Treatment of huntington's disease

Abstract

The present invention describes methods of treating Huntington's disease in a subject in need thereof. The method comprising administrating to the subject in need thereof a therapeutically effective amount of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol or a pharmaceutically acceptable salt thereof.

Description

PAT059999-WO-PCT -1- TREATMENT OF HUNTINGTON’S DISEASE FIELD OF THE INVENTION

[0001] The present invention is directed to methods of treating or ameliorating Huntington’s disease in a subject having a cytosine-adenine-guanine (CAG) repeat length from 40 to 50 of the huntington (HTT) gene, comprising administering an HTT inhibitor compound. BACKGROUND

[0002] Huntington’s disease (HD) is a rare, fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. The disease is characterized by progressive motor abnormalities, cognitive decline, psychiatric and behavioral symptoms. The signs and symptoms of HD develop gradually over many years, commonly leading to a diagnosis based on characteristic motor symptoms (“motor onset”) between the ages of 30 and 50. With disease progression, patients experience functional decline, increasing disability, loss of independence, and premature death within 15-30 years of symptom onset. This gradual deterioration is evidence of the neurodegenerative processes occurring throughout the patient’s lifetime.

[0003] HD is caused by an expansion in the number of CAG repeats in Exon 1 of the huntingtin (HTT) gene. The number of CAG repeats in the HTT gene typically ranges from 6 to 35 in healthy individuals. Individuals with 36 to 39 CAG repeats experience few to no symptoms of HD. However, individuals with 40 or more CAG repeats are nearly certain to develop HD and experience symptoms of HD.

[0004] In general, HD symptoms worsen progressively and invariably lead to death. HD is often divided into three broad phases. In early stage HD, patients experience minor symptoms but are largely functional and able to work and live independently. In middle stage HD, patients’ symptoms are more prominent including chorea and cognitive decline and they may not be able to work or care for themselves. In late stage HD, patients require assistance for all aspects of daily living, with dementia, mutism, dystonia, and bradykinesia predominating in advanced disease. Death typically occurs within 15-20 years of disease onset, and is usually related to complications of immobility, infection, especially pneumonia, and cardiac disease. The Unified Huntington’s Disease Rating scale (UHDRS) first published in 1996 and revised in 1999 and 2005 is often usedPAT059999-WO-PCT -2- to stage patients with HD based on assessing motor function, cognition, behavior, independence, functional ability and a total functional

[0005] Neuropathologically, HD is primarily characterized by neuronal loss in the striatum and cerebral cortex. Certain neuronal populations are more affected including those within the corpus striatum of the basal ganglia. The mechanism by which polyglutamine aggregation leads to neurodegeneration has been elusive, although insight has emerged from animal models regarding HD pathophysiology. Early synaptic dysfunction is a key characteristic and is manifested by dysregulated glutamate release in striatum followed by progressive disconnection between cortex and striatum. Some of the alterations in late HD could be compensatory mechanisms designed to cope with early synaptic and receptor dysfunctions. These findings suggest that HD treatments need to be designed according to the stage of disease progression, however synaptic dysfunction and loss occur early and continue throughout disease progression.

[0006] To date, no treatment has been shown to delay the onset of HD or slow its progression. Treatment is focused on specific symptom management. A patient’s care may include a broad range of physicians to address the various physical and psychological symptoms. Chorea is often linked to cognitive and psychological aspects of the disease such as anxiety and depression. Disabilities in one area usually lead to problems in another.

[0007] There remains an unmet need for effective therapies for treating HD. It is therefore an object herein to provide methods for the treatment of the disease. SUMMARY OF THE INVENTION

[0008] An international application published as WO2020 / 005873 identified a genus of compounds (HTT inhibitors) that can be used as in the treatment of Huntington’s disease (HD), methods of making the same and pharmaceutical formulations of the same, which is incorporated herein by reference in its entirety. One such compound is 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)- 3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol (Compound 1) of the formulaPAT059999-WO-PCT -3- for treating or ameliorating Huntington’s Disease(HD) in a subject having a cytosine-adenine-guanine (CAG) repeat length from 40 to 50 of the huntington (HTT) gene, comprising administering to the subject a HTT inhibitor.

[0010] In an embodiment, the HTT inhibitor is Compound 1 or a pharmaceutically acceptable salt thereof.

[0011] In an embodiment, the subject has normed version of the Huntington’s disease prognostic index (PINHD) score between 0.18 and 4.93 before beginning treatment.

[0012] In an embodiment, the subject has a Unified Huntington’s Disease Rating Scale-Total Functional Score (UHDRS-TFC) score of 11, 12, or 13 before beginning treatment.

[0013] In an embodiment, the subject has a Unified Huntington’s Disease Rating Scale- Independence Scale (UHDRS-IS) of 100 before beginning treatment.

[0014] In an embodiment, the method comprises administering Compound 1 or a pharmaceutically acceptable salt between 1 mg per day to 200 mg per day.

[0015] In an embodiment, the method comprises administering Compound 1 or a pharmaceutically acceptable salt selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg per day; preferably, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, or 100 mg per day; more preferably, 5 mg, 10 mg, and 20 mg per day.

[0016] The present invention also relates to a method of treatment for slowing the decline of motor function, cognitive function, and global function associated of Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound, or a pharmaceutically acceptable salt thereof.PAT059999-WO-PCT -4-

[0017] In an embodiment, motor function, cognitive function, and global function is measured by the Composite Unified Huntington's Disease Scale (cUHDRS).

[0018] The present invention also relates to a method for improving, maintaining or reducing impairment of functional capacity of a subject afflicted with Huntington’s disease (HD), comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof.

[0019] In an embodiment, the functional capacity is measured by the Unified Huntington's Disease Rating Scale-Total Functional Capacity (UHDRS-TFC).

[0020] The present invention also relates to a method of improving, maintaining or reducing motor function impairment of a human patient afflicted with Huntington’s disease (HD), comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof.

[0021] In an embodiment, the motor function impairment is measured by the Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-TMS), the Unified Huntington’s Disease Rating Scale-modified Motor Score (UHDRS-mMS), the Unified Huntington’s Disease Rating Scale (UHDRS)-Chorea score, the Unified Huntington’s Disease Rating Scale (UHDRS)-Dystonia score, Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), hand movement score, gait and balance score, Quantitative motor (Q-Motor) assessment or by timed up and go (TUG) assessment.

[0022] The present invention also relates to a method of reducing mHTT protein levels in a subject in need thereof, the method comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof.

[0023] In an embodiment, the mHTT protein levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid.

[0024] The present invention also relates to a method of stabilizing or decreasing the concentration of neurofilament light chain (NfL) polypeptide in blood serum of a subject having previously been diagnosed with Huntington’s Disease (HD), the method comprising administering to the subject Compound 1 or a pharmaceutically acceptable salt thereof.

[0025] In an embodiment, the NfL levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid.PAT059999-WO-PCT -5- BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. However, the invention both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0027] FIG. 1A depicts the mean percent (%) change in blood mHTT protein across treatment groups from baseline to Week 12.

[0028] FIG. 1B depicts the mean percent (%) change in blood mHTT protein across treatment groups from baseline to Month 12.

[0029] FIG.2 depicts the mean percent (%) change in CSF mHTT protein across treatment groups from baseline to Month 12.

[0030] FIG. 3 depicts the median change in plasma NfL levels (pg / ml) across treatment groups from baseline to Month 12.

[0031] FIG.4 depicts the CSF Nfl trajectories for individual subjects from baseline to month 12.

[0032] FIG. 5A depicts the median change striatum brain volume across treatment groups from baseline to Month 12.

[0033] FIG. 5B depicts the mean change in Total Motor Score (TMS) across treatment groups from baseline to Month 12.

[0034] FIG. 6A depicts the mean change in Composite UHDRS (cUHDRS) across treatment groups from baseline to month 12.

[0035] FIG. 6B depicts the mean change in Total Functional Capacity (TFC) across treatment groups from baseline to month 12.

[0036] FIG. 7 depicts the mean percent (%) change in blood mHTT protein across treatment groups from baseline to Week 12 (in additional Week 12 subjects).PAT059999-WO-PCT -6- DETAILED DESCRIPTION OF THE INVENTION

[0037] Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features of the disclosure are apparent from the following detailed description and the claims.

[0038] Titles or subtitles may be used in the specification for the sole convenience of the reader but are not intended to influence the scope of the present disclosure or to limit any aspect of the disclosure to any subsection, subtitle, or paragraph.  1. Embodiments

[0039] Embodiment 1: A method for treating or ameliorating Huntington’s Disease (HD) in a subject having a cytosine-adenine-guanine (CAG) repeat length from 40 to 50 of the huntington (HTT) gene, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0040] Embodiment 2: The method of embodiment 1, wherein the subject has a normed version of the Huntington's disease prognostic index (PINHD) score between 0.18 and 4.93 before beginning treatment.

[0041] Embodiment 3: The method of embodiment 1, wherein the subject has a Unified Huntington's Disease Rating Scale- Total Functional Score (UHDRS-TFC) score of 11, 12, or 13 before beginning treatment.

[0042] Embodiment 4: The method of embodiment 1, wherein the subject has a Unified Huntington's Disease Rating Scale-Independence Scale (UHDRS-IS) of 100 before beginning treatment.

[0043] Embodiment 5: The method of embodiment 1, wherein Compound 1, or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 5 mg per day, about 10 mg per day, or about 20 mg per day.PAT059999-WO-PCT -7-

[0044] Embodiment 6: A method of treatment for slowing the decline of motor function, cognitive function, and global function associated of disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound, or a pharmaceutically acceptable salt thereof.

[0045] Embodiment 7: The method of embodiment 6, wherein the motor function, cognitive function, and global function is measured by the Composite Unified Huntington's Disease Rating Scale (cUHDRS).

[0046] Embodiment 8: A method of improving, maintaining or reducing impairment of functional capacity of a subject afflicted with Huntington's disease (HD), comprising administering to subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 9: The method of embodiment 8, wherein the functional capacity is measured by the Unified Huntington's Disease Rating Scale-Total Functional Capacity (UHDRS-TFC).

[0048] Embodiment 10: A method of improving, maintaining or reducing motor function impairment of a human patient afflicted with Huntington’s disease (HD), comprising administering to subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0049] Embodiment 11: The method of embodiment 10, wherein the motor function impairment is measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS), the Unified Huntington's Disease Rating Scale (UHDRS) modified Motor Score (mMS), the Unified Huntington's Disease Rating Scale (UHDRS)-Chorea score, the Unified Huntington's Disease Rating Scale (UHDRS)-Dystonia score, Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), hand movement score, gait and balance score, Quantitative motor (Q-Motor) assessment or by timed up and go (TUG) assessment.

[0050] Embodiment 12: A method of reducing mHTT protein levels in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0051] Embodiment 13: The method of embodiment 12, wherein the mHTT protein levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid.PAT059999-WO-PCT -8-

[0052] Embodiment 14: A method of stabilizing or decreasing the concentration of neurofilament light chain (NfL) polypeptide of a subject previously been diagnosed with Huntington's Disease (HD), comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0053] Embodiment 15: The method of embodiment 12, wherein the NfL levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid. 2. Definitions

[0054] As used herein, the singular forms “a,” “an,” and “the,” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0055] As used herein and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one aspect, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another aspect, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another aspect, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0056] When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below those numerical values. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%, 10%, 5%, or 1%. In certain aspects, the term “about” is used to modify a numerical value above and below the stated value by a variance of 10%. In certain aspects, the term “about” is used to modify a numerical value above and below the stated value by a variance of 5%. In certain aspects,PAT059999-WO-PCT -9- the term “about” is used to modify a numerical value above and below the stated value by a variance of 1%.

[0057] The terms “subject” or “patient” are used interchangeably to refer to an individual human suffering from a disease described herein (e.g. Huntington’s Syndrome) that can be treated by administration of a composition described herein.

[0058] When a range of values is listed herein, it is intended to encompass each value and sub- range within that range. For example, “1-5 ng” or a range of “1 ng to 5 ng” is intended to encompass 1 ng, 2 ng, 3 ng, 4 ng, 5 ng, 1-2 ng, 1-3 ng, 1-4 ng, 1-5 ng, 2-3 ng, 2-4 ng, 2-5 ng, 3-4 ng, 3-5 ng, and 4-5 ng.

[0059] It will be further understood that the terms “comprises,” “comprising,” “includes,” and / or “including,” when used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0060] The terms “treat,” “treatment,” “treating” refer to therapeutic treatments, wherein the object is to reverse, alleviate, ameliorate, inhibit, slow down or stop the progression or severity of a disorder. The term “treating” includes, in the alternative, the term "ameliorating," which refers to reducing or alleviating at least one adverse effect or symptom of a condition, disease or disorder. Treatment is generally “effective” if one or more symptoms or clinical markers are reduced. Alternatively, treatment is “effective” if the progression of a disorder is slowed, reduced or halted. That is, “treatment” includes not just the improvement of symptoms or markers, but also a cessation of, or at least slowing of, progress or worsening of symptoms compared to what would be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptom(s), diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, remission (whether partial or total), and / or decreased mortality, whether detectable or undetectable. The term “treatment” of a disease also includes providing relief from the symptoms or side-effects of the disease (including palliative treatment).

