Combination of pridopidine and low dose Anti-dopaminergic medication (ADM) for treating huntington disease and sympto thereof

Abstract

Provided herein a method of treating a human patient afflicted with Huntington disease and / or symptoms thereof, by administering to the patient a pharmaceutically effective amount of pridopidine or its pharmaceutically acceptable salt, and optionally at least one analog compound of pridopidine or its pharmaceutically acceptable salt; and low dose anti-dopaminergic medication (ADM).

Description

P-638896-PCCOMBINATION OF PRIDOPIDINE AND LOW DOSE ANTI-DOPAMINERGIC MEDICATION (ADM) FOR TREATING HUNTINGTON DISEASE AND SYMPTOMS THEREOFFIELD OF THE INVENTION

[0001] Provided herein a method of treating a human patient afflicted with Huntington disease and / or symptoms thereof, by administering to the patient a pharmaceutically effective amount of pridopidine or its pharmaceutically acceptable salt, and optionally at least one analog compound of pridopidine or its pharmaceutically acceptable salt; and low dose anti-dopaminergic medication (ADM).BACKGROUND OF THE INVENTIONHuntington disease

[0002] Huntington disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. The disease is associated with motor, behavioral, functional and cognitive symptoms. Motor disturbances are the defining feature of the disease, with chorea the most evident motor symptom. Although useful for diagnosis, chorea is a poor marker of disease severity. Rather, functional disability and disease severity best correlate with negative motor features such as impairment in fine motor skills, bradykinesia, and gross motor coordination skills, including speech difficulties, gait, and postural dysfunction as well as cognitive impairments [1],

[0003] Genetically, HD belongs to the group of trinucleotides repeat expansion disorders. While individuals with a CAG repeat length of less than 35 located on exon 1 of HTT remain asymptomatic, alleles with 40 or more repeats show full penetrance. Intermediate alleles (36-39 CAG repetitions) bear an increased risk to develop HD. Huntington’s disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a predominant toxic gain of function in the mutant huntingtin (mHTT) protein [2], No therapy has yet proved able to modify the progressive and inexorable functional decline of the disease [3,4], As such, there is a significant unmet medical need to develop medications to ameliorate symptoms of HD, and to delay disease progression.Pridopidine

[0004] Pridopidine (4-[3-(methylsulfonyl)phenyl]-l-propyl-piperidine) is a highly selective Sigma-1 receptor (SIR) ligand with Ki= 57 nM and low affinity for the Sigma-2 receptor (S2R KiP-638896-PC of 5450 nM) [5], Thus, pridopidine has 95-fold higher affinity for the SIR vs the S2R and is a highly selective SIR ligand.

[0005] The SIR is an endoplasmic reticulum (ER) protein located mainly at the mitochondria- associated membrane (MAM), modulating diverse cellular processes including calcium signaling, ion-channel activity, and the ER stress response [6,7], Pridopidine exerts neuroprotective effects, exquisitely mediated via activation of the SIR, as demonstrated in non-clinical models of HD and other neurodegenerative diseases [8-13], Specifically, pridopidine improves key pathophysiological pathways implicated in HD including rescue of mitochondrial-associated membrane (MAM) disruption

[0011] , enhancement of brain-derived neurotrophic factor secretion and signaling

[0013] , restoration of aberrant calcium signaling, rescue of synaptic plasticity and neuronal spine abnormalities

[0011] , enhancement of autophagy, upregulation of mitochondrial function

[0011] , reduction of ER and oxidative stress

[0012] , and rescue of mutant HTT-induced cell death

[0012] ,Anti-dopaminergic medications (ADMs).

[0006] Anti-dopaminergic medications (ADMs), including vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics

[0014] , are used for the treatment of chorea (VMAT2i) and behavioral problems in HD (neuroleptics off label). These medications work by blocking dopamine receptors, particularly the D2 subtype, thereby reducing excessive dopaminergic activity in the brain

[0015] , This mechanism helps alleviate symptoms like chorea and psychiatric disturbances, which are often present in patients with Huntington's disease (HD). However, the therapeutic use of ADMs is frequently accompanied by significant side effects, including extrapy rami dal symptoms, metabolic disturbances, and sedation

[0016] . These adverse effects can severely impact a patient's functionality and cognitive abilities, potentially accelerating disease progression and limiting the overall utility of these medications. cUHDRS: composite Unified Huntington Disease Rating Scale

[0007] The cUHDRS scoring system combines four measurement scales for assessing functional, motor, and cognitive function to provide a quantitative holistic measure of patient experience. The scales included in cUHDRS are the Total Motor Scale (TMS, a motor assessment), Total Functional Capacity (TFC, a functional assessment), the Symbol Digit Modality Test (SDMT, a cognitive assessment), and the Stroop Word Reading Test (SWR, a cognitive assessment). This composite measure characterizes the clinical progression of HD and is strongly associated with brain measures of progressive atrophy in the corticostriatal tract relevant to the disease. The cUHDRS increases the low signal -to-noise ratio (S / N) that afflicts the individual measures and provides a good coverage ofP-638896-PC key features including functional, motor and cognitive assessments in the early HD population

[0017] ,

[0008] As a result of the above features, the cUHDRS shows increased sensitivity to clinical changes especially in early symptomatic HD patients. In addition, cUHDRS has greater statistical power to detect success in clinical trials aiming to slow clinical progression compared to TFC and TMS alone. Therefore, the cUHDRS may be beneficial as an endpoint in interventional clinical trials in the early HD population, where it can assist in maximizing sensitivity while lowering patient burden and reducing sample size for a potentially more efficient trial

[0017] ,

[0009] Genetically, HD belongs to the group of trinucleotides repeat expansion disorders. While individuals with a CAG repeat length of less than 36 located on exon 1 of HTT are unaffected, alleles with 40 or more repeats show full penetrance. Alleles of reduced penetrance (36-39 CAG repeats) bear an increased risk to develop HD. Huntington’s disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a dominant toxic gain of function in the mutant huntingtin (mHTT) protein as well as loss of essential, physiological functions

[0018] ,

[0010] Only three drugs, valbenazine, tetrabenazine and deutetrabenazine, are approved to only treat chorea in HD patients, but no therapy has yet proved able to modify the progressive and inexorable functional decline of the disease. As such, there is a significant unmet medical need to develop medications to ameliorate symptoms of HD, and to delay disease progression

[0019] ,SUMMARY OF THE INVENTION

[0011] In some embodiments, this invention provides a method of treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an antidopaminergics medication (ADM), wherein the ADM and its dose comprise any vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics administered at lower than the recommended dosage.

[0012] In other embodiment, the analog compound of pridopidine is represented by Compounds 1- 7:P-638896-PCBRIEF DESCRIPTION OF THE DRAWINGS

[0013] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, 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:

[0014] Figure 1 presents pridopidine with compounds 1 and 4 and Low dose ADMs improve in global disease progression compared to placebo with Low dose ADMs measured by cUHDRS (see Example 1). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo and Low ADMs in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS.

[0015] Figure 2 presents pridopidine with compounds 1 and 4 and Low dose Tetrabenazine slow the decline in global disease progression measured by cUHDRS compared to placebo with low dose Tetrabenazine (see Example 2). The Data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose Tetrabenazine and placebo& Low dose Tetrabenazine in HD patients. Data is LSMean (SE). Per-protocol population,P-638896-PCChange from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS. Low dose Tetrabenazine is <=50 mg / day.

[0016] Figure 3 presents pridopidine with compounds 1 and 4 and Low dose deutetrabenazine shows an improvement in global disease progression measured by cUHDRS compared to placebo with low dose deutetrabenazine (see Example 3) . The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose deutetrabenazine and placebo and Low dose deutetrabenazine in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS.

[0017] Figure 4 presents pridopidine with compounds 1 and 4 and Low dose quetiapine improvement in global disease progression compared to placebo and Low dose quetiapine, measured by cUHDRS (see Example 4). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose quetiapine and placebo and Low dose quetiapine in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS. Low dose quetiapine <=50 mg / day.

[0018] Figure 5 presents pridopidine with compounds 1 and 4 and Low dose aripiprazole improvement compared to placebo with Low dose aripiprazole in global disease progression measured by cUHDRS (see Example 5). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose aripiprazole and placebo with Low dose aripiprazole in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS. Low dose Aripiprazole <=5 mg / day.

[0019] Figure 6 presents pridopidine with compounds 1 and 4 and Low dose Tiapride (<50 mg / day) showed a statistically significant and clinically meaningful improvement or slowing of decline in global disease progression compared to placebo with Low dose Tiapride as measured by cUHDRS (see Example 6). Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose Tiapride and placebo in HD patients. Positive change indicates improvement. Low dose Tiapride <50 mg / day.

[0020] Figure 7 presents pridopidine with compounds 1 and 4 and Low dose ADMs showed improvement in functional capacity in HD patients compared to placebo (see Example 7). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 with Low ADMs and placebo with low dose ADMs in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 39, 52, 65 and 78 in UHDRS-TFC score.P-638896-PC

[0021] Figure 8 presents pridopidine in combination with compound 1 and 4 and Low ADMs show improvements vs placebo and Low ADMs in cognitive function through 78 weeks as measured by SWR test (Example 8). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo and Low ADMs in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 39, 52, 65 and 78 in SWR.

[0022] Figure 9 presents pridopidine in combination with compound 1 and 4 and Low dose ADMs improves motor function compared to placebo Low dose ADMs through 78 weeks, as measured by TMS scale (see Example 9). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo and Low ADMs in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 39, 52, 65 and 78 in TMS.

[0023] Figure 10 presents pridopidine with compounds 1 and 4 significantly improves motor function compared to placebo with Low dose ADMs through 78 weeks, as measured by Q-Motor- Inter-Onset-Interval-SD-Hand (ms) (see Example 10). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose ADMs and placebo with Low dose ADMs in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 52, 65 and 78 in Q-Motor.

