Lanifibranor for Nonalcoholic Steatohepatitis (NASH)

(NATiV3 Trial)

Recruiting at 453 trial locations

Overseen By Jacques Benun

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Inventiva Pharma

Must be taking: GLP1 receptor agonists, SGLT2 inhibitors

Must not be taking: Insulin, PPAR-gamma agonists

Disqualifiers: Chronic liver disease, Cirrhosis, HIV, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

1000 Participants Needed

Trial Summary

What is the purpose of this trial?

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

Will I have to stop taking my current medications?

The trial requires that you do not change the dose of your current medications, including antidiabetic treatments, vitamin E, and statins, for at least 3 months before joining. If you are on any other long-term medications, their doses should also remain unchanged for 3 months prior to the trial.

What evidence supports the effectiveness of the drug Lanifibranor for treating nonalcoholic steatohepatitis (NASH)?

Lanifibranor is a drug that targets specific pathways involved in NASH, and studies have shown it can reduce liver inflammation and improve liver health in patients with NASH. It works by activating certain receptors (PPARs) that help regulate metabolism and inflammation, which are key factors in the disease. ^{1 2 3 4 5}

Is Lanifibranor safe for humans?

Lanifibranor has been studied for safety in humans, particularly in a 24-week trial for nonalcoholic steatohepatitis (NASH), and the study aimed to assess both its safety and effectiveness. While specific safety outcomes are not detailed in the provided abstracts, the fact that it was evaluated in a controlled clinical trial suggests that its safety profile was considered acceptable for study in humans. ^{1 2 3 5 6}

How is the drug Lanifibranor unique in treating NASH?

Lanifibranor is unique because it is a pan-PPAR agonist, meaning it targets all three types of peroxisome proliferator-activated receptors (PPARα, β/δ, and γ), which helps address multiple aspects of NASH, including metabolism, inflammation, and fibrosis. ^{1 3 5 7 8}

Research Team

Arun J Sanyal, MD

Principal Investigator

VCU Health, Gastroenterology Hepatology and Nutrition, 1200 West Broad Street, Richmond VA23298, USA

Sven Francque, MD

Principal Investigator

Division of Gastroenterology and Hepatology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium

Eligibility Criteria

Adults diagnosed with Non-Alcoholic Steatohepatitis (NASH) and liver fibrosis stages F2 or F3 can join. They must have stable doses of certain diabetes medications for 3 months, a steatosis score ≥1, activity score A3 or A4, and agree to a liver biopsy. Excluded are those with other liver conditions like cirrhosis, alcoholic liver disease, chronic hepatitis B/C, Wilson's disease, iron overload, prior transplant or who had weight loss surgery.

Inclusion Criteria

I am 18 years old or older.

My medications have been the same for the last 3 months.

Would you be willing to undergo a liver biopsy in order to determine your eligibility for the study?

Exclusion Criteria

I have no liver conditions other than NASH or fatty liver.

I have had weight loss surgery.

Do you consume more than 7 alcoholic drinks per week?

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double-blind Placebo-controlled (DBPC) Treatment

Participants receive either lanifibranor or placebo to assess safety and efficacy on NASH resolution and fibrosis improvement

72 weeks

Regular visits for assessments and monitoring

Active Treatment Extension (ATE)

Participants continue receiving lanifibranor to assess long-term safety

48 weeks

Regular visits for safety monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• IVA337
• Lanifibranor
• Placebo

Trial Overview The trial is testing Lanifibranor (IVA337), comparing it against a placebo in adults with NASH and significant scarring of the liver (fibrosis). Participants will be randomly assigned to receive either the drug or placebo to assess its effectiveness and safety.

Participant Groups

Group I: Lanifibranor (IVA 337) (800 mg/day) Experimental Treatment 2 Interventions

2 Lanifibranor tablets 400mg + 1 Placebo to match tablet with food --\> once a day (quaque die, QD)

Group II: Lanifibranor (IVA 337) (1200 mg/day) Experimental Treatment 1 Intervention

3 Lanifibranor tablets 400mg with food --\> once a day (quaque die, QD)

Group III: Matching placebo Placebo Group 1 Intervention

3 Placebo to match tablets with food --\> once a day (quaque die, QD)

Lanifibranor is already approved in United States, European Union for the following indications:

Approved in United States as Lanifibranor for:

• Non-alcoholic steatohepatitis (NASH) with fibrosis stages F2 and F3

Approved in European Union as Lanifibranor for:

• Non-alcoholic steatohepatitis (NASH) with fibrosis stages F2 and F3

Who Is Running the Clinical Trial?

