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

Abstract

The present invention provides compounds, tablets, methods for preparing them, and methods for treating or improving Huntington's disease for use in the treatment of Huntington's disease. [Solution] The present invention provides a tablet formulation of 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol and a method for producing the same.

Description

[[Technical Field]]

[0001] Cross-Reference to Related Applications The present application claims the benefit and priority from U.S. Provisional Patent Application Serial No. 63 / 113,826 filed on November 13, 2020, U.S. Provisional Patent Application Serial No. 63 / 245,927 filed on September 19, 2021, pending U.S. Provisional Patent Application Serial No. 63 / 261,467 filed on September 21, 2021, and U.S. Provisional Patent Application Serial No. 63 / 261,495 filed on September 22, 2021 , and U.S. Provisional Patent Application Serial No. 63 / 255,745 filed on October 14, 2021, the contents of which are hereby expressly incorporated into the present application by reference in their entireties. .

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

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

[0004] ​HD is caused by CAG repeat elongation in HTT, affecting motor, cognitive, mental and functional aspects. Characterized by a decrease in ability. The elongation of the CAG trinucleotide repeat is a mutation. This leads to mHTT (mHTT), which is associated with neurological dysfunction and ultimately death. It is.

[0005] The number of CAG repeats in the HTT gene ranges from 6 to 35 in healthy individuals. Disease penetration The degree appears to be reduced for individuals with 36-39 CAG repeats, but C is 40 or higher. Individuals with AG repeats almost certainly develop the disease. (European Journal of Neurology) As described in ology, 2017, pp. 24-34, the clinical diagnosis of HD is confirmed family History or positive genetic test (i.e., confirmation of CAG repeat extension ≥ 36), and Huntington's disease lineage. Defined by a single rating scale (Unified Huntington's Disease Rating Scale) (UHDRS) The onset of motor impairment is assessed using the Diagnostic Confidence Score (DCS) of the Transmuscular Motor Score (TMS). DCS is 0 (HD). The range is (no suggested movement abnormality) to 4 (movement abnormality with a ≥99% probability of being caused by HD), Core 4 is based on the definition of "motor-onset" or "overt" HD.

[0006] Typically, the age of onset (i.e., when DCS reaches 4) is in the range of 30 to 50 years old, and clinical diagnosis The average survival period after transection is 15-20 years. Currently, the focus is more on "function" after the onset of the disease than on motor symptoms. The stage of the disease is determined by loss (i.e., assessment of functional ability) (e.g., Neuro (See *logy*, 1979, 29, pp. 1-3, or *Neurology*, 1981, 31, pp. 1333-1335.) . Measures of Total Functional Capability (TFC) (see, for example, Movement Disorders, 1996, 11, pp. 136-142). (to be done) is a component of UHDRS, where the independent level of humans with HD is 0 (all The range for care is from 13 (completely dependent) to 13 (completely independent). This includes the ability to work, manage household finances, manage household chores, and manage daily life activities. The functional status of HD patients is assessed in relation to their ability to perform the necessary procedures and the level of care required. It is based on the Total Functional Capacity (TFC) of the UHDRS, and hemorrhagic disease is classified into stages 1-5. It can be divided into stages. Also, HD categorization based on TFC score (Shoulson and Fahn scores) (Also called "Ji") is the initial stage of HD (corresponding to Stage 1 or 2 based on the TFC score), Intermediate or intermediate stage of HD (corresponding to stage 3 based on TFC score), and HD As an advanced or late-stage (corresponding to stage 4 or 5 based on the TFC score) This will also be explained.

[0007] The international application published as International Application No. 2020 / 005873 is used in the HD treatment. This application identifies the types of compounds that can produce such compounds, methods for producing them, and pharmaceutical formulations thereof. , that compound is IC 50 In the assay, inhibiting endogenous Huntington's protein (HTT) The patent application also provides data demonstrating this. In that application, it is disclosed as a particularly potent inhibitor of HTT. One of the compounds being studied is 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1, 2,3]Triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazol-2-yl)pheno Since then, Lu has been producing in vivo human HTT in gene-transformed mouse models of Huntington's disease. It has been found to be effective in reducing the risk of death (results have not yet been published). Currently, only symptomatic treatment is available. Therefore, to date, there has been no way to slow the progression of HD. There are no small molecule therapies available for this. Therefore, small molecule disease-modifying therapies for HD ( In other words, treatment options that can slow the progression of the disease are necessary. [Prior art documents] [Patent Documents]

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

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

[0010] In one embodiment, the present invention uses 2-[3-(2,2,6,6-tetramethylpiperidine-4- (Iyl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazol-2- Ilphenol (hereinafter referred to as Compound 1), or a pharmaceutically acceptable salt thereof (Compound 1 is the total amount of the tablet) The granular excipients (present in an amount of approximately 1% to 30% by mass) and extragranular excipients are included. It is a tablet, The granular excipients include microcrystalline cellulose and a diluent, and the microcrystalline cellulose and diluent The ratio of the active ingredient to the active ingredient is approximately 1:1 to 1:4, and microcrystalline cellulose accounts for approximately 15% by mass of the total mass of the tablet. It is present in an amount of approximately 25% by mass, and the disintegrant is present in an amount of approximately 1% to 3% of the total mass of the tablet. Povidone is present in the tablet in an amount of approximately 1% to 5% of the total mass. The present invention relates to tablets in which the extragranular excipients include a further amount of diluent and a further amount of disintegrant.

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

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

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

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

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

[0016] In another embodiment, the amount of compound 1 in the tablet is 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg g, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 13 The dosage can be selected from 5 mg or 140 mg.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0034] In another embodiment, the tablet contains compound 1 in an amount of about 10% by mass of the tablet, and the granular excipient is It contains microcrystalline cellulose and lactose monohydrate in a ratio of approximately 1:2, and microcrystalline cellulose The disintegrant is present in an amount of approximately 20% by mass of the tablet, and the disintegrant is present in an amount of 1% to approximately 3% by mass of the tablet. It is present in the tablet, and povidone is present in an amount of approximately 2% by mass of the tablet, and the extragranular excipient is the tablet. An additional amount of lactose monohydrate in an amount of approximately 10% to 25% by mass of the tablet, and approximately 1% to 5% by mass of the tablet. Contains a further amount of disintegrant in a % amount, and approximately 0.5% to 2% by mass of poloxamer in the tablet. It is.

[0035] In another embodiment, the tablet contains approximately 0.25% to approximately 2% by mass of colloidal silicon dioxide. It also includes.

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

[0037] The present invention also relates to a method for producing tablets, comprising the step of wet granulation of an internal excipient, and the result The process involves drying the resulting in-granule blend and mixing the external excipient with the in-granule excipient. The method comprises the steps of: and compressing the resulting mixture to form a tablet. ru.

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

[0039] In one aspect, the present invention also provides a means of treating Huntington's disease in a subject that requires it or A method of improvement comprising administering a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof, to the subject. The present invention relates to a method comprising the step of administering a tablet having [a specific characteristic].

[0040] In another aspect, the present invention also relates to a compound in a treatment for slowing the progression of Huntington's disease. 1, or with respect to the use of a pharmaceutically acceptable salt thereof, hereby compound 1, or a pharmaceutically acceptable The effect of treatment using that salt is that between exon 49 and exon 50 in HTT mRNA By producing an inframe stop codon, it slows the progression of Huntington's disease. The effect of treatment using compound 1, or a pharmaceutically acceptable salt thereof, which slows the progression of tons' disease is The effect of treatment using compound 1 or a pharmaceutically acceptable salt thereof, which is a disease-modifying treatment, is , slows the decline in motor function associated with Huntington's disease, compound 1, or pharmaceutically acceptable The effect of treatment using the salt of this compound slows cognitive decline associated with Huntington's disease and compounds 1. The effect of treatment using a pharmaceutically acceptable salt thereof is related to Huntington's disease. It slows psychiatric decline, and Compound 1, or its pharmaceutically acceptable salt. The effect of treatment using compound 1 is to slow the decline in functional ability associated with Huntington's disease, and compound 1 The effects of treatment using pharmaceutically acceptable salts thereof are related to the progression of Huntington's disease pathophysiology. Slow down the pace. [Brief explanation of the drawing]

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

[0042] Unless otherwise stated, all technical and scientific terms used herein This disclosure has the same meaning as it would be generally understood by a person skilled in the art in which this disclosure pertains. Methods and materials similar to or equivalent to those described in the details may be used in the implementation or testing of this disclosure. While it may be used in this context, the materials, methods, and examples are merely illustrative and not limited to this. It is not intended to do so. Other features of this disclosure are described in the following detailed description and claims. It is clear from the surrounding area.

[0043] Titles or subtitles may be used in this specification solely for the convenience of the reader, but this They may also affect the scope of this disclosure or any aspect of this disclosure or any subsection. It is not intended to be limited to subtitles or paragraphs.

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

[0045] As used in this specification and in the claims, one or more elements are listed as follows: The phrase "at least one" applies to any one or more elements in the element list. It means at least one element that is included, but is not specifically listed within the element list. It is not necessary to include at least one loose element; any pair of elements in the element list is acceptable. It should be understood that there is no need to exclude combinations. Also, this definition means that, at least The phrase "and one more" refers to an element other than the one specifically identified within the list of elements mentioned. Whether related to these elements or not, they can exist as needed. To make possible. Therefore, as a non-restrictive example, "at least one of A and B" (or equivalent) (where "at least one of A or B," or equivalently "at least one of A and / or B") is a state In this case, there must be at least one A where B does not exist, and two or more A (other than B if necessary). It can refer to a prime (including a prime), and in another embodiment, at least one in which A does not exist, as needed It can refer to two or more B (including elements other than A as necessary), and in another embodiment, At least one, optionally two or more A's and at least one, optionally two or more B's This can refer to other elements (including, if necessary), etc.

[0046] When the term "approximately" is used with a range of numbers, it implies the upper limit of those numbers. The range is modified by widening the lower limit. Generally, the term "approximately" is used in this specification. In the book, a certain number is described as being above the stated value by a variance of 20%, 10%, 5%, or 1%. Used to make adjustments below. In certain aspects, the term "approximately" means that a number is approximately A 10% variance is used to adjust the value above and below the stated value. In certain contexts, the term "approximately" means that a numerical value is described by a 5% variance. It is also used to make adjustments to the upper and lower. In certain aspects, the term "about" is used It is used to adjust a given number to be above or below its stated value by a 1% variance. ru.

[0047] The terms "subject" or "patient" refer to the effects of administering the compositions described herein. The following diseases can be treated using this method (e.g., Huntington's syndrome): It is used interchangeably to refer to individual people who are suffering from the disease.

[0048] When a range of values ​​is listed herein, each value and subrange within that range is included. It is intended to do so. For example, the range "1-5ng" or "1ng-5ng" means 1ng, 2ng, 3ng, 4ng, 5ng, 1~2ng, 1~3ng, 1~4ng, 1~5ng, 2~3ng, 2~4ng, 2~5ng, 3~4ng, 3 It is intended to include ~5ng and 4~5ng.

[0049] "comprises", "comprising", "includes", and / or The term "including" as used herein refers to the characteristics described. Identifying the presence of integers, processes, operations, elements, and / or components, but not one or more others. The presence or addition of features, integers, processes, operations, elements, components, and / or groups thereof is not excluded. Let us understand this even better.

[0050] The terms "treat," "treatment," and "treating" The purpose is to reverse, reduce, improve, or inhibit the progression or severity of the disability. The term "treatment" refers to a therapeutic procedure that slows down or stops something. Alternatively, the term "improvement" may be used to describe a condition, disease, or disorder. This refers to reducing or alleviating at least one adverse effect or symptom. Treatment generally involves 1 It is "effective" if one or more symptoms or clinical markers are reduced. Alternatively, the treatment is It is "effective" when the progression of the disability is slowed, reduced, or stopped. In other words, "treatment" "This refers not only to the improvement of symptoms or markers, but also to the comparison with what would have been expected without treatment." Compared to, including a cessation or at least slowing of the progression or worsening of symptoms. Beneficial or desired clinical results. The results may include a reduction in one or more symptoms, whether detectable or undetectable. To reduce the severity of the disease, stabilize the condition (i.e., prevent worsening), or slow or moderate the progression of the disease. Slowness, relief or reduction of symptoms, remission (whether partial or complete), and / or death This includes, but is not limited to, a reduction in the mortality rate. Also, the term "treatment" of a disease is... This includes providing relief from the symptoms or side effects of a disease (including symptomatic treatment).

[0051] When used herein, the term “excipient” refers to an agent used to deliver a therapeutic agent to a target. Used as a carrier or vehicle, or for handling or storage properties of pharmaceutical compositions. To improve this, or to separate the dosage units of the composition into different forms, such as capsules suitable for oral administration. Alternatively, it may be added to a pharmaceutical composition to enable or facilitate the formation of tablets. This refers to any substance that is not a therapeutic agent in itself. Excipients include, for example, diluents. Disintegrants, binders, adhesives, surfactants, lubricants, flow enhancers, surface modifiers, unpleasant taste or Substances, flavors, dyes, fragrances, and other substances added to mask or neutralize odors. This includes, but is not limited to, substances added to improve the appearance of the composition.

[0052] The terms "HD" or "Huntington's disease," as used herein, refer to motor, cognitive, and cognitive disorders. Characterized by a decline in psychiatric and functional abilities, and a CAG linkage in the huntingtin gene. This refers to neurodegenerative disorders caused by PET elongation.

[0053] When used herein, the term "in-granule" refers to the component incorporated into the formulation before granulation. This refers to components located within or in part of the granular structure.

[0054] When used herein, the term "extragranular" refers to an ingredient incorporated into the formulation after granulation. This refers to the components located outside the granular structure.

[0055] The terms "administer" or "administer" as used herein refer to the presence of extracorporeal substances. This refers to the act of physically delivering a substance to a target.

[0056] The terms "overt HD" or "overt Huntington's disease" are used herein in accordance with the law. A diagnosis of hepatitis (HD) that is established in practice {e.g., a confirmed family history or a positive genetic test (CAG)}. Based on confirmation of repeat extension ≥ 36, and onset of motor impairment [Huntington's disease unified rating scale ( The diagnostic confidence score (DCS), defined by the total motor score (TMS) of the UHDRS, is 4. This refers to the following. In one aspect, the terms "overt HD" or "overt Huntington's disease" are used to describe the present condition. When used in a detailed document, a clinically established diagnosis of HD [e.g., confirmed family history] Based on a history or positive genetic test (confirmation of CAG repeat elongation ≥ 36), and onset of motor impairment [examples] For example, it is defined by the Total Motor Score (TMS) of the Unified Rating Scale for Huntington's Disease (UHDRS). This refers to patients who have a diagnostic confidence score (DCS) of 4.

[0057] The terms "pre-manifest HD" or "pre-manifest Huntington's disease" are defined herein as follows: When used, for example, standard scales, for example, clinical scales [for example, Huntington's disease unified assessment] If the diagnostic confidence score (DCS), defined by the total motor score (TMS) of the scale (UHDRS), is <4 The onset of clinically established motor impairments is assessed based on [the following]. If there is no genetic diagnosis for HD [e.g., based on a positive genetic test (confirmation of CAG repeat extension ≥ 40)], This refers to having ]. In one embodiment, it is referred to as "asymptomatic HD" or "asymptomatic Huntington's disease". When used herein, the term means, for example, a standard scale, for example, a clinical scale [for example, The diagnostic criteria are defined by the Total Motor Score (TMS) of the Unified Rating Scale for Huntington's Disease (UHDRS). Assessment is performed according to a clinically established method based on a DCS score of <4. There is no onset of motor impairment, and a genetic diagnosis of HD [for example, a positive gene test (CAG repeat extension)] This refers to patients who have [a condition based on confirmation of length ≥ 40].

[0058] "To slow the progression of HD," "To slow the progression of Huntington's disease," "The progression of HD The terms "to slow the progression of Huntington's disease" or "to slow the progression of Huntington's disease" are used herein. When used, it reduces the rate of progression of Huntington's disease (for example, Huntington's disease (To reduce the rate of progression between stages), to delay the onset of Huntington's disease, Delaying the onset of symptoms associated with Huntington's disease, and symptoms associated with Huntington's disease To reduce the rate of progression of (one or more symptoms) (for example, to reduce the annual rate of decline) (to do so), or one of the following selected from reducing the rate of progression of the pathophysiology of Huntington's disease. or multiple treatment effects (for example, the standard scales described above or below in this specification, e.g., clinical scales) According to or according to neuroimaging evaluation criteria, for example, compared to placebo or natural history control group This refers to the treatment effect compared to [another treatment].

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

[0060] When used herein, the term "reduce" means, for example, to reduce a treatment over a year. This refers to a decrease of, for example, 5%, 10%, 20%, 30%, 40%, 50%, 60%, or 70%.

