Copper complexes for the treatment of neurodegenerative disorders

Abstract

The present disclosure relates to the use of CuPTSM in methods and compositions for treating a subject with a neurodegenerative disease. The subject may have, for example, amyotrophic lateral sclerosis (ALS).

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 878,581, filed July 25, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Neurodegenerative diseases are increasingly prevalent age-dependent disorders due in part to the growing elderly population [Heemels, Nature (2016) 539:179].

[0003] For example, amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, Lou Gehrig's disease, or Charcot's disease, is estimated to affect 30,000 Americans and over 400,000 people worldwide at any one time. Approximately 5,000 Americans are diagnosed with ALS each year. The disease causes the unrelenting death of motor neurons, resulting in progressive paralysis that kills its victims within 1-5 years on average. Most people diagnosed with ALS live 3-5 years after the first signs of the disease. About 10% of people with ALS survive at least 10 years. The variable rate of disease progression makes prognosis difficult to predict and makes developing a therapy challenging.

[0004] Only two drugs (riluzole and edaravone) are FDA approved for the treatment of ALS, and while both can slow disease progression and extend life by up to several months in a subset of patients, neither can treat or cure the disease.

[0005] Some inherited forms of ALS result from genetic mutations that alter an enzyme abundant in cells called copper-zinc superoxide dismutase (Cu-Zn superoxide dismutase, now commonly referred to as SOD1). This enzyme helps keep cells safe from metabolic waste that could cause damage if not neutralized.

[0006] CuATSM is a serotype of superoxide dismutase SOD1 by rigorous standards established in the art. G93A It has been shown to be protective in high-expressing mice. However, the high copper affinity of CuATSM makes it an inefficient delivery vehicle because it bypasses the transport systems that naturally limit copper transport to the central nervous system ("CNS").

[0007] Thus, there is a need in the art for improved therapeutic agents that can treat neurological diseases and / or copper deficiency related disorders. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Heemels, Nature (2016) 539:179 pages [Non-Patent Document 2] Int. J. Rad. Appl. Instr., part B, 1987, pp. 14, 59. [Non-Patent Document 3] Goodman and Gillman's The Pharmaceutical Basis of Therapeutics (eds. Alfred Goodman Gilman, Louis S. Goodman, and Alfred Gilman, 6th ed., 1980) [Non-Patent Document 4] "Remington's: The Science and Practice of Pharmacy", 21st edition, Lippincott Williams and Wilkins, 2005 [Non-Patent Document 5] Remington's Pharmaceutical Sciences, 18th edition, (Mack Publishing Company, Easton, Pa., 1990) [Non-Patent Document 6] Hatzipetros et al., 2015, J. Visualized Experiments. doi:10.3791 / 53257 Summary of the Invention [Problem to be solved by the invention]

[0009] The present disclosure provides methods and compositions for treating neurodegenerative disorders in a subject in need thereof. In particular, one aspect provided herein is a method for treating or preventing neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of copper PTSM (CuPTSM). It has surprisingly been found that CuPTSM is effective in treating ALS symptoms at significantly lower doses and with significantly less in vivo drug exposure than CuATSM. [Means for solving the problem]

[0010] In various embodiments, treating the subject comprises administering a therapeutically effective amount of copper PTSM (CuPTSM).

[0011] In various embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, and Alzheimer's disease.

[0012] In various embodiments, the neurodegenerative disease is ALS. In various embodiments, the ALS is familial or sporadic.

[0013] In various embodiments, the subject is treatment naive. In various embodiments, the subject has received prior treatment for ALS.

[0014] In various embodiments, the therapeutically effective dose of CuPTSM is between 0.01 mg / kg / day and 12 mg / kg / day.

[0015] In various embodiments, the subject is a human and the human has a genetic mutation associated with ALS, hi various embodiments, the genetic mutation associated with ALS comprises a mutation in the SOD1 gene.

[0016] In various embodiments, CuPTSM is administered to a subject in combination with an additional ALS treatment therapy.

[0017] In various embodiments, CuPTSM is administered at a dose that achieves a plasma Cmax of about 50-640 ng / mL in the subject.

[0018] In another aspect, provided herein is a pharmaceutical composition comprising CuPTSM and a pharma- ceutically acceptable excipient.

