CROSS-REFERENCE TO RELATED APPLICATION

This application is the U.S. national stage application of International Patent Application No. PCT/EP2018/059969, filed Apr. 18, 2018.

STATEMENT REGARDING SEQUENCE LISTING

The Sequence Listing for this application is labeled “Seq-List.txt” which was created on May 20, 2022 and is 4659 bytes.

The present invention relates to a combination therapy for the treatment of inflammatory, metabolic, fibrotic and cholestatic diseases.

1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one (Elafibranor, or ELA, formerly named GFT505), disclosed in WO2004005233, 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 PSC (primary sclerosing cholangitis), or liver diseases, in particular non-alcoholic fatty liver diseases (NAFLD) such as non-alcoholic 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. 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, γGT, 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 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.

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, metabolic, fibrotic and cholestatic diseases.

SUMMARY OF INVENTION

The present invention relates to a combination product comprising:

(i) a PPAR agonist, in particular a compound of formula (I), or a pharmaceutically acceptable salt thereof:


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;
Ra represents a hydrogen atom, an unsubstituted (C1-C6)alkyl group, a (C6-C14)aryl group or a (C1-C6)alkyl group that is substituted by one or more halogen atoms, a (C1-C6)alkoxy or a (C1-C6)alkylthio group, (C3-C14)cycloalkyl groups, (C3-C14)cycloalkylthio groups or heterocyclic groups;
Rb represents a (C1-C6)alkyl group substituted by at least a —COORc group, wherein
Rc represents a hydrogen atom, or a (C1-C6)alkyl group that is substituted or not by one or more halogen atoms, (C3-C14)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, (C3-C14)cycloalkyl groups or heterocyclic groups and
(ii) an anti-NASH, anti-fibrotic or anti-cholestatic agent.

In a particular embodiment of the compound of formula (I):

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 (C3-C14)cycloalkyl group, in particular a (C1-C6)alkyl or (C3-C14)cycloalkyl group substituted or not by one or more halogen atoms;

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.

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;

Ra represents a (C1-C6)alkyl or (C3-C14)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.

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;

Ra represents a (C1-C6)alkyl or (C3-C14)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

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.

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.

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 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-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 acid, and 2-[2,6-dimethyl-4-[3-[4-(methylthio) phenyl]-3-oxo-propyl]phenoxy]-2-methyl-propanoic acid isopropyl ester.

In a particular embodiment of the invention, component (ii) is an anti-NASH agent.

Illustrative, non-limiting, anti-NASH agents useful in the practice of the present invention include:Acetyl-CoA carboxylase inhibitors;Adenosine A3 receptor agonists;Aldosterone antagonists and Mineralocorticoid antagonists;AMP activated protein kinase stimulator;Amylin receptor agonist and Calcitonin receptor agonists;Angiopoietin-related protein-3 inhibitors;Anti-LPS antibodies;Apical sodium-codependent bile acid transporter inhibitors;Betaine anhydrous or RM-003;bioactive lipids;Cannabinoid CB1 receptor antagonists;Dual cannabinoid CB1 receptor/iNOS inhibitor;Caspase inhibitors;Cathepsin inhibitors;CCR antagonists;CCR3 chemokine modulators and eotaxin 2 ligand inhibitors;Diacylglycerol-O-acyltransferase (DGAT) inhibitors;Dipeptidyl peptidase IV (DPP4) inhibitors;Insulin ligand and insulin receptor agonists;Insulin sensitizer and MCH receptor-1 antagonist;NOX (NADPH oxidase) inhibitors, such as dual NOX 1 and 4 inhibitors;Extracellular matrix protein modulators;Stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugates (FABAC);Fatty Acid Synthase (FAS) Inhibitors;Fibroblast Growth Factor 19 (FGF-19) receptor ligands, such as Recombinant Fibroblast Growth Factor 19 (FGF-19) protein, or functional engineered variant of the FGF-19 protein;Fibroblast Growth Factor 21 (FGF-21) receptor ligands such as Fibroblast Growth Factor 21 (FGF-21) protein, or functional engineered variant of the FGF-21 protein;Farnesoid X receptor (FXR) agonists;Galectin 3 inhibitors;Glucagon-like peptide-1 (GLP-1) analogs and GLP-1 receptor agonists;G-protein coupled receptor (GPCR) modulators;G-protein coupled receptor 84 antagonist, connective tissue growth factor ligand inhibitor and Free fatty acid receptor 1 agonists;Hedgehog cell-signalling pathway inhibitors;Integrin inhibitors;ketohexokinase inhibitorsLeukotriene (LT)/Phosphodiesterase (PDE)/Lipoxygenase (LO) inhibitors;Lysyl oxidase homolog 2 inhibitors (LOXL2 inhibitors);Macrolides;Methyl CpG binding protein 2 modulator and Transglutaminase inhibitors;miRNA antagonists;Mitochondrial carrier family inhibitor and Mitochondrial phosphate carrier protein inhibitor;Monoclonal antibodies;Myeloperoxidase inhibitors;mTOR modulators;NAD-dependent deacetylase sirtuin stimulator; PDE 5 inhibitor;Nicotinic Acid Receptor (GPR109) Agonists;nuclear receptor ligands;P2Y13 protein agonists;Phenylalanine hydroxylase stimulators;Protease-activated receptor (PAR)-2 antagonists;Protein kinase modulators;PPAR alpha agonists;PPAR gamma agonists;PPAR delta agonists;PPARalpha/gamma agonists;PPARalpha/delta agonists;PPAR gamma/delta;PPAR alpha/gamma/delta agonists or PPAR pan-agonists;Rho-associated protein kinase 2 (ROCK2) inhibitors;Sodium-GLucose Transport (SGLT) 1 inhibitors;Sodium-glucose transport (SGLT) 2 inhibitors;Stearoyl-CoA desaturase-1 inhibitors;signal-regulating kinase 1 (ASK1) inhibitors;thyroid receptor β (THR β) agonists;Toll Like Receptor 2 (TLR-2) antagonists;Toll Like Receptor 4 (TLR-4) antagonists;Type I natural killer T cells inhibitors;Tyrosine kinase receptor (RTK) modulators;Urate anion exchanger 1 inhibitors and Xanthine oxidase inhibitors;Vascular adhesion protein-1 (VAP-1) inhibitors; andVitamin D receptor (VDR) agonists.

In a further particular embodiment of the invention, component (ii) is an anti-NASH agent.

In a particular embodiment, the anti-NASH agent is selected from:Acetyl-CoA carboxylase inhibitors;Anti-LPS antibodies;Apical sodium-codependent bile acid transporter inhibitors;bioactive lipids;Cannabinoid CB1 receptor antagonists;Dual cannabinoid CB1 receptor/iNOS inhibitor;Caspase inhibitors;Cathepsin inhibitors;CCR antagonists;Diacylglycerol-O-acyltransferase (DGAT) inhibitors;Dipeptidyl peptidase IV (DPP4) inhibitors;NOX (NADPH oxidase) inhibitors, such as dual NOX 1 and 4 inhibitors;Extracellular matrix protein modulators;Stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugates (FABAC);Fibroblast Growth Factor 19 (FGF-19) receptor ligands, such as Recombinant Fibroblast Growth Factor 19 (FGF-19) protein, or functional engineered variant of the FGF-19 protein; Fibroblast Growth Factor 21 (FGF-21) receptor ligands such as Fibroblast Growth Factor 21 (FGF-21) protein, or functional engineered variant of the FGF-21 protein;Farnesoid X receptor (FXR) agonists;Galectin 3 inhibitors;Glucagon-like peptide-1 (GLP-1) analogs;G-protein coupled receptor (GPCR) modulators;Integrin inhibitors;Leukotriene (LT)/Phosphodiesterase (PDE)/Lipoxygenase (LO) inhibitors;Macrolides;miRNA antagonists;Monoclonal antibodies;mTOR modulators;nuclear receptor ligands;P2Y13 protein agonists;Protease-activated receptor (PAR)-2 antagonists;Protein kinase modulators;PPAR alpha agonists;PPAR gamma agonists;PPAR delta agonists;PPARalpha/gamma agonists;PPARalpha/delta agonists;PPAR gamma/delta;PPAR alpha/gamma/delta agonists or PPAR pan-agonists;Rho-associated protein kinase 2 (ROCK2) inhibitors;Sodium-glucose transport (SGLT) 2 inhibitors;signal-regulating kinase 1 (ASK1) inhibitors;thyroid receptor β (THR β) agonists;Toll Like Receptor 4 (TLR-4) antagonists;Tyrosine kinase receptor (RTK) modulators;Vascular adhesion protein-1 (VAP-1) inhibitors; andVitamin D receptor (VDR) agonists.

