CN116635016A

CN116635016A - Tablet for treating huntington's disease and preparation method thereof

Info

Publication number: CN116635016A
Application number: CN202180076653.6A
Authority: CN
Inventors: 史瓦希·平拿曼涅尼; 阿坎·纳希尔·屋丁; 曼达·瓦森·达利
Original assignee: PTC Therapeutics Inc
Current assignee: PTC Therapeutics Inc
Priority date: 2020-11-13
Filing date: 2021-11-12
Publication date: 2023-08-22

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 Reference to Related Applications

The present application claims the benefits and priorities of pending U.S. provisional patent application Ser. No. 63/113,826 filed 11/13/2020, pending U.S. provisional patent application Ser. No. 63/245,927 filed 2021/9/21, pending U.S. provisional patent application Ser. No. 63/261,467 filed 2021/9/22, and pending U.S. provisional patent application Ser. No. 63/261,495 filed 2021/10/14, the contents of which are expressly incorporated herein by reference in their entirety.

Technical Field

The present application relates generally to immediate release (immediate release) tablets of small molecule compounds for the treatment of huntington's disease and methods of making the same.

Background

Huntington's Disease (HD) is a rare genetic neurodegenerative Disease caused by mutations in the Huntington (HTT) gene. Such diseases can lead to behavioral, cognitive and motor disorders. These symptoms gradually reduce the quality of life of the individual and eventually lead to death within 15 to 25 years of the appearance of overt clinical motor symptoms. Parents with huntington gene mutations have a 50% likelihood of inheriting such mutations for each of their children. It is estimated that approximately every 1 million people has one person carrying a mutated huntington gene. Current HD therapies can control the severity of symptoms, but no approved therapies currently slow the progression of the disease.

HD is caused by repeated amplification of CAGs in HTT and is characterized by decline in motor, cognitive, mental and functional abilities. CAG trinucleotide repeat amplification results in mutated huntingtin (mHTT) associated with neurological dysfunction and eventual death.

In healthy individuals, the number of CAG repeats in the HTT gene is 6 to 35. Individuals carrying 36 to 39 CAG repeats have reduced exonic rates of the disease, but individuals with 40 or more CAG repeats almost certainly will have the disease. As described in European Journal of Neurology,2017,24-34, clinical diagnosis of HD is based on: confirmed family history or positive gene detection (i.e., confirmed CAG repeat amplification. Gtoreq.36); and the occurrence of motor impairment as defined by the universal rating scale for huntington's disease (UHDRS), a total motor function score (TMS) Diagnostic Confidence Score (DCS) ranging from 0 (no motor abnormality suggests HD to 4 (99% or more may be due to HD) where 4 defines "motor impairment" or "symptomatic" HD.

Typically, the age of onset (i.e., once DCS reaches 4) is between 30 and 50 years, with an average survival of 15 to 20 years after clinical confirmation. Currently, the "loss of function" after onset (i.e., assessment of functional capacity) rather than motor symptoms determines the stage of the disease (see, e.g., neurology,1979,29,1-3; or Neurology,1981,31,1333-1335). A full functional capability (TFC) assessment scale (see, e.g., movement Disorders,1996,11,136-142) is an integral part of UHDRS, where the level of independence of HD patients ranges from 0 (complete dependence on all cares) to 13 (complete independence). The scale evaluates the functional status of HD patients in terms of work capacity, handling home finances, managing households, performing activities of daily living and required care levels. HD disease progression is classified into phases 1 to 5 according to the UHDRS full functional capacity assessment (TFC). HD classification based on TFC scores (also referred to as Shoulson and Fahn phases) is also described as early HD (corresponding to TFC score phase 1 or 2), mid HD (corresponding to TFC score phase 3), and late HD (corresponding to TFC score phase 4 or 5).

The international application published as WO2020/005873 identifies a class of compounds useful in the treatment of HD, methods for their preparation and pharmaceutical formulations thereof. It is also in IC ₅₀ Data indicating that these compounds inhibit endogenous Huntingtin (HTT) are provided in the assay. A particularly potent HTT inhibitor 2- [3- (2, 6-tetramethylpiperidin-4-yl) -3H- [1,2,3 is disclosed in this application]Triazolo [4,5-c ]]Pyridazin-6-yl]-5- (2H-1, 2, 3-triazol-2-yl) phenol was found to be useful in a transgenic mouse model of huntington's diseaseEffectively reduces the generation of human HTT in vivo (the result is not published yet). At present, only symptomatic treatment is possible. Thus, no small molecule therapy has been available to date to slow the progression of HD. Thus, there is a need for small molecule disease modifying therapies (i.e., therapeutic options that slow down disease progression) for HD.

Disclosure of Invention

In one aspect, the present invention relates to a tablet comprising 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 (hereinafter referred to as compound 1) or a pharmaceutically acceptable salt thereof, an intragranular excipient and an extragranular excipient as an active ingredient, wherein the content of compound 1 is about 1 to about 30% by weight based on the total weight of the tablet,

wherein the intragranular excipients comprise microcrystalline cellulose and a diluent, wherein the ratio of microcrystalline cellulose to diluent is from about 1:1 to about 1:4, the microcrystalline cellulose is present in an amount from about 15% to about 25% by weight of the total weight of the tablet, the disintegrant is present in an amount from about 1% to about 3% of the total weight of the tablet, and the povidone is present in an amount from about 1% to about 5% of the total weight of the tablet, and

Wherein the extra-granular excipient comprises an additional amount of diluent and an additional amount of disintegrant.

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

In one aspect, the amount of compound 1 in the tablet is 1mg to 200mg.

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

In another aspect, the amount 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.

In another aspect, the amount 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.

In another aspect, the amount 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.

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 and 100mg.

On the other hand, the content of compound 1 in the tablet is selected from 1mg, 5mg, 10mg, 20mg, 30mg and 50mg.

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

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

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

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

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 extra-granular excipient and the intra-granular excipient further comprises a surfactant. In one such aspect, the surfactant is a poloxamer (poloxamer).

In one aspect, the disintegrant is croscarmellose sodium.

In one aspect, the extra-granular excipient further comprises a lubricant. In one such aspect, the lubricant is magnesium stearate.

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

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

In one aspect, the intragranular excipients have been wet granulated.

In another aspect, the tablet comprises compound 1 in an amount of about 10% by weight of the tablet, the intragranular excipient comprises microcrystalline cellulose and lactose monohydrate in a ratio of about 1:2, and microcrystalline cellulose is present in an amount of about 20% by weight of the tablet, the disintegrant is present in an amount of 1% to about 3% by weight of the tablet, the povidone is present in an amount of about 2% by weight of the tablet, and the extragranular excipient comprises lactose monohydrate in an amount of about 10% to about 25% by weight of the tablet, the disintegrant is present in an amount of about 1% to about 5% by weight of the tablet, and the poloxamer is present in an amount of about 0.5% to about 2% by weight of the tablet.

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

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

The invention also relates to a process for preparing a tablet comprising wet granulating an extragranular excipient, drying the resulting intragranular mixture, mixing the extragranular excipient with the intragranular excipient, and compressing the resulting mixture to form a tablet.

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

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

In another aspect, the invention also relates to the use of compound 1, or a pharmaceutically acceptable salt thereof, in the treatment of slowing the progression of huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows the progression of huntington's disease by generating an in-frame stop codon between exons 49 and 50 of HTT mRNA; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof to slow the progression of huntington's disease is a disease modifying therapy; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof reduces motor dysfunction associated with huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows cognitive decline associated with huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof reduces the mental retardation associated with huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows the decline in functional capacity associated with huntington's disease; wherein the effect of treatment with compound 1 or a pharmaceutically acceptable salt thereof slows the progression of the pathophysiology of huntington's disease.

Drawings

Fig. 1 is a graph of individual plasma concentrations of compound 1 over time following oral administration of 30mg of compound 1 suspension (21 batches) in 0.5% hydroxypropyl methylcellulose (HPMC) in water to male cynomolgus monkeys (group 1 (Leg 1)).

Fig. 2 is a graph of mean plasma concentration of compound 1 over time following oral administration of 30mg of compound 1 suspension (21 batches) in 0.5% hydroxypropyl methylcellulose (HPMC) in water to male cynomolgus monkeys (group 1).

Fig. 3 is a graph of individual plasma concentrations of compound 1 over time following oral administration of tablet a (dry granulated 15 lot) containing 30mg of compound 1 to male cynomolgus monkeys (group 2).

Fig. 4 is a graph of mean plasma concentration of compound 1 over time following oral administration of tablet a (dry granulated 15 batches) containing 30mg of compound 1 to male cynomolgus monkeys (group 2).

Fig. 5 is a graph of individual plasma concentrations of compound 1 over time following oral administration of tablet B (wet granulated 20 batches) containing 30mg of compound 1 to male cynomolgus monkeys (group 3).

Fig. 6 is a graph of individual plasma concentrations of compound 1 over time following oral administration of tablet B (wet granulated 20 batches) containing 30mg of compound 1 to male cynomolgus monkeys (group 3).

Figure 7 is a dissolution profile (percentage of compound 1 dissolved as a function of time) of a 23-lot production of 5mg tablets stored at 75% relative humidity, 50 ℃ for 2 weeks or at 40 ℃ for 1 month before and after storage.

Figure 8 is a dissolution profile (percentage of compound 1 dissolved as a function of time) of a 23-lot 50mg tablet stored at 75% relative humidity 50 ℃ for 2 weeks or at 40 ℃ for 1 month before and after storage.

Fig. 9 shows dose-dependent reduction of HTT mRNA in whole blood drawn from healthy volunteers participating in single-dose escalation (SAD) and multiple-dose escalation studies of phase I clinical trials.

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

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

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

Figure 11 shows modeling 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 after treatment with compound 1 at a daily dose of 30 mg. For HTT mRNA, half-life is estimated to be about 24 hours. HTT mRNA in fig. 11A reached steady state after about 5 days. For HTT proteins, half-life is estimated to be 5-7 days, so steady state levels of HTT protein take about 6 weeks from the start of treatment.

Fig. 12 compares the trace of HTT mRNA (fig. 12A) and protein (fig. 12B) reduction seen in multiple escalated dose studies with those of the half-life predictions for HTT mRNA and protein shown in fig. 11.

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

Fig. 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 90mg of compound 1, as described in the single incremental dose (SAD) study in example 10, section 1. The results indicate that HTT splicing effect of compound 1 is reversible and persists for 72 hours after cessation of treatment.

Fig. 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 30mg of compound 1, as described in the Multiple Ascending Dose (MAD) study of example 10, part 2. HTT splicing was monitored after the last dose on day 14 as a percentage of the remaining HTT to baseline (day 0 prior to dose).

Fig. 16 is a bar graph showing huntingtin mRNA and protein levels (100 mg Loading Dose (LD) for 2 days, 30mg administration for 21 days) in whole blood from MAD cohort 2.3, as described in example 10, in percent of baseline, 24 hours after the last administration of vehicle or compound 1 to humans. The results showed that HTT mRNA was reduced to steady state. HTT protein levels take longer to administer to achieve maximum steady state decrease.

Detailed Description

Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill 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, the materials, methods and embodiments are illustrative only and not limiting. Other features of the invention will be apparent from the following detailed description and from the claims.

Headings or sub-headings are used in the specification only for convenience of the reader and are not intended to affect the scope of the invention or limit any aspect of the invention to any section, sub-heading or paragraph.

1. Definition of the definition

In the present invention, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

As used herein and in the claims, the phrase "at least one" with reference to one or more lists of elements is understood to mean at least one element selected from any one or more of the list of elements, but does not necessarily include at least one of each element explicitly listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that there are optionally some elements in addition to those explicitly listed in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those explicitly listed elements. Thus, as a 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") may refer, in one aspect, to at least one, optionally including more than one, a, with no B present (and optionally including elements other than B); another aspect refers to at least one, optionally including more than one, B, absent a (and optionally including elements other than a); in another aspect, 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 connection with a range of values, it modifies the range by extending the boundaries above and below the values. In general, the term "about" is used herein to modify a numerical value to 20%, 10%, 5% or 1% above and below the indicated value. In certain aspects, the term "about" is used herein to modify a numerical value above and below 10% of the indicated value. In certain aspects, the term "about" is used herein to modify a numerical value above and below the indicated value by 5%. In certain aspects, the term "about" is used herein to modify a numerical value above and below 1% of the indicated value.

The terms "subject" or "patient" are used interchangeably to refer to a human individual suffering from a disorder described herein (e.g., huntington's syndrome) that may be treated by administration of a composition described herein.

When numerical ranges are set forth herein, it is intended to cover each and every value and subrange within the range. 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 will be further understood that the terms "comprises" and/or "comprising," when used herein, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

The term "treatment" refers to therapeutic treatment in which the aim is to reverse, alleviate, ameliorate, inhibit, slow or stop the progression or severity of a disease. Alternatively, the term "treatment" includes the term "amelioration" which refers to the reduction or alleviation of at least one adverse reaction or symptom of a condition, disease, or disorder. Treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, a treatment is "effective" if the progression of the disease is slowed, reduced, or stopped. That is, "treating" includes not only improvement of symptoms or markers as compared to the situation expected without treatment, but also stopping or at least slowing the progression or worsening of symptoms. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the state of disease, remission (whether partial or total), and/or reduced mortality, whether detectable or undetectable. The term "treatment" of a disease also includes alleviation of symptoms or side effects of the disease (including palliative treatment).

The term "excipient" as used herein refers to any substance that is not a therapeutic agent per se, but is used as a carrier or vehicle for delivering the therapeutic agent to a subject or adding to a pharmaceutical composition to improve the handling or storage characteristics of the pharmaceutical composition or to allow or facilitate the formation of a dosage unit of the composition into a discrete article, such as a capsule or tablet suitable for oral administration. Excipients include, but are not limited to, diluents, disintegrants, binders, adhesives, surfactants, lubricants, glidants, surface modifying agents, substances added to mask or eliminate unpleasant tastes or odors, flavoring agents, 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 repeated amplification of CAG in the huntington's gene characterized by reduced motor, cognitive, mental and functional abilities.