[0024] Figure 11 presents pridopidine with compounds 1 and 4 significantly improves motor function compared to placebo with low doses ADMs through 78 weeks, as measured by Q-Motor- Pro-Sup-Inter-Tap-Interval-SD-Hand (ms) (see Example 10). The data is from PROOF-HD phase 3 trial. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose ADMs and placebo with low dose ADMs in HD patients. Data is LSMean (SE). Per-protocol population, Change from baseline to Weeks 26, 52, 65 and 78 in Q-Motor.DETAILED DESCRIPTION OF THE INVENTION

[0025] In the following detailed description, numerous specific details are set forth to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well- known methods, procedures, and components have not been described in detail so as not to obscure the present invention.P-638896-PCComposition

[0026] In some embodiments, provided herein a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising low dose of anti-dopaminergic medication (ADM); for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject.The composition comprising pridopidine

[0027] In some embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof for the combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises for use in the methods of this invention comprises pridopidine salt. In another embodiment, the composition comprises pridopidine base. In some embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and at least one analog compound of pridopidine (Compound 1-7) or pharmaceutically acceptable salt thereof represented by the following structures:P-638896-PC

[0028] In some embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof for use in the methods of this invention comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 1 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 2 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 3 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 4 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 5 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 6 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 1 and Compound 4 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and at least Compound 1 or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and at least Compound 4 or pharmaceutically acceptable salt thereof.

[0029] In some embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof for use in the methods of this invention comprises an effective amount of between 5 mg -180 mg pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises between 10 mg -100 mg pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises between 30 mg -90 mg pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises 45 mg pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises 90 mg.

[0030] In some embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof for use in the methods of this invention comprises administering an effective amount of between 5 mg / day -180 mg / day pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, administering between 10 mg / day -100 mg / day pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, administering 45 mg twice a day pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, administering 90 mg / day pridopidine or pharmaceutically acceptable salt thereof.P-638896-PC

[0031] In another embodiment, the pharmaceutical composition comprises between 0.001%-10% w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.05%- 10% w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.001%-0.1%, 0.001%-0.05%, 0.05%-0.1%, 0.05%-0.15%, 0.05%-0.2%, 0.05%-0.5%, 0.05%- 2%, 0.05%-3%, 0.05%-4%, 0.05%-5%, 0.1%-0.4%, 0.15%-0.3%, 0.15%-0.5 % w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine. Each represents a separate embodiment of this invention.

[0032] In another embodiment, the pharmaceutical composition comprises between 0.001%- 0.1%, 0.001%-0.05%, 0.05%-0.1%, 0.05%-0.15%, 0.05%-0.2%, 0.05%-0.5%, 0.05%-2%, 0.05%- 3%, 0.05%-4%, 0.05%-5%, 0.1%-0.4%, 0.15%-0.3%, 0.15%-0.5 % w / w of each of the analog compound 1 or pharmaceutical acceptable salt thereof relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.001%-0.1%, 0.001%-0.05%, 0.05%-0.1%, 0.05%-0.15%, 0.05%-0.2%, 0.05%-0.5%, 0.05%-2%, 0.05%-3%, 0.05%-4%, 0.05%-5%, 0.1%-0.4%, 0.15%-0.3%, 0.15%-0.5 % w / w of each of the analog compound 4 or pharmaceutical acceptable salt thereof relative to pridopidine.

[0033] In some embodiments, the pridopidine or the analog compound of pridopidine (each compound 1-7) of pharmaceutical composition of this invention, is in the form of a salt. In another embodiment, the salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid-phosphate, sulphate, bisulfate, formate, gluconate, glucaronate, saccharate, isonicotinate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, gentisinate, mal onate, mandelate, methanesulfonate, ethanesulfonate, naphthal ene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, bitartrate, and toluene-p- sulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate) salt. Each represents a separate embodiment of this invention. In another embodiment, the pridopidine is in the form of HC1. In another embodiment, the analog compound of pridopidine is in the form of HC1.The composition comprising anti-dopaminergic medication (AMD)

[0034] In some embodiment, provided herein a composition comprising low dose anti-dopaminergic medication (ADM) for use in the methods of this invention. In some embodiments, the anti- dopaminergic medication (ADM) comprises vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics. In some embodiments, the ADM and its low dose comprise anyP-638896-PC vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics administered at lower than the recommended dosage.

[0035] The anti-dopaminergic medication comprises Valbenazine, Tetrabenazine, deutetrabenazine, Aripiprazole, Quetiapine, Tiapride, Risperidone or Olanzapine. In another embodiment, the composition comprises Valbenazine. In another embodiment, the composition comprises Tetrabenazine. In another embodiment, the composition comprises deutetrabenazine. In another embodiment, the composition comprises Aripiprazole. In another embodiment, the composition comprises Quetiapine. In another embodiment, the composition comprises Tiapride. In another embodiment, the composition comprises Risperidone. In another embodiment, the composition comprises Olanzapine.

[0036] In some embodiment the combination therapy for the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease in a subject, comprises administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising low dose of anti-dopaminergic medication (ADM); wherein the dose of the ADM is lower than the recommended dosage. In another embodiment, the dose of the ADM is lower by at least 5%, 10%, 20%, 30% or 50% by weight of the recommended dosage. In another embodiment, the dose of the ADM is lower by at least 5 %- 50% by weight of the recommended dosage.

[0037] In some embodiment the combination therapy for the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease in a subject, comprises administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising low dose of anti-dopaminergic medication (ADM); wherein the dose of the ADMs is lower by at less than 50% recommended dosage The term “low dose anti- antidopaminergic medication” refers herein to anti- antidopaminergic medication dosage lower by at less than 50% recommended dosage. Specifically, low dose tetrabenazine refers to daily use of less than 50 mg / day when administered with a composition comprising pridopidine. Low dose Valbenazine refers to daily use of less than 40 mg / day when administered with a composition comprising pridopidine. Low dose deutetrabenazine refers to daily use of less than 30 mg / day when administered with a composition comprising pridopidine. Low dose Aripiprazole refers to daily use of less than 5 mg / day when administered with a composition comprising pridopidine. Low dose Quetiapine refers to daily use of less than 50 mg / day when administered with aP-638896-PC composition comprising pridopidine. Low dose Tiapride refers to daily use of less than 50 mg / day when administered with a composition comprising pridopidine. Low dose Risperidone refers to daily use of less than 0.5 mg / day when administered with a composition comprising pridopidine. Low dose Olanzapine refers to daily use of less than 5 mg / day when administered with a composition comprising pridopidine.

[0038] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Valbenazine in an amount lower than or equal to 40 mg / day.

[0039] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Tetrabenazine in an amount lower than or equal to 50 mg / day.

[0040] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering deutetrabenazine in an amount lower than 30 mg / day.

[0041] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Aripiprazole in an amount lower than or equal to 5 mg / day.

[0042] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Quetiapine in an amount lower than or equal to 50 mg / day.

[0043] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Tiapride in an amount lower than or equal to 50 mg / day.

[0044] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Risperidone in an amount lower than or equal to 0.5 mg / day.

[0045] In one embodiment, the composition comprising low dose of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of HuntingtonP-638896-PC disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Olanzapine in an amount lower than or equal to 5 mg / day.Valbenazine

[0046] Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor. Valbenazine is used for management of involuntary movements (chorea) in Huntington’s disease

[0020] ,

[0047] In some embodiments, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Valbenazine in an amount lower than or equal to 40 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day; between 30 mg / day to 40 mg / day.Tetrabenazine

[0048] Tetrabenazine is a vesicular monoamine transporter 2 (VMAT) inhibitor used for the management of chorea associated with Huntington's Disease. Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vehicles

[0021] ,

[0049] In some embodiments, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Tetrabenazine in an amount lower than or equal to 50 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering between 10 mg / day to 20 mg / day; between 6.25 mg / day-12.5 mg / day; between 12.5 mg / day -25 mg / day; between 25 mg / day -37.5 mg / day; between 37.5 mg / day -50 mg / day; between 20 mg / day to 30 mg / day; between 30 mg / day to 40 mg / day; or between 40 mg / day to 50 mg / day.Deutetrabenazine

[0050] Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used for the management of chorea associated with Huntington's disease. Deutetrabenazine reversibly depletes the levels of monoamines, such as dopamine, serotonin, norepinephrine, and histamine, from nerveP-638896-PC terminals via its active metabolites. The major circulating metabolites are a-dihydrotetrabenazine [HTBZ] and P-HTBZ that act as reversible inhibitors of VMAT2. Inhibition of VMAT2 results in decreased uptake of monoamines into synaptic terminal and depletion of monoamine stores from nerve terminals

[0022] ,

[0051] In some embodiments, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering deutetrabenazine in an amount lower than 30 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering between 5 mg / day to 15 mg / day; between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day.Aripiprazole

[0052] Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. Aripiprazole is also used as an adjunctive treatment of major depressive disorder. In Huntington' s di sease, Aripiprazole is used off label to manage depression, and also for other symptoms including psychosis and chorea, or uncontrolled, jerky movements

[0023] ,

[0053] In one embodiment, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Aripiprazole in an amount lower than or equal to 5 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering 1 mg / day, 2 mg / day, 3 mg / day or 4 mg / day.Quetiapine

[0054] Quetiapine is a second-generation antipsychotic for certain psychiatric conditions, including schizophrenia, a condition marked by a disconnection from reality, and bipolar disorder, which is characterized by extreme mood swings, including manic and depressive episodes. In Huntington’s disease, Quetiapine is used off label to manage certain behavioral symptoms, including psychotic problems, agitation, irritability, insomnia and to manage chorea

[0024] ,

[0055] In one embodiment, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression ofP-638896-PCHuntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Quetiapine in an amount lower than or equal to 50 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day; between 30 mg / day to 40 mg / day; or between 40 mg / day to 50 mg / day.Tiapride

[0056] Tiapride is a selective dopamine D2 and D3 receptor antagonist Blocking these dopamine receptors improves the regulation of behavioral, sleep, and motor function disturbances

[0025] ,

[0057] In one embodiment, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Tiapride in an amount lower than or equal to 50 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day; between 30 mg / day to 40 mg / day; or between 40 mg / day to 50 mg / day.RisperidoneRisperidone is a second-generation antipsychotic medication used to treat several mental health disorders including schizophrenia, bipolar mania, psychosis, or as an adjunct in severe depression. Risperidone binds with a very high affinity to 5-HT2A receptors, approximately 10-20-fold greater than the drug's binding affinity to D2 receptors. Risperidone is used off label in subjects Huntington's disease, specifically to address psychiatric symptoms and motor functioning

[0026] ,

[0058] In one embodiment, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Risperidone in an amount lower than or equal to 0.5 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering 0.1 mg / day, 0.2 mg / day, 0.3 mg / day or 0.4 mg / day.Olanzapine

[0059] Olanzapine is an antipsychotic drug used in the management of schizophrenia, bipolar 1 disorder, and agitation associated with these disorders. The activity of olanzapine is achieved by the antagonism of multiple neuronal receptors including the dopamine receptor DI, D2, D3 and D4 in the brain, the serotonin receptors 5HT2A, 5HT2C, 5HT3 and 5HT6, the alpha-1 adrenergicP-638896-PC receptor, the histamine receptor Hl and multiple muscarinic receptors. In Huntington's disease patients Olanzapine is used off label for managing behavioral changes, mainly in patients with severe psychiatric symptoms at the onset

[0027] .