[0061] The terms "HD" or "Huntington's disease", as used herein, refer to the neurodegenerative disorder, characterized by motor, cognitive, psychiatric and functional capacity decline, and caused by CAG repeat expansions in the huntingtin gene.PAT059999-WO-PCT -10-

[0062] The terms “administer” or “administration” as used herein, refer to the act of physically delivering a substance as it exists outside the into a subject.

[0063] The terms "manifest HD" or "manifest Huntington's disease", as used herein, refer to having diagnosis of HD as clinically established {e.g. on the basis of: confirmed family history or positive genetic test (confirmation of CAG repeat expansion ^36); and onset of motor disturbances [diagnostic confidence score (DCS) of 4, as defined by the Unified Huntington Rating Scale (UHDRS) total motor score (TMS)]. In one aspect, the term "manifest HD" or "manifest Huntington's disease", as used herein, refers to a patient having diagnosis of HD as clinically established [e.g. on the basis of confirmed family history or positive genetic test (confirmation of CAG repeat expansion ^36)]; and onset of motor disturbances [e.g. on the basis of diagnostic confidence score (DCS) of 4, as defined by the Unified Huntington Rating Scale (UHDRS) total motor score (TMS)].

[0064] The terms "pre-manifest HD" or "pre-manifest Huntington's disease", as used herein, refer to having genetic diagnosis of HD [e.g. on the basis of: positive genetic test (confirmation of CAG repeat expansion ^40) without onset of motor disturbances as clinically stablished, for example, as assessed according to standard scales, such as, clinical scales [e.g. on the basis of a diagnostic confidence score (DCS) of <4, as defined by the Unified Huntington Rating Scale (UHDRS) total motor score (TMS)]. In one aspect, term "pre-manifest HD" or "pre-manifest Huntington's disease", as used herein, refers to a patient having genetic diagnosis of HD [e.g. on the basis of: positive genetic test (confirmation of CAG repeat expansion ^40)] without onset of motor disturbances as clinically stablished, for example, as assessed according to standard scales, such as, clinical scales [e.g. on the basis of a diagnostic confidence score (DCS) of <4, as defined by the Unified Huntington Rating Scale (UHDRS) total motor score (TMS)].

[0065] The terms "slowing progression of HD", "slowing progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease", as used herein, refer to, one or more treatment effects selected from reducing the rate of Huntington's disease progression (e.g. reducing the rate of progression between stages of Huntington's disease); delaying the onset of Huntington's disease; delaying the onset of symptoms associated with Huntington's disease; reducing the rate of progression (e.g. reducing the annual rate of decline) of symptoms (e.g. one or more symptoms) associated with Huntington's disease; or reducing the ratePAT059999-WO-PCT -11- of progression of Huntington's disease pathophysiology (e.g. treatment effects compared to placebo or compared to natural history group; e.g. according to standard scales, such as clinical scales, herein above or below, or according to neuroimaging measures).

[0066] The term "rate of progression", as used herein, refers, for example, to the annual rate of change (e.g. decline) or the rate of change (e.g. decline) per year, for example as assessed according to standard scales, such as clinical scales, or according to neuroimaging measures.

[0067] The term "reducing", as used herein, refers to e.g.5%, 10%, 20%, 30%, 40%, 50%, 60% or 70% reduction, for example, per year of treatment.

[0068] The term "delaying", as used herein, refers to delay for at least e.g.0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 years.

[0069] The terms "slowing progression of HD", "slowing progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease", as used herein, refer to delaying the onset of Huntington's disease, e.g. increasing time for the onset of Huntington's disease as defined herein. In another aspect, the terms refer to reducing the rate of progression between stages of Huntington's disease, for example, reducing the rate of progression from an initial stage of HD into a more advanced stage of HD, as assessed, for example, compared to placebo, according to standard scales, such as clinical scales [e.g. according to the UHDRS total functional capacity (TFC) scale, for example, in Neurology, 1979, 29, 1-3]. In another aspect, it refers to reducing the rate of progression from stage 1 of HD into stage 2 of HD (e.g. compared to placebo). In another aspect, the terms refer to reducing the rate of progression from stage 2 of HD into stage 3 of HD (e.g. compared to placebo). In another aspect, the terms refer to reducing the rate of progression from stage 3 of HD into stage 4 of HD (e.g. compared to placebo). In another aspect, the terms refer to reducing the rate of progression from stage 4 of HD into stage 5 of HD (e.g. compared to placebo). In another aspect, the terms refer to reducing the rate of progression from early HD into middle stage HD (e.g. compared to placebo). In another aspect, the terms refer to reducing the rate of progression from middle stage HD into advanced HD (e.g. compared to placebo).

[0070] The term "reducing the rate of progression", as used herein, refers, for example, to increasing time for progression of stage of HD (e.g. compared to placebo).PAT059999-WO-PCT -12-

[0071] The terms "slowing progression of HD", "slowing progression of Huntington's disease", "to slow the progression of HD" or "to progression of Huntington's disease", as used herein, refer to delaying the onset of Huntington's disease (e.g. increasing time for the onset of Huntington's disease as defined herein) by at least 25% (e.g. by 25% or more, such as from 25% to 50%).

[0072] The term "onset of Huntington's disease", as used herein, refers to clinical diagnosis of HD as generally established [e.g. onset of motor disturbances based on diagnostic confidence score (DCS) of 4, as defined by the Unified Huntington Rating Scale (UHDRS) total motor score (TMS)].

[0073] The terms "slowing progression of HD", "slowing progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease", as used herein, refer to delaying the onset of symptoms associated with Huntington's disease, e.g. increasing time for the onset of one or more symptom associated with Huntington's disease selected from decline of motor function associated with Huntington's disease, cognitive decline associated with Huntington's disease, psychiatric decline associated with Huntington's disease and decline of functional capacity associated with Huntington's disease, as defined herein. In another aspect, the terms refer to reducing the rate of progression of one or more symptom associated with Huntington's disease selected from decline of motor function associated with Huntington's disease, cognitive decline associated with Huntington's disease, psychiatric decline associated with Huntington's disease and decline of functional capacity associated with Huntington's disease, as defined herein. The term "reducing the rate of', as used herein, refers, for example, to increasing time for onset or increasing time for a rise of severity (e.g. compared to placebo). In another aspect, the terms "slowing progression of HD", "slowing progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease", as used herein, refer to reducing the rate of progression of pre-manifest HD into manifest HD [i.e. delaying the onset of manifest HD; e.g. compared to placebo; e.g. as assessed by a diagnostic confidence score (DCS) of 4, as defined by the Unified Huntington Rating Scale (UHDRS) total motor score (TMS)].

[0074] The terms "slowing progression of HD", "slowing progression of Huntington's disease", "to slow the progression of HD" or "to slow the progression of Huntington's disease", as used herein, refer to slowing the progression of Huntington's disease pathophysiology.PAT059999-WO-PCT -13-

[0075] The term "slowing the progression of Huntington's disease pathophysiology", as used herein, refers to reducing the rate of of Huntington's disease pathophysiology, for example, as assessed by magnetic resonance imaging (MRI) [e.g. by neuroimaging measures, such as in Lancet Neural. 2013, 12 (7), 637-649]. For example, it refers to reducing the rate (e.g. reducing the annual rate, for example, versus placebo) of brain (e.g. whole brain, caudate, striatum or cortex) volume loss (e.g. % from baseline volume) associated with Huntington's disease (e.g. as assessed by MRI).

[0076] The term "motor function", as used herein, refers to motor features of HD comprising, for example, one or more selected from the group consisting of ocular motor function, dysarthria, chorea, postural stability and gait.

[0077] The term "decline of motor function", as used herein, refers to decreased motor function (e.g. from normal motor function or from previous clinic visit). Decline of motor function may be assessed, for example, according to standard scales, such as clinical scales (e.g. UHDRS motor assessment scale, as measured by the UHDRS Total Motors Score; e.g. in Movement Disorders, 1996, 11, 136-142).

[0078] The terms "slowing the decline of motor function" or "to slow the decline of motor function", as used herein, refer to reducing the rate of decline of motor function (e.g. compared to placebo; e.g. reduction in the annual rate of decline of motor function, for example, versus placebo; e.g. as assessed by the UHDRS Total Motors Score).

[0079] The term "reducing the rate", as used herein, refers to increasing time for onset or increasing time for a rise of severity (e.g. compared to placebo; e.g. reduction in the annual rate of decline, for example, versus placebo).

[0080] The term "cognitive decline", as used herein, refers to decreased cognitive abilities (e.g. from normal cognition function or from previous clinic visit). In one aspect, the term refers to, for example, decline of one or more cognition functions selected from the group consisting of attention, processing speed, visuospatial processing, timing, emotion processing, memory, verbal fluency, psychomotor function, and executive function. Cognitive decline may be assessed, for example, according to standard scales, such as clinical scales [e.g. as assessed by the Symbol Digit Modalities Test, the Stroop Word Reading Test, the Montreal Cognitive Assessment or the HD Cognitive Assessment Battery (comprising the Symbol Digit Modalities Test, Trail Making TestPAT059999-WO-PCT -14- B, One Touch Stockings, Paced Tapping, Emotion Recognition Test, Hopkins Verbal Learning Test); e.g. in Movement Disorders, 2014, 29 , 1281-1288).

[0081] The terms "slowing cognitive decline" or "to slow cognitive decline", as used herein, refer to reducing the rate of cognitive decline (e.g. compared to placebo; e.g. reduction in the annual rate of cognitive decline versus placebo; e.g. as assessed by the Symbol Digit Modalities Test, by the Stroop Word Reading Test, by the Montreal Cognitive Assessment or by the HD Cognitive Assessment Battery). The term "reducing the rate", as used herein, refers to increasing time for onset or increasing time for a rise of severity (e.g. compared to placebo; e.g. reduction in the annual rate of decline, for example, versus placebo).

[0082] The term "psychiatric decline", as used herein, refers to decreased psychiatric function (e.g. from normal psychiatric function or from previous clinic visit). In one aspect, the term refers to, for example, one or more psychiatric functions selected from the group consisting of apathy, anxiety, depression obsessive compulsive behavior, suicidal thoughts, irritability and agitation. Psychiatric decline may be assessed, for example, according to standard scales, such as clinical scales (e.g. as assessed by the Apathy Evaluation Scale or by the Hospital Anxiety and Depression Scale; e.g. in Movement Disorders, 2016, 31 (10), 1466-1478, Movement Disorders, 2015, 30 (14), 1954-1960).

[0083] The terms "slowing psychiatric decline" or "to slow psychiatric decline", as used herein, refer to reducing the rate of psychiatric decline (e.g. compared to placebo; e.g. reduction in the annual rate of psychiatric decline versus placebo; e.g. as assessed by the Apathy Evaluation Scale or by the Hospital Anxiety and Depression Scale). The term "reducing the rate", as used herein, refers to increasing time for onset or increasing time for a rise of severity (e.g. compared to placebo; e.g. reduction in the annual rate of decline, for example, versus placebo).

[0084] The term "functional capacity", as used herein, refers, for example, to the ability to work, handle financial affairs, manage domestic chores, perform activities of daily living, and level of care needed. Functional capacity comprises, for example, one or more selected from the group consisting of capacity to work, capacity to handle financial affairs, capacity to manage domestic chores, capacity to perform activities of daily living, and level of care needed.

[0085] The term "decline of functional capacity", as used herein, refers to decreased functional capacity (e.g. from normal functional capacity or from previous clinic visit). Decline of functionalPAT059999-WO-PCT -15- capacity may be assessed, for example, according to standard scales, such as clinical scales (e.g. UHDRS functional assessment scale and scale, and UHDRS Total Functional Capacity Scale e.g. in Movement Disorders, 1996, 11, 136-142).

[0086] The terms "slowing the decline of functional capacity" or "to slow the decline of functional capacity", as used herein, refer to reducing the rate of decline of functional capacity (e.g. compared to placebo; e.g. reduction in the annual rate of decline of functional capacity versus placebo; e.g. as assessed by the UHDRS functional assessment scale and independence scale or by the UHDRS Total Functional Capacity Scale). The term "reducing the rate", as used herein, refers to increasing time for onset or increasing time for a rise of severity (e.g. compared to placebo; e.g. reduction in the annual rate of decline, for example, versus placebo).

[0087] The term "decline", as used herein, refers, for example, to worsening over time (e.g. annually or per year) of a condition or of a particular feature of a condition, for example as assessed according to standard scales, such as clinical scales.

[0088] The terms "Unified Huntington’s Disease Rating Scale" or "UHDRS" as used herein, refer to the clinical rating scale developed by the Huntington Study Group (e.g. in Movement Disorders, 1996, 11, 136-142, which is incorporated fully herein by reference), which assesses domains of clinical performance and capacity in HD. The UHDRS comprises rating scales for motor function, cognitive function and functional capacity. It yields scores assessing primary features of HD (e.g. motor and cognitive) and overall functional impact of these features.