[0019] In various embodiments, the pharma- ceutically acceptable excipient comprises a cellulose and a surfactant. In various embodiments, the cellulose is methylcellulose. In various embodiments, the surfactant is a polysorbate. In various embodiments, the polysorbate is TWEEN-80®. [Brief description of the drawings]

[0020] [Figure 1] Figure 1A is a graph illustrating the plasma concentration of CuPTSM over a 6-hour period following administration of a single bolus dose of 30 mg / kg. Figure 1B is a graph illustrating the plasma concentration of CuATSM over a 6-hour period following administration of a single bolus dose of 30 mg / kg. [Diagram 2] Figure 2A is a graph illustrating the spinal cord concentration of CuPTSM over a 6-hour period following administration of a single bolus dose of 30 mg / kg. Figure 2B is a graph illustrating the spinal cord concentration of CuATSM over a 6-hour period following administration of a single bolus dose of 30 mg / kg. [Diagram 3]FIG. 3A shows a simulated experiment using PK parameters obtained from the experiments in FIG. 1A and FIG. 1B, assuming linear pharmacokinetics. Plasma concentrations (ng / mL, Plasma Conc.) in mice administered 6 mg / kg CuPTSM, 30 mg / kg CuATSM, or 100 mg / kg CuATSM are shown over time (hours). FIG. 3B shows a simulated experiment using PK parameters obtained from the experiments in FIG. 1A and FIG. 1B, assuming linear pharmacokinetics. Spinal cord concentrations (ng / mL, Spinal Cord Cons.) in mice administered 6 mg / kg CuPTSM, 30 mg / kg CuATSM, or 100 mg / kg CuATSM are shown over time (hours). [Figure 4A] FIG. 1 is a set of figures illustrating the percentage of the population that developed paresis onset throughout the study. [Figure 4B] FIG. 1 illustrates the efficacy of 6 mg / kg CuPTSM, 30 mg / kg CuATSM or 100 mg / kg CuATSM as measured by the onset of paresis compared to mice receiving vehicle alone. [Figure 5A] FIG. 1 is a set of figures tracking the percent survival of each treatment group throughout the study. [Figure 5B] FIG. 1 illustrates the lifespan of mice given 6 mg / kg CuPTSM, 30 mg / kg CuATSM, or 100 mg / kg CuATSM versus mice receiving vehicle. [Figure 6] Figure 6A shows the percent survival over time of mice given 6 mg / kg CuATSM compared to a control cohort of mice, and Figure 6B illustrates the percentage of the mouse population that developed onset of paresis given 6 mg / kg CuATSM compared to controls. [Figure 7]Figure 7A illustrates the difference in compound muscle action potential (CMAP) measurements between male mice given 2, 6, or 12 mg / kg CuPTSM compared to vehicle, and Figure 7B illustrates the difference in CMAP measurements between mice treated with 10 or 30 mg / kg CuATSM and vehicle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Provided herein is a method for treating a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of CuPTSM. In one embodiment, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, Huntington's disease, and Alzheimer's disease. In one embodiment, the neurodegenerative disease is ALS.

[0022] As mentioned above, CuATSM has been used clinically for the treatment of ALS, but suffers from significant drawbacks that severely limit its use as a therapeutic drug. Moreover, CuATSM has a small, symmetrical structure, which contributes to another limitation associated with this compound. That is, its small structure allows the ATSM ligand component to rapidly form extremely stable crystals, which causes several challenges in the preparation and formulation of this compound and hinders its ability to act as a suitable pharmacological agent. For example, the metal-free ATSM ligand component crystallizes within a few seconds during synthesis in all common reflux solvents. Therefore, it is difficult to add copper sequentially in the final step of the synthesis, especially on an industrial scale required to produce the large quantities required for clinical use.

[0023] To address these challenges, CuPTSM is provided herein as an effective therapeutic for the treatment of neurodegenerative diseases, including ALS. CuPTSM is an asymmetric copper(II) bis(thiosemicarbazone) complex, in which the bis(thiosemicarbazone) ligand is kappa. 4The CuPTSM is coordinated to the copper center in a manner similar to that of CuATSM. This compound was first synthesized in 1987 (Int. J. Rad. Appl. Instr., part B, 1987, 14, 59) and has been used as a tracer for positron emission tomography. CuPTSM differs from CuATSM in the symmetry of the ligand backbone (see structure below). Despite the lower in vivo drug exposure of CuPTSM compared to CuATSM, it has surprisingly been found that CuPTSM is more effective in treating ALS symptoms at significantly lower dosages.

[0024] [ka]

[0025] definition Listed below are definitions of various terms used in this specification. These definitions apply to terms as they are used throughout the specification and claims, unless limited in specific instances, either individually or as part of a larger group.

[0026] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the terminology used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry and peptide chemistry are those well known and commonly employed in the art.

[0027] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, use of the terms "including" as well as other forms such as "include," "includes," and "included" are not limiting.

