Pridopidine for treating juvenile huntington's disease

Abstract

Provided herein a method of treating Juvenile Huntington disease in a subject in need thereof comprising orally administering a pharmaceutical composition comprising pridopidine and / or its analog or a pharmaceutically acceptable salt thereof.

Description

[00104] In some embodiment, the composition for use in the methods of this invention comprises pridopidine or pharmaceutically acceptable salt thereof in combination with at least one of its analog compounds 1-8, or a pharmaceutically acceptable salt thereof: SOjCHj x' i                          so?ch3 SOjCHs                              y       X X                           < N x ZX. Jx h °h x (Compound 1),                ’            (Compound .....x' ......SOj                            SQeCHj Cu Hi? L A. k A                     I N ' " pr ' Pr (Compound 3),                     (Compound 4), SOjCHs                          SC-Ox ■ 'T '"'j                               7    1 o L N    X                             k   N' .--. '' (Compound 6),          x..-+ '(Compounds), 2), wherein the weight ratio between pridopidine or pharmaceutically acceptable salt thereof and at least one of compounds 1-8 or pharmaceutically acceptable salt thereof is in the range of 1:0.00001 to 1:0.001. In other embodiments, the weight ratio between pridopidine or pharmaceutically acceptable salt thereof and at least one of compounds 1-8 or pharmaceutically acceptable salt thereof is in the range of 1:0.0001 to 1:0.1. In other embodiments, the weight ratio between pridopidine or pharmaceutically acceptable salt thereof and at least one of compounds 1-8 or pharmaceutically acceptable salt thereof is in the range of 1:0.005 to 1:0.1. In other embodiments, the weight ratio between pridopidine or pharmaceutically acceptable salt thereof and at least one of compounds 1-8 or pharmaceutically acceptable salt thereof is in the range of 1:0.0001 to 1:0.005.

[00105] In some embodiment, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 1 or pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine in combination with compound 1 or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 2 or pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 3 or pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 4 or pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 5 or pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 6 or pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 7 or pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the method of this invention comprises an amount of pridopidine or pharmaceutically acceptable salt thereof in combination with at least compound 8 or pharmaceutically acceptable salt thereof.

[00106] In other embodiments, the analog compounds 1-8 of pridopidine and their methods of preparation may be found in U.S. Patent Nos. 10,130,621 and 10,406,145 the entire content of each of which is hereby incorporated by reference.

[00107] In an embodiment, the pharmaceutically acceptable salt of pridopidine comprises the hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p-sulphonate salt.

[00108] In an embodiment, the pharmaceutically acceptable salt of compounds 1-8 comprises the hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p-sulphonate salt. Pharmaceutical Compositions

[00109] While the compounds for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredients, optionally in the form of physiologically acceptable salts, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[00110] In an embodiment, the invention provides pharmaceutical compositions comprising the active compound, and / or its analog or pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and / or prophylactic ingredients know and used in the art. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

[00111] The pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy. Preferred routes of administration include oral administration, in particular in tablet, in capsule, in drage, in multiparticulate, in beads, in granules, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical composition of the invention can be manufactured by the skilled person by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.

[00112] Further details on techniques for formulation and administration may be found in the latest edition of Remington’s Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

[00113] As used herein, “effective” as in an amount effective to achieve an end means the quantity of a component that is sufficient to yield an indicated therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit / risk ratio when used in the manner of this disclosure. For example, an amount effective to treat a movement disorder. The specific effective amount varies with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.

[00114] As used herein, an amount of pridopidine as measured in milligrams refers to the milligrams of pridopidine (4-[3-(methylsulfonyl) phenyl]-l-propyl-piperidine) present in a preparation, regardless of the form of the preparation. For example, a unit dose containing “90 mg pridopidine” means the amount of pridopidine in a preparation is 90 mg, regardless of the form of the preparation. Thus, when in the form of a salt, e.g., pridopidine hydrochloride, the weight of the salt form necessary to provide a dose of 90 mg pridopidine would be greater than 90 mg due to the presence of the salt.

[00115] As used herein to “treat” or "treating" encompasses, e.g., reducing a symptom, inducing inhibition, regression, or stasis of the disorder and / or disease. As used herein, “inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and / or disease complication in the subject.

[00116] This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. EXAMPLES Example 1: A clinical study evaluating the pharmacokinetics, safety, and efficacy of pridopidine in Juvenile HD patients

[00117] A double-blind, placebo-controlled trial to evaluate the pharmacokinetics, safety, and efficacy of pridopidine is performed in children and adolescents aged 2-17. Inclusion criteria includes UHDRS TMS > 10. A total of 24-30 male and female adolescent and childhood-onset JHD patients (2 years and older) are planned to be enrolled - up to 24 adolescents (aged 10-17) and at least 6 childhood JHD patients (aged 2-10).