[0060] In one embodiment, the composition comprising an effective amount of ADM for a combination therapy for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprises administering Olanzapine in an amount lower than or equal to 5 mg / day. In another embodiment, the composition for use in the methods described herein comprises administering 1 mg / day, 2 mg / day, 3 mg / day or 4 mg / day.

[0061] In some embodiments provided herein a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound or pharmaceutically acceptable salt thereof; and low-dose anti-dopaminergic medication. In another embodiment, the anti-dopaminergic medication comprises Valbenazine, Tetrabenazine, deutetrabenazine, Aripiprazole, Quetiapine, Tiapride, Risperidone or Olanzapine.Formulation

[0062] 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.

[0063] In some embodiments, the invention provides pharmaceutical compositions for use in the treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease, comprising the active compound (such as pridopidine, ADMs), pharmaceutically acceptable salt together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and / or prophylactic ingredients know and used in the art.

[0064] 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.

[0065] In some embodiments, the pharmaceutical composition for use in the methods of this invention comprises one or more pharmaceutically acceptable carriers or excipients.

[0066] In some embodiments, the pharmaceutically acceptable carriers or excipients are selected from a group consisting of: binder, filler, plasticizer, glidant and lubricant and mixtures thereof.P-638896-PC

[0067] In some embodiments, the binder is selected from a group consisting of: starch, pregeletinized starch, polyethylene oxide, cellulose polymers, hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol and mixtures thereof.

[0068] In some embodiments, the filler is selected from a group consisting of: microcrystalline cellulose, sugar spheres, lactose, sorbitol, dextrose, sucrose, mannitol, dibasic or tribasic calcium phosphate, calcium sulfate, starch, retalac and mixtures thereof.

[0069] In some embodiments, the filler is microcrystalline cellulose and is a silicified microcrystalline cellulose.

[0070] In some embodiments, the filler is lactose. In another embodiment, the filler is a mixture of microcrystalline cellulose and lactose, and wherein the microcrystalline cellulose and is a silicified microcrystalline cellulose. In an embodiment, the filler is microcrystalline cellulose and is a silicified microcrystalline cellulose.

[0071] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose and magnesium stearate as excipients.

[0072] In some embodiments, the lubricant is selected from a group consisting of: sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, talc, glyceryl behenate, glyceryl monostearate, and mixtures thereof.

[0073] In some embodiments, the lubricant is magnesium stearate.

[0074] In some embodiments, the glidant is selected from a group consisting of: starch, pregelatinized starch, silicone dioxide, colloidal silicone dioxide, talc and mixtures thereof.

[0075] In some embodiments, the glidant is colloidal silicone dioxide.The pharmaceutical composition of the invention may be administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route. Preferred routes of administration include oral administration, in particular in tablet, in capsule, in beads, minitablets, multiparticulates, in powder, or in liquid form, and parenteral administration, in particular cutaneous, ophthalmic, eye drops, subcutaneous, intramuscular, or intravenous injection.Method of treating, preventing, or alleviating HD

[0076] Disease progression in HD is defined by clinical rating scales, i.e. The Unified Huntington’s Disease Rating Scale Total Functional Capacity (UHDRS-TFC), cUHDRS, and the HD Integrated Scoring System (HD-ISS) which is a way to categorize the disease progression.

[0077] HD includes four TFC stages:P-638896-PC

[0078] HD1 (TFC 11-13). Early stage. Fully functional at home and at work, maintains typical pre-disease levels of independence when it comes to everyday activities.

[0079] HD2 (TFC 7-10). Early intermediate stage. Patient is still functional at work, but at a lower capacity.

[0080] HD3 (TFC 3-6). Late intermediate stage. Patient can no longer conduct work or manage household responsibilities.

[0081] HD4 (TFC 0-2). advanced stage. Patient is not independent at this stage, but still can reside in their home with help from either family or professionals, although their needs may be better met at an extended care facility.HD includes 4 ISS stages:

[0082] The HD-ISS is an evidence-based staging system that addresses all stages of HD. The ISS defines landmark assessments and cut-off values to identify critical transitions in disease stages. HD- ISS has 4 distinct stages. ISS Stage 0 (pre-symptomatic) includes all HD gene mutation or expansion carriers for whom there is no detectable change in pathological markers, signs or symptoms related to HD. In ISS stage 1, pathological changes indicating neurodegeneration, and an onset of specific signs can be detected, specifically changes to the volume of the caudate and putamen brain substructures. ISS Stage 2 is defined by the presence of definite clinical signs and symptoms, both cognitive and motor, without any decline in function. ISS Stage 3 is accompanied by a decline in functional capacity or independent scale.

[0083] In some embodiments, provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease in a subject, comprising a combination therapy comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising low-dose of anti- dopaminergic medication (ADM).

[0084] A method of treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an antidopaminergics medication (ADM), wherein the ADM and its dose comprise anyP-638896-PC vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics administered at lower than the recommended dosage.

[0085] A method of treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an antidopaminergics medication (ADM), wherein the ADM and its dose comprise any vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics administered at lower by at least 10%, 20%, 30% or 50% of their recommended dosage.

[0086] A method of treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an antidopaminergics medication (ADM), wherein the ADM and its dose comprise any vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics administered at lower by at least 50% of their recommended dosage.

[0087] A method of treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an antidopaminergics medication (ADM), wherein the ADM and its dose comprise: Valbenazine , Tetrabenazine, deutetrabenazine, Aripiprazole, Quetiapine, Tiapride, Risperidone or Olanzapine administered at lower by at least 10%, 20%, 30% or 50% of their recommended dosage.

[0088] A method of treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an antidopaminergics medication (ADM), wherein the ADM and its dose comprise: Valbenazine , Tetrabenazine, deutetrabenazine, Aripiprazole, Quetiapine, Tiapride, Risperidone or Olanzapine administered at lower by at least 50% of their recommended dosage.P-638896-PC

[0089] In some embodiments, provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms thereof in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti-dopaminergic medication (ADM), wherein the ADM and its dose comprise:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

[0090] In some embodiments, provided herein a method of maintaining, reducing or delaying onset of one or more symptoms of Huntington disease in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti-dopaminergic medication (ADM), wherein the ADM and its dose comprise:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.Symptoms of HD

[0091] In some embodiments, this invention is directed to (i) a method for treatment, prevention, alleviation, delaying symptom onsets or slowing of progression of Huntington disease; (ii) a method for improving, maintaining or reducing impairment of functional capacity in a subject with Huntington Disease; (iii) a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington Disease; (iv) a method of improving, maintaining or reducing impairment of cognition in a subject with Huntington Disease; (v) a method of maintaining orP-638896-PC reducing anxiety and depression in a subject with Huntington Disease; (vi) a method of maintaining or reducing anti-inflammatory biomarkers in a subject with Huntington Disease; (vii) a method of increasing levels of Brain-Derived Neurotrophic Factor (BDNF) in a subject with Huntington Disease; (viii) a method of maintaining or reducing levels of neurofilament light chain (NfL) in a subject with Huntington Disease; (ix) a method for improving, maintaining, or reducing of memory impairment in a subject with Huntington Disease; (x) a method for delaying or reducing the deterioration of structural, functional, and metabolic measures in the brain in a subject with Huntington Disease; (xi) a method of delaying the onset, stopping, or slowing the decline of disease progression of Huntington Disease; (xii) a method of improving, maintaining, or reducing impairment or improving of quality of life in a subject with Huntington Disease; (xiii) a method of maintaining, improving, preventing the worsening, or reducing impairment of a physical symptom in a subject with Huntington Disease; (xiv) a method of maintaining, improving, preventing the worsening, or reducing impairment of a mental symptom in a subject with Huntington’s Disease; (xv) a method of improving, preventing the worsening, or reducing of an emotional symptom in a subject with Huntington Disease; (xvi) a method of maintaining or reducing behavioral symptoms or psychiatric symptoms in a subject with Huntington’s Disease; (xvii) a method of maintaining or reducing lack of initiative, apathy, or irritability in a subject with Huntington’s Disease; (xviii) a method of maintaining improving or lessening the decline of reduced lifespan in a subject with Huntington’s Disease in a subject with Huntington’s Disease wherein the method comprises a combination therapy by administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of anti- dopaminergic medication (ADM).

[0092] In other embodiments the ADM and its dose comprise any vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics administered at lower than their recommended dosage. In another embodiment, lower by at least 10%, 20%, 30% or 50% of their recommended dosage. In another embodiment, lower by at least 50% of their recommended dosage.

