Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Lanifibranor in Adults with Non-Cirrhotic Non-Alcoholic Steatohepatitis and Fibrosis Stages F2/F3

The primary objectives of this Phase 3 study are to evaluate the efficacy of **lanifibranor** compared to placebo in achieving resolution of non-alcoholic steatohepatitis (NASH) and improvement of liver fibrosis, as assessed by liver histology, during the double-blind placebo-controlled (DBPC) period. Additionally, the study aims to assess the safety profile of lanifibranor beyond the DBPC period during the double-blind active treatment extension (ATE) period. These objectives are clinically relevant as they address the potential of lanifibranor to modify disease progression in patients with NASH, a condition associated with significant morbidity and mortality due to liver-related complications.

The secondary objectives during the DBPC period include:

• Assessing the effect of lanifibranor compared to placebo on NASH resolution without worsening of fibrosis.
• Evaluating the effect of lanifibranor compared to placebo on the improvement of fibrosis without worsening of NASH.

The clinical trial involves a total of **1114 participants** diagnosed with **non-alcoholic steatohepatitis (NASH)**. The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on their ability to understand the study's nature and comply with its procedures, as well as their willingness to provide informed consent. The trial includes individuals with a histological diagnosis of NASH, confirmed by liver biopsy, and requires participants to have a stable weight for six months prior to screening. Lifestyle considerations include a history of at least one unsuccessful attempt to reduce body weight through diet and/or exercise within the past six years, and participants must agree to follow lifestyle modification recommendations throughout the study. The trial population is characterized by a stable use of certain medications, such as antidiabetic treatments, vitamin E, statins, and anti-obesity treatments, with no significant changes in dosage allowed prior to the baseline visit. The sponsor has not provided specific information regarding the general health status of the participants beyond the inclusion criteria.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy and safety of **lanifibranor** in adult patients with **non-alcoholic steatohepatitis (NASH)** and liver fibrosis stages F2 or F3. The trial is structured into two main periods: a double-blind placebo-controlled (DBPC) period, followed by an active treatment extension (ATE) period. The primary objective during the DBPC period is to assess the effect of lanifibranor on NASH resolution and fibrosis improvement, as determined by liver histology. The ATE period aims to evaluate the safety of lanifibranor beyond the DBPC period. The trial is expected to last until December 2026, with participant recruitment having commenced in January 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological diagnosis of NASH, and stable medication use. The main cohort requires a diagnosis of NASH with specific scores for steatosis, activity, and fibrosis, while an exploratory cohort includes patients with slightly different criteria. Following the screening, participants will attend regular follow-up visits to monitor their health and the effects of the treatment. The end-of-study visit will conclude the participant's involvement, assessing the primary and secondary endpoints, including NASH resolution and fibrosis improvement at Week 72.

The expected length of participant involvement is approximately 72 weeks, with conditions for early termination including significant adverse events or non-compliance with study procedures. Participants are required to maintain stable medication doses and lifestyle modifications throughout the study. The trial's primary endpoint is the resolution of NASH and improvement of fibrosis at Week 72, defined by specific NASH CRN scores. Secondary endpoints include the resolution of NASH without worsening fibrosis and improvement of fibrosis without worsening NASH. The study is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants.

The clinical trial involves the administration of **Lanifibranor**, an experimental medication, which is a chemical compound with the active substance name **LANIFIBRANOR**. It is provided in the form of a **tablet** and is intended for **oral use**. The maximum daily dose is 1200 mg, and the treatment period can extend up to 168 days. Lanifibranor is identified by the sponsor product code IVA337 and is manufactured by INVENTIVA. The primary objective of the trial is to evaluate the efficacy and safety of Lanifibranor in adult patients with non-cirrhotic non-alcoholic steatohepatitis (NASH) and fibrosis stages 2 and 3. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule.

In addition to the experimental treatment, a **placebo** identified as PL1 is used as a comparator in the double-blind, placebo-controlled phase of the study. The placebo is composed of inactive ingredients including lactose monohydrate, microcrystalline cellulose, pre-gelatinized starch, magnesium stearate, Opadry™ II 85F18422, and purified water. The placebo is also administered in a form that mimics the experimental medication to maintain the study's blinding integrity. The placebo is administered with the same frequency and route as Lanifibranor to ensure consistency in the trial's methodology.

The efficacy of lanifibranor in the treatment of non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis stages F2 and F3 will be assessed in a randomized, double-blind, placebo-controlled, multicenter Phase 3 clinical trial. The primary endpoint for efficacy evaluation is the resolution of NASH and improvement of fibrosis at Week 72. This is defined by the NASH Clinical Research Network (CRN) scores, specifically a ballooning score of 0, inflammation score of 0 to 1, and a fibrosis score showing a decrease of at least one stage compared to Baseline.

Secondary endpoints include the resolution of NASH without worsening of fibrosis at Week 72, characterized by a ballooning score of 0, inflammation score of 0 to 1, and no increase in fibrosis score from Baseline. Additionally, improvement of fibrosis without worsening of NASH at Week 72 will be evaluated, defined by a decrease in the NASH CRN fibrosis score by at least one stage from Baseline, with no increase in scores for ballooning, inflammation, or steatosis. These endpoints will be assessed through liver histology, providing a comprehensive evaluation of the treatment's impact on liver health.