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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called lanifibranor for individuals with nonalcoholic steatohepatitis (NASH), a liver condition causing inflammation and damage due to fat buildup. The study aims to determine if lanifibranor can improve liver health in those with NASH and liver fibrosis, indicating some scarring. Participants will receive either lanifibranor or a placebo (a pill with no active medicine) to compare effects. Suitable candidates have been diagnosed with NASH, have type 2 diabetes with obesity or high waist circumference, and exhibit at least three signs of metabolic syndrome, such as high blood pressure or cholesterol. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment for NASH.

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.

Is there any evidence suggesting that lanifibranor is likely to be safe for humans?

Research has shown that lanifibranor has been tested in earlier studies for its safety in treating nonalcoholic steatohepatitis (NASH). One study examined two doses of lanifibranor, 800 mg and 1200 mg, in adults. The results indicated that these doses were generally well-tolerated. Most side effects were mild, such as headaches and nausea. Serious side effects were rare and similar to those experienced by people taking a placebo (a pill with no active drug).

Although data is limited, lanifibranor's progression to a later stage of research suggests it has demonstrated sufficient safety in earlier studies to warrant further testing. This ongoing research appears promising for those considering joining a trial for NASH. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for NASH?

Researchers are excited about lanifibranor for treating Nonalcoholic Steatohepatitis (NASH) because it offers a novel approach compared to current treatments like lifestyle modifications and off-label use of medications such as vitamin E and pioglitazone. Lanifibranor is unique because it is a pan-PPAR agonist, which means it simultaneously targets multiple pathways involved in liver inflammation, fat metabolism, and fibrosis. This multi-target action could potentially lead to more comprehensive improvements in liver health and disease progression. Additionally, lanifibranor is taken as a simple oral tablet, which could make it easier for patients to adhere to the treatment regimen.

What evidence suggests that lanifibranor might be an effective treatment for NASH?

This trial will evaluate the effectiveness of lanifibranor for treating nonalcoholic steatohepatitis (NASH). Participants will receive either 800 mg or 1200 mg of lanifibranor, or a placebo. Research has shown that lanifibranor may help treat NASH, a liver condition. In previous studies, taking 800 mg or 1200 mg of lanifibranor significantly improved NASH without worsening liver scarring. Specifically, 49% of patients taking these doses saw improvement compared to those on a placebo. This suggests that lanifibranor could be a good treatment option for people with NASH, especially those with moderate liver scarring (stages F2 or F3). Overall, the results are promising and show potential benefits for patients with this liver condition. ^{2 4 6 7 8}

Who Is on the 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

Are You a Good Fit for This Trial?

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

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?

You have been diagnosed with Nonalcoholic Steatohepatitis

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

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]

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 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]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2036205

A Randomized, Controlled Trial of the Pan-PPAR Agonist ... Here, we report the results of the NASH Trial to Validate IVA337 Efficacy (NATIVE), a phase 2b, double-blind, randomized, placebo-controlled ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03008070

NCT03008070 | Phase 2b Study in NASH to Assess IVA337 The purpose of this research is to evaluate the efficacy and the safety of two doses of IVA337 (800mg, 1200 mg) per day for 24 weeks versus placebo in adult ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34670042/

A Randomized, Controlled Trial of the Pan-PPAR Agonist ... The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04849728

NCT04849728 | A Phase 3 Study Evaluating Efficacy and ... 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.

5. inventivapharma.com inventivapharma.com/the-new-england-journal-of-medicine-publishes-the-results-of-the-native-phase-iib-clinical-trial-with-lanifibranor-in-nash/

The New England Journal of Medicine publishes ... The New England Journal of Medicine publishes the results of the NATIVE Phase IIb clinical trial with lanifibranor in NASH. October 20, 2021 ...

6. cdn.caymanchem.com cdn.caymanchem.com/cdn/insert/25572.pdf

Lanifibranor SAFETY DATA. This material should be considered hazardous until further information becomes available. Do not ingest, inhale, get in eyes, on skin, ...

7. inventivapharma.com inventivapharma.com/therapeutic-areas/non-alcoholic-steatohepatitis-nash/

Non-alcoholic steatohepatitis (NASH) Due to its mechanism of action, lanifibranor has the potential to address all the key features of NASH: inflammation, steatosis, ballooning, and importantly ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33038502/

A randomised, double-blind, placebo-controlled, multi ... This study will evaluate the efficacy of a 24-week treatment of NASH with lanifibranor based on histological evaluations (SAF score) by biopsy.