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WO 2016/176208 Al 3 November 2016 (03.11.2016) P O P C T

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WO 2016/176208 Al 3 November 2016 (03.11.2016) 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 2016/176208 Al 3 November 2016 (03.11.2016) P O P C T (51) International Patent Classification: SCIACCA, Cathi; C/o Intercept Pharmaceuticals, Inc., C07J 9/00 (2006.01) A61K 9/14 (2006.01) 4760 Eastgate Mall, San Diego, CA 92121 (US). ELIOT, A61K 31/575 (2006.01) A61K 9/20 (2006.01) Lise; C/o Intercept Pharmaceuticals, Inc., 4760 Eastgate Mall, San Diego, CA 92121 (US). EDWARDS, Jeffrey; (21) International Application Number: C/o Intercept Pharmaceuticals, Inc., 4760 Eastgate Mall, PCT/US2016/029369 San Diego, CA 92121 (US). MACCONELL, Leigh A.; (22) International Filing Date: 773 Corinia Court, Encinitas, CA 92024 (US). MAR- 26 April 2016 (26.04.2016) MON, Tonya K.; 11417 Volans Street, San Diego, CA 92126 (US). (25) Filing Language: English (74) Agent: IWAMOTO-FAN, Michelle; 450 W. 15th Street, English (26) Publication Language: Suite 505, New York, NY 1001 1 (US). (30) Priority Data: (81) Designated States (unless otherwise indicated, for every 62/153,040 27 April 2015 (27.04.2015) US kind of national protection available): AE, AG, AL, AM, 62/3 17,933 4 April 2016 (04.04.2016) US AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (71) Applicants: INTERCEPT PHARMACEUTICALS, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, INC. [US/US]; 450 W. 15th Street, Suite 505, New York, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, NY 1001 1 (US). SUMITOMO DAINIPPON PHARMA HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, CO., LTD. [JP/JP]; 6-8, Dosho-machi 2-chome, Chuo-ku, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, Osaka-shi, Osaka, 541-8524 (JP). 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, (72) Inventors: LANCASTER, Richard G.; 4436 Coronado SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, Avenue, San Diego, CA 92107 (US). OLMSTEAD, Kay TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. K.; 1435 Logan Court, Escondido, CA 92027 (US). KAGIHIRO, Masashi; C/o Sumitomo Dainippon Pharma (84) Designated States (unless otherwise indicated, for every Co., Ltd., 1-98, Kasugadenaka 3-chome, Konohana-ku, kind of regional protection available): ARIPO (BW, GH, Osaka-shi, Osaka, 554-0022 (JP). TAOKA, Ikuko; C/o GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Sumitomo Dainippon Pharma Co., Ltd., 1-98, Kasugade TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, naka 3-chome, Konohana-ku, Osaka-shi, Osaka, 554-0022 TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (JP). MATONO, Mitsuhiro; C/o Sumitomo Dainippon DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Pharma Co., Ltd., 3-45, Kasugadenaka 1-chome, Ibaraki- LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, shi, Osaka, 567-0878 (JP). PRUZANSKI, Mark; 421 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Hudson, New York, NY 10014 (US). SHAPIRO, David; GW, KM, ML, MR, NE, SN, TD, TG). 5110 Via Avante, Rancho Santa Fe, CA 92067 (US). Published: HOOSHMAND-RAD, Roya; C/o Intercept Pharmaceutic als, Inc., 4760 Eastgate Mall, San Diego, CA 92121 (US). — with international search report (Art. 21(3)) PENCEK, Richard; C/o Intercept Pharmaceuticals, Inc., 4760 Eastgate Mall, San Diego, CA 92121 (US). (54) Title: COMPOSITIONS OF OBETICHOLIC ACID AND METHODS OF USE (57) Abstract: The disclosure relates to obeticholic acid formulations with improved stability, dissolution, and/or solubility, meth ods of preparing the same for use and methods of treating various diseases and conditions. COMPOSITIONS OF OBETICHOLIC ACID AND METHODS OF USE BACKGROUND [0001] The farnesoid X receptor (FXR), also known as the bile acid receptor (BAR) or NR1H4, is a member of the nuclear receptor superfamily of ligand-activated transcription factors. FXR forms with retinoid X receptor (RXR) a heterodimer receptor crucial for bile acid homeostasis. FXR is expressed in various tissues including the liver, kidney, intestine, colon, ovary, and adrenal gland, and is activated by a variety of naturally occurring bile acids, including the primary bile acid chenodeoxycholic acid (CDCA) and its taurine and glycine conjugates. Upon activation, the FXR-RXR heterodimer binds the promoter region of target genes and regulates their expression. [0002] 6-Ethyl-chenodeoxycholic acid (6-ECDCA, or obeticholic acid, or OCA), a bile acid derivative, shows a potent FXR activating activity, and accordingly offers great promise for the treatment of FXR-mediated diseases or conditions. Thus, there is a need to develop obeticholic acid compositions having desirable dissolution profile and solubility, and possessing advantageous storage stability. SUMMARY [0003] The present disclosure relates to novel formulations of obeticholic acid, an FXR agonist, with improved stability, dissolution, and solubility, methods of preparing the same and methods of using the novel formulations for treating a disease or condition. In certain instances, the disease or condition is primary biliary cirrhosis (PBC), also known as primary biliary cholangitis. In other instances, the disease or condition is primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, or liver fibrosis. In another instance, the disease is NASH. In still other instances, the disease or condition is solid-tumor cancer such as, for example, hepatocellular carcinoma (HCC), colorectal cancer, gastric cancer, liver cancer, breast cancer, kidney cancer, or pancreatic cancer. Further provided herein are novel dosing regimens for administration of obeticholic acid for treatment of the diseases or conditions described herein. [0004] A first aspect of the disclosure relates to a composition comprising obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, wherein obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the particles have a diameter of less than 200 µm. Such compositions include all those described herein. [0005] Another aspect of the disclosure relates to treating a disease or condition described herein in a patient in need thereof by administering a composition that includes obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, where the obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles. [0006] Another aspect of the disclosure relates to treating a disease or condition described herein in a patient in need thereof by administering a composition that includes obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, where the obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the particles have a diameter of 200 µm or less. [0007] Another aspect of the disclosure relates to treating primary biliary cirrhosis (PBC) in a patient in need thereof by administering a composition that includes obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, optionally in a titration period, where the obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the particles have a diameter of 200 µm or less. [0008] In still another aspect of the disclosure is a method of treating primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, or liver fibrosis in a patient in need thereof by administering a composition that includes obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, optionally in a titration period, where the obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles. In one example, at least 50% of the particles have a diameter of 200 µm or less. [0009] In yet another aspect of the disclosure is a method of treating a solid-tumor cancer in a patient in need thereof by administering a composition that includes obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, optionally in a titration period, where the obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles. In one example, at least 50% of the particles have a diameter of 200 µm or less. [0010] In another aspect of the disclosure is a method of treating an autoimmune disease in a patient in need thereof by administering a composition that obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, optionally in a titration period, where the obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles. In one example, at least 50% of the particles have a diameter of 200 µm or less. [0011] In another aspect of the disclosure are methods of treating a disease or condition described herein by administering a obeticholic acid composition described herein where the obeticholic acid composition is administered as part of a treatment regimen that includes a titration period and a starting dose of the obeticholic acid composition at an amount of about 5 mg or 10 mg.
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