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WO 2018/193007 Al 2018/193007 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization lllllllllllllllllllllllllllllllllllllllllll^ International Bureau (10) International Publication Number (43) International Publication Date WO 2018/193007 Al 25 October 2018 (25.10.2018) WIPO I PCT (51) International Patent Classification: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, A61K31/192 (2006.01) A61K31/444 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K31/194 (2006.01) A61P1/16 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K31/5375 (2006.01) A61P17/02 (2006.01) A61K45/06 (2006.01) A61P 29/00 (2006.01) Published: A61K31/435 (2006.01) — with international search report (Art. 21(3)) (21) International Application Number: PCT/EP2018/059969 (22) International Filing Date: 18 April 2018 (18.04.2018) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 17305452.9 18 April 2017 (18.04.2017) EP 18305150.7 13 February 2018 (13.02.2018) EP (71) Applicant: GENFIT [FR/FR]; 885 avenue Eugene Avinee, 59120 LOOS(FR). (72) Inventors: WALCZAK, Robert; Residence Parc d'Isly, 13B rue Delezenne, 59000 LILLE (FR). BELANGER, Carole; 3 Allee du Verger, 59910 BONDUES (FR). LEGRY, Vanessa; 71 rue Bleriot, 59320 EMMERIN (FR). NOEL, Benoit; 9 rue Leonard Danel, 59120 LOOS (FR). DESCAMPS, Emeline; 9 rue Leonard Danel, 59120 LOOS (FR). VIDAL, Guillaume; 36 avenue De Lattre de Tassigny, 59350 SAINT ANDRE LEZ LILLE (FR). WALCZAK, Mathilde; Residence Parc d'Isly, 13B rue Delezenne, 59000 LILLE (FR). DELBAERE, Isabelle; 52 rue Paul Lafargue, 59320 EMMERIN (FR). (74) Agent: CABINET BECKER ET ASSOCIES; 25, rue Louis le Grand, 75002 PARIS (FR). (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. ιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιιι^ (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, Al 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, (54) Title: COMBINATION COMPRISING A PPAR AGONIST SUCH AS ELAFIBRANOR AND AN ACETYL-COA CARBOXY­ 2018/193007 LASE (ACC) INHIBITOR (57) Abstract: The present invention relates to a combination product and its use in therapy. ο WO 2018/193007 PCT/EP2018/059969 1 COMBINATION COMPRISING A PPAR AGONIST SUCH AS ELAFIBRANOR AND AN ACETYL-COA CARBOXYLASE (ACC) INHIBITOR The present invention relates to a combination therapy for the treatment of inflammatory, metabolic, fibrotic and cholestatic diseases. 5 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one (Elafibranor, or ELA, formely named GFT505), disclosed in W02004005233, possesses properties which can be advantageous for the treatment of a number of gastroenterology and liver diseases, in particular cholestatic diseases such as PBC (primary biliary cholangitic) and 10 PSC (primary sclerosing cholangitis), or liver diseases, in particular non-alcoolic fatty liver diseases (NAFLD) such as non-alcoolic steatoHepatitic (NASH). Elafibranor has been tested for clinical efficacy in NASH in a 1-year liver biopsy-based Phase 2b trial (GFT505-212-7), one of the largest interventional studies ever conducted in NASH. 15 Administered to over 800 patients and healthy volunteers to date, elafibranor has demonstrated beneficial properties for NASH, including in particular: improvement of markers of liver dysfunction, including ALAT, ASAT, yGT, ALP; improvement of insulin sensitivity and glucose homeostasis; favorable effects on plasma lipids, including decrease of plasma triglycerides and LDL-C, and increase of HDL-C levels; anti-inflammatory properties; efficacy 20 on histological NASH parameters (steatosis, inflammation, fibrosis) in animal disease models and anti-fibrotic activities. The absence of safety concern has been confirmed in a full toxicological package up to 2-year carcinogenicity studies. Elafibranor is currently being evaluated in a clinical phase 3 study for the treatment of NASH. Evaluation of this molecule for the treatment of PBC in a clinical phase 2 study is also planned. 