The term "intra-granular" as used herein refers to an ingredient that is incorporated into a formulation prior to granulation, i.e., an ingredient that is located within or part of the structure of a granule.

The term "extra-granular" as used herein refers to ingredients that are incorporated into the formulation after granulation, i.e., ingredients that are located outside the structure of the granule.

The term "administration" as used herein refers to the act of physically delivering a substance present in vitro into a subject.

As used herein, the terms "symptomatic HD" or "symptomatic Huntington's disease" refer to clinically diagnosed HD (e.g., based on a confirmed family history or positive gene detection (confirmed CAG repeat amplification. Gtoreq.36) and the occurrence of dyskinesias [ Diagnostic Confidence Score (DCS) defined by the Huntington's disease Universal rating Scale (UHDRS) total motor function score (TMS) is 4]. As used herein, the terms "symptomatic HD" or "symptomatic Huntington's disease" refer to clinically diagnosed HD patients (e.g., based on a confirmed family history or positive gene detection (confirmed CAG repeat amplification. Gtoreq.36) and dyskinesias [ based on a Diagnostic Confidence Score (DCS) defined by the Huntington's disease Universal rating Scale (UHDRS) total motor function score (TMS) is 4].

As used herein, the term "pre-symptomatic HD" or "pre-symptomatic huntington's disease" refers to genetically diagnosed HD [ e.g., based on: positive gene detection (confirmed CAG repeat amplification ≡40), no clinically determined dyskinesias occurred, e.g. assessed according to a standard scale, e.g. a clinical scale [ e.g. defined according to huntington's disease unified rating scale (UHDRS) total motor function score (TMS), diagnostic Confidence Score (DCS) <4]. In one aspect, the term "pre-symptomatic HD" or "pre-symptomatic huntington's disease" refers to a patient genetically diagnosed with HD [ e.g., based on: positive gene testing (confirmed CAG repeat amplification ≡40), with no clinically determined dyskinesias present, e.g. assessed according to a standard scale, e.g. a clinical scale [ e.g. defined according to huntington's disease unified rating scale (UHDRS) total motor function score (TMS), diagnostic Confidence Score (DCS) <4].

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 one or more therapeutic effects selected from the group consisting of: decreasing the rate of huntington's disease progression (e.g., decreasing the rate of progression between huntington's disease phases); delaying the onset of huntington's disease; delaying onset of symptoms associated with huntington's disease; decreasing the rate of progression (e.g., decreasing the rate of annual decline) of symptoms associated with huntington's disease (e.g., one or more symptoms); or to reduce the rate of progression of the pathophysiology of huntington's disease (e.g., therapeutic effect compared to placebo or compared to a natural course control; e.g., measured according to a standard scale such as the clinical scale described above or below, or according to neuroimaging).

The term "rate of progression" as used herein refers to the rate of annual change (e.g., decay) or the rate of annual change (e.g., decay) as assessed, for example, on a standard scale, such as a clinical scale, or on a neuroimaging measurement.

The term "reduced" as used herein refers to, for example, a 5%, 10%, 20%, 30%, 40%, 50%, 60% or 70% decrease in annual treatment.

The term "delay" as used herein refers to a delay of at least, for example, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 years.

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" as used herein refer to delaying the onset of huntington's disease, e.g., increasing the time of huntington's disease onset as defined herein. On the other hand, the term refers to decreasing the rate of progression between stages of huntington's disease, e.g. from the early stages of HD to the more advanced stages of HD, e.g. compared to placebo, according to a standard scale, e.g. a clinical scale [ e.g. according to the UHDRS full functional capability assessment (TFC) scale, e.g. as described in Neurology,1979,29,1-3 ]. On the other hand, the term refers to a decrease in the rate of progression from HD 1 phase to HD 2 phase (e.g., as compared to placebo). On the other hand, the term refers to a decrease in the rate of progression from HD 2 phase to HD 3 phase (e.g., as compared to placebo). On the other hand, the term refers to a decrease in the rate of progression from HD 3 phase to HD 4 phase (e.g., as compared to placebo). On the other hand, the term refers to a decrease in the rate of progression from HD 4 phase to HD 5 phase (e.g., as compared to placebo). On the other hand, the term refers to a decrease in the rate of progression from early HD to mid HD (e.g., as compared to placebo). On the other hand, the term refers to a decrease in the rate of progression from mid-stage HD to late-stage HD (e.g., as compared to placebo).

The term "decrease in the rate of progression" as used herein refers to, for example, increasing the time to progression of each phase of HD (e.g., as compared to placebo).

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 delaying the onset of huntington's disease (e.g., increasing the time of onset of huntington's disease as defined herein) by at least 25% (e.g., 25% or more, e.g., 25% to 50%).

The term "onset of huntington's disease" as used herein refers to a clinical diagnosis of HD that is generally established [ e.g., a Diagnosis Confidence Score (DCS) is a dyskinesia onset of 4, as defined by the huntington's disease unified rating scale (UHDRS) total motor function score (TMS) ].

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 delaying the onset of huntington's disease-related symptoms, e.g., increasing the onset time of one or more symptoms associated with huntington's disease selected from the group consisting of motor function decline associated with huntington's disease, cognitive decline associated with huntington's disease, mental decline associated with huntington's disease, and functional capacity decline associated with huntington's disease as defined herein. In another aspect, the term refers to a decrease in the rate of progression of one or more symptoms associated with huntington's disease selected from the group consisting of motor impairment associated with huntington's disease, cognitive impairment associated with huntington's disease, mental impairment associated with huntington's disease, and functional capacity impairment associated with huntington's disease, as defined herein. The term "rate of decrease" as used herein refers to, for example, an increase in the time to onset of onset or an increase in the time to severity (e.g., as compared to placebo). On the other hand, the terms "slowing the progress of HD", "slowing the progress of huntington's disease", "to slow the progress of HD" or "to slow the progress of huntington's disease" as used herein refer to the rate at which pre-symptomatic HD progresses to symptomatic HD [ i.e., delays the onset of symptomatic HD; for example, compared to placebo; the Diagnostic Confidence Score (DCS) was 4 as defined by the huntington's disease unified rating scale (UHDRS) total motor function score (TMS).

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 slowing the progression of huntington's pathophysiology.

The term "slowing the progression of the pathophysiology of huntington's disease" as used herein refers to reducing the rate of progression of the pathophysiology of huntington's disease, e.g., as assessed by Magnetic Resonance Imaging (MRI) [ e.g., by neuroimaging measures, e.g., as described in Lancet neuroal.2013, 12 (7), 637-649 ]. For example, it refers to reducing the rate of brain (e.g., whole brain, caudate nucleus, striatum, or cortex) volume loss (e.g., percent relative to baseline volume loss) associated with huntington's disease (e.g., as assessed by MRI) (e.g., reducing the rate of annual loss compared to placebo).

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

The term "hypokinesia" as used herein refers to a decrease in motor function (e.g., as compared to normal motor function or previous visits). For example, the decline in motor function may be assessed according to a standard scale, such as a clinical scale (according to a UHDRS rating scale, such as a UHDRS total motor function score (TMS) measurement; e.g., as described in Movement Disorders,1996,11,136-142).

The term "slowing down the decline of motor function" as used herein refers to reducing the decline rate of motor function (e.g., compared to placebo; e.g., reducing the annual decline rate of motor function, e.g., compared to placebo; e.g., as assessed by UHDRS total motor function score).

The term "rate of decrease" as used herein refers to an increase in the time to onset of onset or an increase in the time to severity (e.g., as compared to placebo; e.g., a decrease in the rate of annual decline, e.g., as compared to placebo).

The term "cognitive decline" as used herein refers to a decline in cognitive ability (e.g., as compared to normal cognitive function or previous visits). In one aspect, the term refers to, for example, the decline of one or more cognitive functions selected from the group consisting of attention, processing speed, vision space processing, timing, emotional processing, memory, language fluency, psychomotor function, and executive function. For example, the evaluation may be based on standard scales, such as clinical scales [ e.g., by a symbolic digital pattern test, a stark (Stroop) word reading test, a Montreal cognitive evaluation, or a HD cognitive evaluation combination (including a symbolic digital pattern test, a wire test B, a one-touch stocking, a rhythm tap, a mood recognition test, a Hopkins word learning test); such as those described in Movement Disorders,2014,29 (10), 1281-1288).

The term "slowing cognitive decline" as used herein refers to a reduction in the rate of cognitive decline (e.g., compared to placebo; e.g., a reduction in the rate of annual decline in cognition compared to placebo; e.g., as assessed by a signed digit pattern test, a stent Lu Shanci reading test, a montreal cognitive assessment, or a combination of HD cognitive assessments). The term "rate of decrease" as used herein refers to an increase in the time to onset of onset or an increase in the time to severity (e.g., as compared to placebo; e.g., a decrease in the rate of annual decline, e.g., as compared to placebo).

The term "mental retardation" as used herein refers to a decline in mental function (e.g., as compared to normal mental function or previous visits). 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 retardation may be assessed on a standard scale (e.g., clinical scale) (e.g., by apathy assessment scale or hospital anxiety depression scale; e.g., as described in Movement Disorders,2016,31 (10), 1466-1478,Movement Disorders,2015,30 (14), 1954-1960).

The term "slowing mental deterioration" as used herein refers to a reduction in the rate of mental deterioration (e.g., a reduction in the rate of mental deterioration compared to placebo; e.g., as assessed by the apathy assessment scale or the hospital anxiety depression scale). The term "rate of decrease" as used herein refers to an increase in the time to onset of onset or an increase in the time to severity (e.g., as compared to placebo; e.g., a decrease in the rate of annual decline, e.g., as compared to placebo).

The term "functional capacity" as used herein refers to, for example, the ability to work, process finances, manage housework, conduct activities of daily living, and the level of care required. Functional capabilities include, for example, one or more selected from the group consisting of work capabilities, financial transaction processing capabilities, household management capabilities, activities of daily living, and desired care levels.

The term "decline in functional capacity" as used herein refers to a decline in functional capacity (e.g., as compared to normal functional capacity or previous visits). For example, the decline in functional capability may be assessed according to standard scales, such as clinical scales (e.g., UHDRS functional assessment scale and independence scale, and UHDRS full functional capability assessment scale, e.g., as described in Movement Disorders,1996,11,136-142).

The term "slowing down the decline of functional capacity" as used herein refers to reducing the rate of decline of functional capacity (e.g., compared to placebo; e.g., the rate of decline of annual decline of functional capacity compared to placebo; e.g., as assessed according to the UHDRS functional assessment scale and the independence scale or the UHDRS full functional assessment scale). The term "rate of decrease" as used herein refers to an increase in the time to onset of onset or an increase in the time to severity (e.g., as compared to placebo; e.g., a decrease in the rate of annual decline, e.g., as compared to placebo).

The term "decline" as used herein refers to, for example, a condition or a particular characteristic of a condition worsens over time (e.g., annually), such as assessed according to a standard scale (e.g., clinical scale).

The term "huntington's disease unified rating scale" or "UHDRS" as used herein refers to the field of clinical rating scales developed by the huntington's research group (e.g., as described in Movement Disorders,1996,11,136-142, which is incorporated herein by reference in its entirety) that assess the clinical manifestations and ability of HD. UHDRS includes a rating scale for motor function, cognitive function and functional capacity. It derives scores that assess the HD primary features (e.g., motor and cognitive) and the overall functional impact of these features.

The term "cHDRS" refers to the Huntington's disease comprehensive unified rating scale that provides comprehensive measures of motor, cognitive and overall function (e.g., as described in Neurology,2017,89,2495-2502).

The terms "HD 1 phase", "HD I phase", "huntington's disease phase 1", "huntington's disease phase I", "huntington's disease phase 1" or "huntington's disease phase I" as used herein refer to clinically established HD disease phases [ e.g. assessed according to a standard scale (e.g. clinical scale), e.g. based on a UHDRS full functional capacity assessment (TFC) scale assessment, wherein the TFC score is 11 to 13]. In HD 1, patients have typically been clinically diagnosed with HD, with both life and work completely normal, and remain independent in functional capacity; typically 0 to 8 years after huntington's disease has occurred.

The terms "HD 2 phase", "HD II phase", "huntington's disease phase 2", "huntington's disease phase I", "huntington's disease phase 2" or "huntington's disease phase II" as used herein refer to clinically established HD disease phases [ e.g. assessed according to a standard scale (e.g. clinical scale), e.g. based on a UHDRS full functional capacity assessment (TFC) scale assessment, wherein the TFC score is 7 to 10]. In HD 2, the patient still works normally, but the ability is reduced, while it is somewhat difficult, and in most cases daily activities are performed, usually with little assistance; typically 3 to 13 years after huntington's disease has occurred.

The terms "HD 3 phase", "HD III phase", "huntington's disease phase 3", "huntington's disease phase III", "huntington's disease phase 3" or "huntington's disease phase III" as used herein refer to clinically established HD disease phases [ e.g. assessed according to a standard scale (e.g. clinical scale), e.g. based on a UHDRS full functional capacity assessment (TFC) scale assessment, wherein the TFC score is 4 to 6]. In HD 3, patients often cannot work or handle households anymore, requiring a lot of assistance in daily finance, home responsibility and activities of daily living; typically 5 to 16 years after huntington's disease has occurred.

The terms "HD 4 stage", "HD IV stage", "huntington's disease stage 4", "huntington's disease stage IV", "huntington's disease stage 4" or "huntington's disease stage IV" as used herein refer to clinically established HD disease stages [ e.g., assessed according to a standard scale (e.g., clinical scale), e.g., based on a UHDRS full functional capacity assessment (TFC) scale assessment, wherein the TFC score is 1 to 3]. In HD 4, patients often cannot live independently, but can still live at home with the help of a family or professional, but require a great deal of assistance in finance, housekeeping, and most activities of daily living; typically 9 to 21 years after huntington's disease has occurred.

The terms "HD 5 stage", "HD V stage", "huntington's disease stage 5", "huntington's disease stage V", "huntington's disease stage 5" or "huntington's disease stage V" as used herein refer to clinically established HD disease stages [ e.g., assessed according to a standard scale (e.g., clinical scale), e.g., based on a UHDRS full functional capacity assessment (TFC) scale assessment, wherein the TFC score is 0]. In HD 5, the patient's daily activities typically require full support by a professional care provider; typically 11 to 26 years after huntington's disease has occurred.

