Abstract

Background: Patients with cirrhosis are at increased risk of liver decompensation and HCC which can result in liver transplant or death. There is no available therapy and previous clinical trials have failed to show a benefit in patients with NASH and cirrhosis. Aldafermin, an engineered analog of the human hormone FGF19, improved liver histology in previous non-cirrhotic, phase 2 trials. We report results from ALPINE 4, a 48-week, phase 2b paired liver biopsy study in patients with compensated cirrhosis due to NASH (NCT04210245).

Methods: 160 patients were randomized to receive placebo (PBO, n=56), aldafermin 0.3mg (n=7; enrollment in the 0.3mg arm was discontinued during trial to allow patients exposure to higher doses), 1mg (n=42), or 3 mg (n=55) SC QD at 48 sites in 8 countries. Key inclusion criteria included compensated cirrhosis (CTP-A) with biopsy-proven NASH (NASH CRN criteria). Patients underwent liver biopsy at baseline and week 48. The primary endpoint was the change in Enhanced Liver Fibrosis (ELF) score from baseline to week 48 vs. PBO. Secondary endpoints included fibrosis improvement of ≥1-stage, C4, serum bile acids, Pro-C3, ALT and AST. Primary analysis was performed in the ITT population using MMRM method.

Results: Demographic and baseline characteristics were similar across the trial groups. The mean age was 59.6 (8.2) years and 76% of patients had T2D at baseline. The primary endpoint was achieved with aldafermin 3mg. At week 48, the least-squares (LS) mean difference between aldafermin and PBO in ELF was −0.1 for 1mg and −0.5 for 3mg (P<0.001) (Table 1). Fibrosis improvement of ≥1-stage was achieved in 15%, 21% and 23% patients in the PBO, 1mg and 3mg groups, respectively. Dose-dependent reductions in C4 (LS mean difference vs. PBO: −65% and −72% in 1mg and 3 mg groups), total bile acids (−67%, −82%), the fibrogenesis biomarker Pro-C3 ( −54%, −60%), ALT ( −30%, −35%), and AST (−19%, −28%) were observed. Adverse events were mostly mild and moderate in severity. Six (6%) patients on aldafermin discontinued treatment due to drug-related adverse events. Serious adverse events occurred in 19 (12%) patients, all deemed unrelated to drug. No DILI or HCC was reported in the study.

Conclusion: We herein report positive primary endpoint results in a randomized controlled trial of aldafermin in patients with NASH and compensated cirrhosis. Aldafermin achieved dose-dependent benefits in ELF and other non-invasive markers of both inflammation and fibrosis.