Pridopidine for the treatment of distal hereditary motor neuropathy (DHMN)

Abstract

The present invention relates to a method for treating, reducing the incidence of, suppressing, or inhibiting a motor neuropathy or symptoms thereof, specifically, distal hereditary motor neuropathy (dHMN), by administering a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

Description

P-622173-PC PRIDOPIDINE FOR THE TREATMENT OF MOTOR NEUROPATHIES OR SYMPTOMS THEREOF FIELD OF THE INVENSION

[0001] The present invention relates to methods for treating, reducing the incidence of, suppressing, or inhibiting motor neuropathies, specifically, distal hereditary motor neuropathy (dHMN). BACKGROUND OF THE INVENTION

[0002] Peripheral neuropathy refers to any disorder that affects the peripheral nervous system. One common type of peripheral neuropathy is motor neuropathy, which specifically affects the motor nerves responsible for controlling muscle movement. This condition can lead to a range of symptoms, including muscle weakness, cramps, and atrophy, and it can impact both the upper and lower limbs. As a result, motor neuropathy can significantly impact a person's quality of life, making it difficult to perform everyday tasks and activities. Effective treatment options for motor neuropathy remain limited, making it a crucial area of focus for ongoing research and development.

[0003] The classic phenotype of motor neuropathy typically includes muscle weakness, atrophy, and cramps. Other common symptoms may include fasciculations (involuntary muscle twitches), decreased reflexes, and sensory symptoms such as numbness or tingling (although these are less common in pure motor neuropathies). The pattern of muscle weakness may vary depending on the specific nerves affected, but it typically begins in the distal muscles of the hands and feet and may progress to involve the proximal muscles of the arms and legs.

[0004] Disease onset in motor neuropathy can occur at any age, but it is more commonly seen in adults. The exact age of onset and rate of disease progression can vary widely depending on the underlying cause of the neuropathy.

[0005] Distal Hereditary Motor Neuropathy (DHMN) is a specific type of motor neuropathy that affects the distal parts of the limbs, whereas motor neuropathy can refer to any condition that affects the motor nerves responsible for controlling muscle movement.

[0006] Hereditary motor neuronopathies (HMN) are a heterogenous group of disorders characterized by progressive degeneration of the motor component of the central nervous system. The classic phenotype of distal HMN (dHMN) includes symmetrical, length-dependent motor neuropathy that causes distal muscle weakness and atrophy, which usually appears with foot and hand deformities. dHMNs are heterogenous and may differ in their mode of inheritance, age of onset and clinical progression.P-622173-PC

[0007] Disease onset may occur in childhood or youth, in some forms of the disease, progression slows or stabilizes during adulthood. Additionally, some features of dHMN may include upper limb weakness, vocal cord paresis, diaphragmatic palsy or pyramidal features.

[0008] The clinical heterogeneity of dHMN is based on genetic heterogeneity, and to date, over 30 different genes have been identified as causing dHMN.

[0009] One of the genes identified in dHMN is the SIGMAR1 gene. Several different mutations in the SIGMAR1 gene can lead to dHMN. These include missense mutations and nonsense mutations. In a missense mutation, a single nucleotide changes lead to the substitution of an amino acid, which affects protein morphology and function but maintains low levels of protein function. In a nonsense mutation, a stop codon is introduced instead of an amino acid, resulting in a truncated, non-functional protein.

[0010] The Jerash type of dHMN (dHMNJ), is a distinct form of the disease originally identified in subjects from the Jerash region of Jordan. Clinical signs include progressive distal muscle weakness, pain and discomfort in feet and difficulties walking. Proximal muscles and sensory nerve conduction were unaffected.

[0011] Different mutations and phenotypes are summarized in Figure 1. In addition to the similar, progressive muscle wasting observed, all subjects also showed a positive Babinski response. In the Babinski test, a blunt stimulus is administered to the sole of the foot, and the response assessed. A positive Babinski sign occurs when the big toe moves upward and the other toes fan out. In adults and children over the age of 2 this can be indicative of a disorder of the central nervous system, specifically a dysfunction of the pyramidal tract. The combination of dHMN with pyramidal tract signs (e.g. a positive Babinski sign) is suggested to be a clinical presentation associated with coding sequence mutations in the S1R (Horga et al., SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. Neurology. 2016 Oct 11;87(15):1607-1612, which is incorporated herein by reference).

[0012] In addition to mutations in the SIGMAR1 gene, distal hereditary motor neuropathy (dHMN) can also result from mutations in other genes. These include, among others, mutations in SETX and DCTN1, further highlighting the genetic heterogeneity underlying dHMN. Pridopidine

[0013] Pridopidine (4-[3-(methylsulfonyl) phenyl]-1-propyl-piperidine) is a drug in clinical development for the treatment of HD and ALS. Pridopidine has a selective and high affinity for the sigma-1 receptor (S1R, binding IC50 ~ 100nM), with low-affinity binding to other receptors, including the dopamine D2 / D3 receptors (in the micromolar range).P-622173-PC SUMMARY OF THE INVENTION

[0014] In one embodiment, the present invention provides a method for treating, reducing the incidence of, suppressing, or inhibiting a distal hereditary motor neuropathy (dHMN) or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0015] In one embodiment, the present invention provides a method for treating, reducing the incidence of, suppressing, or inhibiting Jerash type of dHMN in a subject in need thereof comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] 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:

[0017] Figure 1 presents a table presenting genotype and clinical characteristics of SIGMAR1- related dHMN mutations. a. Homozygous unless otherwise denoted. b.+, present; −, absent c.−, absent / lost; +, sluggish; ++, normal; +++, brisk;exaggerated (with clonus). NA, not available The references cited in the Table of Figure 1: 1. Li X, Hu Z, Liu L, Xie Y, Zhan Y, Zi X, Wang J, Wu L, Xia K, Tang B, Zhang R. A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy. Neurology. 2015 Jun 16;84(24):2430-7. doi: 10.1212 / WNL.0000000000001680. Epub 2015 May 15. PMID: 26078401. 2. Lee SY, Kang MG, Park JS, Lee G, Ting AY, Rhee HW. APEX Fingerprinting Reveals the Subcellular Localization of Proteins of Interest. Cell Rep.2016 May 24;15(8):1837- 47. doi: 10.1016 / j.celrep.2016.04.064. Epub 2016 May 12. PMID: 27184847. 3. Ma et al., Mutations in the SIGMAR1 gene cause a distal hereditary motor neuropathy phenotype mimicking ALS: Report of two novel variants. Neuromuscul Disord.2020 Jul;30(7):572-575. 4. Gregianin et al., Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling, Human Molecular Genetics, Volume 25, Issue 17, 1 September 2016, Pages 3741–3753 5. Ververis A, Dajani R, Koutsou P, Aloqaily A, Nelson-Williams C, Loring E, Arafat A, Mubaidin AF, Horany K, Bader MB, Al-Baho Y, Ali B, Muhtaseb A, DeSpenza T Jr, Al-P-622173-PC Qudah AA, Middleton LT, Zamba-Papanicolaou E, Lifton R, Christodoulou K. Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation. J Med Genet.2020 Mar;57(3):178-186. doi: 10.1136 / jmedgenet-2019-106108. Epub 2019 Sep 11. PMID: 31511340; PMCID: PMC7042970. 6. Horga A, Tomaselli PJ, Gonzalez MA, Laurà M, Muntoni F, Manzur AY, Hanna MG, Blake JC, Houlden H, Züchner S, Reilly MM. SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome. Neurology.2016 Oct 11;87(15):1607-1612. doi: 10.1212 / WNL.0000000000003212. Epub 2016 Sep 14. PMID: 27629094; PMCID: PMC5067545.

[0018] Figures 2A-2B show Pridopidine increases S1R-BiP colocalization at the ER membrane. Figure 2A: NIH 3T3 cells expressing BiP-GFP. Figure 2B: NIH 3T3 cells expressing BiP-RFP. The cells were stained with anti-S1R antibodies and imaged. In B, cells were treated with 150 mM pridopidine for 24 hours. Colocalization was assessed using Mander’s coefficient (~30 cells / condition). *p<0.05, ***p<0.001.

[0019] Figure 3 shows Pridopidine increased neuronal cell survival in basal conditions.Pridopidine increased cell viability under basal conditions bỹ 50%. Immortalized mouse striatal cellswere (Q7- wild-type cells) incubated with pridopidine 0.01 µM for 24 hours. Cell viability was assessed using MTT assay. Data are normalized to the control / untreated condition and are represented as the mean ± S.E.M. of 12 independent experiments. *p<0.05 using Kruskal-Wallis test.

[0020] Figure 4 shows Pridopidine increased neuronal cell survival following oxidative stress. Pridopidine increased cell viability under oxidative stress conditions by ˜30%. Immortalized mouse striatal cells (Q7- wild-type cells) were incubated with pridopidine 0.001 µM for 24 hours. Oxidative stress was induced by H2O2(10 µM for 24 hours), which caused a ˜ 20% reduction in cell viability vs. control. Cell viability was assessed using MTT assay Data are normalized to the control / untreated condition and are represented as the mean ± S.E.M. of 3-12 independent experiments.**p<0.01vs H2O2 using Kruskal-Wallis test. Source: Cristina Rego, unpublished data.Figure 5 demonstrates that pridopidine meaningfully slows functional decline in patients with SETX mutations. Data are presented as LS(least square) mean (±SE (standard error)). Statistical analysis based on MMRM (mixed model for repeated measures).

[0021] Figure 6 shows that pridopidine preserves bulbar function in patients with SETX mutation associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM

[0022] Figure 7 shows that pridopidine maintains SVC in patients with SETX mutation associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM.

[0023] Figure 8 shows that pridopidine improves articulation rate in patients with DCTN1 mutation associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM.P-622173-PC

[0024] Figure 9 shows that pridopidine improves quality of life measures in patients with DCTN1 and SETX mutations associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM. n (number of patients) is 6 for pridopidine; n (number of patients) is 8 for placebo.

[0025] Figure 10 shows that pridopidine preserves independence in daily activities in patients with DCTN1 and SETX mutations associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM. n (number of patients) is 6 for pridopidine; n (number of patients) is 8 for placebo.