The terms "early HD", "early huntington's disease", "early HD" or "early huntington's disease" as used herein refer to a disease stage of HD in which the patient is largely functioning and may continue to work and live independently, but one or more of the following symptoms occur: slight involuntary movements, slight loss of coordination and difficulty in thinking about complex problems. On the other hand, as defined herein, the terms "early HD", "early huntington's disease", "HD early" or "huntington's disease early" refer to "HD 2 phase".

The terms "moderate HD", "moderate huntington's disease", "HD intermediate stage", "huntington's disease intermediate stage", "intermediate HD", "intermediate huntington's disease", "HD intermediate" or "huntington's disease intermediate" as used herein refer to disease stages of HD in which the patient may not work, manage his own finances or perform his own housework, but with the aid of which he can eat, wear his clothing and put into focus on personal hygiene. Often, at this stage, chorea, for example, may be prominent, as well as problems with swallowing, balance, tumbling, weight loss, and the ability to solve problems. On the other hand, as defined herein, the terms "intermediate HD", "intermediate huntington's disease", "HD intermediate stage", "huntington's disease intermediate stage", "intermediate HD", "intermediate huntington's disease", "HD intermediate" or "huntington's disease intermediate" refer to "HD 3 stage".

The terms "advanced HD", "advanced huntington's disease", "HD advanced", "huntington's disease advanced", "advanced HD" or "advanced huntington's disease", "HD end" or "huntington's disease end" as used herein refer to a disease stage of HD in which the patient requires assistance in all activities of daily living. Typically, at this stage, for example, chorea may be severe, but more commonly it is replaced by rigidity, dystonia and bradykinesia. On the other hand, as defined herein, the terms "advanced HD", "advanced huntington's disease", "HD advanced", "huntington's disease advanced", "terminal HD" or "terminal huntington's disease", "HD terminal" or "huntington's disease terminal" refer to "HD 4 phase" or "HD 5 phase".

The term "juvenile HD" or "juvenile huntington's disease" as used herein refers to a clinically established diagnosis of HD { e.g., based on: confirmed family history or positive gene detection (i.e., confirmed CAG repeat amplification 2:36 (SEQ ID NO: 22)); and symptom onset age <21 years }.

The term "juvenile HD" or "juvenile huntington's disease" as used herein refers to being affected by HD { e.g., based on: confirmed family history or positive gene detection (i.e., confirmed CAG repeat amplification 2:36 (SEQ ID NO: 22)); and the symptom onset age <21 years of patient.

The term "pediatric HD" or "pediatric huntington's disease" as used herein refers to a patient affected by HD { based on, for example: confirmed family history or positive gene detection (i.e., confirmed CAG repeat amplification 2:36 (SEQ ID NO: 22)) and clinical diagnosis } and patients <18 years of age.

The terms "HD patient", "huntington's disease patient", "patient suffering from huntington's disease" or "patient suffering from HD" refer to HD patients as defined herein.

The term "treatment" or "therapy" as used herein refers to obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, stabilizing or improving progression of HD phases (e.g., as compared to placebo). One aspect of the treatment is, for example, that the treatment should have minimal adverse effects on the patient, e.g., the agent used should be highly safe, e.g., not cause adverse side effects. In another aspect, the term "method of treatment" as used herein refers to "a method for treatment".

The term "intermittent dosing regimen" or "intermittent dosing schedule" as used herein refers to a dosing regimen comprising administration of compound 1 followed by a rest period. 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 refers in particular to the period of time during which the patient is not administering compound 1 (i.e. the period of time during which the administration of compound 1 treatment is stopped). For example, if compound 1 is administered daily, a rest period will be if daily administration is stopped for a period of time, e.g., several days, or the plasma concentration of compound 1 is maintained below therapeutic levels for a period of time, e.g., several days. The period of administration and/or the dose of compound 1 may be the same or different between the periods. The total treatment time (i.e., number of treatment cycles) may also vary from patient to patient, for example, based on the particular patient being treated (e.g., phase I HD patient).

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

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

In one aspect, the term "administration" or "once daily administration of compound 1" as used herein refers to administration of a tablet containing 1mg to 100mg of compound 1 once daily.

On the other hand, tablets containing 1mg to 200mg of compound 1 were administered once daily.

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

In another aspect, the amount of compound 1 in a tablet administered once daily 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.

In another aspect, the amount of compound 1 in the tablet administered once a day 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.

In another aspect, the amount of compound 1 in the tablet administered once a day 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.

On the other hand, the content of compound 1 in the tablets administered once a day is selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 50mg, 60mg, 65mg, 70mg and 100mg.

On the other hand, the content of compound 1 in the tablets administered once a day is selected from 1mg, 5mg, 10mg, 20mg, 30mg and 50mg.

In another aspect, the amount of compound 1 in the tablet administered once a day is selected from 1mg, 5mg or 50mg.

In another aspect, the amount of compound 1 in the tablet administered once a day is selected from 5mg or 50mg.

On the other hand, the content of compound 1 in the tablets administered once a day is selected from 5mg, 10mg, 20mg and 30mg.

On the other hand, the content of compound 1 in the tablets administered once a day is selected from 5mg, 10mg and 20mg.

In the context of administration of compound 1, the term "weekly" or "once a week" or "QW" herein refers to administration of a dose of compound 1 once a week, wherein the doses are administered, for example, on the same day of the week.

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

On the other hand, compound 1 was administered at a dose of 35mg once a week, 70mg once a week and 140mg once a week.

In the context of administration of compound 1, the term "twice weekly" or "BIW" herein refers to the administration of one dose of compound 1 twice weekly, wherein each dose is administered at regular time intervals of 48 to 72 hours on different days of the week.

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

On the other hand, compound 1 is administered in a dose of 10mg to 20mg twice weekly, for example about 15mg twice weekly, 30mg to 40mg twice weekly, for example 35mg twice weekly, and 50mg to 90mg twice weekly, for example 70mg twice weekly.

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

The term "disease-modifying therapy" or "disease-modifying treatment" as used herein refers to a drug (i.e., a disease-modifying drug) that can modify or alter the progression of a condition or disorder or disease (e.g., HD as defined herein).

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

The term "patient" as used herein refers to a subject that is ill and will benefit from treatment.

The term "subject in need thereof" as used herein means that the subject (patient) would benefit biologically, medically or quality of life from the treatment if it were to receive the treatment.

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

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

2. Compounds of formula (I)

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

In one aspect, the amount of compound 1 in the tablet is selected from the group consisting of 5 to 30 wt%, 5 to 25 wt%, 10 to 20 wt% and 10 wt% based on the total weight of the tablet.

In one aspect, the amount of compound 1 in the tablet is 1mg to 200mg.

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

Tablets of compound 1 may be prepared by direct compression by mixing compound 1 with excipients and compressing them to form tablets. Tablets of compound 1 may also be prepared by other methods including wet granulation or dry granulation. When granulation is used, compound 1 may be an inter-particle and/or an extra-particle component of a tablet. In one aspect of the invention, compound 1 is an intragranular ingredient of a tablet. Compound 1 may be mixed with at least one intragranular excipient and wet or dry granulated to form an intragranular mixture for use in the preparation of tablets. In one aspect of the invention, a tablet is prepared by a process 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 the resulting mixture to form a tablet.

3. Excipient

In one aspect, the tablets provided herein comprise an excipient selected from the group consisting of diluents, binders, surfactants, disintegrants, glidants, and lubricants. In the case of the tablets provided herein, some excipients are only intragranular or extragranular excipients, while others are both intragranular and extragranular excipients.

a. Diluent agent

Diluents are excipients used to dilute the ingredients (e.g., active ingredients) of a formulation, adjust them to an amount suitable for the formulation, and in some cases, to impart stability or improve formability. Examples of diluents include sugars (e.g., lactose or glucose), sugar alcohols (e.g., mannitol, xylitol, maltitol, sorbitol, isomalt), and crystalline cellulose. Lactose, glucose, sucrose, fructose, maltose, trehalose. Microcrystalline cellulose may also be included in the tablets of the invention as a diluent in tablet formulations, and as an intragranular excipient. However, the term "diluent" as used herein refers to diluents other than microcrystalline cellulose.

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

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

b. Adhesive agent

Binders are classified as excipients that impart tackiness to maintain quality after forming tablets. The amount of binder in the tablets provided herein varies depending on, for example, the type of binder (properties such as molecular weight, solubility and viscosity), the type and amount of other excipients, the type and amount of the compound, and the dosage form (granulation and tabletting) of the formulation step thereof.

Examples of binders that may be used include hydroxypropyl cellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl starch, corn starch, pea starch, pregelatinized starch, acacia, tragacanth, modified gums, gelatin, and povidone.

In one aspect, povidone is included in the tablets of the present invention as an intragranular excipient and is present in an amount of from 1% to about 5%, alternatively from 1.5% to about 4%, alternatively from about 2% to about 3%, alternatively from about 2% by weight of the total weight of the tablet.

c. Disintegrating agent

Disintegrants are excipients that function to disintegrate tablets by absorbing water, swelling upon administration, thereby promoting the release of the active ingredient. In one aspect of the present tablet, the 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) of the total weight of the tablet in each of the intra-and extra-granular portions of the tablet. In another aspect, the disintegrant is present in an amount of about 2.5 weight percent of the total weight of the tablet in each of the intra-and extra-granular portions of the tablet.

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

d. Surface active agent

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

Non-limiting examples of surfactants that may be used include quaternary ammonium compounds (e.g., sodium dioctylsulfosuccinate), polyoxyethylene alkylphenyl ethers (e.g., nonylphenol ether 9, nonylphenol ether 10, and octylphenyl ether 9), poloxamers (polyoxyethylene and polyoxypropylene block copolymers, such as poloxamer 407), polyoxyethylene fatty acid glycerides and oils (e.g., polyoxyethylene (8), caprylic/capric monoglyceride and diglycerides, polyoxyethylene (35) castor oil, and polyoxyethylene (40) hydrogenated castor oil), polyvinyl alkyl ethers (e.g., polyoxyethylene (20) cetyl-stearyl ether), polyoxyethylene fatty acid esters (e.g., polyoxyethylene (40) stearate), polyoxyethylene sorbitan esters (e.g., polysorbate 20, and polysorbate 80 (e.g., tween 80)), propylene glycol fatty acid esters (e.g., propylene laurate), sodium lauryl sulfate, fatty acids, and salts thereof (e.g., oleic acid, sodium oleate, and triethanolamine), glycerol fatty acid esters (e.g., sorbitan laurate, sorbitan monooleate, sorbitan monopalmitate, and sorbitan monostearate), tyloxapol (tyrosol), and mixtures thereof.

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

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

e. Lubricant

A lubricant is an excipient that can be used to reduce friction between equipment and the granular mixture during compression to form tablets. Examples of suitable lubricants include glyceryl behenate, glyceryl behenate (glyceryl behaptate), alone or in combination; sodium stearyl fumarate, stearic acid, and salts thereof (including magnesium stearate, calcium stearate, and sodium stearate); hydrogenated vegetable oil; colloidal silica; talc; a wax; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene glycol; sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. When a lubricant is used in the tablet of the present invention, magnesium stearate is preferred.

In one aspect, the lubricant is included as an extra-granular excipient by weight based on the total weight of the tablet. In another aspect, the lubricant is included as an extra-granular excipient in an amount selected from the group consisting of 0.5% to about 3% by weight and 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 extra-granular 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 anti-tacking agents. Examples of glidants include colloidal silicon dioxide, hydrated sodium thioaluminate and talc. In one aspect of the present tablet, the glidant is included as an extra-granular excipient. When present, the glidant is present in an amount selected from about 0.25% to about 2% by weight and about 0.25% to about 1% by weight of the total weight of the tablet. When present, glidants comprise about 0.5% by weight of the total weight of the tablet.

g. Other excipients

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

4. Coating layer

The tablets of the invention are optionally coated with a film suitable for immediate release tablets, such as film coatings comprising polyvinyl alcohol and hydroxypropyl methylcellulose.

5. Tablet preparation method

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

stage one (intragranular step):

(a) The povidone is dissolved in water and,

(b) The remaining intragranular components are screened, for example #30 mesh,

(c) The sieved ingredients are mixed to form granules,

(d) Wetting the particles with povidone solution and mixing until optimal particles are obtained,

(e) The best granules are dried, preferably until a moisture content of about 2% is reached,

(f) The dried granules are passed through a sieve of a specific size, for example a #20 mesh sieve.

Stage two (extra-granular stage)

(a) All extra-granular excipients, except the lubricant (e.g., magnesium stearate), are sieved, e.g., #20 mesh,

(b) The sieved extra-granular excipients are added to the first stage of grinding granules and mixed,

(c) The lubricant is sieved, for example using a #30 mesh sieve, and added to the mixture, and further mixed,

stage three (tabletting)

The mixture from the last step of stage two above is compressed into tablets using a tablet press and optionally each tablet is film coated.

6. Tablet characteristics

The tablets of compound 1 according to the invention preferably have all of the following characteristics:

rapidly disintegrating 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 in the tablet has stability.

7. Use of compound 1

The tablets of compound 1 provided herein are useful for treating or ameliorating huntington's disease.