Other anti-NASH agents include KB-GE-001 and NGM-386 and NGM-395, NC-10, and TCM-606F. Further anti-NASH agents include icosabutate, NC-101, NAIA-101 colesevelam, and PRC-4016.

In a particular embodiment of the invention, component (ii) is an anti-fibrotic agent. Illustrative, non-limiting, anti-fibrotic agents useful in the practice of the present invention include:Adenosine A3 receptor agonists;Angiotensin II receptor blockers;antisense oligonucleotides targeting transforming growth factor beta 2 (TGF-β2);Bioactive lipids;Caspase inhibitors;Cannabinoid CB2 receptor mimetics;Dual Farnesoid X receptor (FXR)/TGR5 agonists;NOX (NADPH oxidase) inhibitors, such as dual NOX 1 and 4 inhibitors;Galectin 3 inhibitors;Hedgehog cell-signalling pathway inhibitors;Immunomodulators;Integrin inhibitors;Macrophage mannose receptor modulators;Metalloprotease-9 (MMP-9) stimulators;Monoclonal antibodies;NF-kappa B inhibitors;Non-Steroid Anti-Inflammatory Drugs (NSAIDs);PDGFR modulators;PPAR alpha agonists;PPAR gamma agonists;PPAR delta agonists;PPARalpha/gamma agonists;PPARalpha/delta agonists;PPAR gamma/delta; andPPAR alpha/gamma/delta agonists or PPAR pan-agonists.

In a further particular embodiment the anti-fibrotic agent is selected in the group consisting of:antisense oligonucleotides targeting transforming growth factor beta 2 (TGF-β2);Bioactive lipids;Caspase inhibitors;Cannabinoid CB2 receptor mimetics;Dual Farnesoid X receptor (FXR)/TGR5 agonists;NOX (NADPH oxidase) inhibitors, such as dual NOX 1 and 4 inhibitors;Galectin 3 inhibitors;Immunomodulators;Integrin inhibitors;Macrophage mannose receptor modulators;Metalloprotease-9 (MMP-9) stimulators;Monoclonal antibodies;NF-kappa B inhibitors;Non-Steroid Anti-Inflammatory Drugs (NSAIDs);PDGFR modulators;PPAR alpha agonists;PPAR gamma agonists;PPAR delta agonists;PPARalpha/gamma agonists;PPARalpha/delta agonists;PPAR gamma/delta; andPPAR alpha/gamma/delta agonists or PPAR pan-agonists.

Other anti-fibrotic agents include HEC-585, INV-240, RNAi therapeutic (Silence Therapeutics) and SAMiRNA program (Bioneer Corp).

Other illustrative antifibrotic agents include pirfenidone or receptor tyrosine kinase inhibitors (RTKIs) such as Nintedanib, Sorafenib and other RTKIs, or angiotensin II (AT1) receptor blockers, or CTGF inhibitor, or any antifibrotic compound susceptible to interfere with the TGFβ and BMP-activated pathways including activators of the latent TGFβ complex such as MMP2, MMP9, THBS1 or cell-surface integrins, TGFβ receptors type I (TGFBRI) or type II (TGFBRII) and their ligands such as TGFβ, Activin, inhibin, Nodal, anti-Müllerian hormone, GDFs or BMPs, auxiliary co-receptors (also known as type Ill receptors), or components of the SMAD-dependent canonical pathway including regulatory or inhibitory SMAD proteins, or members of the SMAD-independent or non-canonical pathways including various branches of MAPK signaling, TAK1, Rho-like GTPase signaling pathways, phosphatidylinositol-3 kinase/AKT pathways, TGFβ-induced EMT process, or canonical and non-canonical Hedgehog signaling pathways including Hh ligands or target genes, or any members of the WNT, or Notch pathways which are susceptible to influence TGFβ.

In a particular embodiment of the invention, component (ii) is an anti-cholestatic agent. Illustrative, non-limiting, anti-cholestatic agents useful in the practice of the present invention include:apical sodium-codependent bile acid transporter inhibitors (ASBTi);Bile acids;cathepsin inhibitors;CCR antagonists;CD40 inhibitors;CD80 inhibitors;NOX (NADPH oxidase) inhibitors, such as dual NOX 1 and 4 inhibitors;Farnesoid X receptor (FXR) agonists;Fibroblast Growth Factor (FGF) 19 recombinant;Fractalkine ligand inhibitors;ileal sodium bile acid cotransporter inhibitors;Monoclonal antibodies;PPAR alpha agonists;PPAR gamma agonists;PPAR delta agonists;PPAR alpha/gamma agonists;PPAR alpha/delta agonists;PPAR gamma/delta; andPPAR alpha/gamma/delta agonists or PPAR pan-agonists.

In a particular embodiment, the anti-cholestatic agent is selected in the group consisting of:apical sodium-codependent bile acid transporter inhibitors (ASBTi);Bile acids;cathepsin inhibitors;CCR antagonists;CD40 inhibitors;CD80 inhibitors;NOX (NADPH oxidase) inhibitors;Farnesoid X receptor (FXR) agonists;Fibroblast Growth Factor (FGF) 19 recombinant;Fractalkine ligand inhibitors;ileal sodium bile acid cotransporter inhibitors;Monoclonal antibodies;PPAR alpha agonists;PPAR gamma agonists;PPAR delta agonists;PPAR alpha/gamma agonists;PPAR alpha/delta agonists;PPAR gamma/delta;PPAR alpha/gamma/delta agonists or PPAR pan-agonists.

Illustrative acetyl-CoA carboxylase inhibitors include, but are not limited to GS-0976, ND-654, AC-8632, PF05221304, CP640186, Gemcabene, MK-4074, and PF05175157.

Illustrative adenosine A3 receptor agonists include but are not limited to 2-(1-Hexynyl)-N-methyladenosine, Piclidenoson CF-101 (IB-MECA), Namodenoson CF-102, 2-CI-IB-MECA, CP-532,903, Inosine, LUF-6000, and MRS-3558.

Illustrative aldosterone antagonists and mineralocorticoid receptor antagonists include, but are not limited to, Apararenone (MT 3995), Amiloride, Spironolactone, Eplerenone, Canrenone and potassium canrenoate, progesterone, drospirenone, gestodene, and benidipine.

Illustrative AMP activated protein kinase stimulators include, but are not limited to PXL-770, MB-11055 Debio-0930B metformin, CNX-012, O-304, mangiferin calcium salt, eltrombopag, carotuximab, and Imeglimin.

Illustrative Amylin receptor agonist and Calcitonin receptor agonists include, but are not limited to, KBP-042 and KBP-089.

Illustrative angiopoietin-related protein-3 inhibitors include, but are not limited to ARO-ANG3, IONIS-ANGGPTL3-LRx or AKCEA-ANGPTL3LRx, evinacumab, and ALN-ANG.

According to the invention, the term “angiotensin type 1 receptor antagonists” as used herein includes, but is not limited to, Irbesartan.

According to the invention, the term “anti-LPS antibodies” as used herein includes, but is not limited to IMM-124-E.

Illustrative antisense oligonucleotide targeting transforming growth factor beta 2 include, but are not limited to ASPH-0047, IMC-TR1 and ISTH-0047.

Illustrative apical sodium-codependent bile acid transporter inhibitor include, but are not limited to A-4250, volixibat, maralixibat formerly SHP-625, GSK-2330672, elobixibat and CJ-14199.

Illustrative bile acids include, but are not limited to obeticholic acid (OCA) and UDCA, norursodeoxycholic acid, and ursodiol.

Illustrative bioactive lipids include, but are not limited to 5-hydroxyeicosapentaenoic acid (15-HEPE, DS-102).

