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 )

This Phase 3 study is conducted to evaluate lanifibranor in adults with NASH and liver fibrosis histological stage F2 or F3

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)

Eligibility Criteria:
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:

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. No qualitative change in 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): for at least 3 months
   2. Vitamin E (if at a dose ≥400 IU/day): for at least 6 months
   3. Statins: for at least 3 months
4. No qualitative change in dose for all other chronically administered drugs 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. AST\<0.6 ULN if the liver biopsy has to be performed in the scope of the study
8. Abnormal synthetic liver function as defined by Screening central laboratory evaluation
9. Haemoglobin \<110 g/L (11 g/dL) for females and \<120 g/L (12 g/dL) for males
10. Patient currently receiving any approved treatment for NASH or obesity
11. Current or recent history (\<5 years) of significant alcohol consumption
12. 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:
13. HbA1c \>9% at Screening
14. Diabetes mellitus other than type 2
15. Current treatment with insulin
16. Treatment with PPAR-gamma agonists (thiazolidinediones \[TZDs\]) 12 months before screening or historical biopsy.

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

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