[0061] When used herein, the term "to delay" means, for example, at least 0. Five years, at least one year, at least two years, at least three years, at least four years, less At least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years , for at least 10 years, at least 11 years, at least 12 years, at least 13 years, less Both refer to delaying the process by 14 years or at least 15 years.

[0062] "To slow the progression of HD," "To slow the progression of Huntington's disease," "The progression of HD The terms "to slow the progression of Huntington's disease" or "to slow the progression of Huntington's disease" are used herein. When used in this context, it delays the onset of Huntington's disease as defined herein. This refers to, for example, increasing the time it takes for Huntington's disease to develop. This term is based on standard scales, such as clinical scales [e.g., Neurology, 1979, 29, As assessed on pages 1-3, for example, according to the Total Functional Competence (TFC) scale of the UHDRS. For example, compared to a placebo, it reduces the rate of progression between stages of Huntington's disease. For example, reducing the rate of progression from the early stages of HD to more advanced stages of HD. In another aspect, this term refers to the speed of progression from HD Stage 1 to HD Stage 2. It refers to a reduction (for example, compared to a placebo). In another aspect, this term refers to the status of HD. This refers to reducing the rate of progression from Stage 2 to HD Stage 3 (for example, compared to a placebo). In another aspect, this term refers to reducing the rate of progression from HD stage 3 to HD stage 4. It refers to (for example, compared to a placebo). In another aspect, this term refers to the stage of HD. This refers to reducing the rate of progression from stage 4 to HD stage 5 (for example, compared to a placebo). In another aspect, this term refers to reducing the rate of progress from the initial HD to the mid-stage HD. For example, it refers to (compared to a placebo). In another aspect, this term refers to a medium-stage HD or This refers to reducing the rate of progression to advanced hemoglobin (HD) (for example, compared to a placebo).

[0063] The term "reducing the rate of progress," as used herein, for example, HD This refers to increasing the time it takes for a stage to progress (for example, compared to a placebo). .

[0064] "To slow the progression of HD," "To slow the progression of Huntington's disease," "The progression of HD The terms "to slow the progression of Huntington's disease" or "to slow the progression of Huntington's disease" are used herein. When used, it reduces the incidence of Huntington's disease by at least 25% (e.g., 25% or more, e.g., 2 Delays the onset of Huntington's disease by 5% to 50% (for example, as defined herein). This refers to increasing the time it takes to do something.

[0065] The term “onset of Huntington’s disease” is used herein in a generally established sense. Clinical diagnosis of HD [for example, the whole motor score (TMS) of the Huntington's Disease Unified Rating Scale (UHDRS)] [Onset of motor impairment based on a diagnostic confidence score (DCS) of 4 as defined by To point.

[0066] "To slow the progression of HD," "To slow the progression of Huntington's disease," "The progression of HD The terms "to slow the progression of Huntington's disease" or "to slow the progression of Huntington's disease" are used herein. When used in this context, the onset of symptoms associated with Huntington's disease as defined herein. Delaying the onset of the disease, for example, the motor function decline associated with Huntington's disease. Cognitive impairment associated with the disease, psychiatric impairment associated with Huntington's disease, and Huntington's disease One or more Huntington's disease-related functional impairments selected from those associated with the disease. This refers to increasing the time it takes for symptoms to develop. In another aspect, this term refers to the present specification. As defined in the book, Huntington's disease is associated with decreased motor function, and Huntington's disease is associated with Related cognitive decline, psychiatric decline associated with Huntington's disease, and related to Huntington's disease One or more symptoms associated with Huntington's disease, selected from a series of functional impairments. This refers to reducing the speed of travel. The term "reducing the speed of travel" is used herein. When used, for example, to increase the time it takes to develop symptoms or to increase the severity. This refers to increasing the time spent (for example, compared to a placebo). In another aspect, it refers to "the progress of HD." To slow down the progression of Huntington's disease, to slow down the progression of HD The terms "to slow the progression of Huntington's disease" or "to slow the progression of Huntington's disease" are used herein. In some cases, the rate of progression from asymptomatic HD to overt HD is reduced [i.e., Huntington's disease, for example] The Diagnostic Confidence Score (DCS), defined by the Total Motor Score (TMS) of the Universal Human Driving Scale (UHDRS), is 4 As assessed by this, for example, the onset of overt HD compared to placebo This refers to causing a delay.

[0067] "To slow the progression of HD," "To slow the progression of Huntington's disease," "The progression of HD The terms "to slow the progression of Huntington's disease" or "to slow the progression of Huntington's disease" are used herein. When used, it slows the pathophysiological progression of Huntington's disease. It refers to.

[0068] The term "slowing the progression of the pathophysiology of Huntington's disease" is used herein. In such cases, for example, by magnetic resonance imaging (MRI) [e.g., Lancet Neural. 2013, 12( 7) As assessed by the neuroimaging evaluation criteria on pages 637-649, etc., haunch This refers to reducing the rate of progression of the pathophysiology of Huntington's disease. For example, this term is used in the context of Huntington's disease. The rate of volume loss in the brain (e.g., whole brain, caudate nucleus, striatum, or cortex) associated with the disease (e.g., Reduce the % from the line volume (for example, as assessed by MRI) (for example) This refers to reducing the annual rate of change compared to a placebo.

[0069] When used herein, the term "motor function" refers to, for example, the motor function of the eyes, articulation, etc. HD includes one or more selected from the group consisting of disability, chorea, postural instability, and gait. It refers to the characteristics of the movement.

[0070] The term "decreased motor function" as used herein means a decrease in motor function (for example) This refers to a decline in motor function (from normal motor function or from past clinic visits). A decline in motor function is, for example, For example, standard scales, such as clinical scales (e.g., Movement Disorders, 1996, 11, 136-142) For example, the UHDRS motor assessment scale measured by the UHDRS total motor score on the page. Assessment can be performed according to the degree.

[0071] The phrase "to slow down the decline in motor function" or "in order to slow down the decline in motor function" When used herein, it reduces the rate of decline in motor function (e.g., the total motor function of UHDRS). As assessed by the score, for example, compared to a placebo, for example, to a placebo In contrast, it refers to reducing the annual rate of decline in motor function, for example.

[0072] The term "reducing speed" as used herein means the time it takes to develop Increase the time or the time it takes for the severity to increase (for example, compared to placebo) In comparison, for example, compared to a placebo, it refers to reducing the annual rate of decline.

[0073] When used herein, the term "cognitive decline" refers to a decline in cognitive ability (for example, This refers to (from normal cognitive function or from past clinic visits). In one aspect, this term means, For example, attention, processing speed, visuospatial processing, timing, emotional processing, memory, speech fluency, precision This refers to a decline in one or more cognitive functions selected from the group consisting of neuromotor function and executive function. Cognitive decline can be assessed, for example, according to standard scales, such as clinical scales. For example, in Movement Disorders, 2014, 29(10), pp. 1281-1288, for example, symbols and numbers Modality tests, Stroop Word Reading Test, Montreal Cognitive Assessment The HD Cognitive Assessment Battery (Symbol-Numeric Modality Test, Trail Making) Test B, One Touch Stockings, Paced Tap As assessed by tests including the PING, affect recognition tests, and Hopkins language learning tests. ].

[0074] The phrases "to slow cognitive decline" or "in order to slow cognitive decline" are not intended to be used in this context. When used in detailed writing, it reduces the rate of cognitive decline (e.g., symbol-number modality testing). , Stroopword Reading Test, Montreal Cognitive Assessment or HD Cognitive Assessment As assessed by the performance battery, for example, compared to a placebo, For example, it refers to reducing the rate of cognitive decline per year compared to a placebo. The term "increasing the time it takes to develop or Increases the time it takes for the severity to increase (for example, compared to a placebo, for example, a placebo) This refers to reducing the annual rate of decline in sevoflation (for example, reducing the rate of decline per year).

[0075] The term "psychiatric decline," as used herein, means a decline in psychiatric function. (For example, from normal psychiatric function or from past clinic visits). This term is used, for example, to describe emotional blunting, anxiety, depression, obsessive-compulsive behavior, suicidal ideation, irritability, and agitation. This refers to one or more psychiatric functions selected from a group consisting of the following: For example, assessment can be performed according to a standard scale, such as a clinical scale (e.g., Movement Diagnosis). soders, 2016, 31(10), pp. 1466-1478 Movement Disorders, 2015, 30(14), 1954 ~On page 1960, for example, by the Emotional Blurring Rating Scale, or by the Hospital Anxiety and Depression Scale Therefore, as assessed.

[0076] The phrase "to slow down psychiatric decline" or "in order to slow down psychiatric decline" When used herein, it reduces the rate of psychiatric decline (e.g., affective blunting assessment). As assessed by scales, or by the Hospital Anxiety and Depression Scale, for example, Compared to a placebo, for example, it reduces the rate of annual psychiatric decline compared to a placebo. This refers to the act of reducing speed. The term "reducing speed" as used herein means until the onset of symptoms. To increase the time required or to increase the time required for the severity to rise (for example, Compared to a racebo, for example, compared to a placebo, for example, reducing the annual rate of decline. To point.

[0077] When used herein, the term "functional ability" means, for example, the ability to perform a job. The ability to manage household finances, the ability to manage household chores, the ability to carry out daily life activities, and This refers to the required level of care. Functional ability includes, for example, the ability to work and manage household finances. The ability to manage household chores, the ability to carry out daily living activities, and the necessary care Includes one or more selected from the group consisting of level A.

[0078] The term "decreased functional ability" is used herein to mean a decrease in functional ability ( For example, this refers to a decrease in functional ability (from normal functional ability or from past clinic visits). Below are, for example, standard scales, for example, clinical scales (e.g., Movement Disorders, 1996, 11, 1) Pages 36-142, for example, the UHDRS functional assessment scale and independent scales, and UHDRS Assessment can be conducted according to the Global Functional Ability Scale.

[0079] "To slow down the decline in functional ability" or "In order to slow down the decline in functional ability" When used herein, the term refers to reducing the rate of decline in functional ability (e.g., UHDRS). Assessment by functional assessment scales and independent scales, or by the UHDRS Total Functional Competency Scale. As mentioned, for example, compared to a placebo, for example, functional ability compared to a placebo This refers to reducing the annual rate of decline. The term "reducing the rate of decline" is a direct translation of the original meaning. When used in detailed texts, it increases the time it takes for the onset of symptoms or the time it takes for the severity to increase. Increase the time (for example, compared to a placebo, for example, compared to a placebo, for example, per year) This refers to reducing the rate of decline.

[0080] When used herein, the term "decline" refers to, for example, a standard scale, for example, a clinical scale. As assessed in accordance with the following, for example, the time course of a certain state or a specific characteristic of a certain state It refers to a deterioration (for example, an annual or yearly deterioration).

[0081] The terms "Huntington's Disease Unified Rating Scale" or "UHDRS" are used herein. In this case, a clinical rating scale developed by the Huntington Research Group (for example, by reference) (This is fully incorporated herein in Movement Disorders, 1996, 11, pp. 136-142) This refers to the UHDR scale, which assesses the clinical performance and capabilities of HD. S includes rating scales for motor function, cognitive function, and functional ability. UHDRS is HD The main characteristics (e.g., motor and cognitive) and the overall functional impact of these characteristics are assessed. It brings a score that will earn you points.

[0082] The term "cHDRS" refers to a composite assessment criterion that provides a combined assessment of motor, cognitive, and overall physical function. The Unified Rating Scale for Intington's Disease (for example, in Neurology, 2017, 89, pp. 2495-2502) To point.

[0083] "HD Stage 1", "HD Stage I", "Huntington's Disease Stage 1", "Huntington "Stage I of the disease," "Huntington's disease stage 1," or "Huntington's disease stage 1" When used herein, the term refers to the clinically established stages of hepatitis [e.g., the stage]. Sub-scales, for example, according to clinical scales, such as the Total Functional Capacity (TFC) scale of the UHDRS. As assessed, the TFC score here is 11-13. In HD Stage 1, Typically, patients have a clinical diagnosis of HD and are fully functional at home and at work. It maintains independence in terms of functional ability, and typically occurs 0 to 8 years after the onset of Huntington's disease. It is taking time.

[0084] "HD Stage 2", "HD Stage II", "Huntington's Disease Stage 2", "Huntington" "Stage II of Huntington's disease," "Stage 2 of Huntington's disease," or "Stage II of Huntington's disease" When used herein, the term refers to the clinically established stages of hepatitis [e.g., Standard scales, for example, clinical scales, based on the Total Functional Capacity (TFC) scale of the UHDRS, etc. As assessed, the TFC score here refers to a range of 7-10. In HD Stage 2, Typically, patients are still functional in the workplace, but their abilities are diminished and they have some impairments. Despite the harm, they can carry out most of their daily activities and usually require very little assistance. This is necessary, and typically occurs 3 to 13 years after the onset of Huntington's disease.

[0085] "HD Stage 3", "HD Stage III", "Huntington's Disease Stage 3", "Huntington "Huntington's disease stage III," "Huntington's disease stage 3," or "Huntington's disease stage II" When used herein, the term "I" refers to the clinically established stages of hepatitis [e.g., , according to standard scales, for example, clinical scales, based on, for example, the Total Functional Capacity (TFC) scale of the UHDRS As assessed, the TFC score here refers to 4-6. In HD Stage 3... Typically, the patient is no longer able to work or manage household chores, and struggles with daily finances. They require substantial assistance with household chores and daily living activities, and typically have Huntington's disease. Five to sixteen years have passed since the onset of the condition.

[0086] "HD Stage 4", "HD Stage IV", "Huntington's Disease Stage 4", "Huntington "Stage IV of Huntington's disease," "Stage 4 of Huntington's disease," or "Stage IV of Huntington's disease" When used herein, the term refers to the clinically established stages of hepatitis [e.g., Standard scales, for example, clinical scales, based on the Total Functional Capacity (TFC) scale of the UHDRS, etc. As assessed, the TFC score here refers to a range of 1-3. In HD Stage 4, Typically, the patient is not independent but still lives at home with the help of either family or a professional. They can reside there. However, they are not substantively responsible for household finances, housework, and most daily living activities. These patients require significant support and typically 9 to 21 years have passed since the onset of Huntington's disease.

[0087] "HD Stage 5", "HD Stage V", "Huntington's Disease Stage 5", "Huntington "Stage V of Huntington's disease," "Stage 5 of Huntington's disease," or "Stage V of Huntington's disease" When used herein, the term refers to the clinically established stages of hepatitis [e.g., the stage]. Sub-scales, for example, according to clinical scales, such as the Total Functional Capacity (TFC) scale of the UHDRS. As assessed, the TFC score here is 0. In HD Stage 5, typically The patient requires full support for daily activities through professional care, and typically has a hunched chest. 11 to 26 years have passed since the onset of Nton's disease.

[0088] "Early HD", "Early Huntington's disease", "Early stage HD", or "Early stage Huntington's disease" When used herein, the term "Tinchington's disease" refers, for example, to small, involuntary movements. , one of the following selected from the group consisting of slight motor coordination disorders and complex thinking difficulties Despite suffering from multiple illnesses, the patients are mostly functional and able to work and live independently. This refers to the stage of hemorrhagic disease (HD) that can be continued. In other words, it is called "early HD" or "early hunting syndrome." The terms "Huntington's disease," "early-stage HD," or "early-stage Huntington's disease" are used. This refers to "HD Stage 2" as defined herein.

[0089] "Moderate HD", "Moderate Huntington's disease", "HD at a moderate stage", "Moderate stage Huntington's disease, mid-stage HD, mid-stage Huntington's disease, mid-stage The terms "stage HD" or "mid-stage Huntington's disease" are used herein. In such cases, the patient may be unable to work or manage their household finances. or unable to do household chores, but able to eat and get dressed with assistance. This refers to the stage of hemodialysis where the patient is able to take care of their personal hygiene. Typically, at this stage... For example, chorea is prominent, and it affects swallowing, maintaining balance, falls, weight loss, and problem-solving. There may be problems. In other forms, "moderate HD", "moderate Huntington's disease", "moderate Stage HD, moderate stage Huntington's disease, mid-stage HD, mid-stage S "Tage's Huntington's disease," "mid-stage HD," or "mid-stage Huntington's disease" The term refers to “HD Stage 3” as defined herein.

[0090] "Advanced HD", "Advanced Huntington's disease", "HD at advanced stage", "Advanced stage Huntington's disease of the late stage, late HD, or late stage Huntington's disease, late stage HD Or, when used herein, the term “late-stage Huntington’s disease” refers to a patient. However, this refers to the stage of hemorrhagic disease in which the patient requires support in all daily living activities. Typically, this On stage, for example, chorea can be severe, but it can also manifest as rigidity, dystonia, and bradykinesia. Therefore, they are more often replaced. In other forms, "advanced HD" and "advanced Huntington" are used. "Disease", "HD in the advanced stage", "Huntington's disease in the advanced stage", "late HD", or "Late-stage Huntington's disease," "late-stage HD," or "late-stage Huntington's disease" The term refers to “HD Stage 4” or “HD Stage 5” as defined herein.

