Placebo-controlled, Proof-of-concept Study to Evaluate the Safety and Efficacy of Lanifibranor Alone and in Combination With SGLT2 Inhibitor EmpaGliflozin in patiEnts With NASH and Type 2 Diabetes Mellitus

Inclusion criteria

• Male or female, aged ≥ 18 years at the time of signing informed consent
• Diagnosis of NASH, based on histology or cT1≥875ms assessed by LiverMultiScan or cT1≥825ms assessed by LiverMultiScan and hepatic fat content ≥ 10% assessed by MRI-PDFF at screening
• HbA1c at screening ≥ 7.0 and ≤ 10.0%, on diet alone, or on metformin and/or dipeptidyl peptidase 4 inhibitor (DPP-IVi) therapy. Both with doses to be stable for 3 months
• Negative pregnancy test at Screening for females of childbearing potential or at least two-year post-menopausal.

Exclusion criteria

Liver-related:

• Documented causes of chronic liver disease other than NASH
• Histologically documented liver cirrhosis (fibrosis stage F4)
• History or current diagnosis of hepatocellular carcinoma (HCC)
• History of or planned liver transplant
• Documented history of human immunodeficiency virus (HIV) infection
• ALT or AST > 5 × upper limit of normal (ULN)
• Abnormal liver function as defined by central laboratory evaluation:

Albumin < LLN INR ≥ 1.3 (unless patient is on anticoagulants) Total bilirubin level ≥ 1.5 mg/dL (25.7 µmol/L) (patients with a documented history of Gilbert's syndrome can be enrolled if direct bilirubin is ≤ 0.45 mg/dL (7.7 μmol/L) )

• Hemoglobin < 110 g/L (11 g/dL) for females and < 120 g/L (12 g/dL) for males
• WBC < LLN. A lower count is acceptable in patients with benign ethnic neutropenia, if considered to be clinical insignificant by the investigator
• Platelet count < 140,000/µL
• ALP > 2 × ULN
• Patient currently receiving any approved treatment for NASH or obesity
• Current or recent history (< 5 years) of significant alcohol consumption
• Administration of drugs known to produce hepatic steatosis in the 6 months prior to Screening.

Diabetes related:

• Diabetes mellitus other than type 2
• Diabetic ketoacidosis at Screening
• Current treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA), insulin or sulfonylurea or treatment within the last 3 months prior to Screening
• Patients on pioglitazone in the last 12 months prior to Screening.
• Patients on metformin, DPP-IVi, thiazide or furosemide diuretics, beta-blockers, or other chronic medications with known adverse effects on glucose tolerance levels, unless on stable doses in last 3 months

Obesity related:

• BMI>45 kg/m2 at screening
• Introduction of an anti-obesity drug or restrictive bariatric surgery in the past 12 months prior to Screening or planned bariatric surgery through Week 24.

Cardiovascular related:

• History of or current unstable cardiac dysrhythmias 22. Unstable heart failure 23. Uncontrolled hypertension 24. Stroke or transient ischemic attack

General safety:

• Significant systemic or major illnesses other than liver disease and pulmonary disease, organ transplantation, serious psychiatric disease, that, in the opinion of the investigator, would preclude treatment with lanifibranor and/or adequate follow up 26. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value < 60 mL/min 27. Concomitant treatment with PPAR-⍺ agonists (fibrates) 28. Patients on Vitamin E at doses ≥ 400 IU/day; doses of ≥ 400 IU/day are allowed when no qualitative change in dose for 6 months prior to Screening 29. Have a known hypersensitivity to any of the IMPs 30. Previous exposure to lanifibranor or empagliflozin 31. Present pregnancy/lactation 32. Metallic implant of any sort that prevents MRI examination 33. Participation in any clinical trial of an approved or non approved investigational medicinal product/device within 3 months from Screening or five half-lives of the investigational drug from Screening.