to placebo).

As used herein, the term "functional capacity" refers to the ability to, for example, work, handle finances, manage household chores, perform activities of daily living, and required levels of care. Functional ability includes, for example, one or more selected from ability to work, manage financial affairs, manage household chores, perform activities of daily living, and required level of care.

As used herein, the term "decreased functional capacity" refers to a decrease in functional capacity (eg, compared to normal functional capacity or a previous medical visit). For example, standard scales, such as clinical scales (such as UHDRS Functional Assessment Scale and Independence Scale, and UHDRS Global Functional Capacity Assessment Scale, such as described in Movement Disorders, 1996, 11, 136-142) can be used. Assess for decline in functional capacity.

As used herein, the term "slowing down the decline in functional capacity" refers to reducing the rate of decline in functional capacity (e.g., compared to placebo; e.g., a decrease in the annual rate of decline in functional capacity compared to placebo; e.g., according to the UHDRS Functional Assessment Scale and Independence Scale or UHDRS Comprehensive Functional Capacity Assessment Scale). As used herein, the term "reduced rate" refers to prolonging the time to onset of onset or increasing the time to severity (eg, compared to placebo; eg, reducing the rate of annual decline, eg, compared to placebo).

As used herein, the term "decline" refers to, for example, deterioration of a condition or a specific characteristic of a condition over time (eg, yearly), eg, as assessed according to a standard scale (eg, a clinical scale).

As used herein, the term "Uniform Huntington's Disease Rating Scale" or "UHDRS" refers to a clinical rating scale developed by the Huntington Research Group (eg, as described in Movement Disorders, 1996, 11, 136-142, which is incorporated by reference in its entirety). included in this application), this scale assesses domains of clinical presentation and competence in HD. The UHDRS includes rating scales for motor function, cognitive function, and functional capacity. It yields scores that assess key features of HD (such as motor and cognition) and the overall functional impact of those features.

The term "cHDRS" refers to the Huntington's Disease Composite Uniform Rating Scale, which provides a composite measure of motor, cognitive and global function (eg as described in Neurology, 2017, 89, 2495-2502).

As used herein, 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" are Refers to a clinically defined HD disease stage [eg assessed according to a standard scale (eg clinical scale), eg based on the UHDRS Total Functional Capacity Assessment (TFC) scale, where the TFC score is 11 to 13]. In HD stage 1, usually the patient is clinically diagnosed with HD, lives and works completely normally, and is functionally independent; usually 0 to 8 years after the onset of Huntington's disease.

As used herein, the terms "HD stage 2", "HD stage II", "Huntington's disease stage 2", "Huntington's disease stage I", "Huntington's disease stage 2" or "Huntington's disease stage II" are Refers to a clinically defined HD disease stage [eg assessed according to a standard scale (eg clinical scale), eg based on the UHDRS Total Functional Capacity Assessment (TFC) scale, where the TFC score is 7 to 10]. In HD stage 2, usually, the patient is still able to function normally but with reduced ability to perform daily activities in most cases, albeit with some difficulty, usually with minimal assistance; usually 3 years after the onset of Huntington's disease to 13 years.

As used herein, 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" are Refers to a clinically defined HD disease stage [eg assessed according to a standard scale (eg clinical scale), eg based on the UHDRS Total Functional Capacity Assessment (TFC) scale, where the TFC score is 4 to 6]. In HD stage 3, patients are often no longer able to work or manage household chores and need a lot of help with day-to-day finances, family responsibilities, and activities of daily living; usually 5 to 16 years after the onset of Huntington's disease.

As used herein, 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" are Refers to a clinically defined HD disease stage [eg assessed according to a standard scale (eg clinical scale), eg based on the UHDRS Total Functional Capacity Assessment (TFC) scale, where the TFC score is 1 to 3]. In HD stage 4, the person is usually unable to live independently but is able to live at home with the help of family or professionals, but needs a lot of help with finances, housework, and most activities of daily living; usually after the onset of Huntington's disease9 to 21 years.

As used herein, 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" are Refers to a clinically determined HD disease stage [eg assessed according to a standard scale (eg clinical scale), eg based on the UHDRS Total Functional Capacity Assessment (TFC) scale, where the TFC score is 0]. In HD stage 5, the patient typically requires the full support of a professional nursing staff for daily activities; usually 11 to 26 years after the onset of Huntington's disease.

As used herein, the terms "early HD", "early Huntington's disease", "early HD" or "early Huntington's disease" refer to the disease stage of HD in which the patient is largely functional and can continue to work independently and Living with one or more of the following symptoms: mild involuntary movements, mild loss of coordination, and difficulty thinking about complex problems. On the other hand, the terms "early HD", "early Huntington's disease", "early HD" or "early Huntington's disease" refer to "HD stage 2", as defined herein.

As used herein, the terms "moderate HD", "moderate Huntington's disease", "intermediate stage HD", "intermediate stage Huntington's disease", "intermediate HD", "intermediate Huntington's disease", "intermediate HD" or "Intermediate Huntington's disease" refers to the disease stage of HD in which patients may not be able to work, manage their own finances, or perform their own household chores, but are able to eat, dress, and maintain personal hygiene with assistance. Often, at this stage, for example, chorea may be prominent, as well as problems with swallowing, balance, falling, weight loss, and problem-solving. On the other hand, as defined herein, the terms "moderate HD", "moderate Huntington's disease", "intermediate stage HD", "intermediate stage Huntington's disease", "intermediate HD", "intermediate Huntington's disease", "Intermediate HD" or "intermediate Huntington's disease" means "HD stage 3".

As used herein, the terms "advanced HD", "advanced Huntington's disease", "late HD", "advanced Huntington's disease", "advanced HD" or "advanced Huntington's disease", "end HD" or "Huntington's disease "End stage" refers to the disease stage of HD in which the patient needs assistance with all activities of daily living. Often, at this stage, for example, chorea may be severe, but more often it is replaced by rigidity, dystonia, and bradykinesia. In another aspect, the terms "advanced HD", "advanced Huntington's disease", "late HD", "advanced Huntington's disease", "end HD" or "end-stage Huntington's disease", "end HD", as defined herein Or "end-stage Huntington's disease" means "HD stage 4" or "HD stage 5".

As used herein, the term "juvenile HD" or "juvenile Huntington's disease" refers to a clinically established diagnosis of HD {eg based on: confirmed family history or positive genetic testing (i.e. confirmed CAG repeat expansion 2:36 (SEQ ID NO :22)); and age of onset of symptoms <21 years old}.

As used herein, the term "juvenile HD" or "juvenile Huntington's disease" means affected by HD {eg based on: confirmed family history or positive genetic testing (i.e. confirmed CAG repeat expansion 2:36 (SEQ ID NO:22) )}; and the age of symptom onset <21 years old.

As used herein, the term "children with HD" or "children with Huntington's disease" refers to patients affected by HD {e.g. based on: confirmed family history or positive genetic testing (i.e. confirmed CAG repeat expansion 2:36 (SEQ ID NO: 22)) and clinical diagnosis} and age <18 years.

The term "HD patient", "Huntington's disease patient", "patient with Huntington's disease" or "patient with HD" refers to a HD patient as defined herein.

As used herein, the terms "treatment" or "therapy" refer to obtaining a beneficial or desired result, eg, a clinical result. Beneficial or desired outcomes may include, but are not limited to, stabilization or improved HD stage progression (eg, compared to placebo). One aspect of treatment is, for example, that the treatment should have minimal adverse effects on the patient, eg, the agents used should be highly safe, eg, not produce adverse side effects. On the other hand, the term "method of treatment" as used herein means "method for treatment".

As used herein, the term "intermittent dosing regimen" or "intermittent dosing schedule" refers to a dosing regimen that includes administration of Compound 1 followed by a period of rest. For example, Compound 1 is administered according to an intermittent dosing regimen of at least two cycles, each cycle comprising (a) a dosing period followed by (b) a rest period.

The term "rest period" as used herein specifically refers to a period of time when the patient is not administered Compound 1 (ie, a period of time during which the treatment with Compound 1 is stopped). For example, if Compound 1 is administered daily, it would be a rest period if the daily administration is discontinued for a period of time, eg, a few days, or the plasma concentration of Compound 1 is maintained below therapeutic levels for a period of time, eg, a few days. The dosing period and/or the dose of Compound 1 may be the same or different between cycles. The total duration of treatment (ie, number of treatment cycles) may also vary from patient to patient, eg, based on the specific patient being treated (eg, a stage I HD patient).

In another aspect, the intermittent dosing regimen comprises at least two cycles, each cycle comprising (a) a dosing period of administering a therapeutically effective amount of Compound 1 to said patient, followed by (b) a rest period. As used herein, the term "intermittent dosing regimen" or "intermittent dosing schedule" refers to the dosing regimen of Compound 1 alone (i.e., monotherapy) or the dosing regimen of Compound 1 in combination with at least one other active ingredient (i.e., combination therapy). treat). On the other hand, the term "intermittent dosing regimen" or "intermittent dosing schedule" refers to repeated treatment/stopping treatment, wherein Compound 1 is administered at regular intervals in a periodic manner, for example once a day, every 2 days, every 3 days, Once every 4 days, once a week, or twice a week.

In the context of administering a drug, the term "once a day" or "once a day" or "QD" herein refers to the administration of a dose of drug once a day, wherein the dose is administered, for example, on the same day of the week.

In one aspect, the term "administering" or "administering Compound 1 once a day" as used herein refers to administering a tablet containing 1 mg to 100 mg of Compound 1 once a day.

In another aspect, a tablet containing 1 mg to 200 mg of Compound 1 is administered once a day.

On the other hand, the content of Compound 1 in the tablet administered once a day is 1 mg to 100 mg.

On the other hand, the content of Compound 1 in the tablet administered once a day 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 , 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg and 200mg.

On the other hand, the content of Compound 1 in the tablet administered once a day 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 , 100mg, 110mg, 120mg, 135mg and 140mg.

On the other hand, the content of Compound 1 in the tablet administered once a day 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 , 110mg, 120mg, 135mg and 140mg.

In another aspect, the once-daily tablet contains Compound 1 in an amount 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.

In another aspect, the once-a-day tablet contains Compound 1 in an amount selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 50 mg.

In another aspect, the once-daily tablet contains Compound 1 in an amount 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.

In another aspect, the once-a-day tablet contains Compound 1 in an amount selected from 1 mg, 5 mg or 50 mg.

In another aspect, the once-a-day tablet contains Compound 1 in an amount selected from 5 mg or 50 mg.

In another aspect, the once-a-day tablet contains Compound 1 in an amount selected from 5 mg, 10 mg, 20 mg and 30 mg.

In another aspect, the once-a-day tablet contains Compound 1 in an amount selected from 5 mg, 10 mg and 20 mg.

In the context of administering Compound 1, the term "once a week" or "once a week" or "QW" herein refers to administering a dose of Compound 1 once a week, wherein said dose is administered, for example, on the same day every week.

In one aspect, the term "administering" or "administering Compound 1 once a week" as used herein refers to administering 25 mg to 100 mg of Compound 1 once a week, administering 25 mg to 200 mg of Compound 1 once a week, and administering 50 mg once a week Compound 1 to 200 mg.

In another aspect, Compound 1 was administered at doses of 35 mg once a week, 70 mg once a week and 140 mg once a week.

In the context of administering Compound 1, the term "twice a week" or "twice a week" or "BIW" herein refers to the administration of a dose of Compound 1 twice a week, wherein each dose is administered on different days of the week at 48 to Administered at regular intervals of 72 hours.

In one aspect, the term "administering" or "twice-weekly administration of Compound 1" as used herein refers to twice-weekly administration of 10 mg to 100 mg of Compound 1, twice-weekly administration of 10 mg to 200 mg of Compound 1, and twice-weekly administration of 25 mg Compound 1 to 100 mg.

In another aspect, Compound 1 is administered at a dose of 10 mg to 20 mg twice a week, such as about 15 mg twice a week, 30 mg to 40 mg twice a week, such as 35 mg twice a week, and 50 mg to 90 mg twice a week, such as 70mg twice a week.

The term "about" in relation to a value X means, for example, X ± 15%, including all values within that range.

As used herein, the term "disease-modifying therapy" or "disease-modifying treatment" refers to a drug (ie, a disease-modifying drug) that alleviates or alters the course of a condition or disorder or disease (eg, HD as defined herein).

The term/term "subject" herein refers to a mammalian organism, preferably a human being (male or female).

The term "patient" as used herein refers to a subject with a disease who will benefit from treatment.

The term "subject in need" as used herein means that said subject (patient) would benefit biologically, medically or in quality of life from said treatment if receiving said treatment.

As used herein, the term "therapeutically effective amount" or "effective dose" of Compound 1 refers to the dose of Compound 1 that will elicit a biological or medical response in a subject. In another embodiment, the term refers to a dose of Compound 1 that, when administered to a subject, is at least in part effective to ameliorate a condition, disorder or disease.

The term "one or more" means one or more than one (eg, 2, 3, 4, 5, etc.).