[0091] The terms "juvenile HD" or "juvenile Huntington's disease" are used herein. This refers to a clinically established diagnosis of hepatitis (e.g., confirmed family history or genetic testing). Based on a positive test result (i.e., confirmation of CAG repeat extension 2:36 (SEQ ID NO: 22)), symptoms appear by age 21. The disease developed.

[0092] The terms "juvenile HD" or "juvenile Huntington's disease" are used herein. , affected by HD {for example, confirmed family history or positive genetic test (i.e., Based on confirmation of CAG repeat extension 2:36 (sequence number 22), <patients who developed symptoms by the age of 21 It refers to a person.

[0093] The terms “childhood HD” or “childhood Huntington’s disease” are used herein to mean “HD.” It is affected by {for example, a confirmed family history or a positive genetic test (i.e., CAG Based on confirmation of repeat extension 2:36 (sequence number 22) and clinical diagnosis, it refers to patients who are <18 years of age. .

[0094] "HD patient", "Huntington's disease patient", "Patient with Huntington's disease", or "Having HD" The term "patient having" refers to a patient having HD as defined herein.

[0095] The terms “to treat,” “to treat,” “treatment,” or “therapy” are used herein. When used, it refers to obtaining beneficial or desired results, such as clinical outcomes. The desired outcome is the stabilization or improvement of HD stage progression (e.g., compared to placebo). This may include, but is not limited to, the following: One aspect of the procedure is, for example, when the above procedure is performed on the patient. The harmful effects should be minimized, for example, the drugs used should have no harmful side effects. It should have a high level of safety without causing any harm. In another aspect, " The term "method for placement" is used herein to mean "method for treatment". To point.

[0096] The terms “intermittent dosing regimen” or “intermittent dosing schedule” are used herein. In this case, it means an administration regimen that includes administering compound 1, followed by a drug-free period. For example, compound 1 is administered according to an intermittent dosing schedule of at least two cycles. Each cycle includes (a) a medication period and (b) a medication-free period.

[0097] As used herein, the term “drug-free period” means, in particular, when a patient is given compound 1. This refers to the period during which it is not used (i.e., the period during which treatment using compound 1 is refrained from). If compound 1 is administered on a daily basis, then the daily dose will be used for a certain period of time, for example, several times. Interruption for several days, or the plasma concentration of compound 1 remains below the therapeutic level for a period, for example, several days. If maintained at this level, a drug-free period may exist. The duration and / or dosage of compound 1 is: The duration of treatment may be the same or different between cycles. Also, the entire treatment period (i.e., treatment) The number of cycles for treatment depends, for example, on the specific patient being treated (e.g., a patient with stage I hemodialysis). Based on this, it can vary from patient to patient.

[0098] In another embodiment, the intermittent dosing schedule includes at least two cycles, each A cycle is defined as (a) a period of administration in which a therapeutically effective amount of compound 1 is administered to the patient, and thereafter (b) Includes a drug-free period. This is called an "intermittent dosing regimen" or "intermittent dosing schedule". As used herein, the term refers to a dosing regimen for compound 1 alone (i.e., monotherapy). treatment) or administration for administering Compound 1 in combination with at least one additional active ingredient regimen (i.e., combination therapy). In another aspect, the term "intermittent administration regimen" or "intermittent administration schedule" refers to a repeated on-off treatment, wherein Compound 1 is administered periodically at regular intervals, for example once daily, every 2 days, every 3 days, every 4 days, once a week, or twice a week.

[0099] In the context of drug administration, the terms "once daily", "once per day" or "QD", as used in the present specification, mean administering one dose of the drug once each day, wherein the dose is, for example administered at the same time each day.

[0100] In one aspect, the terms "administering" or "once daily administration of Compound 1", as used herein , refer to the amount of Compound 1 in a tablet ranging from 1 mg to 100 mg, administered once daily .

[0101] In another aspect, the amount of Compound 1 in the tablet ranges from 1 mg to 200 mg, administered once daily .

[0102] In another aspect, the amount of Compound 1 in the tablet ranges from 1 mg to 100 mg, administered once daily .

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

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

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

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

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

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

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

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

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

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

[0113] In the context of administering compound 1, the terms "once a week," "once a week," or "QW" are: In this specification, administering one dose of compound 1 once each week means, where the dose is: For example, it might be administered on the same day of the week each week.

[0114] In one embodiment, the terms “administer” or “administer compound 1 once a week” are used herein. If used, once a week in the range of 25mg to 100mg, once a week in the range of 25mg to 200mg, and 50mg to 20 This refers to Compound 1, which is administered in a selectable amount ranging from once a week within the range of 0 mg.

[0115] In another embodiment, compound 1 is administered at a dose of 35 mg once per week, 70 mg once per week, or 140 mg once per week, selected from these doses. It is administered in a dose that can be used.

[0116] In the context of administering compound 1, the terms "twice a week," "twice a week," or "BIW" are: In this specification, administering one dose of compound 1 twice each week means that each dose is equal to each It is administered at regular intervals ranging from 48 to 72 hours on separate days per week.

[0117] In one aspect, the terms "administering" or "twice weekly administration of Compound 1" as used herein refers to Compound 1 administered in an amount selected from twice weekly in the range of 10 mg to 100 mg, twice weekly in the range of 10 mg to 200 mg, and twice weekly in the range of 25 mg to 100 mg when the terms are used.

[0118] In another aspect, Compound 1 is administered in an amount selected from twice weekly in the range of 10 mg to 20 mg, for example twice weekly at about 15 mg, twice weekly in the range of 30 mg to 4 0 mg, for example twice weekly at 35 mg, and twice weekly in the range of 50 mg to 90 mg, for example twice weekly at 70 mg .

[0119] The term "about" as it relates to a numerical value X means, for example, X±15% (including all values within this range) .

[0120] The terms "disease-modifying therapy" or "disease-modifying treatment" as used herein, as defined in the present specification, refer to a drug (i.e., a disease-modifying drug) that can modify or alter the course of a condition, disorder or disease such as HD .

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

[0122] The term "patient" as used herein refers to a subject who has a disease state and can benefit from treatment.

[0123] The term "subject in need thereof" as used herein refers to such a subject (patient) However, to gain biological, medical, or quality-of-life benefits from the procedure. This refers to measures that enable such actions.

[0124] The terms “therapeutic effective dose” or “effective dose” of Compound 1, as used herein, This refers to the amount of compound 1 that induces the target biological or medical response. In another embodiment, this The term means that when administered to a subject, it improves at least partially the condition, disorder, or disease. This refers to the amount of compound 1 that is effective for that purpose.

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

[0126] 2.Compound The active ingredient of the tablet composition disclosed herein is 2-[3-(2,2,6,6-tetramethylpiper Lysine-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazolo) Zol-2-yl)phenol (compound 1) or a pharmaceutically acceptable salt thereof. Compound 1 and A suitable method for producing it is disclosed in International Application No. 2020 / 005873 (compound 163 in that publication). It is being done.

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

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

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

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

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

[0132] In another embodiment, the amount of compound 1 in the tablet is 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg g, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 13 The dosage can be selected from 5 mg or 140 mg.

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

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

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

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

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

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

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

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

[0141] The tablets of compound 1 are made by mixing compound 1 with an excipient and compressing them to form tablets. It can be produced by direct compression. The tablets of compound 1 can be produced by wet granulation or It can also be produced by other methods, including dry granulation. When granulation is used, the chemical Substance 1 may be an intragranular and / or extragranular component of the tablet. In one aspect of the present invention, compound 1 is , it is an internal component of the tablet. Compound 1 is mixed with at least one internal excipient, and wet or dry The material can be dried and granulated to form an intragranular blend used in the manufacture of tablets. In one embodiment, the tablet is made by mixing compound 1 with at least one granular excipient and wet granulating the mixture. The process involves forming an in-granule blend and mixing the in-granule blend with at least one excipient. By a method comprising the steps of: preparing the mixture and compressing the resulting mixture to form tablets. It is made.

[0142] 3. Excipients In one embodiment, the tablets provided herein include a diluent, a binder, a surfactant, a disintegrant, and a fluid. The tablets provided herein contain an excipient selected from the group consisting of motion enhancers and lubricants. In the form of the preparation, one excipient may be either an intragranular excipient or an extragranular excipient, while other excipients may be This includes both in-granule and out-granule excipients.

[0143] a. Diluent Diluents are used to dilute the components of a formulation, such as the active ingredient, and adjust them to the appropriate amount for the formulation. Excipients used for this purpose, and in some cases to impart stability or improved moldability. Examples of diluents include sugars, such as lactose or glucose, sugar alcohols, for example. Mannitol, xylitol, maltitol, sorbitol, isomalt and crystalline se Lullose, lactose, glucose, sucrose, fructose, maltose, trehalose Examples include microcrystalline cellulose, which acts as a diluent in tablet formulations. This can be achieved and is included as an in-granule excipient in the tablets of the present invention. However, the "diluent" and As used herein, the term refers to diluents other than microcrystalline cellulose.

[0144] In one embodiment, microcrystalline cellulose is included as an internal excipient in the tablets of the present invention. The amount is in the range of approximately 15% to 25% by mass of the total mass of the tablet, and approximately 15% to 20% by mass. Selected from the group. In another embodiment, the tablets of the present invention are included as in-granule excipients. The amount of microcrystalline cellulose is approximately 20% by mass of the total mass of the tablet. In one embodiment, the granular excipient is formed The diluents included in the agent are in groups consisting of ratios ranging from approximately 1:1 to approximately 1:4, and from approximately 1:1 to approximately 1:2. It exists in a ratio of microcrystalline cellulose to diluent selected from. In another embodiment, intragranular The diluent included as an excipient is present in a ratio of approximately 1:2. In one embodiment, intragranular excipient The amount of diluent contained in the preparation is approximately 15% to 40% by mass of the total mass of the tablet, and approximately 20% by mass. Selected from the group consisting of a range of % to approximately 40% by mass. In another embodiment, included as an in-granular excipient. The amount of diluent included is approximately 40% by mass of the total mass of the tablets. The diluent is included as an excipient outside the granules. In one embodiment, the diluent is approximately 5% to approximately 25% by mass of the total mass of the tablet, and approximately 1% by mass The diluent is present in an amount selected from the group ranging from 0% by mass to approximately 25% by mass. In another embodiment, when included as a formant, the diluent is in an amount of about 20% by mass of the total mass of the tablet. It exists there.

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

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

[0147] Examples of binders that can be used include hydroxypropylcellulose and hypromelo. cellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose Sugars, hydroxypropyl starch, corn starch, pea starch, alpha Examples include fermented starch, acacia, tragacanth, modified gum, gelatin, and povidone. It can be done.

[0148] In one embodiment, the tablet of the present invention contains povidone as an in-granular excipient, and the tablet 1% to about 5% by mass, or 1.5% to about 4% by mass, or about 2% to about 3% by mass of the total mass, or It exists in an amount of approximately 2% by mass.

[0149] c. Disintegrant The disintegrant absorbs water after administration, causing the tablet to swell and disintegrate, thereby activating the active ingredients. An excipient that functions to promote the release of sexual components. In one embodiment of the tablet of the present invention, disintegration The agent is included as both an intragranular excipient and an extragranular excipient. In one embodiment, the amount of the disintegrant is Approximately 1% to 5% of the total mass of the tablet in both the inner and outer parts of the tablet. The amount is selected from the group consisting of approximately 1% by mass to approximately 3% by mass, and approximately 1.5% by mass to approximately 2.5% by mass. In another embodiment, the amount of disintegrant is such that in the inner and outer portions of the tablet, This represents approximately 2.5% of the total mass.

[0150] Examples of suitable disintegrants include sodium starch glycolate, crospovidone, and cross-linking agents. Alginic acid, cross-linked starch, cross-linked sodium alginate, carmellose Carmellose calcium, croscarmellose sodium, glycerin fatty acid ester , low-substituted sodium carboxymethyl starch and partially gelatinized starch Examples include: In one embodiment, the disintegrant is carmellose sodium.

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

[0152] Non-limiting examples of surfactants that can be used include quaternary ammonium compounds. For example, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl (alklphenyl) ethers, such as nonoxynol 9, nonoxynol 10, and octoxynol 9, Poloxamer (Polyoxyethylene and Polyoxypropylene Bromide) Acetyl copolymers (e.g., poloxamer 407), polyoxyethylene fatty acid glycerides and oils For example, polyoxyethylene (8), caprylic / capric acid mono- and diglycerides, poly Oxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil, polyethylene Alkyl ethers, for example, polyoxyethylene (20) cetostearyl ether, polyoxy Ethylene (polyoxyethelene) fatty acid esters, for example, polyoxyethylene (40) steryl Polyoxyethylene sorbitan esters, such as polysorbate 20 and polysorbate Tween 80 (e.g., Tween 80), propylene glycol fatty esters, e.g., propylene laurate Lentil glycol, sodium lauryl sulfate, fatty acids and their salts, such as oleic acid, oleic acid, oleic acid Sodium oleate and triethanolamine oleate, glyceryl fatty acid ester, e.g. For example, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmate Examples include sorbitan monostearate, tyroxapol, and mixtures thereof. ru.

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

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

[0155] e. Lubricants The lubricant reduces friction between the apparatus and the granulated mixture during compression to form tablets. It is an excipient that can be used for this purpose. Examples of suitable lubricants include glyceryl behenate. Lyl, glyceryl behaptate; sodium stearyl fumarate, stearin Acids, as well as magnesium stearate, calcium stearate, and sodium stearate. Salt containing um; hydrogenated vegetable oil; colloidal silica; talc; wax; boric acid; sodium benzoate Thorium; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; polyethylene Sodium glycol; sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate Nesium may be listed individually or in combination. A lubricant is used in the tablets of the present invention. In this case, the lubricant is preferably magnesium stearate.

[0156] In one embodiment, the lubricant is included as an extragranular excipient in proportion to the total mass of the tablet. In this embodiment, the amount of lubricant included as an excipient outside the granules is 0.5% to approximately 3% of the total mass of the tablet. and selected from the group consisting of a range of approximately 1% by mass to approximately 2% by mass. In another embodiment, an extragranular excipient and The amount of lubricant contained is approximately 1.5% by mass of the total mass of the tablet. The lubricant is preferably It is magnesium stearate.

[0157] f. Flow promoter Flow accelerators are excipients used as anti-adhesion agents. An example of a flow accelerator is... Lloyd's silicon dioxide, hydrated sodium sulfoaluminate and talc are examples. In one embodiment of the tablets of the present invention, the flow promoter is used as an extragranular excipient. It is included. If a flow accelerator is present, it is present in a quantity of approximately 0.25% of the total mass of the tablet. It exists in an amount selected from the group consisting of a quantity of % to approximately 2 mass%, and approximately 0.25 mass% to approximately 1 mass%. If a flow accelerator is present, it is present in an amount of approximately 0.5% by mass of the total mass of the tablet. It exists there.

[0158] g. Other excipients The tablets provided herein may contain various excipients other than those described herein. Examples of agents include solubility enhancers, stabilizers, pH adjusters, coating agents, and pigments. However, it is not limited to these.

[0159] 4. Coating The tablets of the present invention contain polyvinyl alcohol and hydroxypropyl methylcellulose. A film suitable for immediate-release tablets such as those with film coating, and can be coated as needed. It is being done.

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

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

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

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

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

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

[0166] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is used as a disease-modifying treatment. By treating or improving Antington's disease, exon 49 and exon in the HTT mRNA transcript are improved. An in-frame stop codon is produced between Son 50 and the next, resulting in a decrease in mRNA, and The reduction of wild-type and mutant HTT proteins has one or more of the following effects:

[0167] (i) Slowing of the rate of decline in motor function loss associated with Huntington's disease. Here, compound 1 is used The slowing of the rate of decline in motor function associated with Huntington's disease after the treatment is due to a decrease in mRNA, and This was demonstrated by a decrease in wild-type and mutant HTT proteins, or by comparison with placebo. Motor function includes eye movement, speech disorders, dystonia, chorea, postural stability, and gait. A group is selected from among these, and a standard clinical scale is used, for example, the UHDRS exercise assessment scale (e.g., Mo Assessment can be performed using Vement Disorders, 1996, pp. 11, 136-142. It will be marked.

