Method of prolonging the survival of a subject with als

Abstract

This invention provides a method of prolonging the survival of subjects afflicted with ALS by administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof.

Description

FIELD OF THE INVENTION

[0001] This invention provides a method of prolonging the survival of subjects afflicted with ALS by administering a composition comprising pridopidine or pharmaceutically acceptable salt thereof. BACKGROUND OF THE INVENTION Amyotrophic Lateral Sclerosis

[0002] Amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease characterized by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord (Peters 2015). This rapidly progressing fatal disease leads to weakness of limb, respiratory, and bulbar muscles. Patients progressively lose control of voluntary muscles, leading to loss of limb function and the ability to chew, swallow, speak and eventually breathe.

[0003] ALS is a rare condition, having a mean incidence rate of 2.8 / 100,000 in Europe and 1.8 / 100,000 in North America, and a mean prevalence rate of 5.40 / 100,000 in Europe and 3.40 / 100,000 in North America (Bozzoni 2016).

[0004] About 10% of ALS cases are classified as familial (fALS), whereas the remaining 90% are classified as sporadic (sALS) and occur randomly (Riva 2016). Over 60% of patients die within 3 years of presentation, usually from respiratory failure and about 10% survive for more than 10 years (Zou 2016). There are currently three approved drugs for the treatment of ALS, all of which confer a modest effect on disease progression and survival.

[0005] Clinical manifestations of ALS include muscle weakness and hypotrophy, fasciculations and cramps, spastic hypertonus, and hyperreflexia are the main clinical manifestations. Some patients also display dysarthria, dysphagia, and respiratory weakness. Non-motor symptoms include behavioral disturbances, dysexecutive impairment, and frontotemporal dementia.

[0006] The neuropathological features of ALS include muscle atrophy, loss of anterior horn cells, and sclerosis of the spinal cord lateral columns (Martel 2016). Gliosis, defined as activation of astrocytes and microglia, is also a hallmark of ALS. Pridopidine

[0007] The chemical name of pridopidine is 4-(3-(Methylsulfonyl) phenyl)-!-propylpiperidine, and its Chemical Registry Number is CAS 346688-38-8 (CSID:7971505, 2016). The Chemical Registry number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790 2016). Processes of synthesis of pridopidine and a pharmaceutically acceptable salt thereof are disclosed in U.S. Patent No. 7,923,459 and PCT Application Publication No. WO 2017 / 015609. U.S. Patent No. RE46,117 discloses pridopidine for the treatment of a variety of diseases and disorders.

[0008] Pridopidine is a high affinity and highly selective SIR ligand which has ~ 30-fold higher affinity towards the SIR vs D3Rs, and ~500-fold higher affinity vs D2Rs. Selective binding of pridopidine for the SIR with no dopamine D2 / D3R binding was confirmed using positron emission tomography (PET) imaging in rats (Sahlholm, 2015), and in humans (TV7820-IMG-10082). The neuroprotective properties of pridopidine are demonstrated in preclinical models of AES and other neurodegenerative diseases and are mediated by its activation of the SIR, as its silencing by genetic or pharmacological methods abolishes the protective effects of pridopidine.

[0009] The SIR is a highly conserved transmembrane protein located in the endoplasmic reticulum (ER) and specifically enriched in the subregions contacting mitochondria (Mitochondria-Associated Membranes, MAM). The SIR is highly enriched in the CNS. The SIR is a key component of the ER-Mitochondria axis, and is thus implicated in cellular differentiation, neuroplasticity, neuroprotection, and cognitive function in the brain. SUMMARY OF THE INVENTION

[0010] The invention provides a method for prolonging the survival of a subj ect with ALS wherein the method comprises administering to the subject a composition comprising pridopidine or a pharmaceutically acceptable salt thereof. In one embodiment, the method prolongs the survival of a subject with ALS by at least 2 months, 4 months, 6 months, 10 months, 12 months, or 24 months compared to a subject not treated with pridopidine. In another embodiment, the pridopidine salt is pridopidine hydrochloride. BRIEF DESCRIPTION OF THE FIGURES

[0015] Figure 1: Presents Product-Limit Survival Estimates with number of subjects at risk and 95% Hall-Wellner bands. Pridopidine shows a clinical meaningful effect on survival probability compared to placebo.

[0016] Figure 2: Significant increase in survival in patients treated with pridopidine compared to matched subjects from PRO-ACT.

[0017] Figure 3: Significant increase in survival in Definite, Probable and Early Subgroup of ALS patients treated with pridopidine compared to matched subjects from PRO-ACT. DETAILED DESCRIPTION OF THE INVENTION

[0018] The invention provides for prolonging the survival of a subject with ALS, comprising administering to the subject an amount of pridopidine or pharmaceutically acceptable salt thereof effective to prolong the survival of a subject with ALS.

[0019] ALS diagnosis is done by El Escorial. Diagnosis of ALS involves an in-depth evaluation and multiple diagnostic tests. The definitive diagnosis is established by considering the progressive upper (UMN) and lower motor neuron (LMN) loss. (Brooks, B. R. El escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis, in Journal of the Neurological Sciences (1994).

[0020] Clinically Definite ALS according to El Escorial is defined on clinical evidence alone by the presence of UMN, as well as LMN signs, in three regions.

[0021] Clinically Probable ALS according to El Escorial is defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs.

[0022] Clinically Probable with Labs according to El Escorial is defined when clinical signs of UMN and LMN dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN signs defined by EMG criteria are present in at least two limbs, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes.

[0023] Clinically Possible ALS according to El Escorial is defined when clinical signs of UMN and LMN dysfunction are found together in only one region or UMN signs are found alone in two or more regions; or LMN signs are found rostral to UMN signs and the diagnosis of Clinically Probable - Laboratory-supported ALS cannot be proven by evidence on clinical grounds in conjunction with electrodiagnostic, neurophysiologic, neuroimaging or clinical laboratory studies. Other diagnoses must have been excluded to accept a diagnosis of Clinically Possible ALS

[0024] In some embodiments, the ALS subject to be treated is defined as clinically definite ALS. In some embodiments the ALS subject is defined as clinically probable ALS. In some embodiments, the ALS subject is defined as clinically probable with labs. In some embodiments the ALS subject is defined as clinically possible ALS.

[0025] In some embodiments, ALS is sporadic ALS.

[0026] In some embodiments, the ALS is familial ALS (FALS). In some embodiments the ALS is juvenile ALS (JALS).

[0027] In some embodiments ALS is not FALS. In some embodiments the ALS is not juvenile ALS (JALS).

[0028] In some embodiments, the type of ALS is classic, bulbar, flail arm, flail leg, pyramidal and respiratory ALS, progressive muscular atrophy, primary lateral sclerosis or progressive bulbar palsy.

[0029] In some embodiments, the subject carries a mutant version of a gene that causes or contributes to ALS pathogenesis. In some embodiments the mutant version of the gene is selected from the group of genes consisting of the superoxide dismutase 1 (SOD1), TAR DNA-binding protein (TARDBP) encoding TDP-43, fused in sarcoma (FUS), p62 (SQSTM1), ubiliquin-2 (UBQLN2), TANK-binding kinase 1 (TBK1), profilin 1 (PFN1), VCP or p97 (VCP), angiogenin (ANG), optineurin (OPTN), C9orf72, Sigma-1 Receptor (SIR), Tubulin alpha-4A (TUBA4A), Dynactin (DCTN1),, hnRNPAl (HNRNPA1), Matrin 3(MATR3), Coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) genes and any combination thereof.

