AASLD The Liver Meeting, Virginia, United States Of America, 13 - 16 November 2020, pp.23
NASH is a major cause of liver related mortality for which there are no approved drugs. A phase 2B trial of a PPAR α/δ agonist elafibranor (Ela) showed histological improvement in those with NASH, high disease activity and F2/3 fibrosis. We here report the interim results of the Phase 3 RESOLVE-IT trial of Ela in this population.
In this multicenter, randomized, double-blind, placebo (Pbo)-controlled study, adult patients with NASH, non-alcoholic fatty liver disease activity score (NAS) ≥4 and fibrosis stages F1–F3, were randomized (2:1) to receive Ela 120 mg/day or Pbo. The primary endpoint for the planned surrogate efficacy analysis at week 72 was NASH resolution without worsening of fibrosis in patients with F2/3. Other histological and biochemical markers of NASH and fibrosis and safety were also evaluated.
Surrogate efficacy was assessed in 1070 patients [Ela n=717, Pbo n=353; mean age 55; 50% with type 2 diabetes (T2D); 61% male]. The primary endpoint assessed by intention to treat was not met. 138 (19.2%) patients in the Ela group and 52 (14.7%) patients in the Pbo group achieved resolution of NASH without worsening of fibrosis (p=0.066). The estimate of the between treatment groups difference in response rates was 4.3% (99% CI: -1.7, 10.4%). Sensitivity and other analyses of NASH histological features did not significantly modify the overall results. The response rates for the key secondary endpoint, fibrosis improvement of ≥ 1 stage, were 24.5% and 22.4% for patients who received Ela and Pbo, respectively (N.S.). There were no significant changes in insulin resistance or glucose parameters, but a significant difference was achieved for reduction in non HDL-cholesterol and triglycerides, as well as for the hepatic markers ALT, GGT, but not for AST (Table 1). There was significant reduction in inflammatory markers haptoglobin and fibrinogen. There was no significant difference in liver stiffness measured by VCTE. No significant histological benefit was shown in pre-specified sub-populations, but favorable trends were observed for T2D, NAS≥6 and HbA1c>6.0%. Treatment with Ela was generally well tolerated.
Ela 120 mg daily for 72 weeks did not achieve resolution of NASH without worsening of fibrosis in adult patients with NASH and significant fibrosis. Despite absence of safety signals, the RESOLVE-IT trial was discontinued due to the limited effect of Ela on surrogate efficacy endpoints.