[0168] (ii) Slowing of the rate of cognitive decline associated with Huntington's disease. Treatment with compound 1. The slowing rate of cognitive decline associated with Huntington's disease afterward is due to a decrease in mRNA, as well as wild-type and This is demonstrated by a decrease in mutant HTT protein, or by comparison with placebo, and cognitive function The brain encompasses attention, processing speed, visuospatial processing, timing, emotional processing, memory, speech fluency, and mental capacity. Selected from a group consisting of motor function and executive function, and using standard clinical scales, such as symbolic and digital modal scales. The Lithi test, the Stroopword reading test, the Montreal Cognitive Assessment or This is the HD Cognitive Assessment Battery (e.g., Movement Disorders, 2014, 29(10), 1281). ~Page 1288, Symbol / Number Modality Test, Trail Making Test B, One Touch (Including chisel stocking, pasting tapping, affect recognition tests, and Hopkins language learning tests) Assessment is performed through use.

[0169] (iii) Slowing of the rate of psychiatric decline associated with Huntington's disease. Here, compound 1 was used. The slowing of the rate of psychiatric decline associated with Huntington's disease after treatment is due to a decrease in mRNA, as well as This is demonstrated by a decrease in wild-type and mutant HTT proteins, or by comparison with placebo. Psychiatric decline includes emotional blunting, anxiety, depression, obsessive-compulsive behavior, suicidal ideation, irritability, and agitation. Selected from the group consisting of, for example, Movement Disorders, 2016, 31(10), pp. 1466-1478. Standard clinical scales in Movement Disorders, 2015, 30(14), pp. 1954-1960, for example. Assessment can be performed using the Emotional Blurring Rating Scale or the Hospital Anxiety and Depression Scale. Commented.

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

[0171] (v) Slow progression of the pathophysiology of Huntington's disease. Here, after treatment with compound 1, Slow progression of the pathophysiology of Huntington's disease associated with Chinton's disease [e.g., brain (e.g., whole brain)] [Reduction in the rate of volume loss (e.g., %) of the caudate nucleus, striatum, or cortex] This is due to a decrease in mRNA, as well as a decrease in wild-type and mutant HTT proteins, or a placebo. This is demonstrated by comparison with standard techniques, such as MRI (e.g., by neuroimaging evaluation criteria). It is used and assessed (see, for example, Lancet Neural. 2013, 12(7), pp. 637-649). I want to be illuminated.

[0172] (vi) Slowing onset of Huntington's disease or symptoms associated with Huntington's disease. Here, The onset of Huntington's disease or symptoms associated with Huntington's disease after treatment with compound 1. The gradual onset is due to a decrease in mRNA, as well as a decrease in wild-type and mutant HTT proteins. This was demonstrated by comparison with placebo and standard clinical measures, such as health-related measures for Huntington's disease. Quality of Life Questionnaire (HDQoL) (e.g., Movement Disorders, 2018, 33(5), 742) Assessment is performed by using (as described on page 749). Alternatively,

[0173] (vii) Reduction of the decline in quality of life associated with Huntington's disease. Here, compound 1 The onset of Huntington's disease or the onset of Huntington's disease-related symptoms after treatment using [product name] The decrease in mRNA, as well as the decrease in wild-type and mutant HTT proteins, or placebo This is demonstrated by comparison with standard clinical scales, such as the health-related quality scale for Huntington's disease. Life Quality of Life Questionnaire (HDQoL) (e.g., Movement Disorders, 2018, 33(5), pp. 742-749) Assessment is performed by using (in the context of).

[0174] In another embodiment, Huntington's disease is treated using compound 1 or a pharmaceutically acceptable salt thereof. Placing or improving has one or more of the following effects: (i) a favorable therapeutic profile (ii) a file, for example, a preferred safety profile or metabolic profile, or (ii) a preferred off-target effect profiles, for example, favorable psychiatric adverse event profiles, Favorable toxicity (e.g., genotoxicity) or cardiovascular adverse events (e.g., blood pressure, heart rate, electrocardiogram) (Test parameter) profile.

[0175] In one embodiment, a patient requiring it may possess a therapeutically effective amount of compound 1 of the present invention. The tablets are administered orally.

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

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

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

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

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

[0181] In another embodiment, the tablets may be 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg It contains an effective therapeutic dose selected from 70 mg and 100 mg.

[0182] In another embodiment, the tablets may be selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg for therapeutic purposes. It contains potency.

[0183] In another embodiment, the tablets may be 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg It contains an effective therapeutic dose selected from 70 mg and 100 mg.

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

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

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

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

[0188] In one embodiment, a patient requiring it receives a therapeutically effective dose of compound 1 administered once daily. The tablets of the present invention are administered orally.

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

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

[0191] In another embodiment, the tablets are administered once daily in doses of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg. 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 10 0mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg The dosage can be selected from 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, and 200mg. It contains a therapeutically effective amount.

[0192] In another embodiment, the tablets are administered once daily in doses of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg. 35mg, 50mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg It contains an effective therapeutic dose selected from 135 mg and 140 mg.

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

[0194] In another embodiment, the tablets are administered once daily in doses of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg. It contains an effective therapeutic dose selected from 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0195] In another embodiment, the tablets are administered once daily in doses of 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg. It contains the selected therapeutically effective dose.

[0196] In another embodiment, the tablets are administered once daily in doses of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30 mg. It contains an effective therapeutic dose selected from 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

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

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

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

[0200] In another embodiment, the tablets are administered once daily in therapeutic doses selected from 5 mg, 10 mg, and 20 mg. It contains potency.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0221] In another embodiment, the tablet contains 100 mg of a therapeutically effective dose of compound 1.

[0222] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 105 mg.

[0223] In another embodiment, the tablet contains 110 mg of a therapeutically effective dose of compound 1.

[0224] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 115 mg.

[0225] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 120 mg.

[0226] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 125 mg.

[0227] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 130 mg.

[0228] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 135 mg.

[0229] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 140 mg.

[0230] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 145 mg.

[0231] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 150 mg.

[0232] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 155 mg.

[0233] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 160 mg.

[0234] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 165 mg.

[0235] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 170 mg.

[0236] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 175 mg.

[0237] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 180 mg.

[0238] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 185 mg.

[0239] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 190 mg.

[0240] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 195 mg.

[0241] In another embodiment, the tablet contains a therapeutically effective dose of compound 1 at 200 mg.

[0242] In another embodiment, a tablet containing a therapeutically effective amount of compound 1 is administered once daily.

[0243] In another embodiment, a tablet containing a therapeutically effective amount of compound 1 is administered twice daily.

[0244] In another embodiment, a tablet containing a therapeutically effective amount of compound 1 is administered three times a day.

[0245] In another embodiment, a tablet containing a therapeutically effective amount of compound 1 is administered once a week.

[0246] In another embodiment, a tablet containing a therapeutically effective amount of compound 1 is administered once every two weeks. ru.

[0247] In one embodiment, a therapeutically effective amount of compound 1 is used to treat or improve Huntington's disease. For use as a disease-modifying treatment of tablets containing, or pharmaceutically acceptable salts thereof: It is genetically characterized by the elongation of 36-39 CAG repeats in the HTT gene on chromosome 4. Huntington's disease, and the elongation of more than 39 CAG repeats in the HTT gene on chromosome 4. Huntington's disease is selected from a group consisting of Huntington's diseases that are genetically characterized by [specific characteristic]. It includes illness.

[0248] In one embodiment, a therapeutically effective amount of compound 1 is used to treat or improve Huntington's disease. For use as a disease-modifying treatment of tablets containing, or pharmaceutically acceptable salts thereof: Overt Huntington's disease, juvenile Huntington's disease, childhood Huntington's disease, early stage Huntington's disease Huntington's disease, mid-stage Huntington's disease, advanced stage Huntington's disease, st Stage I Huntington's disease, Stage II Huntington's disease, Stage III Huntington's disease, Stage IV Huntington's disease, Stage V Huntington's disease, and asymptomatic Huntington's disease Huntington's disease is included, selected from a group consisting of the following:

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

[0250] In another embodiment, the present invention contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The tablets are administered once or twice a week.

[0251] In another embodiment, the present invention contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The tablets are administered orally.

[0252] In another embodiment, the present invention contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The tablets are provided in the form of a pharmaceutical composition.

[0253] In another embodiment, the present invention contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The tablets are provided in the form of a medical combination.

[0254] In another embodiment, the present invention contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The tablets are administered after gene therapy or treatment using antisense compounds.

[0255] In one embodiment, a treatment to slow the progression of Huntington's disease in a person who needs it A method of administration, wherein one or more tablets containing a therapeutically effective amount of compound 1 are administered to the subject. A method that includes the process of doing so.

[0256] In another aspect, the reduced motor function associated with Huntington's disease in those who require it. A method for treating diarrhea, comprising a treatment containing a therapeutically effective amount of compound 1. A method comprising the step of administering multiple tablets.

[0257] In another aspect, the cognitive decline associated with Huntington's disease in those who require it A treatment method for slowing the reaction, wherein the subject is one or a treatment containing a therapeutically effective amount of compound 1. A method comprising the step of administering multiple tablets.

[0258] In another aspect, Huntington's disease and related psychiatric lows in those who need it A method for treating diarrhea, wherein the subject contains a therapeutically effective amount of compound 1. A method comprising the step of administering one or more tablets.

[0259] In another aspect, the functional abilities associated with Huntington's disease in those who require it A treatment method for slowing the decline, wherein the subject contains a therapeutically effective amount of compound 1. A method comprising the step of administering one or more tablets.

[0260] In another aspect, Huntington's disease and Huntington's disease in the subjects that require it To slow the progression of the pathophysiology of the disease [for example, the brain (e.g., whole brain, caudate nucleus, striatum or cortex)] Reduce the rate of volume loss (e.g., %) from baseline volume) (e.g., MRI-mediated asthma A treatment method for (as described above), comprising a therapeutically effective amount of compound 1 in the subject. A method comprising the step of administering one or more tablets.

[0261] In another aspect, the reduced motor function associated with Huntington's disease in those who require it. A method for treating diarrhea, comprising a treatment containing a therapeutically effective amount of compound 1. Or the process includes administering multiple tablets, and the motor function is affected by ocular motor function, speech disorders, dystonia, etc. A method selected from the group consisting of chorea, postural stability, and gait.

[0262] In another aspect, the cognitive decline associated with Huntington's disease in those who require it A treatment method for slowing the reaction, wherein the subject is one or a treatment containing a therapeutically effective amount of compound 1. The process involves administering multiple tablets, and cognitive decline affects attention, processing speed, visuospatial processing, and time. Select from the group consisting of ing, emotional processing, memory, speech fluency, psychomotor function, and executive function. The method of doing so.

[0263] In another aspect, Huntington's disease and related psychiatric lows in those who need it A method for treating diarrhea, wherein the subject contains a therapeutically effective amount of compound 1. The process includes administering one or more tablets, and the psychiatric impairment is characterized by emotional blunting, anxiety, and depression. A method selected from the group consisting of illness, obsessive-compulsive behavior, suicidal ideation, irritability, and agitation.

[0264] In another aspect, the functional abilities associated with Huntington's disease in those who require it A treatment method for slowing the decline, wherein the subject contains a therapeutically effective amount of compound 1. The process includes administering one or more tablets, and functional abilities include the ability to work, manage household finances, etc. The ability to manage household chores, the ability to carry out daily living activities, and the necessary care A method comprising one or more selected from the group consisting of levels A.

[0265] In another aspect, Huntington's disease and Huntington's disease in the subjects that require it To slow the progression of the pathophysiology of the disease [for example, the brain (e.g., whole brain, caudate nucleus, striatum or cortex)] Reduce the rate of volume loss (e.g., %) from baseline volume) (e.g., MRI-mediated asthma A treatment method for (as described above), comprising a therapeutically effective amount of compound 1 in the subject. A method comprising the step of administering one or more tablets.

[0266] In one embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound in the range of 1 to 200 mg. A method containing substance 1.

[0267] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose ranging from 1 to 100 mg. A method comprising compound 1.

[0268] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing 1 mg of a therapeutically effective amount of compound 1. Having, methods.

[0269] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 5 mg. Having, methods.

[0270] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 10 mg. Having, methods.

[0271] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 15 mg. Having, methods.

[0272] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 20 mg. Having, methods.

[0273] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 25 mg. Having, methods.

[0274] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 30 mg. Having, methods.

[0275] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 35 mg. Having, methods.

[0276] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 40 mg. Having, methods.

[0277] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 45 mg. Having, methods.

[0278] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 50 mg. Having, methods.

[0279] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 55 mg. Having, methods.

[0280] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 60 mg. Having, methods.

[0281] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 65 mg. Having, methods.

[0282] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 70 mg. Having, methods.

[0283] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 75 mg. Having, methods.

[0284] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing an effective therapeutic dose of compound 1 of 80 mg. Having, methods.

[0285] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing 85 mg of a therapeutically effective dose of compound 1. Having, methods.

[0286] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 90 mg. Having, methods.

[0287] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 95 mg. Having, methods.

[0288] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The process includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 100 mg. The method of containing it.

[0289] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 105 mg. The method of containing it.

[0290] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 110 mg. The method of containing it.

[0291] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 115 mg. The method of containing it.

[0292] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 120 mg. The method of containing it.

[0293] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 125 mg. The method of containing it.

[0294] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 130 mg. The method of containing it.

[0295] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 135 mg. The method of containing it.

[0296] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 140 mg. The method of containing it.

[0297] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 145 mg. The method of containing it.

[0298] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 150 mg. The method of containing it.

[0299] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 155 mg. The method of containing it.

[0300] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 160 mg. The method of containing it.

[0301] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 165 mg. The method of containing it.

[0302] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 170 mg. The method of containing it.

[0303] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 175 mg. The method of containing it.

[0304] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 180 mg. The method of containing it.

[0305] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 185 mg. The method of containing it.

[0306] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective dose of compound 1 of 190 mg. The method of containing it.

[0307] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 195 mg. The method of containing it.

[0308] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The procedure includes administering one or more tablets, each tablet containing a therapeutically effective amount of compound 1 of 200 mg. The method of containing it.

[0309] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. This involves administering multiple tablets once a day.

[0310] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. This involves administering multiple tablets twice a day.

[0311] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. This involves administering multiple tablets three times a day.

[0312] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. This involves administering multiple tablets once a week.

[0313] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. This involves administering multiple tablets once every two weeks.

[0314] In one embodiment, a method for treating or improving Huntington's disease in a person requiring it is: The subject contains one or a pharmaceutically acceptable amount of compound 1 or a pharmaceutically acceptable salt thereof. The process involves administering multiple tablets, and Huntington's disease is diagnosed with 36 HTT genes on chromosome 4. Huntington's disease, genetically characterized by the extension of ~39 CAG repeats, and on chromosome 4 Han is genetically characterized by more than 39 CAG repeat elongations in the HTT gene. A method selected from the group consisting of Chinton's disease.

[0315] In one embodiment, a method for treating or improving Huntington's disease in a person requiring it is: The subject contains one or a pharmaceutically acceptable amount of compound 1 or a pharmaceutically acceptable salt thereof. The procedure involves administering multiple tablets, and includes the stages of Huntington's disease, such as overt Huntington's disease and juvenile Huntington's disease. Huntington's disease, childhood Huntington's disease, early stage Huntington's disease, middle stage Huntington's disease Huntington's disease, advanced stage Huntington's disease, stage I Huntington's disease, stage I Stage I Huntington's disease, Stage III Huntington's disease, Stage IV Huntington's disease, A method selected from the group consisting of stage V Huntington's disease and asymptomatic Huntington's disease.

[0316] In one embodiment, a method for treating or improving Huntington's disease in a person requiring it is: The subject contains one or a pharmaceutically acceptable amount of compound 1 or a pharmaceutically acceptable salt thereof. The process includes administering multiple tablets according to an intermittent dosing schedule.

[0317] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. This includes the process of administering multiple tablets once a day, once a week, or twice a week.

[0318] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. This includes the step of administering multiple tablets orally.

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

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

[0321] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. This involves administering a therapeutically effective amount of the compound to the target after gene therapy or treatment using an antisense compound. The process of administering one or more tablets containing substance 1, or a pharmaceutically acceptable salt thereof. include.

[0322] In another embodiment, a method for treating or improving Huntington's disease in a person requiring it. The subject contains one or a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. The administration of multiple tablets revealed inflation between exon 49 and exon 50 in HTT mRNA. This process includes the production of a stop codon.

[0323] In another aspect, a method for slowing the progression of Huntington's disease in a person who needs it is: The subject contains one or a pharmaceutically acceptable amount of compound 1 or a pharmaceutically acceptable salt thereof. By administering multiple tablets, an inframe was created between exon 49 and exon 50 in HTT mRNA. This process includes the production of a stop codon. [Examples]

[0324] The following examples include illustrative embodiments of the present invention. These examples should be construed as limiting. It shouldn't be done.

