BACKGROUND: Management of nonalcoholic steatohepatitis (NASH) is an unmet 
clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated 
receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic 
pathways in the pathogenesis of NASH.
METHODS: In this phase 2b, double-blind, randomized, placebo-controlled trial, 
patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 
ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 
weeks. The primary end point was a decrease of at least 2 points in the SAF-A 
score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring 
system that incorporates scores for ballooning and inflammation) without 
worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores 
indicating more-severe disease activity. Secondary end points included 
resolution of NASH and regression of fibrosis.
RESULTS: A total of 247 patients underwent randomization, of whom 103 (42%) had 
type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced 
fibrosis. The percentage of patients who had a decrease of at least 2 points in 
the SAF-A score without worsening of fibrosis was significantly higher among 
those who received the 1200-mg dose, but not among those who received the 800-mg 
dose, of lanifibranor than among those who received placebo (1200-mg dose vs. 
placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, 
P = 0.07). 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 39%, 
respectively, vs. 22%), improvement in fibrosis stage of at least 1 without 
worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH 
plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 
9%). Liver enzyme levels decreased and the levels of the majority of lipid, 
inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The 
dropout rate for adverse events was less than 5% and was similar across the 
trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain 
occurred more frequently with lanifibranor than with placebo.
CONCLUSIONS: In this phase 2b trial involving patients with active NASH, the 
percentage of patients who had a decrease of at least 2 points in the SAF-A 
score without worsening of fibrosis was significantly higher with the 1200-mg 
dose of lanifibranor than with placebo. These findings support further 
assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; 
NATIVE ClinicalTrials.gov number, NCT03008070.).