[0028] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to a measurable value such as an amount, a time period, and the like, the term "about" is meant to encompass a variation of ±20% or ±10% from the specified value, including ±5%, ±1%, and ±0.1%, as such variations are appropriate for carrying out the disclosed methods.

[0029] As used in this specification and in the claims, the term "comprising" may include "consisting of" and "consisting essentially of" embodiments. The terms "comprise(s)", "include(s)", "having", "has", "may", "contain(s)" and variants thereof are intended herein to be open-ended transitional phrases, terms or words that require the presence of the specified ingredients / steps and allow for the presence of other ingredients / steps. However, such descriptions should also be construed as describing compositions or processes that "consist of" and "consist essentially of" the recited compounds, which permit only the presence of the specified compounds together with any pharma- ceutically acceptable carriers, and exclude other compounds.

[0030] The term "treatment" refers to the application of one or more specific procedures used to ameliorate a disease. In certain embodiments, the specific procedure is the administration of one or more pharmaceutical agents. "Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention used to attempt to modify the natural history of the individual or cell. Treatment includes, but is not limited to, administration of a pharmaceutical composition, and can be performed either prophylactically or after the initiation of a pathological event or contact with a pathogenic agent. Treatment includes any desired effect on the symptoms or pathology of a disease or condition, and may include, for example, a minimal change or improvement in one or more measurable markers of the disease or condition, and may include, for example, a minimal change or improvement in one or more measurable markers of the disease or condition being treated.

[0031] The term "prevent" or "prevention" as used herein means that there will be no onset of any disorder or disease where none occurs, or no further onset of a disorder or disease where onset of a disorder or disease is already present. Also considered is the ability of something to prevent some or all of the symptoms associated with a disorder or disease.

[0032] As used herein, the term "use" includes, where appropriate and conveniently, any one or more of the following embodiments of the invention, namely, use in the treatment of ALS, use in the manufacture of pharmaceutical compositions, e.g., use in the manufacture of medicaments, for use in the treatment of these diseases; methods of use of the compounds of the invention in the treatment of these diseases; pharmaceutical formulations having the compounds of the invention for the treatment of these diseases; and compounds of the invention for use in the treatment of these diseases. In one embodiment, the use of CuPTSM for use as a medicament is provided herein.

[0033] As used herein, the terms "patient," "individual," or "subject" are intended to include organisms, e.g., prokaryotic and eukaryotic organisms, that may be afflicted or affected by a disease, disorder, or condition associated with protein kinase activity. Examples of subjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and non-human transgenic animals. In certain embodiments, the subject is a human, e.g., a human afflicted, at risk of afflicting, or potentially capable of afflicting, schizophrenia. In another embodiment, the subject is a cell.

[0034] When used in relation to the methods of treatment / prevention and use of the compounds and pharmaceutical compositions thereof described herein, an individual "in need thereof" may be an individual who has been diagnosed with or previously treated for the condition to be treated. In the context of prevention, an individual in need thereof may also be an individual who is at risk for the condition (e.g., family history of the condition, lifestyle factors indicative of risk for the condition, etc.). Typically, when a step of administering a compound of the invention is disclosed herein, the invention further contemplates a step of identifying an individual or subject in need of the particular treatment to be administered or having the particular condition to be treated.

[0035] In some embodiments, the individual is a mammal, including but not limited to a cow, horse, cat, rabbit, dog, rodent, or primate. In some embodiments, the mammal is a primate. In some embodiments, the primate is a human. In some embodiments, the individual is a human, including adults, children, and premature infants. In some embodiments, the individual is a non-mammal. In some variations, the primate is a non-human primate, such as chimpanzees and other ape and monkey species. The term "individual" does not denote a particular age or sex.

[0036] As used herein, the terms "effective amount," "pharmacologically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. That result may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0037] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present invention and a pharma- ceutical acceptable carrier. A pharmaceutical composition facilitates administration of a compound to a patient or subject. Multiple techniques for administering a compound exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0038] As used herein, the terms "combination," "therapeutic combination," or "pharmaceutical combination" refer to either a fixed combination in a dosage unit form, or a loose combination, or a kit-of-parts for combined administration, in which two or more therapeutic agents may be administered independently, either simultaneously or separately within a time interval, particularly which time interval allows the combination partners to exhibit a cooperative, e.g., synergistic, effect.

[0039] The term "sporadic" refers to non-hereditary neurodegenerative diseases, such as ALS. Sporadic ALS accounts for approximately 90% of cases, and the affected individual is the only member of the family who has the disease. The cause of sporadic ALS is not well understood, but may be due to a combination of environmental and genetic risk factors.

