A Phase 3 Study Evaluating Long-term Efficacy and Safety of Lanifibranor in Adult Patients With (NASH) and Fibrosis 2 (F2)/Fibrosis 3 (F3) Stage of Liver Fibrosis (NATiV3)

Primary objectives

This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis stage 2 or 3 and consists of 2 parts - Part 1 and Part 2, with the following primary objectives:

Part 1 To assess the effect of lanifibranor compared to placebo on NASH resolution and improvement of fibrosis assessed by liver histology.

Part 2 To assess the effect of lanifibranor compared to placebo on delaying NASH disease progression measured by a composite endpoint that includes progression to cirrhosis, liver-related clinical outcome events, or all-cause death.

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 compared to placebo on other key histological features of NASH
• To assess the effect of lanifibranor compared to placebo on NASH resolution and improvement of fibrosis in diabetic patients
• To assess the effect of lanifibranor compared to placebo on liver function tests
• To assess the effect of lanifibranor compared to placebo on glycaemic parameters
• To assess the effect of lanifibranor compared to placebo on lipid parameters
• To assess the effect of lanifibranor compared to placebo on liver stiffness
• To assess the effect of lanifibranor compared to placebo on health-related quality of life
• To assess the long-term safety (up to 7 years) of lanifibranor
• To assess population PK modeling of lanifibranor using sparse sampling scheme

Inclusion Criteria:

1. Male or female, aged ≥18 years at the time of signing informed consent
2. Upon central biopsy reading process: diagnosis of NASH according to the Steatosis-Activity-Fibrosis (SAF):
   1. Steatosis score ≥1
   2. Activity score: A3 or A4
   3. Fibrosis score: F2 or F3
3. Stable dose for the drugs listed below:
   1. Antidiabetic treatment if glucagon-like peptide-1 receptor agonists (GLP1 receptor agonists) or sodium-glucose co-transporter-2 inhibitors (SGLT2 inhibitors): Stable dose for at least 3 months
   2. Vitamin E (if at a dose ≥400 IU/day): Stable dose for at least 6 months
   3. Statins: Stable dose for at least 3 months
4. All other chronically administered drugs must be stable for at least 3 months prior to Screening
5. Weight stable for 6 months prior to Screening and between the qualifying liver biopsy and Baseline (no more than 5% change for both periods)
6. 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:

1. Documented causes of chronic liver disease other than NASH
2. Histologically documented liver cirrhosis (fibrosis stage F4)
3. History or current diagnosis of hepatocellular carcinoma HCC
4. History of or planned liver transplant
5. Positive human immunodeficiency virus (HIV) serology
6. ALT or AST >5 × ULN
7. Abnormal synthetic liver function as defined by Screening central laboratory evaluation
8. Haemoglobin <110 g/L (11 g/dL) for females and <120 g/L (12 g/dL) for males
9. Patient currently receiving any approved treatment for NASH or obesity
10. Current or recent history (<5 years) of significant alcohol consumption
11. 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:

12. HbA1c >9% at Screening
13. Diabetes mellitus other than type 2
14. Current treatment with insulin
15. Previous or current treatment with PPAR-gamma agonists (thiazolidinediones [TZDs])

    Obesity related:

16. 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:

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

    General safety:

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