[0325] (Example 1) Six development batches (1-6) of tablets of compound 1 were weighed and sieved through a 35-mesh net. By using direct compression, the mixture is then mixed under low shear and compressed into tablets. The mixture was prepared. However, the flow was not appropriate, and sticking to the tablet punch was observed during tableting. Two batches of placebo tablets (7 and 8) were prepared in the same manner without compound 1. The composition of Chi is shown in TABLE 1 below.

[0326] [Table 1]

[0327] (Example 2) The problems of flow resistance and sticking associated with direct compression found in the batch of Example 1 have been resolved. To achieve this, we introduced dry granulation using roller compression, weighed the components, and used a 35-mesh granulation process. The mixture is then sieved, mixed using a turbo mixer, and subsequently compressed with rollers. Three other batches (9, 10, and 11) were prepared by the following method. Subsequently, the ribbons were crushed. Then, pass it through a 20-gauge mesh and use a Turbula mixer to remove extragranular components. The mixture was then compressed using a tablet compressor. Good blend uniformity was achieved. All three The batch composition is the same, with equal mass percent of lactose monohydrate and mcc (41 each). It was similar to batch 6 above, except that it contained 0.5%. Different roller compression parameters (rotational speed, screw speed, and pressure) were used. Batch 9 produced the best ribbon during roller compression. Batch 11 stuck to the roll. The ribbon was fragile, while batch 12 produced discontinuous ribbons.

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

[0329] (Example 3) To mitigate the wetting problem observed in Example 2, a surfactant was introduced into the formulation. We decided to do so. Directly compress batches 13 and 14, respectively, with 5 w / w% sodium lauryl sulfate (SL A 50 mg concentration of compound 1 was used with S) and 1% poloxamer 188. Chi 13 contains even more of the surrounding suspended compound 1 than batch 9 tested in Example 2. It showed undissolved granules, and drug release was minimal. Batch 14 containing 1% poloxamer 188 It showed better dissolution performance because there were no granules floating on the surface of the dissolution medium. It appeared that the inclusion of poloxamer reduced the wetting of the granules of compound 1. However, during the dissolution experiment at 50 revolutions per minute, a mounding phenomenon was observed, Complete drug release was only observed when the dollar speed increased to 150 rpm at the 75-minute mark.

[0330] Furthermore, the direct compression batch 17 contains a low concentration of microcrystalline cellulose and a surfactant called poro. A similar preparation was made using Xamer 407. This batch showed poor processability. There was a problem.

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

[0332] [Table 2]

[0333] (Example 4) To minimize the bulging phenomenon in the dissolution container, wet granulation batches 15 and 16 , a smaller amount of Avicel PH102, and 0.5 w / w% and 2.5 w / w% polyvinylpyrrolidone (P) respectively. The preparation was carried out using VP)K30 and 1% poloxamer 407. Wet granulation was performed using a mortar and pestle. The process was carried out as follows: The components inside the granules were passed through a No. 20 mesh sieve and blended. Povidone K30 was dissolved in water to obtain a granulation fluid. Next, the pre-blend was prepared using a mortar and pestle. The granules were wet-granulated with a povidone K30 solution to obtain optimal granules. The wet mass was approximately 2% water. The granules were dried in a 60°C tray oven until the desired content was achieved. The dried granules were then placed in No. 20. It was passed through a sieve and then sieved through a No. 20 mesh and blended with the granular excipient. Mix the smoothing blend with magnesium stearate sifted through a No. 35 mesh sieve, The final blend was obtained.

[0334] Batch 15 is an optimal formulation that shows almost no buildup when dissolved at 50 rpm. It was found that batch 16, containing 2.5 w / w% PVP K30, was inferior to batch 15 in terms of dissolution performance. It was found that this was due to a higher level of PVP K30 binder, causing the granules to be The most likely explanation was that it was due to greater compression.

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

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

[0337] (Example 5) Further dry granulation batch 20, containing 41% microcrystalline cellulose (mcc) and lactol in the granular blend. Prepared using lactose monohydrate, however, without using mcc or lactose monohydrate as an extragranular component. Ta.

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

[0339] [Table 3]

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

[0341] Furthermore, batches 15, 16, and 17 were tested at 80°C and 5% relative humidity, and at 80°C and 75% relative humidity. After storage at humidity, decomposition tests were conducted on the 7th and 14th days. At lower humidity levels, the test was performed. No decomposition was found in any of the materials, and all three samples tested at higher humidity levels were also found to be decomposed. In the case of the device, the breakdown was minimal and equivalent.

[0342] The dissolution stability of batch 15 was tested at various paddle speeds (50, 65, and 75 revolutions per minute) and with The test was conducted under rapid temperature conditions. The percentage of drug released at each time point was higher with increasing rate. 81%, 88%, and 95% of the release occurred during the first 5 minutes at each velocity, respectively. It was found that in 0.01 N HCl, at a paddle speed of 75 rpm, at room temperature, 40°C, or 65°C. When tested, the release rate was even faster, with initial release percentages of 95.4%, 92.6%, and 96.4%, respectively. That was the case.

[0343] Based on the above results, batches 15 (wet granulation) and 20 (dry granulation) were analyzed for pharmacokinetics (pharmokin). It was selected for further testing involving etics.

[0344] (Example 7) In fasted male cynomolgus monkeys, after oral (PO) administration of three formulations of the compound, compound 1 The following study was conducted to evaluate exposure to [the substance]. One of the formulations (batch 21) was 0 The test involved a suspension of 6 w / w% compound 1 in 0.5 w / w% hydroxypropyl methylcellulose (HPMC). The other two formulations tested were wet-granulated batches prepared as described in Example 4 above. The tablets were from batch 15 and dry granulation batch 20.

[0345] The monkeys were divided into three groups of four animals each. The monkeys were fed on the afternoon of the day before administration. The remaining food was removed at 7 pm. The food was returned 4 hours after administration. Each monkey was given a rubber... Compound 1 (6 mg / ml in suspension batch 21) is administered orally at a dose of 30 mg via oral gastric tube, feeding tube, or tablet. Mixture 1 (5 ml), two tablets of 15 mg each from wet granulation batch 15 or dry granulation batch 20. The animals were given samples, and after each administration, 3 ml of deionized water was used to flush them in. The blood samples were then taken as follows: Time points: Before administration (0), 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours Blood samples were collected from each monkey at 12, 24, and 48 hours. Each sample was stored at 8°C. Centrifuge at 3,000 × g for 5 minutes at room temperature to collect the plasma, and freeze on dry ice until tested. The results were obtained. Plasma concentrations were determined by LC-MS / MS. Pharmacokinetic parameters were determined.

[0346] Oral suspension formulation of compound 1 at a dose of 30 mg in 0.5% HPMC water in male cynomolgus monkeys (Batch 21 A plot of individual plasma concentrations of compound 1 after oral administration (Leg 1) is provided in Figure 1. The four monkeys in the study are referred to as "Mky 15-218" and "Mky 15-1" in Figure 1 and the other figures below. These are identified as "72", "Mky 16-108", and "Mky 170004". Mean blood count at each time point. The plot of serum concentration for Leg 1 is provided in Figure 2. The results are summarized in Table 4 below. It is being criticized.

[0347] [Table 4]

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

[0349] Tablet formulation A (wet granulation batch 15) 30 mg / unit obtained from each monkey after oral administration in animals. Plots of plasma concentrations at each time point (Leg 2) are provided in Figure 3. Mean plasma concentration at each time point. The plot is provided in Figure 4. The results of Leg 2 of the study are summarized in Table 5. It is.

[0350] [Table 5]

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

[0352] Tablet formulation B (dry granulation batch 20) 30 mg / unit obtained from each monkey after oral administration in animals. Plots of plasma concentrations at each time point (Leg 3) are provided in Figure 5. Mean plasma concentration at each time point. The plot is provided in Figure 6. The results of Leg 3 of the study are summarized in Table 6. Here, * represents the AUC from the suspension formulation. last This shows p<0.05 when compared to [another value].

[0353] [Table 6]

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

[0355] Average dose normalized AUC last Based on the values, tablet formulation A (wet granulation batch 15) takes 455 hours * kg * n Although the exposure was g / mL / mg, this was 12 times the exposure from the suspension formulation (369 hours * kg * ng / mL / mg). The percentage is 4±23%. Tablet formulation B (dry granulation batch 20) had an exposure of 237 hours *kg*ng / mL / mg. However, this is 58 ± 10% of the exposure from the suspension formulation. Therefore, the AUC from solid formulation A is... It was found to be quite comparable to the AUC from the suspension formulation. However, from solid formulation B The AUC was significantly lower compared to the value from the suspension formulation (P<0.05). In other words, These studies show that compound 1 is a suspension formulation produced by dry granulation (formulation batch 20) or In tablets produced by wet granulation (formulation batch 15) rather than in tablets, bioavailability This indicates that it was significantly higher.

[0356] (Example 8) It can be scaled up during the tableting process, easily processed, and has excellent features including rapid dissolution. In order to identify excipients that have the specified physical characteristics and the concentration of each excipient, as a starting point Further research was conducted using tablets from batch 15 of the wet granulation formulation. It was particularly suitable for the wet granulation method. By selecting multiple grades of lactose and cellulose, the total amount of granular excipients is increased. That's impressive. The povidone concentration was increased from 1%-2% to 5% in three different batches. Furthermore, the total amount of lactose monohydrate used in the formulation was increased, and the mc of lactose monohydrate was increased. The ratio of c was reduced. Examples of the three formulations prepared and tested are provided in TABLE 7 below. For each of the following formulations, a 500-gram batch of Compound 1 was prepared, with 50 g of Compound 1 per batch.

[0357] [Table 7]

[0358] Tablets produced by wet granulation using the aforementioned composition were coated, but the coating The ng did not affect the collapse time. The following TABLE 8 shows the results from batches 23-25 ​​above. The results obtained from testing the tablet cores generated are shown, and some contain 5 mg of compound 1(A). It contained, while the others contained 50 mg of compound 1(B).

[0359] [Table 8]

[0360] In batch 22, which had a PVP level of 1%, sticking occurred, and when the formulation was scaled up to 500g... The formulation exhibited a large amount of fine particles. Due to this problem, compression of this lot was abandoned. did.

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

[0362] For batch 24 with a PVP level of 5%, the disintegration time of the generated tablets was up to 17 minutes. The width increased. Also, the final blend of batch 24 was a combination of granular and powdered excipients. It showed separation.

[0363] Batch 25, which has a PVP level of 3%, is between the collapse time of batch 23 and the collapse time of batch 24. The decay time is shown, which indicates the role of PVP as a binder.

[0364] (Example 9) As mentioned above, batch 23 (containing 2% PVP) contains 5 mg and 50 mg of compound 1 respectively. After storing the generated tablets at 50°C for 2 weeks and then at 40°C / 75% relative humidity for 1 month Stability tests were conducted. Dissolution was performed in apparatus II in 500 ml of 0.01 N HCl at a rate of 75 times per minute. The tablets were stirred by turning. The tablets were chemically stable as no increase in the related substances was observed. Qualitative analysis was performed. The resulting dissolution profiles are shown in Figure 8 (5 mg tablet) and Figure 9 (50 mg tablet). The dissolution profile shows the immediate release of compound 1 from each tablet, and is higher. Even after being stored at high temperatures and humidity levels, it maintains a profile comparable to its initial state.

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

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

[0367] Secondary research objectives (i) Characterize the pharmacokinetics of compound 1 at a single dose in healthy subjects, (ii) healthy In the subjects, the pharmacokinetics of administered compound 1 for 14 or 21 days are characterized. (iii) assess the QTc and drug concentration effect of compound 1 after repeated dose escalation, (iv) ) In healthy subjects, assess the safety and tolerability after administering compound 1 for 7 days. (v) In healthy subjects, the safety of a single dose of compound 1 administered in a fed state and To characterize tolerability, and (vi) in healthy subjects, the 28-day period of administration of compound 1. To characterize the pharmacokinetics up to that point.

[0368] Exploratory research purpose (i) Against huntingtin (HTT) premRNA splicing in the blood of healthy subjects, (ii) To explore the effect of a single dose of compound 1, and to investigate the HTT premRNA in the blood of healthy subjects. For 14 or 21 days of administered compound 1, the effects on issing and HTT protein levels. (ii) To explore the effects of HTT premRNA splicing in the blood of healthy subjects, To explore the effects of a single dose of compound 1 administered (with food), and (iii) healthy individuals The administered chemical reaction to HTT premRNA splicing and HTT protein levels in elephant blood. Explore the effects of compound 1 over a period of up to 28 days.

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

[0370] Research method The study was monitored by the Safety Review Committee (SRC). The SRC's intent was to ensure that the treatment was effective. The goal was to avoid imposing excessive risks. Safety and acceptability were considered in Part 1 (single-stage). From a certain dose level in Part 2 (Multiple Dose Elevation [MAD]) to the next highest dose level Before the gradual increase to the bell, and before starting Part 3 (CSF), Part 4 (FE), and Part 5, each of the following... Assessment was conducted by SRC across the hortas.

[0371] The SRC consists of the following staff: the Principal Investigator or their representative (the representative will be responsible if the Principal Investigator is unable to respond). (m), consisting of a sponsor's medical monitor or agent (must be a physician) Other internal or external experts may be invited to participate in the review or to provide consultation. I sometimes receive them.

[0372] Multiple parts of the research are not necessarily carried out in numerical order and may be conducted simultaneously. SRC met before the start of Part 5 of the study to determine the dosage to be used in Part 5. Combined. Dosage (may include loading dose and maintenance dose) is determined before commencing Part 5, based on available SAD And selected based on MAD data. SRC plans inter-cohort meetings within Part 5. It wasn't there.

[0373] Part 1 (SAD) The single-dose escalation (SAD) part of the study involved randomized participation in healthy men and women. Furthermore, it was a double-blind study and included a placebo control.

[0374] Five dose levels were tested in five cohorts (cohorts 1.1 to 1.5), each containing eight participants. The plan was to select a further cohort to evaluate. It is possible.

[0375] The initial dose in the first cohort was determined in accordance with the FDA guidance on the recommended maximum starting dose (MRSD) and And in accordance with EMA guidelines, the most susceptible species, the (male) rat, was subjected to NOAEL (Observed Adverse Effect). The estimated human equivalent dose (HED) was ≤1 / 10 (at levels with no effect). (NOAEL in rats) The value is 6 mg / kg. This value is for germ cell detachment in the epididymis and testes in male rats. This was determined by observation. HED was calculated to be 0.97 mg / kg, which corresponds to 68 mg in a 70 kg person. This was the estimated dose. When this dose was adjusted to 1 / 10, the dose for the first cohort became 6.8 mg, The actual dose administered will be 5 mg.

[0376] In cohort 1.1, sentinel was administered to two subjects (one subject received compound (One subject received one dose of the drug, and one subject received a placebo.) Clinically significant safety issues were observed. If not administered, the remaining subjects in this cohort were given the dose at least 24 hours later. The six subjects (five subjects received compound 1 and one subject received a placebo) were divided into two groups. It can be administered as such. Cohort 1.1 was the only cohort to have sentinel therapy performed. In subsequent cohort studies, it was possible to administer the drug to all eight subjects as a single group. ru.

[0377] After administration to each cohort was completed, a meeting had to be held regarding dose escalation. The dose levels for the next cohort were determined based on PK and safety from the previous cohort. It was possible to do so. The dose escalation was related to the relationship between the mean exposure in the cohort and the mean exposure at NOAEL. It was decided by the department in charge.

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

[0379] If the average AUC is ≥1 / 10 to <1 / 5 of the AUC at NOAEL, the dose can be increased up to 100%. This is possible. In other words, subsequent doses can be up to twice the previous dose.

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

[0381] The highest dose level is associated with an average exposure not exceeding half of the AUC in NOAEL, and furthermore... The dose escalation was not carried out. The dose escalation will continue unless the criteria for discontinuing the dose escalation are met. It was decided that it would be done.

[0382] Eligibility was to be assessed during a screening period of up to 28 days. The target group was Patients were required to visit the clinic the day before administration (-1 day). On the morning of day 1, for at least 10 hours After fasting overnight, compound 1 or placebo was administered orally. On day 8, the subjects were required to... After all research procedures were completed, patients were discharged from the clinic if medically appropriate. A follow-up phone call regarding sexual activity will be made four weeks (±1 week) after discharge on the eighth day.

[0383] Part 2 (MAD) The multiple escalation (MAD) part of the study involved randomized participation in healthy men and women. The study was double-blind and included a placebo control. Up to five regimens were tested, each for 8 minutes. The study was planned to be conducted in up to five cohorts of human subjects (cohorts 2.1-2.5). Six subjects in the group will receive compound 1, and two subjects will receive a placebo. The subjects of cohorts 2.1 and 2.2 were administered for 14 days, and the subjects of cohorts 2.3 to 2.5 were administered for 14 days. The elephants were to be administered the drug for up to 21 days.

