TABLET FOR USE IN TREATING HUNTINGTON'S DISEASE AND METHOD OF MAKING THE SAME

FIELD OF THE INVENTION

The invention generally relates to immediate release pharmaceutical tablets of a small molecule compound for use in treating Huntington's Disease and methods of making the same.

BACKGROUND

Huntington's Disease (HD) is a rare inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. The disorder results in behavioral, cognitive, and motor impairments. These symptoms progressively reduce an individual's quality of life, and ultimately lead to death within 15 to 25 years of overt clinical motoric onset. Each child of a parent with a mutation in the huntingtin gene has a 50% chance of inheriting the mutation. It is estimated that around one person in 10,000 carries the mutated huntingtin gene. Current HD therapies manage the severity of the symptoms, but there are currently no therapeutics approved that slow the progression of the disease.

HD is caused by CAG repeat expansions in HTT and is characterized by motor, cognitive, psychiatric and functional capacity decline. The CAG trinucleotide repeat expansion results in a mutant huntingtin protein (mHTT), which is associated with neural dysfunction and ultimately death.

The number of CAG repeats in the HTT gene ranges from 6 to 35 in healthy individuals. Disease penetrance is seen to be reduced for individuals carrying 36 to 39 CAG repeats, however those with 40 or more CAG repeats are almost certain to develop the disease. As described in European Journal of Neurology, 2017, 24-34, clinical diagnosis of HD is based on: confirmed family history or positive genetic test (i.e. confirmation of CAG repeat expansion ≥36), and onset of motor disturbance as defined by the Unified Huntington's Disease Rating Scale (UHDRS), with a total motor score (TMS) diagnostic confidence score (DCS), which ranges from 0 (no motor abnormalities suggestive of HI)) to 4 (motor abnormalities ≥99°,0 likely to be due to HD), wherein a score of 4 defines “motor onset” or “manifest” HD.

Typically, age of onset (i.e. once the DCS reaches 4) ranges between 30 to 50 years and average duration of survival after clinical diagnosis is 15 to 20 years. Currently, after onset, loss of “function” (i.e. assessment of functional capacities), rather than motor signs, determines disease stage (see, e.g. Neurology, 1979, 29, 1-3; or Neurology, 1981, 31, 1333-1335). The Total Functional Capacity (TFC) scale (see, e.g. Movement Disorders, 1996, 11, 136-142) is a component of the UHDRS, where the level of independence of a person with HD ranges from 0 (fully dependent for all care) to 13 (fully independent). 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 (TFC), III) is divided into stages 1 to 5 of disease progression. The categorization of HD, based on TFC score (also referred to as Shoulson and Fahn stages), are also described as early stage of 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).

An international application published as WO2020/005873 identified a genus of compounds that can be used in the treatment of HD, methods of making the same and pharmaceutical formulations of the same. It also provided data showing that the compounds inhibited endogenous Huntington protein (HTT), in an IC₅₀, assay. One of the compounds disclosed in that application as a particularly potent inhibitor of HTT, 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 has since been found to be effective in reducing human HTT production in vivo in transgenic mouse models of Huntington's disease (results not yet published). At present, only symptomatic treatments are available. Thus, to date, there is no small molecule therapy available to slow the progression of HD. Accordingly, there is a need for small molecule disease-modifying therapies for HD (i.e. therapeutic options that can slow disease progression).

SUMMARY OF THE INVENTION

In one aspect the invention relates to a tablet comprising, as an active ingredient, 2-[3-(2,2,6,6-tetramethylpiperidin-4-yl)-3H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl]-5-(2H-1,2,3-triazol-2-yl)phenol (hereinafter Compound 1), or a pharmaceutically acceptable salt thereof, wherein Compound 1 is present in an amount of from about 1% to about 30% by weight of the total weight of the tablet, an intragranular excipient, and an extragranular excipient,

- wherein the intragranular excipient comprises microcrystalline cellulose and a diluent, wherein the ratio of microcrystalline cellulose to diluent is about 1:1 to about 1:4 and microcrystalline cellulose is present in an amount of about 15% to about 25% by weight of the total weight of the tablet, a disintegrant in an amount of about 1% to 3% of the total weight of the tablet, and povidone in an amount of about 1% to about 5% by weight of the total weight of the tablet, and
- wherein the extragranular excipient comprises an additional amount of the diluent and an additional amount of the disintegrant.

In one aspect Compound 1 is present in an amount of about 5% to about 25% of the total weight of the tablet. In another aspect Compound 1 is present at about 10% of the total weight of the tablet.

In one aspect, the amount of Compound 1 in the tablet is in a range from 1 mg to 200 mg.