[0093] In other embodiments the ADM and its dose comprise Valbenazine, Tetrabenazine, deutetrabenazine, Aripiprazole, Quetiapine, Tiapride, Risperidone or Olanzapine administered at lower than their recommended dosage. In another embodiment, administered at lower by at least 10%, 20%, 30% or 50% of their recommended dosage. In another embodiment, lower than 50% of their recommended dosage.

[0094] In other embodiments the ADM and its dose comprise Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equalP-638896-PC to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; and the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

[0095] In another embodiment, the one or more symptoms are measured by Total Functional Capacity (TFC), Unified Huntington's Disease Rating Scale (UHDRS), UHDRS Independence Score (IS), composite UHDRS (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q- Motor) assessment, UHDRS modified Motor Score (mMS), UHDRS-Chorea score, UHDRS- Dystonia score, Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), eye movement score, hand movement score, gait and balance score, timed up and go (TUG) assessment, Huntington Disease Health Index (HD-HI), and Digitomotography (finger tapping) assessment, UHDRS TMS score, UHDRS TMS score minus chorea, UHDRS TMS score minus dystonia, HD-Quality of Life scale (HD-QoL), Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), Problem Behaviors Assessment (PBA) total score, PBA for depressed mood, PBA for irritability, PBA for lack of initiative or apathy, PBA for obsessivecompulsiveness, PBA for disoriented behavior, Apathy Evaluation Scale (AES), PBA for disoriented behavior, Problem Behaviors Assessment-Short form (PBA-S), PBA short form total score, PBA short form apathy sub-item, Interview-based Impression of Change plus Caregiver Input (CIBIC-Plus), Physical Disability Score (PDS), Functional Assessment (FA), Clinical Global Impression of Change (CGLC), Clinician Global Impression of Severity (CGI-S), Patient Global Impression of Change (PGLC), Patient Global Impression of Severity (PGLS), cognitive assessment battery (CAB), abbreviated Montreal Cognitive Assessment (MoCA) scale, Trail Making Test B assessment, EuroQol 5-Dimension 5-Level (EQ-5D-5L), Walk-12, Modified Physical Performance Test (mPPT), trail making test B (TMT-B), HD Cognitive Assessment Battery (HD-CAB), which includes 6 tests, The Leiter International Performance Scale, and the Peabody Picture Vocabulary Test, Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), Beck Hopelessness Scale, Centre for Epidemiological Studies - Depression Scale (CES-D), Patient Health Questionnaire, Center for Epidemiological Studies Depression Scale for Children (CES-DC), Clinically Useful Depression Outcome Scale, Diagnostic Inventory for Depression, Edinburgh Postnatal Depression Scale (EPDS), Inventory of Depressive Symptomatology, Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale, Kutcher Adolescent Depression Scale (KADS), Major Depression Inventory (MDI), Montgomery-Asberg Depression Rating Scale (MADRS), Mood and Feelings Questionnaire (MFQ), Zung Self-Rating Depression Scale, Cornell Scale for Depression in Dementia (CSDD), State-Trait Anxiety Inventory (STAI), Fear Survey Schedule, Beck Anxiety Inventory (BAI),P-638896-PCBrief Fear of Negative Evaluation Scale - BFNE, Clinician Administered PTSD Scale (CAPS), Daily Assessment of Symptoms - Anxiety, Generalized Anxiety Disorder 7 (GAD-7), Hamilton Anxiety Scale (HAM-A), Hospital Anxiety and Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom Scale - Self- Report Version, Social Phobia Inventory (SPIN), Trauma Screening Questionnaire, Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), or Zung Self-Rating Anxiety Scale, 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.

[0096] In another embodiment, the one or more symptoms are measured by Total Functional Capacity (TFC), Unified Huntington's Disease Rating Scale (UHDRS), UHDRS Independence Score (IS), composite UHDRS (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q- Motor) assessment, UHDRS modified Motor Score (mMS), UHDRS-Chorea score, UHDRS- Dystonia score, eye movement score, hand movement score, gait and balance score, timed up and go (TUG) assessment, Huntington Disease Health Index (HD-HI), Digitomotography (finger tapping) assessment, UHDRS TMS score, Problem Behaviors Assessment (PBA) total score, PBA for depressed mood, PBA for irritability, PBA for lack of initiative or apathy, PBA for obsessivecompulsiveness, PBA for disoriented behavior, trail making test B (TMT-B), HD Cognitive Assessment Battery (HD-CAB), Hamilton Rating Scale for Depression (HAM-D), Problem Behaviors Assessment-Short (PBA-S) scale, Hamilton Anxiety Scale (HAM-A), Hospital Anxiety and Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), Post-traumatic stress disorder (PTSD) Symptom Scale - Self-Report Version, PBA short form apathy sub-item, Apathy Evaluation Scale (AES), HD-Quality of Life scale (HD-QoL), Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), cognitive assessment battery (CAB).

[0097] In some embodiments, this invention is directed to a method for improving, maintaining or reducing impairment, of functional capacity, impairment of motor function, cognition and impairment of quality of life in a subject with Huntington Disease wherein the functional capacity, motor function, cognition and quality of life are measured by a composite Unified Huntington's Disease Rating Scale (cUHDRS).

[0098] In some embodiments, this invention is directed to a method for improving, maintaining or reducing impairment of functional capacity, in a subject with Huntington Disease wherein the functional capacity is measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC).P-638896-PC

[0099] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of functional capacity in a subject with Huntington’s disease, wherein the functional capacity is measured by evaluation of Total Functional Capacity (TFC) in accordance with the Unified Huntington’s Disease Rating Scale (UHDRS) subscale of Total Functional Capacity (TFC).

[0100] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of motor function in a subject with Huntington’s disease wherein the motor function impairment is measured by the composite Unified Huntington's Disease Ratings Scale (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q-Motor) assessment, Unified Huntington's Disease Rating Scale (UHDRS), 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), eye movement score, hand movement score, gait and balance score, timed up and go (TUG) assessment, The Huntington Disease Health Index (HD-HI), and / or Digitomotography (finger tapping) assessment. In another embodiment, the motor functional impairment is measured by digitomotography (speeded index finger tapping), dysdiadochomotography (pronation / supination hand tapping), manumotography and choreomotography (grip force and chorea analysis), and / or pedomotography (speeded foot tapping).

[0101] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of motor function, wherein the motor function may comprise motor mobility, gait and balance, dystonia, finger tap impairments and / or chorea.

[0102] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of motor function, wherein the motor function comprises gait and balance, bradykinesia, finger tapping, and / or pronation supination.

[0103] In some embodiments this invention is directed to a method of improving, maintaining or reducing impairment of motor mobility in a subject with Huntington’s disease, wherein the motor function impairment is measured by UHDRS Total Motor Score (TMS) score, the UHDRS TMS score minus chorea, and / or UHDRS TMS score minus dystonia.

[0104] In some embodiments, this invention is directed to a method of maintaining or reducing the level of dystonia or slowing the worsening of dystonia in a subject with Huntington’s disease, wherein the motor function impairment is measured by UHDRS TMS dystonia score.

[0105] In some embodiments, this invention is directed to a method of reducing or maintaining or slowing the worsening of gait and balance in a subject with Huntington’s disease, wherein the motor function impairment is measured by UHDRS TMS gait and balance score.P-638896-PC

[0106] In some embodiments, this invention is directed to a method of reducing or maintaining or slowing the worsening of chorea in a subject with Huntington’s disease, wherein the motor function impairment is measured by UHDRS TMS chorea score.

[0107] In some embodiments, this invention is directed to a method of reducing or maintaining or slowing the worsening of finger tap speed frequency, finger tap Inter-Onset-Interval, finger tap Inter- Tap-Interval, finger tap inter-peak interval, pronate / supinate hand tapping frequency, hand tapping inter-onset interval, grip force tongue force or any combination thereof in a subject with Huntington’s disease, wherein the motor function impairment is measured by Q-Motor subscales for each mentioned impairment.

[0108] In some embodiments, this invention is directed to a method of improving, maintaining or learning the decline in a human patient’s behavior and / or psychiatric state in a subject with Huntington’s disease, wherein the behavior and / or psychiatric state is measured by one or any of the following scales; Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT), Problem Behaviors Assessment-Short form (PBA-s), The Problem Behaviors Assessment (PBA) total score, The Problem Behaviors Assessment for depressed mood, The Problem Behaviors Assessment for irritability, The Problem Behaviors Assessment for lack of initiative or apathy, The Problem Behaviors Assessment for obsessive-compulsiveness, or by the Problem Behaviors Assessment for disoriented behavior.

[0109] In some embodiments, this invention is directed to a method of improving, maintaining or learning the decline of cognitive impairments in a subject with Huntington’s disease, wherein the cognitive impairment is measured by one or any of the following scales: The trail making test B (TMT-B), The HD Cognitive Assessment Battery (HD-CAB), The Leiter International Performance Scale and the Peabody Picture Vocabulary Test.

[0110] In some embodiments, this invention is directed to a method of maintaining or reducing depression in a subj ect with Huntington’ s disease, wherein the depression is measured by Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), Beck Hopelessness Scale, Centre for Epidemiological Studies - Depression Scale (CES-D), Patient Health Questionnaire, Center for Epidemiological Studies Depression Scale for Children (CES-DC), Clinically Useful Depression Outcome Scale, Diagnostic Inventory for Depression, Edinburgh Postnatal Depression Scale (EPDS), Inventory of Depressive Symptomatology, Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale, Kutcher Adolescent Depression Scale (KADS), Maj or Depression Inventory (MDI), Montgomery-Asberg Depression Rating Scale (MADRS), Mood and Feelings Questionnaire (MFQ), Zung Self-Rating Depression Scale, or Cornell Scale for Depression in Dementia (CSDD).P-638896-PC

[0111] In some embodiments, this invention is directed to a method of maintaining or reducing anxiety in a subject with Huntington’s disease, wherein the anxiety impairment is measured by one of the following anxiety rating scales: the State-Trait Anxiety Inventory (STAI), the problem Behaviors Assessment-Short (PBA-S) scale, the Fear Survey Schedule, Beck Anxiety Inventory (BAI), Brief Fear of Negative Evaluation Scale - BFNE, Clinician Administered PTSD Scale (CAPS), Daily Assessment of Symptoms - Anxiety, Generalized Anxiety Disorder 7 (GAD-7), Hamilton Anxiety Scale (HAM-A), Hospital Anxiety and Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom Scale - Self- Report Version, Social Phobia Inventory (SPIN), Trauma Screening Questionnaire, Yale-Brown Obsessive Compulsive Scale (Y-BOCS), or the Zung Self-Rating Anxiety Scale.