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

(i) Slowing the rate of decline of motor function associated with huntington's disease, wherein a decrease in motor function associated with huntington's disease following treatment with compound 1 is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins or a comparison to placebo; wherein the motor function is selected from the group consisting of eye movement function, dysarthria, dystonia, chorea, postural stability and gait; and, by using standard clinical scales, such as the UHDRS exercise assessment scale (e.g., described in Movement Disorders,1996,11,136-142);

(ii) Slowing the cognitive decline rate associated with huntington's disease, wherein a decrease in cognitive decline rate associated with huntington's disease following treatment with compound 1 is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins or in comparison to placebo; wherein the cognitive function is selected from the group consisting of attention, processing speed, vision spatial processing, timing, mood processing, memory, language fluency, psychomotor function, and executive function; and, by using standard clinical scales for evaluation, such as a symbolic digital pattern test, a stoneley Lu Shanci reading test, a montreal cognitive evaluation, or a HD cognitive evaluation combination [ (including symbolic digital pattern test, wire test B, one-touch stocking (One Touch Stockings), rhythmic tapping, emotion recognition test, hopkins word learning test); for example Movement Disorders,2014,29 (10), 1281-1288;

(iii) Slowing the rate of mental retardation associated with huntington's disease, wherein a decrease in mental retardation associated with huntington's disease following treatment with compound 1 is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins or a comparison to placebo; wherein the mental retardation is selected from apathy, anxiety, depression, compulsive behavior, suicidal thoughts, irritability and agitation; and, using a standard clinical scale for evaluation, such as an apathy evaluation scale or a hospital anxiety depression scale; for example Movement Disorders,2016,31 (10), 1466-1478,Movement Disorders,2015,30 (14), 1954-1960;

(iv) Slowing down the rate of decline in functional capacity associated with huntington's disease, wherein a decrease in the rate of decline in functional capacity associated with huntington's disease following treatment with compound 1 is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins or a comparison to placebo; wherein the functional capability is selected from the group consisting of work capability, capability to handle financial transactions, capability to manage household tasks, capability to perform activities of daily living, and a desired level of care; and, by using standard clinical scales, such as UHDRS full functional capability assessment scales, functional assessment scales, and independence scale assessments (e.g., as described in Movement Disorders,1996,11,136-142).

(v) Slowing the progression of huntington's pathophysiology, wherein the progression of huntington's disease pathophysiology associated with huntington's disease following treatment with compound 1 is slowed [ e.g., brain (e.g., whole brain, caudate nucleus, striatum, or cortex) volume loss rate (e.g., percent decrease relative to baseline volume) is reduced ] as indicated by mRNA reduction and wild-type and mutant HTT proteins reduction or by comparison with placebo, and assessed using standard techniques (e.g., MRI (e.g., by neuroimaging measurement)), see, e.g., lancet nerve.2013, 12 (7), 637-649;

(vi) Slowing down the onset of huntington's disease or the onset of symptoms associated with huntington's disease, wherein the slowing down of huntington's disease onset or huntington's disease-associated symptom onset is indicated by a decrease in mRNA and a decrease in wild-type and mutant HTT proteins or by comparison to placebo, and evaluated using standard clinical scales, such as huntington's disease health-related quality of life questionnaires (HDQoL) (e.g., as described in Movement Disorders,2018,33 (5), 742-749); or alternatively, the first and second heat exchangers may be,

(vii) Reduction of huntington's disease-associated quality of life decline, wherein a reduction in the onset of huntington's disease or a reduction in the onset of huntington's disease-associated symptoms following treatment with compound 1 is indicated by a reduction in mRNA and a reduction in wild-type and mutant HTT proteins or by comparison to placebo, and evaluated using standard clinical scales, such as huntington's disease health-related quality of life questionnaire (HDQoL) (e.g., movement Disorders,2018,33 (5), 742-749).

In another aspect, treatment or amelioration of huntington's disease with compound 1 or a pharmaceutically acceptable salt thereof has one or more of the following effects: (i) Advantageous therapeutic properties, such as advantageous safety properties or metabolic properties; alternatively, (ii) favorable off-target effect properties, such as favorable psychiatric adverse event properties, favorable toxicity (e.g., genotoxicity), or cardiovascular adverse event properties (e.g., blood pressure, heart rate, electrocardiographic parameters).

In one aspect, a patient in need thereof orally administered a tablet of the invention comprising a therapeutically effective amount of compound 1.

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

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

In another aspect, the tablet contains a therapeutically effective amount 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 200 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 135mg, and 140 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 135mg, and 140 mg.

In another aspect, the tablet contains a therapeutically effective amount selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 50mg, 60mg, 65mg, 70mg, and 100 mg.

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

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

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

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

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

In one aspect, a patient in need thereof orally administered a tablet of the invention comprising a therapeutically effective amount of compound 1 times daily.

In another aspect, the tablet contains 1mg to 200mg of compound 1 in a therapeutically effective amount administered 1 time per day.

In another aspect, the tablet contains 1mg to 100mg of compound 1 in a therapeutically effective amount administered 1 time per day.

In another aspect, the tablet contains a therapeutically effective amount 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 administered 1 time per day.

In another aspect, the tablet contains a therapeutically effective amount 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 administered 1 time per day.

In another aspect, the tablet contains a therapeutically effective amount selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 135mg and 140mg administered 1 time per day.

In another aspect, the tablet contains a therapeutically effective amount selected from 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 50mg, 60mg, 65mg, 70mg and 100mg administered 1 time per day.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In another aspect, the tablet comprising a therapeutically effective amount of compound 1 is administered 1 time per day.

In another aspect, the tablet containing a therapeutically effective amount of compound 1 is administered 2 times per day.

In another aspect, the tablet containing a therapeutically effective amount of compound 1 is administered 3 times per day.

In another aspect, the tablet containing a therapeutically effective amount of compound 1 is administered 1 time per week.

In another aspect, the tablet containing a therapeutically effective amount of compound 1 is administered 1 time every 2 weeks.

In one aspect, a tablet comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, is used as a disease modifying therapy in the treatment or amelioration of huntington's disease, including two huntington's diseases selected from the group consisting of: hereditary huntington's disease characterized by 36 to 39 amplifications of the CAG repeat in the HTT gene on chromosome 4; and hereditary huntington's disease characterized by >39 amplifications of the CAG repeat in the HTT gene on chromosome 4.

In one aspect, a tablet comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, is used as a disease modifying therapy in the treatment or amelioration of huntington's disease, including several huntington's diseases selected from the group consisting of: symptomatic huntington's disease, juvenile huntington's disease, childhood huntington's disease, early-stage huntington's disease, mid-stage huntington's disease, late-stage huntington's disease, stage I huntington's disease, stage II huntington's disease, stage III huntington's disease, stage IV huntington's disease, stage V huntington's disease, and premsymptomatic huntington's disease.

In one aspect, a tablet comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is administered according to an intermittent dosing regimen.

In another aspect, a tablet comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is administered 1 or 2 times per week.

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

In another aspect, a tablet comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition.

In another aspect, a tablet comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical combination.

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

In one aspect, a method of treating huntington's disease progression 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 treating a motor dysfunction associated with 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 treating a cognitive decline associated with 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.

In another aspect, a method of treating a mental retardation associated with 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 treating a decrease in functional capacity associated with 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.

On the other hand, a method of treatment for slowing the pathophysiological progression of huntington's disease associated with huntington's disease [ e.g., a reduction in brain (e.g., whole brain, caudate nucleus, striatum, or cortex) volume loss rate (e.g., percent reduction from baseline volume) (e.g., as assessed by MRI) ] in a subject in need thereof, comprises administering to the subject one or more tablets comprising a therapeutically effective amount of compound 1.

In another aspect, a method of treating a motor dysfunction associated with 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; wherein the motor function is selected from the group consisting of eye movement function, dysarthria, dystonia, chorea, postural stability and gait.

In another aspect, a method of treating a cognitive decline associated with 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; wherein the cognitive function is selected from the group consisting of attention, processing speed, vision spatial processing, timing, mood processing, memory, language fluency, psychomotor function, and executive function.

In another aspect, a method of treating a mental retardation associated with 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; wherein the mental retardation is selected from apathy, anxiety, depression, compulsive behavior, suicidal thoughts, irritability and agitation.

In another aspect, a method of treating a decrease in functional capacity associated with 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; wherein the functional capability is selected from the group consisting of work capability, capability to handle financial transactions, capability to manage household tasks, capability to conduct activities of daily living, and a desired level of care.

On the other hand, a method of treatment for slowing the pathophysiological progression of huntington's disease associated with huntington's disease [ e.g., a reduction in the rate of brain (e.g., whole brain, caudate nucleus, striatum, or cortex) volume loss (e.g., as a percentage of baseline volume reduction) (e.g., as assessed by MRI) ] in a subject in need thereof, comprises administering to the subject one or more tablets comprising a therapeutically effective amount of compound 1.

In one aspect, a method of treating or ameliorating 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 200mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 100mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 1mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 5mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 10mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 15mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 20mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 25mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 30mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 35mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 40mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 45mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 50mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 55mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 60mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 65mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 70mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 75mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 80mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 85mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 90mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 95mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 100mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 105mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 110mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 115mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 120mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 125mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 130mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 135mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 140mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 145mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 150mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 155mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 160mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 165mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 170mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 175mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 180mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 185mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 190mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 195mg of therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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 200mg of the therapeutically effective amount of compound 1.

In another aspect, a method of treating or ameliorating 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, 1 time per day.

In another aspect, a method of treating or ameliorating 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, 2 times per day.

In another aspect, a method of treating or ameliorating 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, 3 times per day.

In another aspect, a method of treating or ameliorating 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, 1 time per week.

In another aspect, a method of treating or ameliorating 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, 1 time every 2 weeks.

In one aspect, a method of treating or ameliorating 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 the huntington's disease comprises two huntington's diseases selected from the group consisting of: hereditary huntington's disease characterized by 36 to 39 amplifications of the CAG repeat in the HTT gene on chromosome 4; and hereditary huntington's disease characterized by >39 amplifications of the CAG repeat sequence of the HTT gene on chromosome 4.

In one aspect, a method of treating or ameliorating 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, or a pharmaceutically acceptable salt thereof, wherein the huntington's disease comprises a compound comprising at least one huntington's disease selected from the group consisting of: symptomatic huntington's disease, juvenile huntington's disease, childhood huntington's disease, early-stage huntington's disease, mid-stage huntington's disease, late-stage huntington's disease, stage I huntington's disease, stage II huntington's disease, stage III huntington's disease, stage IV huntington's disease, stage V huntington's disease, and premsymptomatic huntington's disease.

In another aspect, a method of treating or ameliorating 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, according to an intermittent dosing regimen.

In another aspect, a method of treating or ameliorating 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, once daily, 1 time per week, or 2 times per week.

In another aspect, a method of treating or ameliorating 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.

In another aspect, a method of treating or ameliorating 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, in the form of a pharmaceutical composition.

In another aspect, a method of treating or ameliorating 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, in a pharmaceutical combination.

In another aspect, a method of treating or ameliorating 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 following gene therapy or treatment with an antisense compound.

In another aspect, a method of treating or ameliorating 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 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 comprising a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, to produce an in-frame stop codon between exons 49 and 50 in HTT mRNA.

Examples

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

Example 1

Six experimental batches (1-6) of tablets of compound 1 were prepared using direct compression: the components were weighed, sieved through a #35 sieve, then low shear mixed, and compressed into tablets. However, the flow was insufficient and sticking to the tablet punches was observed at the time of tabletting. Two placebo tablets (7 and 8) were prepared in the same manner without compound 1. The composition of each batch is shown in table 1 below.

TABLE 1

Example 2

To solve the poor direct compression flowability and blocking problems found for each batch in example 1, three additional batches (9, 10 and 11) of tablets were prepared using roller compaction dry granulation were introduced: the components were weighed, sieved through a #35 sieve, mixed using a turbula mixer, and then crushed. The ribbons were then crushed and passed through a #20 sieve and the other extra-granular ingredients were mixed using a turbula mixer and then compressed in a tablet press. Good mixing uniformity is realized. All three batches were identical and similar in composition to the 6 batches described above, except that they contained equal weight percentages of lactose monohydrate and microcrystalline cellulose (mcc) (41.5% each). However, different compaction parameters (roller speed, screw speed and pressure) were used for each batch. The rolled ribbons produced in lot 9 are best. Batch 11 sticks to the roll and the ribbon is brittle, while batch 12 produces a discontinuous ribbon.

The dissolution test was performed on dry granulation batch 9, but due to the wetting problem of compound 1, there were particles floating on the dissolution medium surface.

Example 3

To alleviate the wetting problem observed in example 2, it was decided to add a surfactant to the formulation. Direct compression batches 13 and 14 were prepared using 5% w/w sodium dodecyl sulfate (SLS) and 1% poloxamer 188, respectively, and compound 1 at a concentration of 50 mg. As 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 dissolution medium surface. Thus, inclusion of poloxamer appears to reduce the wetting problem of the particles of compound 1. However, a build-up phenomenon was observed during the dissolution experiment carried out at 50 revolutions per minute (rpm), and complete release of the drug was observed only when the paddle speed was increased to 150rpm at 75 minutes.

Direct compression lot 17 was also prepared in a similar manner, using lower concentrations of microcrystalline cellulose and poloxamer 407 as surfactants. This batch has a problem of poor processability.

13. The composition of batches 14 and 17 is summarized in table 2 below.

TABLE 2

Example 4

To minimize the build-up in the dissolution vessel, wet granulation batches 15 and 16 were prepared with lower levels of Avicel PH102 and 0.5% w/w and 2.5% w/w povidone (PVP) K30 and 1% poloxamer 407, respectively. Wet granulation was performed using a mortar and pestle. The intragranular ingredients were passed through a #20 mesh screen and mixed. And dissolving povidone K30 in water to obtain a granulating liquid. The premix was then wet granulated with povidone K30 solution using a mortar and pestle to obtain the best granules. The wet mass was dried in a tray oven at 60 ℃ until the moisture content reached about 2%. The dried granules were passed through a #20 mesh screen and mixed with an extragranular excipient screened through a #20 mesh screen. The unlubricated mixture was mixed with magnesium stearate sieved through a #35 mesh sieve to obtain the final mixture.

15 batches were found to be the best formulation with little build up when dissolved at 50 rpm. The 16 batches containing 2.5% w/w PVP K30 were found to be inferior to the 15 batches in terms of dissolution performance, probably due to the higher content of PVP K30 binder leading to tighter particles.

Wet granulation 18 batches were also prepared in the same manner as described above using a lower level of Avicel PH102 (10% w/w) to test whether the build-up in dissolution could be further reduced. However, at the time of dissolution test, the batch failed to completely release compound 1.

Wet granulation batch 19 was also prepared in a similar manner as described above, but with 30% mcc in both the intra-and extra-granular blends. This batch also suffers from stacking and poor integrity.