[0384] Part 2 was administered to at least two cohorts of Part 1, and safety parameters were reviewed. Then, each SAD PK parameter is calculated, and a MAD administration simulation of the corresponding SAD dose is performed. Once the procedure is completed, it can be started. A selection of specific dose levels is available. Based on available SAD PK data, simulations, and general safety observed in Part 1 It was assumed that this would be communicated. After the dose level was evaluated in each individual format, a pharmacokinetic simulation was performed. Rations were conducted to determine the variation within the administration interval. In Cohort 2.3 The doses administered on days 1 and 2 are less than the selected dose for the remainder of the scheduled doses. This was also performed with a high loading dose. For cohorts 2.4 and 2.5, a similar administration schedule was used. You can select a method. This is guaranteed by the data collected and analyzed during the study. In that case, alternative dosing schedules can be considered for all cohorts in Part 2. Cut.

[0385] Eligibility was to be assessed during a screening period of up to 28 days. The target group was The patient was to have a check-up at the clinic the day before administration (-1 day). Each morning during the administration period (i.e., from day 1 to day 21), after fasting for at least 10 hours overnight, the chemical compound The subjects were to be administered either substance 1 or placebo orally. The subjects were those who received their final dose (i.e., on day 21 or day 28). Seven days after the first day, once all necessary research procedures have been completed, if medically appropriate. The patient was discharged. The target group was those who underwent PK 7 days after discharge (i.e., up to day 28 or day 35). And patients who return to the clinic on an outpatient basis for the collection of PD (mRNA and HTT protein) samples. The safety follow-up will be conducted via telephone or outpatient visit on day 49 (±7 days). That's what I did.

[0386] Part 3 (CSF) The concentrations of compound 1 in plasma and CSF were measured in healthy male and female subjects using an open label. The design was to be assessed. Compound 1 at a single dose was administered to one cohort of 6 subjects. The dosage level for Part 3 was determined to be administered daily for 7 days to cohort 3.1). The decision will be based on the review of safety, acceptability, and PK data in Part 2. If the dosage needed to be further determined during development, that dosage and schedule should be noted. This was applied to this part of the research.

[0387] Eligibility was to be assessed during a screening period of up to 28 days. The target group was Each patient was to be checked at the clinic the day before administration (-1 day). On the mornings of days 1 to 7, Compound 1 was administered orally after fasting for at least 10 hours overnight. Continuous sampling of CSF and plasma was performed on day 7. The precise timing of CSF and blood sampling (samples) will be determined by the results of Part 1 and Part 2. The decision was to be made based on the following criteria. The subjects were those who completed all necessary research procedures on the 9th day. Afterward, if medically appropriate, the patient will be discharged from the clinic. Regarding safety The follow-up phone call was scheduled to be made four weeks (±1 week) after the patient's discharge on the ninth day.

[0388] Part 4 (FE) The Food Effects (FE) part involves up to three cohorts of six subjects each, consisting of healthy men and women. It was a parallel open-label part in the sexual object. Compound 1 up to 3 dose levels It was decided to administer it 30 minutes after starting a high-fat, high-calorie breakfast. Part 4 This can be started if sufficient data from Part 1 is available. The quantity level is determined in Parts 1 and 2 based on the available safety, tolerability, and PK. The selection will be based on a review of the data.

[0389] Eligibility was to be assessed during a screening period of up to 28 days. The target group was The patient was to have a check-up at the clinic the day before administration (-1 day). At breakfast on the 1st day, Formula 1 was administered orally after consuming a standardized, high-fat, high-calorie breakfast. The subjects will be included on day 8, after all necessary research procedures have been completed, if medically appropriate. The patient will be discharged from the clinic. A follow-up phone call regarding safety will be made 4 weeks after discharge on day 8. It was decided to perform the procedure within a few weeks (±1 week).

[0390] Part 5 (Multiple doses over up to 28 days [MD28D]) Part 5 involves randomized controlled trials of multiple doses over up to 28 days in healthy men and women. The study was double-blind and included a placebo-controlled assessment. Each study involved eight participants. We will plan up to three cohorts. Before the start of Part 5, the SRC will complete Parts 1 and 2. Based on the data available from the completed cohort, the dosage for this part of the study (loading dose and (May include maintenance doses), administration regimen (including feeding or fasting states), and duration (28 The group met to select (up to 24 hours). Six subjects within each cohort were selected for the compound One subject received the drug, and two subjects received a placebo. The total dose on each day was The dose should not exceed the dose established as well-tolerated in Part 1 (SAD). .

[0391] Eligibility was to be assessed during a screening period of up to 28 days. The target group was The patient was to undergo a check-up at the clinic the day before administration (-1 day). On each administration day, the given criterion According to the regimen determined by the SRC for each selected hort, the following morning after fasting overnight or at the standard Compound 1 or placebo was administered orally either after breakfast following a semi-high-fat meal. The elephants were medically appropriate seven days after the final dose, once all necessary research procedures were completed. In that case, the patient was discharged from the clinic. The target period was 7 days after discharge from the clinic. Later, for the collection of PK and PD (mRNA and HTT protein) samples and for safety assessment. Then, the patient was to return to the clinic as an outpatient. Day 1 and the day of the expected maximum exposure (that is, On the second day, or on the 29th day if a loading dose is not used, the patient will be 24 hours It was assumed that monitoring would be performed using a Holter monitoring device in between.

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

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

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

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

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

[0397] Inclusion Criteria The following criteria must be met by all individuals whose participation in the study should be considered. I don't know.

[0398] For Parts 1, 2, 4, and 5, the subjects are healthy men or women. At the time of cleaning, the participants were between 18 and 65 years old, including both ends. For Part 3, healthy men or women The subjects were aged 50-65 years at the time of screening, including both extremes.

[0399] Participants must understand the nature of the research and have not yet performed any research-related procedures. Unless you provide a signed and dated written informed consent No.

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

[0401] Medical history, physical examination, clinical test results, ECG records (for example, for men, QTcF ≤ 450 mmHg) Based on medical assessments including QTcF ≤ 470 milliseconds (for women and men) and vital signs. The patient must be determined to be healthy by the clinical trial researchers. Values ​​outside the range must be repeated. It can be repaid.

[0402] For male subjects and women of childbearing potential, two types of treatment were administered throughout the duration of the study and for 30 days after the final dose. The methods of contraception must be actively used.

[0403] Postmenopausal women must have experienced spontaneous amenorrhea for ≥12 months (Sk (Follicle-stimulating hormone (FSH) levels are ≥30 mIU / mL at the time of fertilization.) Women who have undergone sterilization surgery. This refers to cases where a hysterectomy, bilateral oophorectomy, or bilateral tubal ligation occurred within 6 months prior to screening. She is defined as a woman who received the treatment.

[0404] All women of childbearing age should have a negative serum pregnancy test result and be -1 day pregnant at the time of screening. A negative urine pregnancy test result is required.

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

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

[0407] Part 4 only: The target is those who willingly consume all high-fat breakfast items within the specified time frame, and consume It must be possible to do so.

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

[0409] Have you participated in any clinical research on any drug or device within 60 days prior to screening? Or, if you expect to participate in a clinical study of any drug or device during the duration of this study The target.

[0410] In the opinion of the clinical trial investigator, there is a risk of adverse effects on the safety of the subjects, or Past or ongoing medical conditions (e.g., comorbidities) that may impair the assessment of research results. diseases, psychiatric conditions), past medical history, and physical findings.

[0411] Abnormalities in general neurological test results.

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

[0413] Invalidating informed consent or the subject's ability to comply with protocol requirements Any psychological or emotional problems, any disorders, or actions that are likely to be restricted A treatment.

[0414] During screening, positive results for hepatitis B surface antigen, positive results for hepatitis C antibody, or human immunodeficiency virus (HVM) were observed. Positive result for HIV antibody test.

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

[0416] Excessive alcohol consumption within the 6 months prior to screening (regular alcohol consumption is (For men, ≥21 units per week; for women, ≥14 units per week). 1 unit (8g) This is equivalent to 1 / 2 pint (280 mL) of beer, 1 mark (25 mL) of spirits, or 1 small glass of wine. (Equivalent to 125 mL)

[0417] The subject is either a smoker or uses other nicotine-containing products. Former smokers are screened. You must quit smoking for more than three months before leaning.

[0418] At the time of screening or on the first day of each treatment period, urinary drug screening and cotinine screening are performed. Positive for leaning or alcohol breath test.

[0419] Pregnant or breastfeeding women.

[0420] The subject has already received compound 1.

[0421] Part 3 only: Contraindications for lumbar puncture, e.g., hypothrombocytopenia, international standardization of prothrombin time. Abnormalities in the PT-INR ratio, spinal cord malformations, or other conditions that may lead to the exclusion of lumbar puncture at the discretion of the clinical trial investigator. Spinal cord condition.

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

[0423] Evaluation Criteria Effectiveness Where can the following PK parameters be applied to the PK of day 1 (single dose) of part 1 be implemented? Assessed herein [Part 1 (SAD), Part 2 (MAD, Day 1), Part 4 (FE), and Part 5 (MD28D, Day 1)]: C max ; maximum observed plasma concentration, C max / D; dose-normalized C max (Part 1 on ly), T max ; time to reach C max , AUC 0-24 (area under the concentration-time curve from 0 to 24 hours), AUC 0- 72 (area under the concentration-time curve from 0 to 72 hours), AUC 0-tau (for Part 2 only, linear up / log down trapezoidal method calculated area under the concentration-time curve over the dosing interv al), AUC 0-t (area under the concentration-time curve from time zero to time t calculated by linear up / log down trapezoidal method , where t is the time of the last measured (or measurable) concentration (C t ) (Part 1 and 4 on ly), AUC 0-t / D (dose-normalized AUC from time zero to the last quantifiable concentration , Part 1 only), AUC 0-inf (area under the concentration-time curve from time zero to infinity calculated by linear up / log down trapezoidal method , AUC 0-inf = AUC 0-t + C t / λ z , where λ z is the terminal phase elimination rate constant (Part 1 and 4 only), AUC 0-inf / D (dose-normalized AUC from time zero to infinity , Part 1 only), λ z (apparent terminal elimination rate constant (terminal rate constant) calculated by linear regression of the terminal linear portion of the log concentration versus time curve , Part 1 and 4 only ), t 1 / 2 (ln(2) / λ z The apparent terminal phase half-life calculated as follows (parts 1 and 4 only), CL / F( Dose / AUC 0-inf The whole body clearance calculated as (parts 1 and 4 only), and V z / F(dose / (λ z *AUC 0-inf (The apparent volume of distribution calculated as...).

[0424] For the PK parameters listed below, please specify where they apply to PK on day 14, day 21, or day 28 (multiple doses). Assessed that it would be feasible [Part 2 (MAD) Cohort 2.1 and 2.2 (Day 14), Co Hort 2.3-2.5 (Day 21), and Part 5 (MAD) Cohort 5.1-5.3 (Day 28): C max (between administrations) (Maximum plasma concentration observed over intervals), T max (C over the administration interval) max Time until it reaches (between), C min (Minimum concentration over the dosing interval), C avg (Average concentration over the dosing interval), AUC 0-tau (line Area under the concentration-time curve within the dosing interval, calculated by the trapezoidal (top) / logarithmic (bottom) method, AUC. 0-tau / D(dose standardized AUC 0-tau ), λ z (By linear regression of the terminal linear portion of the logarithmic concentration-time curve) The apparent terminal phase disappearance rate constant (calculated as t) 1 / 2 (ln(2) / λ z As calculated Terminal phase half-life, CL / F (dose / AUC) 0-tau (Calculated as the whole body clearance), V z / F(for Quantity / (λ z *AUC 0-tau(Apparent volume of distribution calculated as AUCR) auc (AUC 0-tau Accumulation based on Ratio: AUC at the final dose 0-tau AUC on day 1 0-tau ), and AUCR cmax (C max Accumulation ratio based on: final throw C at the time max Day 1 C max ).

[0425] The following PK parameters were used on day 14 of Part 2 (Cohorts 2.1 and 2.2) or day 21 of Part 2 ( The final dose on day 28 of cohort 2.3-2.5 (cohort 5.1-5.3), and on day 7 (multiple doses). (Single dose) [Part 3 (Day 7)] PK:C max (Maximum observed plasma concentration), T max (C max Until it reaches (Time), AUC 0.5~12 (Calculated using the linear (top) / logarithmic (bottom) trapezoidal method, concentration over 0.5-12 hours) Regarding the area under the degree-time curve and the CSF / plasma ratio (the ratio of CSF concentration to plasma concentration (Part 3 only)): We assessed where it would be feasible.

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

[0427] From baseline to each scheduled point in time, and from those points in time to EOS Changes in Lusine, from baseline to each scheduled point in time, and from those points in time to EO Changes in ECG parameters up to S, from baseline to each scheduled time point, Changes in clinical laboratory values ​​from that point to EOS, changes in C-SSRS score from baseline (part 2. Parts 3 and 5 only), adverse events (AEs) that occurred under treatment up to end-of-situation (EOS), and the study drug. AEs that occurred during treatment leading to premature discontinuation, serious adverse events that occurred during treatment up to end-ossicle ( SAE), as well as abnormal physical examination results.

[0428] statistical methods Pharmacokinetics A list of individual subjects was provided. The average individual plasma concentration-time profile for compound 1 was also provided. The data for each group was presented in a chart.

[0429] The PK variable is defined using the arithmetic mean, standard deviation, geometric mean, median, minimum, maximum, and CV%. This was decided upon as a summary.

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

[0431] To assess the effects of food, chemical reactions were observed in fasting (Part 1) and eating (Part 4) states. The PK parameters of substance 1 are shown in charts and graphs, and descriptive statistics are prepared. Dose level Statistical analysis per unit, for compound 1, treatment in the feeding state as a test (Part 4) and As a reference, the procedure using the same dose in a fasted state (Part 1) was used in six subjects. It was decided to be done.

[0432] The main PK parameter is C max AUC 0-t , and AUC 0-inf It was assumed that this was the case. First, C max , AUC 0-t , and AUC 0-inf The PK parameters are to be transformed by natural logarithms, and these logarithmic transformations The mean of the selected parameters is used as the only fixed factor in a linear model using treatment (fasting state). A linear model of compound 1 administered under a feeding state versus compound 1 administered under a feeding state. The following was used to estimate the difference between these means (logarithmic scale) and its 90% confidence interval (CI). By raising it to a power, the ratio of the geometric mean and the corresponding CI were formed. max AUC 0-t , and AUC 0-inf All 90% CI results for GMR fall within the 80.00%–125.00% interval. In that case, it was concluded that there was no effect from the food.

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

[0434] For continuous demographic variables (e.g., age, height, and weight), summary statistics (mean, The report should provide the median, standard deviation, minimum, maximum, and number of available findings. This provides a list of individual subjects in the demographic data.

[0435] This method summarizes qualitative demographic characteristics (sex, race) using quantitative and percentage figures. This was done to include other baseline characteristics of the subjects (e.g., medical history, clinical findings from physical examination, medications). This list only includes the history and the inclusion / exclusion checklist.

[0436] ECG variables, vital sign measurements, and laboratory measurements are calculated using the mean, median, standard deviation, and minimum values. Using the maximum value, the number of available findings, and the change from baseline, at each point in time... The C-SSRS parameters were analyzed using descriptive statistics where appropriate. This was decided upon. ECG data, vital sign data, laboratory measurements and individual C-SSRS data This document provides a list of elephants (only for parts 2, 3, and 5).

[0437] This method only descriptively compares the distribution of these parameters between treatment groups (fasting or feeding). It was decided that statistical inference would be performed.

[0438] Holter analysis / plasma concentration-QTc effect of compound 1 can be performed, and the results can be reported separately. It was to be provided.

[0439] Results of Phase 1 research A very important objective of the Phase 1 clinical trial with healthy volunteers is to assess HTT mRNA and protein The objective was to establish the target dose range of compound 1 for reducing quality. This clinical trial was conducted to determine the target dose range of compound 1 for reducing quality. The study consisted of single-dose escalation (SAD) and multi-dose escalation (MAD) cohorts. Administration in this context is well-tolerated, there are no known safety concerns, and the HTT mRNA dose is dose-dependent. Sex splicing was observed. The study duration of the MAD cohort was longer, and H Longer-term evaluation of TT mRNA splicing and HTT protein decline is possible. In the MAD cohort, compound 1 showed a long drug half-life, lasting up to 72 hours after the final dose. It was demonstrated that the slicing was maintained.