[0040] The term "familial" refers to an inherited neurodegenerative disease, such as ALS. Familial ALS accounts for about 10% of cases, with more than one person in a family having ALS, and sometimes relatives also have frontotemporal dementia. People with familial ALS often begin to show symptoms at a younger age than those with sporadic ALS. Familial ALS is most often autosomal dominant.

[0041] "Elimination half-life" is used in its usual sense as per Goodman and Gillman's The Pharmaceutical Basis of Therapeutics (Alfred Goodman Gilman, Louis S. Goodman, and Alfred Gilman, eds., 6th ed., 1980). Briefly, the term is meant to encompass a quantitative measure of the time course of drug elimination. The elimination of most drugs is exponential (i.e., follows first-order kinetics) because the drug concentration does not usually approach the concentration required for saturation of the elimination process. The rate of an exponential process may be represented by a rate constant, k, which represents the fraction of change per unit time, or by the half-life, t1 / 2, which is the time required for 50% of the process to be completed. The units of these two constants are time-1 and time, respectively. The first-order rate constant and the half-life of a reaction are simply correlated (k×t1 / 2=0.693) and may therefore be interchanged. First-order elimination kinetics dictates that a constant proportion of drug is lost per unit time, so that a logarithmic plot of drug concentration versus time is linear at all times after the initial distribution phase (i.e., after drug absorption and distribution are complete). Drug elimination half-life can be accurately determined from such a graph. "Absorption half-life" is defined as the amount of time required for half of a dose of CuPTSM to be absorbed.

[0042] Treatment Method The methods described herein include administering a therapeutic amount of CuPTSM to a subject in need thereof. A "therapeutically effective amount" is an amount of CuPTSM that, when administered by itself to a patient, effectively treats a neurodegenerative disease. In a given example, an amount that proves to be a "therapeutically effective amount" for a particular subject may not be effective for 100% of subjects similarly treated for the disease or condition under consideration, even if that dosage is deemed a "therapeutically effective amount" by a skilled practitioner. The amount of CuPTSM that corresponds to a therapeutically effective amount strongly depends on the type of disease, the stage of the disease, the age of the patient being treated, and other facts.

[0043] In one aspect, provided herein is a method of treating or preventing ALS in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of CuPTSM.

[0044] In another embodiment, provided herein is a use of CuPTSM for manufacturing a medicament for treating ALS in a subject.

[0045] In different embodiments, CuPTSM can effectively treat ALS, depending on the effective amount of CuPTSM used.

[0046] In certain embodiments, the therapeutically effective dose of CuPTSM is between 0.01 mg / kg / day and 12 mg / kg / day.

[0047] In certain embodiments, the dose of CuPTSM for treatment is about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg g, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, or 72 mg. In one embodiment, the dosage of CuPTSM for treatment is about 0.1 mg to 72 mg per day.

[0048] In certain embodiments, the dose of CuPTSM for treatment is 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg per day. , 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, or 72mg. In one embodiment, the dosage of CuPTSM for treatment is 0.1mg to 72mg per day.

[0049] In certain embodiments, the dose of CuPTSM for treatment is about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg g, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, or 64 mg. In one embodiment, the dosage of CuPTSM for treatment is about 0.1 mg to 64 mg per day.

[0050] In certain embodiments, the dose of CuPTSM for treatment is 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg per day. , 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, or 64 mg. In one embodiment, the dosage of CuPTSM for treatment is 0.1 mg to 64 mg per day.

[0051] In certain embodiments, the dosage of CuPTSM for treatment is about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, or 51 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 0.1 mg to 51 mg per day.

[0052] In certain embodiments, the dose of CuPTSM for treatment is 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, or 51 mg per day. In one embodiment, the dose of CuPTSM for treatment is 0.1 mg to 51 mg per day.

[0053] In certain embodiments, the dosage of CuPTSM for treatment is about 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, or 39 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 0.1 mg to 39 mg per day.

[0054] In certain embodiments, the dosage of CuPTSM for treatment is 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, or 39 mg per day. In one embodiment, the dosage of CuPTSM for treatment is 0.1 mg to 39 mg per day.

[0055] In certain embodiments, the dosage of CuPTSM for treatment is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, or 26 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 1 mg to 26 mg per day.

[0056] In certain embodiments, the dosage of CuPTSM for treatment is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, or 26 mg per day. In one embodiment, the dosage of CuPTSM for treatment is 1 mg to 26 mg per day.

[0057] In certain embodiments, the dosage of CuPTSM for treatment is about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, or 26 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 5 mg to 26 mg per day.

[0058] In certain embodiments, the dosage of CuPTSM for treatment is 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, or 26 mg per day. In one embodiment, the dosage of CuPTSM for treatment is 5 mg to 26 mg per day.