[0030] In some embodiments, the subject has rapid pre-baseline progression wherein the prebaseline progression is expressed by the ALSFRS-R slope. In other embodiments, the pre-baseline slope in ALSFRS-R (delta-FRS) is defined as 48 minus the baseline ALSFRS-R total score then divided by the number of months from onset of symptomatic weakness to the Baseline Visit.

[0031] In some embodiments the ALS subject is defined as a faster progressor. In some embodiments the ALS subject is defined as a faster progressor based on ALSFRS-R pre-baseline slope. In other embodiments the ALS subject has a pre-baseline slope > 0.75. In other embodiments, the ALS subject has a pre-baseline slope of > 0.9. In other embodiments, the ALS subject has a pre-baseline slope of > 0.95. In other embodiments, the ALS subject has a prebaseline slope of> 1.

[0032] In some embodiments the ALS subject is defined as an early ALS subject. In other embodiments early ALS is defined by time from symptom onset. In some embodiments, the early ALS subject is <12 months from symptom onset. In some embodiments, the early ALS subject is <18 months from symptom onset. In some embodiments the early ALS subject is <20 months from symptom onset. In some embodiments the ALS subject is <24 months from symptom onset.

[0033] In some embodiments, the subject is an early ALS subject and faster progressor. In other embodiments, the ALS subjects is <12 months from symptom onset, with a pre-baseline slope >  0.75. In other embodiments, the ALS subjects is <12 months from symptom onset, with a prebaseline slope > 0.9. In other embodiments, the ALS subjects is <12 months from symptom onset, with a pre-baseline slope > 0.95. In other embodiments, the ALS subjects is <12 months from symptom onset, with a pre-baseline slope > 1. In other embodiments, the ALS subjects is <18 months from symptom onset, with a pre-baseline slope > 0.75. In other embodiments, the ALS subjects is <18 months from symptom onset, with a pre-baseline slope > 0.9. In other embodiments, the ALS subjects is <18 months from symptom onset, with a pre-baseline slope > 0.95. In other embodiments, the ALS subjects is <18 months from symptom onset, with a prebaseline slope > 1. In other embodiments, the ALS subjects is <20 months from symptom onset, with a pre-baseline slope > 0.75. In other embodiments, the ALS subjects is <20 months from symptom onset, with a pre-baseline slope > 0.9. In other embodiments, the ALS subjects is <20 months from symptom onset, with a pre-baseline slope > 0.95. In other embodiments, the ALS subjects is <24 months from symptom onset, with a pre-baseline slope > 1. In other embodiments, the ALS subjects is <14 months from symptom onset, with a pre-baseline slope > 0.75. In other embodiments, the ALS subjects is <24 months from symptom onset, with a pre-baseline slope > 0.9. In other embodiments, the ALS subjects is <24 months from symptom onset, with a prebaseline slope > 0.95. In other embodiments, the ALS subjects is <24 months from symptom onset, with a pre-baseline slope > 1.

[0034] In some embodiments, provided herein a method for prolonging the survival of a subject with ALS wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof.

[0035] In some embodiments, provided herein a method prolonging the survival of a subject with ALS wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof wherein the method prolongs the survival of a subject with ALS by at least 4 months. In another embodiment by at least 6 months. In another embodiment for at least 8 months. In another embodiment by at least 10 months. In another embodiment for between 4 to 24 months.

[0036] In some embodiments, provided herein a method prolonging the survival of a subject with ALS wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof, wherein the method prolongs the survival of a subject with ALS by at least between 2-24 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 2 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 4 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 6 months compared to a subject not treated with pridopidine. In another embodiments, the method prolongs the survival of a subject with ALS by at least 8 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 10 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 12 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 14 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 16 months compared to a subject not treated with pridopidine. In another embodiments, the method prolongs the survival of a subject with ALS by at least 18 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 20 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 22 months compared to a subject not treated with pridopidine. In another embodiment, the method prolongs the survival of a subject with ALS by at least 24 months compared to a subject not treated with pridopidine.

[0037] In some embodiments, provided herein a method for prolonging the survival of a subject with ALS wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof, for at least 12 weeks, at least 20 weeks, at least 24 weeks, at least 26 weeks, at least 52 weeks, at least 78 weeks, chronically.

[0038] In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated 24 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated 18 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated 12 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated 10 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated 6 months before symptoms onset.

[0039] In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated at least 24 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated at least 18 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated at least 12 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated at least 10 months before symptoms onset. In another embodiment, the administration of the composition comprising pridopidine or pharmaceutically acceptable salt thereof is initiated at least 6 months before symptoms onset.

[0040] some embodiments, provided herein a method for prolonging the survival of a subject with ALS wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof wherein, the administration of the composition comprising pridopidine or a pharmaceutically acceptable salt thereof is initiated 24, 18, 12, 10 or 6 months before symptoms onset and the composition is administered continuously. In another embodiment, the composition is administered chronically.

[0041] In other embodiments, the symptoms of ALS include impaired functionality, impaired respiratory function, impaired bulbar function, impaired speech, impaired muscle strength or any combination thereof.

[0011] In other embodiments, the symptom is impairment in muscle strength.

[0042] In some embodiments, the symptom is impairment in speech. In other embodiments, the impairment of speech comprises reduced speaking rate, reduced phonation time, reduced articulation rate and reduced articulation precision.

[0043] In some embodiments, impairment in functionality comprises speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing and hygiene, turning in bed and adjusting bed clothes, walking, climbing stairs, dyspnea, orthopnea, respiratory insufficiency or any combination thereof.

[0044] In some embodiments, the respiratory function is assessed by slow vital capacity (SVC) or forced vital capacity (FVC) or by the ALSFRS-R-Respiratory sub-domain.

[0045] In some embodiments, the bulbar function is measured by the ALSFRS-R bulbar subdomain (Q1-Q3) score. In other embodiments, the bulbar function is measured by the CNS-BFS. In other embodiments, the bulbar function comprises of impaired speech, swallowing or salivation.

[0046] In some embodiments of the invention, use of a composition comprising pridopidine or pharmaceutically acceptable salt thereof in combination with Trehalose (SLS-005), CNM-Au8 nanocrystalline gold, ABBV-CLS-7262 or combination thereof, results in prolonging the survival of a subject with ALS in a subject in need.

[0047] In an embodiment of the invention, pridopidine or pharmaceutically acceptable salt is administered daily.

[0048] In some embodiments of the invention, pridopidine or pharmaceutically acceptable salt is administered more often than once daily.

[0049] In some embodiments of the invention, pridopidine or pharmaceutically acceptable salt is administered twice daily. In an embodiment of the invention, pridopidine is administered thrice daily.

[0050] In some embodiments of the invention, pridopidine or pharmaceutically acceptable salt is administered less often than once daily, for example, on alternate days, three times per week, twice per week or once per week.

[0051] In some embodiments of the invention, pridopidine or pharmaceutically acceptable salt is administered daily, twice a week, three times a week or more often than once daily.

[0052] In an embodiment of the invention, pridopidine or pharmaceutically acceptable salt is administered orally.

[0053] In some embodiments, a unit dose of the pharmaceutical composition contains 10-250 mg pridopidine or pharmaceutically acceptable salt. In some embodiments the composition comprises 45 mg, 67.5 mg, 90 mg, or 112.5 mg of pridopidine or pharmaceutically acceptable salt.

