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WO 2019/060634 Al 28 March 2019 (28.03.2019) W 1P O PCT

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WO 2019/060634 Al 28 March 2019 (28.03.2019) W 1P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/060634 Al 28 March 2019 (28.03.2019) W 1P O PCT (51) International Patent Classification: Declarations under Rule 4.17: A61K 7/54 (2006.01) C07H 15/203 (2006.01) — as to applicant's entitlement to apply for and be granted a C07C 323/41 (2006.01) patent (Rule 4.17(H)) (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/US20 18/052080 earlier application (Rule 4.17(Hi)) (22) International Filing Date: Published: 20 September 2018 (20.09.2018) — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the (25) Filing Language: English claims and to be republished in the event of receipt of (26) Publication Language: English amendments (Rule 48.2(h)) (30) Priority Data: 62/561,101 20 September 2017 (20.09.2017) US (71) Applicant: THIOGENESIS THERAPEUTICS, INC. [US/US]; 32 Royal Road, Belmont, MA 02478 (US). (72) Inventors: STANTON, Vincent, P., Jr.; 32 Royal Road, Belmont, MA 02478 (US). RIOUX, Patrice, P.; 4795 Keswick Court, San Diego, CA 92130 (US). BARSKI, Pi- otr; Zacisze 2, PL-8 1-823 Sopot (PL). WITT, Dariusz; An- tygony 49/5, PL-80-299 Gdansk (PL). (74) Agent: ELLISON, Jeffrey, J. et al; Clark & Elbing LLP, 101 Federal Street, 15th Floor, Boston, MA 021 10 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : AR PO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). - o © (54) Title: METHODS FOR THE TREATMENT OF CYSTEAMINE SENSITIVE DISORDERS (57) Abstract: The invention features methods for the treatment of cystinosis and other cysteamine sensitive disorders in a subject including administration of a disulfide convertible to cysteamine in vivo. The methods can include the separate administration of a o reducing agent to the subject to increase the bioavailablity and extend the plasma pharmacokinetic profile of the cysteamine produced following administration of the disulfide. The methods permit sustained cysteamine plasma concentrations in a subject. o METHODS FOR THE TREATMENT OF CYSTEAMINE SENSITIVE DISORDERS FIELD OF THE INVENTION The invention features compositions and methods for treating cysteamine sensitive symptoms, syndromes and diseases. BACKGROUND OF THE INVENTION Cysteamine is a naturally occurring aminothiol , generated in vivo via catabolism of pantetheine. Preclinical and early stage clinical studies suggest that cysteamine may be therapeutically active in a variety of diseases, but broad clinical development has been hampered by a lack of a convenient dosing regimen and poor toxicology. Cysteamine has several mechanisms of action, most of them relating to the reducing capacity of its thiol moiety. Cysteamine was first studied clinically in the 1950s as radioprotectant for cancer patients undergoing radiation therapy and as a treatment for radiation poisoning. The thiol group of cysteamine can reduce free radicals and other oxidized compounds that may be detrimental to cells, thereby contributing to redox homeostasis. Cysteamine can also indirectly neutralize harmful oxidants by increasing levels of other antioxidant thiols such as glutathione and cysteine. For example cysteamine can participate in thiol-disulfide exchange with cystine, the dimeric oxidized form of cysteine to form a cysteamine-cysteine disulfide and a free cysteine. Cysteamine can also form disulfides with cysteine residues of proteins, thereby affecting protein structure and function. Cysteamine can inhibit enzymes including transglutaminases, caspases, matrix metalloproteinases and glutaminyl cyclase. Cysteamine is a chelating agent, with particular affinity for copper. Cysteamine also blocks secretion of certain peptide hormones including somatostatin. Diseases for which there is preclinical or clinical evidence for cysteamine therapeutic benefit include neurodegenerative diseases, including Alheimer's disease, Huntington's disease and Parkinson's disease; inflammatory and fibrotic diseases of the kidney, liver and lung ; metabolic diseases including diabetes, metabolic syndrome and the spectrum of fatty liver diseases; infectious diseases, including viral, bacterial and parasitic