Elafibranor, an Agonist of the Peroxisome Proliferator−Activated Receptor−α and −δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

Background & Aims Elafibranoris an agonist of the peroxisome proliferator−activated receptor-α and peroxisome proliferator−activated receptor-δ. Elafibranorimproves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranorin an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis(NASH). Methods Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor80 mg (n = 93), elafibranor120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranorwere compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver diseaseactivity score. Results In intention-to- treat analysis, there was no significant difference between the elafibranorand placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranorgroup vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02−5.24; P = .045), based on a post-hoc analysisfor the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver diseaseactivity score ≥4 (n = 234), elafibranor120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22−8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32–9.40; P = .013). Patients with NASH resolution after receiving elafibranor120 mg had reduced liver fibrosis stages compared with those without NASH resolution (mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P P Conclusions A post-hoc analysisof data from trial of patients with NASH showed that elafibranor(120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to- treat analysisand in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranorwas well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.