[0054] In an embodiment, between 10 - 225 mg pridopidine or pharmaceutically acceptable salt is administered to the patient per day. In another embodiment, between 45-180 mg pridopidine or pharmaceutically acceptable salt is administered to the patient per day. In another embodiment, 10 mg, 22.5 mg, 45 mg, 67.5, mg, 90 mg, 100 mg, 112.5 mg, 125 mg, 135 mg, 150 mg, or 180 mg pridopidine or pharmaceutically acceptable salt is administered to the patient per day.

[0055] In one embodiment, the pharmaceutical composition is administered twice per day. In another embodiment, an equal amount of the pharmaceutical composition is administered at each administration.

[0056] In an embodiment, the two doses are administered at least 6 hours apart, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours apart. In some embodiments, the pharmaceutical composition is administered for at least 12 weeks, at least 20 weeks, at least 24 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks, chronically.

[0057] In an embodiment of the invention, pridopidine is pridopidine hydrochloride.

[0058] In an embodiment of the invention, the subject is a human subject.

[0059] The invention also provides pridopidine or a pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS.

[0060] The invention also provides a pharmaceutical composition comprising an effective amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS.

[0061] The invention further provides a method for prolonging the survival of a subject with ALS comprising administering to a subject in need thereof a composition comprising an amount of pridopidine or pharmaceutically acceptable salt thereof effective to prolonging the survival of a subject.

[0062] In an embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof, an analog of pridopidine, and an amount of a second compound, for example a compound useful in treating patients with ALS.

[0063] In an embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof, one or more analogs of pridopidine, and an amount of a second compound, for example a compound useful in treating patients with ALS.

[0064] In an embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof and an amount of a second compound, for example a compound useful in treating patients with ALS.

[0065] In some embodiments, the second compound is riluzole, edaravone, SLS-005 (Trehalose), CNM-Au8 nanocrystalline gold or ABBV-CLS-7262.

[0066] In an embodiment, the pharmaceutical composition for use in prolonging the survival of a subject with ALS, comprises pridopidine or pharmaceutically acceptable salt thereof and at least one pridopidine’s analog or pharmaceutically acceptable salt thereof of compounds of Formula 17:

[0067] In other embodiments, the composition for use in the methods of this invention comprises pridopidine or pharmaceutically acceptable salt thereof and at least one of pridopidine’s analog compounds 1-7 or pharmaceutically acceptable salt thereof. In another embodiment, the composition 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, compound 1 and compound 4 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, 2, 3, 4, 5, 6, 7 or a pharmaceutically acceptable salt thereof or any combination thereof.

[0068] In another embodiment, the pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt and at least one of pridopidine’s analog compounds 1-7 or pharmaceutically acceptable salt thereof for use in the methods of this invention, comprises between 0%-10% w / w of each of the pridopidine’s analog compound relative to pridopidine. In another embodiment, the pharmaceutical composition comprises between 0.005%-5% 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%-1% 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%-3% 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 0.005%-0.1% w / w, 0.05%-0.1% w / w, 0.05%-0.15% w / w, 0.05%-0.2% w / w, 0.05%-0.5% w / w, 0.05%-2% w / w, 0.05%-3%w / w, 0.05%-4% w / w, 0.05%-5%w / w, 0.1%-0.4% w / w, 0.15%-0.3% w / w, 0.15%-0.5 % w / w of each of the analog compounds 1-7 or pharmaceutical acceptable salt thereof relative to pridopidine.

[0069] In some embodiments, provided herein a method of prolonging the survival of a subject with ALS, wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof and at least one of pridopidine’s analog of compounds 1-7 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises further administering a second composition comprising a second compound which is administered simultaneously or contemporaneously with the composition comprising pridopidine and pridopidine’s analog.

[0070] In some embodiments, provided herein a method of prolonging the survival of a subject with ALS, wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof and Compound 1 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises further administering a second composition comprising a second compound which is administered simultaneously or contemporaneously with the composition comprising pridopidine and pridopidine’s analog.

[0071] In some embodiments, provided herein a method of prolonging the survival of a subject with ALS, wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof and Compound 4 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises further administering a second composition comprising a second compound which is administered simultaneously or contemporaneously with the composition comprising pridopidine and pridopidine’s analog.

[0072] In some embodiments, provided herein a method of prolonging the survival of a subject with ALS, wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of pridopidine or pharmaceutically acceptable salt thereof Compound 1 and Compound 4 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises further administering a second composition comprising a second compound which is administered simultaneously or contemporaneously with the composition comprising pridopidine and pridopidine’s analog.

[0073] In some embodiments, provided herein a method of prolonging the survival of a subject with ALS, wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of at least one of pridopidine’s analog of compounds 1-7 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 1 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 2 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 3 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 4 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 5 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 6 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 7 or pharmaceutically acceptable salt thereof.

[0074] In some embodiments, provided herein a method of prolonging the survival of a subject with ALS, wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of at least one of pridopidine’s analog of compounds 1-7 or pharmaceutically acceptable salt thereof and a composition comprising a Second compound which is administered simultaneously or contemporaneously with the composition comprising at least one of Compounds 1-7.

[0075] In some embodiments, provided herein a method for prolonging the survival of a subject with ALS by maintaining, improving, or lessening the decline of symptoms associated with ALS in a subject in need thereof wherein the symptom is impaired: functionality, respiratory function, bulbar function, speech, muscle strength or any combination thereof, wherein the method comprises administering to the subject a composition comprising a therapeutically acceptable amount of at least one of pridopidine’s analog of compounds 1-7 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 1 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 2 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 3 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 4 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 5 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 6 or pharmaceutically acceptable salt thereof. In other embodiments, the method comprises administering a composition comprising Compound 7 or pharmaceutically acceptable salt thereof.

[0076] In other embodiments, the Pridopidine’s analog compound is Compound 1 or pharmaceutically acceptable salt thereof. In other embodiments, the analog compound is Compound 2. In other embodiments, the analog compound is Compound 3. In other embodiments, the analog compound is Compound 4. In other embodiments, the analog compound is Compound 5. In other embodiments, the analog compound is Compound 6. In other embodiments, the analog compound is Compound 7.

[0077] In an embodiment, the pharmaceutical composition is in a unit dosage form, useful in treating subject afflicted with ALS, which comprises: a) an amount of pridopidine or a pharmaceutically acceptable salt. b) an amount of a Second compound, wherein the respective amounts of said Second compound and said pridopidine in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.

[0078] In some embodiments, the Second compound is riluzole, edaravone, SLS-005 (Trehalose), DNL343, CNM-Au8 nanocrystalline gold or ABBV-CLS-7262.

[0079] In an embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS as an add-on therapy to a Second compound which is riluzole. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS as an add-on therapy to a Second compound which is edaravone. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for prolonging the survival of a subject with ALS as an add-on therapy to a Second compound SLS-005 (Trehalose). In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS as an add-on therapy to a Second compound CNM-Au8 nanocrystalline gold. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS as an add-on therapy to a Second compound ABBV-CLS-7262.

[0080] In an embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS simultaneously or contemporaneously with a Second compound which is riluzole. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS simultaneously or contemporaneously with a Second compound which is edaravone. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS simultaneously or contemporaneously with a Second compound which is dextromethorphan / quinidine. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS simultaneously or contemporaneously with a Second compound which is laquinimod. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS simultaneously or contemporaneously with a Second compound which is SLS-005 (Trehalose). In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS simultaneously or contemporaneously with a Second compound which is CNM-Au8 nanocrystalline gold. In another embodiment, the pharmaceutical composition comprises an amount of pridopidine or pharmaceutically acceptable salt thereof for use in prolonging the survival of a subject with ALS simultaneously or contemporaneously with a Second compound which is ABBV-CLS-7262.