infections; hypercholesterolemia; ischemic disease including ischemic heart disease or stroke; sickle cell anemia; inherited mitochondrial disorders; hereditary diseases caused by mutation of arginine to cysteine; and cancer. Unfortunately cysteamine has very unpleasant sensory properties (foul odor and bitter taste) and can produce body odor and halitosis when ingested in therapeutically effective amounts (over one gram per day in adolescents and adults). Most patients also experience gastrointestinal side effects including anorexia, nausea, vomiting, and/or stomach pain. The halitosis, body odor and gastrointestinal side effects have all been associated with high peak cysteamine blood levels (frequently over 50-fold higher than endogenous cysteamine levels in healthy subjects). Furthermore, the elimination half-life of cysteamine is only about 25 minutes, which necessitates frequent dosing. In summary there are problems with the organoleptic properties (bitter taste, bad smell), pharmacology (sub-therapeutic blood levels for much of the inter-dose interval), toxicology (gastrointestinal and other side effects) and stability (short shelf life due to oxidation) of the existing oral formulations of cysteamine. Many of these problems are intrinsic to the drug, a volatile thiol compound. As a consequence many cystinosis patients are not fully compliant with cysteamine therapy and as a result suffer from disease progression. Clinical development has been hindered by the inability of the cysteamine formulations to deliver therapeutic levels of drug over sustained time periods with acceptable toxicology. Accordingly, there is a need for improved treatment regimens, including improved cysteamine producing compounds, improved formulations and improved dosing regimens, that can produce sustained elevated blood levels of cysteamine while reducing peak concentrations and raising trough concentrations so as to provide improved efficacy while minimizing side effects. Further, in view of the known inter-patient variation in cysteamine pharmacokinetics, compositions that enable individualization of dosing regimens are needed to improve efficacy and reduce toxicity. SUMMARY OF THE INVENTION In a first aspect, the invention features a method for treating a cysteamine sensitive disorder in a subject including administering to the subject a dose of from 50 to 150 milligrams per kilogram of body weight (mg/kg) (e.g., 60±1 0 , 70±1 0, 80±1 0, 90±1 0, 100±25, 110±20, 120±1 0 , 130±1 0 , or 140±1 0 mg/kg) of compound 1: or a pharmaceutically acceptable salt thereof, one or more times daily (e.g., one, two, or three times daily). In particular embodiments, within 2 hours (e.g., within 30 minutes, 1 hour, 90 minutes, or 2 hours) of the administering of the dose no reducing agent is administered to the subject. In particular embodiments, between 2 hours and 8 hours after the administering of the dose a reducing agent is administered to the subject. In particular embodiments, the reducing agent is administered 3+1 hours, 4±1 hours, 5±1 hours, 6±1 hours, 7±1 hours, or 4±2 hours, after the administering of the dose of compound 1 or a pharmaceutically acceptable salt. In one embodiment, the reducing agent is selected from glutathione, glutathione diethyl ester, gamma glutamylcysteine, dihydrolipoic acid, N-acetylcysteine, homocysteine, pantetheine, 4-phosphopantetheine, dephospho-coenzyme A , coenzyme A , vitamin E , and ascorbic acid. In particular embodiments, wherein the compound 1, or a pharmaceutically acceptable salt thereof, is formulated for immediate release. In particular embodiments the compound 1, or a pharmaceutically acceptable salt thereof, is formulated as a powder and the dosage form is a sachet. In particular embodiments, a pantetheinase inducing agent selected from the group including PPAR alpha agonists, PPAR gamma agonists, or Nrf2 inducing agents is administered to the subject. In one embodiment, the pantetheinase inducing agent is an isothiocyanate present in cruciferous vegetables, a sulforaphane, S-allyl cysteine, diallyl trisulfide, oxidized fat, omega-3 fatty acids, or oleylethanolamide. In particular embodiments, within 30 minutes (e.g., 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, or 30
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