Lanifibranor is Inventiva’s leading drug candidate for the treatment of non-alcoholic steatohepatitis (NASH) and systemic sclerosis (SSc).

It belongs to the family of pan-peroxisome proliferator-activated receptor (PPAR) agonists and activates the three forms of PPARs (α, δ, γ) in a moderate and balanced manner.

Lanifibranor has shown in clinical Phase I and IIa studies that it is safe and efficacious. Its safety profile in those studies was comparable to placebo. Equally, preclinical toxicology data in rodents and primates showed no safety concerns and preliminary results from a 2-year carcinogenicity study in rodents showed no increased incidence of bladder cancer often observed with other drug-candidates of the PPARγ agonist family.

Inventiva believes that lanifibranor’s excellent safety characteristics are due to its moderate and balanced profile, its unique binding mode into the PPARγ ligand domain and its original chemical structure.

Lanifibranor in non-alcoholic steatohepatitis (NASH)

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), a condition where excess fat is stored in the liver (steatosis). The liver of NASH patients also shows signs of inflammation and liver cell injury (ballooning) and may deteriorate further to become fibrotic and finally cirrhotic.

Pan-PPAR agonists like lanifibranor are involved in the regulation of lipid metabolism, inflammation, insulin resistance and fibrogenesis. Extensive preclinical studies have shown that lanifibranor can improve all aspects of NASH: inflammation, steatosis, ballooning and fibrosis. Especially the aspect of treating fibrosis is crucial as NASH patients with severe fibrosis are exposed to an increased risk to develop irreversible cirrhosis*.

Inventiva investigated lanifibranor in various preclinical models which show the main metabolic and hepatic features present in NASH patients** (for further information, please review the “Publication” section of this website here). In those models, lanifibranor normalised insulin sensitivity while controlling body weight gain, the adiposity index, and serum triglyceride increase. It also decreased liver steatosis, inflammation, and ballooning and demonstrated the prevention of liver fibrosis. In addition, lanifibranor inhibited the expression of (pro)fibrotic and inflammasome genes. In all models, lanifibranor displayed an anti-fibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists.

Source: Inventiva S.A. proprietary data

Lanifibranor is currently being tested in a Phase IIb clinical trial called NATIVE. The trial is open and recruiting patients. Headline results are expected in the second half of 2019.

In addition, Dr. Kenneth Cusi, Chief of the Division of Endocrinology, Diabetes & Metabolism in the Department of Medicine at the University of Florida, Gainesville, has selected lanifibranor for an investigator-initiated Phase II trial to evaluate the efficacy and safety of lanifibranor on intrahepatic triglycerides and hepatic insulin sensitivity in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). The trial is planned to commence enrolment in the second half of 2018. For a recording of a presentation on the study by Dr. Cusi, Pierre Broqua, CSO and co-founder of Inventiva, and Jean-Louis Abitbol, Chief Medical Officer of Inventiva, please click here.

Read more on NASH here.

*American Association for The Study of Liver Diseases practice guideline.
**G Wettstein et al, Hepatology Communications, Vol.1, Issue 6 (2017).

Lanifibranor in Systemic Sclerosis (SSC)

Systemic sclerosis (SSc) is a complex disease where a dysfunctional immune system leads to the overproduction of collagen and damaged blood vessels causing scarring of skin and internal organs. 
There is a strong rationale supporting the use of a pan-PPAR agonist like lanifibranor as a therapeutic concept for SSc. Based on skin and lung biopsies from SSc patients, it is known that both PPARα and PPARγ gene expression is repressed and that PPARγ activation blocks fibrotic processes in fibroblasts from SSc patients. 
Furthermore, adiponectin levels in skin and sera inversely correlate to disease activity in diffuse cutaneous systemic sclerosis (dcSSc), the most severe form of the disease. Lanifibranor has shown to increase adiponectin levels in a clinical Phase IIa study. 
Finally, preclinical studies in mice demonstrate the anti-fibrotic activity of lanifibranor in skin, lung, and kidney with positive effects on lung functional capacity, pulmonary artery pressure, right ventricular systolic pressure and hypertrophy. Lanifibranor therefore addresses the most relevant clinical features of SSc as indicated below.
Lanifibranor has received orphan drug designation for SSc in the USA and the European Union.

Lanifibranor is currently being studied in a Phase IIb clinical trial called FASST to treat dcSSc. Enrolment has been completed for this trial and results are expected in early 2019.

Read more on SSc here.

Lanifibranor has received orphan drug designation for SSc in the USA and the European Union.