[00118] The study is conducted in two sequential parts. Part 1 (4 weeks) is conducted to establish the dose to be used in Part 2 (52 weeks).

[00119] A single dose level of pridopidine is administered orally twice daily. A dose level which is expected to yield, in pediatric JHD patients, an exposure of Cmax between 200800 ng / ml and / or AUC0-24 of 1000-10,000 hxng / ml.

[00120] Part 1 comprises 6 patients treated for a total of 4 weeks (based on dose estimated in the PopPK model) (2 weeks up titration once daily (qd) followed by 2 weeks of twice-daily (bid) (full daily dose). Once all 6 patients have completed their participation in Part 1 (and reached steady state on the full dose), and data from their 4-week PK profile have been collected, PK analysis is performed to confirm the appropriate dose to be used in Part 2.

[00121] In Part 2 of the study, subjects are enrolled after PK analysis of Part 1 is completed. Part 2 patients are treated at the dose level confirmed after the Part 1 PK analysis.

[00122] The safety and tolerability of pridopidine are assessed throughout the study via ongoing collection of adverse events, and evaluation of Safety laboratory assessments, Columbia Suicide Severity Rating Scale (C-SSRS) and ECG monitoring at specific visits. Primary endpoint:

[00123] To evaluate the effect of pridopidine on motor function using Unified Huntington Disease Rating Scale (UHDRS)-Total Motor Score (TMS). UHDRS-TMS is evaluated at baseline (Day 1) and at Weeks 4, 13, 26 and 52.

[00124] For all subjects, PK analyses are performed at baseline, and at each study visit (2 hours post-dose). Secondary endpoints:

[00125] To evaluate the effect of pridopidine on the disease biomarker plasma neurofilament light (NfL) protein. NfL is evaluated at baseline and at Weeks 13, 26 and 52.

[00126] To evaluate the effect of pridopidine on imaging parameters using Volumetric magnetic resonance imaging (MRI) of the caudate and putamen, Functional MRI (fMRI), and Metabolic imaging using 18F-fluoro-2-deoxy-D-glucose (18FDG)-PET. Imaging is performed at baseline and at Weeks 26 and 52.

[00127] To evaluate the effect of pridopidine on motor function using Quantitative motor (Q-Motor) finger tapping (Digitomotography).

[00128] To evaluate the effect of pridopidine on cognition using the Leiter International Performance Scale and the Peabody Picture Vocabulary Test.

[00129] Seizure frequency and duration.

[00130] Pediatric Quality of Life Inventory (PedsQL).

[00131] To evaluate the effect of pridopidine on psychiatric measures using Problem Behaviors Assessment - Short Form (PBA-s).

[00132] To assess the safety and tolerability of pridopidine over a 52-week treatment period via ongoing collection of adverse events (AEs) and Safety and tolerability of pridopidine are assessed throughout the study via ongoing collection of adverse events and Columbia-Suicide Severity Rating Scale (C-SSRS), which is assessed at every in-clinic visit. In addition, evaluation of safety laboratory parameters, and electrocardiogram (ECG) monitoring are performed on Day 1 and in Weeks 4, 13, 26 and 52.

[00133] To assess the PK of pridopidine and its main metabolite over a 52-week treatment period. For all patients, PK analyses are performed at baseline and at each study visit (2 hours post-dose). A full PK profile is performed for the first 6 patients in Part 1 of the study at baseline (Day 1), at Week 2 (steady state on once daily) and at Week 4 (steady state on full, twice-daily dose). PK samples are collected at the following timepoints: t = 0 (pre-dose), 0.5, 1, 2, 4, 8, 10, 12 and 24-hours post-dose. Example 2: Case study: Pridopidine treatment in an HD patient with CAG>50:

[00134] This case study reports on the effects of pridopidine 45 mg bid in a patient with CAG> 50. CAG> 50 is associated with juvenile HD. The effects of pridopidine were compared to the effects of placebo on patients with CAG > 50 (n=4).

[00135] In the following Methods and Results sections 45 mg bid pridopidine refers to a composition comprising pridopidine HC1 with Compound 1 (in the range of 0.07% w / w-0.09% w / w from pridopidine) and Compound 4 (in the range of 0.10-0.12% w / w from pridopidine). 45 mg refers to the base form of pridopidine. Methods:

[00136] All patients began treatment with a 2-week titration period (45 mg once a day) followed by full-dose treatment for 63-78 weeks.

