Compositions and methods for the treatment of primary biliary cholangitis

Abstract

The present invention relates to a pharmaceutical composition comprising elafibranor or a pharmaceutically acceptable salt thereof for use in treating primary biliary cholangitis (PBC) in subjects intolerant to ursodeoxycholic acid (UDCA).

Description

Technical Field

[0001] Primary biliary cholangitis (PBC) is a rare, chronic, autoimmune - etiology progressive liver disease characterized by damage to the intrahepatic bile ducts in untreated patients, which can progress to liver fibrosis, cirrhosis, liver decompensation, and death unless the patient undergoes liver transplantation. PBC affects women disproportionately to men (approximately 10:1) and is typically diagnosed in patients between 40 and 60 years of age. In Europe, North America, Asia, and Australia, the incidence of PBC has been reported to range from 0.33 to 5.8 per 100,000 inhabitants, and the prevalence of PBC has been reported to range from 1.91 to 40.2 per 100,000 inhabitants.

Background Art

[0002] More than 60% of newly diagnosed cases are asymptomatic. Most of the asymptomatic patients will develop symptoms within 10 years. The most common symptoms of PBC are fatigue and pruritus (Crosignani A et al., Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008;14(21):3313 - 3327). The mechanisms underlying these symptoms are not well understood and are not correlated with disease stage or clinical outcome.

[0003] PBC represents one of the major indications for liver transplantation. Thus, although rare, PBC remains an important cause of mortality in Western countries. PBC has also been identified as an important risk factor for hepatocellular carcinoma.

[0004] PBC is characterized by cholestasis caused by autoimmune breakdown of the bile ducts, resulting in progressive impairment of bile flow within the liver. This leads to elevated hepatocyte bile acid concentrations, which are toxic to the liver. This hepatocyte damage is associated with a local inflammatory response, leading to an early abnormal increase in serum alkaline phosphatase (ALP) levels. In fact, elevated ALP levels are associated with a 2.0–2.5 times higher risk of liver transplantation or death compared to the risk associated with normal levels. Later in disease progression, abnormally elevated bilirubin levels are also a strong predictor of outcomes with a 5.1–10.7 times higher risk of liver transplantation or death compared to the risk associated with normal levels.

[0005] The only approved drug for treating patients with PBC is ursodeoxycholic acid (UDCA), and more recently, Ocaliva® (oveticolic acid, OCA).

[0006] UDCA (ursodeoxycholic acid) has been shown to improve ALP and bilirubin levels and slow histological progression, thereby increasing survival without liver transplantation. However, up to 40% of patients treated with UDCA have a suboptimal response (Ali AH et al., Orphan drugs in development for primary biliary cirrhosis: challenges and progress. Orphan Drugs: Research and Reviews. 2015;5:83~97). Furthermore, ALP levels have been shown to remain elevated in up to 70% of patients currently being treated or intolerant to UDCA (Lammers WJ et al., Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014; 147(6):1338~1349).

[0007] Furthermore, 3-5% of patients are intolerant to UDCA. "Intolerance to UDCA" means one of the following: - Pregnant women; patients with complete bile duct obstruction of extrahepatic origin; patients with extensive intrahepatic obstruction; patients with calcified cholesterol stones, radiopaque stones, or radiopaque bile pigment stones that cause gallbladder dysfunction; patients with acute inflammation of the gallbladder or biliary tract; patients with frequent biliary colic; or patients who are hypersensitive to Ursodiol® or any component of the preparation, or who have any other contraindications to treatment with UDCA. or - Inability to comply with UDCA medication due to serious adverse events or serious conditions. Serious adverse events or serious conditions that may lead to intolerance include: leukopenia; ulcers; immunosuppression and resulting fever; uncontrollable or otherwise unexplained diarrhea; pneumonia; pharyngitis; otitis media; bronchopneumonia; bronchitis; oral moniliitis; abscess formation; dysuria or watery diarrhea; gastric burning; tubulointerstitial nephritis; leukocytoclastic vasculitis; skin rash; thrombocytopenia; recurrent wheezing chest, cough or interstitial lung disease; hepatic complications, such as cholangiopathic syndrome, pruritus, cholangitis, ascites, increased cholestasis, portal hypertension or hepatocyte failure; convulsions; nausea; vomiting; sleep disturbances; or diabetes. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] WO2004 / 005233 [Patent Document 2] WO2005 / 005369 [Patent Document 3] WO2011 / 144579 [Patent Document 4] WO2007 / 147879 [Non-patent literature]

[0009] [Non-Patent Document 1] Crosignani A et al. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008;14(21):3313~3327 [Non-Patent Document 2] Ali AH et al. Orphan drugs in development for primary biliary cirrhosis: challenges and progress. Orphan Drugs: Research and Reviews. 2015;5:83~97 [Non-Patent Document 3] Lammers WJ et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014; 147(6):1338~1349 [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] Given the efficacy and tolerability issues of currently available treatment options, there is an unmet need for therapeutic options for patients with PBC that enable the treatment of PBC in patients intolerant to UDCA. [Means for solving the problem]

[0011] Elafibranol (2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid) is a drug currently being tested in a critical Phase III study for the treatment of PBC. Elafibranol has also been evaluated in a Phase II study for the treatment of PBC. The Phase II results for PBC show that the mean relative change (%) from baseline to endpoint in serum ALP was -48.3% in the elafibranol 80 mg treatment group, -40.6% in the elafibranol 120 mg treatment group, and 3.2% in the placebo group. The absolute change from baseline in serum ALP was statistically significantly different from placebo at endpoint in both the elafibranol 80 mg treatment group (p<0.001) and the elafibranol 120 mg treatment group.