[0059] In certain embodiments, the dosage of CuPTSM for treatment is about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 1 mg to 20 mg per day.

[0060] In certain embodiments, the dosage of CuPTSM for treatment is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg per day. In one embodiment, the dosage of CuPTSM for treatment is 1 mg to 20 mg per day.

[0061] In certain embodiments, the dosage of CuPTSM for treatment is about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 5 mg to 20 mg per day.

[0062] In certain embodiments, the dosage of CuPTSM for treatment is 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg per day. In one embodiment, the dosage of CuPTSM for treatment is 5 mg to 20 mg per day.

[0063] In certain embodiments, the dosage of CuPTSM for treatment is about 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 10 mg to 20 mg per day.

[0064] In certain embodiments, the dosage of CuPTSM for treatment is 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg per day. In one embodiment, the dosage of CuPTSM for treatment is 10 mg to 20 mg per day.

[0065] In certain embodiments, the dosage of CuPTSM for treatment is about 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, or 18 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 10 mg to 18 mg per day.

[0066] In certain embodiments, the dosage of CuPTSM for treatment is 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, or 18 mg per day. In one embodiment, the dosage of CuPTSM for treatment is 10 mg to 18 mg per day.

[0067] In certain embodiments, the dosage of CuPTSM for treatment is about 12 mg, 13 mg, 14 mg, 15 mg, or 16 mg per day. In one embodiment, the dosage of CuPTSM for treatment is about 12 mg to 16 mg per day.

[0068] In certain embodiments, the dosage of CuPTSM for treatment is 12 mg, 13 mg, 14 mg, 15 mg, or 16 mg per day, hi one embodiment, the dosage of CuPTSM for treatment is 12 mg to 16 mg per day.

[0069] In certain embodiments, the dosage of CuPTSM for treatment is about 13 mg, 14 mg, or 15 mg per day, hi one embodiment, the dosage of CuPTSM for treatment is about 13 mg to 15 mg per day.

[0070] In certain embodiments, the dosage of CuPTSM for treatment is 13 mg, 14 mg, or 15 mg per day, hi one embodiment, the dosage of CuPTSM for treatment is 13 mg to 15 mg per day.

[0071] In certain embodiments, the dose of CuPTSM for treatment is about 14 mg per day. In certain embodiments, the dose of CuPTSM for treatment is about 14 mg per day.

[0072] In another embodiment, a method of treating ALS in a subject in need thereof is provided herein, wherein the subject is administered a low dose of CuPTSM. As used herein, the term "low dose" refers to a dose that is less than the therapeutically effective amount of the reference compound CuATSM when administered to treat ALS. In some embodiments, the term "low dose" refers to a dose that is one order of magnitude or more lower than the therapeutically effective amount of the reference compound CuATSM when administered to treat ALS. In some embodiments, the term "low dose" refers to a dose that is ½, ⅓, ¼, ⅕, ⅙, ⅙, ⅙, or less than the therapeutically effective amount of the reference compound CuATSM when administered to treat ALS. In some embodiments, the "low dose" of CuPTSM is within a dose or dose range described herein. The amount of CuPTSM should provide an effective treatment of ALS, but preferably the amount is not excessively toxic to the patient (i.e., the amount is preferably within toxicity limits as established by medical guidelines). In some embodiments, limits are set for the total dosage administered, either to prevent excessive toxicity or to provide more effective treatment of ALS, or both.Typically, the amount considered herein is per day.However, half-day and 2-day or 3-day cycles are also considered herein.

[0073] In certain embodiments, the subject in need thereof is treatment naive. In certain embodiments, the subject in need thereof has received prior treatment for ALS other than CuPTSM, which prior treatment was insufficient (e.g., as assessed by the subject and / or physician), was ineffective and / or did not result in a detectable improvement in one or more parameters or symptoms associated with ALS, and / or did not cause a biological effect that correlates with the underlying pathology causing the symptoms of ALS.

[0074] In certain embodiments, the subject in need thereof is a human, the human has a genetic mutation associated with ALS, and the genetic mutation associated with ALS comprises a mutation in the SOD1 gene.

[0075] In one aspect, provided herein is a method of treating or preventing a neurodegenerative disorder associated with superoxide dismutase 1 (SOD1) in a subject in need thereof, comprising administering CuPTSM to the subject. In one embodiment, the SOD1-associated neurodegenerative disorder is SOD1-associated amyotrophic lateral sclerosis (ALS).