[0440] CSF sampling allows for the evaluation of the pharmacokinetics of compound 1 in CSF, and here in CSF The level of compound 1 was compared to the level of compound 1 in plasma. Results from a Phase 1 study Furthermore, the level of compound 1 in CSF is equal to or lower than the level observed in plasma. It has been proven to be high. Due to the food effect portion, a single dose of compound 1 in healthy subjects It became possible to evaluate the pharmacokinetics of compound 1 in plasma after administration.

[0441] As shown in Figure 9A, the SAD cohort received placebo, 5 mg, 15 mg, 45 mg, 90 mg, or 13 mg. Whole blood samples were taken from healthy volunteers 24 hours after administration of one of the 5 mg compounds 1. A dose-dependent decrease in HTT mRNA occurred.

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

[0443] The lowest dose tested in both the SAD and MAD cohorts resulted in a 30-50% target reduction level. The goal was achieved. The half-life of HTT mRNA was estimated to be approximately 24 hours. Therefore, the next day If HTT mRNA is not synthesized, the total amount of HTT mRNA will be approximately 50% of the baseline. This could be predicted. Administration of compound 1 in the SAD cohort affected all HTT mRNA de novo compounds. It essentially inhibited the growth. Therefore, even with higher concentrations of compound 1, the total amount of HTT mRNA was inhibited. This remains at approximately 50% of baseline, corresponding to the amount of HTT mRNA synthesized before administration of compound 1. They were doing it.

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

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

[0446] Figure 10 shows the HTT mRNA and protein that yield steady-state levels of RNA and protein. This is an illustrative diagram of degradation dynamics.

[0447] In untreated cells, the amount of synthesized mRNA or protein is equal to the amount of degradation. This is consistent, and therefore the mRNA and protein levels are the same over time, so mRNA and protein The quality is at a steady state level. Addition of compound 1 includes the inclusion of HTT pseudoexons in the transcript. John triggered a rapid decay of HTT mRNA and approximately 50% of the baseline. This leads to a decrease in HTT mRNA. The half-life of HTT mRNA is approximately 24 hours. Therefore, the drug The amount of HTT mRNA present the day after physical treatment is controlled by the administration of compound 1. In this example, approximately 50% of newly synthesized mRNA was inhibited. Approximately 50% of the RNA is degraded after 24 hours. How much mRNA is at the HTT protein level? It depends on how much is produced. Therefore, a 50% decrease means a 50% decrease in HTT protein. It should cause this. However, the HTT protein has a half-life of about 5-7 days. It takes a longer period to reach a new steady state level. Finally, 50 mRNA % exists, and when the new level of protein decreases to 50% of the original amount, the new constant Reaching a normal state. Changes in HTT protein levels over a longer period in the MAD cohort. That was the assessment. Therefore, after treating healthy subjects for 21 days, blood was drawn from each subject. The amounts of HTT mRNA and protein in the blood samples were measured.

[0448] Figure 16 shows the results 24 hours after the final dose, following administration of the vehicle or compound 1 to humans, as described above. In whole blood samples from MAD cohort 2.3 (30 mg administered for 21 days, followed by 100 mg of LD administered for 2 days) The measured huntingtin mRNA and protein levels are shown as a percentage of the baseline. The results indicate that the decrease in HTT mRNA has reached a steady state. A longer administration period was required for the quality level to reach the maximum steady-state decline. The changes in HTT mRNA observed inside indicate that continuous treatment with compound 1 lowers the steady state of HTT. When the following is acquired over time, the similarity of HTT protein levels in Huntington's disease patients This is expected to lead to a decrease.

[0449] Figure 11 shows the decay rates of HTT mRNA (Figure 11A) and HTT protein (Figure 11B) relative to their half-lives. Based on this model, the time it takes to reach a steady state after treatment with a daily dose of 30 mg of compound 1 is calculated. The graph shows the interim prediction. For HTT mRNA, the half-life is estimated to be approximately 24 hours. The HTT mRNA reached a steady state after approximately 5 days. Regarding the HTT protein, The half-life is estimated to be 5-7 days, and as a result, the steady-state level of the HTT protein This was first achieved approximately six weeks after the start of treatment.

[0450] Figure 12 shows HTT mRNA (Figure 12A) and protein (Figure 12B) observed in multiple dose-escalation studies. The trajectory of the decrease is predicted from the half-lives of HTT mRNA and protein shown in Figure 11. This is being compared to the previous study. The results showed a rapid decrease in HTT mRNA levels, reaching a steady state approximately 4-5 days after treatment. This indicates that the state has been reached. As predicted, the rate of protein decline is considerably slower. Although the condition was chronic, after 21 days of treatment, the amount of HTT protein decreased by approximately 40%. Therefore, Approximately 4-5 weeks after the start of treatment, equivalent steady-state levels of HTT mRNA and protein are reached. I was able to do it.

[0451] As shown in Figure 13, the level of compound 1 in cerebrospinal fluid (CSF) is therefore compound 1 It crosses the blood-brain barrier and is present in free plasma in both humans (Figure 13A) and non-human primates (Figure 13B). This demonstrated a direct phase relationship with the level of compound 1. The two subjects in this cohort were 30 mg. The daily dose was administered. Therefore, compound 1 crossed the blood-brain barrier. The compound found in CSF The level of compound 1 is at least equivalent to, or exceeds, the level observed in plasma. Therefore, it was determined that compound 1 was present in humans and that compound 1 was not excreted. However, this has been proven in humans.

[0452] In the food effects cohort, compound 1 was effective regardless of whether the subjects were fasting or eating. They did not show similar exposure.

[0453] In conclusion, the Phase I study showed that compound 1 crosses the blood-brain barrier and is effective in both the CNS and peripheral regions. It was demonstrated that HTT mRNA and protein were selectively and dose-dependently reduced in this group. These results suggest that exposure to compound 1 in human patients leads to the development of HTT mRNA and HTT protein. It is confirmed that this results in a demonstrably degraded quality.

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

[0455] Prior to the development of this Phase 2 study, compound 1 was used in in vivo and in vitro preclinical pharmacology models. In the comprehensive toxicology program, as well as in ongoing pharmacokinetic studies with healthy volunteers In the Z1 study, it was broadly evaluated. Overall, based on the resulting data, compound 1 Treatment with this method results in a dose-dependent decrease in premRNA splicing and protein transcription. Furthermore, treatment with compound 1 involves a high single dose of 135 mg and a high dose of 30 mg over 21 days. Multiple doses of this dosage have been confirmed to be safe and well-tolerated in clinics. It can be done.

[0456] In a 12-week double-blind study of the present invention, total HTT (tHTT) protein in subjects with HD Quantification of the effect of compound 1 on quality deterioration, and two types of treatment with compound 1 over a 12-week period. This will allow for the evaluation of the safety of the dosage.

[0457] Parallel group design allows for patient recruitment by all treatment arms within the same timeframe, A parallel-group design was chosen. Blood levels of HTT protein, mRNA, and drug response were evaluated in untreated patients. Time-course data for other indicators is unavailable. A parallel architecture with a placebo control was also used. The use of the M design enables direct assessment comparisons to determine the effectiveness of proactive measures. Yes.

[0458] The patient population will identify individuals with active disease who have not yet experienced functional decline. Therefore, we chose to reduce variability in otherwise heterogeneous disease populations. Therefore, in this study, subjects were randomized based on CAG repeat length and symbolic digit modal Baseline of the Stress Test (SDMT), Total Motor Score (TMS), Independent Scale (IS), and Total Functional Ability (TFC) Based on line measurements, patients are enrolled in the clinical trial. These factors are those that have not yet experienced functional decline. Targeting individuals with active disease who do not exhibit (or who may show disease progression that would allow them to accept intervention) Used to determine and register. Huntington's disease prognosis prediction index (PI) HD ) or its norm Defined Prognostic Index (PIN) HD Using the score of ), it is possible to predict the likelihood of HD progression. Yes, it is possible. The PIN score is used at baseline to identify eligible participants for the study. It is calculated based on that.

[0459] Based on the dynamics of compound 1-mediated HTT reduction in humans, the tHTT protein in HD patients The maximum reduction in quality is expected to be achieved in 4-6 weeks. With a 12-week treatment regimen... The steady-state decline in tHTT was observed in a Phase 2 study, followed by a one-year open-label extension trial. Furthermore, it can be demonstrated that this condition is maintained over time with continuous treatment using compound 1. The Z2 study focused on changes in tHTT protein from baseline and safety as the primary endpoints. In addition, the cognitive and motor skills of the subject are measured by the Unified Rating Scale for Huntington's Disease (UHDRS). An exploratory clinical outcome endpoint to assess the effect of compound 1 on function. It includes. UHDRS is used to assess disease progression in multiple areas. It has been extensively researched and developed. It addresses cognitive impairment, motor function loss, and the tail of the brain. Accelerated loss of nucleus and putamen volume is a very important feature of this disorder, and quality of oculi It has a significant impact on IF. Wearable devices enable more sensitive initial motion changes. Assessment is also included as an exploratory endpoint in the Phase 2 study, over a period of 12 weeks. These endpoint studies will help determine the rate of change in the disease at an earlier stage. Insights into this topic are provided, and crucial metrics that can serve as early indicators of HD progression are identified.

[0460] Risk / Benefit Assessment As stated, HD is a relentlessly progressing neurodegenerative disorder. In the early stages of the disease... The patient shows only slight symptoms, and as the disease progresses, involuntary movements such as writhing occur. The movement becomes more pronounced, voluntary motor function declines, and speech and swallowing are gradually impaired. At times, aggressive disinhibited behaviors become more frequent. In the final stage of the disease, the patient is unable to walk on their own. It is characterized by severe inability to speak, swallow, or receive care, and ultimately leads to full-time care. Care becomes necessary, and ultimately death typically occurs 15 to 18 years after the onset of symptoms (Caron, N, Wright, G and Hayden, M; (2020a), Huntington Disease; Seattle, WA; University (See of Washington)

[0461] Currently, there are no disease-modifying interventions approved for use in hemodialysis (HD), and without intervention... Therefore, the patient population that will be included in this clinical trial will have ongoing disease progression, loss of function, and inevitably Ultimately, one will face death. Inevitable disease progression and inevitable disease mortality rates are not met in HD. This indicates a specific medical need that has not been addressed. A decrease in mHTT is an important treatment target. It has been identified as a target.

[0462] As mentioned above, in the Phase 1 study, multiple administrations of compound 1 were observed to affect HTT mRNA and protein It was associated with a significant decline in quality. Pharmacokinetics and pharmacokinetics based on interim data from a Phase 1 study. Scientific (PKPD) modeling suggests that exposure to 10 mg and 20 mg QD doses leads to a decrease in HTT protein. The established target range of 30% to 50% accurately encompasses the low levels of full-length HTT mRNA. It was determined that it was related to the following. Therefore, the 10 mg and 20 mg QD doses were related to this phase. In the Z2 study, it is expected to be associated with therapeutic benefits and a final slowing of disease progression.

[0463] The results of the Phase 1 study showed that a single dose ranging from 5 mg to 135 mg, and a duration of up to 21 days, were effective. This study provided evidence of the stability and tolerability of compound 1 in multiple doses of 15 mg and 30 mg. In the study, compound 1 was found to be safe and generally well-tolerated. In both the standard dose (SAD) portion and the multiple dose escalation (MAD) portion, the overall incidence of adverse events (AEs) was... The results were equivalent between the subjects who received the racebo and those who received compound 1. This was considered dose-limiting toxicity. No adverse events occurred, and all adverse events (AEs) were resolved by the deadline for the interim analysis. Furthermore, no clinically significant study abnormalities or abnormalities were observed at any dose of any part of the study. There was no information available regarding electrocardiograms (ECGs).

[0464] Phase 1 studies include data and safety monitoring to carefully monitor the stability of the subject. The Tarling Committee (DSMB) exists. Based on preclinical and clinical data to date, the compound 1 has a favorable risk / benefit profile in subjects with HD.

[0465] Main research objective (i) The frequency of adverse events (TEAEs) that occurred under treatment, as well as clinical laboratory values, electrocardiogram (ECG), and (ii) abnormalities in ital signs, slit-lamp eye examination and physical examination, and (ii) total blood As assessed by a decrease in huntingtin protein (HTT) levels, Safety and effectiveness of two treatment regimens, Compound 1 and Placebo, in subjects with Ton's disease (HD). The pharmacodynamic effects are evaluated. This aspect evaluates the safety, tolerability, and pharmacology of compound 1, as well as HD. The aim is to demonstrate a decrease in HTT mRNA and HTT protein in patients.

[0466] Secondary research objectives (i) Effects of compound 1 on HTT mRNA in blood and mHTT protein in cerebrospinal fluid (CSF), (ii) Determine the reduction of blood mutant huntingtin protein (mHTT) levels. These include blood-based biomarkers, CSF-based biomarkers, and phospholipids for Huntington's disease. The intention is to demonstrate the effect of compound 1 on radiation biomarkers.

[0467] Exploratory research purpose (i) Changes in whole brain, caudate nucleus, and putamen volume via volumetric magnetic resonance imaging (vMRI) (ii) assess the effect of compound 1, and (ii) assess the effect of changes in ventricular volume via MRI. (iii) the concentration of neurofilament light chain (NfL) protein in plasma and CSF (iv) After 12 weeks of treatment, the Huntington's disease unified evaluation The uniform scale (UHDRS), as well as (a) the symbol-number modality test (SDMT), (b) the total motor score (TMS), (c (d) Independent scales, (e) Total Functional Capacity (TFC), (f) Gait and movement assessment using a wearable accelerometer. (f) Clinical General Impression of Change (CGI-C), and (g) Quality of Life in Huntington's Disease This includes assessments that utilize each of its subcomponents, including the questionnaire (HDQoL). Assess changes in related scales.

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

[0469] Clinical endpoints Key safety endpoints TEAE, abnormal test results, ECG, vital signs, slit-lamp eye examination, and physical examination We evaluate the safety profile that can be characterized in this way.

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

[0471] Biomarker endpoints (i) Percentage decrease in HTT protein in CSF, (ii) Neurofilament reduction in plasma and CSF Changes in the chain (NfL), and (iii) changes in caudate nucleus, putamen, and ventricular volume on volumetric MRI imaging. ification.

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

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

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

[0475] Biomarker endpoints (i) Percentage decrease in HTT protein in CSF, (ii) Neurofilament reduction in plasma and CSF Changes in the chain (NfL), and (iii) changes in caudate nucleus, putamen, and ventricular volume on volumetric MRI imaging. ification.

[0476] Research design / method The Phase 2 study involved administering 10 mg and 20 mg of compound after 12 weeks of treatment to subjects with hemodialysis (HD). To evaluate the safety and efficacy of substance 1 and to determine the HTT protein-reducing effect of these doses. This is a randomized, parallel-arm dose-finding study, including a placebo control.

[0477] Individuals who have signed informed consent will be selected to determine their eligibility for the study. Enter the cleaning process. During screening, potential targets are identified by the target gene mutation. Natural mutation status is confirmed by clinical trial researchers (historical gene sequencing or within the study (in - Study) Meet the registration criteria (through one of the gene sequencing assessments) Further evaluation will be conducted to confirm that all registration criteria are met during screening. The subjects undergo a baseline assessment and receive treatment for a total of 12 weeks (plus or minus the number of visits). In this study, participants were randomly assigned in a 1:1:1 ratio to receive either 10 mg or 20 mg of the research drug or a placebo. The treatment will be administered once a day, in the morning, with less than the first meal of the day, once the subject has been assigned to the treatment. Each participant takes the assigned dose of the investigational drug two hours prior to the procedure. The subjects are selected every 28 days after randomization. You will return to the clinic on approximately the 29th, 57th, and 85th day, or in lieu of your own visit. Then, they are asked to receive home care services and undergo a research assessment. On the 85th day, The elephant receives its final dose of the investigational drug and completes the research assessment to the end. On day 113, A To collect E data, follow-up safety information is collected via telephone / telemedicine. There is a visit.

[0478] Justification of sample size Sample size is calculated from baseline total HTT protein in the blood at the fifth visit. This is based on the mean change (primary endpoint). The effect size (i.e., the difference in treatment) is 0.85. Using a scale of 85% of one standard deviation, a 90% confidence interval is obtained at a two-sided alpha level of 0.05. To achieve the desired output, 31 subjects would be needed. Assuming an interruption rate of 10%, approximately The 35 participants will be randomized to receive each dosage.