[0012] Therefore, treatment with elafibranol resulted in a consistent and statistically significant reduction in plasma ALP levels from baseline compared to placebo. Furthermore, elafibranol is safe and well-tolerated by patients.

[0013] Therefore, the present invention relates to a pharmaceutical composition comprising elafibranol or a pharmaceutically acceptable salt thereof for use in treating PBC in patients intolerant to UDCA.

[0014] The present invention further relates to a pharmaceutical composition comprising elafibranol or a pharmaceutically acceptable salt thereof for use in a method of treating PBC in subjects having PBC and being intolerant to UDCA.

[0015] The present invention also relates to a method for treating PBC in a subject with UDCA intolerance that does not induce and / or exacerbate at least one adverse event associated with PBC, the method comprising administering to the subject a therapeutically effective dose of elafibranol or a therapeutically effective dose of a pharmaceutically acceptable salt thereof.

[0016] The present invention further relates to a method for treating PBC in a subject intolerant to UDCA, said method comprising administering to said subject a therapeutically effective amount of elafibranor or a pharmaceutically acceptable salt thereof.

[0017] The present invention also relates to a method for treating PBC in a subject having PBC and intolerant to UDCA treatment, said method comprising administering to said subject a therapeutically effective amount of elafibranor or a pharmaceutically acceptable salt thereof.

[0018] Exemplary methods for synthesizing elafibranor include those described in PCT applications WO2004 / 005233, WO2005 / 005369 and WO2011 / 144579.

[0019] According to the present invention, the pharmaceutical composition of the present invention may comprise a stereoisomer of elafibranor or GFT1007, or a salt of elafibranor or GFT1007.

[0020] In some embodiments of the present invention, GFT1007, i.e., the active metabolite of elafibranor, is used. GFT1007 is 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid. Its properties and synthesis are described in PCT application WO2007 / 147879, where it is referred to as compound 1.

[0021] Stereoisomers are isomeric compounds that have the same molecular formula and sequence of bonded atoms but differ in the 3D-dimensional orientation of those atoms in space. Stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformational isomers and tautomers.

[0022] Elafibranol or GFT1007 can be formulated as pharmaceutically acceptable salts, particularly as acid or base salts suitable for pharmaceutically acceptable use. Salts of elafibranol or GFT1007 incorporated herein 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 a previously purified compound.

[0023] In detail, "medically acceptable salts" include inorganic and organic salts. Counterions may be selected from the following non-exclusive list: ammonia, L-arginine, benetamine, benzathine, tert-butylamine (erbumin), calcium hydroxide, choline hydroxide, deanol, diethanolamine (2,2'-iminobis(ethanol), diethylamine, epolamine (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)-ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydravamin, 1H-imidazole, L-lysine, magnesium hydroxide, meglumine (N-methyl-glucamine), 4-( 2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, sodium hydroxide, triethanolamine (2,2',2''-nitrilo-tris(ethanol)), tromethamine, zinc hydroxide, especially tromethamine, potassium, sodium, benetamine, benzathine, L-arginine, ethanolamine, meglumine, glycine, erbumin, L-lysine, epolamine, choline, preferably tromethamine, potassium, sodium, benetamine, benzathine, L-arginine, more preferably tromethamine, potassium, sodium, L-arginine, more preferably tromethamine.

[0024] In certain embodiments, the present invention relates to ellafibranol or GFT1007, ammonia, L-arginine, benetamine, benzathine, tert-butylamine (erbumin), calcium, chlorine, deanol, diethanolamine (2,2'-iminobis(ethanol), diethylamine, epolamine (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)-ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydravamin, 1H-imidazole, L-lysine, magnesium, meglumine (N-methyl-glucamine), 4-(2 The salts of (-hydroxyethyl)-morpholine, piperazine, potassium, sodium, triethanolamine (2,2',2''-nitrilo-tris(ethanol)), tromethamine, or zinc are carried out. In further specific embodiments, the salt of ellafibranol or GFT1007 is selected from salts of tromethamine, potassium, sodium, L-arginine, benetamine, benzathine, ethanolamine, meglumine, glycine, erbumin, L-lysine, choline, epolamine, magnesium, or 2-amino-2-methyl-propan-1-ol of ellafibranol or GFT1007.

[0025] Elafibranol or GFT1007 (especially elafibranol) or a salt thereof of the pharmaceutical may be formulated in a pharmaceutical composition.

