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WO 2014/031901 Al 27 February 2014 (27.02.2014) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/031901 Al 27 February 2014 (27.02.2014) P O P C T (51) International Patent Classification: GALLOP, Mark A.; 812 Boyce Avenue, Palo Alto, Cali Λ 61Κ 31/225 (2006.01) A61P 35/00 (2006.01) fornia 94301-3003 (US). A61K 31/5375 (2006.01) A61P 43/00 (2006.01) (74) Agents: WORRALL, Timothy A. et al; Dorsey & Whit A61P 17/06 (2006.01) A61P 37/06 (2006.01) ney LLP, 1400 Wewatta Street, Suite 400, Denver, Color A61P 29/00 (2006.01) A61P 37/00 (2006.01) ado 80202 (US). A61P 25/00 (2006.01) A61K 45/06 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/US20 13/056278 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 22 August 2013 (22.08.2013) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English 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, (30) Priority Data: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 61/692,168 22 August 2012 (22..08.2012) US TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 61/692,174 22 August 2012 (22..08.2012) u s ZW. 61/692,179 22 August 2012 (22..08.2012) u s 61/713,961 15 October 2012 (15..10.2012) u s (84) Designated States (unless otherwise indicated, for every 61/713,897 15 October 2012 (15..10.2012) u s kind of regional protection available): ARIPO (BW, GH, 61/733,234 4 December 2012 (04..12.2012) u s GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/736,906 13 December 2012 (13..12.2012) u s UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/769,5 13 26 February 2013 (26..02.2013) u s TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/837,796 2 1 June 2013 (21..06.2013) u s EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 61/841,5 13 1 July 2013 (01..07.2013) u s MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 61/864,064 9 August 2013 (09..08.2013) u s TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicant: XENOPORT, INC. [US/US]; 3410 Central Expressway, Santa Clara, California 9505 1 (US). Declarations under Rule 4.17 : (72) Inventors; and — as to applicant's entitlement to apply for and be granted a (71) Applicants : CUNDY, Kenneth C. [US/US]; 45 Summit patent (Rule 4.1 7(H)) Ridge Place, Redwood City, California 94062 (US). — as to the applicant's entitlement to claim the priority of the LISSIN, Dmitri V [RU/US]; 3410 Central Expressway, earlier application (Rule 4.1 7(in)) Santa Clara, California 9505 1 (US). SHREENIWAS, Re- vati [US/US]; 819 Sutter Drive, Palo Alto, California Published: 94303 (US). — with international search report (Art. 21(3)) (72) Inventors: WUSTROW, David J.; 116 Vallecitos Way, — before the expiration of the time limit for amending the Los Gatos, California 95032 (US). VIRSIK, Peter A.; 13 1 claims and to be republished in the event of receipt of Escanyo Way, Portola Valley, California 94028 (US). amendments (Rule 48.2(h)) (54) Title: METHODS OF USE FOR MONOMETHYL FUMARATE AND PRODRUGS THEREOF (57) Abstract: Methods of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeut - ically effective amount of a compound selected from: (i) monomethyl fumarate, (ii) a prodrug of monomethyl fumarate, and (iii) combinations thereof, wherein the disease is chosen from balo concentric sclerosis, bronchiolitis obliterans organizing pneumonia, central nervous system vasculitis, Charcott- Marie-Tooth Disease, childhood ataxia with central nervous system hypomyelination, diabetic retinopathy, graft versus host disease, monomelic amyotrophy, neurodegeneration with brain iron accumulation, neurosarc - oidosis, pareneoplastic syndromes, subacute necrotizing myelopathy, Susac syndrome and transverse myelitis. METHODS OF USE FOR MONOMETHYL FUMARATE AND PRODRUGS THEREOF Cross Reference to Related Applications [001] This application claims priority to U.S. Provisional Application Serial Nos. 61/736,906, filed December 13, 2012; 61/864,064, filed August 9, 2013; 61/692,179, filed August 22, 2012; 61/692,168, filed August 22, 2012; 61/713,897, filed October 15, 2012; 61/733,234, filed December 4, 2012; 61/769,513, filed February 26, 2013; 61/841,513, filed July 1, 2013; 61/692,174, filed August 22, 2012; 61/713,961, filed October 15, 2012; and 61/837,796, filed June 21, 2013; the contents of each of which are incorporated herein by reference in their entirety. Technical Field [002] Disclosed herein are methods of using monomethyl fumarate and