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

[0480] Inclusion Criteria Individuals eligible to participate in this study must meet all of the following inclusion criteria. The body is included. (i) Outpatients who are male or female and 25 years of age or older (including 25 years of age), (ii) Subject (or legal The certified representative will willingly provide informed consent and adhere to all protocols. (iii) willing to comply with the requirements and be able to do so, (iii) 42-50 cytosine-adenosides including both ends (iv) UHDRS-independent, genetically confirmed HD diagnosis with ng-guanine (CAG) repeat length. (v) A norm defined for the scale score of 100, (v) a TFC score of 13, and (vi) an HD score. The prediction index is 0.18 to 4.93, including both ends, (vii) Women of childbearing potential (WOCBP): during administration and of the investigational drug You must agree to use a highly effective method of contraception for six months after the suspension.

[0481] WOCBP is defined as a woman who is capable of becoming pregnant from menarche until menopause, unless she is permanently infertile. Permanent infertility is defined as a hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without other medical causes. High follicle-stimulating hormone (FSH) levels in the postmenstrual range may indicate the presence of hormonal contraceptives or hormone replacement therapy. It can be used to check the postmenopausal status of women who are not using it. However, for 12 months If there is no amenorrhea, a single FSH measurement is insufficient. Highly effective contraception is consistently When used correctly, this contraceptive method can achieve a failure rate of less than 1% per year. It is defined as follows, and it includes (a) oral (WOCBPs using oral contraceptives are screened (The patient must be stable with the same pill for at least 3 months prior to the start of treatment), administered vaginally or transdermally. Combinations of contraceptives that inhibit ovulation (including those containing estrogen and progestogen) (b) Hormone contraceptives containing (b) oral (WOCBPs using oral contraceptives are screen (Must be stable with the same pill for at least 3 months prior to treatment), for injection, implantable, uterine Contraceptives administered via an internal device or an intrauterine hormone-releasing system, including those that inhibit ovulation. (c) Hormone contraceptives containing only progestogens associated with harm, or (c) bilateral tubal occlusion Contraceptives associated with vasectomy, contraceptives chosen from a partner who has had a vasectomy, or abstinence. It is included.

[0482] (viii) Sexually active, fertile males while taking the research drug and the research drug For six months after the suspension, condoms must be used during sexual intercourse, and during this period, children You must not conceive a child or donate sperm. This is to prevent potential drug delivery via semen. Therefore, it is also necessary for men who have had their vas deferens removed to use condoms.

[0483] Main exclusion criteria If an individual meets or is meeting any of the following exclusion criteria, they will not be included in this study. You are ineligible to participate. (i) You are unable to swallow or attempt to swallow oral tablets. (ii) within 90 days prior to screening or within 5 half-lives, or for the duration of this study. At any time during the period, investigational drugs specific to HD that target RNA or DNA, such as antiseptics Experimental drugs including lance oligonucleotides, cell transplants, or any other experimental brain surgery (iii) A history of exposure to any gene therapy for HD treatment, (iv) 9 prior to screening Within 0 days, or at any time during the duration of this study, the research clinical trial or research paradigm (e.g.) (v) participation in exercise / physical activity, cognitive therapy, brain stimulation, etc., (v) implanted deep brain stimuli (vi) Presence of a cataract device, (vi) Family history of early-onset cataract, or cataract scoring system (lens opacity classification) System III) Using the test, the presence of cataracts at baseline, (vii) CSF homeostasis and Pathologies of the brain or spinal cord that may obstruct circulation, elevated intracranial pressure (for CSF drainage) (including the presence of a cannula or implanted CNS catheter), malformations, and / or tumors, (vi ii) Any general anesthesia planned during the 12-week screening or study (ix) Hospitalization for major medical or surgical procedures, (ix) Colombia Suicide Severity Rating Scale (C-SSRS) Significant suicide risk with a moderate risk rating or a higher score, as measured by [the relevant method]. (x) Major depressive episode, psychosis, or confusional state as assessed by the clinical trial investigator. (xi) Risk of violent behavior, or interference with the lumbar puncture procedure or safety assessment. (xii) whether there is any history of brain or spinal cord disease, or whether there is evidence of local recurrence or metastasis. Regardless, a history of treated or untreated malignant tumors of any organ system within the past five years (skin) (other than localized basal cell carcinoma or in-vivo cervical cancer), (xiii) protocol-specific Any medical history or condition that may interfere with the ability to complete the assessment (e.g., buried (Conditions that interfere with shunts, MRI operations), (xiv) at least 6 weeks prior to screening, Except for those receiving a stable dose, the dosing regimen is not expected to change during the study. (xvi) Regarding the use of antidepressants or benzodiazepines accompanied by (xvi), for a duration of one month or more, A risk level of alcohol consumption, as assessed by clinical trial researchers, in accordance with the World Health Organization. (xvii) Lifetime history of high-risk drugs or alcohol, in the opinion of the clinical trial investigator, It may have adverse effects on safety or may impair the assessment of research results. (xviii) Presence of clinically significant disease, (xviii) Estimated glomerular filtration rate <60 mL / min at screening Current significant renal impairment, defined as a rate, (xvix) normal at the time of screening. Liver function test values ​​(aspartate transaminase, alanine transaminase) elevated to three times the upper limit. (Alanine phosphatase, alanine phosphatase) causes current liver dysfunction, (xx) pregnancy (xxi) Screen Drugs that are moderate or potent inhibitors of CYP3A4, or scripts taken within one week of the start of treatment. Use of a drug that is a moderate or strong inhibitor of CYP3A4 within two weeks of training, or or the plan for the use of drugs that are moderate or potent CYP3A4 inhibitors or inducers during the study period .

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

[0485] Tablets of the active investigational product of compound 1 and the matching placebo reference product were administered orally via QD. The investigational drug product of compound 1 is a film-coated tablet for oral administration. It is a dosage form. It consists of round tablets coated in white to off-white, available in 10 mg and 20 mg doses. The tablets are available in two dosage strengths, each containing the drug substance of Compound 1, and a microcrystalline form of the compound. Crystalline cellulose, lactose monohydrate, povidone K30, croscarmellose sodium, It contains an excipient selected from poloxamer 407 and magnesium stearate. The 10mg and 20mg tablets are available in two different sizes. The placebo tablets contain the same official dosage. It contains a formant and has the same appearance as the 10 mg and 20 mg tablets of Compound 1. They are manufactured in the same tablet size.

[0486] Evidence regarding the safety of the selected dose is from ongoing Phase 1 studies and to date. Provided by the results of a comprehensive preclinical toxicology program. In a Phase 1 study, 5 mg A single dose in the range of ~135 mg, as well as multiple doses of 15 mg and 30 mg over 14 days, are safe. Generally, it was well-received.

[0487] A 30%–50% reduction in the target mHTT is associated with a reduction in patient pathology and expected therapeutic benefits. This is the scope of the study. In the Phase 1 study, compound 1 mediated HTT premRNA splicing. The study showed dose-dependent effects across all cohorts in both the SAD and MAD portions of the study. Yes. After a 14-day treatment with 15 mg and 30 mg of compound 1, full-length HTT mRNA was found, respectively. A mean decrease of 40% and 60% was observed in Bell's serotonin levels. Based on these clinical data, PK-PD con Using a partition model, we can determine the percentage of mRNA reduction at potentially possible clinical doses. We simulated the stage (and therefore the expected magnitude of the HTT protein decline).

[0488] The predicted percentage reduction in total length HTT mRNA at the selected 10 mg QD and 20 mg QD doses was... It is within the target range of 30-50% from the line. HD bacterial artificial chromosome gene transfer mouse Preclinical data from the mouse model showed that mice underwent HTT premRNA splicing after administration of compound 1. A strong correlation was observed between the level and the degree of protein deficiency. Therefore, the observed preclinical HT Changes in T mRNA are expected to result in similar decreases in HTT protein levels in HD patients. Therefore, the clinical and preclinical safety data to date, as well as the clinical data and drug Based on the expected decrease in HTT mRNA and protein derived from kinetic-pharmacodynamic modeling Therefore, the 10 mg and 20 mg doses are safe, well-tolerated, and suitable for subjects with hemodialysis. It is expected to be beneficial.

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

[0490] safety standards Safety assessment includes observation of TEAEs, clinical tests, vital signs, ECG, C-SSRS, and detailed information. This includes an eye examination using a gap lamp and a physical examination.

[0491] Effectiveness Criteria The assessment of effectiveness includes (i) serum HTT protein and NfL in CSF, (ii) UHDRS, and (iii) CG. This includes (iv) wearable accelerometers for motor function, and (v) neuroimaging (vMRI) analysis. .

[0492] Enrichment Criteria Enrichment is used to detect the drug effect (if any) in a randomly selected population. A characteristic of selecting research populations that are more likely to be detected than those that could be, any patient Defined as a positive use. Due to a highly variable population of patients with HD. The enrichment strategies for this Phase 2 study include daily life activities, work, and household finances. Although the ability for self-care is preserved, performance on motor and cognitive tests is low, and for 3 years Select individuals who are expected to experience functional impacts on their daily activities within a certain period. This is intended. UHDRS TMS and SDMT are assessed at the time of screening (CAG repeat Based on the confirmed HD prognosis index for asymptomatic HD patients (along with length of life and age), It is used to identify groups.

[0493] Huntington's disease prognosis index (PI) HD ) or a prognostic index (PIN) defined by its norm HD ) This can be used to predict the likelihood of HD progression, with a higher score indicating a greater risk of functional decline. This indicates that the PI is high. HDThe natural course survival curve created using a specific PI HD This shows the disease trajectory in patients with a score. PIN HD Based on the score, researchers can It becomes possible to predict disease progression with high accuracy in studied populations. Historically Disease progression is generally indexed by the product of CAG and age (CAG-Age Product) (CAP). This is a kind of loading score for CAG elongation, which has age and several variants. Yes. When CAP is supplemented with UHDRS's TMS and SDMT, the predictability of HD progression increases. Using enrichment criteria, subjects with HD and no functional degradation (TFC and IS) It is possible to identify the group (which is measured) and measure the change in blood HTT levels after treatment. This can be done. In this group, the initial stage HD showed an increase in mHTT levels in CSF compared to the control. As has been observed, it is possible to experience a decrease in HTT without any measures taken to reduce it. It is highly likely.

[0494] At baseline in this study, the cognitive and motor functions of the subjects were measured by the SDMT score and Assessment is performed using the TMS score. Registered subjects are assessed by TFC and IS. As stated, there is no functional impairment. The subjects were measured by IRT before randomization. The calculated PIN HD Based on the calculated score, it will be included in the study. Including both ends, the range is 0.18 to 4.93. -line PIN HD Subjects with a score are eligible to enroll in the clinical trial. The following formula is PIN HD It is used to calculate the score. PI HD= 51 × (TMS) + (-34) × SDMT + 7 × (age) × (CAG - 34)

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

[0496] Using the registered HD database (periodic data updates 5), 0.18~4.9 is included in the study. PIN range of 3 HD The score has been identified.

[0497] Pharmacokinetics Pharmacokinetic assessment involves plasma C trough (Including the 3rd, 4th, and 5th visits.) The accumulation ratio in plasma (at the 3rd, 4th, and 5th visits) and CSF (at the 5th visit) was calculated. I will report it.

[0498] statistical methods Using a repeated measures analysis model (repeated at each visit), each dose of total HTT protein in the blood was measured. This will be compared to a placebo. This model will include administration, visits, interaction between administration and visits, and base Slines are included. Nominal p-values ​​and 95% confidence intervals (activity) for each pairwise comparison at the 5th visit. This model provides a drug-versus-placebo comparison. PIN is used as a stratification factor. HD Includes. Blood HTT tannins The same analysis used for protein analysis is used for serum HTT mRNA. Dose-response relationship Explore the relevant information. Demographic and baseline characteristics, pharmacokinetics, safety, and efficacy. Sexual endpoints will be descriptively summarized by treatment group. Blood and CSF assessments will be performed. To understand the relationship between UHDRS and its components, a statistical model is applied.

[0499] Results of Phase 2 Study The primary objective of the randomized, placebo-controlled, 12-week Phase 2a dose-finding study was: Safety of two treatment regimens, compound 1 and placebo, in subjects with Huntington's disease. The primary objective is to evaluate the sexual and pharmacodynamic effects. Adverse events occurring during treatment are also evaluated. Frequency of (TEAE); clinical laboratory values, electrocardiogram (ECG), vital signs, slit-lamp eye examination. Abnormal physical examination results; and decreased blood total huntingtin protein (HTT) levels. Comment.

[0500] A secondary objective of this study is to obtain HTT mRNA in the blood and mHTT protein in cerebrospinal fluid (CSF). The effect of compound 1 on, and the reduction of blood mutant huntingtin protein (mHTT) levels. I will make a decision.

[0501] The exploratory purpose of this study is to use volumetric magnetic resonance imaging (vMRI) to examine the whole brain, caudate nucleus, Furthermore, the effect of compound 1 on changes in putamen volume was assessed, and ventricular volume was measured via vMRI. The effects of the changes were assessed, and neurofilament light chain (NfL) protein in plasma and CSF was evaluated. The effect of compound 1 on concentration was assessed, and after 12 weeks of treatment, Huntington's disease was diagnosed. This includes assessments using the Universal Higher Performance Rating Scale (UHDRS) and each of its subcomponents. Next, assess changes in related scales. The UHDRS subcomponents are (a) symbolic numerals and modalities. (b) Structural Balance Test (SDMT), (c) Total Motor Score (TMS), (d) Independent Scales, (e) Total Functional Ability (TFC) (f) Gait and movement assessment using wearable accelerometers, and (g) Assessment of the qualitative effectiveness of the Huntington's disease Quality of Life Questionnaire (HDQoL). Used for commenting.

[0502] For the purpose of this study regarding pharmacokinetics, the concentration of compound 1 in subjects with hemoglobin (HD) was evaluated. Worthy.

Claims

1. The active ingredient is 2-[3-(2,2,6,6-tetramethylpiperidine-4-yl)-3H-[1,2,3]tri Zoro[4,5-c]pyridazine-6-yl]-5-(2H-1,2,3-triazole-2-yl)phenol (hereinafter, Compound 1), or a pharmaceutically acceptable salt thereof (Compound 1 is approximately 5% to 30% of the total mass of the tablet). A tablet containing an internal excipient (present in a certain percentage amount), an internal excipient, and an external excipient, wherein the internal excipient The excipients include microcrystalline cellulose and a diluent, and the microcrystalline cellulose and the diluent The ratio is approximately 1:1 to 1:4, and microcrystalline cellulose accounts for approximately 15% to 25% of the total mass of the tablet. It is present in mass percent, and the disintegrant is present in an amount of approximately 1% to 3% of the total mass of the tablet. Povidone is present in an amount of 1% to approximately 5% by mass of the total mass of the tablet, and the extragranular excipients are further... A tablet containing a certain amount of diluent and a further amount of disintegrant.

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

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

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

5. The amounts of compound 1 in the tablets are 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg. , 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg , 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 1 Claim 4, selected from 65 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg. The tablets described above.

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

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

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

9. The ratio of microcrystalline cellulose to diluent in the granular excipient is approximately 1:2, as described in claim 1. Tablets.

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

11. Claim that at least one of the extragranular excipient and the intragranular excipient further comprises a surfactant. The tablets described in item 1.

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

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

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

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

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

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

18. The mass of the extragranular excipient is approximately 15% to approximately 30% by mass of the total mass of the tablet, as described in claim 1. tablet.

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

20. Compound 1 is present in an amount of 10% by mass of the tablet, and the granular excipient is microcrystalline in a ratio of approximately 1:

2. It contains cellulose and lactose monohydrate, with microcrystalline cellulose making up approximately 20% of the tablet's composition. It is present in a certain percentage amount, and the disintegrant is present in an amount of approximately 1% to 3% by mass of the tablet. Vidone is present in an amount of approximately 2% by mass of the tablet, and the extragranular excipients are present in an amount of approximately 10% to 25% by mass of the tablet. Lactose monohydrate in mass% of the tablet, a disintegrant in an amount of approximately 1% to 5% of the tablet's mass, and the tablet A tablet according to claim 1, comprising an amount of approximately 0.5% to approximately 2% by mass of poloxamer.

21. The excipient further contains colloidal silicon dioxide in an amount of approximately 0.25% to 1% by mass of the tablet. The tablet according to claim 20.

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

23. A method for producing the tablet described in claim 1, comprising the steps of wet granulation of an extragranular excipient and The process involves drying the resulting in-granule blend and mixing the external excipient with the in-granule excipient. A method comprising the steps of: taking a certain step and compressing the resulting mixture to form a tablet.

24. The claim further includes a step of coating the resulting compressed tablets with a film. The method described in item 23.

25. A method for treating or improving Huntington's disease in a subject that requires it, The present invention according to claim 1, wherein the present invention contains a therapeutically effective amount of compound 1, or a pharmaceutically acceptable salt thereof. A method comprising the step of administering a tablet orally.

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

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

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

29. The tablets contain 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg of compound 1. The method according to claim 28.

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

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