[0076] In certain embodiments, CuPTSM is administered to a subject in combination with additional ALS treatment therapy. Current treatments for ALS include administration of riluzole and edaravone, which have been shown to be moderately effective. Other therapies for ALS include medications to treat certain symptoms associated with the disease, such as muscle relaxants such as baclofen or diazepam, which may be prescribed to treat muscle spasms, spasticity, and spasticity. Gabapentin may be prescribed to help manage pain. These medications, such as amitriptyline, trihexyphenidyl, scopaderm, and glycopyrrolate, may be administered to treat excess saliva in the mouth due to swallowing disorders. Medication may also be required to treat constipation, fatigue, depression, sleep difficulties, and emotional dysregulation associated with ALS.

[0077] In certain embodiments, CuPTSM is administered at a dose that achieves a plasma Cmax of about 50-650 ng / mL in the subject. The term "Cmax" is defined as the maximum concentration of active CuPTSM or CuATSM achieved in the plasma or spinal cord following drug administration.

[0078] Pharmaceutical Compositions The formulation of therapeutic compositions and their subsequent administration (dosing) is within the skill of those in the art. Dosing depends on the severity and responsiveness of the condition being treated, with the course of treatment lasting from several days to several months, or until a sufficient diminution of the condition is achieved. Optimal dosing regimens can be calculated from measurements of drug accumulation in the patient's body.

[0079] Those skilled in the art can easily determine optimal dosages, dosing methods, and repetition rates. Optimal dosages may vary depending on the relative potency of CuPTSM, and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models. In general, dosages are 0.01 μg to 100 g / kg of body weight and may be given once or more daily, weekly, monthly, or yearly, or even once every 2 to 20 years. Those skilled in the art can easily estimate repetition rates of dosing based on the measured residence time and concentration of the drug in bodily fluids or tissues. After successful treatment, it may be desirable for the patient to undergo maintenance therapy to prevent recurrence of the condition, with CuPTSM administered at a maintenance dose ranging from 0.01 μg to 100 g / kg of body weight once or more daily to once every 20 years.

[0080] Different dosage regimes may be used to treat ALS. In some embodiments, a daily dosage is administered once, twice, three or four times a day for 3, 4, 5, 6, 7, 8, 9 or 10 days, such as any of the exemplary dosages described above. Depending on the stage and severity of the disease to be treated, a higher dosage may be used for a shorter treatment period (e.g., up to 5 days), or a lower dosage may be used for a longer treatment period (e.g., 10 days or more, or several weeks or a month or more). In some embodiments, a once or twice daily dosage is administered every other day.

[0081] In one embodiment, CuPTSM may be administered alone or in combination with at least one pharma- ceutically acceptable excipient. The expression "pharma- ceutically acceptable" means acceptable for use in the pharmaceutical and veterinary arts, i.e., not unacceptably toxic or otherwise unsuitable. Examples of pharma- ceutically acceptable adjuvants include diluents, excipients, and the like. For general guidance on drug formulation, see Remington's: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, 2005.

[0082] CuPTSM may be administered in pure form or in a suitable pharmaceutical composition by any of the accepted modes of administration or agents known in the art. CuPTSM may be administered, for example, orally, nasally, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, intracisternally, or rectally. The dosage form may be, for example, a solid, semi-solid, lyophilized powder, or liquid dosage form, such as, for example, a unit dosage form suitable for easy administration of a precise dosage, for example, a tablet, pill, soft elastic or hard gelatin capsule, powder, solution, suspension, suppository, aerosol, and the like. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil; sesame oil, olive oil, corn oil and cocoa butter; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline and phosphate buffer solution; and other compatible substances that are usually used in pharmaceutical preparations. A particular route of administration is oral, in particular a route where a convenient daily dosage regimen can be adjusted according to the degree of severity of the disease to be treated.

[0083] Auxiliaries and adjuvants may include, for example, preservatives, wetting agents, suspending agents, sweetening agents, flavorings, fragrances, emulsifying agents, and dispensing agents. Emulsifying agents may include polysorbates such as TWEEN®, e.g., TWEEN-20® and TWEEN-80®. TWEEN-80 is a C 64 H 124 O 26 It is derived from polyethoxylated sorbitan and oleic acid and is also called polyoxyethylene (20) sorbitan monooleate and (x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl). Prevention of the action of microorganisms is generally achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonicity agents, such as sugars, sodium chloride, and the like, may also be included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Auxiliaries may also include wetting agents, emulsifying agents, pH buffering agents, and antioxidants, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, and the like.

[0084] Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others known in the art. The dosage forms can contain pacifying agents and can be of a composition that releases the CuPTSM in a specific part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The CuPTSM can also be in a microencapsulated form, if appropriate, with one or more of the excipients mentioned above.

[0085] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared by, for example, dissolving, dispersing, etc., CuPTSM and any pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc.; solubilizers and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; or mixtures of these substances, etc., to form a solution or suspension.