[0026] Figure 11 shows that pridopidine preserves communication function in patients with DCTN1 and SETX mutations associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM. n (number of patients) is 6 for pridopidine; n (number of patients) is 8 for placebo.

[0027] Figure 12 shows that pridopidine stabilizes emotional well-being in patients with DCTN1 and SETX mutations associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM. n (number of patients) is 6 for pridopidine; n (number of patients) is 8 for placebo.

[0028] Figure 13 shows that pridopidine mitigates symptom progression in versus placebo in patients with DCTN1 and SETX mutations associated with dHMN. Data are presented as LS mean (±SE). Statistical analysis based on MMRM. n (number of patients) is 6 for pridopidine; n (number of patients) is 8 for placebo.

[0029] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0030] In the following detailed description, numerous specific details are set forth in order 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-622173-PC Methods of treating

[0031] In one aspect, the present invention provides a method for treating, reducing the incidence of, suppressing, or inhibiting a neuropathy or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising a selective S1R agonist.

[0032] In one aspect, the present invention provides a method for treating, reducing the incidence of, suppressing, or inhibiting motor neuropathy or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising a selective S1R agonist.

[0033] In one aspect, the present invention provides a method for treating, reducing the incidence of, suppressing, or inhibiting distal hereditary motor neuropathy (dHMN) or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising a selective S1R agonist. In another embodiment, the distal hereditary motor neuropathy (dHMN) is Jerash type of dHMN.

[0034] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a neuropathy or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0035] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a motor neuropathy or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising pridopidine or pharmaceutically acceptable salt thereof.

[0036] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a neuropathy or symptoms thereof in a subject in need thereof, wherein the neuropathy is associated with missense mutations in S1R thereof, comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0037] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a neuropathy or symptoms thereof in a subject in need thereof, wherein the neuropathy is associated with mutations in SETX gene, comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0038] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a neuropathy or symptoms thereof in a subject in need thereof, wherein the neuropathy is associated with mutations in DCTN1 gene, comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0039] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a distal hereditary motor neuropathy (dHMN) or symptoms thereof in aP-622173-PC subject in need thereof comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0040] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a distal hereditary motor neuropathy (dHMN) or symptoms thereof in a subject in need thereof, wherein the distal hereditary motor neuropathy is associated with mitochondrial dysfunction, comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0041] In some embodiments, provided herein a method for treating, reducing the incidence of, suppressing, or inhibiting a Jerash type of dHMN.or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

[0042] In some embodiments, the symptoms of neuropathy, motor neuropathy, distal hereditary motor neuropathy (dHMN), Jerash type dHMN, comprise weight loss or hearing loss, functional decline, reduced quality of life in patients.

[0043] In some embodiments, functional decline comprises decline in motor ability, decline in bulbar function, decline in bulbar SVC, decline in articulation rate, decline in fine motor function, loss of distal motor strength and coordination, respiratory involvement, or combination thereof.

[0044] In some embodiments, provided herein a method for reducing weight loss (increase weight), reducing hearing loss of a subject with distal hereditary motor neuropathy (dHMN) comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof. In another embodiment the distal hereditary motor neuropathy (dHMN) is Jerash type of dHMN.

[0045] In some embodiments, provided herein a method for increasing weight, of a subject with distal hereditary motor neuropathy (dHMN) comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof. In another embodiment the distal hereditary motor neuropathy (dHMN) is Jerash type of dHMN.

[0046] In some embodiments, provided herein a method for improve hearing or reduce the hearing loss, of a subject with distal hereditary motor neuropathy (dHMN) comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof. In another embodiment the distal hereditary motor neuropathy (dHMN) is Jerash type of dHMN.

[0047] In some embodiments, the S1R agonist is pridopidine, or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the S1R agonist is a deuterated analog of pridopidine.P-622173-PC

[0049] In some embodiments, the composition used in the methods provided herein comprises pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1-7 or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, compounds 1-7 are presented by a structure of:

[0051] In some embodiments of the method of the invention as described herein, the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments of the method of the invention as described herein, the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments of the method of the invention as described herein, the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof with compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments of the method of the invention as described herein, pridopidine is in a base form or in a pharmaceutically acceptable salt form.P-622173-PC

[0055] In some embodiments, the pharmaceutically acceptable salt of pridopidine comprises pridopidine hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D-tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0056] In some embodiments of the method of the invention as described herein, the composition is administered via systemic administration. In other embodiments, the composition is administered via oral administration.

[0057] In some embodiments of the method of the invention as described herein, the composition is formulated as an oral liquid, solid, semi-solid dosage form, an injectable, dermal / transdermal dosage form, or an inhalable form.

[0058] In some embodiments of the method of the invention as described herein, the composition is formulated as an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule, or a tablet.

[0059] In some embodiments of the method of the invention as described herein, the composition is administered once daily, twice daily, three times a day, or less often than once daily.

[0060] In some embodiments of the method of the invention as described herein, the composition is administered in one dose, two doses, or three doses per day.

[0061] In some embodiments of the method of the invention as described herein, the motor neuropathy is distal hereditary motor neuropathy.

[0062] In some embodiments, the motor neuropathy is distal hereditary motor neuropathy (dHMN). In other embodiments, the distal hereditary motor neuropathy (dHMN) is Jerash type of dHMN.

