Methods of treating amyotrophic lateral sclerosis

Abstract

The present disclosure provides herein, inter alia, methods of treating patients diagnosed with amyotrophic lateral sclerosis (ALS).

Description

METHODS OF TREATING AMYOTROPHIC LATERAL SCLEROSISBACKGROUND

[0001] Amyotrophic lateral sclerosis (ALS) disease is a nervous system disease that affects motor neurons, the nerve cells in the brain and spinal cord that control voluntary muscle movement and breathing. ALS is progressive; the disease gets worse over time.

[0002] Eukaryotic translation initiation factor 2B (eIF2B) is an important node in the Integrated Stress Response (ISR), a pathway implicated in the pathophysiology of several neurological conditions, including ALS.

[0003] There is currently an unmet need for treatments for patients with ALS.SUMMARY

[0004] The present disclosure relates to methods of treating amyotrophic lateral sclerosis (ALS) disease.

[0005] In one aspect, provided are methods of treating a patient diagnosed with ALS, comprising administering to the patient a compound of Formula I:or a pharmaceutically acceptable salt thereof, at a dose of about 120mg or about 240 mg. In some embodiments, the administering achieves a therapeutic effect.

[0006] Also provided herein are methods of achieving a therapeutic effect in a patient diagnosed with ALS, comprising administering to the patient a compound of Formula I:or a pharmaceutically acceptable salt thereof, at a dose of about 120mg or about 240 mg.

[0007] In some embodiments, the compound is a pharmaceutically acceptable salt of Formula I.

[0008] In some embodiments, the compound is:

[0009] In some embodiments, the dose is about 120 mg. In some embodiments, the dose is about 240 mg.DETAILED DESCRIPTIONDefinitions

[0010] As used herein, the singular forms “a,” “an,” and “the” include plural referents, unless the context clearly dictates otherwise. By way of example, “a compound” means one compound or more than one compound.

[0011] As used herein, the terms “about,” “approximately,” and “comparable to,” when used in reference to a value, refer to a value that is similar to the referenced value in the context of that referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about,” “approximately,” and “comparable to” in that context. For example, in some embodiments, the terms “about,” “approximately,” and “comparable to” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0012] As used herein, the term “activation,” “activate,” “activating,” and the like in reference to a protein-activator (e.g., agonist) interaction means positively affecting (e.g., increasing) the activity or function of the protein (e.g., eIF2B, eIF2a, or component of the eIF2 or ISR pathway) relative to the activity or function of the protein in the absence of the activator. In some embodiments, activation refers to an increase in the activity of a signal transduction pathway or signaling pathway (e.g., eIF2B, eIF2a, or component of the eIF2 or ISR pathway). Thus, activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease (e.g., level of eIF2B, eIF2a, or component of the eIF2 or ISR pathway associated with a neurodegenerative disease). Activation may include, at least in part, partially or totally increasing stimulation, increasing or enabling activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein (e.g., eIF2B, eIF2a, or component of the eIF2 or ISR pathway) that may modulate thelevel of another protein or increase cell survival (e.g., increase in eIF2a activity may increase cell survival in cells that may or may not have a reduction in eIF2a activity relative to a non-disease control).

[0013] As used herein, the term “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or the implantation of a slow- release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0014] As used herein, “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” is intended to include A and B, A or B, A (alone), and B (alone). Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” is intended to include A, B, and C; A, B, or C; A or B; A or C; B or C; A and B; A and C; B and C; A (alone); B (alone); and C (alone).

[0015] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a neurodegenerative disease) means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. For example, a symptom of a disease or condition associated with an impaired function of the eIF2B may be a symptom that results (entirely or partially) from a decrease in eIF2B activity (e.g. decrease in eIF2B activity or levels, increase in eIF2a phosphorylation or activity of phosphorylated eIF2a, or reduced eIF2 activity of the ISR signaling pathway). As used herein, what is described as being associated with a disease, ifacausative agent, could be a target for treatment of the disease. For example, a disease associated with decreased eIF2 activity or eIF2 pathway activity, may be treated with an agent effective for increasing the level or activity of eIF2 or eIF2 pathway or a decrease in phosphorylated eIF2a activity or the ISR pathway. For example, a disease associated with phosphorylated eIF2a may be treated with an agent effective for decreasing the level of activity of phosphorylated eIF2a or a downstream component or effector of phosphorylated eIF2a. For example, a disease associated with eIF2a may be treated with an agent effective for increasing the level of activity of eIF2 or a downstream component or effector of eIF2.

[0016] The terms “disease”, “disorder”, and “condition” are used interchangeably herein.

[0017] As used herein, “eIF2B” refers to the heteropentameric eukaryotic translation initiation factor 2B. eIF2B is composed of five subunits: eIF2Bl, eIF2B2, eIF2B3, eIF2B4, and eIF2B5. eIF2Bl refers to the protein associated with Entrez gene 1967, OMIM 606686, Uniprot Q14232, and / or RefSeq (protein) NP_001405. eIF2B2 refers to the protein associated with Entrez gene 8892, OMIM 606454, Uniprot P49770, and / or RefSeq (protein) NP_055054. eIF2B3 refers to the protein associated with Entrez gene 8891, OMIM 606273, Uniprot Q9NR50, and / or RefSeq (protein) NP_065098. eIF2B4 refers to the protein associated with Entrez gene 8890, OMIM 606687, Uniprot Q9UI10, and / or RefSeq (protein) NP_751945. eIF2B5 refers to the protein associated with Entrez gene 8893, OMIM 603945, Uniprot Q 13144, and / or RefSeq (protein) NP_003898.