25 In view of its excellent therapeutic and pharmacological profile, elafibranor is a very promising molecule that could potentially be used in combined pharmacological approaches to target parallel or complementary key pathways involved in a high number of inflammatory, 30 metabolic, fibrotic and cholestatic diseases. SUMMARY OF INVENTION 35 The present invention relates to a combination product comprising: WO 2018/193007 PCT/EP2018/059969 (i) a PPAR agonist, in particular a compound of formula (I), or a pharmaceutically acceptable salt thereof: 5 in which: Y1 represents a halogen, a Ra, or Ga-Ra group; A represents a CH=CH or a CH2-CH2 group; Y2 represents a Gb-Rb group; Ga and Gb, identical or different, represent an atom of oxygen or sulfur; 10 Ra represents a hydrogen atom, an unsubstituted (C1-C6)alkyl group, a (06-014)aryl group or a (C1-C6)alkyl group that is substituted by one or more halogen atoms, a (C1- C6)alkoxy or a (01-C6)alkylthio group, (03-014)cycloalkyl groups, (03- C14)cycloalkylthio groups or heterocyclic groups; Rb represents a (C1-C6)alkyl group substituted by at least a -COORc group, wherein 15 Rc represents a hydrogen atom, or a (C1-C6)alkyl group that is substituted or not by one or more halogen atoms, (03-014)cycloalkyl groups, or heterocyclic groups; and Y4 and Y5, identical or different, representing a (C1-C6)alkyl group that is substituted or not by one or more halogen atoms, (03-014)cycloalkyl groups or heterocyclic groups. 20 and (ii) an anti-NASH, anti-fibrotic or anti-cholestatic agent. In a particular embodiment of the compound of formula (I): 25 Y1 represents a halogen, a Ra, or a Ga-Ra group; A represents a CH=CH group; Y2 represents a Gb-Rb group; Ga and Gb, identical or different, represent an atom of oxygen or sulfur; Ra represents a (C1-C6)alkyl or (03-014)cycloalkyl group, in particular a (C1-C6)alkyl 30 or (03-014)cycloalkyl group substituted or not by one or more halogen atoms; WO 2018/193007 PCT/EP2018/059969 3 Rb represents a (C1-C6)alkyl group substituted by a -COOR3 group, wherein Rc represents a hydrogen atom or an alkyl group having from one to four carbon atoms; and Y4 and Y5 independently represent a (C1-C4)alkyl group. 5 In a particular embodiment of the compound of formula (I): Y1 represents a Ra or Ga-Ra group; A represents a CH2-CH2 group; Y2 represents a Gb-Rb group; Ga represents an atom of oxygen or sulfur and Gb represents an atom of oxygen; 10 Ra represents a (C1-C6)alkyl or (03-014)cycloalkyl group; Rb represents a (C1-C6)alkyl group substituted by at least a -COORc group, wherein Rc represents a hydrogen atom or (C1-C4)alkyl group; and Y4 and Y5 independently represent a (C1-C4)alkyl group. 15 In a particular embodiment of the compound of formula (I): Y1 represents a halogen atom or a Ra or Ga-Ra group; A represents a CH2-CH2 group; Y2 represents a Gb-Rb group; Ga represents an atom of oxygen or sulfur and Gb represents an atom of oxygen; 20 Ra represents a (C1-C6)alkyl or (03-014)cycloalkyl group that is substituted by one or more halogen atoms; Rb represents a (C1-C6)alkyl group substituted or not by one or more halogen atoms and substituted by at least a -COORc group, wherein Rc represents a hydrogen atom or a (C1-C4)alkyl group; and 25 Y4 and Y5 represent a (C1-C4)alkyl group. In a particular embodiment of the compound of formula (I), Gb is an oxygen atom and Rb is (C1-C6)alkyl group substituted by a -COORc group, wherein Rc represents a hydrogen atom or an unsubstituted linear or branched (C1-C4)alkyl group. 30 In a particular embodiment of the compound of formula (I), Y1 is a (C1-C6)alkylthio group that comprises a (C1-C6)alkyl group that is linear or branched that is substituted or not by one or more halogen atoms. 35 In a particular embodiment, the compound of formula (I) is selected in the group consisting of 1 -[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxy WO 2018/193007 PCT/EP2018/059969 4 phenyl]prop-2-en-1-one (Elafibranor or GFT505), 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4- isopropyloxy carbonyldimethylmethyloxyphenyl]prop-2-en-1 -one, 1 -[4-methylthiophenyl]-3- [3,5-dimethyl-4-tertbutyloxycarbonyldimethylmethyloxyphenyl] prop-2-en-1 -one, 1 -[4- trifluoromethylphenyl]-3-[3,5-dimethyl-4-tertbutyloxycarbonyl dimethylmethyloxyphenyl]prop- 5 2-en-1-one, 1-[4-trifluoromethylphenyl]-3-[3,5-dimethyl-4- carboxydimethylmethyloxyphenyl]prop-2-en-1 -one, 1 -[4-trifluoromethyl oxyphenyl]-3-[3,5- dimethyl-4-tertbutyloxycarbonyldimethylmethyloxy phenyl] prop-2-en-1-one, 1-[4- trifluoromethyloxyphenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyl oxyphenyl]prop-2-en-1- one, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl] phenoxy]-2-methylpropanoic 10 acid, and 2-[2,6-dimethyl-4-[3-[4-(methylthio) phenyl]-3-oxo-propyl]phenoxy]-2-methyl- propanoic acid isopropyl ester.
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