Example 5

Additional dry granulation batch 20 was prepared using an intragranular blend containing 41% microcrystalline cellulose (mcc) and lactose monohydrate, but no microcrystalline cellulose (mcc) or lactose monohydrate in the extragranular component.

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

TABLE 3 Table 3

Example 6

The dissolution performance of batches 9, 14, 15, 16, 17, 18 and 20 was tested in 500ml of 0.01n HCl while stirring with paddles at 50rpm for 60 minutes, increasing to 75rpm for 75 minutes, increasing to 150rpm for 90 minutes, and withdrawing 5ml at each of 5, 10, 15, 20, 30, 45, 60, 75 and 90 minutes.

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

The dissolution stability of batch 15 was tested at various paddle speeds (50, 65 and 75 revolutions per minute) and acceleration temperature conditions. We found that the faster the paddle speed, the higher the percentage of drug released at each time point, and that at each paddle speed, the initial release for the first 5 minutes was 81%, 88% and 95%, respectively. The release rates were even faster when tested in 0.01N HCl at room temperature, 40 ℃ or 65 ℃ at a paddle speed of 75rpm, with initial release percentages of 95.4, 92.6 and 96.4, respectively.

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

Example 7

Compound 1 exposure after three formulations of fasted male cynomolgus monkey oral (PO) compound 1 was evaluated as follows. One of the formulations (21 batches) was a suspension of 6% w/w compound 1 in 0.5% w/w hydroxypropyl methylcellulose (HPMC). The other two formulations tested were tablets from wet granulation 15 batches and dry granulation 20 batches prepared as described in example 4 above.

Cynomolgus monkeys were divided into three groups of four. Cynomolgus monkeys were fed in the afternoon the day before dosing, and the remaining food was cleared at 7 pm. Refeeding was performed four hours after administration. Each cynomolgus monkey receives a 30mg oral dose of compound 1 (21 batches of 5ml of 6mg/ml compound 1 suspension, wet granulating 15 batches or dry granulating 20 batches of 2 tablets per cynomolgus monkey, 15mg per tablet) via a rubber mouth feeding tube or via a tablet, after each dose is rinsed with 3 ml deionized water. Blood samples were drawn from each cynomolgus monkey at the following time points: pre-dosing (0), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 48 hours. Each sample was centrifuged at 3000xg at 8 ℃ for 5 minutes, plasma was collected and frozen on dry ice until testing. Plasma concentrations were determined by LC-MS/MS. Pharmacokinetic parameters were determined.

Individual plasma concentration profiles of compound 1 following oral administration of 30mg of an oral compound 1 suspension in 0.5% HPMC in water (lot 21) in male cynomolgus monkeys (group 1) are provided in figure 1. Four cynomolgus monkeys in the study were labeled "Mky 15-218", "Mky-172", "Mky 16-108" and "Mky 170004" in fig. 1 and other figures below. Average plasma concentrations at each time point in group 1 are provided in figure 2. The results are summarized in table 4 below:

TABLE 4 Table 4

As shown in table 4, after oral administration of the suspension formulation (21 batches) at 30 mg/animal (group 1), a maximum plasma concentration (average 111±47.6 ng/mL) was observed at 6 to 12 hours after administration. The average half-life after oral administration was 20.7 hours. The average total exposure of 30 mg/animal of compound 1 (group 1) was 2515±788 hours ng/mL, and AUClast normalized based on dose was 369±138 hours kg ng/mL/mg.

Individual plasma concentration profiles obtained from each cynomolgus monkey after oral administration of 30 mg/animal (group 2) of tablet formulation a (wet granulation 15 batch) are provided in figure 3. Mean plasma concentration profiles for each time point are provided in figure 4. The results of study group 2 are summarized in table 5:

TABLE 5

As shown in table 5, after oral administration of tablet formulation a (wet granulated 15 batches) at 30 mg/animal (group 2), a maximum plasma concentration (average 124±58.8 ng/mL) was observed at 6 to 8 hours after administration. The average half-life after oral administration was 28.0±10.3 hours. The average total exposure of 30 mg/animal of compound 1 (group 2) was 3110±997 hours ng/mL, based on dose normalized AUC _last 455.+ -. 151 hours kg ng/mL/mg.

Tablet formulation B (wet method) was orally administered at 30 mg/animal (group 3)15 batches of pellets), individual plasma concentration profiles obtained from each cynomolgus monkey are provided in fig. 5. Mean plasma concentration profiles for each time point are provided in figure 6. The results of the study in group 4 are summarized in table 6, where x represents AUC with suspension formulations _last Comparison with p<0.05。

TABLE 6

As can be seen from table 6, after oral administration of tablet formulation B (dry granulation 20 batches) at 30 mg/animal (group 3), a maximum plasma concentration (average 73.5±37.2 ng/mL) was observed at 6 hours after administration. The average half-life after oral administration was 26.4±4.20 hours. The average total exposure of 30 mg/animal of compound 1 (group 3) was 1524±562 hours ng/mL and based on dose normalized AUC _last 237.+ -. 102 hours kg ng/mL/mg.

AUC normalized based on mean dose _last The value for exposure of tablet formulation a (wet granulation 20 lot) was 455 hours kg ng/mL/mg, which is 124±23% of the suspension formulation exposure (369 hours kg ng/mL/mg). The exposure of tablet formulation B (dry granulated 15 lot) was 237 hours x kg x ng/mL/mg, which is 58±10% of the suspension formulation exposure. Thus, the AUC of solid formulation a was found to be very similar to the AUC of the suspension formulation. However, AUC of solid formulation B was significantly reduced compared to the value of suspension formulation (P <0.05). In other words, these studies showed that the bioavailability of compound 1 in the wet granulation prepared tablet (20 lot formulation) was significantly higher than the suspension formulation or the dry granulation prepared tablet (15 lot formulation).

Example 8

Other studies were conducted using wet granulation formulation 20 batches of tablets as a starting point to determine excipients and the concentration of each excipient that can be scaled up and easily processed during tabletting, which have excellent physical properties, including fast dissolution properties. Lactose and cellulose brand are chosen which are particularly suited for wet granulation processes and increase the total content of excipients in the granule. The povidone concentration was increased from 1% to 2% to 5% in three different batches. The total lactose monohydrate content used in the formulation also increases and the mcc to lactose monohydrate ratio decreases. Examples of the three formulations prepared and tested are provided in table 7 below. 500g each batch containing 50g of Compound 1 was prepared according to the following formulation.

TABLE 7

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

TABLE 8

22 batches were adhered and PVP content was 1% and when the formulation was scaled up to 500g, a large amount of fines appeared in the formulation. Because of these problems, the batch was stopped from tabletting.

23 batches with PVP content of 2% were found to be compressible into tablets without blocking problems.

For 24 batches, the PVP content was 5%, and the disintegration time of the prepared tablets increased significantly to 17 minutes. The final mixture of batch 24 also showed separation between the granular and powdered extra-granular excipients.

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

Example 9

23 batches (containing 2% PVP) containing 5mg and 50mg of Compound 1, respectively, as described above, were tested for stability after storage at 50℃for 2 weeks and at 40℃for 1 month at 75% relative humidity. The elution was performed in 500ml of 0.01N HCl, instrument II, and stirred at 75 revolutions per minute. The tablets showed chemical stability and no increase in related substances was observed. The resulting dissolution curves are shown in fig. 8 (5 mg tablet) and fig. 9 (50 mg tablet). The dissolution profile shows that compound 1 is released immediately from each tablet and is comparable to the initial profile even after storage at higher temperatures and humidity.

Example 10: first-stage clinical study protocol

A first dose escalation study was initiated to evaluate the safety and pharmacokinetics of compound 1 oral tablets (5 mg and 50 mg) in healthy subjects compared to placebo.

The main research purpose is as follows:

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

Secondary study purposes:

(i) Characterization of the pharmacokinetics of single dose compound 1 in healthy subjects; (ii) Characterization of the pharmacokinetics of compound 1 administration for 14 days or up to 21 days in healthy subjects; (iii) Evaluating QTc and drug concentration effects of compound 1 after repeated escalation doses; (iv) Assessing the safety and tolerability of compound 1 in healthy subjects 7 days after administration; (v) Characterization of safety and tolerability of single dose compound 1 administration in fed state in healthy subjects; and (vi) characterizing the pharmacokinetics of compound 1 when administered in healthy subjects for up to 28 days.

Exploratory study purposes:

(i) Exploring the effect of single administration of compound 1 on Huntington (HTT) pre-mRNA splicing in the blood of healthy subjects; (ii) Exploring the effect of compound 1 administration for 14 days or up to 21 days on HTT pre-mRNA splicing and HTT protein levels in the blood of healthy subjects; (iii) Exploring the effect of single administration (feeding) of compound 1 on HTT pre-mRNA splicing in the blood of healthy subjects; (iv) The effect of compound 1 administration on HTT pre-mRNA splicing and HTT protein levels in the blood of healthy subjects was explored for up to 28 days.

Study design:

one study was performed in 5 parts: single increment dose (SAD) (part 1), multiple increment dose (MAD) (part 2), cerebrospinal fluid and blood collection (part 3), food effect (part 4), and multiple administrations up to 28 days after administration of compound 1 (part 5). Part 1, part 2 and part 5 employ double blindness; parts 3 and 4 use open labels. Note that parts 3, 4 and 5 may be performed simultaneously.

The research method comprises the following steps:

the study was supervised by the Security Review Committee (SRC). The purpose of SRC is to ensure that treatment does not pose an undue risk to the subject. The safety and tolerability of each cohort was assessed by the SRC both before the rise from one dose level to the next higher dose level in part 1 (single increment dose [ SAD ]) and part 2 (multiple increment dose [ MAD ]), and before starting part 3 (CSF), part 4 (FE), and part 5.

The SRC consists of: a chief researcher or representative (delegate only if the chief researcher is not present); sponsor medical supervisors or representatives (necessarily doctors); other internal or external specialists may be invited to participate in the examination or consult with it.

The various parts of the study are not necessarily in numerical order and may be performed simultaneously. The SRC held the conference before part 5 began, determining the dose used in this study. Based on the available SAD and MAD data, the dose (possibly including loading dose and maintenance dose) is selected before part 5 begins. The SRC does not plan to hold conferences between the part 5 queues. Part 1 (SAD):

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

Five dose levels were 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 queues.

The initial dose of the first cohort was less than or equal to 1/10 of the Human Equivalent Dose (HED) estimated from NOAEL (no visible deleterious effect level) of most susceptible species (male) rats, according to FDA guidelines for maximum recommended initial dose (MRSD) and EMA guidelines. NOAEL of the rats was 6mg/kg. This is a value set by observing germ cell shedding in epididymis and testis of male rats. The calculated HED was 0.97mg/kg; the human scale-up of 70kg is 68mg. Adjusting this dose to 1/10, the dose in the first cohort is 6.8; the actual dose was 5mg.

In cohort 1.1, sentinel dosing was performed in 2 subjects (1 subject took compound 1,1 subject took placebo). If no clinically significant safety issues were observed, the remaining subjects in the cohort were dosed at least 24 hours later. The remaining 6 subjects (5 subjects taking compound 1 and 1 subject taking placebo) can be administered as a group. Queue 1.1 is the only queue that performs sentinel dosing. In the subsequent cohort, all 8 subjects could be dosed as a group.

After each queue has completed dosing, an up-dosing conference will be held. The dose level for the next cohort will be based on PK and safety for the previous cohort. The incremental increase in dose is determined by the relationship between the average exposure in the queue and NOAEL exposure.

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

If the average area under the curve (AUC) is 1/10 of the NOAEL and < 1/5 of the NOAEL, the dose can be increased by at most 100%. I.e. the subsequent dose may be up to twice the previous dose.

If the average area under the curve (AUC) is 1/5 of the NOAEL and < 1/2 of the NOAEL, the dose can be increased by 50% at maximum. I.e. the subsequent dose may be up to 1.5 times the previous dose.

The highest dose level correlates to 1/2 of the AUC at which the average exposure does not exceed NOAEL; no additional incrementing is performed. The dose escalation will continue unless the dose escalation stop criteria are met.

Group inclusion will be assessed over a screening period of up to 28 days. The subjects were hospitalized 1 day (day-1) prior to dosing. Compound 1 or placebo was administered orally in the morning on day 1 after a overnight fast of at least 10 hours. After completion of all necessary study procedures and if medically appropriate, the subjects were discharged on day 8. After discharge on day 8, a 4 week (±1 week) secure telephone follow-up was performed.

Part 2 (MAD):

the multiple escalated dose (MAD) portion of the study was a randomized, double-blind, and placebo-controlled study conducted in healthy male and female subjects. Five protocols were planned to be tested in 5 cohorts of 8 subjects each (cohorts 2.1 to 2.5). In each cohort, 6 subjects received compound 1,2 subjects received placebo. Subjects in cohorts 2.1 and 2.2 were dosed for 14 days, 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, the safety parameters have been reviewed, the respective sadpk parameters have been calculated, and the MAD dosing simulation of the corresponding SAD dose has been performed, part 2 may begin. The selection of a particular multi-dose level depends on the available sadpk data, simulation, and general safety observed in section 1. After evaluating the dose level in a once daily fashion, pharmacokinetic modeling will be performed to determine fluctuations within the dosing interval. In cohort 2.3, day 1 and day 2 dosing will employ a loading dose that is higher than the selected dose for the remaining days of the planned dose. Queues 2.4 and 2.5 select similar dosing regimens. If the data collected and analyzed during the study indicated that it is necessary, it is contemplated that an alternating dosing regimen may be employed for all of the cohorts in section 2.

Group inclusion will be assessed over a screening period of up to 28 days. The subjects were hospitalized 1 day (day-1) prior to dosing. Compound 1 or placebo was administered orally following a overnight fast of at least 10 hours in the morning of each day of the scheduled dosing period (i.e., day 1 to day 21). The subjects will be discharged 7 days after the last dose (i.e. day 21 or up to day 28) and after completion of all necessary study procedures and if medically appropriate. The subjects will be reviewed out of the home 7 days (i.e., day 28 or up to day 35) to collect PK and PD (mRNA and HTT protein) samples. A secure telephone follow-up or outpatient review was performed on day 49 (+ -7 days).