[0026] The pharmaceutical compositions used in the present invention may include one or more excipients or vehicles acceptable in a pharmaceutical context (e.g., physiological saline solution, physiological solution, isotonic solution, etc., which are suitable for pharmaceutical use and well known to those skilled in the art). The compositions may also include one or more activators or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc. Useful activators or vehicles (liquid and / or for injection and / or solid) for these formulations include, in detail, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oil, acacia, liposomes, etc. Elafibranol may be formulated for enteral or parenteral administration. For example, elafibranol may be formulated for oral, intravascular (e.g., intravenous or intra-arterial), intramuscular, intraperitoneal, subcutaneous, transdermal, or nasal administration. The pharmaceutical compositions may be in solid or liquid dosage forms. Exemplary formulations include, but are not limited to, injectable suspensions, or orally administered suspensions, gels, oils, pills, tablets, suppositories, powders, gel caps, capsules, aerosols, ointments, creams, patches, or galenic dosage forms for long-term release and / or sustained release.

[0027] When disclosed herein, the term “treatment” or “to treat” means improvement or prevention of a disease or disorder, or at least one symptom that can be identified therefrom. This also means improvement or prevention of at least one measurable physical parameter associated with the disease or disorder being treated, which is not necessarily identifiable in the subject. “Treatment” or “to treat” further means physically inhibiting or slowing the progression of the disease or disorder, physiologically stabilizing recognizable symptoms, such as stabilizing a physical parameter, or both. “Treatment” or “to treat” also means delaying the onset of the disease or disorder. In some specific embodiments, the compound of interest is administered as a preventive measure. In this context, “prevention” or “to prevent” means a reduction in the risk of acquiring the specified disease or disorder.

[0028] The terms “patient,” “subject,” and “individual” are used interchangeably herein and refer to any human or non-human mammalian subject, including humans, laboratory, domestic, wild, or farm animals. In certain non-limiting embodiments, the patient, subject, or individual is human. Preferably, the subject is a human patient of any age and sex, here including newborns, infants, children, and adults. Preferably, the patient is between 40 and 60 years of age. Preferably, the patient is female.

[0029] As detailed above, 3-5% of patients are intolerant to UDCA. "Intolerance to UDCA" or "intolerance to treatment with UDCA" means one of the following: - Pregnant women; patients with complete bile duct obstruction of extrahepatic origin; patients with extensive intrahepatic obstruction; patients with calcified cholesterol stones, radiolucent stones, or radiolucent bile pigment stones that cause gallbladder dysfunction; patients with acute inflammation of the gallbladder or biliary tract; patients with frequent biliary colic; or patients who are hypersensitive to Ursodiol® or any component of the preparation, or who have any other contraindications to treatment with UDCA. or - Inability to comply with UDCA medication due to serious adverse events or serious conditions. Among the serious adverse events or serious conditions that may lead to intolerance, you may cite: leukopenia; ulcers; immunosuppression and resulting fever; uncontrollable or otherwise unexplained diarrhea; pneumonia; pharyngitis; otitis media; bronchopneumonia; bronchitis; oral moniliitis; abscess formation; dysuria or loose, watery diarrhea; gastric burning; tubulointerstitial nephritis; leukocytoclastic vasculitis; skin rash; thrombocytopenia; recurrent wheezing chest, cough or interstitial lung disease; hepatic complications, e.g., cholangiopathic syndrome, pruritus, cholangitis, ascites, increased cholestasis, portal hypertension or hepatocyte failure; convulsions; nausea; vomiting; sleep disturbances; or diabetes.

[0030] As used herein, the term “therapeutic dose” refers to the amount of elafibranol that prevents, eliminates, or reduces PBC and one of its adverse events. In particular, the amount of elafibranol pharmacopoeci salt is intended to be the amount of the free form of elafibranol in the pharmacopoeci salt.

[0031] The amount to be administered can be adapted by those skilled in the art. In particular, the dosage and regimen of administration may be a function of the stage and severity of the PBC to be treated, as well as a function of the weight, age and overall health of the patient to be treated, and a function of the physician's judgment.

[0032] In certain embodiments, elafibranol or a pharmaceutically acceptable salt thereof is administered in doses ranging from 10 mg to 200 mg per dose, preferably varying between 80 mg and 120 mg per dose. In further specific embodiments, elafibranol or a pharmaceutically acceptable salt thereof is administered in doses of 80 mg per dose. In yet another specific embodiment, elafibranol or a pharmaceutically acceptable salt thereof is administered in doses of 120 mg per dose.

[0033] In yet another embodiment, ellafibranol, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same is administered orally. Preferably, ellafibranol, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same is administered orally once daily.

[0034] According to one embodiment, the pharmaceutical composition is in solid dosage form, for example, a tablet. In a further specific embodiment, the tablet contains 10 mg to 200 mg of elafibranol or a pharmaceutically acceptable salt thereof, for example, 80 mg to 120 mg of elafibranol or a pharmaceutically acceptable salt thereof. For example, the tablet may contain 80 mg of elafibranol or a pharmaceutically acceptable salt thereof, or 120 mg of elafibranol or a pharmaceutically acceptable salt thereof.

[0035] In yet another embodiment, a tablet containing 80 mg of elafibranol is administered orally once daily.