2. Compound

The active ingredient of the tablet composition disclosed herein is 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 (Compound 1) or a pharmaceutically acceptable salt thereof. Compound 1 and a suitable method for its preparation are disclosed in WO2020/005873 (compound 163 in that publication).

In one aspect, the content of Compound 1 in the tablet is selected from 5% to 30% by weight, 5% to 25% by weight, 10% to 20% by weight and 10% by weight based on the total weight of the tablet.

In one aspect, the content of Compound 1 in the tablet is 1 mg to 200 mg.

On the other hand, the content of Compound 1 in the tablet is 1 mg to 100 mg.

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

On the other hand, the content of compound 1 in the tablet is selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg , 120mg, 135mg and 140mg.

On the other hand, the content of compound 1 in the tablet is selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg , 135mg and 140mg.

In another aspect, the content 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.

In another aspect, the content of Compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 50 mg.

In another aspect, the content 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.

In another aspect, the content of Compound 1 in the tablet is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 50 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 1 mg, 5 mg or 50 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 5 mg or 50 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 5 mg, 10 mg, 20 mg and 30 mg.

In another aspect, the content of Compound 1 in the tablet is selected from 5 mg, 10 mg and 20 mg.

Tablets of Compound 1 can be prepared by direct compression, by mixing Compound 1 with excipients and compressing them to form tablets. Tablets of Compound 1 can also be prepared by other methods, including wet granulation or dry granulation. When granulation is used, Compound 1 may be the intergranular and/or extragranular component of the tablet. In one aspect of the invention, Compound 1 is the 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 mixture for the manufacture of tablets. In one aspect of the present invention, by comprising mixing Compound 1 with at least one intragranular excipient and wet granulating the mixture to form an intragranular mixture, mixing the intragranular mixture with at least one extragranular excipient and compressing Tablets are prepared by forming the resulting mixture into tablets.

3. Excipients

In one aspect, the tablets provided herein comprise excipients selected from diluents, binders, surfactants, disintegrants, glidants and lubricants. In the tablet aspects provided herein, some excipients are only intragranular or extragranular excipients, while others are both intragranular and extragranular excipients.

a. Thinner

Diluents are excipients used to dilute formulation ingredients such as active ingredients, adjust them to an amount suitable for the formulation, and in some cases, serve to impart stability or improve 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, trehalose. Microcrystalline cellulose can also be used as a diluent in tablet formulations, and it is included in the tablets of the present invention as an intragranular excipient. However, the term "diluent" as used herein refers to diluents other than microcrystalline cellulose.

In one aspect, the amount of microcrystalline cellulose contained in the tablet of the invention as an intragranular excipient is selected from the group consisting of about 15% to about 25% by weight, and about 15% to about 20% by weight, based on the total weight of the tablet. . On the other hand, the content of microcrystalline cellulose contained in the tablet of the present invention as an intragranular excipient is about 20% by weight based on the total weight of the tablet. In one aspect, the diluent is included as an intragranular excipient in a ratio of microcrystalline cellulose to diluent selected from about 1:1 to about 1:4, and about 1:1 to about 1:2. On the other hand, the content of the diluent contained as the intragranular excipient is about 1:2 ratio of microcrystalline cellulose and diluent. In one aspect, the diluent is included as an intragranular excipient in an amount selected from about 15% to about 40% by weight, and about 20% to about 40% by weight, based on the total weight of the tablet. On the other hand, the diluent is included as an intragranular excipient in an amount of about 40% of the total weight of the tablet. In one aspect, when the diluent is included as an extragranular excipient, it is selected from about 5% to about 25% by weight, and about 10% to about 25% by weight of the total tablet weight. On the other hand, when the diluent is included as an extragranular excipient, it comprises about 20% by weight of the total tablet weight.

In one embodiment, the diluent is lactose, preferably lactose monohydrate.

b.Adhesive

Binders are classified as excipients which impart stickiness to maintain quality after tablet formation. The content of the binder in the tablet provided herein depends on, for example, the type of binder (properties such as molecular weight, solubility, and viscosity), the type and content of other excipients, the type and content of the complex, and the dosage form of its formulation steps ( Granulation method and tabletting method) vary.

Examples of binders that can be used include hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, corn starch, pea starch , Pregelatinized Starch, Gum Arabic, Gum Tragacanth, Modified Gum, Gelatin and Povidone.

In one aspect, povidone is included in the tablet of the present invention as an intragranular excipient, and its content is 1% to about 5% by weight, or 1.5% to about 4% by weight, or From about 2% to about 3% by weight, or about 2% by weight.

c. Disintegrant

Disintegrants are excipients whose role is to cause tablet disintegration by absorbing water, swelling and thereby facilitating the release of the active ingredient after administration. In one aspect of the present tablet, a disintegrant is included as both an intragranular and an extragranular excipient. In one aspect, the disintegrant is present in an amount selected from about 1% to about 5%, about 1% to about 3%, and about 1.5% to about 2.5% (by weight). On the other hand, the content of the disintegrant is about 2.5% by weight of the total weight of the tablet in each of the intragranular part and the extragranular part of the tablet.

Examples of suitable disintegrants include sodium starch glycolate, crospovidone, cross-linked alginic acid, cross-linked starch, cross-linked sodium alginate, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose Sodium cellulose, glycerin fatty acid ester, low-substituted sodium carboxymethyl starch and partially pregelatinized starch. In one embodiment, the disintegrant is sodium carboxymethylcellulose.

d.Surfactant

Surfactants are excipients used to improve the dissolution of active agents. Surfactants may be included as intragranular and/or extragranular excipients. In one embodiment, the surfactant is included as an intragranular excipient, while in another embodiment it is included as an extragranular excipient.

Non-limiting examples of surfactants that can be used include quaternary ammonium compounds (such as dioctyl sodium sulfosuccinate), polyoxyethylene alkylphenyl ethers (such as nonoxynol 9, nonoxynol 10, and octyl Phenol ether9), poloxamers (polyoxyethylene and polyoxypropylene block copolymers, e.g. Poloxamer 407), polyoxyethylene fatty acid glycerides and oils (e.g. polyoxyethylene (8), caprylic acid/ Capric monoglycerides and diglycerides, polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil), polyvinyl alkyl ethers (such as polyoxyethylene (20) cetyl-octadecyl alkyl ethers), polyoxyethylene fatty acid esters (such as polyoxyethylene (40) stearate), polyoxyethylene sorbitan esters (such as polysorbate 20 and polysorbate 80 (such as Tween 80)), propylene glycol fatty acid esters (e.g. propylene glycol laurate), sodium lauryl sulfate, fatty acids and their salts (e.g. oleic acid, sodium oleate and triethanolamine oleate), glycerin fatty acid esters (e.g. sorbitan lauryl esters, sorbitan monooleate, sorbitan monopalmitate, and sorbitan monostearate), tyloxapol, and mixtures thereof.

In one aspect, the surfactant is included in the tablet in an amount suitably selected from about 0.5% to about 2%, and about 0.5% to about 1.5%. On the other hand, the amount of surfactant contained in the tablet is preferably about 1%.

The surfactant contained in the present tablet is a poloxamer, preferably poloxamer 407.

e. Lubricant

A lubricant is an excipient that is used to reduce friction between the equipment and the granulated mixture during compression to form a tablet. Examples of suitable lubricants include glyceryl behenate, glycerylbehaptate; sodium stearyl fumarate, stearic acid and salts thereof (including magnesium stearate, calcium stearate), alone or in combination. and sodium stearate); hydrogenated vegetable oil; colloidal silicon dioxide; 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. Magnesium stearate is preferred when lubricants are used in the tablets of the present invention.

In one aspect, lubricants are included as extragranular excipients by weight based on the total weight of the tablet. In another aspect, the lubricant is included as an extragranular excipient in an amount selected from 0.5% to about 3% by weight, and from about 1% to about 2% by weight, based on the total weight of the tablet. On the other hand, the lubricant is included as an extragranular excipient in an amount of about 1.5% by weight based on the total weight of the tablet. The lubricant is preferably magnesium stearate.

f. Glidant

Glidants are excipients that act as antiadherents. Examples of glidants include colloidal silicon dioxide, sodium sulfoaluminate hydrate, and talc. In one aspect of the present tablet, a glidant is included as an extragranular excipient. When present, glidants are present in an amount selected from about 0.25% to about 2% by weight, and about 0.25% to about 1% by weight, based on the total weight of the tablet. When present, glidants comprise about 0.5% by weight of the total tablet weight.

g. Other excipients

The tablets provided herein may contain various excipients in addition to the above-mentioned excipients. Examples of other excipients include, but are not limited to, solubility enhancers, stabilizers, pH adjusters, coating agents, and pigments.

4. Coating

Tablets of the invention are optionally provided with a film coating suitable for immediate release tablets, for example a film coating comprising polyvinyl alcohol and hydroxypropylmethylcellulose.

5. Tablet preparation method

In one aspect, the invention is a method of making a tablet of the invention using wet granulation. This can suitably be done in three stages according to the following steps:

Stage 1 (intragranular step):

(a) dissolving povidone in water,

(b) Sieve the remaining granule components, such as #30 mesh sieve,

(c) mixing the sieved ingredients to form granules,

(d) wet the granules with povidone solution and mix until the best granules are obtained,

(e) drying the optimal granules, preferably until a moisture content of about 2% is reached,

(f) Pass the dried granules through a sieve of a specific size, eg #20 mesh.

Stage 2 (extragranular stage)

(a) Sieve all extra-granular excipients except lubricant (e.g. magnesium stearate), e.g. #20 mesh,

(b) adding sieved extragranular excipients to the first stage milled granules and mixing,

(c) sieve the lubricant, for example using a #30 mesh sieve, and add it to the mixture, and mix further,

Phase 3 (tabletting)

The blend from the last step of stage two above is compressed into tablets using a tablet machine, optionally film-coating each tablet.

6. Tablet Features

Tablets of Compound 1 of the present invention preferably have all of the following characteristics:

- Rapid disintegration when dissolved in 0.01N HCl

- Compound 1 has good bioavailability when administered to a subject

- Tablets have physical integrity such as good friability and strength.

- Compound 1 is stable in the tablet.

7. Use of compound 1

The tablet of Compound 1 provided herein can be used to treat or improve Huntington's disease.

In one aspect, using compound 1 or a pharmaceutically acceptable salt thereof as a disease-modifying therapy to treat or improve Huntington's disease is due to the result of an in-frame stop codon between exons 49 and 50 in the HTT mRNA transcript; wherein, The resulting reduction in mRNA and reduction in wild-type and mutant HTT proteins has one or more of the following effects:

(i) slow down the decline rate of motor function loss associated with Huntington's disease, wherein the slowdown of motor function decline rate associated with Huntington's disease after treatment with Compound 1 is indicated by the reduction of mRNA and the reduction of wild-type and mutant HTT proteins or compared to placebo; where motor function is selected from oculomotor function, dysarthria, dystonia, chorea, postural stability, and gait; and, as assessed by use of standard clinical scales, such as the UHDRS Motor Assessment Scale tables (eg as described in Movement Disorders, 1996, 11, 136-142);

(ii) slow down the cognitive decline rate associated with Huntington's disease, wherein the cognitive decline rate associated with Huntington's disease is slowed down by the reduction of mRNA and the reduction of wild-type and mutant HTT proteins after treatment with compound 1 or compared with placebo where cognitive function is selected from attention, processing speed, visuospatial processing, timing, emotional processing, memory, verbal fluency, psychomotor function, and executive function; and, as assessed using standard clinical scales, Examples include the Symbolic Numeral Patterns Test, the Struw Word Reading Test, the Montreal Cognitive Assessment, or the HD Cognitive Assessment Combination [(includes the Symbolic Numeric Patterns Test, Wired Test B, One Touch Stockings, Rhythmic Tapping , Emotion Recognition Test, Hopkins Word Learning Test); such as described in Movement Disorders, 2014, 29(10), 1281-1288];

(iii) slowing down the mental decline rate associated with Huntington's disease, wherein the slowing down of the mental decline rate associated with Huntington's disease after treatment with compound 1 is through the reduction of mRNA and the reduction of wild-type and mutant HTT proteins or compared with placebo where mental decline is selected from apathy, anxiety, depression, compulsive behavior, suicidal ideation, irritability, and agitation; and, assessed using standard clinical scales, such as the Apathy Rating Scale or the Hospital Anxiety and Depression Scale; e.g. MovementDisorders, As described in 2016, 31(10), 1466-1478, Movement Disorders, 2015, 30(14), 1954-1960;

(iv) slow down the rate of functional capacity decline associated with Huntington's disease, wherein the rate of functional capacity decline associated with Huntington's disease is slowed down by the reduction of mRNA and the reduction of wild-type and mutant HTT proteins after treatment with Compound 1 or compared with placebo where functional ability is selected from work ability, ability to manage financial affairs, ability to manage household chores, ability to perform activities of daily living, and level of care required; and, assessed by using standard clinical scales, such as UHDRS comprehensive Functional Capacity Assessment Scale, Functional Assessment Scale, and Independence Scale Assessment (eg, as described in Movement Disorders, 1996, 11, 136-142).

