A Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With (NASH) and Fibrosis Stages F2 and F3 ( NATiV3 )

Primary objectives

This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage F2 or F3 and consists of 2 sequential parts - an initial double-blind placebo-controlled (DBPC) period (Part A) followed by a double-blind active treatment extension (ATE) period (Part B), with the following primary objectives:

Part A To assess the safety and efficacy of lanifibranor compared to placebo on 'NASH resolution and improvement of fibrosis' assessed by liver histology.

Part B To assess the safety of lanifibranor beyond the DBPC period. Secondary objectives

Key secondary objectives of Part 1:

• To assess the effect of lanifibranor compared to placebo on NASH resolution and no worsening of fibrosis
• To assess the effect of lanifibranor compared to placebo on improvement of fibrosis with no worsening of NASH

Other secondary objectives of both Part 1 and Part 2:

• To assess the effect of lanifibranor on other key histological features of NASH (only for DBPC period)
• To assess the effect of lanifibranor on NASH resolution and improvement of fibrosis in diabetic patients (only for DBPC period)
• To assess the effect of lanifibranor on liver tests
• To assess the effect of lanifibranor on glycaemic parameters
• To assess the effect of lanifibranor on lipid parameters
• To assess the effect of lanifibranor on liver stiffness and steatosis assessed by elastography.
• To assess the effect of lanifibranor on health-related quality of life
• To assess the safety of lanifibranor
• To assess population PK modeling through plasma levels of lanifibranor using sparse sampling scheme (only for DBPC period)

Prescreening Criteria:

• Diagnosed with NASH on prior liver biopsy
• Type 2 diabetes with high waist circumference or obesity or hepatic steatosis on ultrasound
• At least 3 of the components of metabolic syndrome

Inclusion criteria

• Male or female, aged ≥18 years at the time of signing informed consent
• Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF):

• Steatosis score ≥1
• Activity score: A3 or A4
• Fibrosis score: F2 or F3
• No qualitative change in dose for the drugs listed below:

• Antidiabetic treatment if glucagon-like peptide-1 receptor agonists (GLP1 receptor agonists) or sodium-glucose co-transporter-2 inhibitors (SGLT2 inhibitors): for at least 3 months
• Vitamin E (if at a dose ≥400 IU/day): for at least 6 months
• Statins: for at least 3 months
• No qualitative change in dose for all other chronically administered drugs for at least 3 months prior to Screening
• Weight stable for 6 months prior to Screening and between the qualifying liver biopsy and Baseline (no more than 5% change for both periods)
• Negative serum pregnancy test at study Screening for females of childbearing potential confirmed by central laboratory. Females of childbearing potential must practice a consistent and proper use of highly effective method of contraception throughout the study and for 1 month after treatment discontinuation.

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
• Positive human immunodeficiency virus (HIV) serology
• ALT or AST >5 × ULN
• AST<0.6 ULN if the liver biopsy has to be performed in the scope of the study
• Abnormal synthetic liver function as defined by Screening central laboratory evaluation
• Haemoglobin <110 g/L (11 g/dL) for females and <120 g/L (12 g/dL) for males
• Patient currently receiving any approved treatment for NASH or obesity
• Current or recent history (<5 years) of significant alcohol consumption
• Treatment with drugs that may cause non-alcoholic fatty liver disease (NAFLD) administered for at least 2 weeks within 12 months prior to qualifying liver biopsy

Glycaemia related:

• HbA1c >9% at Screening
• Diabetes mellitus other than type 2
• Current treatment with insulin
• Treatment with PPAR-gamma agonists (thiazolidinediones [TZDs]) 12 months before screening or historical biopsy.

Obesity related:

• Bariatric surgery: Restrictive procedures are allowed, if performed >6 months prior to the qualifying liver biopsy; malabsorptive procedures and procedures combining both restrictive and malabsorptive methods are not allowed within 5 years of the qualifying liver biopsy.

Cardiovascular related:

• History of heart failure with reduced left ventricular ejection fraction (LVEF)
• Atrial fibrillation requiring anticoagulation
• Unstable heart failure
• Uncontrolled hypertension at Screening (values >160/100 mm Hg)

General safety:

• Women currently breastfeeding
• Previous exposure to lanifibranor
• Participation in any clinical trial investigational medicinal product/device within 3 months from Screening or 5 half-lives from Screening, whichever is longer
• Concomitant treatment with PPAR-alpha agonists (fibrates)