[00137] Efficacy was evaluated using the following clinical endpoints: Change from Baseline to Week 78 in composite UHDRS (cUHDRS) total score, Total Functional Capacity (UHDRS-TFC) score and Stroop Word Reading (SWR) testxm for cognitive assessment. Results: UHDRS-TFC score:

[00138] The UHDRS-TFC score is a commonly used and regulatory-accepted clinical scale used for assessing the functional capacity of subjects with HD and monitoring the disease's progression and severity over time. This score ranges from 0 to 13 and higher scores indicate better functional capacity. A score of 13 means that the individual is entirely functional with no indications of impairment, while a score of 0 indicates complete dependence on others for daily activities.

[00139] All participants in this study had CAG repeats greater than or equal to 50. Participants receiving placebo demonstrated a decline in TFC at all timepoints evaluated. The HD participant receiving pridopidine 45 mg bid (n=l) showed a marked improvement in TFC compared to HD participants (n=4) in the placebo group, up to 78 weeks (Table 1). Pridopidine with compounds 1 and 4 showed a positive treatment effect compared to placebo with change vs placebo of 2.99 points at 26 weeks, 3.06 points at 39 weeks, 3.00 points at 52 weeks, 2.90 points at 65 weeks and at 78 weeks, 3.45 points change (Positive change indicates improvement) (Table 1). Table 1: Pridopidine improves TFC in Juvenile HD patients with CAG repeat length >=50 compared to placebo up to 78 weeks Week Placebo Pridopidine 45 mg bid Pridopidine 45 mg bid vs Placebo N LS Mean change from baseline N LS Mean change from baseline LS Mean change vs placebo 26 4 -0.027 1 2.96 2.99 39 4 -0.097 1 2.96 3.06 52 4 -0.087 1 2.91 3.00 65 4 -0.289 1 2.61 2.90 78 4 -0.512 1 2.93 3.45 Data from a study case. Effect ofpridopidine 45 mg bid in combination with compound 1 and 4 and placebo in EID patients with CAG repeat length >=50, without antidopaminergic drugs. Positive change in TFC indicates improvement. cUHDRS:

[00140] The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a clinical scale used for evaluating the severity and progression of Huntington's disease (HD).

[00141] The cUHDRS is a composite scale assessing overall progression of independent key aspects of HD: functional ability, motor symptoms, and cognitive function. cUHDRS comprises four subscales: Total Functional Capacity (TFC), Total Motor Score (TMS), and 2 cognitive measures: the Symbol-Digit Modality Test (SDMT), and Stroop Word Reading (SWR) Test.

[00142] The cUHDRS shows outstanding test-retest reliability (ICC=0.96) and is superior to its individual components in terms of sensitivity to disease stage and longitudinally providing greater statistical power to detect clinical benefit (Schobel, Scott A., et al. "Motor, cognitive, and functional declines contribute to a single progressive factor in early HD." Neurology 89.24 (2017): 2495-2502).

[00143] The cUHDRS score is a validated scale used for tracking disease progression and evaluating treatment effectiveness in subjects with HD. Higher scores on cUHDRS indicates better overall disease state. By measuring multiple domains, the cUHDRS provides a global and comprehensive assessment of the disease stage.

[00144] All participants in this study had CAG repeats greater than or equal to 50. Participants on placebo showed the predictable decline in cUHDRS at every timepoint up to 78 weeks. Pridopidine with compounds 1 and 4 (n=l) showed positive treatment effect compared to placebo (n=4) on cUHDRS up to 78 weeks. Pridopidine with compounds 1 and 4 showed positive treatment effect compared to placebo with change vs placebo of 2.52 points at 26 weeks, 2.66 points at 39 weeks, 2.49 points at 52 weeks, 2.32 points at 65 weeks and at 78 weeks, 2.52 points change (Positive change indicates improvement) (Table 2). Table 2: Pridopidine improves overall disease progression in Juvenile HD patients with CAG repeat length >=50 compared to placebo up to 78 weeks as measured by cUHDRS Week Placebo Pridopidine 45 mg bid Pridopidine 45 mg bid vs Placebo N LS Mean change from baseline N LS Mean change from baseline LS Mean change vs placebo 26 4 -0.72 1 1.79 2.52 39 4 -0.82 1 1.83 2.66 52 4 -0.82 1 1.67 2.49 65 4 -0.91 1 1.41 2.32 78 4 -1.09 1 1.42 2.52 Data from a study case. Effect ofpridopidine 45 mg bid in combination with compound I and 4 and placebo in HD patients with CAG repeat length >=50, without antidopaminergic drugs CAG>50. Positive change indicates improvement. SWR score:

[00145] The Stroop Word Reading (SWR) test is a validated and widely used clinical measure of cognitive function. The SWR assesses the ability to inhibit cognitive interference and is commonly used to evaluate executive function, including cognitive flexibility and attention al control.

[00146] During the SWR test, individuals were asked to read a list of color names that are printed in colored ink, where the ink color does not match the word. This creates a cognitive conflict that requires the inhibition of a prepotent response to read the word, making the test challenging.