[0063] In some embodiments, the motor neuropathy is associated with mitochondrial dysfunction.

[0064] In some embodiments of the method of the invention as described herein, at least one of compounds 1-7 is in an amount of from 0.005 wt% to 5 wt% of pridopidine or pharmaceutically acceptable salt thereof.

[0065] In some embodiments of the method of the invention as described herein, at least one of compounds 1-7 is in an amount of from 0.005 wt% to 1 wt% of pridopidine or pharmaceutically acceptable salt thereof.

[0066] In some embodiments of the method of the invention as described herein, at least one of compounds 1-7 is in an amount of from 0.01wt% to 1 wt% of pridopidine or pharmaceutically acceptable salt thereof.P-622173-PC

[0067] In some embodiments, this invention provides a composition comprising pridopidine, or a pharmaceutically acceptable salt thereof, or a combination of pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1-7 or a pharmaceutically acceptable salt thereof for use in the methods of this invention.

[0068] In some embodiments, the present invention provides a composition comprising a selective S1R agonist for use in treating, reducing the incidence of, suppressing, or inhibiting a dHMN or symptoms thereof in a subject in need thereof.

[0069] In some embodiments, the present invention provides a composition comprising pridopidine, or a pharmaceutically acceptable salt thereof, or a combination of pridopidine or a pharmaceutically acceptable salt thereof and at least one of compounds 1-7 or a pharmaceutically acceptable salt thereof for use in treating, reducing the incidence of, suppressing, or inhibiting a dHMN or symptoms thereof in a subject in need thereof.

[0070] In some embodiments, the composition for use in the methods of this invention comprises pridopidine, or pharmaceutically acceptable salt thereof. In other embodiments, the pridopidine is neutral / free base. In some embodiments, pridopidine is in its pharmaceutically acceptable salt form.

[0071] In some embodiments, the pharmaceutically acceptable salt of pridopidine comprises pridopidine hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D-tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salt.

[0072] In another embodiment, the pharmaceutically acceptable salt of pridopidine salt is pridopidine hydrochloride.

[0073] In some embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least one of compounds 1-7 or a pharmaceutically acceptable salt thereof:P-622173-PC

[0074] In some embodiments, compounds 1-7 and their methods of preparation may be found in U.S. Patent No.10,130,621 and U.S. Patent No.10,406,145, the entire content of each of which is hereby incorporated by reference.

[0075] In some embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least compound 1 or a pharmaceutically acceptable salt thereof.

[0076] In other embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with compound 4 or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least compound 2 or a pharmaceutically acceptable salt thereof.

[0079] In other embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least compound 3 or a pharmaceutically acceptable salt thereof.P-622173-PC

[0080] In some embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least compound 5 or a pharmaceutically acceptable salt thereof.

[0081] In other embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least compound 6 or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the composition for use in the method of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least compound 7 or a pharmaceutically acceptable salt thereof.

[0083] In other embodiments, the composition for use in the methods of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least one of compounds 1-7, wherein the at least one of compounds 1-7 are in a weight percentage of from 0.005 wt% to 5 wt% of pridopidine or pharmaceutically acceptable salt thereof.

[0084] In other embodiments, the composition for use in the methods of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least one of compounds 1-7, wherein the at least one of compounds 1-7 are in a weight percentage of from 0.005 wt% to 1 wt% of pridopidine or pharmaceutically acceptable salt thereof.

[0085] In other embodiments, the composition for use in the methods of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least one of compounds 1-7, wherein the at least one of compounds 1-7 are in a weight percentage of from 0.01wt% to 5 wt% of pridopidine or pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the composition for use in the methods of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with at least one of compounds 1-7, wherein the at least one of compounds 1-7 are in a weight percentage of from 0.005 wt% to 5 wt%, or from 0.01wt% to 5 wt%, from 0.005 wt% to 1wt%, or from 0.01wt% to 1wt%, or from 0.05 wt% to 0.5wt %, or from 0.05wt% to 1wt % of pridopidine.

[0087] In some embodiments, the composition for use in the methods of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with compound 1 or a pharmaceutically acceptable salt thereof, wherein compound 1 is in a weight percentage of from 0.005 wt% to 5 wt%, or from 0.01wt% to wt5%, or from 0.01wt% to 1wt%, or from 0.05 wt% to 0.5wt %, or from 0.05wt% to 1wt % of pridopidine.

[0088] In other embodiments, the composition for use in the methods of this invention comprises pridopidine or a pharmaceutically acceptable salt thereof in combination with compound 4 or a pharmaceutically acceptable salt thereof, wherein compound 4 is in a weight percentage of fromP-622173-PC 00.005 wt% to 5 wt%, or from 0.01wt% to wt5%, or from 0.01wt% to 1wt%, or from 0.05 wt% to 0.5wt %, or from 0.05wt% to 1wt % of pridopidine.