(v) slowing the progression of Huntington's disease pathophysiology, wherein the progression of Huntington's disease pathophysiology associated with Huntington's disease is slowed after treatment with Compound 1 [e.g. brain (e.g. whole brain, caudate nucleus, striatum or cortex ) rate of volume loss (e.g., percent reduction in volume from baseline)] by reduction in mRNA and reduction in wild-type and mutant HTT protein or by comparison with placebo, and measured using standard techniques (e.g., MRI (e.g., by neuroimaging) )) evaluation (see, eg Lancet Neural. 2013, 12(7), 637-649);

(vi) slowing down the onset of Huntington's disease or the onset of symptoms related to Huntington's disease, wherein the slowing down of the onset of Huntington's disease or the slowing down of the onset of Huntington's disease-related symptoms after treatment with Compound 1 is achieved by the reduction of mRNA and the wild-type and mutant HTT protein may be demonstrated by comparison with placebo and assessed using standard clinical scales such as the Huntington's Disease Health-Related Quality of Life Questionnaire (HDQoL) (e.g. Movement Disorders, 2018, 33(5), 742-749 as described in ); or,

(vii) reducing the decline in quality of life associated with Huntington's disease, wherein the onset of Huntington's disease or the onset of symptoms associated with Huntington's disease is slowed after treatment with compound 1 through the reduction of mRNA and the reduction of wild-type and mutant HTT proteins or through the combination with Placebo comparisons are indicated and assessed using standard clinical scales such as the Huntington's Disease Health-related Quality of Life Questionnaire (HDQoL) (eg as described in Movement Disorders, 2018, 33(5), 742-749).

On the other hand, using Compound 1 or a pharmaceutically acceptable salt thereof to treat or improve Huntington's disease has one or more of the following effects: (i) favorable therapeutic properties, such as favorable safety properties or metabolic properties; or, ( ii) Favorable off-target effect profile, eg favorable psychiatric adverse event profile, favorable toxicity (eg genotoxicity) or cardiovascular adverse event (eg blood pressure, heart rate, ECG parameters) profile.

In one aspect, a tablet of the present invention containing a therapeutically effective amount of Compound 1 is orally administered to a patient in need thereof.

In another aspect, the tablet contains a therapeutically effective amount of Compound 1 from 1 mg to 200 mg.

In another aspect, the tablet contains a therapeutically effective amount of Compound 1 from 1 mg to 100 mg.

In another aspect, the tablet contains an , 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 in a therapeutically effective amount.

In another aspect, the tablet contains an , 135 mg and 140 mg therapeutically effective amounts.

On the other hand, the tablet contains an and a therapeutically effective amount of 140 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from the group consisting of 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.

In another aspect, the tablet contains a therapeutically effective amount selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 50 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from the group consisting of 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.

In another aspect, the tablet contains a therapeutically effective amount selected from 1 mg, 5 mg or 50 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from 5 mg or 50 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from 5 mg, 10 mg, 20 mg and 30 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from 5 mg, 10 mg and 20 mg.

In one aspect, the tablet of the present invention containing a therapeutically effective amount of Compound 1 is orally administered to a patient in need once a day.

In another aspect, the tablet contains a therapeutically effective amount of 1 mg to 200 mg of Compound 1 administered once a day.

In another aspect, the tablet contains a therapeutically effective amount of 1 mg to 100 mg of Compound 1 administered once a day.

In another aspect, the tablet contains an , 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg and 200mg in a therapeutically effective amount administered daily 1 time.

In another aspect, the tablet contains an , 135 mg and 140 mg therapeutically effective doses, administered once a day.

On the other hand, the tablet contains an and a therapeutically effective dose of 140 mg, administered once a day.

In another aspect, the tablet contains a therapeutically effective amount 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 for once-daily administration.

In another aspect, the tablet contains a therapeutically effective amount selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg and 50 mg, administered once a day.

In another aspect, the tablet contains a therapeutically effective amount 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 for once-daily administration.

In another aspect, the tablet contains a therapeutically effective amount selected from 1 mg, 5 mg or 50 mg, administered once a day.

In another aspect, the tablet contains a therapeutically effective amount selected from 5 mg or 50 mg administered once a day.

In another aspect, the tablet contains a therapeutically effective amount selected from 5 mg, 10 mg, 20 mg and 30 mg, administered once a day.

In another aspect, the tablet contains a therapeutically effective amount selected from 5 mg, 10 mg and 20 mg, administered once a day.

In another aspect, the tablet contains 1 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains Compound 1 in a therapeutically effective amount of 5 mg.

In another aspect, the tablet contains 10 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 15 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 20 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 25 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 30 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 35 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains Compound 1 in a therapeutically effective amount of 40 mg.

In another aspect, the tablet contains 45 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 50 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 55 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 60 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 65 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 70 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 75 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 80 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 85 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 90 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 95 mg of Compound 1 in a therapeutically effective amount.

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

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

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

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

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

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

In another aspect, the tablet contains 130 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 135 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 140 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 145 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 150 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 155 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 160 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 165 mg of Compound 1 in a therapeutically effective amount.

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

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

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

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

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

In another aspect, the tablet contains 195 mg of Compound 1 in a therapeutically effective amount.

In another aspect, the tablet contains 200 mg of Compound 1 in a therapeutically effective amount.

In another aspect, said tablet containing a therapeutically effective amount of Compound 1 is administered once a day.

In another aspect, said tablet containing a therapeutically effective amount of Compound 1 is administered twice a day.

In another aspect, said tablet containing a therapeutically effective amount of Compound 1 is administered 3 times a day.

In another aspect, said tablet containing a therapeutically effective amount of Compound 1 is administered once a week.

In another aspect, said tablet containing a therapeutically effective amount of Compound 1 is administered once every two weeks.

In one aspect, the use of a tablet containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof as a disease-modifying therapy in the treatment or improvement of Huntington's disease, which includes two types of Huntington's disease selected from the following Diseases: hereditary Huntington's disease characterized by 36 to 39 expansions of the CAG repeat in the HTT gene on chromosome 4; and hereditary Huntington's disease characterized by >39 expansions of the CAG repeat in the HTT gene on chromosome 4 disease.

In one aspect, a tablet containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is used as a disease-modifying therapy in the treatment or improvement of Huntington's disease, which includes several Huntington's diseases selected from the following Disease: Symptomatic Huntington's disease, Juvenile Huntington's disease, Childhood Huntington's disease, Early Huntington's disease, Intermediate Huntington's disease, Advanced Huntington's disease, Stage I Huntington's disease, Stage II Huntington's disease, Stage III Huntington's disease Huntington's disease, stage IV Huntington's disease, stage V Huntington's disease, and presymptomatic Huntington's disease.

In one aspect, tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof are administered on an intermittent dosing regimen.

In another aspect, a tablet containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered once or twice a week.

In another aspect, a tablet containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

In another aspect, a tablet containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is provided as a pharmaceutical composition.

In another aspect, a tablet containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is provided as a pharmaceutical combination.

In another aspect, a tablet containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered following gene therapy or treatment with an antisense compound.

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

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

In another aspect, a method of treatment for slowing cognitive decline associated with Huntington's disease in a subject in need thereof, comprising administering to said subject one or more tablets containing a therapeutically effective amount of Compound 1 .

In another aspect, a method of treatment for slowing mental decline associated with Huntington's disease in a subject in need thereof, comprising administering to said subject one or more tablets comprising a therapeutically effective amount of Compound 1 .

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

In another aspect, a treatment for slowing the progression of Huntington's disease pathophysiology associated with Huntington's disease [e.g. rate of brain (e.g. whole brain, caudate nucleus, striatum or cortex) volume loss in a subject in need thereof (eg, percent reduction in volume relative to baseline) decrease (eg, assessed by MRI)], comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 .

In another aspect, a method of treatment for slowing the decline of motor function associated with Huntington's disease in a subject in need thereof, comprising administering to said subject one or more tablets containing a therapeutically effective amount of Compound 1 ; wherein said motor function is selected from oculomotor function, dysarthria, dystonia, chorea, postural stability and gait.

In another aspect, a method of treatment for slowing cognitive decline associated with Huntington's disease in a subject in need thereof, comprising administering to said subject one or more tablets containing a therapeutically effective amount of Compound 1 ; wherein the cognitive function is selected from the group consisting of attention, processing speed, visuospatial processing, timing, emotional processing, memory, verbal fluency, psychomotor function, and executive function.

In another aspect, a method of treatment for slowing mental decline associated with Huntington's disease in a subject in need thereof, comprising administering to said subject one or more tablets comprising a therapeutically effective amount of Compound 1; wherein said mental decline is selected from the group consisting of apathy, anxiety, depression, compulsive behaviour, suicidal thoughts, irritability and agitation.

In another aspect, a method of treatment for slowing the decline in functional capacity associated with Huntington's disease in a subject in need thereof, comprising administering to said subject one or more tablets containing a therapeutically effective amount of Compound 1 ; wherein said functional ability is selected from the group consisting of ability to work, ability to handle financial affairs, ability to manage household chores, ability to perform activities of daily living, and required level of care.

In another aspect, treatments that slow down the progression of Huntington's disease pathophysiology associated with Huntington's disease [e.g., rate of brain (eg, whole brain, caudate nucleus, striatum, or cortex) volume loss in subjects in need thereof (eg, percent reduction in volume relative to baseline) decrease (eg, assessed by MRI)], comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 .

In one aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, Each tablet contains 1 to 200 mg of compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 to 100 mg of compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising 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 compound 1 in a therapeutically effective amount.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , applied once a day.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , applied 2 times a day.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , applied 3 times a day.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , applied once a week.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , applied once every 2 weeks.

In one aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, Wherein said Huntington's disease includes two Huntington's diseases selected from the group consisting of: hereditary Huntington's disease characterized by 36 to 39 expansions of the CAG repeat sequence in the HTT gene on chromosome 4; and hereditary Huntington's disease characterized by Hereditary Huntington's disease with >39 CAG repeat expansions in the HTT gene.

In one aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, Wherein said Huntington's disease includes several Huntington's diseases selected from the group consisting of: symptomatic Huntington's disease, juvenile Huntington's disease, childhood Huntington's disease, early Huntington's disease, intermediate Huntington's disease, advanced Huntington's disease, 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, and presymptomatic Huntington's disease.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more compounds containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable compound thereof according to an intermittent dosing regimen. salt tablets.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more compounds containing a therapeutically effective amount once a day, once a week or twice a week 1 or a tablet of a pharmaceutically acceptable salt thereof.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising orally administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof agent.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more compounds containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable compound thereof in the form of a pharmaceutical composition to the subject. salt tablets.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more compounds containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable compound thereof in the form of a pharmaceutical combination to the subject. Tablets with salt.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more compounds containing a therapeutically effective amount of Compound 1 or Tablets of its pharmaceutically acceptable salts.

In another aspect, a method for treating or improving Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , to create an in-frame stop codon between exons 49 and 50 in the HTT mRNA.

In another aspect, a method of slowing the progression of Huntington's disease in a subject in need thereof, comprising administering to the subject one or more tablets containing a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof , to create an in-frame stop codon between exons 49 and 50 in the HTT mRNA.

Example

The following examples include illustrations of various aspects of the invention. These examples should not be construed as limiting the invention.

Example 1

Six experimental batches (1-6) of Compound 1 were prepared as tablets using the direct compression method: the ingredients were first weighed, sieved through a #35 sieve, then low shear blended, and compressed into tablets. However, the flow was insufficient and sticking to the tablet punches was observed during compression. Two batches of placebo tablets (7 and 8) were prepared in the same manner in the absence of compound 1 . The composition of each batch is shown in Table 1 below.

Table 1

Example 2

In order to solve the problem of poor direct compression fluidity and sticking found in each batch in Example 1, dry granulation using roller compaction was introduced to prepare another three batches (9, 10 and 11) of tablets: the components were first weighed , sieved through a #35 sieve, blended with a turbula mixer, and rolled. The ribbons were then crushed and passed through a #20 sieve and blended with the other extragranular ingredients using a turbula mixer and compressed in a tablet machine. Good mixing uniformity is achieved. The composition of all three batches was identical and similar to the six batches above, except that it contained equal weight percentages of lactose monohydrate and microcrystalline cellulose (mcc) (41.5% each). However, different calendering parameters (roller speed, screw speed and pressure) were used for each batch. Batch 9 produced the best rolled strips. Batch 11 stuck to the roll and the ribbon was brittle, while Batch 12 produced discontinuous ribbon.

Dissolution testing was performed on dry granulation batch 9, but due to wetting issues with compound 1, there were particles floating on the surface of the dissolution medium.