In a further particular embodiment, the bioactive lipid may be selected from unsaturated fatty acids such as 25 arachidonic acid, icosapentethyl ester, eicosapentaneoic acid, and docosahexaenoic acid.

Illustrative cannabinoid CB1 receptor antagonists include, but are not limited to namacizumab, GRC-10801, MRI-1569, MRI-1867, DBPR-211, AM-6527: AM-6545, NESS-11-SM, CXB-029, GCC-2680, TM-38837, Org-50189, PF-514273, BMS-812204, ZYO-1, AZD-2207, AZD-1175, otenabant, ibipinabant, surinabant, rimonabant, drinabant, SLV-326, V-24343, and 0-2093.

Illustrative cannabinoid CB2 receptor mimetics include, but are not limited to anabasum (Resunab, JKT-101).

Illustrative caspase inhibitors include, but are not limited to emricasan, belnacasan, nivocasan, IDN-7314, F-573, VX-166, YJP-60107, MX-1122, IDN-6734, TLC-144, SB-234470, IDN-1965, VX-799, SDZ-220-976, and L-709049.

Illustrative cathepsin inhibitors include, but are not limited to VBY-376, VBY-825, VBY-036, VBY-129, VBY-285, Org-219517, LY3000328, RG-7236, and BF/PC-18.

Illustrative CCR antagonists include, but are not limited to CCR2/5 antagonists such as cenicriviroc; PG-092, RAP-310, INCB-10820, RAP-103, PF-04634817, and CCX-872.

Illustrative CD40 inhibitors include, but are not limited to FFp-104, xl-050, DOM-0800, XmAb-5485, KGYY-15, FFP-106, TDI-0028, and ABI-793.

Illustrative CD80 inhibitors include, but are not limited to RhuDex, FPT-155, ToleriMab, galiximab, SCH-212394, IGM-001, ASP-2408, and SCH-204698.

Illustrative CCR3 chemokine modulators and eotaxin 2 ligand inhibitors include, but are not limited to bertilimumab, CM-101 (humanized), CM-102, and RNS-60.

Illustrative diacylglycerol-O-acyltransferase inhibitors include, but are not limited to IONIS-DGAT2Rx (formerly ISIS-DGAT2Rx), LY-3202328, BH-03004, KR-69530, OT-13540, AZD-7687, PF-06865571, PF-06424439, and ABT-046.

Illustrative dipeptidyl peptidase IV inhibitors include, but are not limited to evogliptin, vidagliptin, fotagliptin, alogliptin, saxagliptin, tilogliptin, anagliptin, sitagliptin, retagliptin, melogliptin, gosogliptin, trelagliptin, teneligliptin, dutogliptin, linagliptin, gemigliptin, yogliptin, betagliptin, imigliptin, omarigliptin, vidagliptin, and denagliptin.

Illustrative Fatty Acid Synthase (FAS) inhibitors include, but are not limited to TVB-2640; TVB-3664; TVB-3166, TVB-3150, TVB-3199, TVB-3693BZL-101, 2-octadecynoic acid, MDX-2, Fasnall, MT-061, G28UCM, MG-28, HS-160, GSK-2194069, KD-023, cilostazol.

In a particular embodiment, the FAS inhibitor is a compound selected in the following list of compounds:



In another particular embodiment, the FAS inhibitor is selected from:



In a particular embodiment, the FAS inhibitor is TVB-2640.

Illustrative dual Farnesoid X receptor (FXR)/TGR5 agonists include, but are not limited to INT-767.

Illustrative NOX (NADPH oxidase) inhibitors include, but are not limited to, dual NOX 1&4 inhibitors; GKT-831 (2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione), formerly GKT137831 and GKT-901.

Illustrative extracellular matrix protein modulators include, but are not limited to CNX-024, CNX-025 and SB-030.

Illustrative Farnesoid X receptor (FXR) agonists includes but are not limited to obeticholic acid (OCA), GS-9674, LJN-452 or LJN452, LMB763, EDP-305, AKN-083, INT-767, GNF-5120, LY2562175, INV-33, NTX-023-1, EP-024297, Px-103 and SR-45023.

Illustrative Fractalkine ligand inhibitors include, but are not limited to E-6011 and KAN-0440567.

Illustrative Fibroblast Growth Factor 19 (FGF-19) receptor ligand, Recombinant Fibroblast Growth Factor 19 (FGF-19) protein or functional engineered variant of FGF-19 include, but are not limited to NGM-282.

Illustrative Fibroblast Growth Factor 21 (FGF-21) receptor ligand, Fibroblast Growth Factor 21 (FGF-21) protein, include, but are not limited to PEG-FGF21 (formerly BMS-986036), YH-25348, BMS-986171, YH-25723, LY-3025876 and NNC-0194-0499.

Illustrative Galectin 3 inhibitors include, but are not limited to GR-MD-02, TD-139, ANG-4021, Galectin-3C, LJPC-201, TFD-100, GR-MD-03, GR-MD-04, GM-MD-01, GM-CT-01, GM-CT-02, Gal-100 and Gal-200.

Illustrative Glucagon-like peptide-1 (GLP-1) analogs include, but are not limited to semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, loxenatide, efpeglenatide, taspoglutide, MKC-253, DLP-205 and ORMD-0901.

Illustrative Glucagon-like peptide-1 (GLP-1) receptor agonists include, but are not limited to LY-3305677, and Oxyntomodulin long acting.

Illustrative G-protein coupled receptor (GPCR) modulators include, but are not limited to CNX-023.

Illustrative G-protein coupled receptor 84 antagonist (GPR84 antagonist), connective tissue growth factor ligand inhibitor and Free fatty acid receptor 1 agonist (FFAR1 agonist) include, but are not limited to, PBI-4050, PBI-4265, PBI-4283, and PBI-4299.

Illustrative Hedgehog cell-signalling pathway inhibitors include, but are not limited to Vismodegib, TAK-441, IPI-926, Saridegib, Sonidegib/Erismodegib, BMS-833923/XL139, PF-04449913, Taladegib/LY2940680, ETS-2400, SHR-1539, and CUR61414.

Illustrative ileal sodium bile acid cotransporter inhibitors include, but are not limited to A-4250, GSK-2330672, volixibat, CJ-14199, and elobixibat.

Illustrative immunomodulators include, but are not limited to PBI-4050, PBI-4265, PBI-4283, PBI-4299 and AIC-649.

Illustrative Insulin sensitizer and MCH receptor-1 antagonist include but are not limited to MSDC-0602k, MSDC-0602, CSTI-100 and AMRI.

Illustrative integrin inhibitors include, but are not limited to integrin inhibitors of Pliant Therapeutic, integrin inhibitors of Indalo Therapeutics, integrin inhibitors of St Louis University, ProAgio, and GSK-3008348.

Illustrative ketohexokinase inhibitors include, but are not limited to, JNJ-28165722; JNJ-42065426; JNJ-42152981; JNJ-42740815; JNJ-42740828, and PF-06835919.

Illustrative leukotriene/phosphodiesterase/lipoxygenase inhibitors include, but are not limited to tipelukast (formerly MN-001), tomelukast, sulukast, masilukast, zafirlukast, pranlukast, montelukast, gemilukast, verlukast, aklukast, pobilikast, cinalukast, and iralukast.

Illustrative Lysyl oxidase homolog 2 inhibitors include, but are not limited to, Rappaport, InterMune, Pharmaxis, AB-0023, Simtuzumab, PXS-5382A, and PXS-5338.

Illustrative macrolides include, but are not limited to solithromycin, azithromycin, and erythromycin.

Illustrative macrophage mannose receptor modulators include, but are not limited to AB-0023, MT-1001, [18F]FB18mHSA, Xemys, technetium Tc 99m tilmanocept, and CDX-1307.

Illustrative methyl CpG binding protein 2 modulator and transglutaminase inhibitors include, but are not limited to, cysteamine, EC Cysteamine, enteric-coated cysteamine bitartrate, cysteamine bitartrate (enteric-coated), Bennu, cysteamine bitartrate (enteric-coated), Raptor, cysteamine bitartrate, DR Cysteamine, delayed release enteric coated cysteamine bitartrate, mercaptamine, mercaptamine (enteric-coated), Bennu, mercaptamine (enteric-coated), Raptor, RP-103, RP-104, PROCYSBI, and mercaptamine (enteric-coated).