[0089] The term "cHDRS" refers to the composite Unified Huntington’s Disease Rating Scale, which provides composite measure of motor, cognitive and global functioning (e.g. in Neurology, 2017, 89, 2495-2502).

[0090] The terms "HD stage 1", "HD stage I", "Huntington's disease stage 1", "Huntington's disease stage I", "stage 1 of Huntington's disease" or "stage I of Huntington's disease", as used herein, refer to a disease stage of HD as clinically stablished [e.g. as assessed according to standard scales, for example, clinical scales, such as on the basis of the UHDRS total functional capacity (TFC) scale, wherein the TFC score is from 11 to 13]. At HD stage 1, typically, the patient has been clinically diagnosed with HD, is fully functional at home and at work and maintains independence as regards functional capacities; typically 0 to 8 years from onset of Huntington's disease.PAT059999-WO-PCT -16-

[0091] The terms "HD stage 2", "HD stage II", "Huntington's disease stage 2", "Huntington's disease stage II", "stage 2 of Huntington's or "stage II of Huntington's disease", as used herein, refer to a disease stage of HD as clinically stablished [e.g. as assessed according to standard scales, for example, clinical scales, such as on the basis of the UHDRS total functional capacity (TFC) scale, wherein the TFC score is from 7 to 10]. At HD stage 2, typically, the patient is still functional at work, however at lower capacity, is mostly able to carry out daily activities, despite some difficulties, and usually requires only slight assistance; typically 3 to 13 years from onset of Huntington's disease.

[0092] The terms "HD stage 3", "HD stage Ill", "Huntington's disease stage 3", "Huntington's disease stage Ill", "stage 3 of Huntington's disease" or "stage Ill of Huntington's disease", as used herein, refer to a disease stage of HD as clinically stablished [e.g. as assessed according to standard scales, for example, clinical scales, such as on the basis of the UHDRS total functional capacity (TFC) scale, wherein the TFC score is from 4 to 6]. At HD stage 3, typically, the patient can no longer conduct work or manage household chores, requires substantial help for daily financial affairs, domestic responsibilities, and activities of daily living; typically 5 to 16 years from onset of Huntington's disease.

[0093] The terms "HD stage 4", "HD stage IV", "Huntington's disease stage 4", "Huntington's disease stage IV", "stage 4 of Huntington's disease" or "stage IV of Huntington's disease", as used herein, refer to a disease stage of HD as clinically stablished [e.g. as assessed according to standard scales, for example, clinical scales, such as on the basis of the UHDRS total functional capacity (TFC) scale, wherein the TFC score is from 1 to 3]. At HD stage 4, typically, the patient is not independent, but still can reside at home with help from either family or professionals, however, requiring substantial assistance in financial affairs, domestic chores, and most activities of daily living; typically 9 to 21 years from onset of Huntington's disease.

[0094] The terms "HD stage 5", "HD stage V", "Huntington's disease stage 5", "Huntington's disease stage V", "stage 5 of Huntington's disease" or "stage V of Huntington's disease", as used herein, refer to a disease stage of HD as clinically stablished [e.g. as assessed according to standard scales, for example, clinical scales, such as on the basis of the UHDRS total functional capacity (TFC) scale, wherein the TFC score is 0]. At HD stage 5, typically, the patient needs total supportPAT059999-WO-PCT -17- in daily activities from professional nursing care; typically 11 to 26 years from onset of Huntington's disease.

[0095] The terms "early HD", "early Huntington's disease", "early stage of HD" or "early stage of Huntington's disease", as used herein, refer to a disease stage of HD, wherein the patient is largely functional and may continue to work and live independently, despite suffering from, for example, one or more selected from the group consisting of minor involuntary movements, subtle loss of coordination and difficulty thinking through complex problems. In another aspect, the terms "early HD", "early Huntington's disease", "early stage of HD" or "early stage of Huntington's disease", refer to "HD stage 2", as defined herein.

[0096] The terms "moderate HD", "moderate Huntington's disease", "moderate stage of HD", "moderate stage of Huntington's disease", "middle stage HD", "middle stage Huntington's disease", "middle stage of HD" or "middle stage of Huntington's disease", as used herein, refer to a disease stage of HD, wherein the patient may not be able to work, manage own finances or perform own household chores, but will be able to eat, dress, and attend to personal hygiene with assistance. Typically, at this stage, for example, chorea may be prominent, as well as problems with swallowing, balance, falls, weight loss, and problem solving. In another aspect, the terms "moderate HD", "moderate Huntington's disease", "moderate stage of HD", "moderate stage of Huntington's disease", "middle stage HD", "middle stage Huntington's disease", "middle stage of HD" or "middle stage of Huntington's disease" refer to "HD stage 3", as defined herein.

[0097] The terms "advanced HD", "advanced Huntington's disease", "advanced stage of HD", "advanced stage of Huntington's disease", "late HD" or "late Huntington's disease", "late stage of HD" or "late stage of Huntington's disease", as used herein, refer to a disease stage of HD, wherein the patient requires assistance in all activities of daily living. Typically, at this stage, for example, chorea may be severe, but more often it is replaced by rigidity, dystonia, and bradykinesia. In another aspect, the terms "advanced HD", "advanced Huntington's disease", "advanced stage of HD", "advanced stage of Huntington's disease", "late HD" or "late Huntington's disease", "late stage of HD" or "late stage of Huntington's disease" refers to "HD stage 4" or "HD stage 5", as defined herein.

[0098] The terms "juvenile HD" or "juvenile Huntington's disease", as used herein, refer to diagnosis of HD as clinically stablished {e.g. on the basis of confirmed family history or positivePAT059999-WO-PCT -18- genetic test (i.e. confirmation of CAG repeat expansion 2:36); and onset of symptoms by age< 21 years}.

[0099] The terms "juvenile HD" or "juvenile Huntington's disease", as used herein, refer to a patient affected by HD {e.g. on the basis of confirmed family history or positive genetic test (i.e. confirmation of CAG repeat expansion 2:36) and who has onset of symptoms by age< 21 years.

[0100] The terms "pediatric HD" or "pediatric Huntington's disease", as used herein, refer to a patient affected by HD {e.g. on the basis of confirmed family history or positive genetic test (i.e. confirmation of CAG repeat expansion 2:36) and clinical diagnosis} and who is aged <18 years.

[0101] The terms "HD patient", "Huntington's disease patient", "patient with Huntington's disease" or "patient with HD" refer to a patient with HD, as defined herein.

[0102] The terms "treat" "treating" "treatment" or "therapy", as used herein, refer to obtaining beneficial or desired results, for example, clinical results. Beneficial or desired results can include, but are not limited to, stabilizing or improving progression of stage of HD (e.g. compared to placebo). One aspect of the treatment is, for example, that said treatment should have a minimal adverse effect on the patient, e.g. the agent used should have a high level of safety, for example without producing adverse side effects. In another aspect, the term "method for the treatment", as used herein, refers to "method to treat".

[0103] The terms "intermittent dosing regimen" or "intermittent dosing schedule", as used herein, mean a dosing regimen that comprises administering Compound 1, followed by a resting period. For example, Compound 1 is administered according to an intermittent dosing schedule of at least two cycles, each cycle comprising (a) a dosing period and thereafter (b) a resting period.

[0104] As used herein, the term "resting period" refers, in particular, to a period of time during which the patient is not given Compound 1 (i.e., a period of time wherein the treatment with Compound 1 is withheld). For example, if Compound 1 is given on a daily basis, there would be rest period if the daily administration is discontinued for some time, e.g., for some number of days, or the plasma concentration of Compound 1 is maintained at sub-therapeutic level for some time e.g., for some number of days. The dosing period and / or the dose of Compound 1 can be the same or different between cycles. The total treatment time (i.e., the number of cycles for treatment) mayPAT059999-WO-PCT -19- also vary from patient to patient based, for example, on the particular patient being treated (e.g., Stage I HD patient).

[0105] In another aspect, an intermittent dosing schedule comprises at least two cycles, each cycle comprising (a) a dosing period during which a therapeutically effective amount of Compound 1 is administered to said patient and thereafter (b) a resting period. The terms "intermittent dosing regimen" or "intermittent dosing schedule", as used herein, refer to both a dosing regimen for Compound 1 alone (i.e. monotherapy) or a dosing regimen for administering Compound 1 in combination with at least a further active ingredient (i.e. combination therapy). In another aspect, the terms "intermittent dosing regimen" or "intermittent dosing schedule" refers to repeated on / off treatment, wherein Compound 1 is administered at regular intervals in a periodic manner, for example, once a day, every 2 days, every 3 days, every 4 days, once a week, or twice a week.

[0106] The term "once a day" or "once daily" or "QD" in the context of administering a drug means herein administering one dose of a drug once each day, wherein the dose is, for example, administered on the same day of the week.

[0107] In one aspect, the terms "administering" or "administration of Compound 1 once a day," as used herein, refer to the amount of Compound 1 in a range of from 1 mg to 100 mg, administered once a day.

[0108] In another aspect, the amount of Compound 1 is in a range of from 1 mg to 200 mg, administered once a day.

[0109] In another aspect, the amount of Compound 1 is in a range of from 1 mg to 100 mg, administered once a day.

[0110] In another aspect, the amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg, administered once a day.

[0111] In another aspect, the amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once a day.PAT059999-WO-PCT -20-

[0112] In another aspect, the amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once a day.

[0113] In another aspect, the amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once a day.

[0114] In another aspect, the amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg, administered once a day.

[0115] In another aspect, the amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once a day.

[0116] In another aspect, the amount of Compound 1 is selected from 1 mg, 5 mg or 50 mg, administered once a day.

[0117] In another aspect, the amount of Compound 1 is selected from 5 mg or 50 mg, administered once a day.

[0118] In another aspect, the amount of Compound 1 is selected from 5 mg, 10 mg, 20 mg, and 30 mg, administered once a day.

[0119] In another aspect, the amount of Compound 1 is selected from 5 mg, 10 mg, and 20 mg, administered once a day.

[0120] The term "once a week" or "once weekly" or "QW" in the context of administering Compound 1 means herein administering one dose of Compound 1 once each week, wherein the dose is, for example, administered on the same day each week.

[0121] In one aspect, the terms "administering" or "administration of Compound 1 once a week," as used herein, refer to Compound 1 administered in an amount selected from a range of from 25 mg to 100 mg once a week, a range of from 25 mg to 200 mg once a week, and a range of from 50 mg to 200 mg once a week.

[0122] In another aspect, Compound 1 is administered in an amount selected from 35 mg once a week, 70 mg once a week, and 140 mg once a week.

[0123] The term "twice a week" or "twice weekly" or "BIW' in the context of administering Compound 1 means herein administering one dose of Compound 1 twice each week, wherein eachPAT059999-WO-PCT -21- dose is administered on separate days each week at regular intervals in a range of from 48 to 72 hours.

[0124] In one aspect, the terms "administering" or "administration of Compound 1 twice a week," as used herein, refer to Compound 1 administered in an amount selected from a range of from 10 mg to 100 mg twice a week, a range of from 10 mg to 200 mg twice a week, and a range of from 25 mg to 100 mg twice a week.

[0125] In another aspect, Compound 1 is administered in an amount selected from a range of from 10 mg to 20 mg twice a week, such as about 15 mg twice a week, a range of from 30 mg to 40 mg twice a week, such as 35 mg twice a week, and a range of from 50 mg to 90 mg twice a week, such as 70 mg twice a week.

[0126] The term "about" in relation to a numerical value X means, for example, X ± 15%, including all the values within this range.

[0127] The terms "disease-modifying therapy" or disease-modifying treatment", as used herein, refer to a drug that can modify or change the course of a condition or a disorder or a disease (i.e. a disease-modifying drug), such as HD, as defined herein.

[0128] The term "subject", as used herein, refers to a mammalian organism, preferably a human being (male or female).

[0129] The term "patient", as used herein, refers to a subject who is diseased and would benefit from the treatment.

[0130] The term "a subject in need of", as used herein, refers to a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment.

[0131] The terms "a therapeutically effective amount" or "an effective amount" of Compound 1, as used herein, refer to an amount of Compound 1 that will elicit the biological or medical response of a subject. In another embodiment, the term refers to the amount of Compound 1 that, when administered to a subject, is effective to at least partially ameliorate a condition, or a disorder or a disease.