Example 3

In order to alleviate the wetting problems observed in Example 2, it was decided to include a surfactant in the formulation. Direct compression batches 13 and 14 were prepared with 5% w/w sodium lauryl sulfate (SLS) and 1% poloxamer 188, respectively, and Compound 1 at a concentration of 50 mg. Compared to Batch 9 tested in Example 2, Batch 13 containing SLS showed even more undissolved particles of Compound 1 floating around with minimal drug release. Batch 14 containing 1% Poloxamer 188 showed better dissolution performance with no particles floating on the surface of the dissolution medium. Thus, the inclusion of poloxamers appeared to reduce the wetting problem of Compound 1 particles. However, accumulation was observed during the dissolution experiments performed at 50 revolutions per minute (rpm), and complete drug release was only observed when the paddle speed was increased to 150 rpm at 75 minutes.

Direct compression batch 17 was also prepared in a similar manner with lower concentrations of microcrystalline cellulose and Poloxamer 407 as surfactants. This batch had the problem of poor processability.

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

Table 2

Example 4

To minimize build-up in the dissolution vessel, wet granulation batches 15 and 16 used lower levels of Avicel PH102 with 0.5% w/w and 2.5% w/w Povidone (PVP) K30 and 1% Polol respectively Sham 407 preparation. Wet granulation is performed using a mortar and pestle. The granule ingredients were passed through a #20 mesh screen and mixed. Dissolve povidone K30 in water to obtain granulation liquid. The premix was then wet granulated with povidone K30 solution using a mortar and pestle to obtain optimal granulation. This wet mass was dried in a tray oven at 60°C until a moisture content of about 2% was reached. The dried granules were passed through a #20 mesh sieve and mixed with the extragranular excipients sieved through a #20 mesh sieve. The unlubricated blend was blended with #35 mesh sieved magnesium stearate to obtain the final blend.

Batch 15 was found to be the best formulation with little to no buildup when dissolving at 50 rpm. Batch 16 containing 2.5% w/w PVP K30 was found to be inferior to batch 15 in terms of dissolution performance, most likely due to the higher content of PVP K30 binder resulting in tighter granules.

Wet granulation batches of 18 were also prepared in the same manner as above with a lower content of Avicel PH102 (10% w/w) to test whether the bulk in dissolution could be further reduced. However, this batch failed to fully release Compound 1 when tested in dissolution.

Wet granulation batch 19 was also prepared in a similar manner as above, but with 30% mcc in both the intragranular and extragranular blends. The lot also had issues with buildup and poor integrity.

Example 5

An additional dry process was prepared using 41% microcrystalline cellulose (mcc) and lactose monohydrate in the intragranular blend without any microcrystalline cellulose (mcc) or lactose monohydrate in the extragranular component. grain batch of 20.

The compositions of batches 15, 16, 18, 19 and 20 are summarized in Table 3 below.

table 3

Example 6

The dissolution properties of batches 9, 14, 15, 16, 17, 18, and 20 were tested in 500ml of 0.01N HCl while stirring with a paddle at 50rpm for 60 minutes, increased to 75rpm for 75 minutes, and 150rpm for 90 minutes, 5 ml were withdrawn at 5, 10, 15, 20, 30, 45, 60, 75 and 90 minutes.

Batches 15, 16 and 17 were also tested for degradation at days 7 and 14 of storage at 80°C, 5% relative humidity and 80°C, 75% relative humidity. At lower humidity, no degradation was observed in any of the samples, and at higher humidity levels, degradation was minimal and comparable for all three batches tested.

Batch 15 was tested for dissolution stability at various paddle speeds (50, 65 and 75 rpm) and accelerated temperature conditions. We found that the faster the paddle speed, the higher the percentage of drug released at each time point, and the initial release was 81%, 88%, and 95% in the first 5 minutes at each paddle speed, respectively. The release rate was even faster when tested in 0.01N HCl at room temperature, 40°C or 65°C with a paddle speed of 75 rpm, where the initial percent release was 95.4, 92.6, and 96.4, respectively.

Based on the above results, Batch 15 (wet granulation) and Batch 20 (dry granulation) were selected for further pharmacokinetic testing.

Example 7

A study was conducted to evaluate Compound 1 exposure following oral (PO) administration of three formulations of Compound 1 in fasted male cynomolgus monkeys as described below. One of the formulations (21 batches) was a suspension of 6% w/w compound 1 in 0.5% w/w hydroxypropylmethylcellulose (HPMC). The other two formulations tested were tablets from wet granulated batch 15 and dry granulated batch 20 prepared as described in Example 4 above.

Cynomolgus monkeys were divided into three groups of four animals each. Cynomolgus monkeys were fed in the afternoon of the day before dosing, and the remaining food was removed at 7 pm. Refeed four hours after dosing. Each cynomolgus monkey received a 30 mg oral dose of Compound 1 via rubber oral feeding tube or via tablet (21 batches of 5 ml of 6 mg/ml Compound 1 suspension, wet granulated batches of 15 or dry granulated batches of 20 tablet/cynomolgus monkey, each tablet 15mg), rinse with 3ml of deionized water after each dose. Blood samples were drawn from each cynomolgus monkey at the following time points: pre-dose (0), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours. Plasma was collected by centrifuging each sample at 3000 xg for 5 minutes at 8°C and frozen on dry ice until assayed. Plasma concentrations were determined by LC-MS/MS. Determine pharmacokinetic parameters.

Individual plasma concentration profiles of Compound 1 following oral administration of 30 mg of an oral suspension of Compound 1 in 0.5% HPMC in water (batch 21 ) to male cynomolgus monkeys (Group 1 ) are provided in FIG. 1 . The four cynomolgus monkeys in the study are labeled "Mky 15-218", "Mky 15-172", "Mky 16-108" and "Mky 170004" in Figure 1 and the other figures below. Mean plasma concentrations at each time point in Group 1 are provided in Figure 2. The results are summarized in Table 4 below:

Table 4

As shown in Table 4, after oral administration of the suspension formulation (21 batches) at 30 mg/animal (group 1), maximum plasma concentrations (average 111 ± 47.6 ng) were observed 6 to 12 hours after administration /mL). The mean half-life after oral administration is 20.7 hours. The mean total exposure of Compound 1 (Group 1) at 30 mg/animal was 2515±788 hours*ng/mL, and the dose-normalized AUClast was 369±138 hours*kg*ng/mL/mg.

The individual plasma concentration profiles obtained from each cynomolgus monkey following oral administration of 30 mg/animal (group 2) of tablet formulation A (15 batches wet granulated) are presented in FIG. 3 . The mean plasma concentration graph for each time point is provided in Figure 4. The results of Group 2 of the study are summarized in Table 5:

table 5

As shown in Table 5, following oral administration of tablet formulation A (15 batches of wet granulation) at 30 mg/animal (group 2), maximum plasma concentrations (average 124 ±58.8ng/mL). The mean half-life after oral administration was 28.0 ± 10.3 hours. The mean total exposure of Compound 1 (Group 2) at 30 mg/animal was 3110±997 hours*ng/mL, and the dose-normalized AUC _last was 455±151 hours*kg*ng/mL/mg.

The individual plasma concentration profiles obtained from each cynomolgus monkey following oral administration of 30 mg/animal (group 3) of tablet formulation B (15 batches of wet granulation) are presented in FIG. 5 . A graph of mean plasma concentrations for each time point is provided in FIG. 6 . The results of the study of Group 4 are summarized in Table 6, where * indicates p<0.05 compared to the AUC _last of the suspension formulation.

Table 6

As can be seen from Table 6, after oral administration of tablet formulation B (20 batches of dry granulation) at 30 mg/animal (group 3), maximum plasma concentrations (average 73.5 ±37.2ng/mL). The mean half-life after oral administration was 26.4±4.20 hours. The mean total exposure of Compound 1 (Group 3) at 30 mg/animal was 1524±562 hours*ng/mL, and the dose-normalized AUC _last was 237±102 hours*kg*ng/mL/mg.

Based on the average dose normalized AUC _last value, the exposure of tablet formulation A (20 batches of wet granulation) is 455 hours*kg*ng/mL/mg, which is the exposure of the suspension formulation (369 hours*kg*ng /mL/mg) of 124±23%. The exposure of tablet formulation B (15 batches of dry granulation) was 237 hours*kg*ng/mL/mg, which is 58±10% of the exposure of the suspension formulation. Therefore, the AUC of solid formulation A was found to be very similar to that of the suspension formulation. However, the AUC of solid formulation B was significantly lower (P<0.05) compared to the value of the suspension formulation. In other words, these studies showed that the bioavailability of Compound 1 was significantly higher in tablets prepared by wet granulation (20 batch formulations) than in suspension formulations or dry granulated tablets (15 batch formulations).

Example 8

Using a wet granulation formulation of 20 batches of tablets as a starting point, additional studies were performed to identify the excipients and concentrations of each excipient that were scalable and easy to process during tableting, which had excellent Physical properties, including rapid dissolution properties. Lactose and cellulose grades were selected that are particularly suitable for the wet granulation process and the total excipient content within the granules was increased. Povidone concentrations were increased from 1% to 2% to 5% in three different batches. The total amount of lactose monohydrate used in the formulation was also increased and the ratio of mcc to lactose monohydrate decreased. Examples of three formulations prepared and tested are provided in Table 7 below. 500 g batches containing 50 g of Compound 1 were prepared according to the following recipe.

Table 7

Tablets prepared by wet granulation with the above composition were coated, but the coating did not affect the disintegration time. Table 8 below shows the results of testing tablet cores prepared from batches 23-25 above, some containing 5 mg (A) of Compound 1 and others containing 50 mg (B) of Compound 1 .

Table 8

Adhesion occurred in 22 batches, and the PVP content was 1%. When the preparation was enlarged to 500g, a large amount of fine powder appeared in the preparation. Tabletting was discontinued for this batch due to these issues.

Batch 23 at 2% PVP was found to be compressible into tablets without sticking problems.

For batch 24, the PVP content was 5%, and the disintegration time of the prepared tablets increased significantly to 17 minutes. The final blend of batch 24 also showed separation between granules and powdered extragranular excipients.

The disintegration time of batch 25 with 3% PVP was between batches 23 and 24, indicating the role of PVP as a binder.

Example 9

Tablets prepared from 23 batches (containing 2% PVP) containing 5 mg and 50 mg of Compound 1, respectively, as described above were tested after storage at 50°C for 2 weeks and at 40°C for 1 month at 75% relative humidity agent stability. Dissolution was carried out in 500ml 0.01N HCl, apparatus II, stirring at 75 rev/min. Tablets showed chemical stability, no increase of related substances was observed. The resulting dissolution profiles are shown in Figure 8 (5 mg tablet) and Figure 9 (50 mg tablet). The dissolution profile showed that Compound 1 was released from each tablet immediately and was comparable to the initial profile even after storage at higher temperature and humidity.

Example 10: Phase I clinical research protocol

A phase 1 dose-escalation study was initiated to evaluate the safety and pharmacokinetics of Compound 1 oral tablet (5 mg and 50 mg) compared to placebo in healthy subjects.

Main research purposes:

(i) To characterize the safety and tolerability of single ascending doses of Compound 1 in healthy subjects; (ii) To characterize the safety and tolerability of Compound 1 administered in healthy subjects for 14 days or up to 21 days (iii) characterize the pharmacokinetics of compound 1 in plasma and cerebrospinal fluid (CSF) after administration for 7 days in healthy subjects; (iv) characterize the effect of food on healthy subjects after administering a single dose of compound 1 Effect of pharmacokinetics (PK) in plasma; and (v) Characterization of the safety and tolerability of Compound 1 when administered in healthy subjects for up to 28 days.

Secondary research purposes:

(i) characterize the pharmacokinetics of a single dose of Compound 1 in healthy subjects; (ii) characterize the pharmacokinetics of Compound 1 administered in healthy subjects for 14 days or up to 21 days; (iii) evaluate QTc and drug concentration effect of compound 1 after repeated ascending doses; (iv) assess the safety and tolerability of compound 1 after 7 days of administration in healthy subjects; (v) characterize healthy subjects administered in fed state Safety and tolerability of a single dose of Compound 1; and (vi) Characterization of the pharmacokinetics of Compound 1 when administered in healthy subjects for up to 28 days.

Purpose of exploratory research:

(i) explore the effect of Compound 1 single administration on the splicing of Huntington (HTT) precursor mRNA in the blood of healthy subjects; The effect of pre-mRNA splicing and HTT protein levels; (iii) explore the effect of compound 1 single administration (feeding) on the splicing of HTT pre-mRNA in the blood of healthy subjects; (iv) explore the effect of compound 1 administration up to 28 Effects of time of day on HTT pre-mRNA splicing and HTT protein levels in blood of healthy subjects.

Research design:

The phase 1 study was conducted in 5 parts: single ascending dose (SAD) (part 1), multiple ascending dose (MAD) (part 2), CSF and blood collection 7 days after compound 1 administration (part 3) , food effects (Part 4), and multiple dosing up to 28 days (Part 5). Parts 1, 2, and 5 were double-blind; parts 3 and 4 were open-label. Note that parts 3, 4 and 5 can be done concurrently.

Research methods:

The study was overseen by a Safety Review Committee (SRC). The purpose of the SRC is to ensure that the treatment does not pose undue risk to the subject. Before escalating from one dose level to the next higher dose level in Part 1 (Single Ascending Dose [SAD]) and Part 2 (Multiple Ascending Dose [MAD]), and before starting Part 3 (CSF) Before , Part 4 (FE) and Part 5, the safety and tolerability of each cohort were assessed by the SRC.