Part 3 (CSF):

the concentration of compound 1 in plasma and CSF will be assessed in an open label design for healthy male and female subjects. A single dose of compound 1 was administered daily to 6 subjects in the cohort for 7 days (cohort 3.1). Dose levels for part 3 will be determined based on examination of safety, tolerability and PK data for study parts 1 and 2. Although the MAD dose will be further determined in the development, the dose and schedule will be applied to this part of the study.

Group inclusion will be assessed over a screening period of up to 28 days. The subjects were hospitalized 1 day (day-1) prior to dosing. Compound 1 was administered orally daily after a overnight fast of at least 10 hours in the morning from day 1 to day 7. CSF and plasma were sampled continuously for drug concentration testing on day 7. The exact time of CSF and blood sample will be determined from the results of parts 1 and 2. After completion of all necessary study procedures and if medically appropriate, the subjects were discharged on day 9. After discharge on day 9, a 4 week (±1 week) secure telephone follow-up was performed.

Part 4 (FE):

the Food Effect (FE) portion is a parallel, open label portion of healthy male and female subjects, up to 3 cohorts, 6 subjects each. Compound 1 was administered at up to 3 dose levels 30 minutes after a high fat, high calorie breakfast. When sufficient portion 1 data can be provided, portion 4 can be initiated. The dose level for this fraction will be selected based on the examination of safety, tolerability and PK data for fractions 1 and 2.

Group inclusion will be assessed over a screening period of up to 28 days. The subjects were hospitalized 1 day (day-1) prior to dosing. In the morning on day 1, compound 1 was orally administered after ingestion of a standardized high fat, high calorie breakfast. After completion of all necessary study procedures and if medically appropriate, the subjects were discharged on day 8. After discharge on day 8, a 4 week (±1 week) secure telephone follow-up was performed.

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

part 5 is a multi-dose randomized, double-blind, and placebo-controlled evaluation of healthy male and female subjects for up to 28 days. A maximum of 3 cohorts were planned, 8 subjects per cohort. Before part 5 begins, the SRC will select the dose (possibly including loading dose and maintenance dose), dosing regimen (including fed or fasted state) and duration (up to 28 days) based on the data provided by the part 1 and part 2 completed queues. In each cohort, 6 subjects received compound 1,2 subjects received placebo. The total dose on any day must not exceed the tolerance dose determined in section 1 (SAD).

Group inclusion will be assessed over a screening period of up to 28 days. The subjects were hospitalized 1 day (day-1) prior to dosing. On each day of dosing, compound 1 or placebo was orally administered in the morning after a evening fast or after a standard high fat post meal, according to SRC determination to select a regimen for a given cohort. The subjects will be discharged 7 days after the last dose and after completion of all necessary study procedures and if medically appropriate. Subjects will be reviewed out of the clinic 7 days after discharge to collect PK and PD (mRNA and HTT protein) samples and develop safety assessments. On day 1 and the day of expected maximum exposure (i.e., day 2 or, if no loading dose is used, day 29), the subject will be monitored using a 24-hour dynamic electrocardiogram monitoring device.

Study population:

part 1: up to 48 male and female subjects between 18 and 65 years of age (inclusive of 18 years and 65 years of age).

Part 2: up to 40 male and female subjects between 18 and 65 years of age (inclusive of 18 years and 65 years of age).

Part 3: 6 male and female subjects between 50 and 65 years of age (including 50 years and 65 years of age).

Part 4: up to 18 male and female subjects between 18 and 65 years of age (inclusive of 18 years and 65 years).

Part 5: up to 24 male and female subjects between 18 and 65 years of age (inclusive of 18 years and 65 years of age).

Group entry criteria:

consider that all subjects participating in the study must meet the following criteria:

for parts 1, 2, 4 and 5: healthy male or female subjects aged 18 to 65 years (18 years and 65 years inclusive) at the time of screening. For part 3, healthy male or female subjects aged 50 to 65 years (including 50 years and 65 years) at the time of screening.

The subject must know the nature of the study and must sign and date on a written informed consent prior to any study-related procedures.

When screening, the Body Mass Index (BMI) is more than or equal to 18.5kg/m ² And is less than or equal to 30.0kg/m ² The weight of the male subject is more than or equal to 50.0kg, and the weight of the female subject is more than or equal to 45.0kg.

The subject is determined to be healthy by the researcher based on medical assessments, including medical history, physical examination, laboratory examination results, ECG recordings (e.g., male QTcF.ltoreq.450 ms, female QTcF.ltoreq.470 ms) and vital signs. Values outside the range may be repeated once.

Male and female subjects with fertility potential must be willing to use 2 contraceptive methods during the study and within 30 days after the last administration.

Postmenopausal female subjects must have spontaneous amenorrhea (follicle stimulating hormone (FSH) at screening of > 30 mIU/mL) for > 12 months. Women with surgical sterilization are defined as women who underwent hysterectomy, bilateral ovariectomy or bilateral tubal ligation more than or equal to 6 months prior to screening.

All fertile female subjects must be negative in serum pregnancy test results at screening and negative in urine pregnancy test results at day-1.

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

Only part 3: the subject must be willing to receive a lumbar puncture for CSF sampling.

Only part 4: the subject must be willing and able to eat all high fat breakfast in the specified time frame.

Exclusion criteria:

subjects meeting any of the following conditions will be excluded:

subjects enrolled in any drug or device clinical study 60 days prior to screening, or those expected to participate in any drug or device clinical study during the present study.

It appears to the investigator that past or current medical conditions (e.g., concomitant diseases, mental disorders), medical history, physical examination results may adversely affect the safety of the subject or may impair assessment of the study results.

The general nervous system checks for abnormalities.

There were any clinically significant abnormalities during screening.

Any psychological, emotional problem, any disease or treatment resulting therefrom that may invalidate informed consent or limit the ability of a subject to follow the regimen requirements.

The screening result is positive for hepatitis B surface antigen, positive for hepatitis C antibody or positive for Human Immunodeficiency Virus (HIV) antibody.

Plasma was donated within 7 days prior to dosing. Donation or blood loss (excluding screen blood draw or menstrual flow) from 50mL to 499mL within 30 days prior to dosing, or exceeding 499mL within 56 days prior to dosing.

Excessive drinking within 6 months before screening (regular drinking of 21 units or more per week for male subjects and 14 units or more per week for female subjects). 1 unit (8 g) corresponds to 1/2 pint (280 mL) of beer, 1 glass (25 mL) of spirit or a small glass (125 mL) of wine.

The subject is a smoker or uses other nicotine-containing products. The abstinence person must quit smoking for >3 months before screening.

Urine drug screening, cotinine (cotinine) screening or alcohol exhalation test were positive at screening or day 1 of each treatment period.

Pregnant or lactating females.

The subject had previously received compound 1.

Only part 3: contraindications for lumbar puncture, such as low platelet count, abnormal prothrombin time international normalized ratio (PT-INR), spinal deformity, or other spinal disease that may interfere with lumbar puncture at the discretion of the researcher.

Treatment time

Part 1: 1 day; part 2: 14 days (queues 2.1 and 2.2) or up to 21 days (queues 2.3 to 2.5); first, the

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

Evaluation criteria:

curative effect:

if applicable, on day 1 (single dose) PK [ part 1 (SAD), part 2 (MAD, day 1), part 4 (FE) and part 5 (MD 28D, day 1)]The following PK parameters were evaluated: c (C) _max The method comprises the steps of carrying out a first treatment on the surface of the Maximum plasma concentration observed, C _max D; dose normalization C _max (part 1 only); t (T) _max The method comprises the steps of carrying out a first treatment on the surface of the Reach C _max Time of (2); AUC (AUC) _0-24 (area under the 0-24 hour concentration-time curve); AUC (AUC) _0-72 (area under the 0-72 hour concentration-time curve); AUC (AUC) _0-tau (the area under the concentration-time curve in the dosing interval, calculated by ascending linear/descending logarithmic trapezium, is only applicable to part 2); AUC (AUC) _0-t (area under the concentration-time curve from time zero to time t, where t is the last measured (or measurable) concentration (C _t ) Calculated by a linear upward/logarithmic downward trapezoidal method (only parts 1 and 4); AUC (AUC) _0-t /D (dose normalized AUC from time zero to last quantifiable concentration, part 1 only); AUC (AUC) _0-inf The method comprises the steps of carrying out a first treatment on the surface of the (area under the concentration-time curve from time zero to infinity, AUC) _0-inf ＝AUC _0-t +C _t /λ _z Wherein lambda is _z Is the terminal elimination rate constant, calculated by ascending linear/descending logarithmic trapezium (only parts 1 and 4); AUC (AUC) _0-inf D (dose normalized AUC from zero to infinity, part 1 only); lambda (lambda) _z (apparent end elimination rate constants, calculated by linear regression of the logarithmic concentration versus the end linear portion of the time curve, only parts 1 and 4); t is t _1/2 (apparent terminal half-life in ln (2)/λ) _z Calculation, only part 1 and part 4); CL/F (overall clearance, in dose/AUC _0-inf Calculation, only part 1 and part 4); and V _z F (apparent distribution volume, in dose/(lambda) _z *AUC _0-inf Calculated)).

On day 14, day 21, or day 28 (multi-dose) PK, the following PK parameters were evaluated [ part 2 (MAD) queues 2.1 and 2.2 (day 14), queues 2.3 to 2.5 (day 21), and part 5 (MAD) queues 5.1 to 5.3 (day 28)]：C _max (maximum plasma concentration observed during dosing interval); t (T) _max (C is reached within the dosing interval) _max Is a time of (2); c (C) _min (minimum concentration within dosing interval); c (C) _avg (average concentration over the dosing interval); AUC (AUC) _0-tau (area under concentration-time curve in dosing interval, calculated by ascending linear/descending logarithmic trapezoid method); AUC (AUC) _0-tau /D (dose normalized AUC) _0-tau )；λ _z (apparent end elimination constant, calculated by linear regression of the logarithmic concentration versus the end linear portion of the time curve); t is t _1/2 (apparent terminal half-life in ln (2)/λ) _z Calculating; CL/F (overall clearance, in dose/AUC _0-tau Calculating; v (V) _z F (apparent distribution volume, in dose/(lambda) _z *AUC _0-tau Calculation); AUCR (autonomous Underwater vehicle control) _auc (cumulative ratio, based on AUC) _0-tau : final dose AUC _0-tau * AUC on day 1 _0-tau ) The method comprises the steps of carrying out a first treatment on the surface of the And AUCR _cmax (cumulative ratio, based on C) _max : last dose C _max * Day 1C _max )。

The following PK parameters were assessed for part 2, day 14 (cohorts 2.1 and 2.2) or part 2, day 21 (cohorts 2.3 to 2.5) or part 5, day 28 (cohorts 5.1 to 5.3) and 7 day (multi-dose) PK [ part 3 (day 7) ], last dose:

C _max (maximum plasma concentration observed); t (T) _max (reach C _max Is a time of (2); AUC (AUC) _0.5-12 (area under concentration-time curve from time 0.5 hours to 12 hours, calculated by ascending linear/descending logarithmic trapezoid method); and CSF/plasma ratio (CSF and plasma concentration ratio (part 3 only).

Safety:

the following parameters are defined as parameters regarding safety and tolerability:

changes in vital signs from baseline to each predetermined time point to end of study (EOS); changes in ECG parameters from baseline to each predetermined time point to the end of the study; clinical laboratory testing changes from baseline to each predetermined time point to the end of the study; changes in C-SSRS score from baseline (only parts 2, 3, and 5); adverse Events (AEs) that occurred with treatment by the end of the study; adverse Events (AEs) that occurred in the treatment leading to premature discontinuation of study drug; serious Adverse Events (SAE) occurred in the treatment by the end of the study; physical examination is abnormal.

The statistical method comprises the following steps:

pharmacokinetics:

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

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

The plasma trough concentration was visually observed to determine whether steady state conditions were reached.

To evaluate the effect of food, PK parameters for compound 1 under fasted (part 1) and fed (part 4) conditions will be graphically displayed and descriptive statistics performed. Statistical analysis of each dose level of compound 1 was performed on 6 subjects using the treatment in fed state as a trial (part 4) and the same dose of treatment in fasted state as a reference (part 1).

The primary PK parameter is C _max 、AUC _0-t And AUC _0-inf . PK parameter C _max 、AUC _0-t And AUC _0-inf First, natural logarithmic transformation was performed, and the average value of these logarithmic transformation parameters was estimated by a linear model of treatment as the only fixed factor (compound 1 administered in fed state versus compound 1 administered in fasted state). The difference of these averages (logarithmic scale) and its 90% Confidence Interval (CI) are exponentiated to form the Geometric Mean Ratio (GMR) and the corresponding CI for that ratio. If C _max 、AUC _0-t And AUC _0-inf All 90% ci results of GMR included in the interval 80.00% -125.00% lead to the conclusion that no food effect is present.

Safety:

all safety parameters are summarized in terms of dose levels in parts 1 to 5.

Summary statistics (mean, median, standard deviation, minimum, maximum and number of available observations) of continuous demographic variables (e.g., age, height and weight) will be provided. A list of demographic data for a single subject will be provided.

Qualitative demographics (gender, race) will be summarized by counts and percentages. Only other baseline subject characteristics (e.g., medical history, physical examination clinical outcome, past medication, and inclusion/exclusion checklists) are listed.

ECG variables, vital sign measurements, and laboratory measurements at each time point are summarized using mean, median, standard deviation, minimum, maximum, number of available observations, and changes from baseline. The C-SSRS parameters will be analyzed using descriptive statistics where appropriate. ECG data, vital sign data, laboratory measurements, and a list of C-SSRS (parts 2, 3, and 5 only) for a single subject will be provided.

The distribution of these parameters between treatment groups (fasted or fed) was only described. No statistical inference was made.

Dynamic electrocardiography/compound 1 plasma concentration-QTc effects can be performed and the results will be provided in a separate report.

Results of the first-stage study

The main purpose of the phase 1 healthy volunteer trial was to establish a target dose range for compound 1 that reduced HTT mRNA and protein. The trial consisted of a single incremental dose (SAD) and multiple incremental dose (MAD) cohort. The dosing tolerance was good in all cohorts, and no safety-related findings were shown to demonstrate dose-dependent splicing of HTT mRNA. The study duration of the MAD cohort was longer, enabling longer term assessment of HTT mRNA splicing and HTT protein reduction. The MAD cohort showed that compound 1 exhibited a longer drug half-life, maintaining splicing for up to 72 hours after the last dose.