[0089] In some embodiments, this invention provides a composition comprising a deuterated analog of pridopidine for use in the methods of this invention. The term “deuterated-analog” refers to a "deuterium-enriched” compound that the abundance of deuterium at any relevant site of the compound is more than the abundance of deuterium naturally occurring at that site in an amount of the compound. The naturally occurring distribution of deuterium is about 0.0156%. Thus, in a "deuterium-enriched” compound, the abundance of deuterium at any of its relevant sites is more than 0.0156% and can range from more than 0.0156% to 100%. Deuterium-enriched compounds may be obtained by exchanging hydrogen with deuterium or synthesizing the compound with deuterium- enriched starting materials.

[0090] In some embodiments, the examples of deuterated analogs of pridopidine and their methods of preparation may be found in U.S. Application Publication No. 2013 / 0197031, U.S. Application Publication No.2016 / 0166559, and U.S. Application Publication No.2019 / 0015401, the entire content of each of which is hereby incorporated by reference.

[0091] In other embodiments, a deuterated analog of pridopidine is selected from:.

[0092] For the methods and use disclosed herein, the route of administration can be, e.g., oral. Routes of administration can also be classified by whether the effect is local (e.g., in topical administration) or systemic (e.g., in enteral or parenteral administration). “Local administration” as used herein shall mean administration of a compound or composition directly to where its action is desired, and specifically excludes systemic administration.

[0093] “Topical administration” of a compound or composition as used herein shall mean application of the compound or composition to body surfaces such as the skin or mucous membranes such as eyes.P-622173-PC

[0094] The pridopidine or the selective S1R agonist and the pharmaceutical compositions comprising the same as described herein may be administered by oral administration, topical administration, systemic administration, local administration.

[0095] In some embodiments, the composition described herein for use in the method of the invention is administered via systemic administration. In other embodiments, the composition is administered via oral administration.

[0096] In some embodiments, the composition is formulated as an oral liquid, solid, semi-solid dosage form, an injectable, dermal / transdermal dosage form, an ophthalmic dosage form, or an inhalable form. In some embodiments, the composition is formulated as an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or as a tablet.

[0097] In some embodiments, the composition described herein for use in the method of the invention is administered once daily, twice daily, three times a day, or less than once daily.

[0098] In some embodiment, the composition disclosed herein for use in the method of this invention is administered in one dose, two doses, or three doses per day.