[0112] In some embodiments, behavioral symptoms or psychiatric symptoms may include lack of initiative, apathy, or irritability.

[0113] In some embodiments, this invention is directed to a method of maintaining or reducing apathy in a subject with Huntington’s disease, wherein the apathy impairment is measured by one of the following apathy rating scales: The Problem Behaviors Assessment (PBA) total score, the Problem Behaviors Assessment-short form (PBA-s), The Problem Behaviors Assessment for lack of initiative or apathy, The Problem Behaviors Assessment short form apathy sub-item, The Apathy Evaluation Scale (AES) and The Problem Behaviors Assessment for disoriented behavior.

[0114] In some embodiments, this invention is directed to a method of maintaining or reducing irritability in a subject with Huntington’s disease, wherein the irritability impairment is measured by one of the following irritability rating scales: The Problem Behaviors Assessment (PBA) total score, the Problem Behaviors Assessment-short form (PBA-s). The human patient's behavior and / or psychiatric state may also be measured by the Problem Behaviors Assessment for irritability.

[0115] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of reduction of metabolic measures in the brain in a subject with Huntington’s disease, wherein quality of life is measured by 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.

[0116] In some embodiments, this invention is directed to a method of improving, maintaining or reducing impairment of reduction of patient’s quality of life, and reduced lifespan, in a subject with Huntington’s disease, wherein quality of life is measured by the Resource Utilization in Dementia-Lite (RUD-Lite), EuroQol 5-Dimensional Health-Related Quality of Life Scale (EQ- 5D), including for example Proxy Version (EQ-5D Proxy).P-638896-PC

[0117] In some embodiments, this invention is directed to a method of delaying the onset of disease progression, stop disease progression or slowing the decline of disease progression in a subject with Huntington’s disease, wherein disease progression is measured by Clinical Global Impression of Change (CGIC), Clinical Interview-Based Impression (CIBI), and the Global Deterioration Scale (GDS)In some embodiments of the methods of the invention, the subject has >36 CAG repeats in the Huntingtin gene. In some embodiments of the methods of this invention, the HD subject has been diagnosed as having at least 36 CAG repeats in the huntingtin gene.

[0118] In some embodiments provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms thereof in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and at least one analog compound of pridopidine (Compounds 1-7) or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti-dopaminergic medication (ADM).

[0119] In some embodiments provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms thereof in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and at least Compound 1 and / or Compound 4 or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti-dopaminergic medication (ADM).

[0120] In some embodiments provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms thereof in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and at least one analog compound of pridopidine (Compounds 1-7) or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti-dopaminergic medication (ADM), wherein the ADM and its dose comprise:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

[0121] In some embodiments provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of oneP-638896-PC or more symptoms thereof in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and Compound 1 or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti- dopaminergic medication (ADM), wherein the ADM and its dose comprise:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

[0122] In some embodiments provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms thereof in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and Compound 4 or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti- dopaminergic medication (ADM), wherein the ADM and its dose comprise:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

[0123] In some embodiments provided herein a method of treatment, prevention, alleviation, slowing of progression of Huntington disease or maintaining, reducing or delaying onset of one or more symptoms thereof in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and Compound 1 and Compound 4 or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an anti-dopaminergic medication (ADM), wherein the ADM and its dose comprise: Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day;P-638896-PC wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

[0124] In some embodiments the composition comprising pridopidine, and the composition comprising ADM are administered sequentially or concomitantly in either order.

[0125] In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof is administered once a day. In another embodiment, the composition comprising pridopidine or pharmaceutically acceptable salt thereof and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof is administered twice per day. In another embodiment, the composition is administered three times per day. In another embodiment, the composition is administered daily, weekly, bi-weekly, every two weeks, every month, every 2 months, once in 3 months, once in 6 months, once a year, together or before or after the second compound in the combination.

[0126] In another embodiment, the composition comprising ADM is administered once a day. In another embodiment, the composition comprising ADM is administered twice per day. In another embodiment, the composition comprising ADM is administered three times per day. In another embodiment, the composition is administered daily, weekly, bi-weekly, every two weeks, every month, every 2 months, once in 3 months, once in 6 months, once a year, together or before or after the second compound in the combination.

[0127] In another embodiment, wherein the composition comprising pridopidine or pharmaceutically acceptable salt thereof and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof, and the composition comprising ADM are each independently administered once a day. In another embodiment, the compositions are each independently administered twice per day. In another embodiment, the compositions are each independently administered three times per day. In another embodiment, the compositions are each independently administered once a week, twice weekly, three times a week. In another embodiment, the compositions are each independently administered once daily, twice daily, three times daily, four times daily, or less than once a day. In some embodiments, the compositions are administered at different intervals.

[0128] In some embodiments the composition comprising pridopidine, and the composition comprising ADM for use in the methods of this invention each independently administered or through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route. In other embodiments, the composition comprising pridopidine, and the composition comprising ADM for use in the methods of this invention are each orally administered.P-638896-PC

[0129] In another embodiment, the composition comprising ADM is administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical, intracranial, or intradermal route. In another embodiment, the composition comprises pridopidine and optionally at least one analog compound of pridopidine is administered through an oral route.

[0130] In an embodiment of the methods of the invention, the combination therapy provided herein is for at least 12 weeks. In another embodiment of the methods of the invention, the combination therapy provided herein is for at least 26 weeks. In another embodiment of the methods of the invention, the combination therapy is for at least 52 weeks. In another embodiment of the methods of the invention, the combination therapy is for at least 65 weeks. In another embodiment of the methods of the invention, the combination therapy is for at least 78 weeks. In another embodiment of the methods of the invention, the combination therapy is for at least 1, 2, 3, 4 or 5 years. In another embodiment, the combination therapy is for over 5 years, over 6 years, over 7 years, over 8 years, over 9 years, or over 10 years.

[0131] In an embodiment, the treatment provided herein comprises reducing one or more symptoms of Huntington disease.

[0132] “Combination therapy” refers herein to the treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of Huntington disease (HD) in a subject by administering a combination of a composition comprising pridopidine or pharmaceutically acceptable salt thereof, optionally and at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a second composition comprising low dose of ADM.

[0133] 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 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.

[0134] As used herein, an amount of pridopidine as measured in milligrams refers to the milligrams of pridopidine (4- [3 -(methyl sulfonyl) phenyl]- 1-propyl-piperi dine) 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 base 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, theP-638896-PC 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.

[0135] In some embodiments, “inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and / or disease complication in the subject.EXAMPLESPROOF-HD - Clinical study to assess the effect pridopidine and compound 1 and / or 4 and Low dose ADMs in patients with HD.

[0136] PROOF-HD was a 78-week, phase 3, multicenter, randomized, double-blind, placebo- controlled, parallel-group study designed to assess the effectiveness and safety of pridopidine and compound 1 and / or 4 and Low dose ADMs effect in patients with HD.

[0137] The study demonstrated that the combination of pridopidine with compound 1 and 4 and Low dose ADMs have a positive impact in HD patients by maintaining and mitigating the decline in functional capacity, cognitive abilities and motor function as detailed in the various measurements described below.

[0138] In the results presented below, unless specified otherwise, low dose ADMs refer to a combination of low dose tetrabenazine (<50 mg), deutetrabenazine (<30 mg), aripiprazole (<5 mg), tiapride (<50 mg), and quetiapine (<50 mg / day).EXAMPLE 1Pridopidine with compounds 1 and 4 with Low dose ADMs show a statistically significant and clinically meaningful improvement in global disease progression as measured by cUHDRS.

[0139] The composite Unified Huntington's Disease Rating Scale (cUHDRS) is a validated and sensitive clinical scale for evaluating the disease progression of HD patients. Global progression in HD as measured by the cUHDRS includes function, motor and cognitive assessment and is the most sensitive scale to evaluate patients’ overall function and disease state. cUHDRS provides a quantitative holistic measure of patient experience. The scales included in cUHDRS are the Total Motor Scale (TMS, a motor assessment), Total Functional Capacity (TFC, a functional assessment), the Symbol Digit Modality Test (SDMT, a cognitive assessment), and the Stroop Word Reading Test (SWR, a cognitive assessment).P-638896-PC

[0140] This composite measure characterizes the clinical progression of HD and is strongly associated with brain measures of progressive atrophy in the corticostriatal tract relevant to the disease. The cUHDRS increases the low signal -to-noise ratio (S / N) that afflicts the individual measures and provides a good coverage of key features including functional, motor, and cognitive assessments in the early HD population

[0028]

[0141] Pridopidine with compounds 1 and 4 with Low dose ADMs showed significant improvement in cUHDRS compared to the placebo with Low dose ADMs group at Week 26 (DO.75, p=0.04), Week 39 (DO.4), and Week 52 (DO.73, p=0.09) and meaningful slowing of decline in cUHDRS at Week 65 (AO.45) and Week 78 (AO.43) as shown in Figure 1 and Table 1.Table 1: Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo & Low ADMs in HD patients. Positive change indicates improvement.EXAMPLE 2Pridopidine with compounds 1 and 4 and Low dose Tetrabenazine (<=50 mg / day) showed a clinically meaningful improvement or slowing of decline in global disease progression compared to placebo and low dose Tetrabenazine as measured by cUHDRS.