The SRC is composed of the following personnel: the Principal Investigator or representative (a representative is appointed only in the absence of the Principal Investigator); the sponsor's medical supervisor or representative (must be a physician); other internal or external experts may be invited to participate in the review or consult with them.

The various parts of the study do not have to be done in numerical order and can be done concurrently. The SRC meets prior to the start of Part 5 to determine the doses to be used in this part of the study. Based on available SAD and MAD data, select a dose (possibly including loading and maintenance doses) prior to the start of Part 5. The SRC does not plan to hold meetings between the Part 5 cohorts. Part 1 (SAD):

The single ascending dose (SAD) portion of the study was a randomized, double-blind, placebo-controlled study in healthy male and female subjects.

Five dose levels are planned to be tested in 5 cohorts of 8 subjects each (cohorts 1.1 to 1.5). However, the sponsor may choose to evaluate one or more additional cohorts.

According to FDA guidelines on maximum recommended starting dose (MRSD) and EMA guidelines, the initial dose of the first cohort is ≤ human equivalent dose (HED) estimated based on the NOAEL (no observable adverse effect level) of the most sensitive species (male) rats ) of 1/10. The NOAEL for rats is 6 mg/kg. This is the value set by the observed shedding of germ cells in the epididymis and testis of male rats. The calculated HED is 0.97 mg/kg; scaled up to 68 mg for a 70 kg human. Adjusting this dose to 1/10, the dose of the first cohort is 6.8; the actual administered dose is 5 mg.

In cohort 1.1, sentinel dosing was performed in 2 subjects (1 subject received compound 1 and 1 subject received placebo). The remaining subjects in the cohort were dosed at least 24 hours later if no clinically significant safety concerns were observed. The remaining 6 subjects (5 subjects taking compound 1 and 1 subject taking placebo) can be dosed as a group. Cohort 1.1 was the only cohort that performed sentinel administration. In subsequent cohorts, all 8 subjects can be dosed as a cohort.

After each cohort completes dosing, a dose escalation meeting will be held. Dose levels for the next cohort will be based on the PK and safety profile of the previous cohort. Incremental increases in dose were determined from the mean exposure in the cohort in relation to the NOAEL exposure.

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

The dose can be increased by up to 100% if the mean area under the curve (AUC) is ≥ 1/10 of the NOAEL and < 1/5 of the NOAEL. That is, subsequent doses may be up to twice the previous dose.

The dose can be increased by up to 50% if the mean area under the curve (AUC) is ≥ 1/5 of the NOAEL and < 1/2 of the NOAEL. That is, subsequent doses may be up to 1.5 times the previous dose.

The highest dose level was associated with 1/2 the AUC at which the mean exposure did not exceed the NOAEL; no additional escalation was performed. Dose escalation will continue unless dose escalation stop criteria are met.

Eligibility will be assessed during a screening period of up to 28 days. Subjects were hospitalized 1 day before dosing (Day -1). On the morning of Day 1, Compound 1 or placebo was administered orally after an overnight fast of at least 10 hours. Subjects were discharged on Day 8 after completion of all required study procedures and if medically appropriate. After discharge on day 8, a 4-week (± 1 week) safety telephone follow-up was conducted.

Part 2 (MAD):

The Multiple Ascending Dose (MAD) portion of the study was a randomized, double-blind, placebo-controlled study in healthy male and female subjects. It is planned to test five regimens in 5 cohorts of 8 subjects each (cohorts 2.1 to 2.5). In each cohort, 6 subjects received compound 1 and 2 subjects received placebo. Subjects in cohorts 2.1 and 2.2 were dosed for 14 days and subjects in cohorts 2.3 to 2.5 were dosed for up to 21 days.

Once at least 2 cohorts in part 1 have been dosed, safety parameters have been reviewed, their respective SADPK parameters have been calculated, and MAD dosing simulations for the corresponding SAD doses have been performed, part 2 can begin. The selection of specific multiple dose levels depends on available SAD PK data, simulations, and the general safety profile observed in Part 1. After evaluating dose levels on a once-daily basis, pharmacokinetic simulations will be performed to determine fluctuations within the dosing interval. In Cohort 2.3, dosing on Days 1 and 2 will be at a loading dose higher than the selected dose for the remaining days of the planned dosing. Cohorts 2.4 and 2.5 chose similar dosing regimens. Alternate dosing regimens may be considered for all cohorts in Part 2 if data collected and analyzed during the study indicate this is necessary.

Eligibility will be assessed during a screening period of up to 28 days. Subjects were hospitalized 1 day before dosing (Day -1). Compound 1 or placebo was administered orally after an overnight fast of at least 10 hours each morning of the scheduled dosing period (ie, Day 1 to Day 21). Subjects will be discharged 7 days after the last dose (ie, Day 21 or until Day 28) and after completion of all required study procedures and if medically appropriate. Subjects will be re-examined in the outpatient clinic 7 days after discharge (ie, day 28 or until day 35) to collect PK and PD (mRNA and HTT protein) samples. Safety telephone follow-up or outpatient follow-up on day 49 (±7 days).

Part 3 (CSF):

Compound 1 concentrations in plasma and CSF will be assessed in an open-label design in healthy male and female subjects. A single daily dose of Compound 1 was administered to 6 subjects in a cohort for 7 days (cohort 3.1). Dose levels for Part 3 will be determined based on a review of safety, tolerability and PK data from Parts 1 and 2 of the study. While the MAD dose will be further determined in development, this dose and schedule will be used for this portion of the study.

Eligibility will be assessed during a screening period of up to 28 days. Subjects were hospitalized 1 day before dosing (Day -1). Compound 1 was administered orally daily on the morning of Days 1 through 7 after an overnight fast of at least 10 hours. Serial CSF and plasma sampling was performed on day 7 for drug concentration testing. The exact timing of CSF and blood samples will be determined based on the results of Part 1 and Part 2. Subjects were discharged on Day 9 after completion of all required study procedures and if medically appropriate. After discharge on day 9, a 4-week (± 1 week) safety telephone follow-up was conducted.

Part 4 (FE):

The food effect (FE) portion is a parallel, open-label portion of healthy male and female subjects in up to 3 cohorts of 6 subjects each. Up to 3 dose levels of Compound 1 were administered 30 minutes after a high-fat, high-calorie breakfast. Part 4 can be initiated when sufficient Part 1 data is available. Dose levels for this part will be selected based on a review of safety, tolerability and PK data from Parts 1 and 2.

Eligibility will be assessed during a screening period of up to 28 days. Subjects were hospitalized 1 day before dosing (Day -1). On the morning of Day 1, Compound 1 was administered orally after ingestion of a standardized high-fat, high-calorie breakfast. Subjects were discharged on Day 8 after completion of all required study procedures and if medically appropriate. After discharge on day 8, a 4-week (± 1 week) safety telephone follow-up was conducted.

Part 5 (multiple doses up to 28 days [MD28D]):

Part 5 is a randomized, double-blind and placebo-controlled evaluation of multiple doses up to 28 days in healthy male and female subjects. A maximum of 3 cohorts of 8 subjects per cohort are planned. Prior to the start of Part 5, the SRC will meet to select dose (possibly including loading and maintenance doses), dosing regimen (including fed or fasted state), and duration based on data provided by Part 1 and Part 2 completed cohorts (up to 28 days). In each cohort, 6 subjects received compound 1 and 2 subjects received placebo. The total dose on any one day must not exceed the tolerated dose established in Section 1 (SAD).

Eligibility will be assessed during a screening period of up to 28 days. Subjects were hospitalized 1 day before dosing (Day -1). On each day of dosing, Compound 1 or placebo was administered orally in the morning following an evening fast or a standard high-fat meal, according to the regimen selected for a given cohort as determined by the SRC. Subjects will be discharged 7 days after the last dose and after completion of all required study procedures and if medically appropriate. Subjects will be re-examined in the outpatient clinic 7 days after discharge to collect PK and PD (mRNA and HTT protein) samples and conduct safety assessments. Subjects will be monitored using a 24-hour Holter monitoring device on Day 1 and on the day of expected maximum exposure (ie, Day 2 or, if no loading dose is used, Day 29).

Research groups:

Part 1: Up to 48 male and female subjects aged 18 to 65, inclusive.

Part 2: Up to 40 male and female subjects aged 18 to 65, inclusive.

Part 3: 6 male and female subjects aged 50 to 65 (including 50 and 65).

Part 4: Up to 18 male and female subjects aged 18 to 65, inclusive.

Part 5: Up to 24 male and female subjects aged 18 to 65, inclusive.

Inclusion criteria:

All subjects considered for study participation must meet the following criteria:

For Part 1, Part 2, Part 4, and Part 5: healthy male or female subjects aged 18 to 65 years, inclusive, at Screening. For Part 3, healthy male or female subjects aged 50 to 65 years, inclusive, at Screening.

Subjects must understand the nature of the study and must sign and date a written informed consent form prior to any study-related procedure.

At the time of screening, body mass index (BMI) ≥ 18.5kg/m ² and ≤ 30.0kg/m ² , male subjects weigh ≥ 50.0kg, and female subjects weigh ≥ 45.0kg.

Subjects were determined to be healthy by the investigator based on medical evaluation, including medical history, physical examination, laboratory test results, ECG records (eg, QTcF ≤ 450 ms for males, QTcF ≤ 470 ms for females), and vital signs. Values out of range can be repeated once.

Male and female subjects of reproductive potential must be willing to use 2 methods of contraception during the study and for 30 days after the last dose.

Postmenopausal female subjects must have spontaneous amenorrhea (follicle-stimulating hormone (FSH) ≥30mIU/mL at screening) for ≥12 months. Surgically sterilized women were defined as women who had undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation ≥ 6 months before screening.

All female subjects of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1.

Male subjects must agree not to donate sperm during the study and for at least 3 months after the last dose.

Part 3 only: Subject must be willing to undergo a lumbar puncture for CSF sampling.

Part 4 only: Subject must be willing and able to eat the entire high-fat breakfast within the allotted time frame.

Exclusion criteria:

Subjects who meet any of the following criteria will be excluded:

Subjects who participated in any drug or device clinical research within 60 days before screening, or subjects who are expected to participate in any drug or device clinical research during this study.

In the investigator's opinion, previous or current medical conditions (e.g., concomitant diseases, mental illness), medical history, and physical examination results may adversely affect the safety of the subjects or may impair the evaluation of the study results.

General neurological examination was abnormal.

Any clinically significant abnormalities during screening.

Any psychological, emotional problem, any disease, or resulting treatment that may invalidate informed consent or limit the subject's ability to comply with protocol requirements.

Screening results are positive for hepatitis B surface antigen, positive for hepatitis C antibodies, or positive for human immunodeficiency virus (HIV) antibodies.

Donate plasma within 7 days prior to dosing. Donate or lose blood (excluding screening blood draw or menstrual blood volume) 50 mL to 499 mL within 30 days prior to dosing, or more than 499 mL within 56 days prior to dosing.

Excessive alcohol consumption within 6 months prior to screening (regular alcohol consumption ≥ 21 units per week for male subjects and ≥ 14 units per week for female subjects). 1 unit (8g) is equivalent to 1/2 pint (280mL) of beer, 1 measuring glass (25mL) of spirits or a small glass (125mL) of wine.

Subjects were smokers or used other nicotine-containing products. Ex-smokers must have quit smoking >3 months prior to screening.

Positive urine drug screen, cotinine screen, or alcohol breath test at Screening or on Day 1 of each treatment period.

Women who are pregnant or breastfeeding.

Subjects had previously received Compound 1.

Part 3 only: Contraindications to lumbar puncture, such as low platelet count, abnormal prothrombin time international normalized ratio (PT-INR), spinal deformity, or other spinal disorders that preclude lumbar puncture in the investigator's judgment.

Healing period

Part 1: 1 day; Part 2: 14 days (cohorts 2.1 and 2.2) or up to 21 days (cohorts 2.3 to 2.5);

Part 3: 7 days; Part 4: 1 day; Part 5: up to 28 days.