CSF sampling enables evaluation of the pharmacokinetics of compound 1 in CSF, wherein the level of compound 1 in CSF is compared to the level of compound 1 in plasma. Phase 1 studies indicate that the level of compound 1 in CSF is equal to or greater than that observed in plasma. The food affecting moiety enables evaluation of the pharmacokinetics of compound 1 in plasma following administration of a single dose of compound 1 in healthy subjects.

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

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

The lowest dose tested in both SAD and MAD queues achieved a 30-50% reduction in target levels. The half-life of HTT mRNA is estimated to be about 24 hours. Thus, after one day, if HTT mRNA is not synthesized, the total amount of HTT mRNA is expected to be about 50% of baseline. Administration of compound 1 in the SAD cohort inhibited substantially all de novo HTT mRNA synthesis. Thus, even with higher concentrations of compound 1, the total HTT mRNA remained at about 50% of baseline, representing the content of HTT mRNA synthesized prior to administration of compound 1.

The measurement results of HTT mRNA in whole blood of subjects in SAD cohorts are shown in fig. 14. The results also indicate that HTT splicing effects of compound 1 are reversible and last 72 hours after cessation of treatment.

The results of HTT RNA measurements in whole blood of human subjects taking placebo or 15 or 30mg of compound 1 as described in the Multiple Ascending Dose (MAD) study above are shown in fig. 15. HTT splicing was monitored after the last dose on day 14, calculated as the percentage of HTT remaining relative to baseline (day 0 before dose).

FIG. 10 schematically depicts HTT mRNA and protein degradation kinetics resulting in steady-state levels of RNA and protein.

In untreated cells, mRNA and protein are at steady state levels, as the amount of synthesized mRNA or protein matches the amount of degradation, so the mRNA and protein levels remain unchanged over time. Addition of compound 1 triggers inclusion of HTT pseudoexons into transcripts, resulting in rapid decay of HTT mRNA and reduction of HTT mRNA to about 50% of baseline. The half-life of HTT mRNA is about 24 hours. Thus, the amount of HTT mRNA present one day after drug treatment is regulated by the dose of compound 1. In this example, 50% of newly synthesized mRNA was inhibited. Of the HTT mRNA synthesized prior to treatment, about 50% 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, HTT proteins have half-lives of about 5-7 days, so it takes longer to reach new steady state levels. Finally, a new steady state is reached in which 50% mrna is present and new protein levels are reduced to 50% of the original amount. Changes in HTT protein levels in the MAD queue were evaluated over a longer period of time. Thus, healthy subjects were treated for 21 days, and then the content of HTT mRNA and protein in blood samples of each subject was measured.

FIG. 16 shows the levels of huntingtin mRNA and protein (100 mg Loading Dose (LD) for 2 days, 30mg administration for 21 days) in whole blood from MAD cohort 2.3, as described above, in percent of baseline, 24 hours after the last administration of vehicle or compound 1 to humans. The results showed that HTT mRNA was reduced to steady state. HTT protein levels take longer to administer to achieve maximum steady state decrease. It is expected that when HTT steady state decreases over time as treatment continues with compound 1, the observed change in HTT mRNA in the blood will result in a similar decrease in HTT protein levels in huntington's disease patients.

Figure 11 shows modeling 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 after treatment with compound 1 at a daily dose of 30 mg. For HTT mRNA, half-life is estimated to be about 24 hours. HTT mRNA reaches steady state after about 5 days. For HTT proteins, half-life is estimated to be 5-7 days, so steady state levels of HTT protein can only be reached about 6 weeks from the start of treatment.

Figure 12 compares the trace of HTT mRNA (figure 12A) and protein (figure 12B) reduction seen in multiple dose escalation studies with those predicted from half-life of HTT mRNA and protein as shown in figure 11. The results indicated that HTT mRNA levels decreased rapidly and reached steady state after about 4-5 days of treatment. As predicted, the protein decreased at a much slower rate, but after 21 days of treatment, the amount of HTT protein decreased by about 40%. Thus, equivalent steady state levels of HTT mRNA and protein can be achieved after about 4-5 weeks after initiation of treatment.

As shown in fig. 13, the level of compound 1 in cerebrospinal fluid (CSF) suggests that compound 1 thus crosses the blood brain barrier and is directly related to the level of compound 1 in human (fig. 13A) and non-human primate (fig. 13B) free plasma. Two subjects in the cohort received a 30mg dose per day. Thus, compound 1 crosses the blood brain barrier. The level of compound 1 found in CSF is at least equal to or higher than that observed in plasma, thus proving that compound 1 is not affected by efflux in humans.

In the food effect cohort, compound 1 showed similar exposure regardless of whether the subject was fasted or fed.

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

Example 11: scheme for phase two clinical study

Phase 2 clinical study was a randomized, placebo-controlled, dose-finding study for 12 weeks to evaluate the safety and efficacy of compound 1 in huntington's disease subjects.

Prior to the development of this phase 2 study, compound 1 has been extensively evaluated in preclinical pharmacological models, both in vitro and in vivo, in comprehensive toxicology planning, and in phase 1 studies conducted in healthy volunteers. Taken together, the data obtained demonstrate that compound 1 treatment resulted in reduced dose-dependent pre-mRNA splicing and protein transcription, and that compound 1 was clinically safe and well-tolerated at single doses up to 135mg, and at doses up to 30mg, for 21 days of treatment.

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

Parallel group designs were chosen because they allowed for the recruitment of all treatment group patients over the same time frame. The time course of HTT protein, mRNA and other drug response indicators in the blood of untreated patients is not available. The use of a parallel design with simultaneous placebo control allows for direct evaluation comparisons to determine the effect of positive treatment.

By identifying active disease subjects that have not experienced functional decline, a patient population is selected that reduces variability in other heterogeneous disease populations. In this study, at randomization, subjects will thus enroll in the trial based on the CAG repeat length and symbol digital pattern test (SDMT), total motor function score (TMS), independence Scale (IS), and baseline measurements of full functional capacity assessment (TFC). These factors will be used to identify and recruit active disease subjects that have not undergone functional decline, indicating that disease progression may be intervened. Huntington's disease Predictive Index (PI) _HD ) Or a standardized version (PIN) _HD ) The score may be used to predict the likelihood of HD progression. PIN (personal identification number) Scores will be calculated at baseline to identify subjects eligible to participate in the study.

According to the kinetics of compound 1 mediated reduction of human HTT, it is expected that between 4 and 6 weeks the greatest reduction in HTT protein will be achieved in HD patients. The 12 week dosing regimen may further demonstrate that steady-state decline in tttt remains stable over time following continued treatment with compound 1 in a phase 2 study, followed by a one year open label extension study. In addition to the primary endpoints of change in httt protein and safety relative to baseline, phase 2 studies included exploratory clinical outcome endpoints to assess the impact of compound 1 on cognitive and motor functions in subjects, as assessed on the huntington's disease unified rating scale (UHDRS). UHDRS has been widely studied and developed for assessing disease progression in a variety of fields. Cognitive impairment, loss of motor function, and accelerated decrease in brain volume in caudate and putamen are key features of this disease, with a significant impact on quality of life. Assessment of more sensitive and early motor changes by wearable devices will also be included as an exploratory endpoint in phase 2 studies. Research at these endpoints will help to gain insight into the rate of change in early disease and determine key measures that may be an indicator of early HD progression within 12 weeks.

Risk/benefit assessment

As described above, HD is a severe progressive neurodegenerative disease. Early in the course of the disease, the patient exhibits mild symptoms; as the disease progresses, unintentional torsion movements become more pronounced, voluntary motor ability declines, language and swallowing function become increasingly impaired, and aggressive and uninhibited behavior becomes more frequent. Advanced disease is characterized by severe inability to walk, speak, swallow or care for oneself, eventually requiring full-time care, and eventually dying usually 15 to 18 years after symptoms appear (see Caron, N, wright, G and Hayden, M (2020 a), huntington Disease; seattle, WA; university of Washington).

There is currently no approved disease modifying intervention for HD and, if no intervention is available, the patient population incorporating the trial will be faced with continued disease progression, loss of function and inevitable death. The inevitable disease progression and mortality of the disease indicates HD is a highly unmet medical need. Reduction of mHTT has been identified as an important therapeutic target.

As described above, multiple doses of compound 1 were associated with significant reductions in HTT mRNA and protein in phase 1 studies. Based on pharmacokinetic-pharmacodynamic (PKPD) models of mid-phase study data, exposure at QD doses of 10mg and 20mg was determined to be associated with a decrease in full-length HTT mRNA levels, with HTT protein reductions accurately achieving a target range of 30% to 50% of the determined mean. Thus, QD doses of 10mg and 20mg are expected to be associated with therapeutic benefits in this phase 2 study and ultimately slowing disease progression.

Phase 1 studies provide evidence of safety and tolerability of compound 1 in single doses ranging from 5mg to 135mg, multiple doses ranging from 15mg to 30mg, for durations up to 21 days. In phase 1 studies, compound 1 was safe and generally well tolerated. The overall incidence of AEs in subjects receiving placebo and subjects receiving compound 1 was comparable in the single escalated dose (SAD) and multiple escalated dose (MAD) portions of the phase 1 study. No event considered dose limiting toxicity occurred and all Adverse Events (AEs) were resolved at the mid-analysis expiration date. In any part of the study, no clinically significant laboratory abnormalities or Electrocardiogram (ECG) findings were seen at any dose.

Phase 1 studies are provided with data and safety monitoring committee (DSMB) that closely monitors the safety of subjects. According to preclinical and clinical data to date, compound 1 has good risk/benefit profile in HD subjects.

The main research purpose is as follows:

safety and pharmacodynamic effects of 2 treatment regimens and placebo of compound 1 in Huntington's Disease (HD) subjects were evaluated according to the following evaluation: (i) Adverse events in Treatment (TEAE) occurrences and laboratory values, electrocardiogram (ECG), vital signs, slit lamp eye examination and physical examination abnormalities; (ii) A decrease in the total Huntingtin (HTT) level in the blood. This aspect is intended to demonstrate the safety, tolerability and pharmacology of compound 1 and to reduce HTT mRNA and HTT protein in HD patients.

Secondary study purposes:

(i) Determining the effect of compound 1 on HTTmRNA in blood and mHTT protein in cerebrospinal fluid (CSF); (ii) Mutant huntingtin (mHTT) levels in the blood are reduced. This aspect is intended to demonstrate the effect of compound 1 on blood, CSF and radioactive biomarkers of huntington's disease.

Exploratory study purposes:

(i) Assessing the effect of compound 1 on whole brain, caudate nucleus and putamen volume changes by volumetric magnetic resonance imaging (vMRI); (ii) assessing the effect on ventricular volume change by vMRI; (iii) Assessing the effect of compound 1 on plasma and CSF neurofilament light chain (NfL) protein concentration; (iv) Assessing changes after 12 weeks of treatment using a correlation scale, which would include using the huntington's disease unified rating scale (UHDRS) and each subcomponent thereof, including (a) a Signed Digital Model Test (SDMT), (b) a total motor function score (TMS), (c) an independence scale, (d) a full functional capacity assessment (TFC); (e) assessing gait and movement by the wearable accelerometer; (f) clinical global impression of change (CGI-C); (g) huntington's disease quality of life questionnaire (HDQoL).

Pharmacokinetic targets:

the concentration of compound 1 in HD subjects was assessed.

Clinical endpoint:

The main safety endpoint:

safety profiles characterized by TEAE, laboratory abnormalities, ECG, vital signs, slit lamp eye examination, and physical examination were assessed.

The main curative effect end point:

changes in total HTT protein in blood from baseline at 5 th review.

Biomarker endpoint:

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

Secondary endpoint:

(i) Changes in blood HTT mRNA from baseline at 3, 4 and 5 replicates; (ii) change in CSF mHTT from baseline at 5 th review; (iii) Changes in blood mHTT protein from baseline at 5 th review.

Exploratory endpoint:

(i) Changes in whole brain, caudate nucleus, putamen and ventricular volumes from baseline (assessed by vMRI); (ii) Changes in plasma and cerebrospinal fluid NfL protein concentrations from baseline; (iii) The change in UHDRS score from baseline for each sub-scale, including SDMT, TMS, independence scale, and TFC; (iv) a change in total UHDRS from baseline; (v) Changes in gait and motor functions assessed by the wearable accelerometer from baseline; (vi) a change assessed by CGI-C; (vii) changes from baseline in HDQoL questionnaires.

Pharmacokinetic endpoint

(i) Plasma trough concentration of Compound 1 at 3 rd, 4 th and 5 th reviews (C _trough ) And a cumulative ratio; and (i) the cumulative ratio of compound 1 in CSF at 5 th review.

Biomarker endpoint:

Study design/method:

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

Individuals who sign informed consent will enter into a screening to determine eligibility for the enrollment study. At the time of screening, the status of the gene mutation in the potential subjects will be confirmed by the investigator (either by past gene sequencing or by assessment of gene sequencing in the study) and other assessments performed to confirm that they meet the inclusion criteria. Subjects meeting all of the inclusion criteria at screening will receive baseline assessment and be randomized to either 10mg or 20mg study drug or placebo groups at a 1:1:1 randomization ratio for 12 weeks of treatment (plus or minus window period). Once the treatment is dispensed, the subjects will take the study medication dose dispensed to them once a day in the morning at least 2 hours prior to the first meal of the day. Subjects will be required to return to the hospital every 28 days (about days 29, 57 and 85) after randomization or receive home care services instead of going to the review in person to develop study assessments. On day 85, subjects will take their last dose of study medication and complete the end of study assessment. Subsequent secure access will be made to collect AEs by phone/telemedicine on day 113.

Sample size proof:

the sample amount was based on the average change in total HTT protein of the blood from baseline at the 5 th review (primary endpoint). Using an effector of 0.85 (i.e., the magnitude of the treatment difference is 85% of one standard deviation), 31 subjects would be required to achieve 90% statistical efficacy at 2-sided alpha levels of 0.05. Assuming a withdrawal rate of 10%, approximately 35 subjects will be randomly assigned to each dose.