[0036] Explanation of Figures and Tables Abbreviations used in figures, tables, and text: Ab antibody ABV (Alcohol by Volume) ADR (Alternative Discrimination Reaction) Adverse events (AEs) AESI (Adverse Events of Particular Note) AFP Alpha-Fetoprotein AIH autoimmune hepatitis ALD (Alcoholic Liver Disease) ALP (Alkaline Phosphatase) ALT (Alanine Aminotransferase) AMA anti-mitochondrial antibody ANA antinuclear antibody ANCOVA analysis of covariance AST (Aspartate Aminotransferase) AT aminotransferase AUCss: Area under the curve in a steady state BP (Blood Pressure) BUN (Blood Urea Nitrogen) C4 Serum 7α-hydroxy-4-cholesten-3-one CA Cholic Acid CCl4 Carbon tetrachloride CDCA Chenodeoxycholic Acid CI confidence interval CK-18 Cytokeratin-18 CKD-EPI Chronic Kidney Disease-Epidemiology Collaborative Research CPK creatine phosphokinase CRF Case Report CRO (Clinical Research Organization) CSR Clinical Trial Report CT (Computed Tomography) CYP Cytochrome P450 DB double-blind DCA Deoxycholic Acid DDI drug-drug interaction DILI (Drug-Induced Liver Injury) DSUR Development Periodic Safety Update EAIR exposure-adjusted incidence rate ECG (Electrocardiogram) eCRF Electronic Case Report Form eGFR (Expected Glomerular Filtration Rate) ELF-enhanced hepatic fibrosis ELISA enzyme-linked immunosorbent assay End of EOT treatment ePRO Electronic Patient Reporting Outcomes FGF19 Fibroblast Growth Factor 19 FPG (Fasting Plasma Glucose) GCA Glycocholic Acid GCDCA (glycocodecoxycholic acid) GCP (Good Clinical Practice) Guidelines for Conducting Clinical Trials of Pharmaceuticals GDCA (Glycodeoxycholic Acid) GGT (Gamma-Glutamyl Transferase) GLCA Glycolic Acid HAV (Hepatitis A virus) HBsAg Hepatitis B surface antigen hCG (Human chorionic gonadotropin) HCV (Hepatitis C virus) HCV Ab Hepatitis C Virus Antibody HDL-C (High-Density Lipoprotein Cholesterol) hHSC (human hepatic stellate cells) HIV (Human Immunodeficiency Virus) HRQoL (Health-related Quality of Life) hsCRP: Highly sensitive C-reactive protein ICE complications ICF Informed Consent Form IgG (Immunoglobulin G) IgM (Immunoglobulin M) IL Interleukin INR International Standardization Ratio IRT (Interactive Response Technology) ITT (Intentional Therapy) LCA Lithocholic Acid LDL-C (low-density lipoprotein cholesterol) LLN lower normal limit LTE long-term continuation LVDB Last Visit Double-Blind Study MCP (Monocyte Chemotropic Protein) MDR3 Multidrug Resistance Protein 3 Dietary modifications in MDRD (Medical Disease-Related Rheumatism) MELD-Na End-Stage Liver Disease Model - Sodium Mixed-effects model for repeated measurements (MMRM) MRI (Magnetic Resonance Imaging) NA Not applicable NASH (Non-Alcoholic Steatohepatitis) NF-κB nuclear factor kappa B NOAEL No Adverse Effect Level NRS (Numerical Rating Scale) OATP1B3 Organic Anion Transport Polypeptide 1B3 OCA Obeticholic Acid PAI Plasminogen Activator Inhibitor Primary biliary cholangitis (PBC) PBI (Placebo-Based Multiple Imputation) PDGF (Platelet-derived growth factor) PGIC Patient Overall Impression Rating Scale - Change PGIS Patient Overall Impression Rating Scale - Severity PK (Pharmacokinetics) PKS Pharmacokinetic Settings PP protocol compliance PPAR (Peroxisome Proliferator-Activated Receptor) PRO Patient-Reported Outcomes PSC Primary Sclerosing Cholangitis PT Prothrombin Time QoL (Quality of Life) RNA (ribonucleic acid) SADR (Severe Adverse Drug Reaction) SAE (Serious Adverse Event) SAP Statistical Analysis Plan SD standard deviation SMA smooth muscle antibody SOP (Standard Operating Procedure) SS safety settings Unpredictable and serious side effects suspected to be related to SUSAR SV screening visit TB Total Bilirubin Total Cholesterol (TC) TCA taurocholic acid TCDCA (Taurochenodeoxycholic Acid) TDCA Taurodeoxycholic Acid TE Transient Elastography TG Triglycerides TGF-β Transforming Growth Factor Beta TIPS: Transjugular intrahepatic portosystemic shunt TLCA Taurolithocholic Acid TNFα (tumor necrosis factor-alpha) Trt treatment UDCA Ursodeoxycholic Acid ULN normal upper limit Urine ACR (Urinary Albumin to Creatine Ratio) UV-LLNA UV-Local Lymph Node Assay VLDL (Very Low-Density Lipoprotein) WBC white blood cell count WOCBP (Women who may be pregnant) [Brief explanation of the drawing]

[0037] [Figure 1] Relative change from baseline in serum alkaline phosphatase at endpoint - primary efficacy endpoint - primary and supporting analyses. ALP = alkaline phosphatase, ANCOVA = analysis of covariance, CI = confidence interval, EOT = end of treatment, SD = standard deviation, tr = treatment. a. Nonparametric randomized ANCOVA using baseline ALP as a covariate. p-values ​​were calculated under the null hypothesis (based on re-randomization of the population), and estimates and CIs were calculated under the alternative hypothesis (based on repeated random sampling). b. ANCOVA using baseline ALP as a covariate and without interaction terms. [Figure 2] Mean alkaline phosphatase levels from baseline to 12 weeks in the treatment group [Figure 3] Mean relative change in alkaline phosphatase from baseline to 12 weeks in the treatment group. [Modes for carrying out the invention] [Examples]

[0038] (Example 1) Drugs used Elafibranol (2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid) was supplied as 80 mg round tablets with a white to off-white coating and no markings.

