The FGF19 analogue aldafermin improves non-invasive tests in patients with non-alcoholic steatohepatitis

Background and Aims: Nonalcoholic steatohepatitis (NASH) represents an epidemic health crisis with broad impact on public health. Developing therapeutics for NASH poses a vexing challenge, which requires invasive procedures such as liver biopsy. Several inexpensive, simple, commonly used non-invasive tests (NITs), such as AST to platelet ratio index (APRI) and FIB-4 index, can predict liver-related outcomes and have been used to identify high-risk NASH patients from primary care settings. Aldafermin (previously known as NGM282), a non-tumorigenic FGF19 analogue, significantly inhibited bile acid synthesis, reduced steatosis, hepatic inflammation and fibrosis in patients with NASH. Here we report the effect of aldafermin on NITs in phase 2 studies in patients with NASH. Method: In part 1 of the study, 82 subjects were randomized to aldafermin 3 mg (n = 27) or 6 mg (n = 28) vs. placebo (n = 27) as a daily SC injection for 12 weeks. In part 2 of the study, 94 subjects received open-label aldafermin 0.3 mg (n = 23),1 mg (n = 49) or 3 mg (n = 22) for 12 weeks for dose-range finding. Key inclusion criteria included biopsy-proven NASH with NAS ≥ 4 (at least 1 point in each component), Stage 1–3 fibrosis and absolute liver fat content (LFC) by MRI-PDFF ≥ 8%. APRI, FIB-4, fatty liver index (FLI) and ratio of triglyceride and HDL (TG/HDL) were evaluated at baseline (BL) and week 12 (W12). Results: At BL, mean APRI, FIB-4, FLI and TG/HDL values were similar across all groups. At W12, aldafermin-treated patients showed reductions in NITs of fibrosis (APRI and FIB-4) and fatty liver (FLI) (Table 1). In contrast, no improvement was seen with placebo-treated subjects. Improvements were observed as early as 2 weeks on aldafermin and were maintained throughout treatment duration. TG/HDL ratio decreased significantly with aldafermin treatment. [Table presented] Conclusion: Aldafermin therapy produced improvements in several simple and inexpensive NITs of liver fibrosis, steatosis and cardiovascular risk. These NITs may be useful for monitoring early treatment response to aldafermin.