Illustrative miRNA antagonists include, but are not limited to RG-125 (formerly AZD4076), RGLS-5040, RG-101, MGN-5804, and MRG-201.

Illustrative metalloprotease-9 (MMP-9) stimulators include, but are not limited to MMP-9 stimulator of Elastomics Ab.

Illustrative mitochondrial carrier family inhibitor and Mitochondrial phosphate carrier protein inhibitor include, but are not limited to TRO-19622, Trophos, olesoxime, RG-6083, or RO-7090919.

Illustrative myeloperoxidase inhibitors include, but are not limited to PF-06667272.

Illustrative monoclonal antibodies (mAbs) include, but are not limited to bertilimumab, NGM-313, IL-20 targeting mAbs, fresolimumab (antiTGFβ) (formerly GC1008), timolumab formerly BTT-1023, namacizumab, omalizumab, ranibizumab, bevacizumab, lebrikizumab, epratuzumab, felvizumab, matuzumab, monalizumab, reslizumab, foralumab (NI-0401, anti-CD3), simtizumab (GS-6624) mAb against LOXL2, ustekinumab, an anti-TNF antibody, and inebilizumab.

Illustrative monoclonal antibodies are selected in the group consisting of anti-IL20 mAbs, anti-TGFβ antibodies, anti-CD3 antibodies, anti-LOXL2 antibodies and anti-TNF antibodies.

Illustrative mTOR modulators include, but are not limited to MSDC-0602 and AAV gene therapy co-administered with SVP-sirolimus.

Illustrative NAD-dependent deacetylase sirtuin stimulator; PDE 5 inhibitor include, but are not limited to NS-0200.

Illustrative NF-kappa B inhibitors include, but are not limited to LC-280126.

Illustrative Nicotinic Acid Receptor (GPR109) Agonists include, but are not limited to ARI-3037MO, MMF, LUF 6283, Acifran, IBC 293, MK-1903, GSK256073, MK-6892, MK-0354, SLx-4090, lomitapide, lexibulin, apabetalone, acifran, laropiprant, daporinad, anacetrapib, INCB-19602, ST-07-02, lomefloxacin, Niacin, and controlled release/laropiprant.

Illustrative non-steroid anti-inflammatory drugs (NSAIDs) include, but are not limited to F-351, salicylates (aspirin), acetaminophen, propionic acid derivatives (ibuprofen, naproxen), acetic acid derivatives (indomethacin, diclofenac), enolic acid derivatives (piroxicam, phenylbutazone), anthranilic acid derivatives (meclofenalmic acid, flufenamic acid), selective COX-2 inhibitors (celecoxib, parecoxib), and sulfonanilides (nimesulide).

Illustrative nuclear receptor ligands include, but are not limited to DUR-928 (formerly DV 928).

Illustrative P2Y13 protein agonists include, but are not limited to CER-209.

Illustrative PDGFR modulators include, but are not limited to BOT-501 and BOT-191.

Illustrative phenylalanine hydroxylase stimulators include, but are not limited to Pegvaliase, sapropterin, AAV-PAH, CDX-6114, sepiapterin, RMN-168, ALTU-236, ETX-101, HepaStem, rolipram, and alprostadil.

Illustrative PPAR alpha agonists include, but are not limited to fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, and SR10171.

Illustrative PPAR gamma agonists include, but are not limited to, Pioglitazone, deuterated pioglitazone, Rosiglitazone, efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, and ALL-4.

Illustrative PPAR delta agonists include, but are not limited to GW501516 (Endurabol or ({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid)), MBX8025 (Seladelpar or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methyl phenoxy]acetic acid), L165041, HPP-593, and NCP-1046.

Illustrative PPAR alpha/gamma agonists (also named glitazars) include, but are not limited to Saroglitazar, Aleglitazar, Muraglitazar, Tesaglitazar, and DSP-8658.

In addition to elafibranor, illustrative PPAR alpha/delta agonists include, without limitation, T913659.

Illustrative PPAR gamma/delta agonist include, but are not limited to a conjugated linoleic acid (CLA) and T3D-959.

Illustrative PPAR alpha/gamma/delta agonists or “PPAR pan-agonists”, include, but are not limited to IVA337 (Lanifibranor), TTA (tetradecylthioacetic acid), Bavachinin, GW4148, GW9135, Bezafibrate, Lobeglitazone and CS038.

Illustrative protease-activated receptor (PAR)-2 antagonists include, but are not limited to PZ-235 and NP-003.

Illustrative protein kinase modulators include, but are not limited to CNX-014, MB-11055, ALF-1, mangiferin, amlexanox, GS-444217, REG-101 and valine.

Illustrative Rho-associated protein kinase 2 (ROCK2) inhibitors include, but are not limited to KD-025, TRX-101, BA-1049, LYC-53976, INS-117548 and RKI-1447.

Illustrative signal-regulating kinase 1 (ASK1) inhibitors include, but are not limited to selonsertib (formerly GS-4997).

Illustrative sodium-glucose transport (SGLT) 1 inhibitors include, but are not limited to LX-4212/LX-4211/sotagliflozin, SAR-439954, LIK-066 (Licoglifozin), LX-2761, GSK-161235, LP-925219, KGA-2727, SAR-7226, SAR-474832, SY-008, and AVX-3030.

Illustrative sodium-glucose transport (SGLT) 2 inhibitors include, but are not limited to remogliflozin, dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin, ipragliflozin, tianagliflozin, canagliflozin, tofogliflozin, janagliflozin, bexagliflozin, luseogliflozin, sergliflozin, HEC-44616, AST-1935 and PLD-101.

Illustrative stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugates include, but are not limited to aramchol, GRC-9332, steamchol, TSN-2998, GSK-1940029 and XEN-801.

Illustrative thyroid hormone receptor β (THR β) agonists include, but are not limited to VK-2809, MGL-3196, MGL-3745, SKL-14763, sobetirome, BCT-304, ZYT-1, MB-07811 and eprotirome.

Illustrative Toll Like Receptor 2 and 4 (TLR-2) antagonists include, but are not limited to CI-201 also known as VB-201.

Illustrative Toll Like Receptor 4 (TLR-4) antagonists include, but are not limited to naltrexone, JKB-121 also known as Nalmefene, M-62812, resatorvid, dendrophilin, CS-4771, AyuV-1, AyuV-25, NI-0101, EDA-HPVE7 and eritoran.

Illustrative Type I natural killer T cells inhibitors include but are not limited to GRI-0621.

Illustrative Receptor tyrosine kinase (RTK) modulators include, but are not limited to CNX-025, KBP-7018, nintedanib and sorafenib.

Illustrative urate anion exchanger 1 inhibitors and xanthine oxidase inhibitors include, but are not limited to, lesinurad, RLBN-1001, verinurad, KUX-1151, and lesinurad+allopurinol.

Illustrative vascular adhesion protein-1 (VAP-1) inhibitors also named Amine Oxidase Copper containing 2 (AOC3), include, but are not limited to BI-1467335 formerly PXS-4728A, CP-664511, PRX-167700, ASP-8232, RTU-1096, RTU-007 and BTT-1023.

Illustrative vitamin D receptor (VDR) agonists include, but are not limited to calciferol, alfacalcidol, 1,25-dihydroxyvitamin D3, Vitamin D2, Vitamin D3, calcitriol, Vitamin D4, Vitamin D5, dihydrotachysterol, calcipotriol, tacalcitol 1,24-dihydroxyvitamin D3 and paricalcitol.

According to the present invention, the term “PPAR(s) agonists” refers the Peroxisome Proliferator Activated Receptor agonists, which are a class of drugs which plays a central role in lipid and glucose homeostasis. PPARα mainly influences fatty acid metabolism and its activation lowers lipid levels, while PPARγ is mostly involved in the regulation of the adipogenesis, energy balance, and lipid biosynthesis. PPARδ participates in fatty acid oxidation, mostly in skeletal and cardiac muscles, but it also regulates blood glucose and cholesterol levels.