[0018] As used herein, an “effective amount” is an amount sufficient to accomplish a stated purpose. An example of an “effective amount” is an amount sufficient to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered for treatment in a particular subject or subject population. In some embodiments, phrases “therapeutically effective amount” and “effective amount” are used interchangeably.

[0019] As used herein, the term “modulation” refers to an increase or decrease in the level of a target molecule or the function of a target molecule. In some embodiments, modulation of eIF2B, eIF2a, or a component of the eIF2 or ISR pathway may result in reduction of the severity of one or more symptoms of a disease associated with eIF2B, eIF2a, or a component of the eIF2 or ISR pathway (e.g., a neurodegenerative condition) or a disease that is not caused by eIF2B, eIF2a, or a component of the eIF2 pathway or ISR pathway but may benefit from modulation of eIF2B, eIF2a, or a component of the eIF2 or ISR pathway. The term “modulator” refers to modulation of (e.g., an increase or decrease in) the level of a target molecule or the function of a target molecule . In embodiments, a modulator of eIF2B, eIF2a, or component of the eIF2 or ISR pathway is a neuroprotectant.

[0020] The term “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0021] As used herein, a “patient” refers to any animal suffering from or diagnosed with a disease, disorder, or condition, such as ALS, including, but not limited to, mammals, primates, and humans. In certain embodiments, the patient may be a non-human mammal such as, for example, a cat, a dog, or a horse. In a preferred embodiment, the patient is a human subject.

[0022] As used herein, “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention withoutcausing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0023] As used herein, “treat,” “treating,” or “treatment” refers to a method of alleviating or abrogating a disease and / or its attendant symptoms.

[0024] As used herein, “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid or organic acids such as sulfonic acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, mono-malic acid, mono oxalic acid, tartaric acid such as mono tartaric acid (e.g., (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or (-)-amino acids or mixtures thereof), and the like. These salts can be prepared by methods known to those skilled in the art.

[0025] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods of Treatment

[0027] Provided herein are methods of treating ALS with an ISR modulator. In various embodiments, provided methods achieve one or more therapeutic effects.

[0028] In one aspect, provided herein are methods of treating a patient diagnosed with ALS, comprising administering to the patient a compound of Formula I:or a pharmaceutically acceptable salt thereof, at a dose of about 120 mg or about 240 mg.

[0029] In certain embodiments, the administering achieves a therapeutic effect.

[0030] In another aspect, provided herein are methods of achieving a therapeutic effect in a patient diagnosed with ALS, comprising administering to the patient a compound of Formula I:or a pharmaceutically acceptable salt thereof, at a dose of about 120mg or about 240 mg.

[0031] In certain embodiments, the compound is a pharmaceutically acceptable salt of Formula I.

[0032] In certain embodiments, the compound is:

[0033] In certain embodiments, the dose is between about 120 mg and about 240 mg. In certain embodiments, the dose is about 120 mg. In certain embodiments, the dose is about 240 mg.ISR Modulators

[0034] In some embodiments, a compound for treatment of ALS of the disclosure is capable of modulating the ISR signaling pathway. In some embodiments, the ISR signaling pathway modulator is an eIF2B activator.

[0035] In some embodiments, the ISR signaling pathway modulator is a compound described in international patent applications PCT / US2017 / 031367 and PCT / US2019 / 055850, incorporated herein by reference in their entirety.EXAMPLES

[0036] The invention is further described in detail by reference to the following examples but are not intended to be limited to the following examples. These examples encompass any and all variations of the illustrations with the intention of providing those of ordinary skill in the art with complete disclosure and description of how to make and use the subject invention and are not intended to limit the scope of what is regarded as the invention.Example 1. Evaluation of ABBV-CLS-7262

[0037] This example describes HEALEY ALS Platform Trial to investigate the safety and efficacy of ABBV-CLS-7262 in patients with ALS.

[0038] Patients diagnosed with sporadic or familial ALS and are greater than or equal to 18 years are enrolled. Patients received the compound of Formula II orally at a dose of 120 mg or 240 mg.EQUIVALENTS / OTHER EMBODIMENTS

[0039] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMSWhat we claim:

1. A method of treating a patient diagnosed with amyotrophic lateral sclerosis (ALS), comprising administering to the patient a compound of Formula I:or a pharmaceutically acceptable salt thereof, at a dose of about 120 mg or about 240 mg.

2. The method of claim 1, wherein the administering achieves a therapeutic effect.

3. A method of achieving a therapeutic effect in a patient diagnosed with amyotrophic lateral sclerosis (ALS), comprising administering to the patient a compound of Formula I:or a pharmaceutically acceptable salt thereof, at a dose of about 120mg or about 240 mg.

4. The method of any one of claims 1-3, wherein the compound is a pharmaceutically acceptable salt of Formula I.

5. The method of any one of claims 1-4, wherein the compound is a compound of FormulaII:

6. The method of any one of claims 1-5, wherein the dose is about 120 mg.5 7. The method of any one of claims 1-5, wherein the dose is about 240 mg.

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