The first half of this year was marked with bad news in the NASH field, first with the negative results of elafibranor (Genfit) RESOLVE-IT Phase 3 trial, followed by a complete response letter from the FDA concerning Intercept’s obeticholic acid. Other dead ends that follow selonsertib (Gilead) failed Phase 3 trial last year.
Elafibranor, a PPARalpha PPARdelta dual agonist developed by Genfit that showed promising results in a Phase 2b trial (results published here: https://pubmed.ncbi.nlm.nih.gov/26874076/) failed to demonstrate significant differences on NASH resolution without worsening of fibrosis in the RESOLVE-IT Phase 3 trial. RESOLVE-IT was a trial in n=1,070 adults with NASH and fibrosis comparing elafibranor to placebo. At the end of the trial, the primary outcome (NASH resolution without worsening of fibrosis) was 19.2% for elafibranor vs 14.7% for placebo without significant difference. (Press Release: https://ir.genfit.com/news-releases/news-release-details/genfit-announces-results-interim-analysis-resolve-it-phase-3)
This trial was surprising by the high number of NASH resolution in the placebo group, different from what was observed in other trials. Once again, it shows that it is difficult to reach significant differences in this field, especially with monotherapy, is it because methods to measures the benefit of these treatments in clinical trials (via biopsies) are not precise enough, or that NASH is a disease that is the result of different metabolic processes and that we need to test combinations of treatments to see medical benefits…
Nevertheless, we can spot some good news for this field, first the positive results of lanifibranor (a pan-PPARagonist from Inventiva) Phase 2b trial. They show a statistically significant decrease of at least two points in the SAF activity score (combining hepatocellular inflammation and ballooning), compared to baseline, with no worsening of fibrosis (49% of patients in the lanifibranor 1200mg/day dose group vs
27% with placebo). And a better resolution of NASH with no worsening of fibrosis in both dose groups (800mg/day and 1200mg/day). Lanifibranor is also tested in a Phase 2 in T2D patients with NAFLD.
We are also waiting for the results of ongoing trials with diabetes drugs as semaglutide (A GLP-1 of Novo Nordisk available for T2D) that showed remarkable weight loss in diabetes and non diabetic obese patients. More interestingly, the collaboration between Novo Nordisk and Gilead with a Phase 2 testing a combination of semaglutide (GLP-1), cilofexor (FXR agonist), and firsocostat (ACC inhibitor) that will target different pathways involved in NASH. The trial is registered as completed on CT.gov with results to come probably soon.
Some hope for a disease with no available treatment…
Photo: Sakramir, Getty Images