In a more particular embodiment, the compound of formula (I) is Elafibranor, or a pharmaceutically acceptable salt thereof.

In a particular embodiment of the combination product of the invention:component (i) is Elafibranor or a pharmaceutically acceptable salt thereof; andcomponent (ii) is selected from GKT-831, aramchol, SHP-625, emricasan, saroglitazar, IMM-124-E, GS-9674, NGM-282, A-4250, GR-MD-02, GS-4997, F-351, solithromycin, remogliflozin, BTT-1023, IVA-337 (Lanifibranor), JKB-121 (Nalmefene), KD-025, MSDC-0602 or MSDC-0602k, PBI-4050, PEG-FGF21, tipelukast, VK-2809, MGL-3196, GS-0976, RG-125, volixibat, pioglitazone, semaglutide, GSK2330672, MBX-8025, CP-640186, Selonsertib, GKT-831, PXS-4728A, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), icosapentethyl ester, KD-025, DUR-928, and Gemcabene, in particular Selonsertib, GKT-831, PXS-4728A, Aramchol, PBI-4050, MSDC-0602k, VK-2809, MGL-3196, Vismodegib, CF-102 (Namodenoson), MT-3995 (Apararenone), JKB-121 (Nalmefene), emricasan, KD-025, and DUR-928.

In a particular embodiment of the combination product of the invention:component (i) is Elafibranor or a pharmaceutically acceptable salt thereof; andcomponent (ii) is selected from GKT-831, aramchol, SHP-625, emricasan, saroglitazar, IMM-124-E, GS-9674, NGM-282, A-4250, GR-MD-02, GS-4997, LJN-452, F-351, solithromycin, remogliflozin, BTT-1023, IVA-337 (Lanifibranor), JKB-121, KD-025, MSDC-0602, PBI-4050, PEG-FGF21, tipelukast, VK-2809, MGL-3196, GS-0976, pentasa, RG-125, volixibat, pioglitazone, ursodeoxycholic acid, semaglutide, GSK2330672, and MBX-8025, in particular from aramchol, SHP-625, emricasan, saroglitazar, IMM-124-E, GS-9674, NGM-282, A-4250, GR-MD-02, GS-4997, LJN-452, F-351, solithromycin, remogliflozin, BTT-1023, IVA-337 (Lanifibranor), JKB-121, KD-025, MSDC-0602, PBI-4050, PEG-FGF21, tipelukast, VK-2809, MGL-3196, GS-0976, RG-125, volixibat, pioglitazone, ursodeoxycholic acid, semaglutide, GSK2330672, and MBX-8025.

In a particular embodiment of the combination product of the invention:component (i) is Elafibranor or a pharmaceutically acceptable salt thereof; andcomponent (ii) is selected from GKT-831, aramchol, SHP-625, emricasan, saroglitazar, IMM-124-E, GS-9674, NGM-282, A-4250, GR-MD-02, GS-4997, F-351, solithromycin, remogliflozin, BTT-1023, IVA-337 (Lanifibranor), JKB-121, KD-025, MSDC-0602, PBI-4050, PEG-FGF21, tipelukast, VK-2809, MGL-3196, GS-0976, pentasa, RG-125, volixibat, pioglitazone, semaglutide, GSK2330672, and MBX-8025.

In a particular embodiment, the combination product is a combination of ELA and GKT-831, ELA and Selonsertib, ELA and GS-0976 or ELA and Pentasa.

In a particular embodiment, the combination product is a combination of ELA and GS-0976, ELA and CP-640186, ELA and Selonsertib, ELA and GKT-831 (formerly GKT137831), ELA and BI-1467335/PXS-4728A, ELA and Aramchol, ELA and PBI-4050, ELA and MSDC-0602k, ELA and VK-2809, ELA and MGL-3196, ELA and Vismodegib, ELA and CF-102 (Namodenoson), ELA and MT-3995 (Apararenone), ELA and JKB-121 (Nalmefene), ELA and Emricasan, ELA and KD-025, ELA and DUR-928, or ELA and Gemcabene.

In a particular embodiment, the combination product is a combination of ELA and Selonsertib, ELA and GKT-831 (formerly GKT137831), ELA and BI-1467335/PXS-4728A, ELA and Aramchol, ELA and PBI-4050, ELA and MSDC-0602k, ELA and VK-2809, ELA and MGL-3196, ELA and Vismodegib, ELA and CF-102 (Namodenoson), ELA and MT-3995 (Apararenone), ELA and JKB-121 (Nalmefene), ELA and Emricasan, ELA and KD-025, and ELA and DUR-928.

In a further particular variant of this embodiment, component (ii) is not OCA or CVC.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is selected from an ACC inhibitor, an ASK1 inhibitor, a dual NOX1 and NOX4, a VAP-1 inhibitor, a stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugate, a GPR84 antagonist/FFAR1 agonist or immunomodulator, a mTOR modulator or insulin sensitizer, a THRβ agonist, a hedgehog signaling pathway inhibitor, an adenosine A3 receptor agonist, an aldosterone receptor antagonist, a TLR-4 antagonist, a caspase inhibitor, a ROCK2 inhibitor, and a nuclear receptor ligand.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is an ACC inhibitor (in particular GS-0976 or CP-640186 or Gemcabene), an ASK1 inhibitor (in particular Selonsertib), a dual NOX1 and NOX4 inhibitor (in particular GKT-831, formerly GKT137831), a VAP-1 inhibitor (in particular BI-1467335/PXS-4728A), a stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugate (in particular Aramchol), a GPR84 antagonist/FFAR1 agonist or immunomodulator (in particular PBI-4050), a mTOR modulator or insulin sensitizer (in particular MSDC-0602k), a THRb agonist (in particular VK-2809 or MGL-3196), a hedgehog signaling pathway inhibitor (in particular Vismodegib), an adenosine A3 receptor agonist (in particular CF-102 (Namodenoson)), an aldosterone receptor antagonist (in particular MT-3995 (Apararenone)), a TLR-4 antagonist (in particular JKB-121 (Nalmefene)), a caspase inhibitor (in particular emricasan), a ROCK2 inhibitor (in particular KD-025), and a nuclear receptor ligand (in particular DUR-928).

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is an ASK1 inhibitor, a dual NOX1 and NOX4, a VAP-1 inhibitor, a stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugate, a GPR84 antagonist/FFAR1 agonist or immunomodulator, a mTOR modulator or insulin sensitizer, a THRβ agonist, a hedgehog signaling pathway inhibitor, an adenosine A3 receptor agonist, an aldosterone receptor antagonist, a TLR-4 antagonist, a caspase inhibitor, a ROCK2 inhibitor, and a nuclear receptor ligand.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is an ASK1 inhibitor (in particular Selonsertib), a dual NOX1 and NOX4 inhibitor (in particular GKT-831, formerly GKT137831), a VAP-1 inhibitor (in particular BI-1467335/PXS-4728A), a stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugate (in particular Aramchol), a GPR84 antagonist/FFAR1 agonist or immunomodulator (in particular PBI-4050), a mTOR modulator or insulin sensitizer (in particular MSDC-0602k), a THRb agonist (in particular VK-2809 or MGL-3196), a hedgehog signaling pathway inhibitor (in particular Vismodegib), an adenosine A3 receptor agonist (in particular CF-102 (Namodenoson)), an aldosterone receptor antagonist (in particular MT-3995 (Apararenone)), a TLR-4 antagonist (in particular JKB-121 (Nalmefene)), a caspase inhibitor (in particular emricasan), a ROCK2 inhibitor (in particular KD-025), and a nuclear receptor ligand (in particular DUR-928).

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is an ACC inhibitor.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is GS-0976, CP-640186 or Gemcabene.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is GS-0976.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is CP-640186.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is Gemcabene.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is an ASK1 inhibitor.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is Selonsertib.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a dual NOX1 and NOX4 inhibitor.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is GKT-831.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a VAP-1 inhibitor.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is BI-1467335/PXS-4728A.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a stearoyl CoA desaturase-1 inhibitors/fatty acid bile acid conjugate.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is Aramchol.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a GPR84 antagonist/FFAR1 agonist.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is PBI-4050.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a mTOR modulator or insulin sensitizer.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is in particular MSDC-0602k.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a THRβ agonist.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is VK-2809 or MGL-3196.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is VK-2809.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is MGL-3196.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a Hedgehog cell signaling pathway inhibitor.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is Vismodegib.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is an Adenosine A3 receptor agonist.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is CF-102 (Namodenoson).