Planned patient population:

approximately 200 adult male and female subjects will be enrolled.

Group entry criteria:

individuals eligible to participate in the study include individuals meeting all of the following group inclusion criteria: (i) Ambulatory male or female patients aged 25 years (including 25 years old) and older; (ii) The subject (or a legal authorized representative) is willing and able to provide informed consent and adhere to all agreement requirements; (iii) The gene confirmed diagnosis of HD, cytosine-adenine-guanine (CAG) repeat lengths of 42 to 50, including 42 and 50; (iv) a UHDRS-independence scale score of 100; (v) TFC score 13; (vi) The normalized predictive index of HD scores is between 0.18 and 4.93, including 0.18 and 4.93; (vii) women of child bearing age (WOCBP): it must be agreed to use an efficient contraceptive method during the dosing period and within 6 months after discontinuation of study drug.

WOCBP is defined as a female with fertility after menstrual beginner, pre-menopausal, unless permanently sterile. Permanent sterilization procedures include hysterectomy, bilateral tubectomy, and bilateral ovariectomy. Postmenopausal status is defined as the absence of menses for 12 consecutive months without other medical reasons. Women not using hormonal contraception or hormone replacement therapy can be confirmed to be in postmenopausal status by high Follicle Stimulating Hormone (FSH) levels in the postmenopausal range. However, in the absence of 12 month amenorrhea, a single FSH measurement is insufficient. A high-efficiency contraceptive method is defined as a method that has a failure rate of less than 1% per year for sustained correct use, comprising several methods selected from the group consisting of: (a) A combined (estrogenic and progestogenic) hormonal contraceptive method associated with ovulation inhibition, comprising an oral contraceptive (WOCBP using an oral contraceptive should be stable with the same drug for at least 3 months prior to screening), intravaginal or transdermal administration of the contraceptive; (b) Progestogen-only hormonal contraceptives associated with ovulation inhibition including oral contraceptives (WOCBP using an oral contraceptive should be stable with the same drug for at least 3 months prior to screening) contraceptive drug administration by injection, implantation, intrauterine device or intrauterine hormone delivery system; or, (c) contraception associated with bilateral tubal occlusion, mate vasectomy, or abstinence.

(viii) Men who are sexually active and fertile must use the condom during intercourse during the study medication and within 6 months after cessation of the study medication, and should not take children or donate sperm during this period. Men undergoing vasectomy also need condoms to prevent drug delivery through the semen.

The main exclusion criteria:

no qualification for participation in the study was met if any of the following exclusion criteria were met: (i) inability or reluctance to swallow oral tablets; (ii) The use of experimental drugs, including HD-specific study drugs targeting RNA or DNA, such as antisense oligonucleotides, cell transplantation, or any other experimental brain surgery, is accepted 90 days or within 5 half-lives prior to screening or at any time during the study; (iii) any history of gene therapy exposure for the treatment of HD; (iv) Participation in a research trial or study paradigm (e.g., motor/physical activity, cognitive therapy, brain stimulation, etc.) during the 90 days prior to screening or at any time during the study; (v) the presence of an implanted deep brain stimulation device; (vi) The cataract grading system (lens clouding classification system III) was used to check for family history of early onset cataract or the presence of cataract at baseline; (vii) Brain and spinal pathologies, elevated intracranial pressure (including the presence of shunts or implanted CNS catheters for CSF drainage), malformations and/or tumors that may interfere with CSF homeostasis and circulation; (viii) Scheduled for any major medical or surgical hospitalization involving general anesthesia within 12 weeks after screening or during the study; (ix) Significant suicide risk at a medium risk level or higher score, as measured by the columbia suicide severity rating scale (C-SSRS); (x) Risk of major depressive episode, psychosis, mental confusion state, or violent behavior assessed by the investigator; (xi) Any history of brain or spinal disease that would interfere with the lumbar puncture process or safety assessment; (xii) History of malignancy of any organ system (except for local basal cell carcinoma of the skin or cervical cancer in situ) over the last 5 years, whether treated or untreated, whether there is evidence of local recurrence or metastasis; (xiii) Any medical history or condition that would interfere with the ability of the completion plan to specify an assessment (e.g., implantation of a shunt, a condition that impedes MRI scanning); (xiv) Antidepressants or benzodiazepines are used unless a stable dose is received at least 6 weeks prior to screening and the dose regimen is not expected to change during the study; (xvi) The history of life-long drug consumption or alcohol consumption assessed by the investigator is at a high risk drinking level as deemed by the world health organization for a duration of 1 month or more; (xvii) Researchers believe that clinically significant medical conditions may adversely affect the safety of the subject or impair assessment of the study outcome; (xviii) The screening time is defined as the current significant kidney damage with estimated glomerular filtration rate <60 mL/min; (xvix) impaired current liver function results in a 3-fold increase in liver function tests (aspartate aminotransferase, alanine phosphatase) to the upper normal limit upon screening; (xx) Pregnancy, scheduled to become pregnant during the course of the test or currently nursing; (xxi) Medium or potent CYP3A4 inhibitor drugs were used within 1 week after screening or medium or potent CYP3A4 inducer drugs were used within 2 weeks after screening or medium or potent CYP3A4 inhibitor or inducer drugs were planned to be used during the study.

Study and reference products, dosages and modes of administration:

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

QDs were orally administered with compound 1 activity study product and matched placebo reference product tablets. Compound 1 study drug product is a film coated tablet dosage form for oral administration. The white to off-white round coated tablets will provide two dosage specifications of 10mg and 20mg, each containing compound 1 drug substance and an excipient selected from microcrystalline cellulose, lactose monohydrate, povidone K30, croscarmellose sodium, poloxamer 407, and magnesium stearate. Tablets of 10mg and 20mg will provide 2 different sizes. Placebo tablets contained the same pharmacopoeia excipients and were manufactured in the same tablet size with the same appearance matching the 10mg and 20mg compound 1 tablets.

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

The goal of a 30% to 50% decrease in mHTT is a range associated with a decrease in pathology and the expected therapeutic benefit of the patient. In phase 1 studies, compound 1 mediated HTT pre-mRNA splicing was dose-dependent in all cohorts of the SAD and MAD portions of the study. An average 40% and 60% decrease in full-length HTT mRNA levels was observed after 14 days of treatment with 15mg and 30mg of compound 1, respectively. Based on these clinical data, the PK-PD binding model was used to model the percentage of mRNA decrease (and thus the expected magnitude of HTT protein decrease) at other potential clinical doses.

At selected doses of 10mg QD and 20mg QD, the predicted percent reduction of full length HTT mRNA from baseline is in the target range of 30% to 50%. Preclinical data in bacterial artificial chromosome transgenic mouse models of HD show that there is a strong correlation between mouse HTT pre-mRNA splice levels and the extent of protein reduction following compound 1 administration. Thus, the observed preclinical HTTmRNA changes are expected to result in a similar decrease in HTT protein levels in HD patients. Thus, based on all clinical and preclinical safety data so far, and the expected reduction of HTT mRNA and protein from clinical data and pharmacokinetic-pharmacodynamic models, doses of 10mg and 20mg are expected to be safe, well tolerated and beneficial for HD subjects.

Reference products, dosages and modes of administration:

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

Safety standard:

safety assessments will include TEAE, clinical laboratory, vital signs, electrocardiogram, C-SSRS, slit lamp ophthalmic and physical examinations observed.

Standard of efficacy:

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 criterion

Enrichment is defined as the prospective use of any patient characteristic to select a study population in which drug effects, if indeed present, are more likely to be detected than an unselected population. Because of the large variability in HD patient populations, the enrichment strategy of phase 2 studies was aimed at selecting those subjects who retained daily life, work, financial and self-care capabilities, but exhibited reduced performance in motor and cognitive tests, expected to have an affected daily life activity function within 3 years. TMS and SDMT assessments of UHDRS (as well as CAG repeat length and age) will be performed at the time of screening and used to identify this population by means of validated HD predictive indices for pre-symptomatic HD patients.

Huntington's disease Predictive Index (PI) _HD ) Or a standardized version (PIN) _HD ) The higher the score, the greater the risk of demonstrating functional decline, which can be used to predict the likelihood of HD progression. Using PI _HD The generated natural course survival curve shows that the specific PI is provided _HD Disease trace of scored patients. PIN (personal identification number) _HD Scoring enables researchers to predict disease progression in a study population with a high degree of certainty. Disease progression has been previously indicated generally by the CAG-age product (CAP), which is a load score of age and CAG amplification, with multiple variants. HD progression prediction probability increases when CAP is combined with TMS and SDMT of UHDRS. Using these enrichment criteria, a group of subjects with HD and no functional decline (measured by TFC and IS) can be identified and changes in blood HTT levels after treatment can be measured. Without HTT reduction treatment, the group of subjects may experience decline because it has been found that the early stages of HD are characterized by an increase in mHTT levels in cerebrospinal fluid as compared to the control group.

At the baseline of the study, the cognitive and motor functions of the subjects will be assessed by SDMT and TMS scores, respectively. Based on the evaluation of TFC and IS, the group-entering subjects should not exhibit functional decline. The subject will be based on the PIN calculated by the IRT prior to randomization _HD Score calculations were included in the study. Baseline PIN _HD Subjects with scores between 0.18 and 4.93 (including 0.18 and 4.93) will be eligible for trial participation. The following formula will be used to calculate the PIN _HD Score:

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

PI _HD The score is converted to a normalized score using the following conversion formula:

PIN _HD ＝(PI _HD -883)/1044

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

Pharmacokinetics:

pharmacokinetic assessments will include plasma concentrations C (at 3 rd, 4 th and 5 th reviews) _trough . The cumulative ratio in plasma (at 3 rd, 4 th and 5 th reviews) and CSF (at 5 th review) will be calculated and reported.

The statistical method comprises the following steps:

a repeat measurement analysis model (repeat at review) will be used to compare the total HTT protein in blood for each dose to placebo. The model will include dose, review of interactive dose and baseline. The nominal p-value and 95% confidence interval for each pairwise comparison of 5 th review (active drug versus placebo) will be provided. The model will include a PIN _HD As a layering factor. Identical fractions for blood HTT proteinsThe assay will be used for blood HTT mRNA. Dose response relationships will be explored. Demographic and baseline characteristics, treatments, safety, and efficacy endpoints will be summarized descriptively in dose groups. Statistical models will be applied to understand the relationship between the UHDRS and its components and blood and cerebrospinal fluid assessments.

Results of the second phase study

The main objective of the randomized, placebo-controlled, dose-explored study, 2a over 12 weeks, was to evaluate the safety and pharmacodynamic effects of both treatment regimens of compound 1 and placebo in huntington's disease subjects. The main objective is to evaluate the occurrence of adverse events (TEAE) in the treatment; laboratory values, electrocardiogram (ECG), vital signs, slit lamp eye examination, and physical examination abnormalities; and a decrease in the total Huntingtin (HTT) level in the blood.

A secondary objective of this study was to determine the effect of compound 1 on HTTmRNA in blood and mHTT protein in cerebrospinal fluid (CSF); and (ii) a decrease in the level of mutant huntingtin (mHTT) in the blood.

The exploratory objective of this study was to evaluate the effect of compound 1 on whole brain, caudate core and shell core volume changes by volumetric magnetic resonance imaging (vMRI); assessing the effect on ventricular volume change by vMRI; assessing the effect of compound 1 on plasma and CSF neurofilament light chain (NfL) protein concentration; the change in the relevant scale assessment after 12 weeks of treatment will be assessed, which will include the use of the huntington's disease unified rating scale (UHDRS) and the assessment of each subcomponent thereof. Qualitative efficacy is assessed using UHDRS subcomponents, including (a) a Signed Digital Model Test (SDMT), (b) a total motor function score (TMS), (c) an independence scale, (d) a comprehensive functional capability assessment (TFC); (e) assessing gait and movement by the wearable accelerometer; (f) clinical global impression of change (CGI-C); and (g) huntington's disease quality of life questionnaire (HDQoL).

The pharmacokinetic goal of this study was to assess the concentration of compound 1 in HD subjects.

Claims

1. A tablet comprising 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 (hereinafter referred to as compound 1) or a pharmaceutically acceptable salt thereof, an intragranular excipient and an extragranular excipient as an active ingredient, wherein compound 1 comprises 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 microcrystalline cellulose to diluent is from about 1:1 to about 1:4, and microcrystalline cellulose comprises from about 15% to about 25% by weight of the total weight of the tablet; wherein the disintegrant comprises about 1% to about 3% of the total weight of the tablet; wherein povidone comprises from 1% to about 5% of the total weight of the tablet; and wherein the extra-granular excipient comprises an additional amount of diluent and an additional amount of disintegrant.

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

3. The tablet of claim 2, wherein compound 1 is present in an amount of about 10% of the total weight of the tablet.

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

5. The tablet of claim 4, wherein the amount 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 of claim 1, wherein the amount of compound 1 in the tablet is about 1mg to 100mg.

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

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 extra-granular 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 extra-granular excipient and the intra-granular 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 extra-granular 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 extra-granular 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 extra-granular excipient is from about 15% to about 30% by weight of the total weight of the tablet.

19. The tablet of claim 1, wherein the intragranular excipients have been wet granulated.

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

21. The tablet of claim 20, wherein the extra-granular excipient further comprises colloidal silica in an amount of about 0.25% to about 1% by weight of the tablet.

22. The tablet of claim 20, wherein the extra-granular excipient further comprises magnesium stearate in an amount of about 0.5% to about 2% by weight of the tablet.

23. A process for preparing the tablet of claim 1, the process comprising wet granulating an extragranular excipient, drying the resulting intragranular mixture, mixing the extragranular excipient with the intragranular excipient, and compressing the resulting mixture to form a tablet.

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

25. A method of treating or ameliorating huntington's disease in a subject in need thereof, the method comprising orally administering to the subject a tablet of claim 1 comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

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

27. The method of claim 26, wherein the therapeutically effective amount of compound 1 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.

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

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

30. The method of claim 25, wherein the tablet is administered once daily.