[0099] The term "pharmaceutically acceptable salt” as used herein, in some embodiments, refers to those salts that are safe and effective for pharmaceutical use in mammals and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D-tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. [000100] In some embodiments of the method of the invention as described herein, the pharmaceutically acceptable salt of pridopidine is a hydrochloride salt. [000101] In some embodiments, the pharmaceutical compositions for the method of the invention comprise a selective S1R agonist, e.g., pridopidine, or a deuterated analog thereof, or a pharmaceutically acceptable salt thereof, or at least one of compounds 1-7 or a pharmaceutically acceptable salt, in admixture with pharmaceutically acceptable auxiliaries, and optionally otherP-622173-PC therapeutic agents. The auxiliaries must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. [000102] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration via an implant. The compositions may be prepared by any method well known in the art of pharmacy. [000103] Pharmaceutical compositions include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration via an implant. The compositions may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing in association compounds used in the invention or combinations thereof with any auxiliary agent. The auxiliary agent(s), also named accessory ingredient(s), include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrates, lubricants, colorants, flavoring agents, antioxidants, and wetting agents. [000104] Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, dragées or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus or paste. The compositions can further be processed into a suppository or enema for rectal administration. [000105] In some embodiments, the pharmaceutical composition, as herein before described, is in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described. [000106] For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use. For transdermal administration, e.g., gels, patches or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration e.g., by nasal inhalation include fine dusts or mist which may be generated by means of metered dose pressurized aerosols, nebulizers or insufflators. [000107] The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered. [000108] The term “treatment” as used herein refers to the administering of a therapeutic amount of the composition as described herein which is effective to ameliorate undesired diseases, disorders, including symptoms associated with a diseases or disorders, to prevent the manifestation of suchP-622173-PC diseases, disorders, including symptoms associated with a diseases or disorders before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease form occurring or a combination of two or more of the above. [000109] The "effective amount" for purposes disclosed herein is determined by such considerations as may be known in the art. The amount must be effective to achieve the desired therapeutic effect as described above, depending, inter alia, on the type and severity of the disease to be treated and the treatment regimen. In some embodiment a composition comprising pridopidine or pharmaceutically acceptable salt thereof is between 1-400 mg / day, administered once daily, twice daily, three times per day or less often than once a day. As generally known, an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, on factors such as age and gender, etc. [000110] In some embodiments, pridopidine is administered in a daily dose of 1 mg / day-400 mg / day. In some embodiments, pridopidine is administered in a daily dose of 1 mg / day-300 mg / day. In other embodiments, pridopidine is administered in a daily dose of 1 mg / day-90 mg / day. [000111] In some embodiments, pridopidine is administered in a daily dose of 20 mg / day-90 mg / day. In some embodiments, pridopidine is administered in a daily dose of 45 mg / day-90 mg / day. In other embodiments, pridopidine is administered in a daily dose of 20 mg / day-50 mg / day. [000112] In some embodiments, pridopidine is administered in a daily dose of 1 mg / day-10 mg / day. In other embodiments, pridopidine is administered in a daily dose of 10 mg / day-20 mg / day. In some embodiments, pridopidine is administered in a daily dose of 20 mg / day-30 mg / day. In further embodiments, pridopidine is administered in a daily dose of 30 mg / day-40 mg / day. In further embodiments, pridopidine is administered in a daily dose of 40 mg / day-180mg / day. In other embodiments, pridopidine is administered in a daily dose of 40 mg / day-50 mg / day. In some embodiments, pridopidine is administered in a daily dose of 50 mg / day-60 mg / day. In other embodiments, pridopidine is administered in a daily dose of 60 mg / day-70 mg / day. In some embodiments, pridopidine is administered in a daily dose of 70 mg / day-80 mg / day. In other embodiments, pridopidine is administered in a daily dose of 80 mg / day-90 mg / day. In some embodiments, pridopidine is administered in a daily dose of 90 mg / day-100 mg / day. In other embodiments, pridopidine is administered in a daily dose of 100 mg / day-150 mg / day. In further embodiments, pridopidine is administered in a daily dose of 150 mg / day-200 mg / day. In some embodiments, pridopidine is administered in a daily dose of 200 mg / day-250 mg / day. In otherP-622173-PC embodiments, pridopidine is administered in a daily dose of 250 mg / day-300 mg / day. In some embodiments, pridopidine is administered in a daily dose of 300 mg / day-350 mg / day. In certain embodiments, pridopidine is administered in a daily dose of 350 mg / day-400 mg / day. [000113] The following examples are presented to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. EXAMPLE 1 Pridopidine restores cellular pathologies associated with DHMN [000114] Distal hereditary motor neuropathy (DHMN) is a genetically heterogeneous disorder characterized by progressive motor neuron dysfunction, often linked to defects in axonal transport, RNA processing, and cellular stress responses. Variants in DCTN1 (encoding dynactin 1, a core component of the dynein–dynactin motor complex) and SETX (encoding senataxin, an RNA / DNA helicase) are associated with dHMN (Irobi J, Dierick I, Jordanova A, Claeys KG, De Jonghe P, Timmerman V. Unraveling the genetics of distal hereditary motor neuronopathies. Neuromolecular Med. 2006;8(1-2):131-46. doi: 10.1385 / nmm:8:1-2:131. PMID: 16775372; Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet.2004 Oct 1;13 Spec No 2:R195-202. doi: 10.1093 / hmg / ddh226. PMID: 15358725). DCTN1 disrupt axonal transport and vesicle trafficking, leading to distal motor neuron degeneration. Similarly, mutations in SETX impair transcriptional stress responses and DNA repair, resulting in motor neuron vulnerability. Both genes have been implicated in DHMN and related lower motor neuron syndromes, making patients with DCTN1 or SETX variants a genetically defined subgroup in which therapeutic effects can be specifically evaluated. [000115] Accordingly, analysis from subjects carrying mutations in the DHMN-related genes DCTN and SETX was done to assess the effect of pridopidine on functional assessments compared to placebo treated subjects with these mutations. Change from baseline in functional measures over 24 weeks is presented. Pridopidine slows functional decline in DHMN patients carrying SETX mutations. [000116] The ALSFRS-R total score provides a global measure of patient function across bulbar, motor, and respiratory domains, with higher scores reflecting better outcomes.In patients carrying SETX mutations, analyses of LSMean change from baseline showed that pridopidine (n=3) treatment led to markedly better preservation of function compared with placebo (n-6). By Week 24, placebo patients had declined by −4.67 points from baseline, showing substantial loss of function. In contrast,P-622173-PC patients treated with pridopidine declined by only −2.33 points, maintaining much higher levels of daily function (change vs placebo +2.34). Notably, at Week 8, placebo patients had already worsened (−1.50), while pridopidine patients showed improvement (+0.50), indicating an early therapeutic benefit that was sustained through Week 16 and Week 24. The 2.34-point separation at Week 24 is widely recognized as clinically meaningful in motor neuron diseases, highlighting pridopidine’s potential to slow functional decline (Figure 5). Pridopidine preserves bulbar function in patients with SETX mutation associated with dHMN [000117] Bulbar function, assessed by the ALSFRS-R bulbar subscale, was analyzed as LSMean change from baseline. In the placebo group (n=6), bulbar scores declined progressively from baseline with mean changes of −0.5 at Week 8, −1.0 at Week 16, and −1.17 at Week 24.In contrast, patients treated with pridopidine (n=3) maintained stable bulbar function. At Week 8 and Week 16, no decline from baseline was observed (0.0 ± 0.0 and 0.0 ± 0.7, respectively). By Week 24, the decline under pridopidine was much smaller (−0.67), compared to placebo (−1.17) (Figure 6). Pridopidine preserves respiratory capacity in patients with SETX mutation