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is an aldosterone receptor antagonist.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is MT-3995 (Apararenone).

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a TLR-4 antagonist.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is JKB-121 (Nalmefene).

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a nuclear receptor ligand.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is Emricasan.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is a ROCK2 inhibitor.

In a more particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is KD-025.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is nuclear receptor ligand.

In a particular embodiment, component (i) is Elafibranor or a pharmaceutically acceptable salt thereof, and component (ii) is DUR-928.

In a particular embodiment, the combination product of the invention further comprises at least one other therapeutically active agent selected from JAK/STAT inhibitors and other anti-inflammatory agent and/or an immunosuppressant agent.

Illustrative anti-inflammatory and/or immunosuppressant agents comprise glucocorticoids, NSAIDS, cyclophosphamide, nitrosoureas, folic acid analogs, purine analogs, pyrimidine analogs, methotrexate, azathioprine, mercaptopurine, ciclosporin, myriocin, tacrolimus, sirolimus, mycophenolic acid derivatives, fingolimod and other sphingosine-1-phosphate receptor modulators, monoclonal and/or polyclonal antibodies against such targets as proinflammatory cytokines and proinflammatory cytokine receptors, T-cell receptor and integrins.

In another particular embodiment the combination of the invention may further comprise at least one therapeutically active agent with known antifibrotic activity such as pirfenidone or receptor tyrosine kinase inhibitors (RTKIs) such as Nintedanib, Sorafenib and other RTKIs, or angiotensin II (AT1) receptor blockers, or CTGF inhibitor, or any antifibrotic compound susceptible to interfere with the TGFβ and BMP-activated pathways including activators of the latent TGFβ complex such as MMP2, MMP9, THBS1 or cell-surface integrins, TGFβ receptors type I (TGFBRI) or type II (TGFBRII) and their ligands such as TGFβ, Activin, inhibin, Nodal, anti-Müllerian hormone, GDFs or BMPs, auxiliary co-receptors (also known as type Ill receptors), or components of the SMAD-dependent canonical pathway including regulatory or inhibitory SMAD proteins, or members of the SMAD-independent or non-canonical pathways including various branches of MAPK signaling, TAK1, Rho-like GTPase signaling pathways, phosphatidylinositol-3 kinase/AKT pathways, TGFβ-induced EMT process, or canonical and non-canonical Hedgehog signaling pathways including Hh ligands or target genes, or any members of the WNT, or Notch pathways which are susceptible to influence TGFβ signaling.

In a specific embodiment of the invention, the other therapeutically active agent is a PPAR agonist.

In another particular embodiment, the PPAR agonist is a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPAR alpha/delta dual agonist, a PPAR gamma/delta dual agonist or a PPAR alpha/gamma/delta pan agonist.

In a particular embodiment, the other therapeutically active agent is:at least one PPAR-alpha agonist;at least one PPAR-gamma agonist;at least one PPAR-delta agonist;at least one PPAR-alpha/delta dual agonist;at least one PPAR-alpha agonist and at least one PPAR delta agonist;at least one PPAR-alpha/gamma dual agonist;at least one PPAR-alpha agonist and at least one PPAR gamma agonist;at least one PPAR-gamma/delta dual agonist;at least one PPAR-gamma agonist and at least one PPAR delta agonist;at least one PPAR-alpha/gamma/delta pan agonist; andat least one PPAR-alpha agonist, at least one PPAR-gamma agonist and at least one PPAR-delta agonist.

In a particular embodiment, the combination product of the invention is a composition comprising components (i) and (ii) as described above, and a pharmaceutically acceptable carrier.

In a particular embodiment, the combination product is a kit of parts comprising components (i) and (ii) as described above, for sequential, separate or simultaneous use.

In a further embodiment, components (i) and (ii) are formulated in an injectable suspension, a gel, an oil, a pill, a tablet, a suppository, a powder, a capsule, an aerosol, an ointment, a cream, a patch, or means of galenic forms for a prolonged and/or slow release.

The present invention also relates to the combination product according to the invention, for use as a medicament.

The invention also relates to the combination product herein disclosed, for use in a method for the treatment of a disease. In another embodiment, the invention relates to a method for the treatment of a disease, comprising administering to a subject in need thereof a therapeutically effective amount of the combination product herein discloses. In another embodiment, it is provided the use of a combination product according to the invention, for the manufacture of a medicament for the treatment of a disease.

In particular, the combination product of the present invention is useful for the treatment of diseases such as immune, inflammatory, metabolic, fibrotic and cholestatic diseases. In a particular embodiment, the disease is selected in the group consisting of metabolic liver diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver diseases, alcohol-induced liver diseases, infectious agent induced liver diseases, inflammatory liver diseases, immune system dysfunction-mediated liver diseases, dyslipidemia, cardiovascular diseases, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC), Primary Biliary Cholangitis (PBC), biliary atresia, progressive familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel diseases, Crohn's disease, ulcerative colitis, keloid, old myocardial infarction, scleroderma/systemic sclerosis, inflammatory diseases, neurodegenerative diseases, cancers, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, meningioma associated with neurofibromatosis, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, myeloproliferative/myelodisplastic diseases, mastocytosis, dermatofibrosarcoma, solid tumors including breast, lung, thyroid or colorectal cancer, a prostate cancer, liver fibrosis or cirrhosis of any origin, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, infectious agent-induced liver fibrosis or cirrhosis, parasite infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV-infection induced liver fibrosis or cirrhosis, HCV-infection induced liver fibrosis or cirrhosis, HIV-infection induced liver fibrosis or cirrhosis, dual HCV and HIV-infection induced liver fibrosis or cirrhosis, radiation- or chemotherapy-induced fibrosis or cirrhosis, biliary tract fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease, gut fibrosis of any etiology, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestine (e.g. small intestine) fibrosis, colon fibrosis, stomach fibrosis, skin fibrosis, epidermis fibrosis, endodermis fibrosis, skin fibrosis due to scleroderma/systemic sclerosis, lung fibrosis, lung fibrosis consecutive to chronic inflammatory airway diseases, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), heart fibrosis, kidney fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue (e.g. mediastinum or retroperitoneum) fibrosis, bone marrow fibrosis, joint fibrosis, tendon fibrosis, cartilage fibrosis, pancreas fibrosis, uterus fibrosis, nervous system fibrosis, testis fibrosis, ovary fibrosis, adrenal gland fibrosis, artery fibrosis, vein fibrosis, eye fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal workers' pneumoconiosis), proliferative fibrosis, neoplastic fibrosis, peri-implantational fibrosis and asbestosis, arthrofibrosis, adhesive capsulitis.

In a most preferred embodiment, the disease is selected in the group consisting of metabolic liver diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver diseases, alcohol-induced liver diseases, infectious agent induced liver diseases, inflammatory liver diseases, immune system dysfunction-mediated liver diseases, dyslipidemia, cardiovascular diseases, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC), Primary Biliary Cholangitis (PBC), biliary atresia, progressive familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel diseases, Crohn's disease, ulcerative colitis, liver cancer, hepatocallular carcinoma, gastrointestinal cancer, gastric cancer, colorectal cancer, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, infectious agent-induced liver fibrosis or cirrhosis, parasite infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV-infection induced liver fibrosis or cirrhosis, HCV-infection induced liver fibrosis or cirrhosis, HIV-infection induced liver fibrosis or cirrhosis, dual HCV and HIV-infection induced liver fibrosis or cirrhosis, radiation- or chemotherapy-induced fibrosis or cirrhosis, biliary tract fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease, gut fibrosis of any etiology, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestine (e.g. small intestine) fibrosis, colon fibrosis, stomach fibrosis, lung fibrosis, lung fibrosis consecutive to chronic inflammatory airway diseases, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF).

In a further aspect, the invention relates to the combination of the invention, for use in the inhibition of proliferation and/or activation of fibroblasts responsible for the production of collagen fibers and/or responsible for the production of the extracellular matrix.