[0132] The term "one or more" refers to either one or a number above one (e.g.2, 3, 4, 5, etc.).PAT059999-WO-PCT -22- 3. Compound

[0133] An active ingredient for the methods of use disclosed herein is 2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yl)phenol (Compound 1) or a pharmaceutically acceptable salt thereof. Compound 1 and a suitable method of making it are disclosed in WO2020 / 005873 (compound 163 in that publication). 4. Methods of Use of Compound 1

[0134] Methods described herein are sufficiently effective to ameliorate at least one symptom of HD in a human subject as assessed by a clinically relevant test, score or scale. In certain embodiments, the at least one symptom is impaired global function, impaired motor function, impaired cognitive function, impaired daily function, impaired attention, impaired visuoperceptual processing, impaired working memory, impaired psychomotor speed, impaired verbal motor output, impaired degree of independence, impaired apathy, impaired learning ability, impaired mental concentration, impaired speech, depression, irritability, anger, impaired mobility, impaired self-care, pain, discomfort, anxiety, suicidal ideation, and suicidal behavior, or a combination thereof. Non-limiting examples of such clinically relevant tests, scores and scales include the following. Diagnosis and clinical assessment of HD stages

[0135] A number of clinical and diagnostic measures are used to assess the signs and symptoms of HD. These measures differentiate between various HD stages. For example, the Unified Huntington’s Disease Rating Scale (UHDRS) assesses motor, functional, cognitive and behavioral domains. Composite Unified Huntington's Disease Rating Scale (cUHDRS)

[0136] The cUHDRS assesses motor function, cognitive function, and global function. The outcome measure is comprised of an equally weighted sum of Z scores of the TFC, the TMS, the SDMT, and the SWR scores from the UHDRS. It is a multidomain measure of clinical decline that tracks underlying progressive brain changes and is related to changes in daily functional ability. The cUHDRS is described in greater detail by Schobel el al., Neurology 2017; 89:2495-2502. In certain embodiments, methods improve the subject’s cUHDRS rating by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points.PAT059999-WO-PCT -23-

[0137] In one aspect, motor function, cognitive function, and global function is measured by Composite Unified Huntington's Disease (cUHDRS). Prognostic Index for Huntington's Disease

[0138] In one aspect, HD subject selection is determined with the use of the Prognostic Index for Huntington's Disease, or a derivative thereof (Long JD et al., Movement Disorders, 2017, 32(2), 256-263, the contents of which are herein incorporated by reference in their entirety). This prognostic index uses four components to predict probability of motor diagnosis, (1) total motor score (TMS) from the Unified Huntington's Disease Rating Scale (UHDRS), (2) Symbol Digit Modality Test (SDMT), (3) base-line age, and (4) cytosine-adenine-guanine (CAG) expansion.

[0139] In one aspect, the prognostic index for Huntington's Disease is calculated with the following formula: PIHD = 51 x TMS+ (-34) x SDMT + 7 x Age x (CAG-34), wherein larger values for PIHD indicate greater risk of diagnosis or onset of symptoms.

[0140] In one aspect, the prognostic index for Huntington's Disease is calculated with the following normalized formula that gives standard deviation units to be interpreted in the context of 50% 10-year survival: PINHD = (PIHD - 883) / 1044, wherein PINHD < 0 indicates greater than 50% 10-year survival, and PINHD> 0 suggests less than 50% 10-year survival.

[0141] In one aspect, the prognostic index may be used to identify subjects who will develop symptoms of HD within several years, but that do not yet have clinically diagnosable symptoms. Further, these asymptomatic patients may be selected for and receive treatment using Compound 1 during the asymptomatic period.

[0142] In a one aspect, the subject has a normed version of the Huntington’s disease prognostic index (PINHD) score between 0.18 and 4.93 before beginning treatment with Compound 1. Total Functional Capacity (TFC) Scale

[0143] The Total Functional Capacity (TFC) scale (e.g. in Movement Disorders, 1996, 11, 136- 142) is a component of the UHDRS and ranges from 0 (fully dependent for all care) to 13 (fully independent) the level of independence of a person with HD (referred to herein as “UHDRS-TFC” score). This scale assesses functional status of a HD patient in terms of ability to work, handle household finances, manage domestic chores, perform activities of daily living, and level of care needed. Based on the UHDRS total functional capacity (UHDRS-TFC), HD is divided into stagesPAT059999-WO-PCT -24- 1 to 5 of disease progression. The categorization of HD, based on TFC score (also referred to as Shoulson and Fahn stages), are also as early stage HD (corresponding to stages 1 or 2, based on TFC score), moderate stage or mid stage HD (corresponding to stage 3, based on TFC score) and advanced stage or late stage HD (corresponding to stage 4 or 5, based on TFC score).

[0144] In one aspect, functional capacity is measured by the UHDRS-TFC.

[0145] In one aspect, the subject has a UHDRS-TFC score of 11 before beginning treatment with Compound 1.

[0146] In another aspect, the subject has a UHDRS-TFC score of 12 before beginning treatment with Compound 1.

[0147] In another aspect, the subject has a UHDRS-TFC score of 13 before beginning treatment with Compound 1.

[0148] In a further aspect, the subject has a UHDRS-TFC score of 11, 12, or 13 before beginning treatment with Compound 1. Independence Score (IS)

[0149] The “UHDRS-IS” comprises part of the UHDRS functional assessments (Huntington’s Study Group 1996). It is a rating scale where the patient’s degree of independence is given in percentage, from 10% (tube fed, total bed care) to 100% (no special care needed). Scores must end in 0 or 5 (e.g., 10%, 15%, 20%...).

[0150] In one aspect, the HD subject has an UHDRS-IS of 100% before beginning treatment with Compound 1. Total Motor Score (TMS)

[0151] In one aspect, motor function impairment is measured by the Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-TMS), the Unified Huntington’s Disease Rating Scale- modified Motor Score (UHDRS-mMS), the Unified Huntington’s Disease Rating Scale (UHDRS)-Chorea score, the Unified Huntington’s Disease Rating Scale (UHDRS)-Dystonia score, Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), hand movement score, gait and balance score, Quantitative motor (Q-Motor) assessment or by timed up and go (TUG) assessment (WO2020250234).PAT059999-WO-PCT -25-

[0152] In one aspect, treating or ameliorating Huntington’s Disease with Compound 1, or a pharmaceutically acceptable salt thereof, as a disease-modifying therapy, results from the production of an in-frame stop codon between exons 49 and 50 in the HTT mRNA transcript; wherein, the resulting decrease in mRNA and reduction of wildtype and mutant HTT protein has one or more of the following effects:

[0153] (i) slowed rate of decline in loss of motor function associated with Huntington's disease, wherein the slowed rate of decline of motor function associated with Huntington's disease after treatment with Compound 1 is shown by decrease in mRNA and reduction of wildtype and mutant HTT protein or by comparison to placebo; wherein, motor function is selected from the group consisting of ocular motor function, dysarthria, dystonia, chorea, postural stability and gait; and, is assessed by using standard clinical scales, such as the UHDRS motor assessment scale (e.g. in Movement Disorders, 1996, 11, 136-142);

[0154] (ii) slowed rate of cognitive decline associated with Huntington's disease, wherein the slowed rate of cognitive decline associated with Huntington's disease after treatment with Compound 1 is shown by decrease in mRNA and reduction of wildtype and mutant HTT protein or by comparison to placebo; wherein, cognitive function is selected from the group consisting of attention, processing speed, visuospatial processing, timing, emotion processing, memory, verbal fluency, psychomotor function, and executive function; and, is assessed by using standard clinical scales, such as the Symbol Digit Modalities Test, the Stroop Word Reading Test, the Montreal Cognitive Assessment or the HD Cognitive Assessment Battery (comprising the Symbol Digit Modalities Test, Trail Making Test B, One Touch Stockings, Paced Tapping, Emotion Recognition Test, Hopkins Verbal Learning Test); e.g. in Movement Disorders, 2014, 29 (10), 1281-1288];

[0155] (iii) slowed rate of psychiatric decline associated with Huntington's disease, wherein the slowed rate of psychiatric decline associated with Huntington's disease after treatment with Compound 1 is shown by decrease in mRNA and reduction of wildtype and mutant HTT protein or by comparison to placebo; wherein, psychiatric decline is selected from the group consisting of apathy, anxiety, depression, obsessive compulsive behavior, suicidal thoughts, irritability and agitation; and, is assessed by using standard clinical scales, such as the Apathy Evaluation Scale or by the Hospital Anxiety and Depression Scale; e.g. in Movement Disorders, 2016, 31 (10), 1466-1478, Movement Disorders, 2015, 30 (14), 1954-1960];PAT059999-WO-PCT -26-

[0156] (iv) slowed rate of decline of functional capacity associated with Huntington's disease, wherein the slowed rate of decline of associated with Huntington's disease after treatment with Compound 1 is shown by decrease in mRNA and reduction of wildtype and mutant HTT protein or by comparison to placebo; wherein, functional capacity is selected from the group consisting of capacity to work, capacity to handle financial affairs, capacity to manage domestic chores, capacity to perform activities of daily living, and level of care needed; and, is assessed by using standard clinical scales, such as the UHDRS Total Functional Capacity, Functional Assessment and Independence scales (e.g. in Movement Disorders, 1996, 11, 136-142);

[0157] (v) slowed progression of Huntington's disease pathophysiology, wherein the slowed progression of Huntington's disease pathophysiology associated with Huntington's disease [e.g. reducing the rate of brain (e.g. whole brain, caudate, striatum or cortex) volume loss (e.g. % from baseline volume)] after treatment with Compound 1 is shown by decrease in mRNA and reduction of wildtype and mutant HTT protein or by comparison to placebo, and assessed using standard techniques, such as MRI (e.g. by neuroimaging measures)(see, .e.g. Lancet Neural.2013, 12 (7), 637-649);

[0158] (vi) slowed onset of Huntington's disease or the onset of symptoms associated with Huntington's disease, wherein the slowed onset of Huntington's disease or the onset of symptoms associated with Huntington's disease after treatment with Compound 1 is shown by decrease in mRNA and reduction of wildtype and mutant HTT protein or by comparison to placebo, and assessed by using standard clinical scales, such as the Huntington's Disease Health-related Quality of Life questionnaire (HDQoL) (e.g. in Movement Disorders, 2018, 33 (5), 742-749); or,

[0159] (vii) reduced decline in quality of life associated with Huntington's disease, wherein the slowed onset of Huntington's disease or the onset of symptoms associated with Huntington's disease after treatment with Compound 1 is shown by decrease in mRNA and reduction of wildtype and mutant HTT protein or by comparison to placebo, and is assessed by using standard clinical scales, such as the Huntington's Disease Health-related Quality of Life questionnaire (HDQoL) (e.g. in Movement Disorders, 2018, 33 (5), 742-749).

[0160] In another aspect, treating or ameliorating Huntington’s Disease with Compound 1, or a pharmaceutically acceptable salt thereof, has one or more of the following effects: (i) a favorable therapeutic profile, such as a favorable safety profile or metabolic profile; or, (ii) a favorable off- target effect profile, such as a favorable psychiatric adverse event profile, a favorable toxicity (e.g.PAT059999-WO-PCT -27- genotoxicity) or cardiovascular adverse event (e.g. blood pressure, heart rate, electrocardiography parameters) profile.

[0161] In one aspect, a patient in need thereof is orally administered a therapeutically effective amount of Compound 1.

[0162] In another aspect, the therapeutically effective amount of Compound 1 is in a range of from 1 mg to 200 mg.

[0163] In another aspect, the therapeutically effective amount of Compound 1 is in a range of from 1 mg to 100 mg.

[0164] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg.

[0165] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0166] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg.

[0167] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0168] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg.

[0169] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg.

[0170] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg or 50 mg.PAT059999-WO-PCT -28-

[0171] In another aspect, the therapeutically effective amount of Compound 1 is selected from 5 mg or 50 mg.

[0172] In another aspect, the therapeutically effective amount of Compound 1 is selected from 5 mg, 10 mg, 20 mg, and 30 mg.

[0173] In another aspect, the therapeutically effective amount of Compound 1 is selected from 5 mg, 10 mg, and 20 mg.

[0174] In one aspect, a patient in need thereof is orally administered a therapeutically effective amount of Compound 1, administered once a day.

[0175] In another aspect, the therapeutically effective amount of Compound 1 is in a range of from 1 mg to 200 mg, administered once a day.

[0176] In another aspect, the therapeutically effective amount of Compound 1 is in a range of from 1 mg to 100 mg, administered once a day.

[0177] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, and 200 mg, administered once a day.

[0178] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once a day.

[0179] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 135 mg, and 140 mg, administered once a day.

[0180] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once a day.PAT059999-WO-PCT -29-

[0181] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg, once a day.

[0182] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 65 mg, 70 mg, and 100 mg, administered once a day.

[0183] In another aspect, the therapeutically effective amount of Compound 1 is selected from 1 mg, 5 mg or 50 mg, administered once a day.

[0184] In another aspect, the therapeutically effective amount of Compound 1 is selected from 5 mg or 50 mg, administered once a day.

[0185] In another aspect, the therapeutically effective amount of Compound 1 is selected from 5 mg, 10 mg, 20 mg, and 30 mg, administered once a day.

[0186] In another aspect, the therapeutically effective amount of Compound 1 is selected from 5 mg, 10 mg, and 20 mg, administered once a day.

[0187] In another aspect, the therapeutically effective amount of Compound 1 is 1 mg.

[0188] In another aspect, the therapeutically effective amount of Compound 1 is 5 mg.

[0189] In another aspect, the therapeutically effective amount of Compound 1 is 10 mg.

[0190] In another aspect, the therapeutically effective amount of Compound 1 is 15 mg.

[0191] In another aspect, the therapeutically effective amount of Compound 1 is 20 mg.

[0192] In another aspect, the therapeutically effective amount of Compound 1 is 25 mg.

