Drug name: Elafibranor
Mechanism: PPAR alpha and delta dual agonist
Stage: Phase 3
Next readout: Topline RESOLVE-IT data expected in Q1 2020
Intercept’s OCA beat Genfit’s elafibranor to approval for primary biliary cholangitis and is on track to do so in NASH as well, but the French biotech is hopeful its candidate could be better. For starters, it has a different mechanism: Elafibranor is a dual agonist of PPAR-alpha and PPAR-delta, which are nuclear receptors, a type of protein found inside cells that plays a role in cellular metabolism. The company raised $135 million in its IPO last March, earmarking about $50 million to bring elafibranor through FDA and EMA filings for NASH.
Genfit expects to report topline interim data from its phase 3 RESOLVE-IT study in the first quarter of 2020 and recently got the go-ahead from a data and safety monitoring board to continue the study. The board reviewed data from patients who have been on elafibranor for as long as three years and found that no patients have suffered interface hepatitis, a condition in which liver cells are inflamed and destroyed and one that caused Cymabay to end the NASH study of its PPAR drug.
That said, it hasn’t all been smooth sailing for elafibranor. In 2015, the drug missed the primary endpoint in a phase 2 study in NASH, a failure that Genfit chalked up to the use of too many study sites and the inclusion of too many patients with early-stage NASH. Take out data from those patients, and the trial was a success, Genfit said at the time. It went on to design phase 3 studies to focus on patients with more severe disease—that is, patients with a score of 4 or greater on a scale of fatty liver disease activity (NAS) ranging from 0 to 8.
The RESOLVE-IT study has the primary endpoint of NASH resolution with no worsening of fibrosis, meaning an improvement in the underlying processes of NASH—such as liver inflammation—without liver scarring getting worse. Vantage reminded us in June that this is the same endpoint that elafibranor missed in the phase 2 study back in 2015.
“That Genfit pushed into phase 3 based on a multiple post-hoc analysis of a failed trial is probably the biggest red flag here, though there are also mechanistic concerns when it comes to PPAR agonism,” Vantage wrote.
But Genfit is all in on elafibranor. It is testing the drug in combination with an SGLT2 inhibitor and a GLP-1 receptor agonist in a proof-of-concept study in NASH and is also working on a noninvasive test for NASH, NIS4, which it’s test-driving on data from the RESOLVE-IT trial.