[0039] Placebo tablets corresponding to elafibranol 80 mg (the same size as the corresponding active tablet) were supplied as unmarked, round tablets coated in white to off-white. The placebo tablets contained the same excipients as the active formulation, as well as lactose monohydrate (which was used in place of the active ingredient).

[0040] (Example 2) ALP level results The mean relative change (%) from baseline to endpoint in serum ALP was -48.3% in the elafibranol 80 mg treatment group, -40.6% in the elafibranol 120 mg treatment group, and 3.2% in the placebo group.

[0041] In the primary efficacy analysis, conducted using a non-parametric, randomized ANCOVA with baseline ALP as a covariate, each dose demonstrated a statistically significant therapeutic effect compared to placebo (p<0.001). The estimated therapeutic effect was -52.0% (95% CI [-62.5;-41.5]) in the elafibranol 80 mg treatment group and -43.9% (95% CI [-55.7;-32.1]) in the elafibranol 120 mg treatment group (Figure 1).

[0042] A supporting analysis of the primary efficacy using ANCOVA with baseline ALP as a covariate was consistent with the primary efficacy analysis. The estimated treatment response was -51.4% (95% CI [-63.3;-39.5]) in the elafibranol 80 mg treatment group and -43.9% (95% CI [-55.8;-31.9]) in the elafibranol 120 mg treatment group (Figure 1).

[0043] The mean (95% CI) ALP levels from baseline to 12 weeks are shown for each treatment group in Figure 2. Both the elafibranol 80 mg and 120 mg treatment groups showed a decrease in mean ALP levels over the 12-week study.

[0044] Figure 3 shows the mean (95% CI) relative change (%) in ALP levels from baseline to 12 weeks for each treatment group. The mean relative change (%) from baseline shows that ALP levels decreased over time, starting at 2 weeks and continuing to 12 weeks, in both the elafibranol 80 mg and 120 mg treatment groups.

[0045] The relative change from baseline in serum ALP was statistically significantly different from placebo at endpoint in both the elafibranol 80 mg and elafibranol 120 mg treatment groups.

[0046] (Example 3) Clinical trials of PBC A double-blind, randomized, placebo-controlled phase 3 study and an open-label, long-term continuation clinical trial will be conducted in patients with primary biliary cholangitis who are intolerant to ursodeoxycholic acid to evaluate the efficacy and safety of treatment with orally administered elafibranol (80 g daily).

[0047] During the DB period, patients were randomized in a 2:1 ratio to receive either elafibranol 80 mg or placebo once daily. The DB period continued until the last completion week 52 (V6) or up to 104 weeks of DB, whichever occurred first, and further safety and clinical outcome data were collected using the DB method. After the DB period, all patients received elafibranol 80 mg daily for up to 5 years during the LTE period.

[0048] Key evaluation criteria The primary endpoint is to evaluate the efficacy of elafibranol (80 mg / day) over 52 weeks compared to placebo for cholestasis in patients intolerant to ursodeoxycholic acid (UDCA).

[0049] Secondary purpose The secondary objectives are as follows: 1) To evaluate the effect of elafibranol (80 mg / day) on normalizing alkaline phosphatase (ALP) levels over 52 weeks compared to placebo. 2) To evaluate the efficacy of elafibranol (80 mg / day) over 52 weeks compared to placebo for pruritus. 3) Evaluate the efficacy of elafibranol (80 mg / day) over 52 weeks compared to placebo for the following conditions: a) Hepatobiliary tract injury and liver function markers b) Inflammation and hepatic fibrosis c) Lipid parameters d) Bile acids e) Patient-reported outcomes (PROs) for pruritus. f) Patient-reported fatigue g) Patient-reported sleep h) Health-related Quality of Life (HRQoL) i) Health benefits j) Histological examination of the liver (both efficacy and safety criteria) k) Safety and tolerability 4) Determine the pharmacokinetic (PK) parameters of elafibranol and its active metabolite GFT1007 in steady state following daily oral administration of 80 mg in PBC patients who are intolerant to UDCA treatment. 5) Evaluate the effects of elafibranol (80 mg / day) on the following during the LTE period. a) Safety and tolerability b) Maintaining effectiveness from the DB period