According to the present invention, the term “autoimmune diseases” is used to designate a condition that arises from an abnormal immune response of the body against substances and tissues normally present in the body. The disease may be restricted to certain organs (e.g. in type I diabetes or autoimmune thyroiditis) or involve a particular tissue in different places (e.g. in Goodpasture's disease, affection of the basement membrane in the lung and the kidney).

The term “inflammation” is used to designate a condition that arise from a protective response involving host cells, blood vessels, and proteins and other mediators which may serve to eliminate the cause of cell/tissue injury, as well as the necrotic cells/tissues resulting from the original insult, and to initiate the process of repair. The inflammatory reaction may be manifested by pain, heat, redness, swelling, blood vessels dilatation, blood flow increase and loss of function.

According to the present invention, the terms “fibrosis”, “fibrotic disease”, “fibrotic disorder” and declinations thereof denote a pathological condition of excessive deposition of fibrous connective tissue in an organ or tissue. More specifically, fibrosis is a pathological process, which includes a persistent fibrotic scar formation and overproduction of extracellular matrix by the connective tissue, as a response to tissue damage. Physiologically, the deposit of connective tissue can obliterate the architecture and function of the underlying organ or tissue.

According to the present invention, the fibrosis or fibrotic disorder may be associated with any organ or tissue fibrosis. Illustrative, non-limiting examples of particular organ fibrosis include liver, gut, kidney, skin, epidermis, endodermis, muscle, tendon, cartilage, heart, pancreas, lung, uterus, nervous system, testis, penis, ovary, adrenal gland, artery, vein, colon, intestine (e.g. small intestine), biliary tract, soft tissue (e.g. mediastinum or retroperitoneum), bone marrow, joint or stomach fibrosis, in particular liver, kidney, skin, epidermis, endodermis, muscle, tendon, cartilage, heart, pancreas, lung, uterus, nervous system, testis, ovary, adrenal gland, artery, vein, colon, intestine (e.g. small intestine), biliary tract, soft tissue (e.g. mediastinum or retroperitoneum), bone marrow, joint, eye or stomach fibrosis.

According to the present invention, the terms “cholestasis” or “cholestatic disease”, or “cholestatic disorder” and declinations thereof denote a pathological condition defined by a decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through intra-or extrahepatic bile ducts. Therefore, the clinical definition of cholestasis is any condition in which substances normally excreted into bile are retained.

In a particular embodiment, the fibrotic disorder is selected in the group consisting of a liver, gut, lung, heart, kidney, muscle, skin, soft tissue (e.g. mediastinum or retroperitoneum), bone marrow, intestinal, and joint (e.g. knee, shoulder or other joints) fibrosis.

In a preferred embodiment, the fibrotic disorder is selected in the group consisting of liver, lung, skin, kidney and intestinal fibrosis.

In a more preferred embodiment of the present invention, treated fibrotic disorder is selected in the group consisting of the following non exhaustive list of fibrotic disorders: non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, idiopathic pulmonary fibrosis, skin fibrosis, eye fibrosis (such as capsular fibrosis), endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal workers' pneumoconiosis), proliferative fibrosis, neoplastic fibrosis, lung fibrosis consecutive to chronic inflammatory airway disease (COPD, asthma, emphysema, smoker's lung, tuberculosis), alcohol or drug-induced liver fibrosis, liver cirrhosis, infection-induced liver fibrosis, radiation or chemotherapeutic-induced fibrosis, nephrogenic systemic fibrosis, Crohn's disease, ulcerative colitis, keloid, old myocardial infarction, scleroderma/systemic sclerosis, arthrofibrosis, some forms of adhesive capsulitis, chronic fibrosing cholangiopathies such as Primary Sclerosing Cholangitis (PSC) and Primary Biliary Cholangitis (PBC), biliary atresia, progressive familial intrahepatic cholestasis type 3 (PFIC3), peri-implantational fibrosis and asbestosis.

Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes (hepato-cellular cholestasis) or to obstruction of bile flow through intra-or extrahepatic bile ducts (obstructive cholestasis). In clinical practice, cholestasis is any condition in which the flow of bile from the liver is slowed or blocked. According to a particular embodiment of the invention, the cholestestatic disease is selected in the group consisting of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Intrahepatic Cholestasis of Pregnancy, Progressive Familial Intrahepatic Cholestasis, Biliary atresia, Cholelithiasis, Infectious Cholangitis, Cholangitis associated with Langerhans cell histiocytosis, Alagille syndrome, Nonsyndromic ductal paucity, Drug-induced cholestasis, and Total parenteral nutrition-associated cholestasis. In a preferred embodiment, the cholestatic disease is PBC or PSC, in particular PBC.

Examples of inflammatory diseases, fibrotic diseases, metabolic diseases and cholestatic diseases include metabolic liver diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver diseases, alcohol-induced liver diseases, infectious agent induced liver diseases, inflammatory liver diseases, immune system dysfunction-mediated liver diseases, dyslipidemia, cardiovascular diseases, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC), Primary Biliary Cholangitis (PBC), biliary atresia, progressive familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel diseases, Crohn's disease, ulcerative colitis, keloid, old myocardial infarction, scleroderma/systemic sclerosis, inflammatory diseases, neurodegenerative diseases, cancers, liver cancer, hepatocallular carcinoma, gastrointestinal cancer, gastric cancer, meningioma associated with neurofibromatosis, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, myeloproliferative/myelodisplastic diseases, mastocytosis, dermatofibrosarcoma, solid tumors including breast, lung, thyroid or colorectal cancer, a prostate cancer, liver fibrosis or cirrhosis of any origin, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, infectious agent-induced liver fibrosis or cirrhosis, parasite infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV-infection induced liver fibrosis or cirrhosis, HCV-infection induced liver fibrosis or cirrhosis, HIV-infection induced liver fibrosis or cirrhosis, dual HCV and HIV-infection induced liver fibrosis or cirrhosis, radiation- or chemotherapy-induced fibrosis or cirrhosis, biliary tract fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease, gut fibrosis of any etiology, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestine (e.g. small intestine) fibrosis, colon fibrosis, stomach fibrosis, skin fibrosis, epidermis fibrosis, endodermis fibrosis, skin fibrosis due to scleroderma/systemic sclerosis, lung fibrosis, lung fibrosis consecutive to chronic inflammatory airway diseases, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), heart fibrosis, kidney fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue (e.g. mediastinum or retroperitoneum) fibrosis, bone marrow fibrosis, joint fibrosis, tendon fibrosis, cartilage fibrosis, pancreas fibrosis, uterus fibrosis, nervous system fibrosis, testis fibrosis, ovary fibrosis, adrenal gland fibrosis, artery fibrosis, vein fibrosis, eye fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal workers' pneumoconiosis), proliferative fibrosis, neoplastic fibrosis, peri-implantational fibrosis and asbestosis, arthrofibrosis, adhesive capsulitis.

Preferably, the disease is selected in the group consisting of metabolic liver diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver diseases, alcohol-induced liver diseases, infectious agent induced liver diseases, inflammatory liver diseases, immune system dysfunction-mediated liver diseases, dyslipidemia, cardiovascular diseases, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathies such as Primary Sclerosing Cholangitis (PSC), Primary Biliary Cholangitis (PBC), biliary atresia, progressive familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel diseases, Crohn's disease, ulcerative colitis, liver cancer, hepatocallular carcinoma, gastrointestinal cancer, gastric cancer, colorectal cancer, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, infectious agent-induced liver fibrosis or cirrhosis, parasite infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV-infection induced liver fibrosis or cirrhosis, HCV-infection induced liver fibrosis or cirrhosis, HIV-infection induced liver fibrosis or cirrhosis, dual HCV and HIV-infection induced liver fibrosis or cirrhosis, radiation- or chemotherapy-induced fibrosis or cirrhosis, biliary tract fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease, gut fibrosis of any etiology, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestine (e.g. small intestine) fibrosis, colon fibrosis, stomach fibrosis, lung fibrosis, lung fibrosis consecutive to chronic inflammatory airway diseases, such as COPD, asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF).