[0142] Pridopidine with compounds 1 and 4 and Low dose Tetrabenazine showed slowing of decline in cUHDRS compared to the placebo & low dose Tetrabenazine group at Week 26 (A 0.5), Week 39 (A0.55), Week 52 (A0.4). Week 65 (A0.39) and Week 78 (A0.37) as shown in Figure 2 and Table 2.P-638896-PCTable 2: Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose Tetrabenazine and placebo & Low dose Tetrabenazine in HD patients. Positive change indicates improvement.EXAMPLE 3Pridopidine with compounds 1 and 4 and Low dose deutetrabenazine (<30 mg / day) showed an improvement in global disease progression as measured by cUHDRS compared to placebo with low dose deutetrabenazine.

[0143] Pridopidine with compounds 1 and 4 and Low dose deutetrabenazine showed an improvement in global disease progression compared to the placebo group at Week 26 (AO.66 points), Week 39 (AO.16 points), Week 52 (AO.16 points), Week 65 (AO.6 points), and Week 78 (AO.45 points) as shown in Figure 3 and Table 3.Table 3: Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose deutetrabenazine and placebo and Low dose deutetrabenazine in HD patients. Positive change indicates improvement.P-638896-PCEXAMPLE 4Pridopidine with compounds 1 and 4 and Low dose quetiapine (<=50 mg / day) showed improvement or slowing of decline in global disease progression compared to placebo with low dose quetiapine as measured by cUHDRS.

[0144] Pridopidine with compounds 1 and 4 and Low dose quetiapine (<=50 mg / day) showed improvement in cUHDRS compared to the placebo and Low dose quetiapine group at Week 26 (A 0.97), Week 39 (Al.11), Week 52 (A0.89), Week 65 (A0.83) an, week 78 (A0.76) as shown in Figure 4 and Table 4.Table 4: Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose quetiapine and placebo and Low dose quetiapine in HD patients. Positive change indicates improvement.EXAMPLE 5Pridopidine with compounds 1 and 4 and Low dose aripiprazole (<=5mg / day) showed a statistically significant and clinically meaningful improvement or slowing of decline in global disease progression compared to placebo with Low dose aripiprazole as measured by cUHDRS.

[0145] Pridopidine with compounds 1 and 4 and Low dose aripiprazole show meaningful improvement in cUHDRS compared to the placebo and Low dose aripiprazole group at Week 26(Al.94), Week 39 (A2.08), Week 52 (Al.86), Week 65 ( Al.79) and Week 78 (A2.17), as shown in Figure 5 and Table 5.P-638896-PCTable 5: Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose aripiprazole and placebo in HD patients. Positive change indicates improvement. Low dose aripiprazole <= 5mg / day.EXAMPLE 6Pridopidine with compounds 1 and 4 and Low dose Tiapride (<50 mg / day) showed a statistically significant and clinically meaningful improvement or slowing of decline in global disease progression compared to placebo with Low dose Tiapride as measured by cUHDRS.

[0146] Pridopidine with compounds 1 and 4 and Low dose Tiapride show meaningful improvement in cUHDRS compared to the placebo and Low dose Tiapride group at Week 26 (A 1.95), Week 39 (A2.23), Week 52 (A 1.92), Week 65 (A 2.06) and Week 78 (A 2.25) as shown in Figure 6 and Table 6.Table 6: Change from baseline to Weeks 26, 39, 52, 65 and 78 in cUHDRS score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low dose Tiapride and placebo in HD patients. Positive change indicates improvement. Low dose Tiapride <50 mg / day.EXAMPLE 7P-638896-PCPridopidine with compounds 1 and 4 and Low dose ADMs showed improvement in functional capacity in HD patients compared to placebo.

[0147] The UHDRS-TFC is a validated and widely used clinical scale for assessing the functional capacity of subjects with HD, assessing patient’s disease stage. This score ranges from 0 to 13 with higher scores indicating 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.

[0148] Pridopidine with compounds 1 and 4 with Low dose ADMs showed improvement in UHDRS-TFC compared to the placebo with Low dose ADMs group at Week 26 (A 0.79, p=0.07), Week 39 (A 0.21), and Week 52 (A 0.72) and meaningful slowing of decline in UHDRS-TFC at Week 65 (A 0.20) and Week 78 (A 0.32) as shown in Figure 7 and Table 7.Table 7: Change from baseline to Weeks 26, 39, 52, 65 and 78 in UHDRS-TFC score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs vs placebo and Low ADMs in HD patients. Positive change indicates improvement.EXAMPLE 8Pridopidine in combination with compound 1 and 4 and Low dose ADMs showed improvement in cognitive function compared to placebo with Low dose ADMs as measured by Stroop Word Reading (SWR) test.

[0149] The Stroop Word Reading (SWR) test is a validated and widely used clinical measure of cognitive function. The Stroop Word Reading Test assesses the ability to inhibit cognitive interference and is commonly used to evaluate executive function, including cognitive flexibility and attentional control. This creates a cognitive conflict that requires the inhibition of a prepotent response to read the word, making the test challenging. The SWR score is determined by assessingP-638896-PC 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.

[0150] Pridopidine with compounds 1 and 4 and Low dose ADMs show an improvement on SWR scale compared to placebo with Low dose ADMs up to 78 weeks. Week 26 (A 5.38, p=0.07), Week 39 (A1.78), Week 52 (A2.82), Week 65 (A3.42) and Week 78 (A2.22) as shown in Figure 8 and Table 8.Table 8: Change from baseline to Weeks 26, 39, 52 ,65 and 78 in SWR score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo and Low ADMs in HD patients. Positive change indicates improvement.EXAMPLE 9Pridopidine in combination with compound 1 and 4 and Low ADMs showed meaningful improvement in motor function compared to placebo and Low ADMs as measured by TMS.

[0151] The Total Motor Score (TMS) is a widely used clinical measure for assessing motor function in individuals with Huntington's Disease (HD). The TMS evaluates a range of motor symptoms associated with HD. During the TMS assessment, a clinician observes, and rates various motor tasks performed by the patient. The TMS score is calculated based on the severity and frequency of motor abnormalities, with higher scores indicating more severe motor impairment and progression of the disease.

[0029]

[0152] Pridopidine with compounds 1 and 4 and Low dose ADMs showed improvement in TMS score compared to the placebo and Low dose ADMs group at Week 26 (A-3.11), Week 39 (A - 2.27), Week 52 (A -10.12, p=0.05), Week 65 (A -1.64) and Week 78 (A-2.78) (Negative change in TMS indicates improvement), as shown in Figure 9 and Table 9.P-638896-PCTable 9: Change from baseline to Weeks 26, 52 ,65 and 78 in TMS score.Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo and Low ADMs in HD patients. Negative change indicates improvementEXAMPLE 10Pridopidine in combination with compound 1 and 4 and Low ADMs showed improvement in motor function compared to placebo and Low ADMs as measured by Quantitative Motor (Q-Motor) measures.

[0153] Q-Motor is a quantitative, objective, and sensitive measure of motor function that is widely used in HD clinical trials. The Q-Motor test uses force transducers to provide measures of speed and self-paced tapping of hands and fingers. In the Q-Motor test, the interval between taps of the hand or index finger is measured using a Q-Motor device, which can objectively assess motor impairments. Q-Motor assessments are objective, reliable and highly sensitive. In clinical trials of subjects with HD the Q-Motor tool has proven to be helpful to detect and quantitate subtle motor abnormalities. Thus, Q-Motor assessments reduce rater variability and are not susceptible to placebo effects.

[0030] Pridopidine in combination with compound 1 and 4 and Low dose ADMs show meaningful improvement compared to placebo with Low dose ADMs in motor function as measured by Q- Motor- Pro-Sup-Inter-Onset-Interval-SD-Hand (ms).

[0154] One of the parameters measured during the assessment of motor function is the Pro-Sup- Inter-Onset-Interval-SD-Hand (ms). This parameter evaluates the variability in the time intervals between consecutive pronation-supination movements of the hand.

[0155] In a typical Q-Motor test for assessing this parameter, individuals are asked to perform a series of repetitive pronation (turning the hand palm down) and supination (turning the hand palm up) movements. The Q-Motor device captures the timing of each movement, specifically focusingP-638896-PC on the interval between the onset of one pronation or supination movement and the onset of the next.

[0156] The Pro-Sup-Inter-Onset-Interval-SD-Hand (ms) represents the standard deviation of these intervals, providing a measure of the consistency and regularity of the motor task. In other words, it quantifies how much the intervals between consecutive pronation-supination movements vary over the course of the test.

[0157] In individuals with Huntington's disease (HD), increased variability in the Pro-Sup-Inter- Onset-Interval-SD-Hand (ms) can indicate motor control deficits and impaired coordination. This parameter is valuable in clinical trials for detecting subtle motor abnormalities and tracking changes in motor function over time. The sensitivity and objectivity of the Pro-Sup-Inter-Onset- Interval-SD-Hand (ms) make it a reliable measure for evaluating the effectiveness of therapeutic interventions and understanding the progression of motor impairments in HD.

[0158] Pridopidine with compounds 1 and 4 and Low dose ADMs showed improvement in Pro- Sup-Inter-Onset-Interval-SD-Hand (ms) score compared to the placebo with Low dose ADMs group at Week 26 (A-31.49), Week 52 (A -31.53), Week 65 (A -36.64) and Week 78 (A -19.80) (Negative change indicates improvement), as shown in Figure 10 and Table 10.Table 10: Change from baseline to Weeks 26, 52 ,65 and 78 in Q-Motor- Inter-Onset-Interval-SD-Hand (ms).Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo and Low dose ADMs in HD patients. Negative change indicates improvementPridopidine in combination with compound 1 and 4 and Low ADMs showed meaningful improvement in motor function compared to Placebo with Low dose ADMs as measured by Q- Motor- Pro-Sup-Inter-Tap-Interval-SD-Hand (ms).P-638896-PC

[0159] One of the parameters measured during the assessment of motor function is the Pro-Sup- Inter-Tap-Interval-SD-Hand (ms). This parameter evaluates the variability in the time intervals between consecutive taps during pronation-supination movements of the hand. This metric is crucial for assessing motor function and coordination in clinical settings, especially in the context of Huntington's disease (HD).