[0050] Registration Criteria To be eligible for randomization to this study, patients must meet all of the following enrollment criteria: 1) Written informed consent must be provided, and participants must agree to abide by the research protocol. 2) Male or female between 18 and 75 years of age (including both ends) at the initial screening visit (SV). 3) A clear or likely PBC diagnosis is indicated by the presence of ≥2 of the following three diagnostic criteria: a. History of elevated ALP levels ≥ 6 months prior to randomization (V1) b. Positive for anti-mitochondrial antibody (AMA) titer (immunofluorescence >1 / 40 or M2 positive by enzyme-linked immunosorbent assay [ELISA], or positive for PBC-specific antinuclear antibody (ANA)). c. Liver biopsy consistent with PBC 4) Patients for whom it is safe and practical to proceed with a liver biopsy, and who consent to the following: a.1 Liver biopsy during the screening period (if a biopsy of tissue obtained within 12 months prior to screening is not available) b.1 Liver biopsy after 52 weeks of treatment 5)ALP≧1.67×upper limit of normal (ULN) 6) Total bilirubin (TB) ≤ 2 × ULN. To ensure appropriate representation of patients with moderately advanced disease or those at risk of progression to clinical outcomes, at least 10% of randomized patients will have moderate progression according to the Rotterdam criteria (TB > ULN, or albumin < lower limit of normal [LLN]) and at least 20% (patients at risk of progression) will have TB > 0.6 × ULN. 7) In the 14 days prior to randomization (V1), participants must have at least four available values ​​on the PBC Worst Itch Numeric Rating Scale (NRS) within each 7-day interval, and in the last 14 days prior to randomization (V1), participants must have a total of at least eight values ​​on the PBC Worst Itch NRS. 8) Unable to tolerate UDCA treatment before randomization (≥3 months without UDCA) (standard treatment dose by country) 9) If cortisin is being administered, the dose must be stable for at least 3 months prior to randomization. 10) Medications for the management of pruritus (e.g., cholestyramine, rifampin, naltrexone, or sertraline) must be administered at a stable dose for ≥3 months prior to randomization. 11) Patients taking statins or ezetimibe must be on a stable dose for at least 2 months prior to randomization. 12) Women participating in this study must not be pregnant, or must use highly effective contraception for the entire duration of this study and for one month after the last drug dose. • Absence of the possibility of pregnancy: At least 12 months of cessation of menstruation due to ovarian failure or sterilization, e.g., bilateral oophorectomy, hysterectomy, or medically documented ovarian insufficiency, within the 6 months prior to randomization. Abstinence may be considered appropriate if required by a specific regional Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and / or national regulations (the reliability of abstinence needs to be evaluated in terms of the duration of the clinical study and the patient's preferred normal lifestyle). • Use of highly effective non-hormonal medical contraception (bilateral ductal obstruction, partner's vasectomy, or intrauterine device) for 3 months prior to screening. • Highly effective methods of contraception at the barrier, or highly effective methods of contraception using hormonal preparations (oral, vaginal, or transdermal hormonal preparations combining estrogen and progestogen, with suppression of ovulation; or oral, injectable, or implantable progestogen-only hormonal preparations, with suppression of ovulation or the endogenous hormone-releasing system). Hormonal contraception must be initiated at least one month prior to screening.

[0051] Exclusion criteria: Patients who meet any of the following exclusion criteria are not eligible for randomization to this study: 1) A history or presence of other associated liver diseases, including the following: a) Positive for anti-hepatitis A virus (HAV) immunoglobulin M (IgM) antibody, or positive for hepatitis B surface antigen (HBsAg), or positive for anti-hepatitis C virus (HCV) ribonucleic acid (RNA) (tested in screening for known cured HCV infection or HCV Ab positivity) b) Primary sclerosing cholangitis (PSC) c) Alcoholic liver disease (ALD) d) When a patient is being treated for overlapping AIH with PBC that cannot be explained solely by autoimmune hepatitis (AIH) or an inadequate response to UDCA, or when there is suspicion and evidence of overlapping AIH features. e) Non-alcoholic steatohepatitis (NASH) f) Gilbert's syndrome (exclusion due to the interpretability of bilirubin levels) g) Known history of alpha-1 antitrypsin deficiency 2) Clinically significant hepatic decompensation, including the following: a) History of liver transplantation, current listing on the liver transplant list, and current Model for End-Stage Liver Disease-sodium (MELD-Na) score ≥ 12, linked to liver damage. b) Patients with cirrhosis / portal hypertension, including a history of known esophageal varices, ascites, variceal bleeding, or related interventions (e.g., insertion of variceal bands or transjugular intrahepatic portosystemic shunt [TIPS]), and the presence or history of hepatic encephalopathy, spontaneous bacterial peritonitis, or hepatocellular carcinoma. c) Hepatorenal syndrome (Type I or Type II) 3) Medical conditions that can cause non-hepatic elevation of ALP (e.g., Paget's disease) or shorten life expectancy to <2 years, including known cancers. 4) Patients who have tested positive for human immunodeficiency virus (HIV) type 1 or 2 during screening, or patients who are known to have tested positive for HIV. 5) Evidence of any other unstable or untreated, clinically significant, immunological, endocrine, hematological, gastrointestinal, neurological, or psychiatric disorder, as assessed by the principal investigator. 6) Other clinically significant medical conditions that are not well controlled or are expected to change the need for medication during the study. 7) A history of alcohol abuse, defined as consuming more than 30g of pure alcohol per day for men, or more than 20g of pure alcohol per day for women, or abuse of other substances within one year prior to the screening visit (SV1). 8) For female patients: They are known to be pregnant, have a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or are breastfeeding. 9) The following medications are prohibited as specified below: a) Two months prior to randomization and throughout (until the final study visit): fibrates and glitazone b) Randomization 3 months prior and throughout the study (until the final study visit): obeticholic acid (OCA), azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide, and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproate, isoniazid or nitrofurantoin) c) Randomization 12 months prior and throughout the study (until the final study visit): antibodies or immunotherapies directed against interleukin (IL) or other cytokines or chemokines 10) Patients who are currently participating in, planning to participate in, or have participated in a clinical trial drug study or medical device study containing an active substance within 30 days prior to screening or within the longer of 5 half-lives; patients previously exposed to seladelpar are excluded 11) Patients with prior exposure to elafibranor 12) Serum values of alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) > 5 × ULN 13) Serum albumin < 3.0 g / dL 14) Patients with severe progression according to the Rotterdam criteria (TB > ULN and albumin < LLN) 15) Serum value of international normalized ratio (INR) > 1.3 due to altered liver function 16) Serum value of creatine phosphokinase CPK > 2 × ULN 17) Screening serum creatinine > 1.5 mg / dL 18) Marked kidney diseases including nephrotic syndrome, chronic kidney disease (defined as patients with kidney impairment or estimated glomerular filtration rate [eGFR] < 60 mL / min / 1.73 m 2 calculated by diet modification in kidney disease (MDRD)) 19) Platelet count < 150 × 103 / μL 20) Alpha-fetoprotein (AFP) > 20 ng / mL on the fourth-phase liver computed tomography (CT), or magnetic resonance imaging (MRI) suggesting the presence of liver cancer