The term “treatment” or “treating” refers to the curative or preventive of a disorder in a subject in need thereof. The treatment involves the administration of the compound, in particular comprised in a pharmaceutical composition, to a subject having a declared disorder, i.e. to a patient, to cure, delay, reverse, or slow down the progression of the disorder, improving thereby the condition of the subject. A treatment may also be administered to a subject that is healthy or at risk of developing a cholestatic or fibrotic disorder to prevent or delay the disorder.

Therefore, according to the invention, the treatment of an immune, inflammatory, metabolic, fibrotic and cholestatic disease involves the administration of the combination of the present invention, for example in the form of a pharmaceutical composition containing components (i) and (ii) of the combination, to a subject having a declared disorder to cure, delay, reverse or slow down the progression of the disorder, thus improving the condition of the patient or to a healthy subject, in particular a subject who is at risk of developing such disease.

The treatment involves the administration of the combination of the invention to a patient having a declared disorder to cure, delay, or slow down the progress, thus improving the condition of the patient or to a healthy subject, in particular a subject who is at risk of developing an inflammatory, metabolic, fibrotic and cholestatic disease.

The subject to be treated is a mammal, preferably a human. The subject to be treated according to the invention can be selected on the basis of several criteria associated to fibrotic diseases such as previous drug treatments, associated pathologies, genotype, exposure to risk factors, viral infection, as well as on the basis of the detection of any relevant biomarker that can be evaluated by means of imaging methods and immunological, biochemical, enzymatic, chemical, or nucleic acid detection methods.

The subjects to be treated according to the invention can be selected on the basis of several criteria associated to inflammatory, metabolic, fibrotic and cholestatic diseases such as previous drug treatments, associated pathologies, genotype, exposure to risk factors, viral infection, as well as any other relevant biomarker that can be evaluated by means of imaging methods and immunological, biochemical, enzymatic, chemical, or nucleic acid detection method.

In a particular embodiment, the treatment of an inflammatory, metabolic, fibrotic and cholestatic disease may comprise the administration of a composition comprising at least two compounds of formula (I). In this embodiment, the administered component (ii) is provided in the same composition as the at least two compounds of formula (I), or in a separate form, such as in a different composition.

In another embodiment, the combination of the invention is for simultaneous, sequential or separate administration in therapy, therefore being possibly included in different compositions. In case of sequential administration, the compound of formula (I), in particular ELA, may be administrated prior to component (ii), or component (ii) is (are) administrated prior to the compound of formula (I).

A compound of formula (I) may be formulated as pharmaceutically acceptable salts, particularly acid or base salts compatible with pharmaceutical use. Salts of compounds of formula (I) include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. These salts can be obtained during the final purification step of the compound or by incorporating the salt into the previously purified compound.

The pharmaceutical compositions of the present invention can also comprise one or several excipients or vehicles, acceptable within a pharmaceutical context (e.g. saline solutions, physiological solutions, isotonic solutions, etc., compatible with pharmaceutical usage and well-known by one of ordinary skill in the art).

These compositions can also comprise one or several agents or vehicles chosen among dispersants, solubilisers, stabilisers, preservatives, etc. Agents or vehicles useful for these formulations (liquid and/or injectable and/or solid) are particularly methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc.

These compositions can be formulated in the form of injectable suspensions, gels, oils, ointments, pills, tablets, suppositories, powders, gel caps, capsules, aerosols, etc., eventually by means of galenic forms or devices assuring a prolonged and/or slow release.

For this kind of formulation, agents such as cellulose, carbonates or starches can be advantageously used.

The pharmaceutical compositions of the present invention comprising a compound of formula (I) and one or more component(s) (ii) may be administered by different routes and in different forms. For example, the compound(s) may be administered via a systemic way, per os, parenterally, by inhalation, by nasal spray, by nasal instillation, or by injection, such as for example intravenously, by intra-muscular route, by subcutaneous route, by transdermal route, by topical route, by intra-arterial route, etc.

Of course, the route of administration will be adapted to the form of the compounds to be administered, according to procedures well known by those skilled in the art.

Components (i) and (ii) of the combination product of the invention are administered in a therapeutically effective amount. Within the context of the invention, the term “effective amount” refers to an amount of the compound sufficient to produce the desired therapeutic result.

The frequency and/or dose relative to the administration can be adapted by one of ordinary skill in the art, in function of the patient, the pathology, the form of administration, etc. Typically, the combination (such as in the form of a pharmaceutical composition or a kit-of-parts) of the present invention can be administered for the treatment of a fibrotic disease at a dose for component (i) or component (ii), comprised between 0.01 mg/day to 4000 mg/day, such as from 50 mg/day to 2000 mg/day, and particularly from 100 mg/day to 1000 mg/day.

In a preferred embodiment of the invention, ELA is used in combination with component (ii) at a dose comprised between 80 to 120 mg/day for Elafibranor.

In another preferred embodiment, the active ingredients are administered as one or more pharmaceutical composition(s) in the form of a pill or tablet intended for an oral ingestion.

Administration can be performed daily or even several times per day, if necessary.

The invention is further described with reference to the following, non-limiting, examples.

DESCRIPTION OF THE FIGURES

Abbreviations used in the figures, in the tables, and in the text:

α-SMA α-Smooth Muscle Actin

AP-1 Activator Protein 1

ASBTi Apical Sodium-codependent Bile acid Transporter inhibitor

ASK1 Apoptosis Signal-regulating Kinase 1

AT1 Angiotensin II receptor type 1

CLA Conjugated Linoleic Acid

COPD Chronic Obstructive Pulmonary Disease

CTGF Connective Tissue Growth Factor

CVC Cenicriviroc

DGAT DiacylGlycerol-O-AcylTransferase

DMSO DiMethyl SulfOxide

DPP4 DiPeptidyl Peptidase 4

ELISA Enzyme-Linked Immuno Assay

EOB Excess Over Bliss

EOBHSA Excess Over Bliss Highest Single Agent

FABAC Fatty Acid Bile Acid Conjugate

FBS Fetal Bovine Serum

FGF Fibroblast Growth Factor

FXR Farnesoid X Receptor

GDF Growth Differentiation Factor

GLP-1 Glucagon-Like Peptide-1

GPCR G-Protein Coupled Receptor

HBV Hepatitis B Virus

HCV Hepatitis C Virus

15-HEPE 5-HydroxyEicosaPentaEnoic acid

HIV Human Immunodeficiency Virus

HSC Hepatic Stellate Cell

IC50 half maximal Inhibitory Concentration

iNOS inducible Nitric Oxide Synthase

IPF Idiopathic Pulmonary Fibrosis

LO LipOxygenase

LPS LipoPolySaccharide

LT LeukoTriene

MAPK Mitogen-Activated Protein Kinase

MMP-9 Matrix Metalloproteinase 9

MMPase Matrix Metalloproteinase

NADPH Nicotinamide Adenine Dinucleotide PHosphate

NAFLD Non-Alcoholic Fatty Liver Disease

NASH Non-Alcoholic SteatoHepatitis

NF-κB Nuclear Factor-kappa B

NOX NADPH oxidase

NSAIDs Non-Steroid Anti-Inflammatory Drugs

PAR Protease-Activated Receptor

PBC Primary Biliary Cholangitis

PBS Phosphate-Buffered Saline

PDE PhosphoDiEsterase

PDGF Platelet-Derived Growth Factor

PFIC3 Progressive Familial Intrahepatic Cholestasis type 3

PFOR Pyruvate:Ferredoxin OxidoReductase

PPAR Peroxisome Proliferator Activated-Receptor

PPRE PPAR Response Elements

PSC Primary Sclerosing Cholangitis

ROCK Rho-associated protein kinase

RTK Receptor Tyrosine Kinase

SGLT Sodium-GLucose transport

STAT Signal Transducers and Activators of Transcription

TGFβ Transforming Growth Factor β

TGFBRI TGFβ receptors type I

TGFBRII TGFβ receptors type II

THBS1 Thrombospondin 1

THR β Thyroid Hormone Receptor β

TIMP Tissue Inhibitor of MetalloProteinase 1

TLR-4 Toll Like Receptor 4

VAP-1 Vascular Adhesion Protein-1

VDR Vitamin D Receptor