[0193] In another aspect, the therapeutically effective amount of Compound 1 is 30 mg.

[0194] In another aspect, the therapeutically effective amount of Compound 1 is 35 mg.

[0195] In another aspect, the therapeutically effective amount of Compound 1 is 40 mg.

[0196] In another aspect, the therapeutically effective amount of Compound 1 is 45 mg.

[0197] In another aspect, the therapeutically effective amount of Compound 1 is 50 mg.

[0198] In another aspect, the therapeutically effective amount of Compound 1 is 55 mg.

[0199] In another aspect, the therapeutically effective amount of Compound 1 is 60 mg.

[0200] In another aspect, the therapeutically effective amount of Compound 1 is 65 mg.

[0201] In another aspect, the therapeutically effective amount of Compound 1 is 70 mg.

[0202] In another aspect, the therapeutically effective amount of Compound 1 is 75 mg.PAT059999-WO-PCT -30-

[0203] In another aspect, the therapeutically effective amount of Compound 1 is 80 mg.

[0204] In another aspect, the amount of Compound 1 is 85 mg.

[0205] In another aspect, the therapeutically effective amount of Compound 1 is 90 mg.

[0206] In another aspect, the therapeutically effective amount of Compound 1 is 95 mg.

[0207] In another aspect, the therapeutically effective amount of Compound 1 is 100 mg.

[0208] In another aspect, the therapeutically effective amount of Compound 1 is 105 mg.

[0209] In another aspect, the therapeutically effective amount of Compound 1 is 110 mg.

[0210] In another aspect, the therapeutically effective amount of Compound 1 is 115 mg.

[0211] In another aspect, the therapeutically effective amount of Compound 1 is 120 mg.

[0212] In another aspect, the therapeutically effective amount of Compound 1 is 125 mg.

[0213] In another aspect, the therapeutically effective amount of Compound 1 is 130 mg.

[0214] In another aspect, the therapeutically effective amount of Compound 1 is 135 mg.

[0215] In another aspect, the therapeutically effective amount of Compound 1 is 140 mg.

[0216] In another aspect, the therapeutically effective amount of Compound 1 is 145 mg.

[0217] In another aspect, the therapeutically effective amount of Compound 1 is 150 mg.

[0218] In another aspect, the therapeutically effective amount of Compound 1 is 155 mg.

[0219] In another aspect, the therapeutically effective amount of Compound 1 is 160 mg.

[0220] In another aspect, the therapeutically effective amount of Compound 1 is 165 mg.

[0221] In another aspect, the therapeutically effective amount of Compound 1 is 170 mg.

[0222] In another aspect, the therapeutically effective amount of Compound 1 is 175 mg.

[0223] In another aspect, the therapeutically effective amount of Compound 1 is 180 mg.

[0224] In another aspect, the therapeutically effective amount of Compound 1 is 185 mg.

[0225] In another aspect, the therapeutically effective amount of Compound 1 is 190 mg.

[0226] In another aspect, the therapeutically effective amount of Compound 1 is 195 mg.

[0227] In another aspect, the therapeutically effective amount of Compound 1 is 200 mg.

[0228] In another aspect, the therapeutically effective amount of Compound 1 is administered once per day.

[0229] In another aspect, the therapeutically effective amount of Compound 1 is administered twice per day.

[0230] In another aspect, the therapeutically effective amount of Compound 1 is administered three times per day.PAT059999-WO-PCT -31-

[0231] In another aspect, the therapeutically effective amount of Compound 1 is administered once per week.

[0232] In another aspect, the therapeutically effective amount of Compound 1 is administered once every two weeks.

[0233] In one aspect, a use of a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in treating or ameliorating Huntington’s Disease as a disease-modifying therapy, includes Huntington's disease selected from the group consisting of Huntington’s Disease genetically characterized by CAG repeat expansion of from 36 to 39 in the HTT gene on chromosome 4; and, Huntington's disease genetically characterized by CAG repeat expansion of from >39 in the HTT gene on chromosome 4.

[0234] In one aspect, a use of therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in treating or ameliorating Huntington’s Disease (HD) in a subject having a cytosine-adenine-guanine (CAG) repeat length from 40 to 50 of the huntington (HTT) gene.

[0235] In one aspect, a use of a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in treating or ameliorating Huntington’s Disease as a disease-modifying therapy, includes Huntington's disease selected from the group consisting of manifest Huntington's disease, juvenile Huntington's disease, pediatric Huntington's disease, early stage of Huntington's disease, middle stage of Huntington's disease, advanced stage of Huntington's disease, stage I of Huntington's disease, stage II of Huntington's disease, stage Ill of Huntington's disease, stage IV of Huntington's disease, stage V of Huntington's disease, and pre- manifest Huntington's disease.

[0236] In one aspect, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is administered according to an intermittent dosing schedule.

[0237] In another aspect, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week or twice a week.

[0238] In another aspect, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

[0239] In another aspect, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is provided in the form of a pharmaceutical composition.PAT059999-WO-PCT -32-

[0240] In another aspect, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is provided in the a pharmaceutical combination.

[0241] In another aspect, a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, is administered following gene therapy or treatment with an antisense compound.

[0242] In one aspect, a method of treatment for slowing progression of Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1.

[0243] In another aspect, a method of treatment for slowing the decline of motor function, cognitive function, and global function associated of Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1.

[0244] In another aspect, a method of treatment for slowing the decline of motor function associated with Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1.

[0245] In another aspect, a method of improving, maintaining or reducing impairment of functional capacity of a subject afflicted with Huntington's disease (HD), comprising administering to subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0246] In another aspect, a method of treatment for slowing cognitive decline associated with Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1.

[0247] In another aspect, a method of treatment for slowing psychiatric decline associated with Huntington's disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound 1.

[0248] In another aspect, a method of treatment for slowing the decline of functional capacity associated with Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1.

[0249] In another aspect, a method of improving, maintaining or reducing impairment of functional capacity of a subject afflicted with Huntington’s disease, comprising administering toPAT059999-WO-PCT -33- subject a therapeutically effective amount Compound 1, or a pharmaceutically acceptable salt thereof.

[0250] In another aspect, a method of treatment for slowing the progression of Huntington's disease pathophysiology [e.g. reducing the rate of brain (e.g. whole brain, caudate, striatum or cortex) volume loss (e.g. % from baseline volume)] associated with Huntington's disease (e.g. as assessed by MRI)] in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1.

[0251] In another aspect, a method of treatment for slowing the decline of motor function associated with Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1; wherein, motor function is selected from the group consisting of ocular motor function, dysarthria, dystonia, chorea, postural stability and gait.

[0252] In another aspect, a method of treatment for slowing cognitive decline associated with Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1; wherein, cognitive decline is selected from the group consisting of attention, processing speed, visuospatial processing, timing, emotion processing, memory, verbal fluency, psychomotor function, and executive function.

[0253] In another aspect, a method of treatment for slowing psychiatric decline associated with Huntington's disease in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of Compound 1; wherein, psychiatric decline is selected from the group consisting of apathy, anxiety, depression, obsessive compulsive behavior, suicidal thoughts, irritability and agitation.

[0254] In another aspect, a method of treatment for slowing the decline of functional capacity associated with Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1; wherein, functional capacity comprises one or more selected from the group consisting of capacity to work, capacity to handle financial affairs, capacity to manage domestic chores, capacity to perform activities of daily living, and level of care needed.

[0255] In another aspect, a method of treatment for slowing the progression of Huntington's disease pathophysiology [e.g. reducing the rate of brain (e.g. whole brain, caudate, striatum or cortex) volume loss (e.g. % from baseline volume)] associated with Huntington's disease (e.g. asPAT059999-WO-PCT -34- assessed by MRI)] in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of

[0256] In one aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in a range of from 1 to 200 mg.

[0257] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in a range of from 1 to 100 mg.

[0258] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 1 mg.

[0259] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 5 mg.

[0260] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 10 mg.

[0261] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 15 mg.

[0262] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 20 mg.

[0263] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 25 mg.

[0264] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 30 mg.PAT059999-WO-PCT -35-

[0265] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 35 mg.

[0266] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 40 mg.

[0267] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 45 mg.

[0268] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 50 mg.

[0269] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 55 mg.

[0270] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 60 mg.

[0271] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 65 mg.

[0272] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 70 mg.

[0273] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 75 mg.

[0274] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 80 mg.PAT059999-WO-PCT -36-

[0275] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 85 mg.

[0276] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 90 mg.

[0277] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 95 mg.

[0278] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 100 mg.

[0279] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 105 mg.

[0280] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 110 mg.

[0281] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 115 mg.

[0282] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 120 mg.

[0283] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 125 mg.

[0284] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 130 mg.PAT059999-WO-PCT -37-

[0285] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 135 mg.

[0286] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 140 mg.

[0287] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 145 mg.

[0288] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 150 mg.

[0289] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 155 mg.

[0290] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 160 mg.

[0291] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 165 mg.

[0292] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 170 mg.

[0293] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 175 mg.

[0294] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 180 mg.PAT059999-WO-PCT -38-

[0295] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 185 mg.

[0296] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 190 mg.

[0297] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 195 mg.

[0298] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, of 200 mg.

[0299] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, once per day.

[0300] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, twice per day.

[0301] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, three times per day.

[0302] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, once per week.

[0303] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, once every two weeks.

[0304] In one aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein Huntington's disease is selected from the group consisting of Huntington’s Disease genetically characterized by CAGPAT059999-WO-PCT -39- repeat expansion of from 36 to 39 in the HTT gene on chromosome 4; and, Huntington's disease genetically characterized by CAG repeat of from >39 in the HTT gene on chromosome 4.

[0305] In one aspect, a method for treating or ameliorating Huntington’s Disease (HD) in a subject having a cytosine-adenine-guanine (CAG) repeat length from 40 to 50 of the huntington (HTT) gene, comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0306] In one aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, wherein Huntington's disease is selected from the group consisting of manifest Huntington's disease, juvenile Huntington's disease, pediatric Huntington's disease, early stage of Huntington's disease, middle stage of Huntington's disease, advanced stage of Huntington's disease, stage I of Huntington's disease, stage II of Huntington's disease, stage Ill of Huntington's disease, stage IV of Huntington's disease, stage V of Huntington's disease, and pre-manifest Huntington's disease.

[0307] In one aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, according to an intermittent dosing schedule.

[0308] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, once a day, once a week or twice a week.

[0309] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, orally.

[0310] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition.PAT059999-WO-PCT -40-

[0311] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical combination.

[0312] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, following gene therapy or treatment with an antisense compound.

[0313] In another aspect, a method of treating or ameliorating Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to produce an in-frame stop codon between exons 49 and 50 in the HTT mRNA.

[0314] In another aspect, a method of slowing progression of Huntington’s Disease in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, to produce an in-frame stop codon between exons 49 and 50 in the HTT mRNA.

[0315] In one aspect, a method of reducing mHTT protein levels in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0316] In a further aspect, mHTT protein levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid. Neurofilament light chain (NfL)

[0317] NfL is a component of the axoskeleton within neurons, and its release into the cerebrospinal fluid (CSF) and / or plasma is a biomarker of neuronal axonal damage. Plasma NfL increases about 10-12% per year based on natural history data. Thus, the levels of NfL may be a strong monitoring and prognostic biomarker for HD.PAT059999-WO-PCT -41-

[0318] In some aspects, the subject has an elevated level of Neurofilament light chain (NfL). The elevated level of NfL may be greater than a level in normal or healthy subjects, such as subjects of a similar age. In some embodiments, the elevated level of NfL is greater than a reference NfL level.

[0319] In some aspects, the level of NfL is measured in cerebrospinal fluid (CSF). The reference NfL level may be about 100 pg / ml, 200 pg / ml, 300 pg / ml, 400 pg / ml, 500 pg / ml, 600 pg / ml, 700 pg / ml, 800 pg / ml, 900 pg / ml, 1000 pg / ml, 1100 pg / ml, 1200 pg / ml, 1300 pg / ml, 1400 pg / ml, 1500 pg / ml, 1600 pg / ml, 1700 pg / ml, 1800 pg / ml, 1900 pg / ml, 2000 pg / ml, 2500 pg / ml, 3000 pg / ml, 3500 pg / ml, 4000 pg / ml, 4500 pg / ml, or 5000 pg / ml. In some embodiments, the elevated level of NfL is greater than the NfL level in normal or healthy subjects or the reference NfL level by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1500%, 2000%, 2500%, 3000%, 3500%, 4000%, 4500%, or 5000%. In some embodiments, the elevated level of NfL is greater than the NfL level in normal or healthy subjects or the reference NfL level by at least 1%-10%, 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-100%, 100%-200%, 200%-300%, 300%-400%, 400%-500%, 500%- 600%, 600%-700%, 700%-800%, 800%-900%, 900%-1000%, 1000%-2000%, 2000%-3000%, 3000%-4000%, or 4000-5000%.

