Lanifibranor belongs to the family of pan-peroxisome proliferator-activated receptor (PPAR) agonists. It enhances the activity of all three forms of PPARs (α, δ, γ) in a moderate and balanced manner. PPARs are involved in the regulation of lipid metabolism, inflammation, insulin resistance and fibrogenesis which is impaired in people with diabetes, obesity and liver diseases. Extensive preclinical studies have shown that it is the agonism of all three subtypes which is required to obtain improvements in all aspects of NASH: inflammation, steatosis, ballooning and fibrosis.
Different single and dual PPAR agonists have been investigated in clinical trials for their therapeutic potential in NASH. Respective clinical results have demonstrated variable improvements depending on the profile of the tested drug, suggesting that parallel activation of all three isoforms may lead to a more substantial therapeutic benefit for NASH patients.
Inventiva investigated lanifibranor in various preclinical models which show the main metabolic and hepatic features present in NASH patients*. In those models lanifibranor normalised insulin sensitivity while controlling body weight gain, adiposity index, and serum triclyceride increase. It 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.