[0052] Randomization Patients who meet all eligibility criteria will be randomized in a 2:1 ratio to one of the following groups: • Elafibranol 80mg ·placebo

[0053] A centralized randomization system (Interactive Voice / Web Response System (IXRS)) will be used.

[0054] Randomization is stratified at baseline (V1) by two factors: ALP > 3 × ULN or bilirubin > ULN, and mean Worst Itch score ≥ 4 over the 14 days prior to baseline. During the LTE period, all patients will receive elafibranol 80 mg once daily for up to 5 years.

[0055] To ensure enrollment of a reasonable proportion of patients at substantial risk of a moderate disease stage in long-term clinical outcomes, a minimum of 15 patients (at least 10% of all randomized patients) must have TB above ULN or albumin below LLN, and a minimum of 30 patients (at least 20% of all randomized patients) must have TB above 0.6 × ULN.

[0056] Key evaluation criteria The primary endpoint was the response to treatment at 52 weeks, defined as ALP < 1.67 × ULN, TB ≤ ULN, and ALP decrease ≥ 15%.

[0057] Secondary evaluation items Response to ALP standardization-based treatment at 52 weeks Changes in pruritus from baseline to 52 weeks using the PBC Worst Itch NRS score.

[0058] Other secondary outcome measures: 1) Changes in ALP from baseline at 4, 13, 26, 39, and 52 weeks. 2) ALP response, defined as a 10%, 20%, and 40% decrease in ALP from baseline at 52 weeks. 3) Response to treatment at 52 weeks, as follows: a) ALP < 1.5 × ULN, ALP decrease ≥ 40%, and TB ≤ ULN b) ALP < 3 × ULN, AST < 2 × ULN, and TB ≤ 1 mg / dL (Paris I) c) ALP ≤ 1.5 × ULN, AST ≤ 1.5 × ULN, and TB ≤ 1 mg / dL (Paris II) d) TB response rate of 15% change e) Standardization of abnormal TB and / or albumin (Rotterdam) f)TB≦0.6×ULN g) ALP ≤ 1.67 × ULN, and TB ≤ 1 mg / dL h) No worsening of TB at 52 weeks with a TB ≤ ULN level, or no increase from baseline of 0.1 × ULN at 52 weeks. 4) PBC risk score at 52 weeks: United Kingdom (UK) PBC score and GLOBE score 5) Bilirubin-normalized response at 52 weeks (TB ≤ ULN) 6) Albumin-standardized response at 52 weeks 7) Changes in bile duct injury and liver function from baseline to 52 weeks, as measured by AST, ALT, gamma-glutamyltransferase (GGT), 5'NT, total bilirubin and conjugated bilirubin, albumin, INR, and ALP fraction (liver). 8) Changes in inflammatory biomarkers from baseline to 52 weeks, as measured by high-sensitivity C-reactive protein (hsCRP), fibrinogen, haptoglobin, and tumor necrosis factor-alpha (TNF-α). 9) Changes in immune response from baseline to 52 weeks, as measured by immunoglobulin G (IgG) and IgM. 10) Changes from baseline to 52 weeks in biomarkers, non-invasive and invasive measures of liver fibrosis, as measured by enhanced liver fibrosis (ELF) (HA, PIINP, TIMP-1), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor beta (TGF-β), cytokeratin-18 (CK-18) (M65 and M30), Pro-C3, and liver stiffness measured by transient elastography (TE) (continued). 11) Changes in lipid parameters from baseline to 52 weeks, as measured by total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), calculated VLDL-C, and TG. 12) Changes in fasting plasma glucose (FPG) from baseline to 52 weeks 13) Changes from baseline to 52 weeks in bile acids and biomarkers of bile acid synthesis, as measured by bile acids, serum 7α-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF-19). 14) Percentage of patients who did not experience worsening of pruritus from baseline to 52 weeks, as measured by the PBC Worst Itch NRS. 15) Response to the PBC Worst Itch NRS, defined as a decrease of at least 30% from baseline in NRS at 52 weeks in patients with baseline NRS ≥ 4. 