[0320] In other aspects, the level of NfL is measured in plasma. The reference NfL level may be about 1 pg / ml, 2 pg / ml, 3 pg / ml, 4 pg / ml, 5 pg / ml, 6 pg / ml, 7 pg / ml, 8 pg / ml, 9 pg / ml, 10 pg / ml, 11 pg / ml, 12 pg / ml, 13 pg / ml, 14 pg / ml, 15 pg / ml, 16 pg / ml, 17 pg / ml, 18 pg / ml, 19 pg / ml, or 20 pg / ml. In some embodiments, the elevated level of NfL is greater than the NfL level in normal or healthy subjects or the reference NfL level by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, 1500%, 2000%, 2500%, 3000%, 3500%, 4000%, 4500%, or 5000%. In some embodiments, the elevated level of NfL is greater than the NfL level in normal or healthy subjects or the reference NfL level by at least 1%- 10%, 10%-20%, 20%- 30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, 90%-100%, 100%-PAT059999-WO-PCT -42- 200%, 200%-300%, 300%-400%, 400%-500%, 500%-600%, 600%-700%, 700%-800%, 800%- 900%, 900%-1000%, 1000%-2000%, 3000%-4000%, or 4000-5000%.

[0321] In one aspect, a method of stabilizing or decreasing the concentration of neurofilament light chain (NfL) polypeptide of a subject having previously been diagnosed with Huntington's Disease (HD), comprising administering to the subject a therapeutically effective amount of Compound 1, or a pharmaceutically acceptable salt thereof.

[0322] In a further aspect, NfL levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid.