Inventiva Pharma

Lead Sponsor

Trials

8

Recruited

11,600+

Findings from Research

The NATIVE study is a Phase 2b clinical trial assessing the safety and efficacy of lanifibranor, a panPPAR agonist, in treating non-cirrhotic non-alcoholic steatohepatitis (NASH) over 24 weeks, involving adult patients with specific histological criteria.

The primary goal is to achieve a 2-point reduction in the SAF histological score, indicating improved liver inflammation and ballooning without worsening fibrosis, highlighting lanifibranor's potential to address multiple aspects of NASH pathology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study. Sven M, F., Pierre, B., Manal F, A., et al.[2021]

In a systematic review of 10 studies involving patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), treatment with 4 mg saroglitazar significantly reduced liver enzymes, including alanine transaminase (ALT) and aspartate transaminase (AST), indicating improved liver function.

Saroglitazar also led to significant improvements in liver stiffness and metabolic parameters such as glycated hemoglobin, total cholesterol, and triglycerides, suggesting it is an effective and safe treatment option for managing NAFLD and NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of saroglitazar in the treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Bandyopadhyay, S., Samajdar, SS., Das, S.[2023]

Elafibranor, a PPAR-α and PPAR-δ agonist, shows promise in treating nonalcoholic steatohepatitis (NASH) by improving insulin resistance and normalizing serum lipids, which are crucial for managing the disease.

While elafibranor has a favorable safety profile, it can cause reversible increases in serum creatinine, which may limit its use in patients with existing kidney issues, highlighting the need for personalized treatment approaches based on the stage of NAFLD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Westerouen Van Meeteren, MJ., Drenth, JPH., Tjwa, ETTL.[2020]

Elafibranor treatment in a mouse model of NASH significantly reduced liver fat (steatosis) and inflammation, and prevented the progression of liver fibrosis, suggesting its potential efficacy as a treatment for NASH.

The study found that the disease pathways affected by elafibranor in mice closely resemble those in human NASH patients, indicating that while elafibranor shows promise, it may be most effective when used alongside other treatments due to species differences in drug response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men. van den Hoek, AM., Verschuren, L., Caspers, MPM., et al.[2021]

In a phase 2b trial with 247 patients suffering from nonalcoholic steatohepatitis (NASH), the 1200 mg dose of lanifibranor significantly improved disease activity, as indicated by a decrease of at least 2 points in the SAF-A score without worsening fibrosis, compared to placebo (55% vs. 33%).

Lanifibranor also showed promising results in secondary outcomes, including resolution of NASH and improvement in fibrosis, with a low dropout rate for adverse events, suggesting it is a safe and effective treatment option for NASH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. Francque, SM., Bedossa, P., Ratziu, V., et al.[2022]

In the LIVIFY trial involving 120 patients with suspected fibrotic NASH, vonafexor significantly reduced liver fat content after 12 weeks, with the 100 mg and 200 mg doses showing reductions of -6.3% and -5.4% respectively, compared to -2.3% in the placebo group.

Vonafexor was found to be safe, leading to improvements in liver enzymes, body weight, and even renal function, although mild to moderate pruritus was reported in some patients, indicating manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH. Ratziu, V., Harrison, SA., Loustaud-Ratti, V., et al.[2023]

In a 52-week trial involving 276 patients with nonalcoholic steatohepatitis (NASH), elafibranor 120 mg daily showed a significant improvement in resolving NASH without worsening fibrosis compared to placebo, particularly in patients with moderate to severe NASH.

Elafibranor was well tolerated, with no significant weight gain or cardiac events, although it did cause a mild and reversible increase in serum creatinine levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Ratziu, V., Harrison, SA., Francque, S., et al.[2022]

Obeticholic acid (OCA) has shown both safety and efficacy in treating nonalcoholic steatohepatitis (NASH) in phase 3 trials, leading to a new drug application for its approval, which could significantly impact treatment options for this condition.

Elafibranor, on the other hand, did not demonstrate efficacy in its phase 3 trial but is undergoing further assessment, highlighting the ongoing need for effective therapies as the prevalence of NASH increases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging therapies for the treatment of nonalcoholic steatohepatitis: A systematic review. Guirguis, E., Grace, Y., Bolson, A., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study. [2021]

2. France pubmed.ncbi.nlm.nih.gov

Effects of saroglitazar in the treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). [2020]

4. England pubmed.ncbi.nlm.nih.gov

Beneficial effects of elafibranor on NASH in E3L.CETP mice and differences between mice and men. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Emerging therapies for the treatment of nonalcoholic steatohepatitis: A systematic review. [2021]