16) Changes in 5D-Itch from baseline to 52 weeks 17) Changes from baseline to 52 weeks in Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 7a 18) Changes in the Epworth Sleepiness Scale (ESS) from baseline to 52 weeks 19) Changes from baseline to 52 weeks in PBC-40 20) Changes in health utility from baseline to 52 weeks as measured by EQ-5D-5L 21) Initiation of a clinical outcome described as a composite endpoint consisting of the following: a) Progression of non-cirrhotic patients to histological cirrhosis at baseline. b) For patients with baseline MELD-Na ≤ 12 and MELD-Na > 14 c) liver transplantation d) Uncontrolled ascites requiring treatment e) Hospitalization for any of the following new onsets or relapses: i) Varicose vein bleeding ii) Hepatic encephalopathy as defined by a West-Haven / Conn score of 2 or higher. iii) Spontaneous bacterial peritonitis f) death 22) Change from baseline in histological scores a) Fibrosis staging according to Nakanuma scoring b) Bile duct score c) Cholangitis activity d) Interface hepatitis activity e) Disease stage (sum of fibrosis stages based on Nakanuma score and bile duct score) f) Other exploratory scores (fibrosis, portal venitis, bile duct reflex, cholestasis, pericanal fibrosis using modified Ishak scoring) 23) Safety and tolerability as evaluated below a) Serious adverse events (SAEs), adverse events (AEs), adverse events of particular interest (AESIs), physical examination, vital signs, medical history, electrocardiogram (ECG) b) Biochemistry and hematology c) Liver markers d) Renal biomarkers (including urine tests) e) Other biochemical safety markers f) Histological examination 24) PK evaluated by measuring the concentrations of ellafibranol and GF1007 in plasma

[0059] Elafibranol is expected to induce a significant decrease in plasma ALP from baseline to the end of treatment compared to placebo in patients with UDCA intolerance. In addition, elafibranol is expected to induce a significant improvement in at least one of the secondary endpoints in these patients.

Claims

1. A pharmaceutical composition comprising compound 2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid (ellafibranol) or a pharmaceutically acceptable salt thereof for use in treating primary biliary cholangitis (PBC) in patients intolerant to treatment with ursodeoxycholic acid (UDCA).

2. The pharmaceutical composition for use according to claim 1, wherein the patient has a contraindication to being treated with UDCA, or is unable to comply with UDCA administration due to a serious adverse event(s) or serious condition(s).

3. The pharmaceutical composition for use according to claim 2, wherein patients who are contraindicated to treatment with UDCA are: pregnant women; patients with complete bile duct obstruction of extrahepatic origin; patients with extensive intrahepatic obstruction; patients with calcified cholesterol stones, radiopaque stones or radiopaque bile pigment stones that cause gallbladder dysfunction; patients with acute inflammation of the gallbladder or biliary tract; patients with frequent biliary colic; or patients who are hypersensitive to Ursodiol® or any component of the formulation.

4. A pharmaceutical composition for use according to claim 2, wherein a patient who is unable to comply with UDCA medication due to a serious adverse event(s) or serious condition(s) has an adverse event or condition selected from leukopenia; ulcer; immunosuppression and resulting fever; uncontrollable or otherwise inexplicable diarrhea; pneumonia; pharyngitis; otitis media; bronchopneumonia; bronchitis; oral moniliitis; abscess formation; dysuria or watery diarrhea; gastric burning; tubulointerstitial nephritis; leukocytoclastic vasculitis; skin rash; thrombocytopenia; recurrent wheezing chest, cough or interstitial lung disease; hepatic complications; convulsions; nausea; vomiting; sleep disturbances; or diabetes mellitus.

5. A pharmaceutical composition for use according to any one of claims 1 to 4, which is a tablet, an injection suspension, a gel, an oil, a pill, a suppository, a powder, a gel cap, a capsule, an aerosol, or a long-release and / or sustained-release dosage form.

6. A pharmaceutical composition for use according to any one of claims 1 to 5, for oral administration once daily.

7. A pharmaceutical composition for use according to any one of claims 1 to 6, wherein elafibranol or a pharmaceutically acceptable salt thereof is administered in doses varying between 10 mg and 200 mg per dose.

8. A pharmaceutical composition for use according to any one of claims 1 to 7, wherein elafibranol or a pharmaceutically acceptable salt thereof is administered in doses varying between 80 mg and 120 mg per administration.

9. A pharmaceutical composition for use according to claim 8, comprising a tablet containing 80 mg of elafibranol.

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