[0086] Generally, depending on the intended mode of administration, a pharma- ceutically acceptable composition will contain about 1% to about 99% by weight of the CuPTSM described herein and 99% to 1% by weight of pharma- ceutically acceptable excipients. In one example, the composition will be about 5% to about 75% by weight of the CuPTSM described herein, with the remainder being suitable pharmaceutical excipients.

[0087] In various embodiments, the pharmaceutical composition is for treating ALS in a subject in need thereof.

[0088] In various embodiments, the pharmaceutical composition comprises CuPTSM in any of the doses provided herein.

[0089] Actual methods for preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th Edition, (Mack Publishing Company, Easton, Pa., 1990).

[0090] The present invention will be further described in detail by reference to the following experimental examples. These examples are included merely for the purpose of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the present invention. Thus, the present invention should not be construed in any way as being limited to the following examples, but rather as embracing any variations that become evident as a result of the teachings provided herein. EXAMPLES

[0091] Example 1: Pharmacokinetics of CuPTSM compared to CuATSM SOD1 in ALS G93A The transgenic mouse model has been the most widely used animal model since the 1990s. The mice were genetically engineered to overexpress a mutant form of the human Cu / Zn superoxide dismutase 1 (SOD1) gene carrying the ALS-associated glycine to alanine mutation at amino acid position 93 (G93A). Currently, the clinical strategy for the treatment of ALS with CuATSM is to increase the human drug dose until ALS patients show plasma levels equivalent to those seen in mice given 30 mg / kg / day.

[0092] To compare the effects of CuPTSM with CuATSM in vivo, a single bolus of 30 mg / kg CuPTSM or 30 mg / kg CuATSM in an oral suspension of 0.5% methylcellulose / 0.4% TWEEN-80 / 0.9% saline was administered to induce SOD1 activation. G93A The drug was administered to mice. Absorption half-life, elimination half-life and Cmax measurements were performed on both plasma and spinal cord samples to measure drug exposure for CuPTSM or CuATSM for up to 6 hours after drug administration. A decrease in plasma concentrations of CuPTSM was observed over time with an absorption half-life of 0.54 hours, an elimination half-life of 2.44 hours and a plasma Cmax of 1565 ng / mL (Figure 1A). Plasma concentrations of CuATSM reached a plateau and remained constant 6 hours after administration with an absorption half-life of 0.24 hours, an elimination half-life of 13.7 hours and a plasma Cmax of 198 ng / mL (Figure 1B).

[0093] Similar measurements were recorded for the concentrations of CuPTSM and CuATSM in the spinal cord. Similar to the plasma concentrations in mice administered 30 mg / kg CuPTSM, the concentrations decreased over time (Figure 2A), with CuPTSM being found to have an absorption half-life of 1.0 h, an elimination half-life of 1.9 h, and a Cmax of 7.27 ng / mL. Similar to the plasma concentrations, the spinal cord concentrations of CuATSM remained constant even 6 hours after administration (Figure 2B). In the spinal cord, CuATSM had an absorption half-life of 0.65 h, an elimination half-life of 13.8, and a Cmax of 2 ng / mL.

[0094] Using data and parameters from the above experiments using a single bolus of 6 mg / kg CuPTSM, 30 mg / kg CuATSM, or 100 mg / kg CuATSM, plasma and spinal cord concentrations were plotted over time (hours) to illustrate a pharmacokinetic simulation over time. Linear kinetics was assumed. Previous studies using CuPTSM demonstrated that 30 mg / kg CuATSM was well tolerated by mice, while the same dose of CuPTSM was toxic to mice. Plasma concentrations of 30 mg / kg CuATSM and 100 mg / kg CuATSM did not return to 0 ng / mL before the next dose. In contrast, plasma concentration levels of CuPTSM increased after mice were dosed with 6 mg / kg, with plasma levels returning to 0 ng / mL before the next dose (Figure 3A). Similar results were obtained when concentrations were measured in spinal cord samples (Figure 3B).

[0095] Example 2 SOD1 G93A Efficacy of CuPTSM in mice To test the efficacy of CuPTSM compared to CuATSM, mice were tested for delay in paresis and overall lifespan. Mice were given 6 mg / kg CuPTSM (n=32), 30 mg / kg CuATSM (n=32), and 100 mg / kg CuATSM (n=32) once daily to assess disease progression, and SOD1 expression was significantly increased compared to vehicle-only control mice, respectively. G93ADrug-induced changes in mice were identified. Neurological scoring to test the onset of paresis for each mouse was performed throughout the study according to the procedure disclosed in Hatzipetros et al. (2015, J. Visualized Experiments. doi:10.3791 / 53257), which is incorporated herein by reference in its entirety. Briefly, mice were scored on a scale of NS0 (prodromal) to NS4 (humane end point) based on a combination of tail suspension, walking and "righting" tests. Onset of paresis was measured throughout the study (FIG. 4A), and either CuPTSM or CuATSM delayed onset compared to controls. However, when each experimental group was compared to its respective control group, mice administered 6 mg / kg CuPTSM significantly delayed onset of paresis compared to either the 30 mg / kg CuATSM or 100 mg / kg CuATSM dose groups versus their respective control groups (FIG. 4B).