associated with dHMN [000118] Respiratory function, assessed by slow vital capacity (SVC), is a critical determinant of disease progression and survival. Decline in SVC reflects respiratory muscle weakness and is a major hallmark of motor neuron disease. [000119] In patients carrying SETX mutations, analyses of LSMean change from baseline showed that pridopidine treatment preserved and even improved respiratory capacity compared with the steep decline observed under placebo. By Week 8, placebo patients had already worsened (−1.56 points from baseline), while pridopidine patients showed marked improvement (+6.83). At Week 16, respiratory decline deepened in placebo patients (−9.25), whereas pridopidine patients remained near baseline (+0.81). By Week 24, placebo patients declined further (−13.12), while pridopidine patients sustained a clear benefit (+6.08) (Figure 7). Pridopidine improves speech articulation rate in patients with DCTN1 mutation associated with dHMN [000120] Speech function was assessed by the Mean Articulation Rate (syllables / sec), which reflects the ability to produce fluent and intelligible speech. [000121] Analyses of LSMean change from baseline in Mean Articulation Rate (syllables / sec) showed a clear advantage for pridopidine over placebo in patients carrying DCTN1 mutations.P-622173-PC Pridopidine-treated patients carrying DCTN1 mutations demonstrated a clear improvement compared with placebo. At Week 8, treatment benefit (pridopidine vs placebo) in articulation rate was 0.37, and increased to 0.11at Week 16 and 0.07 at Week 24 (Figure 8). Pridopidine improves quality of life measures in patients with DCTN1 and SETX mutations associated with dHMN [000122] The ALS Assessment Questionnaire-40 (ALSAQ-40) is a disease-specific quality-of-life instrument that evaluates physical mobility, activities of daily living, eating and drinking, communication, and emotional function. Higher ALSAQ-40 scores indicate worsening health- related quality of life. [000123] At Week 24, placebo-treated patients showed a marked deterioration, with mean ALSAQ- 40 total score increasing by +10.5 points from baseline. In contrast, patients receiving pridopidine demonstrated a substantially smaller increase of +5.0. The between-group difference was −5.5 favoring pridopidine (Figure 9). Pridopidine preserves activities of daily living in patients with DCTN1 and SETX mutations associated with dHMN [000124] The ALSAQ-40 Activities of Daily Living (ADL) domain assesses patients’ ability to perform everyday tasks such as self-care, mobility, and routine functional independence. Higher scores indicate worsening performance and greater disability. [000125] At Week 24, placebo-treated patients demonstrated a substantial decline in ADL function, with LSM scores increasing by +18.3 points from baseline. In contrast, patients receiving pridopidine showed relative stability, with scores increasing by only +2.2. The between-group difference was −16.1, favoring pridopidine (Figure 10). Pridopidine improves communication function in DHMN patients [000126] The ALSAQ-40 Communication domain assesses patients’ ability to speak, be understood, and effectively interact with others. Higher scores indicate greater impairment and reduce communicative ability. [000127] At Week 24, placebo-treated patients showed a worsening of +10.3 points in communication score. In contrast, pridopidine-treated patients demonstrated an improvement of −1.9 points from baseline. The between-group difference was −12.2, favoring pridopidine (Figure 11).P-622173-PC Pridopidine stabilizes emotional well-being in patients with DCTN1 and SETX mutations associated with dHMN [000128] The ALSAQ-40 Emotional Reactions domain evaluates the psychological impact of disease, including levels of frustration, depression, anxiety, and emotional distress. Higher scores indicate worsening emotional well-being. [000129] At Week 24, placebo-treated patients demonstrated a worsening of +4.0 points from baseline. In contrast, pridopidine-treated patients showed an improvement of −0.7 points, reflecting stabilization and partial relief of emotional burden. The between-group difference was −4.7, favoring pridopidine (Figure 12). Pridopidine reduces overall symptom burden in patients with DCTN1 and SETX mutations associated with dHMN [000130] The ALSAQ-40 Symptom Index provides a composite measure of disease-related symptom severity, integrating across multiple functional and quality-of-life domains, including physical mobility, activities of daily living, communication, eating and drinking, and emotional reactions. Higher scores indicate worsening symptom burden. [000131] At Week 24, placebo-treated patients demonstrated a worsening of +9.6 points from baseline, reflecting a marked increase in overall symptom burden. In contrast, pridopidine-treated patients showed a significantly smaller increase of only +4.8 points. The between-group difference was −4.8, favoring pridopidine (Figure 13). Summary [000132] Across multiple clinically meaningful endpoints, pridopidine demonstrated consistent and convergent benefits over placebo in patients carrying pathogenic variants in DCTN1 or SETX associated with dHMN. [000133] Treatment with pridopidine was associated with preservation of motor and functional ability, including improvements in patient-reported mobility, stabilization of communication, attenuation of bulbar decline, and maintenance of respiratory function as measured by slow vital capacity (SVC). In addition, articulation rate remained stable over time, supporting an effect on speech performance. [000134] Quality-of-life measures (ALSAQ-40 total and domain scores) further demonstrated reduced worsening in activities of daily living, communication, emotional well-being, and overall symptom burden.P-622173-PC [000135] Together, these results provide robust evidence that pridopidine exerts a coherent therapeutic effect across motor, bulbar, respiratory, speech and quality-of-life, supporting its potential as a disease-modifying treatment for DHMN. EXAMPLE 2 Pridopidine restores cellular pathologies associated with dHMN-related S1R mutations. Pridopidine restores S1R localization to MAM. [000136] The S1R variants E138Q and E150K both decrease the S1R localization at the ER membrane, as observed by a ~40% (p<0.01) reduction in colocalization with the ER chaperone protein BiP / GRP78 (Gregianin et al., Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signaling, Human Molecular Genetics, Volume 25, Issue 17, 1 September 2016, Pages 3741–3753, which is incorporated herein by reference). [000137] A similar decrease in S1R-BiP localization is observed in a cellular model of HD. In cells expressing the HD-associated mutant huntingtin with 96 CAG repeats (mHtt96Q), S1R-BiP colocalization is decreased ~2-fold (p<0.001, Figure 2A). Pridopidine treatment (150 mM) significantly increases S1R-BiP colocalization by ~50% (p<0.05, Figure 2B) (Shenkman M, Geva M, Gershoni-Emek N, Hayden MR, Lederkremer GZ. Pridopidine reduces mutant huntingtin- induced endoplasmic reticulum stress by modulation of the Sigma-1 receptor. J Neurochem. 2021 Jul;158(2):467-481. doi: 10.1111 / jnc.15366. Epub 2021 Apr 28. PMID: 33871049., which is incorporated herein by reference). Ca2+ uptake is reduced in cells expressing S1R mutations causing dHMN. [000138] Ca2+ handling following activation of the Ca2+ channel IP3R is impaired in human neuroblastoma cells S1R variants E138Q and E150K. E138Q causes a ~25% reduction in mitochondrial Ca2+ uptake (p<0.01) and E150K a ~35% reduction in mitochondrial Ca2+ uptake (p<0.001). Gregianin et al., Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling, Human Molecular Genetics, Volume 25, Issue 17, 1 September 2016, Pages 3741–3753which is incorporated herein by reference)P-622173-PC EXAMPLE 3 Pridopidine increases mitochondrial Ca2+ handling [000139] Pridopidine increases Ca2+ handline in mice. Mice were treated with pridopidine (30 mg / kg) by oral gavage for 45 days and Ca2+ uptake was then measured. Pridopidine increases Ca2+ handling from striatal neurons from WT mice. EXAMPLE 4 Pridopidine demonstrates neuroprotective effects under basal and oxidative stress conditions. Pridopidine increases neuronal survival under basal conditions [000140] The effect of pridopidine on neuronal survival was assessed in the immortalized striatal cell line Q7. Cells were incubated with pridopidine 0.01 mM for 24 hours, and cell viability assessed by the viability assay. Pridopidine treatment increases cell viability by ~50% (p<0.05, Figure 3). Source: internal study, unpublished data. Pridopidine increases neuronal survival following oxidative stress [000141] The effect of pridopidine on cell survival was assessed in the Q7 immortalized striatal cell line following oxidative stress. Cells were treated with pridopidine 0.001 mM for 24 hours, then exposed to oxidative stress with H2O2 (10 µM for 24 hours). Cell survival was assessed using the MTT cell reduction assay. In H2O2-treated cells, survival is decreased by about 20%. Pridopidine treatment increases cell survival by approximately 30% (p<0.01, Figure 4). Source: internal study unpublished data [000142] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims

P-622173-PC CLAIMS What is claimed is:

1. A method for treating, reducing the incidence of, suppressing, or inhibiting a distal hereditary motor neuropathy (dHMN) or symptoms thereof in a subject in need thereof comprising administering to the subject a composition comprising pridopidine or a pharmaceutical acceptable salt thereof.

2. The method of claim 1, wherein the distal hereditary motor neuropathy (dHMN) is a Jerash type of dHMN.

3. The method of claim 1, wherein the distal hereditary motor neuropathy is associated with mitochondrial dysfunction.

4. The method of claim 1, wherein the composition further comprises at least one of compounds 1-7, or a pharmaceutically acceptable salt thereof:P-622173-PC5. The method of claim 4, wherein said at least one of compounds 1-7 is in an amount of from 0.01 wt% to 1 wt% each of pridopidine.

6. The method of claim 4 or claim 5, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 1 or a pharmaceutically acceptable salt thereof.

7. The method of claim 4 or claim 5, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof.

8. The method of claim 4 or claim 5, wherein the method comprises administering a composition comprising pridopidine or a pharmaceutically acceptable salt thereof with compound 1 or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1-8, wherein the pridopidine is in a base form or in a pharmaceutically acceptable salt form.

10. The method of any one of claims 1-9 wherein the pridopidine salt comprises pridopidine hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, D,L-tartrate, L-tartarate, D- tartarate, pantothenate, bitartrate, ascorbate, succinate, hemisuccinate, maleate, gentisinate, gentisate, fumarate, gluconate, glucaronate, glycolate, saccharate, formate, besylate, benzoate, glutamate, malate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, oxalate, tosylate, naphtalen-2-sulfate, or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

11. The method of any one of the preceding claims, wherein the composition is administered via systemic administration.P-622173-PC 12. The method of claim 11, wherein the composition is administered via oral administration.

13. The method of any one of the preceding claims wherein the composition is formulated as an oral liquid, solid, semi-solid dosage form, an injectable, dermal / transdermal dosage form, an ophthalmic dosage form, or an inhalable form.

14. The method of claim 13, wherein the composition is formulated as an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule, eye drops, or a tablet.

15. The method of any one of the preceding claims, wherein the composition is administered once daily, twice daily, three times a day, or less often than once daily.

16. The method of claim 15, wherein the composition is administered in one dose, two doses, or three doses per day.

Images