In another aspect, the amount of Compound 1 in the tablet is in a range from 1 mg to 100 mg.

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

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

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

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

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

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

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

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

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

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

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

In one aspect, the diluent is lactose monohydrate.

In one aspect, the disintegrant is croscarmellose sodium.

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

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

In one aspect, the disintegrant is croscarmellose sodium.

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

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

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

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

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

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

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

The invention also relates to a method of making the tablet comprising wet granulating the extragranular excipients, drying the resulting intragranular blend, mixing the extragranular excipient with the intragranular excipient, and compressing the resulting mixture to form a tablet.

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

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

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

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of individual plasma concentrations of Compound 1 over time after oral administration of a Compound 1 suspension formulation (Batch 21) in 0.5% hydroxypropyl methyl cellulose (HPMC) in water at 30 mg in Male Cynomolgus Monkeys (Leg 1)

FIG. 2 is a plot of mean plasma concentrations of Compound 1 over time after oral administration of a Compound 1 suspension (Batch 21) in 0.5% HPMC in water at 30 mg in Male Cynomolgus Monkeys (Leg 1).

FIG. 3 is a plot of individual plasma concentrations of Compound 1 over time after oral administration of Tablet Formulation A (dry granulation Batch 15) at 30 mg in Male Cynomolgus Monkeys (Leg 2).

FIG. 4 is a plot of mean plasma concentrations of Compound 1 over time after oral administration of Tablet Formulation A (dry granulation Batch 15) at 30 mg in Male Cynomolgus Monkeys (Leg 2).

FIG. 5 is a plot of individual plasma concentrations of Compound 1 over time after oral administration of Tablet Formulation B (wed granulation Batch 20) at 30 mg in Male Cynomolgus Monkeys (Leg 3).

FIG. 6 is a plot of individual plasma concentrations of Compound 1 over time after oral administration of Tablet Formulation B (wet granulation Batch 20) at 30 mg in Male Cynomolgus Monkeys (Leg 3).

FIG. 7 is dissolution profiles (% dissolved Compound 1 over time) of 5 mg tablets produced from Batch 23 before and after storage at 2 weeks at 50° C. or 1 month at 40° C./75% relative humidity.

FIG. 8 is dissolution profiles (°% dissolved Compound 1 over time) of 50 mg tablets produced from Batch 23 before and after storage at 2 weeks at 50° C. or 1 month at 40° C./75% relative humidity.

FIG. 9 shows a dose-dependent reduction in HTT mRNA in whole blood taken from healthy volunteers participating in a Single Ascending Dose (SAD) and Multiple Ascending Dose study of a Phase I clinical trial.

FIG. 9A shows a lowering of HTT mRNA in whole blood taken from healthy volunteers in the SAD cohort where splicing was evaluated 24 hours after they were administered a one day, single dose of either placebo, 5 mg, 15 mg, 45 mg, 90 mg, or 135 mg of Compound 1.

FIG. 9B shows the lowering of HTT mRNA in whole blood taken from healthy volunteers in the MAD cohort dosed daily with either placebo, 15 mg or 30 mg of Compound 1 for 14 days. HTT splicing was then evaluated by RT-PCR 6 hours after administration of Compound 1 on day 14.

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

FIG. 11 shows graphs that model the rate of HTT mRNA (FIG. 11A) and HTT protein (FIG. 11B) decay based on their half-lives and then predicted the time to reach steady state after Compound 1 treatment at 30 mg daily dose. For HTT mRNA, the half-life is estimated to be about 24 hours. FLT mRNA in FIG. 11A reaches steady state after approximately 5 days. For HTT protein, the half-life is estimated to be 5-7 days and consequently HTT protein steady state levels should take about 6 weeks from the beginning of treatment.

FIG. 12 compares the trajectory of HTT mRNA (FIG. 12A) and protein (FIG. 12B) lowering seen in Multiple Ascending Dose Study with those values predicted from the half-life of HTT mRNA and protein as shown in FIG. 11.

FIG. 13 shows that Compound 1 crosses the Blood Brain Barrier in non-human primates (FIG. 13A) and in humans (FIG. 13B).

FIG. 14 is a plot of % of baseline of HTT RNA measured over time in whole blood of human subjects administered a placebo or a single dose of 90 mg of Compound 1, as described in the Single Ascending Dose (SAD) study in Part 1 of Example 10. The results show that the HTT splicing effect of Compound 1 is reversible and persists for 72 hours post cessation of treatment.