[0160] During a Q-Motor test to measure this parameter, individuals are instructed to perform repetitive pronation (turning the hand palm down) and supination (turning the hand palm up) movements, while also tapping a designated surface at specific intervals. The Q-Motor device records the timing of each tap, focusing on the interval between the onsets of consecutive taps.

[0161] The Pro-Sup-Inter-Tap-Interval-SD-Hand (ms) represents the standard deviation of these intervals, providing a measure of the variability or consistency of the tapping intervals during the pronation-supination movements. A higher standard deviation indicates greater variability, suggesting impaired motor control and coordination.

[0162] In HD, increased variability in the Pro-Sup-Inter-Tap-Interval-SD-Hand (ms) is indicative of motor dysfunction and coordination issues, which are characteristic symptoms of the disease. This parameter is particularly useful in clinical trials for detecting subtle motor abnormalities and monitoring changes in motor function over time. The high sensitivity and objectivity of the Pro-Sup-Inter-Tap-Interval-SD-Hand (ms) make it an effective tool for evaluating therapeutic interventions and understanding the progression of motor impairments in HD.

[0163] Pridopidine with compounds 1 and 4 and Low dose ADMs showed improvement in Pro- Sup-Inter-Onset-Interval-SD-Hand (ms) score compared to the placebo and Low dose ADMs group at Weel 26 (A -22.35), Week 52 (A -28.86), Week 65 (A -29.90) and Week 78 (A -13.33) (Negative change indicates improvement), as shown in Figure 11 and Table 11.P-638896-PCTable 11: Change from baseline to Weeks 26, 52 ,65 and 78 in Q-Motor- Pro-Sup-Inter-Tap- Interval-SD-Hand (ms).Data from PROOF-HD phase 3 trial. Per protocol population. Effect of pridopidine 45 mg bid in combination with compound 1 and 4 and Low ADMs and placebo and low dose ADMs in HD patients. Positive change indicates worsening.

[0164] In summary, pridopidine, in combination with compounds 1 and 4 and Low dose ADMs exhibits remarkable and expected benefits in terms of function, motor skills and cognitive function.P-638896-PCREFERENCES o Mahant N, McCusker EA, Byth K, Graham S. Huntington’s disease: Clinical correlates of disability and progression. Neurology. 2003. o S.J. Tabrizi; R. Ghosh; B. R. Leavitt, Huntingtin Lowering Strategies for Disease Modification in Huntington’s Disease. Neuron, 2019, Vol 101 (5), 801-819. o Frank S, Testa CM, Stamler D, Kayson E, Davis C, Edmondson MC, et al. Effect of deutetrabenazine on chorea among patients with Huntington disease: A randomized clinical trial. JAMA - J Am Med Assoc. 2016. o Shen V, Clarence-Smith K, Hunter C, Jankovic J. Safety and Efficacy of Tetrabenazine and Use of Concomitant Medications During Long-Term, Open-Label Treatment of Chorea Associated with Huntington’s and Other Diseases. Tremor Other Hyperkinet Mov (N Y). 2013. o Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savoia J-M, et al. Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques. Mov Disord [Internet], 2018 Dec 21 [cited 2019 Mar 11]; Available from: http: / / doi.wiley.com / 10.1002 / mds.27565 o Hayashi T, Su T-. The Sigma Receptor: Evolution of the Concept in Neuropsychopharmacology. Curr Neuropharmacol. 2005; 3(4):267-80. o Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE. The sigma- 1 receptor chaperone as an inter-organelle signaling modulator. Trends in Pharmacological Sciences. 2010. o Geva M, Kusko R, Soares H, et al. Pridopidine activates neuroprotective pathways impaired in Huntington Disease. Hum Mol Genet 2016; 25: 3975-3987. o Ryskamp D, Wu L, Wu J, et al. Pridopidine stabilizes mushroom spines in mouse models of Alzheimer’s disease by acting on the sigma-1 receptor. Neurobiol Dis 2019; 124: 489-504. o Francardo V, Geva M, Bez F, et al. Pridopidine Induces Functional Neurorestoration Via the Sigma- 1 Receptor in a Mouse Model of Parkinson’s Disease. Neurother J Am Soc Exp Neurother 2019; 16: 465-479. o Naia L, Ly P, Mota SI, et al. The Sigma- 1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models. Neurother J Am Soc Exp Neurother 2021; 18: 1017-1038.P-638896-PC o Shenkman M, Geva M, Gershoni-Emek N, et al. Pridopidine reduces mutant huntingtin- induced endoplasmic reticulum stress by modulation of the Sigma- 1 receptor. J Neurochem 2021; 158: 467-481. o Lenoir S, Lahaye RA, Vitet H, et al. Pridopidine rescues BDNF / TrkB trafficking dynamics and synapse homeostasis in a Huntington disease brain-on-a-chip model. Neurobiol Dis 2022; 173: 105857. o Nikkhah A. A Brief Review on the Role of Vesicular Monoamine Transported Inhibitors inHyperkinetic Movement Disorders. Iran J Child Neurol. 2021 Summer;15(3):29-33. doi: 10.22037 / ijcn.vl5i3.33144. PMID: 34282360; PMCID: PMC8272547. o Li P, Snyder GL, Vanover KE. Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future. Curr Top Med Chem. 2016;16(29):3385-3403. doi: 10.2174 / 1568026616666160608084834. PMID: 27291902; PMCID: PMC5112764. o Shirzadi AA, Ghaemi SN. Side effects of atypical antipsychotics: extrapy rami dal symptoms and the metabolic syndrome. Harv Rev Psychiatry. 2006 May-Jun; 14(3): 152-64. doi: 10.1080 / 10673220600748486. PMID: 16787887. o Schobel SA, Palermo G, Auinger P, Long JD, Ma S, Khwaja OS, Trundell D, Cudkowicz M, Hersch S, Sampaio C, Dorsey ER, Leavitt BR, Kieburtz KD, Sevigny JJ, Langbehn DR, Tabrizi SJ; TRACK -HD, COHORT, CARE-HD, and 2CARE Huntington Study Group Investigators. Motor, cognitive, and functional declines contribute to a single progressive factor in early HD. Neurology. 2017 Dec 12;89(24):2495-2502. doi: 10.1212 / WNL.0000000000004743. Epub 2017 Nov 15. PMID: 29142089; PMCID: PMC5729794. o Donaldson J, Powell S, Rickards N, Holmans P, Jones L. What is the Pathogenic CAG Expansion Length in Huntington's Disease? J Huntingtons Dis. 2021; 10(1): 175-202. doi: 10.3233 / JHD-200445. PMID: 33579866; PMCID: PMC7990448. o Claassen DO, Ayyagari R, Garcia-Horton V, Zhang S, Alexander J, Leo S. Real-World Adherence to Tetrabenazine or Deutetrabenazine Among Patients With Huntington's Disease: A Retrospective Database Analysis. Neurol Ther. 2022 Mar;l l(l):435-448. doi: 10.1007 / s40120- 021-00309-5. Epub 2021 Dec 14. PMID: 34905160; PMCID: PMC8857359. o Uhlyar S, Rey JA. Valbenazine (Ingrezza): The First FDA- Approved Treatment for Tardive Dyskinesia. P T. 2018 Jun;43(6):328-331. PMID: 29896031; PMCID: PMC5969209. o Yero T, Rey JA. Tetrabenazine (Xenazine), An FDA-Approved Treatment Option For Huntington's Disease-Related Chorea. P T. 2008 Dec;33(12):690-4. PMID: 19750050; PMCID: PMC2730806.P-638896-PC o Dean M, Sung VW. Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease. Drug Des Devel Ther. 2018 Feb 15;12:313-319. doi: 10.2147 / DDDT.S138828. PMID: 29497277; PMCID: PMC5818866. o Ciammola A, Sassone J, Colciago C, Mencacci NE, Poletti B, Ciarmiello A, Squitieri F, Silani V. Aripiprazole in the treatment of Huntington's disease: a case series. Neuropsychiatr Dis Treat. 2009;5: 1-4. Epub 2009 Apr 8. PMID: 19557093; PMCID: PMC2695210. o Alpay M, Koroshetz WJ. Quetiapine in the treatment of behavioral disturbances in patients with Huntington's disease. Psychosomatics. 2006 Jan-Feb;47(l):70-2. doi:10.1176 / appi.psy.47.1.70. PMID: 16384811. o Feleus S, van Schaijk M, Roos RAC, de Bot ST. The Many Faces of Huntington's Chorea Treatment: The Impact of Sudden Withdrawal of Tiapride after 40 Years of Use and a Systematic Review. J Pers Med. 2022 Apr 6;12(4):589. doi: 10.3390 / jpml2040589. PMID: 35455705; PMCID: PMC9025785. o Duff K, Beglinger LJ, O'Rourke ME, Nopoulos P, Paulson HL, Paulsen JS. Risperidone and the treatment of psychiatric, motor, and cognitive symptoms in Huntington's disease. Ann Clin Psychiatry. 2008 Jan-Mar;20(l): l-3. doi: 10.1080 / 10401230701844802. PMID: 18297579; PMCID: PMC3806309. o Squitieri F, Cannella M, Porcellini A, Brusa L, Simonelli M, Ruggieri S. Short-term effects of olanzapine in Huntington disease. Neuropsychiatry Neuropsychol Behav Neurol. 2001 Jan; 14(l):69-72. PMID: 11234911. o Schobel SA, Palermo G, Auinger P, Long JD, Ma S, Khwaja OS, Trundell D, Cudkowicz M, Hersch S, Sampaio C, Dorsey ER, Leavitt BR, Kieburtz KD, Sevigny JJ, Langbehn DR, Tabrizi SJ; TRACK-HD, COHORT, CARE-HD, and 2CARE Huntington Study Group Investigators. Motor, cognitive, and functional declines contribute to a single progressive factor in early HD. Neurology. 2017 Dec 12;89(24):2495-2502. doi: 10.1212 / WNL.0000000000004743. Epub 2017 Nov 15. PMID: 29142089; PMCID: PMC5729794. o Mestre TA, Forjaz MJ, Mahlknecht P, Cardoso F, Ferreira JJ, Reilmann R, Sampaio C, GoetzCG, Cubo E, Martinez-Martin P, Stebbins GT; Members of the Movement Disorder Society Committee on Rating Scales Development. Rating Scales for Motor Symptoms and Signs in Huntington's Disease: Critique and Recommendations. Mov Disord Clin Pract. 2018 Jan 3;5(2): H I- 117. doi: 10.1002 / mdc3.12571. PMID: 30363393; PMCID: PMC6174417. o Reilmann R, McGarry A, Grachev ID, Savoia JM, Borowsky B, Eyal E, Gross N, Langbehn D, Schubert R, Wickenberg AT, Papapetropoulos S, Hayden M, Squitieri F, Kieburtz K, Landwehrmeyer GB; European Huntington's Disease Network; Huntington Study Group investigators. Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD):P-638896-PC a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 2019 Feb; 18(2): 165-176. doi: 10.1016 / S1474-4422(18)30391-0. Epub 2018 Dec 15. PMID: 30563778.