[0081] In an embodiment, the pharmaceutical composition comprises an amount of a compound which is riluzole for use in prolonging the survival of a subject with ALS as an add-on therapy to pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises an amount of a compound which is edaravone for use in prolonging the survival of a subject with ALS as an add-on therapy to pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises an amount of a compound which is dextromethorphan / quinidine for use in prolonging the survival of a subject with ALS as an add-on therapy to pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises an amount of a compound which is laquinimod for use in prolonging the survival of a subject with ALS as an add-on therapy to pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises an amount of a combination of SLS-005 (Trehalose) for use in prolonging the survival of a subject with ALS as an add-on therapy to pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises an amount of a combination of CNM-Au8 nanocrystalline gold, for use in prolonging the survival of a subject with ALS as an add-on therapy to pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutical composition comprises an amount of a combination of ABBV-CLS-7262, for use in prolonging the survival of a subject with ALS as an add-on therapy to pridopidine or pharmaceutically acceptable salt thereof.

[0082] In an embodiment, the methods of the present invention further comprise administering to the subject a therapeutically effective amount of a Second compound which is riluzole or edaravone. In an embodiment, the methods of the present invention further comprise administering to the subject a therapeutically effective amount of a Second compound which is dextromethorphan / quinidine. In an embodiment, the methods of the present invention further comprise administering to the subject a therapeutically effective amount of a Second compound which is SLS-005 (Trehalose).

[0083] In an embodiment, the methods of the present invention further comprise administering to the subject a therapeutically effective amount of a Second compound which is Au8 nanocrystalline gold. In an embodiment, the methods of the present invention further comprise administering to the subject a therapeutically effective amount of a Second compound which is ABBV-CLS-7262. In an embodiment, the Second compound is riluzole. In another embodiment, the Second compound is edaravone. In another embodiment, the Second compound is dextromethorphan / quinidine. In another embodiment, the Second compound is laquinimod. In an embodiment, the Second compound is SLS-005 (Trehalose). In an embodiment, the Second compound is Au8 nanocrystalline gold. In an embodiment, the Second compound is ABBV-CLS-7262.

[0084] In an embodiment of the invention, pridopidine or pharmaceutically acceptable salt thereof and the Second compound are administered in one unit. In another embodiment the pridopidine and the Second compound are administered in more than one unit.

[0085] In an embodiment, the amount of pridopidine and the amount of the Second compound are administered simultaneously. In an embodiment, the amount of pridopidine and the amount of the Second compound are administered contemporaneously.

[0086] In another embodiment, the administration of the Second compound precedes the administration of pridopidine or pharmaceutically acceptable salt thereof. In another embodiment, the administration of pridopidine or pharmaceutically acceptable salt thereof precedes the administration of the Second compound.

[0087] In an embodiment, a subject is receiving edaravone therapy prior to initiating pridopidine therapy. In another embodiment, a subject is receiving riluzole prior to initiating pridopidine therapy. In another embodiment, a subject is receiving laquinimod prior to initiating pridopidine therapy. In an embodiment, a subject is receiving SLS-005 (Trehalose) therapy prior to initiating pridopidine therapy. In an embodiment, a subject is receiving CNM-Au8 nanocrystalline gold therapy prior to initiating pridopidine therapy. In an embodiment, a subject is receiving ABBV-CLS-7262 therapy prior to initiating pridopidine therapy.

[0088] In another embodiment, a subject is receiving edaravone therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating pridopidine therapy. In another embodiment, a subject is receiving riluzole therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating pridopidine therapy. In another embodiment, a subject is receiving dextromethorphan / quinidine therapy for at least 1 week, 2 weeks, 4 weeks, or 6 weeks prior to initiating pridopidine therapy. In another embodiment, a subject is receiving SLS-005 (Trehalose) therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating pridopidine therapy. In another embodiment, a subject is receiving CNM-Au8 nanocrystalline gold therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating pridopidine therapy. In another embodiment, a subject is receiving ABBV-CLS-7262 therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating pridopidine therapy. In an embodiment, a subject is receiving pridopidine therapy prior to initiating edaravone therapy. In another embodiment, a subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating edaravone therapy.

[0089] In an embodiment, a subject is receiving pridopidine therapy prior to initiating riluzole therapy. In another embodiment, a subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating riluzole therapy.

[0090] In an embodiment, a subject is receiving pridopidine therapy prior to initiating laquinimod therapy. In another embodiment, a subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating laquinimod therapy.

[0091] In an embodiment, a subject is receiving pridopidine therapy prior to initiating dextromethorphan / quinidine therapy. In another embodiment, a subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating dextromethorphan / quinidine therapy.

[0092] In an embodiment, a subject is receiving pridopidine therapy prior to initiating SLS-005 (Trehalose) therapy. In another embodiment, a subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to SLS-005 (Trehalose) therapy.

[0093] In an embodiment, a subject is receiving pridopidine therapy prior to initiating CNM-Au8 nanocrystalline gold therapy. In another embodiment, a subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating CNM-Au8 nanocrystalline gold therapy.

[0094] In an embodiment, a subject is receiving pridopidine therapy prior to initiating ABBV-CLS-7262 therapy. In another embodiment, a subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating ABBV-CLS-7262 therapy.

[0095] In an embodiment, between 0.5 mg to 1.5 mg laquinimod is administered to the patient per day.

[0096] In another embodiment, 0.5 mg, or 1.0 mg laquinimod is administered to the patient per day. In an embodiment, laquinimod is administered orally.

[0097] In an embodiment, between 10-200 mg riluzole is administered to the patient per day. In another embodiment, 50 mg, 100 mg, or 200 mg riluzole is administered to the patient per day.

[0098] In an embodiment, riluzole is administered orally. In an embodiment dextromethorphan / quinidine is administered orally.

[0099] In an embodiment, between 5-60 mg edaravone is administered to the patient per day. In another embodiment, 30 mg, or 60 mg edaravone is administered to the patient per day.

[0100] In an embodiment, edaravone is administered by intravenous infusion. In another embodiment, edaravone is administered once per day for 10 days followed by a 14-day drug-free period. In another embodiment, edaravone is administered once per day for 14 days followed by a 14-day drug-free period.

[0101] In an embodiment SLS-005 (Trehalose) is administered byintravenously. In another embodiment, SLS-005 (Trehalose) is administered in a weekly dose of between 0.05-1 g / kg / weekly. In another embodiment SLS-005 (Trehalose) is administered in a weekly dose of between 0.1-0.5 g / kg / week, 0.25-0.75 g / kg / week or 0.6-1 g / kg / week.

[0102] In an embodiment CNM-Au8 nanocrystalline gold is administered orally. In another embodiment, CNM-Au8 nanocrystalline gold is administered in a daily dose between 5-50 mg / day. In another embodiment CNM-Au8 nanocrystalline gold is administered in a daily dose of between 5-10 mg / day, 15-20 mg / day, 15-30 mg / day, 20-30 mg / day. In another embodiment, CNM-Au8 nanocrystalline gold is administered once a day, twice a day or more than twice a day.

[0103] In an embodiment ABBV-CLS-7262 is administered orally. In another embodiment, ABBV-CLS-7262 is administered in a daily dose. In another embodiment, ABBV-CLS-7262 is administered once a day, twice a day or more than twice a day.

[0104] In an embodiment, each of the amount of the Second compound when taken alone, and the amount of pridopidine when taken alone is effective to treat a subject. In another embodiment, either the amount of the Second compound when taken alone, or the amount of pridopidine when taken alone, is less effective to treat the subject. In another embodiment, either the amount of the Second compound when taken alone, or the amount of pridopidine when taken alone, is not effective to treat the subject.