[00147] The SWR score is determined by assessing the time it takes to read the list of words and the number of errors made. Higher scores on the SWR test indicate better cognitive performance

[00148] HD participants with CAG repeat length >50 were treated with pridopidine 45 mg bid (n=l) or placebo (n=4) for 78 weeks. Participants received placebo showed the predictable, marked decline in cognitive function as assessed by the SWR. However, patients treated with pridopidine with compounds 1 and 4 showed positive treatment effect compared to placebo at every timepoint, up to 78 weeks. Pridopidine with compounds 1 and 4 showed positive treatment effect compared to placebo with change vs placebo of 14.58 points at 26 weeks, 15.38 points at 39 weeks, 15.44 points at 52 weeks, 12.35 points at 65 weeks and at 78 weeks, 14.28 points change (Positive change indicates improvement) (Table 3). Table 3: Pridopidine improves cognitive function in Juvenile HD patients with CAG repeat length >=50 compared to placebo up to 78 weeks Week Placebo Pridopidine 45 mg bid with compounds 1 and 4 Pridopidine 45 mg bid with compounds 1 and 4 vs Placebo N LS Mean change from baseline N LS Mean change from baseline LS Mean change vs placebo 26 4 -5.79 1 8.78 14.58 39 4 -6.35 1 9.03 15.38 52 4 -5.97 1 9.47 15.44 65 4 -5.51 1 6.84 12.35 78 4 -6.74 1 7.53 14.28 Data from case study. Effect ofpridopidine 45 mg bid in combination with compound 1 and 4 and placebo in HD patients with CAG repeat length >=50, without antidopaminergic drugs CAG>50. Positive change indicates, improvement. Summary

[00149] In Juvenil HD patients, who have CAG repeat length >=50, pridopidine 45 mg bid demonstrates a marked improvement, in functional capacity, cognitive function, and disease progression up to 78 weeks.

Claims

1. A method of treating or lessening the progression of Juvenile Huntington disease in a subject, comprising orally administering to the subject a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof2. A method of maintaining or reducing one or more symptoms or signs of Juvenile Huntington disease (JHD) in a subject, comprising orally administering to the subject a pharmaceutical composition comprising pridopidine and / or its analog or a pharmaceutically acceptable salt thereof wherein the one or more symptoms or signs are selected from the group consisting of motor function impairment, cognitive impairment, a physical symptom, a mental symptom, an emotional symptom, a behavioral symptom, a psychiatric symptom, depression, anxiety, aggression, impulsivity, seizures, and reduced lifespan.

3. The method of claim 2 wherein the symptoms or signs of Juvenile HD comprise motor function.

4. The method of claim 2 wherein the symptoms or signs of Juvenile HD comprise cognitive function in a Juvenile Huntington disease subject.

5. The method of claim 2 wherein the symptoms or signs of Juvenile HD comprise behavioral function in a Juvenile Huntington disease subject.

6. The method of claim 2 wherein the symptoms or signs of Juvenile HD comprise psychiatric function in a Juvenile Huntington disease subject.

7. The. method of any one of claims 1-6, wherein the composition further comprises at least one pridopidine analog of compounds 1-8, or pharmaceutically acceptable salt thereof:SOjCHj sozch3SO2CH3A                                 \.--       -¼ YH J oh k"^t'"i ..                    o.....''(Compound 1),                  " so2ch3 (Compound 2),O2S —    '''—SO,                         SO^H»a a        r11. C1...          (11' r 1 ' r i                         t "i1 ,N.        \ .N.                               I    N .'■' pi '■' Pr (Compound3),                    ''(Compound 4),so2ch3                           so2ch3o. ......J (fl........~ y i   i               r  i xk   N   .1                       k   N' (Compound 6),              +'' ' '' (Compound 5),8. The method of any one of claims 1-7, wherein the human patient experiences onset of symptoms before the age of 20.

9. The method of any one of claims 1-8, wherein the human patient has >50 CAG repeats in the Huntingtin gene.

10. The method of any one of claims 1-8, wherein the pharmaceutical composition is administered once a day, twice per day, or three times per day.

11. The method of any one of claims 1 -3 wherein impairment of the human patient’s motor function is measured by the Unified Huntington’s Disease Rating Scale (UHDRS) Total Motor Score (TMS).

12. The method of any one of claims 1-3 wherein impairment of the human patient’s motor function is assessed by the Quantitative Motor (Q-Motor) battery of tests.

13. The method of any one of claims 1-12 wherein the method further comprises administering a pharmaceutical composition comprising an anti-seizure drug, an antidepression drug, an anxiolytic, tetrabenazine, deutetrabenazine, or a mutant Huntingtin (mHtt) lowering agent.