Claims

P-638896-PCCLAIMSWhat is claimed is:

1. A method of treatment, prevention, alleviation, slowing of progression of Huntington disease (HD) or maintaining, reducing or delaying onset of one or more symptoms of HD in a subject, comprising administering a composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof, and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and a composition comprising a low dose of an antidopaminergics medication (ADM), wherein the ADM and its dose comprise any vesicular monoamine transporter 2 (VMAT2) inhibitors and neuroleptics administered at lower than the recommended dosage.

2. The method of claim 1, wherein the ADM and its dose comprise: Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

3. The method of claim 1, wherein the method comprises administering pridopidine or pharmaceutically acceptable salt thereof in an amount of 90 mg / day.

4. The method of claim 2, wherein the method comprises administering pridopidine or pharmaceutically acceptable salt thereof in an amount of 45 mg twice per day.

5. The method of any one of claims 1-3, wherein the Valbenazine is administered in an amount of lower than or equal to 40 mg / day; between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day; or between 30 mg / day to 40 mg / day.

6. The method of any one of claims 1-3, wherein the Tetrabenazine is administered in an amount of lower than or equal to 50 mg / day; between 5 mg / day to 15 mg / day; between 15 mg / day to 25 mg / day; between 25mg / day to 40 mg / day; or between 35 mg / day to 50 mg / day.

7. The method of any one of claims 1-3, wherein the deutetrabenazine is administered in an amount lower than 30 mg / day; between 5 mg / day to 15 mg / day; between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day.P-638896-PC8. The method of any one of claims 1-3, wherein the Aripiprazole is administered in an amount lower than or equal to 5 mg / day; between 0.5mg / day to 2 mg / day, between 2 mg / day to 4 mg / day, between 3 mg / day to 5 mg / day.

9. The method of any one of claims 1-3, wherein the Quetiapine is administered in an amount lower than or equal to 50 mg / day; between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day; between 30 mg / day to 40 mg / day; or between 40 mg / day to 50 mg / day.

10. The method of any one of claims 1-3, wherein the Tiapride is administered in an amount lower than or equal to 50 mg / day; between 10 mg / day to 20 mg / day; between 20 mg / day to 30 mg / day; between 30 mg / day to 40 mg / day; or between 40 mg / day to 50 mg / day.

11. The method of any one of claims 1-3, wherein the Risperidone is administered in an amount lower than or equal to 0.5 mg / day: between 0.1 mg / day to 0.25 mg / day, between 0.25 mg / day to 0.4 mg / day, between 0.4 mg / day to 0.5 mg / day.

12. The method of any one of claims 1-3, wherein the Olanzapine is administered in an amount lower than or equal to 5 mg / day: between 1 mg / day to 3 mg / day or between 2 mg / day to 5 mg / day.

13. The method of any one of claims 1-12 wherein the analog compound of pridopidine is represented by the structures of compound 1-7 as represented below:P-638896-PC14. The method of any one of claims 1-13, wherein the pridopidine and optionally at least one analog compound of pridopidine is in the form of a salt thereof.

15. The method of claim 14, wherein the salt is selected from the group consisting from hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, phosphate, acid-phosphate, sulphate, bisulfate, formate, gluconate, glucaronate, saccharate, isonicotinate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, gentisinate, malonate, mandelate, methanesulfonate, ethanesulfonate, naphthalene-2-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, pantothenate, bitartrate, and toluene-p-sulfonate, pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salt.

16. The method of claim 14, wherein the pridopidine salt is pridopidine hydrochloride.

17. The method of any one of claims 13-16, wherein the method comprises administering an effective amount of a composition comprising pridopidine or pharmaceutically acceptable salt thereof and Compound 1 or pharmaceutically acceptable salt thereof; and a composition comprising low dose an antidopaminergics medication (ADM), wherein the ADM and its dose comprises:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

18. The method of any one of claims 13-16, wherein the method comprises administering an effective amount of a composition comprising pridopidine or pharmaceutically acceptable salt thereof and Compound 4 or pharmaceutically acceptable salt thereof; and a composition comprising low-dose antidopaminergics medication (ADM), wherein the ADM and its dose comprises:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day;P-638896-PCRisperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

19. The method of any one of claims 13-16, wherein the method comprises administering an effective amount of a composition comprising pridopidine or pharmaceutically acceptable salt thereof with Compound 1 and Compound 4 or pharmaceutically acceptable salt thereof; and a composition comprising low dose antidopaminergics medication (ADM), wherein the ADM and its dose comprises:Valbenazine in an amount lower than or equal to 40 mg / day; Tetrabenazine in an amount lower than or equal to 50 mg / day; deutetrabenazine in an amount lower than 30 mg / day; Aripiprazole in an amount lower than or equal to 5 mg / day; Quetiapine in an amount lower than or equal to 50 mg / day; Tiapride in an amount lower than or equal to 50 mg / day; Risperidone in an amount lower than or equal to 0.5 mg / day; or Olanzapine in an amount lower than or equal to 5 mg / day; wherein the pridopidine or pharmaceutically acceptable salt thereof is administered in an amount of between 5 mg / day to 180 mg / day.

20. The method of any one of claims 1-19, wherein the composition comprising pridopidine and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and the composition comprising low-dose antidopaminergics medication (ADM) are each independently administered through oral, nasal, inhalation, intracranial, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route.

21. The method of claim 20, wherein the composition comprising pridopidine and optionally at least one analog compound of pridopidine or pharmaceutically acceptable salt thereof; and the composition comprising antidopaminergics medication (ADM) are each orally administered.

22. The method of any one of claims 1-21, wherein the composition comprising pridopidine and optionally at least one analog compound or pharmaceutically acceptable salt thereof; and the composition comprising an antidopaminergics medication (ADM) are administered sequentially or concomitantly in either order.

23. The method of claim any one of claims 1-22, wherein the one or more symptoms comprise:P-638896-PC(i) impairment in functional capacity (ii) impairment in motor function (iii) impairment in cognitive function; (iv) reduction in quality of life (v) decline in patient’s mobility (vi) decline in patient’s involuntary movements (vii) dystonia (viii) gait and balance (ix) chorea (x) decline in motor ability as assessed by Q-Motor (xi) decline in patient’s ability to perform activities of daily living (xii) decline in patient’ s behavior and / or psychiatric state (xiii) lack of initiative or apathy (xiv) anxiety (xv) depression (xvi) irritability (xvii) mental symptom or an emotional symptom (xviii) reduced lifespan (xix) memory impairment (xx) elevation in anti-inflammatory biomarkers, reduction in Brain-Derived Neurotrophic Factor (BDNF), increase of neurofilament light chain (NfL); or (xxi) deterioration of structural, functional, and metabolic measures in the brain.

24. The method of claim 23, wherein human patient's functional capacity is measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Functional Capacity (TFC).

25. The method or use of any one of claim 24, wherein the functional capacity, motor function, cognition and quality of life is measured by a composite Unified Huntington's Disease Rating Scale (cUHDRS).

26. The method of claim 25, wherein the motor function impairment is measured by the composite Unified Huntington's Disease Ratings Scale (cUHDRS), Total Motor Score (TMS), Quantitative motor (Q-Motor) assessment, the Unified Huntington's Disease Rating Scale (UHDRS) the Unified Huntington's Disease Rating Scale (UHDRS) modified Motor Score (mMS), and 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), eye movement score, hand movement score, gait and balance score, timed up and go (TUG) assessment, The Huntington Disease Health Index (HD-HI), or by Digitomotography (finger tapping) assessment.

27. The method of claim 23, wherein the motor functional impairment is measured by digitomotography (speeded index finger tapping), dysdiadochomotography (pronation / supination hand tapping), manumotography and choreomotography (grip force and chorea analysis) and pedomotography (speeded foot tapping).

28. The method of claim 23, wherein the patient's mental symptom, emotional symptom, behavioral symptoms, cognition impairment is measured by Problem Behaviors Assessment (PB A) total score, PB A for depressed mood, PB A for irritability, PBA for lack of initiative or apathy, PBA for obsessive-compulsiveness, or by PBA for disoriented behavior, the trailP-638896-PC making test B (TMT-B), The HD Cognitive Assessment Battery (HD-CAB), Hamilton Rating Scale for Depression (HAM-D), Problem Behaviors Assessment-Short (PBA-S) scale, PBA short form apathy sub-item, Apathy Evaluation Scale (AES). Hamilton Anxiety Scale (HAM- A), Hospital Anxiety and Depression Scale (HADS-A), Leibowitz Social Anxiety Scale (LSAS), Overall Anxiety Severity and Impairment Scale (OASIS), Panic and Agoraphobia Scale (PAS), Panic Disorder Severity Scale (PDSS), PTSD Symptom Scale - Self-Report Version, Stroop word reading test (SWR), Symbol Digit Modalities Test (SDMT) or cognitive assessment battery (CAB).

Images