[0105] In an embodiment, pridopidine is administered adjunctively to the Second compound. In another embodiment, the Second compound is administered adjunctively to pridopidine.

[0106] In an embodiment, a loading dose of an amount different from the intended dose is administered for a period of time at the start of the periodic administration.

[0107] In some embodiments the methods of this invention make use of a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and at least one analog Compounds 1-7 or pharmaceutically acceptable salt thereof.

[0108] In other embodiments the methods provided herein make use of a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 1 or pharmaceutically acceptable salt thereof. In other embodiments this invention provides a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 2 or pharmaceutically acceptable salt thereof. In other embodiments this invention provides a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 3 or pharmaceutically acceptable salt thereof. In other embodiments this invention provides a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 4 or pharmaceutically acceptable salt thereof. In other embodiments this invention provides a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 5 or pharmaceutically acceptable salt thereof. In other embodiments this invention provides a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 6 or pharmaceutically acceptable salt thereof. In other embodiments this invention provides a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 7 or pharmaceutically acceptable salt thereof. In other embodiments this invention provides a pharmaceutical composition comprising pridopidine or pharmaceutically acceptable salt thereof and compound 1 and compound 4 or pharmaceutically acceptable salt thereof. In other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt thereof within the composition is between 0.001% w / w to 10% w / w. In other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt thereof within the composition is between 0.001% w / w to 0.05% w / w. In other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt thereof within the composition is between 0.001% w / w to 0.5% w / w. In other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt thereof within the composition is between 0.001% w / w to 0.15% w / w. In other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt thereof within the composition is between 0.01% w / w to 0.15% w / w. In other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt thereof within the composition is between 0.01% w / w to 0. 35% w / w. In other embodiments, the concentration of compounds 1, 2, 3, 4, 5, 6 or 7 or pharmaceutically acceptable salt thereof within the composition is between 0.01 % w / w to 1 % w / w. Pharmaceutically Acceptable Salts

[0109] As used herein, “pridopidine” means pridopidine base or a pharmaceutically acceptable salt thereof, as well as derivatives, for example deuterium-enriched version of pridopidine and salts. Examples of deuterium-enriched pridopidine and salts and their methods of preparation may be found in U.S. Application Publication Nos. 2013-0197031, 2016-0166559 and 2016-0095847, the entire content of each of which is hereby incorporated by reference. In certain embodiments, pridopidine is a pharmaceutically acceptable salt, such as the HC1 salt or tartrate salt. Preferably, in any embodiments of the invention as described herein, pridopidine is in the form of its hydrochloride salt. In some embodiments, “pridopidine” used herein as pridopidine base or a pharmaceutically acceptable salt thereof.

[0110] Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methane sulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like. Such salts may be formed by procedures well known and described in the art.

[0111] “Deuterium-enriched” means 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. Pharmaceutical Compositions

[0112] While the pridopidine for use according to the invention may be administered in the form of the free base, preferred administration of pridopidine, optionally in the form of a physiologically acceptable salt, is in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0113] In an embodiment, the invention provides pharmaceutical compositions comprising the pridopidine or pharmaceutically acceptable salts or derivatives thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and / or prophylactic ingredients known and used in the art including, but not limited to, riluzole, edaravone Nuedexta® (dextromethorphan / quinidine), SLS-005 (Trehalose), CNM-Au8 nanocrystalline gold or ABBV-CLS-7262 .

[0114] In an embodiment, the invention provides pharmaceutical compositions comprising the pridopidine or pharmaceutically acceptable salts or derivatives thereof, together with at least one of pridopidine’s analog of Compounds 1-7 or pharmaceutically acceptable salt thereof.

[0115] In an embodiment, the invention provides pharmaceutical compositions comprising pridopidine or pharmaceutically acceptable salt thereof and at least one of Compounds 1-7. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 1 or pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 2 or pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 3 or pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 4 or pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 5 or pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 6 or pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 7 or pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises pridopidine or pharmaceutically acceptable salt thereof and Compound 1 and Compound 4 or pharmaceutically acceptable salt thereof.

[0116] The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and suitable for administration to a human subject. Combination Therapy

[0117] When the invention comprises a combination of the active compound and an additional one, or more, therapeutic and / or prophylactic ingredients, the combination of the invention may be formulated for its simultaneous or contemporaneous administration, with at least a pharmaceutically acceptable carrier, additive, adjuvant, or vehicle. This has the implication that the combination of the two active compounds may be administered: - as a combination that is part of the same medicament formulation, the two active compounds being then administered simultaneously, or - as a combination of two units, each with one of the active substances giving rise to the possibility of simultaneous or contemporaneous administration. Administration

[0118] The pharmaceutical composition of the invention may be administered by any convenient route which suits the desired therapy. Preferred routes of administration include oral administration, in particular in tablet, in capsule, in dragee, in powder, suspension or in liquid form, intranasal administration, intradermal administration, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical composition of the invention can be manufactured by the skilled person by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.

[0119] Tablets may contain suitable binders, lubricants, disintegrating agents (disintegrants), coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose, and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, com starch, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc, and the like. Disintegrators (disintegrants) include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.

[0120] General techniques and compositions for making dosage forms useful in the present invention are described in the following references: Modem Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds). These references in their entireties are hereby incorporated by reference into this application. Terms

[0121] As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.

[0122] As used herein, “riluzole” means riluzole or a pharmaceutically acceptable salt thereof, as well as derivatives, for example deuterium-enriched version of riluzole and salts. Riluzole is described in Prescribers’ Digital Reference which is hereby incorporated by reference (Riluzole PDR2017).

[0123] As used herein, “edaravone” means edaravone or a pharmaceutically acceptable salt thereof, as well as derivatives, for example deuterium-enriched version of edaravone and salts. Edaravone is described in Prescribers’ Digital Reference which is hereby incorporated by reference (Edaravone PDR2017).

[0124] A “combination of dextromethorphan and quinidine” or “dextromethorphan / quinidine” or “dextromethorphan hydrobromide / quinidine sulfate” refers to a combination of dextromethorphan hydrobromide (20mg) and quinidine sulfate (lOmg) such as Nuedexta®. Nuedexta® is a dmg currently on the market for treating pseudobulbar affect (PBA) in, inter alia, ALS patients. Nuedexta® has been shown to act on sigma-1 and NMDA receptors in the brain. Recent data demonstrate that the combination has an effect on bulbar function in ALS, but not on other aspects of motor functions (Smith 2017).

[0125] Dextromethorphan hydrobromide / quinidine sulfate is described in Prescribers’ Digital Reference which is hereby incorporated by reference (Dextromethorphan hydrobromide / quinidine sulfate PDR 2017).

[0126] CNM-Au8 nanocrystalline gold are small nanocrystals that provide energetic assistance by supporting bioenergetic reactions and eliminating harmful bioproducts of cell metabolism. CNM-Au8 shows neuroprotective effects in preclinical models. CNM-Au8 consists solely of gold nanoparticles, composed of clean-surfaced, faceted, geometrical crystals held in suspension in sodium bicarbonate buffered, pharmaceutical grade water.

[0127] Trehalose (SLS-005) is a low molecular weight disaccharide ((2R,35,45,5R,6R)-2-(hydroxymethyl)-6-[(2R,3R,45,55,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) oxan-2-yl]oxyoxane-3,4,5-triol) that stabilizes protein and activates autophagy, the process that clears waste materials from cells. Trehalose (SLS-005) activates transcription factor EB, which is key to the expression of autophagy-related genes.