[0323] Specific embodiments of the invention will now be demonstrated by reference to the following examples. It should be understood that these examples are disclosed solely by way of illustrating the invention and should not be taken in any way to limit the scope of the present invention. EXAMPLES EXAMPLE I: PHASE 2A CLINICAL STUDY PROTOCOL A Phase 2a, Randomized, Placebo-Controlled, Dose-Ranging Study to Evaluate the Safety and Efficacy of Compound 1 in Subjects with Huntington’s Disease. Prior to the development of this Phase 2 study, Compound 1 was extensively evaluated in in vivo and in vitro preclinical pharmacology models, in a comprehensive toxicology program, and in an ongoing Phase 1 study in healthy volunteers. Together, the resulting data validate that Compound 1 treatment results in dose-dependent pre-mRNA splicing and reduced protein transcription and that Compound 1 treatment is safe and well tolerated in the clinic at single doses as high as 135 mg and multiple doses as high as 30 mg for 21 days. The present 12-month double-blind study with a 6-month Safety Follow-Up will allow for the quantification of the effect of Compound 1 on total huntingtin protein (tHTT) reduction in subjects with HD and evaluation of the safety of Compound 1 over 12 months of treatment. The time course in untreated patients for HTT protein, mRNA, and other indicators of drug response in the blood was not available. However, the use of a concurrent placebo control allowed for a direct assessment comparison to determine the effect of active treatment.PAT059999-WO-PCT -43- The patient population was selected to reduce variability in an otherwise heterogeneous disease population by identifying subjects disease who either have not yet experienced functional decline (Stage 2) or have very limited features of functional decline (Mild Stage 3). This patient population was also selected as the population of subjects most likely to benefit from stabilization of disease from treatment with Compound 1, being those with only limited functional decline due to disease progression. In this study, at randomization, subjects will thus be enrolled in the study based upon CAG repeat length and Baseline measures of the Symbol Digit Modalities Test (SDMT), Total Motor Score (TMS), Independence Scale (IS), and Total Functional Capacity (TFC). These factors were used to identify and enroll subjects with active disease who have not yet experienced functional decline (Stage 2) or who had only very limited features of functional decline (Mild Stage 3), which may indicate a disease progression amenable to intervention. The Huntington’s disease prognostic index (PIHD) or its normed version (PINHD) score can be used to predict likelihood of HD progression. The PINHD score was calculated at Screening to identify subjects eligible for participation in the Stage 2 group in the study, as it predicts progression into Stage 3. The Unified Huntington’s Disease Rating Scale (UHDRS) TFC and IS scores was also calculated at Screening to identify subjects eligible for participation in the Stage 2 or Mild Stage 3 group in the study. Based on the kinetics of Compound 1-mediated HTT lowering in humans, the maximal extent of tHTT protein lowering in blood from HD patients is expected to be achieved between 4 and 6 weeks. The 12-month dosing regimen can further demonstrate that a steady-state decrease in blood tHTT levels is maintained over time with continued Compound 1 treatment. In addition to the primary endpoints of tHTT protein change from Baseline and safety, the Phase 2 study includes exploratory clinical outcome endpoints to assess the effect of Compound 1 on subjects’ cognition and motor function as measured by the UHDRS. The UHDRS has been extensively studied and developed to assess disease progression in multiple domains. The short form of the Problem Behaviors Assessments (PBA-s) has been included for assessment of disease progression in the behavioral domain. Cognitive impairment, motor function loss, and accelerated brain volume loss in the caudate and putamen are key features of this disorder and have a notable impact on quality of life. The assessment of more sensitive and early motor changes via Opal wearablePAT059999-WO-PCT -44- devices will also be included in this study as an exploratory endpoint. Studying these endpoints over 12 months will provide insight into the change in earlier stages of disease and identify key measurements that may be early indicators of HD progression. Risk / Benefit Assessment As described, HD is a relentlessly progressive, neurodegenerative disorder. Early in the course of the disease, patients exhibit subtle symptoms; as the disease progresses, involuntary movements become more pronounced, voluntary motor capabilities decline, and speech and swallowing are increasingly impaired, while aggressive and disinhibited behavior become more frequent. Late-stage disease is marked by severe inability to walk, speak, swallow, or care for oneself, culminating in the need for full-time care and ultimately death, typically 15 to 18 years after the onset of symptoms (see, Caron, N, Wright, G and Hayden, M; (2020a), Huntington Disease; Seattle, WA; University of Washington). There are currently no disease modifying interventions approved for use in HD and, without intervention, the patient population to be included in this trial will face continued disease progression, loss of function, and inevitably, death. The inexorable disease progression and inevitable mortality of the disease indicate that HD represents a high unmet medical need. Reduction of mHTT has been confirmed as an important therapeutic target. As described above, in the Phase 1 study, multiple doses of Compound 1 were associated reductions in HTT mRNA and protein. Pharmacokinetic-pharmacodynamic (PKPD) modeling based on interim data from the Phase 1 study determined that exposures at the 5 mg and 10 mg doses will be associated with reductions of ~10% to 30% in full-length HTT mRNA levels. Decreases in mHTT of between 30% and 50% are targeted for optimal therapeutic benefit, though decreases of 10% have been associated with potential therapeutic benefit. The 5 mg and 10 mg QD doses are thus anticipated to be associated with therapeutic benefit and the eventual slowing of disease progression in this Phase 2a study. The Phase 1 study results provided evidence of Compound 1 safety and tolerability at single doses ranging from 5 mg to 135 mg and multiple doses of 15 mg and 30 mg for durations of up to 21 days. Compound 1 was safe and generally well tolerated. In both the single ascending dose (SAD) and multiple ascending dose (MAD) portions of the Phase 1 study, the overall incidence of AEs was comparable between subjects who received placebo and those who receivedPAT059999-WO-PCT -45- Compound 1. There were no events considered to be dose-limiting toxicities, and all Adverse Events (AEs) were comparable between who received placebo and those who received Compound 1. There were no events considered to be dose-limiting toxicities, and all AEs were resolved at the time of the interim analysis cut-off date. There were also no clinically significant laboratory abnormalities or ECG findings at any dose in either portion of the study. The Phase 1 study will have a Data and Safety Monitoring Board (DSMB) that will closely monitor the safety of subjects. Based on the preclinical and clinical data to date, Compound 1 has a favorable risk / benefit profile in subjects with HD. Primary Objectives: Evaluate the safety of Compound 1 compared with placebo in subjects with Huntington’s disease (HD) and the pharmacodynamic (PD) effects of Compound 1 through the reduction in blood total huntingtin (tHTT) protein levels. Secondary Objectives: Assess the effects of Compound 1 on (i) change in caudate volume via volumetric magnetic resonance imaging (vMRI), (ii) change in composite Unified Huntington’s Disease Rating Scale (cUHDRS), (iii) mutant huntingtin (mHTT) protein in cerebrospinal fluid (CSF) at Month 12, and (iv) blood mHTT levels at Month 12. Exploratory Objectives: Determine the effect of Compound 1 on (i) mHTT protein in CSF at Month 3; (ii) blood mHTT levels at Month 3; (iii) on change in whole brain, and putamen volume via vMRI; (iv) change in ventricular volume via vMRI; (v) change in clinical scales after 12 months of treatment; and (vi) on huntingtin (HTT) mRNA in blood. Pharmacokinetic Objective: Evaluate the concentration of Compound 1 in subjects with HD. Clinical Endpoints: Primary Safety Endpoints:PAT059999-WO-PCT -46- Evaluate the safety profile as characterized by treatment-emergent adverse events (TEAEs) and laboratory abnormalities, chain (NfL) levels in plasma and CSF, electrocardiogram (ECG), vital signs, slit lamp eye examination, Total Neuropathy Score – Clinical (TNSc), Columbia Suicide Severity Rating Scale (C-SSRS) and physical examination Primary Efficacy Endpoint: Change from Baseline in blood total HTT protein at Month 3. Secondary Endpoints: (i) Change from Baseline in caudate volume as assessed via vMRI at Month 12; (ii) Change from Baseline in cUHDRS scores at Month 12; (iii) Change from Baseline in blood tHTT protein at Month 12; (iv) Change from Baseline in CSF mHTT protein at Month 12; and (v) Change from Baseline in blood mHTT protein at Month 12. Exploratory Endpoints: (i) Change from Baseline in CSF mHTT protein at Month 3, (ii) Change from Baseline in blood mHTT protein at Month 3; (iii) Change from Baseline in whole brain, putamen, and ventricular volume (as assessed by vMRI) at Month 12; (iv) Change from Baseline in Unified Huntington’s Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) sub-score at Month 12, (v) Change from Baseline in other UHDRS sub-scores including Total Motor Score (TMS), Symbol Digit Modalities Test (SDMT), and Independence Scale (IS) at Month 12; (vi) Change from Baseline in the short form of the Problem Behaviors Assessment (PBA-s) at Month 12; (vii) Change from Baseline in wearable accelerometer assessment Timed Up and Go (TUG), 2-minute walk distance, and postural sway at Month 12; (viii) Change from Baseline in the Functional Rating Scale (FuRST) 2.0 questionnaire at Month 12; (ix) Change over time in blood HTT mRNA; (x) Change over time in plasma and CSF NfL; and (xi) Change over time in CSF YKL-40. Pharmacokinetic Endpoint Plasma trough concentration (Ctrough) and accumulation ratio of Compound 1 in plasma over time and accumulation ratio of Compound 1 in CSF at Visits 5 through 8. Study Design / Methodology:PAT059999-WO-PCT -47- The Phase 2 study was composed of 2 groups (Stage 2 group and Mild Stage 3 group), further broken into 6 parts (Parts A, B, C, D, F), each of which consist of an active treatment arm and a placebo arm. The Stage 2 group will consist of Parts A, B, and C, and will include subjects who qualify as Stage 2 disease based on the Huntington’s disease Integrated Staging System (HD-ISS) criteria. The Mild Stage 3 group will consist of Parts D, E, and F, and include subjects who qualify as Mild Stage 3 disease based on the HD-ISS criteria. Approximately 144 subjects who satisfied all enrollment criteria at Screening underwent Baseline evaluations and were randomized to Parts A, B, D, or E (depending on their stage of disease, as described above), after which they were randomized to treatment arms within Part A or D (5 mg or matching placebo) or Part B or E (10 mg or matching placebo) in a 2:1 ratio (active treatment to matching placebo) for 12 months. A Data and Safety Monitoring Board (DSMB) will closely monitor the safety of subjects. As specified in the DSMB Charter, the DSMB will undertake an unblinded review of safety data from the 5 and 10 mg dosing groups and provide a recommendation on when Parts C and F (20 mg or matching placebo) can be initiated. At that time, subjects were randomized to any study Part that was currently open for enrollment (depending on their stage of disease) and then to either active treatment or placebo (in a 2:1 ratio) within that Part. Subjects returned to the clinic every month until Visit 5 (Month 3) and then quarterly until Visit 8 (Month 12). Upon completion of Visit 8 (Month 12), subjects had the option to enroll in a Phase 2 long-term extension study, to receive Compound 1. For subjects not enrolled in the Phase 2 long-term extension study, Visit 8 was considered the End of Treatment visit, and there was a Follow-Up Safety Visit (Month 13) via telephone / telehealth to collect adverse event data and an additional Follow-Up Safety Visit on Month 16 (i.e., approximately 4 months after the last dose of study drug) to collect adverse events and to perform slit lamp eye evaluation. A final Follow-Up Safety Visit was on Month 18 via telephone / telehealth to collect adverse event data. Sample Size Justification: The sample size calculation for each disease stage was based on mean change from Baseline in blood tHTT protein at Month 3 (primary endpoint) assuming Compound 1 had thePAT059999-WO-PCT -48- same effect on blood tHTT protein reduction. With an effect size of 0.85 (i.e., the magnitude of treatment difference is 85% of one standard , achievement of 85% power at 2-sided alpha level 0.05 would require 24 subjects. Approximately 24 subjects was randomized to each active treatment arm and approximately 36 additional subjects per disease stage was randomized to placebo. An additional 18 subjects (per disease stage) could have been randomized to the maximum tolerated dose. Planned Number of Patients: Up to 252 adult male and female subjects (126 per disease stage) will be enrolled. Inclusion Criteria: Individuals eligible to participate in this study include those who meet all of the following inclusion criteria: (i) Ambulatory male or female patient aged 25 years and older, inclusive; (ii) Subject (or legally authorized representative) is willing and able to provide informed consent and comply with all protocol requirements; and (iii) Genetically confirmed HD diagnosis with a cytosine-adenine-guanine (CAG) repeat length from 40 to 50, inclusive. Eligibility for HD-ISS Stage 2 Group (Parts A, B, C) requires (iv) A UHDRS-Independence Scale score of 100; (v) A TFC score of 13; and (vi) A normed prognostic index for HD (PINHD)score between 0.18 to 4.93. Eligibility for HD-ISS Mild Stage 3 Group (Parts D, E, F) requires (ix) A UHDRS TFC score of 11 or 12, or a UHDRS TFC score of 13 with an UHDRS IS score of <100. (vii) Women of childbearing potential (WOCBP): must agree to use highly effective methods of contraception during dosing and for 6 months after stopping the study medication. WOCBP are defined as women who are fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Highly effective contraception methods are defined as those that can achieve a failurePAT059999-WO-PCT -49- rate of less than 1% per year when used consistently and correctly and include those selected from (a) combined (estrogen and progestogen hormonal contraception associated with inhibition of ovulation, including contraception that is administered orally (WOCBP using oral contraception should have been stable on the same pill for a minimum of 3 months prior to Screening), intravaginally, or transdermally; (b) progestogen-only hormonal contraception associated with inhibition of ovulation, including contraception that is administered orally (WOCBP using oral contraception should have been stable on the same pill for a minimum of 3 months prior to Screening), via injectable, implantable, intrauterine device or intrauterine hormone-releasing system; or, (c) contraception associated with bilateral tubal occlusion, vasectomized partner or sexual abstinence. (viii) Sexually active and fertile males must use a condom during intercourse while taking study drug and for 6 months after stopping study drug, and should neither father a child nor donate sperm in this period. A condom is required to be used also by vasectomized men in order to prevent potential delivery of the drug via seminal fluid. Main Criteria for Exclusion: Individuals are not eligible to participate in this study if they have met or meet any of the following exclusion criteria: (i) Inability or unwillingness to swallow oral tablets; (ii) Receipt of an experimental agent within 90 days or 5 half-lives prior to Screening or anytime over the duration of this study, including RNA- or DNA-targeted HD specific investigational agents, such as antisense oligonucleotides, cell transplantation, or any other experimental brain surgery; (iii) Any history of gene therapy exposure for the treatment of HD; (iv) Participation in an investigational trial or investigational paradigm (such as exercise / physical activity, cognitive therapy, brain stimulation, etc.) within 90 days prior to Screening or anytime over the duration of this study; (v) Presence of an implanted deep brain stimulation device; (vi) Family history of early onset cataracts or presence of cataracts at Baseline using a cataract grading system (Lens Opacities Classification System III) exam; (vii) Brain and spinal pathology that may interfere with CSF homeostasis and circulation, increased intracranial pressure (including presence of a shunt for the drainage of CSF or an implanted CNS catheter), malformations, and / or tumors; (viii) Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study; (ix) At significant risk of suicide as measured by the Columbia SuicidePAT059999-WO-PCT -50- Severity Rating Scale (C-SSRS) with a moderate risk rating or higher score; (x) Risk of a major depressive episode, psychosis, or violent behavior as assessed by the Investigator; (xi) Any medical history of brain or spinal disease that would interfere with the lumbar puncture process or safety assessments; (xii) History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases; (xiii) Any medical history or condition that would interfere with the ability to complete the protocol-specified assessments (e.g., implanted shunt, conditions precluding MRI scans); (xiv) Antidepressant or benzodiazepine use, unless receiving a stable dose for at least 6 weeks prior to Screening and with a dose regimen that is not anticipated to change during the study; (xvi) history of illicit / illegal drug or alcohol use in the high risk category of risk drinking levels according to the World Health Organization for a duration of 1 month or longer as assessed by the Investigator; (xvii) Clinically significant medical condition, which in the opinion of the Investigator could adversely affect the safety of the subject or impair the assessment of study results; (xviii) Current significant renal impairment defined as estimated glomerular filtration rate <60 mL / min at Screening; (xvix) Current hepatic impairment resulting in elevated liver function test (aspartate transaminase, alanine transaminase, alanine phosphatase) at 3 times the upper limit of normal at Screening; (xx) Pregnancy, planning on becoming pregnant during the course of the trial, or currently breastfeeding; (xxi) Use of medications that are moderate or strong inhibitors of CYP3A4 within 1 week of Screening or medications that are moderate or strong inducers of CYP3A4 within 2 weeks of Screening or planned use of moderate or strong CYP3A4 inhibitor or inducer medications during the study period; and (xxii) A diagnosis of Juvenile-Onset Huntington’s Disease. Investigational and Reference Product, Dosage and Mode of Administration: Compound 1 tablets will be administered orally QD for 12 months. The two investigation product dosing arms will be 5mg and 10 mg for until the DSMB recommends initiation of a 20 mg dose as specified in the DSMB Charter. Compound 1 is a film-coated tablet dosage form for oral administration. Compound 1 active and matching placebo tablets are white to off-white round coated tablets that will be provided in 2 dosage strengths of 5- and 20-mg tablets. The placebo tablets contain the samePAT059999-WO-PCT -51- compendial excipients and is manufactured in the same tablet sizes with the same appearance to match the respective 5-mg or 20-mg tablets. Evidence for the safety of the selected doses is provided by the ongoing Phase 1 study and the results of the comprehensive preclinical toxicology program to date. In the Phase 1 study, single doses ranging from 5 mg to 135 mg and multiple doses for 14 days of 15 mg and 30 mg, and 30 mg for 19 days with 100 mg loading dose for the first 2 days have been safe and generally well tolerated. A target 30% to 50% decrease in mHTT is the range associated with decreased pathology and anticipated therapeutic benefit in patients. In the Phase 1 study, Compound 1-mediated HTT pre-mRNA splicing was dose dependent across all cohorts in both the SAD and MAD portions of the study. Mean decreases in full-length HTT mRNA levels of 40% and 60% were observed after 14 days of treatment with Compound 1 at 15 mg and 30 mg, respectively. On the basis of these clinical data, a PK-PD compartment model was used to simulate percentage of mRNA decreases (and thus the anticipated magnitude of HTT protein lowering) at additional potential clinical doses. At the selected doses of 5 mg, 10 mg, and 20 mg QD, the predicted percent full-length HTT mRNA decreases are 10%, 30%, and 50% respectively, which are within the target range of reduction from baseline. Nonclinical data in a bacterial artificial chromosome (BAC) transgenic mouse model of HD showed a strong correlation between levels of HTT pre-mRNA splicing and the degree of protein lowering following Compound 1 administration. It is therefore anticipated that the observed HTT mRNA changes will result in similar decreases in HTT protein levels at maximal steady state in patients with HD. Thus, based upon the totality of the clinical and nonclinical safety data to date, and the anticipated reduction in HTT mRNA and HTT protein derived from clinical data and pharmacokinetic-pharmacodynamic modeling, the doses of 5 mg, 10 mg and 20 mg are expected to be safe, well tolerated, and beneficial to subjects with HD. Reference Product, Dosage and Mode of Administration: Matching placebo tablets will be administered orally QD. Safety Criteria: Safety assessments will include observed TEAEs, clinical labs, vital signs, ECG, C-SSRS, slit lamp eye examination, and physical examination.PAT059999-WO-PCT -52- Efficacy Criteria: Assessment of efficacy will include analysis of: (i) Blood tHTT protein, (ii) vMRI (caudate volume), (iii) cUHDRS, and (iv) CSF mHTT protein. Safety Criteria: Safety assessments will include observed TEAEs, clinical labs, vital signs, ECG, C-SSRS, slit lamp eye examination, and physical examination. Exploratory Criteria: Assessment will include analysis of: (i) CSF mHTT protein, (ii) blood mHTT protein, vMRI (whole brain, putamen, and ventricular volume), (iii) UHDRS (except behavioral), (iv) PBA-s, (v) Opal wearable device, (vi) FuRST 2.0, (vii) blood HTT mRNA, (viii) plasma and CSF NfL, and (ix) CSF YKL-40. Enrichment Criteria Enrichment is defined as the prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population. Due to the highly variable population of patients with HD, the enrichment strategy for this Phase 2a study was intended to select for subjects who had preserved capacity for activities of daily living, work, finances, and self-care, but had reduced performance on motor and cognitive tests and were predicted to experience functional impact on activities of daily living within 3 years. The TMS and SDMT from the UHDRS will be assessed at Screening (along with CAG repeat length and age) and used to identify this population via a validated HD prognostic index for pre-manifest HD patients. The Huntington’s disease prognostic index (PIHD) or its normed version (PINHD) can be used to predict likelihood of HD progression, with higher scores indicating greater risk of functional decline. Natural history survival curves generated using the PIHD show the disease trajectory in patients with a particular PIHD score. The PINHD score allows researchers to predict disease progression in a studied population with a high degree of certainty. Historically, disease progression was commonly indexed by the CAG-Age Product (CAP), which is a type of burden score of age and CAG expansion that has several variants. When CAP is supplemented with the TMS and SDMT from the UHDRS, predictive likelihood of HD progression increases. Using thesePAT059999-WO-PCT -53- enrichment criteria, a group of subjects with HD and no functional decline (measured via the TFC and IS) can be identified and changes in levels after treatment can be measured. This group is likely to experience decline without HTT lowering treatment as it has been found that earlier stages of HD are marked by increases in mHTT levels in CSF compared to controls. At Screening, subjects’ cognitive and motor functions will be assessed by SDMT and TMS scores, respectively. Enrolled subjects who qualified for the Stage 2 group presented with no functional decline as assessed by the TFC and IS. Subjects in the Stage 2 group were included in the study based on the calculation of PINHD scores as calculated by the IRT prior to randomization. Subjects with PINHDscores between 0.18 and 4.93 inclusive were eligible for enrollment into the Stage 2 group in the study. The following formula will be utilized to calculate the PINHDscore: PIHD=51x(TMS)+(-34)xSDMT+7x (age)x (CAG-34). The PIHD score is converted to a normalized score using the following conversion: PINHD=(PIHD-883) / 1044 The ENROLL HD database (periodic data update 5) was utilized to identify the 0.18 to 4.93 range of PINHD scores for inclusion in the study. Pharmacokinetics: Pharmacokinetic assessment will include plasma Ctrough(Visits 3 through 8). Accumulation ratio will be calculated and reported in plasma (Visits 3 through 5) and CSF (Visits 5 through 8). Statistical Methods: A repeated measure analysis model (repeat on visit) was used to compare each dose with placebo for blood HTT protein levels. The model included treatment, visit, treatment by-visit interaction and baseline blood tHTT, CAG, age, and CAG by age interaction as covariates. Nominal p values and 95% confidence interval for each pairwise comparison at Month 3 (active versus placebo) will be provided. The model will include PINHD as a stratification factor. The same analysis used for blood HTT protein will be used for blood HTT mRNA. Dose-response relationships will be explored. Demographic and baseline characteristics, disposition, safety, and efficacy endpoints will be summarized descriptively by dose group. Statistical models will bePAT059999-WO-PCT -54- applied to understand the relationship between UHDRS and its components to blood and CSF assessments. Phase 2a Study Results At Week 12 (Month 3), treatment with Compound 1 resulted in dose-dependent lowering of HTT mRNA protein levels in blood cells (FIG. 1A), treatment with Compound 1 demonstrated desired CSF exposure with higher concentrations of free drug in the CSF than plasma, treatment with Compound 1 was found to be well tolerated with no treatment-related serious adverse events and no reports of peripheral neuropathy, and CSF Nfl levels remained stable after 12 weeks of treatment with no treatment-related spikes. The patient characteristics at Month 12 of the clinical trial is provided in Table A TABLE A Compound 1 Compound 1 Placebo Overall Category 5mg 10mg %) %)At Month 12, there was evidence of durability of effect, safety and dose-dependent benefit on clinical measures associated with Compound 1 treatment. Treatment with Compound 1 was found to provide dose-dependent and durable lowering of HTT protein levels in blood cells (FIG. 1B), treatment with Compound 1 demonstrated dose-depending lowering of CSF mHTT levels (FIG. 2) consistent with protein lowering in the blood, treatment with Compound 1 demonstrated dose-dependent trends of improvement on key clinical measures including TMS (FIG. 5B), cUHDRS (FIG. 6A), and TFC (FIG. 6B), and treatment with Compound 1 was found to be well tolerated (Table B) with no treatment-related CSF Nfl spikes (FIGs. 3 and 4). In addition, the change in striatum brain volume from Baseline to Month 12 was consistent across treatment groups (FIG. 5A).PAT059999-WO-PCT -55- TABLE B Category Placebo Compound 1 Compound 1 5mg 10mg (N=10)An additional cohort of 81 subjects (Additional Week 12 subjects) were studied. The patient characteristics of the Additional Week 12 Subjects is provided in Table C. Placebo Compound 1 Compound 1 Overall 5mg 10mg 5) )At Week 12, Compound 1 was well tolerated, with no dose-limiting side effects. Treatment with Compound 1 was found to provide dose-dependent lowering of mHTT mRNA protein levels in blood cells (FIG. 7). EXAMPLE II: PHASE 2B CLINICAL STUDY PROTOCOL A Phase 2b, Double-Blind, Randomized Extension Study to Evaluate the Long-Term Safety and Efficacy of Compound 1 in Participants With Huntington’s Disease.PAT059999-WO-PCT -56- Primary Objectives:

[0324] Evaluate the long-term safety of Compound 1 in participants with Huntington’s disease (HD) and the pharmacodynamic effects of Compound 1 through the reduction in blood total huntingtin (tHTT) levels. Secondary Objectives:

[0325] Assess the long-term effects of Compound 1 on (i) change in caudate volume by volumetric magnetic resonance imaging (vMRI), (ii) change in composite Unified Huntington’s Disease Rating Scale (cUHDRS), and (iii) on mutant Huntingtin (mHTT) protein levels in cerebrospinal fluid (CSF) and blood. Exploratory Objectives: Determine the long-term effects of Compound 1 on (i) change in whole brain and putamen volume via vMRI; (ii) change in ventricular volume via vMRI , in participants with HD as assessed by time to disease; (iii) on biomarkers including Huntingtin (HTT) mRNA, neurofilament light chain (NfL), and YKL-40; and (iv) on change in clinical scales of Unified Huntington’s Disease Rating Scale (UHDRS), Problem Behaviors Assessment (PBA-s), Timed Up and Go (TUG), 2- minute walk distance, postural sway, and Functional Rating Scale (FuRST) 2.0 questionnaire. Pharmacokinetic Objective: Evaluate the concentration of Compound 1 in subjects with HD. Clinical Endpoints: Primary Safety Endpoints: Evaluate the safety profile as characterized by treatment-emergent adverse events (TEAEs), laboratory abnormalities, vital signs, physical examination, Columbia Suicide Severity Rating Scale (C-SSRS), Total Neuropathy Score – Clinical (TNSc), slit lamp eye examination, and electrocardiograms (ECG). Primary Efficacy Endpoint: Evaluate blood tHTT protein levels over time. Secondary Endpoints:PAT059999-WO-PCT -57- (i) Change in caudate volume as assessed via vMRI over time; (ii) Change in cUHDRS scores over time; (iii) CSF mHTT protein over time; and (iv) blood tHTT protein levels over time. Exploratory Endpoints: (i) Change in whole brain and putamen volume as assessed by vMRI over time; (ii) Change in ventricular volume as assessed by vMRI over time; (iii) Time to disease progression defined as time from Stage 2 to Mild Stage 3 in participants with Stage 2 HD or the time from Mild Stage 3 to Moderate Stage 3 in participants with Stage 3 HD; (iv) Evaluate blood HTT mRNA levels over time; (v) Evaluate plasma and CSF NfL protein levels over time; (vi) Evaluate CSF YKL-40 levels over time; (vii) Evaluate UHDRS Total Functional Capacity (TFC) subscore over time; (viii) Evaluate other UHDRS subscores, including Total Motor Score (TMS), Symbol Digit Modalities Test (SDMT), and Independence Scale (IS) over time; (ix) Evaluate the short form of the PBA-s over time; (x) Evaluate Opal wearable accelerometer assessment TUG, 2-minute walk distance, and postural sway over time; and (xi) Evaluate the FuRST 2.0 questionnaire over time. Pharmacokinetic Endpoint Calculate steady-state exposure of Compound 1. Study Design / Methodology: The double-blind Phase 2b study evaluates the long-term safety and efficacy of Compound 1 in participants with HD. Participants who completed the Treatment Period in the Phase 2a Study referenced in Example I, fulfill the enrollment criteria, and choose to enroll in this extension study will undergo baseline evaluations and be assessed for 30 additional months. All participants received active Compound 1 in this extension study. Participants who received Compound 1 in the Phase 2a Study referenced in Example I continued at the same dose level they received in that study in a blinded fashion (5, 10, or 20 mg). Participants who received placebo in the Phase 2a Study referenced in Example I were allocated to a Compound 1 dose level according to the same dosing group in which they were previously randomized (5, 10, or 20 mg). A DSMB will also be utilized in this study to closely monitor the safety of participants. Participants visited the clinic approximately 1, 2, and 3 months after the start of the study and then approximately every 3 months thereafter to undergo study-related procedures and safetyPAT059999-WO-PCT -58- assessments. Upon completion of treatment, participants underwent Safety Follow-Up Visits on Months 25, 28, and 30. Planned Number of Patients: Approximately 250 adult male and female subjects will be enrolled. Inclusion Criteria:

[0326] Individuals eligible to participate in this study include those who meet all of the following inclusion criteria: (i) Ambulatory male or female patient aged 25 years and older, inclusive, who completed the Treatment Period in the Phase 2a Study referenced in Example I; (ii) Participant (or legally authorized representative) is willing and able to provide informed consent and comply with all protocol requirements; (iii) Women of childbearing potential (WOCBP): must agree to use highly effective methods of contraception during dosing and for 6 months after stopping the study medication.

[0327] WOCBP are defined as women who are fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Highly effective contraception methods are defined as those that can achieve a failure rate of less than 1% per year when used consistently and correctly and include those selected from (a) combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, including contraception that is administered orally (WOCBP using oral contraception should have been stable on the same pill for a minimum of 3 months prior to Screening), intravaginally, or transdermally; (b) progestogen-only hormonal contraception associated with inhibition of ovulation, including contraception that is administered orally (WOCBP using oral contraception should have been stable on the same pill for a minimum of 3 months prior to Screening), via injectable, implantable, intrauterine device or intrauterine hormone-releasing system; or, (c) contraception associated with bilateral tubal occlusion, vasectomized partner or sexual abstinence.PAT059999-WO-PCT -59-

[0328] (iv) Sexually active and fertile males must use a condom during intercourse while taking study drug and for 6 months after stopping and should neither father a child nor donate sperm in this period. A condom is required to be used also by vasectomized men in order to prevent potential delivery of the drug via seminal fluid. Main Criteria for Exclusion: Individuals are not eligible to participate in this study if they have not previously completed the Treatment Period in the Phase 2a Study referenced in Example I. Study Intervention, Dosage, and Mode of Administration:: Participants who received Compound 1 in the Phase 2a Study referenced in Example I continued at the same dose level they received in that study in a blinded fashion (5, 10, or 20 mg). Participants who received placebo will be allocated to a Compound 1 dose level according to the same dosing group in which they were previously randomized (5, 10, or 20 mg). The study duration is 30 months, including a 24-month treatment phase and 6 months of follow-up after the last dose. Statistical Methods: Demographic and baseline characteristics, disposition, safety, and efficacy endpoints were summarized descriptively by dose group and by timepoint. Exploratory analyses was performed to understand the relationship between UHDRS components to blood and CSF biomarker assessments. For the primary endpoint (blood tHTT protein levels), a mixed model for repeated measures (MMRM) model will be fit using a random intercept and a random slope of change per timepoint. The slope will be compared between treatment groups to explore dose-response relationships. The estimated difference in the change at end of the study will also be provided to determine long-term treatment effect. A similar method will be used for blood and CSF mHTT protein. It will be appreciated that, although specific aspects of the disclosure have been described herein for purposes of illustration, the disclosure described herein is not to be limited in scope by the specific aspects herein disclosed. These aspects are intended as illustrations of several aspects of the disclosure. Any equivalent aspects are intended to be within the scope of this disclosure.PAT059999-WO-PCT -60- Indeed, various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the the foregoing description, which modification also intended to be within the scope of this disclosure. Sample Size Determination: The sample size calculation was based on the number of participants expected to complete 12 months of treatment in the Phase 2a Study referenced in Example I, with the intention of allowing each completing participant the opportunity to participate in this extension study. Therefore, approximately 250 participants was enrolled. Phase 2b Study Results

[0329] The primary objective of the Phase 2b, double-blind randomized, study is to evaluate the long-term safety and pharmacodynamic effects of Compound 1 in subjects with Huntington’s Disease.

[0330] The primary objective is assessed by the occurrence of treatment-emergent adverse events (TEAEs); abnormalities in laboratory values, vital signs; physical examination; C-SSRS; TNSc; slit lamp eye examination, and physical examination; and, blood total huntingtin protein (HTT) levels over time.

[0331] The secondary objectives of the study was to assess the long-term effects of Compound 1 on change in caudate volume by volumetric magnetic resonance imaging (vMRI), (ii) change in composite Unified Huntington's Disease Rating Scale (cUHDRS), and (iii) on mutant Huntingtin (mHTT) protein levels in cerebrospinal fluid (CSF) and blood.

[0332] The exploratory objectives of the study was to assess the long-term effect of Compound 1 on change in whole brain and putamen volume via vMRI, assess the long-term effect of Compound 1 on change in ventricular volume via vMRI, evaluate the long-term effect in participants with HD as assessed by time to disease; determine the long-term effect of Compound 1 on biomarkers including Huntingtin (HTT) mRNA, neurofilament light chain (NfL), and YKL-40; and (iv) assess change in clinical scales of Unified Huntington’s Disease Rating Scale (UHDRS), Problem Behaviors Assessment (PBA-s), Timed Up and Go (TUG), 2-minute walk distance, postural sway, and Functional Rating Scale (FuRST) 2.0 questionnaire.PAT059999-WO-PCT -61- The pharmacokinetic objectives of the study was to evaluate the concentrations of Compound 1 in participants with HD. It will be appreciated that, although specific aspects of the disclosure have been described herein for purposes of illustration, the disclosure described herein is not to be limited in scope by the specific aspects herein disclosed. These aspects are intended as illustrations of several aspects of the disclosure. Any equivalent aspects are intended to be within the scope of this disclosure. Indeed, various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description, which modification also intended to be within the scope of this disclosure. All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

PAT059999-WO-PCT -62- We claim:

1. A method for treating or ameliorating Disease (HD) in a subject having a cytosine-adenine-guanine (CAG) repeat length from 40 to 50 of the huntington (HTT) gene, comprising administering to the subject a therapeutically effective amount of 2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yl)phenol, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the subject has a normed version of the Huntington’s disease prognostic index (PINHD) score between 0.18 and 4.93 before beginning treatment.

3. The method of claim 1, wherein the subject has a Unified Huntington’s Disease Rating Scale- Total Functional Score (UHDRS-TFC) score of 11, 12, or 13 before beginning treatment.

4. The method of claim 1, wherein the subject has a Unified Huntington’s Disease Rating Scale- Independence Scale (UHDRS-IS) of 100 before beginning treatment.

5. The method of claim 1, wherein 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol, or a pharmaceutically acceptable salt thereof is administered orally at a dose of about 5 mg per day, about 10 mg per day, or about 20 mg per day.

6. A method of treatment for slowing the decline of motor function, cognitive function, and global function associated of Huntington's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yl)phenol, or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the motor function, cognitive function, and global function is measured by the Composite Unified Huntington's Disease Rating Scale (cUHDRS).

8. A method of improving, maintaining or reducing impairment of functional capacity of a subject afflicted with Huntington’s disease (HD), comprising administering to subject a therapeutically effective amount of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol, or a pharmaceutically acceptable salt thereof.PAT059999-WO-PCT -63- 9. The method of claim 8, wherein the functional capacity is measured by the Unified Huntington's Disease Rating Scale-Total Capacity (UHDRS-TFC).

10. A method of improving, maintaining or reducing motor function impairment of a human patient afflicted with Huntington’s disease  (HD), comprising administering to subject atherapeutically effective amount of 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H- [1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol, or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the motor function impairment is measured by the Unified Huntington’s Disease Rating Scale-Total Motor Score (UHDRS-TMS), the Unified Huntington’s Disease Rating Scale-modified Motor Score (UHDRS-mMS), the Unified Huntington’s Disease Rating Scale (UHDRS)-Chorea score, the Unified Huntington’s Disease Rating Scale (UHDRS)-Dystonia score, Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), hand movement score, gait and balance score, Quantitative motor (Q-Motor) assessment or by timed up and go (TUG) assessment (WO2020250234).

12. A method of reducing mHTT protein levels in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yl)phenol, or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein the mHTT protein levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid.

14. A method of stabilizing or decreasing the concentration of neurofilament light chain (NfL) polypeptide of a subject having previously been diagnosed with Huntington’s Disease (HD), comprising administering to the subject a therapeutically effective amount of 2-[3-(2,2,6,6- tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2- yl)phenol, or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the NfL levels is measured in blood, in cerebrospinal fluid, or in blood and in cerebrospinal fluid.

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