[0096] Survival of each cohort was also tracked throughout the study. Similar to the paresis study, mice administered 6 mg / kg CuPTSM, 30 mg / kg CuATSM, or 100 mg / kg CuATSM demonstrated increased survival versus their control counterparts (FIG. 5A). When experimental groups were compared to each other, cohorts treated with CuPTSM had significantly improved survival versus groups treated with either dose of CuATSM (FIG. 5B).

[0097] To compare the effect of CuPTSM administered at a much lower dose than CuATSM, mice were administered 6 mg / kg CuATSM and survival and onset of paresis were measured as before. When compared to control mice, the mouse population receiving 6 mg / kg CuATSM did not exhibit any significant difference in survival (Figure 6A). Similarly, no significant improvement in onset of paresis was seen with administration of 6 mg / kg CuATSM compared to controls (Figure 6B).

[0098] Compound muscle action potentials (CMAP) were measured in mice given CuPTSM, CuATSM or vehicle. CMAP is an electrophysiological technique that assesses the functional integrity of motor axons. The sciatic nerve is stimulated using an implanted microelectrode that delivers a small current and the response is measured in the innervated tibialis anterior (TA) muscle using an implanted recording electrode. CMAP signals are reduced in cases of neuromuscular disease, such as in ALS patients, due to motor unit loss, and are associated with increased SOD1 expression. G93A It is known that the male SOD1 G93A It has been shown that in mice, changes in CMAP can occur as early as postnatal day 50 and always worsen thereafter. In this study, mice were treated once daily for 14 days with 2, 6, or 12 mg / kg CuPTSM; 10 or 30 mg / kg CuATSM; or vehicle (control). A total of nine male mice were tested for each condition.

[0099] Prior to drug administration and allocation of mice to cohorts, CMAP was recorded for each mouse to establish a baseline measurement. Mice were then randomized into each treatment cohort and administered the respective compound and dosage of the cohort by oral gavage daily for two weeks. CMAP data was recorded at the end of the two weeks and compared to baseline measurements to calculate percent baseline, thereby illustrating the efficacy of CuPTSM and CuATSM compared to vehicle alone. Male mice administered CuPTSM demonstrated significantly greater changes from baseline at all doses compared to mice treated with vehicle alone (Figure 7A). Cohorts of mice treated with 10 mg / kg or 30 mg / kg CuATSM did not exhibit any significant differences in CMAP measurements compared to vehicle-treated mice (Figure 7B).

[0100] Considering the data, CuPTSM was surprisingly more effective than CuATSM in delaying paresis, improving survival, and preserving the functional integrity of motor axons, despite significantly less drug exposure as measured by pharmacokinetics.

Claims

1. 1. A pharmaceutical composition for use in treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof comprising CuPTSM, wherein said CuPTSM is 【Chemistry 1】 1. A pharmaceutical composition having the formula:

2. 2. The pharmaceutical composition of claim 1, wherein the ALS is familial or sporadic.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject in need thereof is treatment naive.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject in need thereof has undergone prior treatment for ALS.

5. The pharmaceutical composition of claim 1, wherein the CuPTSM is administered at a therapeutically effective dose of 0.01 mg / kg / day to 12 mg / kg / day.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject in need thereof is a human, and the human has a genetic mutation associated with ALS.

7. The pharmaceutical composition of claim 6, wherein the genetic mutation associated with ALS comprises a mutation in the SOD1 gene.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the CuPTSM is administered to the subject in combination with an additional ALS treatment therapy.

9. The pharmaceutical composition of claim 8, wherein the CuPTSM is administered at a dose that achieves a plasma Cmax of about 50-640 ng / mL in the subject.

10. 10. The pharmaceutical composition of claim 1, further comprising a pharma- ceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10, wherein the pharma- ceutically acceptable excipient comprises cellulose and a surfactant.

12. 12. The pharmaceutical composition of claim 11, wherein the cellulose is methylcellulose.

13. 13. The pharmaceutical composition of claim 12, wherein the surfactant is a polysorbate.

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