[0128] ABBV-CLS-7262 is an investigational, orally administered activator of the eukaryotic initiation factor EIF2b. The molecule is an integrated stress response (ISR) inhibitor, also known as ISRIB.

[0129] As used herein, an “amount” or “dose” of pridopidine as measured in milligrams refers to the milligrams of underivatized pridopidine base present in a preparation, regardless of the form of the preparation. A “dose of 45 mg pridopidine” means the amount of pridopidine in a preparation is sufficient to provide 45 mg of underivatized pridopidine base having a naturally occurring isotope distribution, regardless of the form of the preparation. Thus, when in the form of a salt, e.g., a pridopidine hydrochloride, the mass of the salt form necessary to provide a dose of 45 mg underivatized pridopidine base would be greater than 45 mg due to the presence of the additional salt ion. Similarly, when in the form of a deuterium-enriched derivative, the mass of the derivatized form necessary to provide a dose of 45 mg underivatized pridopidine base having a naturally occurring isotope distribution would be greater than 45 mg due to the presence of the additional deuterium.

[0130] By any range disclosed herein, it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, for example, 0.01 mg to 50 mg means that 0.02, 0.03 ... 0.09; 0.1; 0.2 ... 0.9; and 1, 2 ... 49 mg unit amounts are included as embodiments of this invention. By any range of time disclosed herein (i.e. weeks, months, or years), it is meant that all lengths of time of days and / or weeks within the range are specifically disclosed as part of the invention. Thus, for example, 3-6 months means that 3 months and 1 day, 3 months and 1 week, and 4 months are included as embodiments of the invention.

[0131] As used herein, “about” in the context of a numerical value or range means ±10% of the numerical value or range recited or claimed.

[0132] As used herein, “monotherapy” means treatment with a single active agent, for example treatment with pridopidine alone.

[0133] As used herein, “adjunctively” means treatment with or administration of an additional compound (second compound), with a primary compound, for example for increasing the efficacy or safety of the primary compound or for facilitating its activity.

[0134] As used herein, “periodic administration” means repeated / recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc.

[0135] As used herein, “combination” means an assemblage of reagents for use in therapy either by simultaneous or contemporaneous administration. Simultaneous administration refers to administration of an admixture (whether a true mixture, a suspension, an emulsion or other physical combination) of the pridopidine and a second compound (for example, riluzole). In this case, the combination may be the admixture or separate containers of the pridopidine and the second compound that are combined just prior to administration. Contemporaneous administration, or concomitant administration refer to the separate administration of the pridopidine and the second compound (for example, riluzole) at the same time, or at times sufficiently close together that an additive or preferably synergistic activity relative to the activity of either the pridopidine or the second compound alone is observed or in close enough temporal proximately to allow the individual therapeutic effects of each agent to overlap.

[0136] As used herein, “add-on” or “add-on therapy” means an assemblage of reagents for use in therapy, wherein the subject receiving the therapy begins a first treatment regimen of one or more reagents prior to beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time. For example, adding pridopidine therapy to a patient already receiving riluzole therapy.

[0137] As used herein, “effective” when referring to an amount of pridopidine refers to the quantity of pridopidine that is sufficient to yield a desired therapeutic response. In a preferred embodiment, the quantity of pridopidine administered does not result in adverse side-effects (such as toxicity, irritation, or allergic response).

[0138] “Administering to the subject” or “administering to the (human) patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject / patient to relieve, cure, or reduce the symptoms associated with a disease, disorder, or condition, e.g., a pathological condition.

[0139] “Treating” as used herein encompasses inducing inhibition, regression, or stasis of a disease or disorder, or lessening, suppressing, inhibiting, reducing the severity of, eliminating, or substantially eliminating, or ameliorating a symptom of the disease or disorder.

[0140] “Inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and / or disease complication in the subject.

[0141] A “symptom” associated with a disease or disorder includes any clinical or laboratory manifestation associated with the disease or disorder and is not limited to what the subject can feel or observe.

[0142] As used herein, “a subject afflicted with” a disease, disorder or condition means a subject who has been clinically diagnosed to have the disease, disorder, or condition.

[0143] Glial cell-derived neurotrophic factor (GDNF) is a protein encoded by the GDNF gene and is believed to promote the survival of many types of neurons them.

[0144] Brain-derived neurotrophic factor (BDNF) is a protein produced by neurons and serves to keep functioning and to promote the growth of neurons and neurogenesis.

[0145] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. For instance, the elements recited in the method embodiments can be used in the pharmaceutical composition, package, and use embodiments described herein and vice versa.

[0146] All combinations, sub-combinations, and permutations of the various elements of the methods and uses described herein are envisaged and are within the scope of the invention.

[0147] Throughout this application, certain publications and patent application publications are referenced. Full citations for the publications may be found immediately preceding the claims. The disclosures of these publications and patent application publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention relates.

[0148] This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. EXAMPLES Experiment 1 Pridopidine Improves Survival in ALS

[0149] “Survival in ALS clinical trials” refer to the length of time a patient lives without reaching Death or permanent assisted ventilation (PAV).

[0150] “Survival probability” refers to the likelihood that a patient will survive for a specific period after receiving a particular treatment or being diagnosed with the disease.

[0151] “Survival data” is often presented using Kaplan-Meier curves in the context of clinical trials. These curves illustrate the probability of survival over time and are commonly used in studies where the outcome of interest is time to a specific event, such as death.

[0152] “The median survival” (The time to 50% survival probability), indicates the time at which 50% of the participants have died.

[0153] “The log-rank test” is used in survival analysis to compare the survival curves of two or more groups. Pridopidine showed a clinically meaningful impact on survival in ALS patients from the HEALY phase 2 clinical trial.

[0154] The ALS Platform Trial is managed by the Healey Center for ALS at the Massachusetts General Hospital. This was a multicenter, multi-regimen, randomized, placebo-controlled, adaptive platform clinical trial evaluating the safety and efficacy of multiple investigational products simultaneously or sequentially in ALS.

[0155] Treatment duration of placebo-controlled regimens was a maximum of 24-weeks for each regimen. An optional open label extension (OLE) may be offered.

[0156] The specific pridopidine regimen was based on cumulative preclinical and clinical studies that suggest a beneficial effect for pridopidine in ALS. Pridopidine acts primarily as a Sigma-1 Receptor (SIR) agonist.

[0157] The purpose of this clinical study of pridopidine was to evaluate the effect of pridopidine 45 mg BID on ALS disease progression including functional decline, bulbar function, muscle strength, function of upper and lower limb, voice and speech characteristics, respiratory function and biomarker levels in participants with ALS.

[0158] The number of planned participants for the pridopidine regimen is 160.

[0159] There were 2 treatment groups for this regimen, active and placebo. Participants were randomized in a 3:1 ratio to active treatment or placebo (i.e., 120 active: 40 placebo).

[0160] The maximum duration of the placebo-controlled treatment period was 24 weeks. Placebo was shared from 4 regimens in the trial, with a total of 164 subjects on Placebo and 120 subjects on pridopidine. Dosing Regimen

[0161] 45 mg pridopidine was administered twice daily (BID), taken in the morning and in the early afternoon (approximately 7 to 10 hours after the morning dose).

[0162] There was a titration period leading up to the proposed dose whereby participants were initiating pridopidine at 45mg QD and then increasing to 45mg BID after 2 weeks. Inclusion Criteria

[0163] 1. Sporadic or familial ALS diagnosed as clinically possible, probable, lab-supported probable, or definite ALS defined by revised El Escorial criteria (Appendix I).