Evaluation Criteria:

Efficacy:

If available, on Day 1 (single dose) PK [Part 1 (SAD), Part 2 (MAD, Day 1), Part 4 (FE), and Part 5 (MD28D, Day 1)] The following PK parameters were assessed in: C _max ; observed maximum plasma concentration, C _max /D; dose-normalized C _max (Part 1 only); T _max ; time to C _max ; AUC _0-24 (0-24 hours AUC _0-72 (area under the concentration-time curve from 0 to 72 hours); AUC _0-tau (area under the concentration-time curve over the dosing interval via ascending linear/decreasing logarithmic trapezoid method, only applicable to part 2); AUC _0-t (area under the concentration-time curve from time zero to time t, where t is the time of the last measured (or measurable) concentration (C _t ), calculated by Linear up/log down trapezoidal calculation (parts 1 and 4 only); AUC _0-t /D (dose-normalized AUC from time zero to last quantifiable concentration, part 1 only); AUC _{0 -inf} ; (area under the concentration-time curve from time zero to infinity, AUC _0-inf = AUC _0-t + C _t /λ _z , where λ _z is the terminal elimination rate constant, by ascending linear/decreasing log Trapezoidal calculation (parts 1 and 4 only); AUC _0-inf /D (dose normalized AUC from zero to infinity, part 1 only); _λz (apparent terminal elimination rate constant by log concentration Linear regression calculation with the terminal linear part of the time curve, parts 1 and 4 only); t _1/2 (apparent terminal half-life, calculated as ln(2)/ _λz , parts 1 and 4 only ); CL/F (total clearance, calculated as dose/AUC _0-inf , parts 1 and 4 only); and V _z /F (apparent volume of distribution, calculated as dose/(λ _z *AUC _{0- inf} calculation)).

On Day 14, Day 21, or Day 28 (Multiple Dose) PK when feasible, assess the following PK parameters [Part 2 (MAD) Cohorts 2.1 and 2.2 (Day 14), Cohorts 2.3 to 2.5 (Day 21) and Part 5 (MAD) Cohorts 5.1 to 5.3 (Day 28)]: C _max (maximum observed plasma concentration during dosing interval); T _max (time to reach C _max during dosing interval); C _min (minimum concentration over dosing interval); C _avg (average concentration over dosing interval); AUC _0-tau (area under the concentration-time curve over dosing interval, calculated by ascending linear/decreasing logarithmic trapezoidal method) ; AUC _0-tau /D (dose normalized AUC _0-tau ); λ _z (apparent terminal elimination rate constant, calculated by linear regression of the terminal linear portion of the logarithmic concentration versus time curve); t _1/2 (apparent Terminal half-life, calculated as ln(2)/λ _z ); CL/F (total clearance, calculated as dose/AUC _0-tau ); V _z /F (apparent volume of distribution, calculated as dose/(λ _z *AUC _0-tau calculated)); AUCR _auc (cumulative ratio, based on AUC _0-tau : last dose AUC _0-tau */day 1 AUC _0-tau ); and AUCR _cmax (cumulative ratio, based on C _max : last dose C _max */Day 1 C _max ).

Where available, on Day 14 of Part 2 (Cohorts 2.1 and 2.2) or Day 21 of Part 2 (Cohorts 2.3 to 2.5) or Day 28 of Part 5 (Cohorts 5.1 to 5.3) and Day 7 ( Multiple doses) PK [Part 3 (Day 7)] *Final dose assesses the following PK parameters:

C _max (maximum observed plasma concentration); T _max (time to reach C _max ); AUC _0.5-12 (area under the concentration-time curve from time 0.5 hours to 12 hours by ascending linear/descending logarithmic trapezoidal method calculation); and CSF/plasma ratio (CSF and plasma concentration ratio (Part 3 only).

Safety:

The following parameters were defined as those regarding safety and tolerability:

Changes in vital signs from baseline to each scheduled time point to end of study (EOS); changes in ECG parameters from baseline to each scheduled time point to end of study; clinical laboratory tests from baseline to each scheduled time point to end of study change from baseline in C-SSRS scores (parts 2, 3, and 5 only); treatment-emergent adverse events (AEs) by study end; treatment leading to premature discontinuation of study drug Treatment-emergent adverse events (AEs); treatment-emergent serious adverse events (SAEs) by the end of the study; physical examination abnormalities.

statistical methods:

Pharmacokinetics:

A separate subject list is provided. The mean and individual plasma concentration-time profiles of compound 1 for each group are presented graphically.

PK variables will be summarized using arithmetic mean, standard deviation, geometric mean, median, minimum, maximum and CV %.

The attainment of steady-state conditions was determined by visual observation of plasma trough concentrations.

To assess the effect of food, PK parameters of compound 1 under fasted (part 1) and fed (part 4) conditions will be presented graphically and descriptive statistics will be performed. Statistical analysis for each dose level of Compound 1 was performed on 6 subjects using the fed state treatment as test (Part 4) and the fasted state treatment at the same dose as reference (Part 1).

The main PK parameters are C _max , AUC _0-t and AUC _0-inf . The PK parameters C _max , AUC _0-t and AUC _0-inf were first natural log-transformed, and the mean values of these log-transformed parameters were estimated by linear models with treatment as the only fixed factor (Compound 1 administered in the fed state vs. Compound 1) administered in the fasted state. The difference (logarithmic scale) of these means and its 90% confidence interval (CI) were exponentiated to form the geometric mean ratio (GMR) and the corresponding CI for the ratio. If all 90% CI results for the GMRs of C _max , AUC _0-t and AUC _0-inf are contained within the interval of 80.00%-125.00%, it can be concluded that there is no food effect.

Safety:

All safety parameters are summarized by dose level in Sections 1 through 5.

Summary statistics (mean, median, standard deviation, minimum, maximum, and number of available observations) will be provided for continuous demographic variables such as age, height, and weight. A list of demographic data for individual subjects will be provided.

Qualitative demographic characteristics (gender, race) will be summarized by counts and percentages. Only other baseline subject characteristics (eg, medical history, clinical findings on physical examination, previous medications, and inclusion/exclusion checklist) are listed.

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

The distribution of these parameters between each treatment group (fasted or fed) is compared descriptively only. No statistical inferences were made.

Holter analysis/compound 1 plasma concentration-QTc effect can be performed and results will be provided in a separate report.

Results of Phase 1 Study

The primary objective of the Phase 1 trial in healthy volunteers was to establish a target dose range for Compound 1 that lowers HTT mRNA and protein. The trial consisted of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. Dosing was well tolerated in all cohorts with no safety-related findings, demonstrating dose-dependent splicing of HTT mRNA. The study in the MAD cohort was of longer duration and enabled longer-term assessments of HTT mRNA splicing and HTT protein reduction. The MAD cohort demonstrated that compound 1 exhibited a longer drug half-life, maintaining splicing up to 72 hours after the last dose.

CSF sampling enables assessment of the pharmacokinetics of Compound 1 in CSF, where the level of Compound 1 in CSF is compared to the level of Compound 1 in plasma. Results from the Phase 1 study showed that levels of compound 1 in CSF were equal to or greater than those observed in plasma. The food effect section enables an assessment of the pharmacokinetics of Compound 1 in plasma following administration of a single dose of Compound 1 in healthy subjects.

As shown in Figure 9A, the SAD cohort resulted in a dose-dependent decrease in HTT mRNA in whole blood collected from healthy volunteers administered placebo, 5 mg, 15 mg, 45 mg, 90 mg or 135 mg of Compound 1 after 24 hours.

Similarly, the MAD cohort (FIG. 9B) also showed a dose-dependent decrease in HTT mRNA in whole blood collected from healthy volunteers administered placebo, 15 mg or 30 mg of Compound 1 for 14 days. The amount of HTT mRNA was then assessed by RT-PCR 6 hours after compound 1 administration on day 14.

The lowest doses tested in both the SAD and MAD cohorts achieved the 30-50% reduction in the target level. The half-life of HTT mRNA is estimated to be approximately 24 hours. Therefore, after one day, if no HTT mRNA is synthesized, the total amount of HTT mRNA is expected to be approximately 50% of baseline. Administration of Compound 1 in the SAD cohort inhibited essentially all de novo HTT mRNA synthesis. Thus, even with higher concentrations of Compound 1, the total amount of HTT mRNA remained at approximately 50% of baseline, representing the amount of HTT mRNA synthesized prior to Compound 1 administration.

Measurements of HTT mRNA in whole blood of subjects in the SAD cohort are shown in FIG. 14 . The results also showed that the HTT splicing effect of compound 1 was reversible and persisted for 72 hours after cessation of treatment.

Measurements of HTT RNA in whole blood of human subjects administered placebo or 15 or 30 mg of Compound 1 as described above in the Multiple Ascending Dose (MAD) study are shown in FIG. 15 . HTT splicing was monitored after the last dose on day 14, calculated as the percentage of remaining HTT from baseline (day 0 before dosing).

Figure 10 exemplarily depicts the kinetics of HTT mRNA and protein degradation leading to steady state levels of RNA and protein.

In untreated cells, mRNA and protein are at steady-state levels because the amount of mRNA or protein synthesized matches the amount degraded, so the levels of mRNA and protein remain constant over time. Addition of Compound 1 triggers the inclusion of the HTT pseudoexon into transcripts, resulting in a rapid decay of HTT mRNA and a reduction of HTT mRNA to approximately 50% of baseline. The half-life of HTT mRNA is about 24 hours. Thus, after one day of drug treatment, the amount of HTT mRNA present was modulated by the dose of Compound 1. In this example, -50% of newly synthesized mRNA was suppressed. Of the HTT mRNA synthesized before treatment, about 50% were degraded after 24 hours. HTT protein levels depend on how much mRNA is produced. Thus, a 50% reduction in HTT mRNA will result in a 50% reduction in HTT protein. However, the half-life of the HTT protein is approximately 5-7 days, so it takes longer to reach new steady-state levels. Finally, a new steady state is reached where 50% mRNA is present and new protein levels drop to 50% of the original amount. Changes in HTT protein levels in the MAD cohort were assessed over longer time periods. Therefore, healthy subjects were treated for 21 days, and then the levels of HTT mRNA and protein in blood samples of each subject were measured.

Figure 16 shows huntingtin mRNA and protein levels in whole blood from MAD cohort 2.3 (100 mg loading dose (LD) for 2 days, 30 mg for 21 days), as described above, as a percentage of baseline, in Humans were administered vehicle or Compound 1 , 24 hours after the last dose. The results showed that HTT mRNA reduction reached a steady state. HTT protein levels required longer dosing to achieve maximal steady-state reduction. It is expected that the observed changes in HTT mRNA in blood will lead to similar reductions in HTT protein levels in Huntington's disease patients as treatment with compound 1 continues and a steady state reduction in HTT is achieved over time.

Figure 11 shows the modeling of HTT mRNA (Figure 11A) and HTT protein (Figure 11B) decay rates based on their half-lives and then predicting the time to reach steady state following treatment with Compound 1 at a daily dose of 30 mg. For HTT mRNA, the estimated half-life is approximately 24 hours. HTT mRNA reaches steady state after about 5 days. For HTT proteins, the half-life is estimated to be 5-7 days, so steady-state levels of HTT proteins can only be reached approximately 6 weeks after initiation of treatment.

FIG. 12 compares the trajectories of HTT mRNA ( FIG. 12A ) and protein ( FIG. 12B ) reduction seen in multiple dose escalation studies with those predicted from the half-lives of HTT mRNA and protein as shown in FIG. 11 . The results showed that HTT mRNA levels decreased rapidly and reached a steady state after about 4-5 days of treatment. As predicted, the rate of protein reduction was much slower, but after 21 days of treatment, the amount of HTT protein was reduced by approximately 40%. Accordingly, equivalent steady-state levels of HTT mRNA and protein are achieved after about 4-5 weeks after initiation of treatment.

As shown in Figure 13, the levels of Compound 1 in cerebrospinal fluid (CSF) suggest that Compound 1 thus crosses the blood-brain barrier and is comparable to the levels of Compound 1 in free plasma from humans (Figure 13A) and nonhuman primates (Figure 13B). levels are directly related. Two subjects in this cohort received daily doses of 30 mg. Therefore, Compound 1 crossed the blood-brain barrier. The levels of Compound 1 found in CSF were at least equal to or higher than those observed in plasma, thus demonstrating that Compound 1 is not affected by efflux in humans.

In the food-effect cohort, compound 1 showed similar exposures regardless of whether subjects were fasting or eating.

In conclusion, the phase I study demonstrated that compound 1 crosses the blood-brain barrier and selectively reduces HTT mRNA and protein in the CNS and the periphery in a dose-dependent manner. These results demonstrate that exposure of human patients to Compound 1 resulted in a significant reduction in HTT mRNA and HTT protein.

Example 11: Phase II clinical research protocol

The Phase 2 clinical study is a 12-week randomized, placebo-controlled, dose-finding study to evaluate the safety and efficacy of Compound 1 in subjects with Huntington's disease.

Prior to this phase 2 study, compound 1 had been extensively evaluated in in vivo and in vitro preclinical pharmacology models, in an integrated toxicology program, and in a phase 1 study in healthy volunteers. Taken together, the obtained data demonstrate that Compound 1 treatment resulted in dose-dependent reductions in pre-mRNA splicing and protein transcription, and that Compound 1 was clinically safe and well tolerated at single doses of up to 135 mg and multiple doses of up to 30 mg for 21 days of treatment.

This 12-week double-blind study will quantify the effect of compound 1 on the reduction of total HTT (tHTT) protein in HD subjects and evaluate the safety of two doses of compound 1 for 12 weeks.

A parallel-group design was chosen because it allowed recruitment of patients in all treatment groups within the same time frame. The time course of HTT protein, mRNA, and other indicators of drug response in the blood of untreated patients was not available. The use of a parallel design with concurrent placebo control allows direct assessment of comparisons to determine the effect of active treatment.

