A randomized, double-blind, placebo-controlled trial of Aldafermin in patients with nonalcoholic steatohepatitis and compensated cirrhosis.

BACKGROUND AND AIMS: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with non-cirrhotic nonalcoholic steatohepatitis (NASH), however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population.

APPROACH AND RESULTS: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n=7), 1 mg (n=42), 3 mg (n=55), or placebo (n=56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal dose. The primary end point was a change in ELF from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least squares mean difference in the change in ELF was ̶ 0.5 (95% confidence interval [CI], ̶ 0.7 to ̶ 0.2; p=0.0003) between the 3 mg group and the placebo group. 15%, 21% and 23% of patients in the placebo, 1 mg and 3 mg group, respectively, achieved fibrosis improvement ≥1-stage; and 13%, 16% and 20% achieved fibrosis improvement ≥1-stage without NASH worsening. Improvement in ALT, AST, Pro-C3 and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. 0%, 2% and 9% of patients in the placebo, 1 mg and 3 mg group, respectively, discontinued due to treatment-related adverse events.

CONCLUSIONS: Aldafermin 3 mg resulted in significant reduction in ELF in patients with compensated NASH cirrhosis.