FIG. 15 is a plot of % baseline of HTT RNA measured over time in the whole blood of human subject administered a placebo or 15 or 30 mg of Compound 1, as described in the Multiple Ascending Dose (MAD) study described in Part 2 of Example 10. HTT splicing was monitored after the final dose at day 14, calculated as % HTT remaining from baseline (pre-dose day 0).

FIG. 16 is a bar graph showing the huntingtin mRNA and protein levels in whole blood from MAD cohort 2.3 (30 mg administered for 21 days with 100 mg loading dose (LD) for 2 days), as described in Example 10, as a percent of baseline, after administration of vehicle or compound 1 to a human, 24 hours after the last dose. The results show HTT mRNA reduction reached steady state. Longer dosing was required for HTT protein levels to reach maximal steady state reduction.

DETAILED DESCRIPTION OF THE INVENTION

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.

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. Definitions

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.

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.

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, the term “about” is used to modify a numerical value above and below the stated value by a variance of 1%.

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.

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.

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.

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).

The term “excipient” as used herein means any substance, not itself a therapeutic agent, used as a carrier or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of the dose unit of the composition into a discrete article, such as a capsule or tablet suitable for oral administration. Excipients include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, surfactants, lubricants, glidants, surface modifying agents, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve the appearance of the composition.

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.

The term “intragranular” as used herein refers to ingredients that are incorporated into a formulation prior to granulation, i.e. ingredients that are located internally in or part of the granule structure.

The term “extragranular” as used herein, refers to ingredients that are incorporated into a formulation after granulation, i.e. ingredients that are located externally to the granule structure.

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

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)].

The terms “pre-manifest HI)” 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 stabilshed, 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)].

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 rate of progression of Huntington's disease pathophysiology (e.g. treatment effects compared to placebo or compared to natural history control group; e.g. according to standard scales, such as clinical scales, herein above or below, or according to neuroimaging measures).

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.

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.

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.

The terms “slowing progression of HD”, “slowing progression of Huntington's disease”, “to slow the progression of FED” 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).

The term “reducing the rate of progression”, as used herein, refers, for example, to increasing time for progression of stage of HI) (e.g. compared to placebo).

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)].

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)].

The term “slowing the progression of Huntington's disease pathophysiology”, as used herein, refers to reducing the rate of progression 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).

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.

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).

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).

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).

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 Test B, One Touch Stockings, Paced Tapping, Emotion Recognition Test, Hopkins Verbal Learning Test); e.g. in Movement Disorders, 2014, 29 (10), 1281-1288).

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).

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).

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).

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.

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 functional capacity may be assessed, for example, according to standard scales, such as clinical scales (e.g. UHDRS functional assessment scale and independence scale, and UHDRS Total Functional Capacity Scale e.g. in Movement Disorders, 1996, 11, 136-142).

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).

The terms “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.

The terms “Unified Huntington 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.

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

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 1 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.

The terms “HD stage 2”, “HD stage II”, “Huntington's disease stage 2”, “Huntington's disease stage II”, “stage 2 of Huntington's disease” 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.

The terms “HD stage 3”, “HD stage III”, “Huntington's disease stage 3”, “Huntington's disease stage III”, “stage 3 of Huntington's disease” or “stage III 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.

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.

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 support in daily activities from professional nursing care; typically 11 to 26 years from onset of Huntington's disease.

The terms “early FED”, “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.

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 no 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.

The terms “advanced HD”, “advanced Huntington's disease”, “advanced stage of HD”, “advanced stage of Huntington's disease”, “late FID” 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 HI)”, “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.

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 positive genetic test (i.e. confirmation of CAG repeat expansion 2.36 (SEQ ID NO: 22)); and onset of symptoms by age<21 years].

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 (SEQ ID NO: 22))} and who has onset of symptoms by age<21 years.

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 (SEQ ID NO: 22)) and clinical diagnosis) and who is aged <18 years.

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.

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”.

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.

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) may also vary from patient to patient based, for example, on the particular patient being treated (e.g, Stage I HD patient).

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.

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.

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 the tablet in a range of from 1 mg to 100 mg, administered once a day.

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

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

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

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

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

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

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

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

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

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.

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.

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.

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 each dose is administered on separate days each week at regular intervals in a range of from 48 to 72 hours.

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.

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.

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

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.

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

The term “patient”, as used herein, refers to a subject who is diseased and would benefit from the treatment.

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.

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 of Compound 1 that, when administered to a subject, is effective to at least partially ameliorate a condition, or a disorder or a disease.

The term “one or more” refers to either one or a number above one (e.g. 2, 3, 4, 5, etc.).

2. Compound

An active ingredient of the tablet compositions disclosed herein is 2-[3-(2,2,6,6-tetramethyl piperidin-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).

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