Select patient populations and reduce variability in otherwise heterogeneous disease populations by identifying subjects with active disease who have not yet experienced functional decline. In this study, at the time of randomization, subjects will therefore be assessed according to the CAG repeat length and Signed Numeric Pattern Test (SDMT), Total Motor Score (TMS), Independence Scale (IS) and Global Functional Capacity ( Baseline measurements of TFC) were included in the trial. These factors will be used to identify and recruit subjects with active disease who have not experienced functional decline indicating disease progression for intervention. The Huntington's Disease Predictive Index (PI _HD ) or its standardized version (PIN _HD ) score can be used to predict the likelihood of HD progression. PIN scores will be calculated at baseline to identify subjects eligible for this study.

Based on the kinetics of Compound 1-mediated HTT reduction in humans, maximal tHTT protein reduction in HD patients is expected to be achieved between 4 and 6 weeks. The 12-week dosing regimen provided further evidence that the steady-state decline in tHTT remained stable over time following continuous treatment with Compound 1 in a Phase 2 study, followed by a one-year open-label extension study. In addition to the primary endpoint of tHTT protein change from baseline and safety, the Phase 2 study included exploratory clinical outcome endpoints to assess the effect of Compound 1 on subjects' cognitive and motor function, as measured by the Huntington's Disease Harmonized Assessment Scale (UHDRS) assessment. UHDRS has been extensively researched and developed to assess disease progression in multiple domains. Cognitive impairment, loss of motor function, and accelerated loss of brain volume in the caudate and putamen are key features of the disease, with significant impact on quality of life. More sensitive and early assessment of motor changes via a wearable device will also be included in the Phase 2 study as an exploratory endpoint. Studying these endpoints over 12 weeks will provide insight into rates of change early in the disease and identify key measurements that may be early indicators of HD progression.

Risk/Benefit Assessment

As mentioned above, HD is a brutally progressive neurodegenerative disease. Early in the disease course, patients exhibit mild symptoms; as the disease progresses, involuntary writhing movements become more pronounced, voluntary movement declines, language and swallowing are increasingly impaired, and aggressive and uninhibited Behavior becomes more frequent. Advanced disease is characterized by a severe inability to walk, speak, swallow, or care for itself, eventually requiring full-time nursing care, and ultimately death, usually 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).

There are currently no disease-modifying interventions approved for HD, and without interventions, the patient population enrolled in this trial would face continued disease progression, loss of function, and inevitable death. The inexorable disease progression and inevitable mortality of the disease indicate that HD is a high unmet medical need. Reduction of mHTT has been identified as an important therapeutic target.

As noted above, multiple doses of Compound 1 were associated with significant reductions in HTT mRNA and protein in a Phase 1 study. Pharmacokinetic-pharmacodynamic (PKPD) modeling based on interim data from the Phase 1 study determined that exposures at the 10 mg and 20 mg QD doses were associated with reductions in full-length HTT mRNA levels, and that HTT protein reductions were accurately achieved to determine a mean of 30% to 50% of the target range. Therefore, the 10mg and 20mg QD doses are expected to be associated with therapeutic benefit and ultimately slowed disease progression in this phase 2 study.

Results from the Phase 1 study provided evidence of the safety and tolerability of compound 1 in single doses ranging from 5 mg to 135 mg and in multiple doses ranging from 15 mg to 30 mg for up to 21 days. Compound 1 was safe and generally well tolerated in phase 1 studies. In the single ascending dose (SAD) and multiple ascending dose (MAD) portions of the Phase 1 study, the overall incidence of AEs was comparable between subjects who received placebo and those who received Compound 1. No events considered dose-limiting toxicities occurred, and all adverse events (AEs) were resolved by the interim analysis cut-off date. There were also no clinically significant laboratory abnormalities or electrocardiogram (ECG) findings at any dose during any part of the study.

The Phase 1 study had a Data and Safety Monitoring Board (DSMB) that closely monitored subject safety. Compound 1 has a favorable risk/benefit profile in HD subjects based on the preclinical and clinical data to date.

Main research purposes:

The safety and pharmacodynamic effects of the two treatment regimens of Compound 1 and placebo were evaluated in subjects with Huntington's disease (HD) according to the following assessments: (i) Occurrence of treatment adverse events (TEAEs) and laboratory Abnormalities in blood counts, electrocardiogram (ECG), vital signs, slit-lamp eye examination, and physical examination; (ii) decreased blood total huntingtin (HTT) levels. This aspect aims to demonstrate the safety, tolerability and pharmacology of Compound 1 and the reduction of HTT mRNA and HTT protein in HD patients.

Secondary research purposes:

(i) Determine the effect of compound 1 on HTT mRNA in blood and mHTT protein in cerebrospinal fluid (CSF); (ii) reduce the level of mutant huntingtin (mHTT) in blood. This aspect aims to demonstrate the effect of compound 1 on blood, CSF and radioactive biomarkers of Huntington's disease.

Purpose of exploratory research:

(i) The effect of compound 1 on volume changes of the whole brain, caudate nucleus, and putamen assessed by volumetric magnetic resonance imaging (vMRI); (ii) The effect of compound 1 on changes in ventricular volume assessed by vMRI; (iii) The effect of compound 1 on plasma and CSF neurofilament light chain (NfL) protein concentrations; (iv) assess changes after 12 weeks of treatment using relevant scales, which will include assessment using the Unified Huntington's Disease Rating Scale (UHDRS) and each of its subcomponents , including (a) the Signed Numeric Model Test (SDMT), (b) the Total Motor Scale (TMS), (c) the Independence Scale, (d) the Total Functional Capacity Assessment (TFC); (e) (f) Clinical Global Impression of Change (CGI-C); (g) Huntington's Disease Quality of Life Questionnaire (HDQoL).

Pharmacokinetic goals:

Concentrations of Compound 1 were assessed in HD subjects.

Clinical endpoints:

Primary Safety Endpoint:

The safety profile characterized by TEAEs, laboratory abnormalities, ECG, vital signs, slit-lamp eye examination, and physical examination was assessed.

Primary efficacy endpoint:

The change of blood total HTT protein relative to the baseline at the 5th review.

Biomarker endpoints:

(i) Percent reduction of HTT protein in CSF; (ii) changes in neurofilament light chain (NfL) in plasma and CSF; (iii) changes in caudate, putamen, and ventricular volumes in volumetric MRI imaging.

Secondary endpoints:

(i) Changes in blood HTT mRNA from baseline at the 3rd, 4th and 5th review; (ii) Changes in CSF mHTT from baseline at the 5th review; (iii) Blood mHTT protein at the 5th review relative to Changes in baseline.

Exploratory endpoints:

(i) changes from baseline in whole brain, caudate, putamen, and ventricular volumes (as assessed by vMRI); (ii) changes in plasma and CSF NfL protein concentrations from baseline; (iii) UHDRS for each subscale Change from baseline in scores including SDMT, TMS, Independence Scale, and TFC; (iv) change from baseline in total UHDRS; (v) change from baseline in gait and motor function as assessed by wearable accelerometers; (vi) Change assessed by CGI-C; (vii) Change from baseline in HDQoL questionnaire.

pharmacokinetic endpoint

(i) Plasma trough concentration (C _trough ) and cumulative ratio of compound 1 at retests 3, 4, and 5; and (i) cumulative ratio of compound 1 in CSF at retest 5.

Biomarker endpoints:

(i) Percent reduction of HTT protein in CSF; (ii) changes in neurofilament light chain (NfL) in plasma and CSF; (iii) changes in caudate, putamen, and ventricular volumes in volumetric MRI imaging.

Research design/methodology:

The Phase 2 study was a randomized, placebo-controlled, parallel-group, dose-finding study to evaluate the safety and efficacy of Compound 1 at 10 mg and 20 mg and to determine the effect of these doses on subject HTT after 12 weeks of treatment in HD subjects protein reduction effect.

Individuals who sign informed consent will be screened to determine eligibility for inclusion in the study. At screening, the genetic mutation status of potential subjects will be confirmed by the investigator (either by prior genetic sequencing or assessed by on-study genetic sequencing) and other evaluations will be performed to confirm that they meet the inclusion criteria. Subjects who meet all inclusion criteria at screening will receive a baseline assessment and will be randomized 1:1:1 to either 10 mg or 20 mg of study drug or placebo for 12 weeks of treatment (plus or minus visits) window period). Once assigned to treatment, subjects will take their assigned dose of study drug once daily in the morning, at least 2 hours before the first meal of the day. Subjects will be asked to return to the hospital for review every 28 days after randomization (approximately Days 29, 57, and 85) or to receive home care services in lieu of an in-person review for study assessments. On Day 85, subjects will take their last dose of study drug and complete the end-of-study assessment. A follow-up safety visit via telephone/telemedicine will be conducted on Day 113 to collect AEs.

Proof of sample size:

Sample size calculations were based on the mean change from baseline in blood total HTT protein at the 5th review (primary endpoint). Using an effect size of 0.85 (ie the treatment difference size is 85% of one standard deviation), achieving 90% statistical power at a 2-sided alpha level of 0.05 would require 31 subjects. Approximately 35 subjects will be randomly assigned to each dose, assuming a 10% dropout rate.

Number of planned patients:

Approximately 200 adult male and female subjects will be recruited.

Inclusion criteria:

Individuals eligible to participate in this study include those who meet all of the following inclusion criteria: (i) ambulatory male or female patients aged 25 years and over; (ii) subjects (or legally authorized representatives ) willing and able to provide informed consent and comply with all protocol requirements; (iii) genetically confirmed HD with a cytosine-adenine-guanine (CAG) repeat length of 42 to 50, inclusive; (iv) UHDRS - Independence scale score of 100; (v) TFC score of 13; (vi) standardized predictive index of HD score between 0.18 and 4.93 inclusive; (vii) women of childbearing potential (WOCBP): consent must be given before dosing Use highly effective methods of contraception during and for 6 months after discontinuation of study drug.

WOCBP is defined as postmenarchal, premenopausal fertile women unless permanently infertile. Methods of permanent sterilization include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status was defined as the absence of menstruation for 12 consecutive months without other medical reasons. Postmenopausal status in women not using hormonal contraception or hormone replacement therapy is confirmed by high follicle-stimulating hormone (FSH) levels in the postmenopausal range. However, a single FSH measurement is insufficient in the absence of 12 months of amenorrhea. Highly effective contraceptive methods are defined as methods with a failure rate of less than 1% per year when used correctly and consistently, and include several methods selected from the group consisting of: (a) combined (estrogen and progestogen-containing) hormonal methods of contraception associated with ovulation suppression, including Oral contraceptives (WOCBPs using oral contraceptives should have been on the same drug for at least 3 months prior to screening), intravaginal or transdermal contraceptives; (b) progestin-only hormonal contraceptives associated with ovulation suppression , including oral contraceptives (WOCBPs using oral contraceptives should have been on the same drug for at least 3 months prior to screening), administered by injection, implant, intrauterine device, or intrauterine hormone-releasing system; or, (c ) contraception associated with bilateral tubal occlusion, partner vasectomy, or abstinence.

(viii) Sexually active and fertile men must use a condom during intercourse while taking study drug and for 6 months after stopping study drug, and should not have children or donate sperm during this time. Men who have had a vasectomy also need to use a condom to prevent the drug from being delivered through the semen.

Main exclusion criteria:

Ineligible to participate in this study if any of the following exclusion criteria are met: (i) unable or unwilling to swallow oral tablet; (ii) receiving use of experimental drug within 90 days or 5 half-lives prior to screening or at any time during this study , including HD-specific investigational drugs targeting RNA or DNA, such as antisense oligonucleotides, cell transplantation, or any other experimental brain surgery; (iii) any history of exposure to gene therapy for the treatment of HD; (iv) Participation in a research trial or research paradigm (e.g. exercise/physical activity, cognitive therapy, brain stimulation, etc.) within 90 days prior to Screening or at any time during this study; (v) Presence of an implanted deep brain stimulation device; ( vi) family history of premature cataract or presence of cataract at baseline using the cataract grading system (lens opacity classification system III); (vii) brain and spinal pathology, elevated intracranial pressure that may interfere with CSF homeostasis and circulation (including the presence of shunts for CSF drainage or implanted CNS catheters), malformations and/or tumors; (viii) any major medical or surgical hospitalization involving general anesthesia planned within 12 weeks after screening or during the study; (ix) Significant suicide risk at intermediate risk level or higher as measured by the Columbia Suicide Severity Rating Scale (C-SSRS); (x) Investigator-assessed major depressive episode, psychosis, delirium, or violent behavior (xi) any history of brain or spinal disease that would interfere with the lumbar puncture procedure or safety assessment; (xii) history of malignancy in any organ system within the past 5 years (except localized cutaneous basal cell carcinoma or cervical carcinoma in situ), Whether treated or not, with or without evidence of local recurrence or metastasis; (xiii) any medical history or condition that would interfere with the ability to complete protocol-assigned assessments (e.g., implanted shunt, condition that precludes MRI scan); (xiv ) use of antidepressants or benzodiazepines, unless on a stable dose for at least 6 weeks prior to Screening, and the dosage regimen is not expected to change during the study; (xvi) lifetime history of drug use or alcohol abuse as assessed by the Investigator Belonging to the high-risk drinking level identified by the World Health Organization for a period of 1 month or more; (xvii) clinically significant medical conditions that the investigator believes may adversely affect the safety of the subject or impair the evaluation of the study results ; (xviii) current significant renal impairment defined as estimated glomerular filtration rate <60 mL/min at screening; (xvix) current hepatic impairment at screening leading to liver function tests (aspartate aminotransferase, alanine aminotransferase , alanine phosphatase) elevated to 3 times the upper limit of normal; (xx) pregnant, planning to become pregnant during the trial, or currently breastfeeding; (xxi) using a moderate or strong CYP3A4 inhibitor within 1 week of screening Drugs or moderate or strong CYP3A4 inducer drugs used within 2 weeks after screening or planned to use moderate or strong CYP3A4 inhibitors or inducer drugs during the study.