[0164] 2. Age 18 years or older.

[0165] 3. Capable of providing informed consent and complying with study procedures, in the Si’s opinion.

[0166] 4. Time since onset of weakness due to ALS <36 months at the time of the Master Protocol Screening Visit.

[0167] 5. Vital Capacity > 50% of predicted capacity for age, height, and sex at the time of the Master Protocol Screening Visit measured by Slow Vital Capacity (SVC), or, if required due to pandemic-related restrictions, Forced Vital Capacity (FVC) measured in person or via telemedicine, or sustained phonation.

[0168] 6. Participants must either not take riluzole or be on a stable dose of riluzole for > 30 days prior to the Master Protocol Screening Visit. Riluzole-naive participants are permitted in the study.

[0169] 7. Participants must either not take edaravone or have completed at least one cycle of edaravone prior to the Master Protocol Screening Visit. Edaravone-naive participants are permitted in the study.

[0170] 8. Participants must have the ability to swallow pills and liquids at the time of the Master Protocol Screening Visit and, in the Si’s opinion, have the ability to swallow for the duration of the study. Study Objectives

[0171] Primary Efficacy Objective: • To evaluate the efficacy of pridopidine as compared to placebo on ALS disease progression.

[0172] Secondary Efficacy Objective^ • To evaluate the effect of pridopidine on selected secondary measures of disease progression, including survival.

[0173] Safety Objective'. • To evaluate the safety of pridopidine in ALS patients.

[0174] Exploratory Efficacy Objective'. • To evaluate the effect of pridopidine on selected biomarkers and endpoints. Study Endpoints

[0175] Primary Efficacy Endpoint:

[0176] Change in disease severity as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) using a Bayesian repeated measures model that accounts for loss to follow-up due to mortality. Justification -

[0177] The ALSFRS-R measures function in daily activities and is an established scale for monitoring disease progression in ALS. Each type of function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Patients with higher scores have more physical function.

[0178] Secondary Efficacy Endpoints:

[0179] Bulbar Function in Participants with Bulbar Dysfunction Rate of change in ALSFRS-R bulbar subdomain (Q1-Q3) score among participants with bulbar dysfunction at baseline, each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.

[0180] Bulbar function in all Randomized participants Rate of change in ALSFRS-R bulbar subdomain (Q1-Q3) score among all randomized participants. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.

[0181] Speech Rate of change in the speech sub-score of the ALSFRS-R (QI) among all randomized participants. The speech question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 4 and a minimum total score of 0. Patients with higher scores have better speech.

[0182] Respiratory function Rate of change in SVC maximum percent of predicted among all randomized participants,

[0183] Bulbar Function in participants with rapid pre-baseline progression Rate of change in ALSFRS-R bulbar subdomain (Q1-Q3) score among participants with prebaseline slope >0.75 points / month, each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.

[0184] Time to Bulbar Dysfunction Time from baseline to the first observed bulbar dysfunction as measured by an ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain score of less than 12.

[0185] Muscle Strength Rate of change in muscle strength as measured isometrically using hand-held dynamometry HHD. Percent change from baseline among all randomized participants,

[0186] Survival

[0187] Time to death or death equivalent.

[0188] Survival analysis was conducted using Kaplan-Meier product-limit estimates, providing a comprehensive view of survival probabilities along with 95% confidence bounds for each treatment group. To assess the overall survival differences between treatment groups, the log-rank test was employed.

[0189] In the survival analysis results from Definite, Probable and Early (<18 months since symptom onset) patients showed clinically meaningful survival benefit in favor of pridopidine active group compared to placebo-to-pridopidine group, starting from -6 months (180 days), (log rank test: p=0.069)

[0190] At approximately 300 days (-10 months) post first dose, pridopidine active group showed a survival probability of -85% compared to -50% survival probability for placebo-to-pridopidine group. Median was substantially prolonged by -10 months (-300 to 600 days) in the pridopidine active group compared to the placebo-to-pridopidine group, reflecting an approximate doubling of survival time in this subgroup when treated with pridopidine (Figure 1). Pridopidine has a clinically meaningful impact on survival in ALS patients compared to matched ALS patients from PRO-ACT dataset.

[0191] The impact of pridopidine on survival in ALS patients was further assessed by comparing data from the ALS platform trial with data from the large PRO-ACT database (Pooled Resource Open-Access ALS Clinical Trials). The PRO-ACT database serves as a reliable source of well-matched historical controls for ALS trials. It includes data from 16 ALS clinical trials, 1 large observation study, and over 8 million de-identified longitudinally collected data points from over 8,600 people with ALS. This analysis provides valuable insights into the potential benefits of pridopidine beyond the specific trial context, emphasizing its relevance for a wider spectrum of ALS patients. Analysis was done on PRO-ACT dataset with available survival data.

[0192] Propensity score matching was used at baseline to ensure balanced groups, based on key covariates including Time since ALS symptom onset (months), Age at baseline (years), Prebaseline ALSFRS-R Slope (48-ALSFRS-R at baseline) / Time Since Onset, VC% Predicted Baseline Value (SVC or FVC), El Escorial Criteria (Definite or Probable vs. Other) and Site of Onset (Bulbar vs. Other). This baseline matching criteria ensures balance in covariates between data sets.

[0193] The Pridopidine active group (n=120) received pridopidine during the 24-week doubleblind and continued to receive pridopidine during OLE (Open Label Extension). PRO-ACT Matched Active group (n=117, with survival data) were matched at baseline with the mentioned covariates to the Pridopidine Active group (Table 1 and Table 2). Placebo-to-Pridopidine group (n=42) received placebo during the 24-week double-blind period and received pridopidine during OLE (“delayed start”). PRO-ACT Matched Placebo group (n=40, with survival data) matched at baseline to the “Placebo-to-Pridopidine” group with the mentioned covariates above. (Table 1 and Table 2). Table 1: Analysis sets matched at baseline: Group 1 Pridopidine Active N=120 Received pridopidine during the 24-week doubleblind. Received pridopidine during OLE Group 2 PRO-ACT Matched Active N=117 Matched at baseline to the “Pridopidine Active” group Group 3 Placebo-to- Pridopidine N=42 Received placebo during the 24-week double-blind. Received pridopidine during OLE (“delayed start”) Group 4 PRO-ACT Matched Placebo N=40 Matched at baseline to the “Placebo-to-Pridopidine” group 5 Table 2: Well Balanced Baseline Demographics between groups after propensity score matching Baseline characteristics Pridopidine Active PRO-ACT matched Active Placebo to Pridopidine PRO-ACT Matched Placebo n 120 117 42 40 Age (years) 58.54 (10.1) 60.1 (9.49) 57.68 (9.9) 56.62 (9.06) Time since symptom onset (months) 20.95 (8.23) 20.01 (9) 21.82 (9.98 20.31 (9.62 ALSFRSR-R pre-baseline slope 0.75 (0.49) 0.8 (0.73) 0.69 (0.44) 0.71 (0.54) SCV / FVC (%) 81 (0.18) 80 (0.13) 80 (0.17) 77 (0.13) Definite or probable ALS (%) 75 (0.43) 79 (0.41) 71 (0.46) 80 (0.41) Bulbar onset (%) 19 (0.4) 21 (0.41) 24 (0.43) 32 (0.47)

[0194] Kaplan-Meier curves showed clinically meaningful and significant survival benefit, between all groups (Figure 2): 10   1. Pridopidine Active group vs. PRO-ACT matched Active group log-rank test p<0.001. • Median survival was - 23 months in the pridopidine active group vs -13 months for the PRO-ACT matched Active group (-10 months prolongation of survival). 2. Placebo-to-pridopidine group vs. PRO-ACT matched Active group, log-rank p=0.00.4 • Median survival was -21 months in the Placebo-to-pridopidine group vs -13 months for the PRO-ACT matched Active group (-8 months prolongation of survival). 3. Pridopidine Active group vs. PRO-ACT matching placebo to pridopidine group, log-rank P=0.005. • Median survival was - 23 months in the pridopidine active group vs -12 months for the PRO-ACT matched Placebo group (-11 months prolongation of survival). 4. Placebo-to-Pridopidine group vs. PRO-ACT matching placebo to pridopidine group log-rank p=0.081. • Median survival was -21 months in the Placebo-to-pridopidine group vs.~12 months for the PRO-ACT matched Placebo group (-9 months prolongation of survival) Pridopidine showed significantly improved Survival compared to matched PRO-ACT subjects, using Cox Proportional Hazard Ratio Analysis.