prodrugs thereof for treating various diseases. Background [003] Fumaric acid esters (FAEs) are approved in Germany for the treatment of psoriasis, are being evaluated in the United States for the treatment of psoriasis and multiple sclerosis, and have been proposed for use in treating a wide range of immunological, autoimmune, and inflammatory diseases and conditions. [004] FAEs and other fumaric acid derivatives have been proposed for use in treating a wide-variety of diseases and conditions involving immunological, autoimmune, and/or inflammatory processes including psoriasis (Joshi and Strebel, WO 1999/49858; US 6,277,882; Mrowietz and Asadullah, Trends Mol Med 2005, 111(1), 43-48; and Yazdi and Mrowietz, Clinics Dermatology 2008, 26, 522-526); asthma and chronic obstructive pulmonary diseases (Joshi et al., WO 2005/023241 and US 2007/0027076); cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris (Joshi et al., WO 2005/023241; Joshi et al., US 2007/0027076); mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy (Joshi and Strebel, WO 2002/055063, US 2006/0205659, US 6,509,376, US 6,858,750, and US 7,157,423); transplantation (Joshi and Strebel, WO 2002/055063, US 2006/0205659, US 6,359,003, US 6,509,376, and US 7,157,423; and Lehmann et al., Arch Dermatol Res 2002, 294, 399-404); autoimmune diseases (Joshi and Strebel, WO 2002/055063, US 6,509,376, US 7,157,423, and US 2006/0205659) including multiple sclerosis (MS) (Joshi and Strebel, WO 1998/52549 and US 6,436,992; Went and Lieberburg, US 2008/0089896; Schimrigk et al, Eur J Neurology 2006, 13, 604-610; and Schilling et al., Clin Experimental Immunology 2006, 145, 101-107); neurological disorders characterized by extensive demyelination and/or axonal loss including secondary progressive multiple sclerosis and Devic's disease (Gold, WO 2008/096271); ischemia and reperfusion injury (Joshi et al., US 2007/0027076); AGE- induced genome damage (Heidland, WO 2005/027899); inflammatory bowel diseases such as Crohn's disease and ulcerative colitis; arthritis; and others (Nilsson et al., WO 2006/037342 and Nilsson and Muller, WO 2007/042034). [005] The mechanism of action of fumaric acid esters is believed to be mediated by pathways associated with the immunological response. For example, FAEs: invoke a shift from a Thl to Th2 immune response, favorably altering the cytokine profile; inhibit cytokine- induced expression of adhesion molecules such as VCAM-1, ICAM-1 and E-selectin, thereby reducing immune cell extravasation; and deplete lymphocytes through apoptotic mechanisms (Lehmann et al., J Investigative Dermatology 2007, 127, 835-845; Cesser et al., J Investigative Dermatology 2007, 127, 2129-2137; Vandermeeren et al., Biochm Biophys Res Commun 1991, 234, 19-23; and Treumer et al, J Invest Dermatol 2003, 121, 1383-1388). [006] Recent studies suggest that FAEs are inhibitors of NF-κΒ activation, a transcription factor that regulates the inducible expression of proinflammatory mediators (D' Acquisto et al, Molecular Interventions 2002, 2(1), 22-35). Accordingly, FAEs have been proposed for use in treating NF-κΒ mediated diseases (Joshi et al, WO 2002/055066; and Joshi and Strebel, WO 2002/055063, US 2006/0205659, US 7,157,423 and US 6,509,376). Inhibitors of NF-κΒ activation have also been shown to be useful in angiostatic therapy (Tabruyn and Griffioen, Angiogenesis 2008, 11, 101-106), inflammatory bowel disease (Atreya et al, J Intern Med 2008, 263(6), 591-6); and in animal models of diseases involving inflammation including neutrophilic alveolitis, asthma, hepatitis, inflammatory bowel disease, neurodegeneration, ischemia/reperfusion, septic shock, glomerulonephritis, and rheumatoid arthritis (D' Acquisto et al, Molecular Interventions 2002, 2(1), 22-35). [007] Studies also suggest that NF-κΒ inhibition by FAEs may be mediated by interaction with tumor necrosis factor (TNF) signaling. Dimethyl fumarate inhibits TNF- induced tissue factor mRNA and protein expression, TNF -induced DNA binding of NF-KB proteins, and the TNF -induced nuclear entry of activated NF-κΒ proteins, thereby inhibiting inflammatory gene activation (Loewe et al, J Immunology 2002, 168, 4781-4787). TNF signaling pathways are implicated in the pathogenesis of immune-mediated inflammatory diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis (Tracey et al, Pharmacology & Therapetuics 2008, 117, 244-279).
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