Study and Reference Products, Doses and Modes of Administration:

Compound 1 tablets will be administered orally once daily (QD). The two study product dosing groups will be administered 10 mg for 12 weeks and 20 mg for 12 weeks, respectively.

Compound 1 active study product and matching placebo reference product tablets will be administered orally QD. Compound 1 investigational drug product is a film-coated tablet dosage form for oral administration. White to off-white round coated tablets will be available in 10 mg and 20 mg dosage strengths, each containing Compound 1 drug substance and a drug substance selected from microcrystalline cellulose, lactose monohydrate, povidone K30, croscarboxyl Excipients sodium methylcellulose, poloxamer 407 and magnesium stearate. The 10mg and 20mg tablets will be available in 2 different sizes. Placebo tablets contained the same compendial excipients and were manufactured in the same tablet size with identical appearance matching the 10 mg and 20 mg Compound 1 tablets.

Evidence for the safety of the selected dose is provided by the results of the ongoing Phase 1 study and the comprehensive preclinical toxicology program to date. In phase 1 studies, single doses of 5 mg to 135 mg and multiple doses of 15 mg and 30 mg over 14 days were safe and generally well tolerated.

The goal of 30% to 50% reduction in mHTT is the range associated with pathology reduction and expected treatment benefit for patients. In the Phase 1 study, compound 1-mediated splicing of pre-HTT mRNA was dose-dependent in all cohorts in the SAD and MAD portions of the study. After 14 days of treatment with 15 mg and 30 mg of compound 1, respectively, an average reduction of 40% and 60% in the level of full-length HTT mRNA was observed. On the basis of these clinical data, a PK-PD binding model was used to simulate the percentage reduction of mRNA (and thus the expected magnitude of HTT protein reduction) at other potential clinical doses.

At the selected doses of 10 mg QD and 20 mg QD, the predicted percent reduction from baseline in full-length HTT mRNA was within the target range of 30% to 50%. Preclinical data in a bacterial artificial chromosome transgenic mouse model of HD showed a strong correlation between HTT pre-mRNA splicing levels and the degree of protein reduction following compound 1 administration in mice. Thus, the observed preclinical changes in HTT mRNA are expected to result in similar reductions in HTT protein levels in HD patients. Therefore, based on the totality of clinical and preclinical safety data to date, and the expected reduction of HTT mRNA and protein from clinical data and pharmacokinetic-pharmacodynamic modeling, doses of 10 mg and 20 mg are expected to be safe in HD subjects , well tolerated and beneficial.

Reference product, dosage and mode of administration:

Matching placebo tablets will be administered orally once daily (QD).

safety standard:

The safety assessment will include observed TEAEs, clinical laboratory, vital signs, ECG, C-SSRS, slit-lamp ophthalmic examination, and physical examination.

Curative effect standard:

Efficacy assessment will include analysis of: (i) blood HTT protein and CSF NfL, (ii) UHDRS, (iii) CGI-C, (iv) motor function assessed by wearable accelerometer, and (v) neuroimaging (vMRI) .

enrichment standard

Enrichment was defined as the prospective use of any patient characteristic to select a study population in which a drug effect, if at all present, was more likely to be detected than in an unselected population. Because of the wide variation in the HD patient population, the enrichment strategy for the Phase 2 study aimed to select those who retained daily living, work, financial, and self-care capabilities, but had reduced performance on motor and cognitive tests and were expected to improve ADL function within 3 years. Affected subjects. UHDRS TMS and SDMT assessments (as well as CAG repeat length and age) will be performed at screening and used to identify this cohort via the validated HD predictive index of presymptomatic HD patients.

The Huntington's Disease Predictive Index (PI _HD ) or its standardized version (PIN _HD ) can be used to predict the likelihood of HD progression, with higher scores indicating greater risk of functional decline. Natural history survival curves generated using PI _HD show disease trajectories for patients with specific PI _HD scores. The PIN _HD score allowed investigators to predict disease progression in the study population with a high degree of certainty. Historically, disease progression is often indicated by the CAG-age product (CAP), a burden score of age and CAG expansion, which comes in many variants. When CAP was combined with TMS and SDMT of UHDRS, HD progression predictive likelihood increased. Using these enrichment criteria, a group of subjects with HD without functional decline (as measured by TFC and IS) could be identified and changes in blood HTT levels after treatment could be measured. Without HTT-lowering therapy, subjects in this group may experience decline, as it has been found that the early stages of HD are characterized by increased mHTT levels in CSF compared with controls.

At baseline in this study, subjects' cognitive and motor function will be assessed by SDMT and TMS scores, respectively. According to the assessment of TFC and IS, the enrolled subjects should have no functional decline. Subjects will be enrolled in the study based on their PIN _HD score calculated by the IRT prior to randomization. Subjects with a baseline PIN _HD score of 0.18 to 4.93 inclusive will be eligible to participate in the trial. The following formula will be used to calculate the PIN _HD score:

PI _HD = 51x(TMS)+(-34)xSDMT+7x(age)x(CAG-34).

PI _HD scores are converted to standardized scores using the following conversion formula:

PIN _HD = (PI _HD -883)/1044

Subjects with PIN _HD scores ranging from 0.18 to 4.93 as determined using the ENROLL HD database (regular data update 5) were included in the study.

Pharmacokinetics:

The pharmacokinetic assessment will include the plasma concentration _Ctrough (at the 3rd, 4th and 5th recheck). Cumulative ratios in plasma (at retests 3, 4, and 5) and CSF (at retest 5) will be calculated and reported.

statistical methods:

A repeated measures analysis model (repeated on reexamination) will be used to compare blood total HTT protein for each dose to placebo. The model will include dose, recheck, recheck interaction dose and baseline. Nominal p-values and 95% confidence intervals for each pairwise comparison of the 5th reexamination (active drug vs. placebo) will be provided. The model will include PIN _HD as a stratification factor. The same analysis used for blood HTT protein will be used for blood HTT mRNA. Dose-response relationships will be explored. Demographic and baseline characteristics, disposition, safety and efficacy endpoints will be descriptively summarized by dose group. Statistical modeling will be applied to understand the relationship between the UHDRS and its components and the assessment of blood and CSF.

Phase II Study Results

The primary objective of the 12-week phase 2a randomized, placebo-controlled, dose-finding study was to evaluate the safety and pharmacodynamic effects of two treatment regimens of compound 1 and placebo in subjects with Huntington's disease. The primary objectives were to assess the occurrence of treatment adverse events (TEAEs); laboratory values, electrocardiogram (ECG), vital signs, slit-lamp eye examination, and physical examination abnormalities; and decreased blood total huntingtin (HTT) levels.

Secondary objectives of this study were to determine the effect of compound 1 on HTT mRNA in blood and mHTT protein in cerebrospinal fluid (CSF); and (ii) reduction of mutant huntingtin (mHTT) levels in blood.

The exploratory objectives of this study were to assess the effect of compound 1 on changes in whole brain, caudate, and putamen volumes by volumetric magnetic resonance imaging (vMRI); to assess the effects of compound 1 on changes in ventricular volumes by vMRI; to assess the effects of compound 1 on plasma and CSF Effect of neurofilament light chain (NfL) protein concentration; changes in assessments of related scales were assessed after 12 weeks of treatment, which will include assessments using the Unified Huntington's Disease Rating Scale (UHDRS) and each of its subcomponents. Qualitative efficacy was assessed using UHDRS subcomponents, including (a) the Signed Numeric Model Test (SDMT), (b) the Total Motor Scale (TMS), (c) the Independence Scale, and (d) the Total Functional Capacity Assessment (TFC) (e) Gait and movement assessed by wearable accelerometers; (f) Clinical Global Impression of Change (CGI-C); and (g) Huntington's Disease Quality of Life Questionnaire (HDQoL).

The pharmacokinetic objective of this study was to assess the concentration of Compound 1 in HD subjects.

Claims (30)

1. A tablet comprising 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo as an active ingredient [4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol (hereinafter referred to as compound 1) or a pharmaceutically acceptable salt thereof, Intragranular excipients and extragranular excipients, wherein Compound 1 accounts for about 5% to about 30% by weight of the total weight of the tablet; wherein the intragranular excipients comprise microcrystalline cellulose and a diluent; Wherein the ratio of the microcrystalline cellulose to the diluent is about 1:1 to about 1:4, and the microcrystalline cellulose accounts for about 15% by weight to about 25% by weight of the total weight of the tablet; wherein the disintegrant From about 1% to about 3% of the total weight of the tablet; wherein povidone is from 1% to about 5% of the total weight of the tablet; and wherein the extragranular excipient comprises an additional level of diluent and additional disintegrants. 2. The tablet according to claim 1, wherein the content of compound 1 is about 5% to about 25% of the total weight of the tablet. 3. The tablet according to claim 2, wherein the content of compound 1 accounts for about 10% of the total weight of the tablet. 4. The tablet according to claim 1, wherein the content of Compound 1 in the tablet is about 1 mg to 200 mg. 5. The tablet according to claim 4, wherein the content of Compound 1 in the tablet is selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg and 200mg. 6. The tablet according to claim 1, wherein the content of compound 1 in the tablet is about 1 mg to 100 mg. 7. The tablet according to claim 6, wherein the content 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 of claim 1, wherein the diluent is lactose monohydrate. 9. The tablet of claim 1, wherein the ratio of microcrystalline cellulose to diluent in the intragranular excipient is about 1:2. 10. The tablet of claim 1, wherein the extragranular diluent comprises from about 15% to about 30% of the total weight of the tablet. 11. The tablet of claim 1, wherein at least one of the extragranular excipient and the intragranular excipient further comprises a surfactant. 12. The tablet of claim 11, wherein the surfactant is a poloxamer. 13. The tablet of claim 1, wherein the disintegrant is croscarmellose sodium. 14. The tablet of claim 1, wherein the extragranular excipient further comprises a lubricant. 15. The tablet of claim 14, wherein the lubricant is magnesium stearate. 16. The tablet of claim 1, wherein the extragranular excipient further comprises a glidant. 17. The tablet of claim 16, wherein the glidant is colloidal silicon dioxide. 18. The tablet of claim 1, wherein the weight of the extragranular excipient is about 15% to about 30% by weight of the total weight of the tablet. 19. The tablet of claim 1, wherein the intragranular excipient has been wet granulated. 20. The tablet according to claim 1, wherein the content of compound 1 accounts for 10% by weight of the tablet, and the intragranular excipient comprises microcrystalline cellulose and lactose monohydrate in a ratio of about 1:2 , and the content of microcrystalline cellulose accounts for about 20% by weight of the tablet, the content of the disintegrant accounts for about 1% to about 3% by weight of the tablet, and the content of povidone accounts for about 1% by weight of the tablet wherein the extragranular excipients comprise lactose monohydrate in an amount of about 10% to about 25% by weight of the tablet, a disintegrant in an amount of about 1% to about 5% by weight of the tablet, and The poloxamer comprises from about 0.5% to about 2% by weight of the tablet. 21. The tablet of claim 20, wherein the extragranular excipient further comprises colloidal silicon dioxide in an amount from about 0.25% to about 1% by weight of the tablet. 22. The tablet of claim 20, wherein the extragranular excipient further comprises magnesium stearate in an amount from about 0.5% to about 2% by weight of the tablet. 23. A process for the preparation of the tablet of claim 1 comprising wet granulating the extragranular excipient, drying the resulting intragranular mixture, mixing the extragranular excipient with the intragranular excipient , and compress the resulting mixture to form tablets. 24. The method of claim 23, further comprising coating the resulting compressed tablet with a film. 25. A method for treating or improving Huntington's disease in a subject in need thereof, the method comprising orally administering to the subject the compound 1 containing a therapeutically effective amount or pharmaceutically acceptable compound 1 according to claim 1 salt tablets. 26. The method of claim 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 claim 26, wherein the therapeutically effective amount of Compound 1 is selected from the group consisting of 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, and 200mg. 28. The method of claim 25, wherein the tablet contains 1 mg to 100 mg of Compound 1. 29. The tablet of 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 method of claim 25, wherein the tablet is administered once daily.