[0195] In a comprehensive analysis utilizing the Cox Proportional Hazard Ratio model with a matched active set, pridopidine demonstrated remarkable improvements in survival when compared to matched subjects from the PRO-ACT dataset. The hazard ratio for the pridopidine active group versus the PRO-ACT matched active group was 0.416. This signifies a substantial -58% decrease in the risk of death (p< 0.001).

[0196] Furthermore, placebo-to-pridopidine group in comparison to the PRO-ACT matched active subjects have hazard ratio of 0.466, which translates to -53% decrease in the risk of death (p= 0.004) (Table 3).

[0197] In the analysis utilizing Cox Proportional Hazard Ratio model with a matched placebo set from PRO-ACT dataset, pridopidine showed consistent robust and meaningful survival benefits. The hazard ratio for the pridopidine active group versus the PRO-ACT matched placebo group was 0.0495, indicating -50% decrease in the risk of death (p= 0.009). In the placebo-to pridopidine group compared to PRO-ACT matched placebo subjects, the hazard ratio was 0.552, indicating -45% decrease in the risk of death (p=0.065) (Table 4).

[0198] These data support consistent robust and meaningful survival benefit of pridopidine. Table 3: Pridopidine shows significantly improved Survival compared to matched PROACT- active group subjects, using Cox Proportional Hazard Ratio Analysis. Hazard ratio (95% ci) Survival benefit P value pridopidine active group vs the PRO-ACT matched active group 0.416(0.286, 0.605) -58% <0.001 placebo to pridopidine vs PRO-ACT matched active group 0.466 (0.279, 0.780) -53% 0.004 Table 4: Pridopidine shows significantly improved Survival compared to matched PRO- ACT- placebo group subjects, using Cox Proportiona Hazard Ratio Analysis. Hazard ratio (95% CI) Survival benefit P value pridopidine active group vs the PRO-ACT matched placebo group 0.459 (0.293, 0.836) -50% 0.009 placebo to pridopidine vs PROACT matched placebo group 0.552 (0.294, 1.039) -45% 0.065 Pridopidine has a clinically meaningful impact on survival in Definite, Probable and Early Subgroup ofALS patients compared to treatment naive PRO-ACT patients. (Figure 3) 10

[0199] In the survival analysis results from Definite, Probable and Early Subgroup Kaplan-Meier curves showed clinically meaningful and significant survival benefit, between the following groups: 1. Pridopidine Active group vs. PRO-ACT matched Active group log-rank test p=0.119. • Median survival was - 21 months in the pridopidine active group vs -15 months for 15             the PRO-ACT matched Active group (-7 months prolongation of survival). 2. Pridopidine Active group vs. PRO-ACT matching placebo group, log-rank p=0.039. • Median survival was - 21 months in the pridopidine active group vs -9 months for the PRO-ACT matched Placebo group (-12 months prolongation of survival). Table 5: Analysis sets matched at baseline in Definite, Probable and Early Subgroup of ALS patients. Group 1 Pridopidine Active N=36 Received pridopidine during the 24-week double-blind. Received pridopidine during OLE Group 2 PRO-ACT Matched Active N=35 Matched at baseline to the “Pridopidine Active” group Group 3 PRO-ACT Matched Placebo N=10 Matched at baseline to the “Placebo-to-Pridopidine” group Table 6: PRO-ACT vs pridopidine after matching well balanced at baseline in Definite, 5 Probable and Early Subgroup of ALS patients. Baseline characteristics Pridopidine Active PRO-ACT matched Active PRO-ACT Matched Placebo n 36 35 10 Age (years) 58.23 (10.49) 59.81 (10.54) 54.61 (7.57) Time since symptom onset (months) 11.06 (4.3) 12.38 (2.89) 11.6 (4.23) ALSFRSR-R prebaseline slope 1.31 (0.73) 1.1 (0.66) 1.1 (0.89) SCV / FVC (%) 0.8 (0.48) 0.8 (0.17) 0.79 (0.13) Definite or probable ALS (%) 1(0) 1(0) 1(0) Bulbar onset (%) 0.34 (0.48) 0.33 (0.49) 0.2 (0.42) Pridopidine in Definite, Probable and Early Subgroup of ALS patients shows significantly improved Survival compared to matched PRO-ACT subjects, using Cox Proportional Hazard Ratio Analysis.

[0200] In a targeted survival analysis focusing on the Definite, Probable, and Early Subgroup of ALS patients, pridopidine demonstrates a significant improvement in survival outcomes compared to matched PRO-ACT subjects, utilizing Cox Proportional Hazard regression Analysis.

[0201] The hazard ratio for the pridopidine active group compared to the PRO-ACT matched active group was 0.588, This signifies a substantial -41% decrease in the risk of death.

[0202] This data supports consistent robust and meaningful survival benefit of pridopidine. 5 Table 7: Pridopidine showed significantly improved Survival compared to matched PROACT subjects, using Cox Proportional Hazard Ratio Analysis. Hazard ratio (95% CI) Survival benefit pridopidine active group vs the PRO-ACT matched active group 0.588 (0.292, 1.182) 41% REFERENCES AL-SAIF et al. (2011). A Mutation in Sigma-1 Receptor Causes Juvenile Amyotrophic Lateral Sclerosis. ANN NEUROL; 70:913-919. BANCI et al. (2008). SOD1 and Amyotrophic Lateral Sclerosis: Mutations and Oligomerization, PLoS One 3(2):el677. BERNARD-MARISSAL et al. (2015). Dysfunction in endoplasmic reticulummitochondria crosstalk underlies SIGMARI loss of function mediated motor neuron degeneration. BRAIN: 138; 875-890. BILSLAND et al. (2010). Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci USA. 107(47):20523-8. BONNI A. et al. (1999). 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Claims

1. A method for prolonging the survival of a subject with ALS comprising administering to the subject a composition comprising a pridopidine or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method prolongs the survival of a subject with ALS by at least 2 months, 4 months, 6 months, 10 months, 12 months, or 24 months compared to a subject not treated with pridopidine or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the amount of pridopidine or pharmaceutically acceptable salt thereof is administered daily, twice a week, three times a week or more often than once daily.

4. The method of claim 1, wherein the amount of pridopidine or a pharmaceutically acceptable salt thereof is administered orally.

5. The method of claim 1, wherein the amount of pridopidine or a pharmaceutically acceptable salt thereof administered is 10 mg per day to 90 mg per day.

6. The method of claim 1, wherein the pridopidine salt is pridopidine hydrochloride.

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