Positive topline results from a 24-week, randomized, double-blind, placebo-controlled, multicenter, phase 2 study of the FGF19 analogue aldafermin (NGM282) in patients with non-alcoholic steatohepatitis

Background and aims: Aldafermin (NGM282), an engineered FGF19 analogue, significantly inhibited bile acid synthesis, reduced hepatic fibrosis, inflammation and steatosis in previous 12-week NASH trials. Here we report the primary and key results from the 24-week (W24) study with paired liver biopsy. Method: 78 subjects were randomized 1:2 to receive PBO (n = 25) or aldafermin 1 mg (n = 53) SC QD at 9 US study sites. Key inclusion criteria included biopsy-proven NASH with NAS≥4, stage 2–3 fibrosis and absolute liver fat content (LFC) ≥8%. Subjects underwent MRI-PDFF and liver biopsies at baseline (BL) and W24. The primary endpoint was change from BL to W24 in LFC. Histological endpoints included improvement in liver fibrosis by ≥1 stage with no worsening of NASH and resolution of NASH with no worsening of fibrosis (NASH CRN criteria). Results: At W24, treatment with aldafermin resulted in statistically significant reductions in LFC (Table 1). A greater proportion of subjects on aldafermin achieved fibrosis reduction of ≥1-stage without NASH worsening (38% [aldafermin] vs 18% [PBO]), and NASH resolution with no worsening of fibrosis (24% [aldafermin] vs 9% [PBO]). 22% (aldafermin) vs. 0% (PBO) of subjects achieved both histological endpoints (P = 0.015). ALT, AST and fibrogenesis biomarkers (Pro-C3 and ELF) declined rapidly and significantly from BL with aldafermin therapy. AEs were mostly mild and moderate in severity. No difference in gastrointestinal AE was observed between arms. Incidences of SAEs were 12% (PBO) vs 4% (aldafermin), and discontinuations due to AE 4% (PBO) vs 0% (aldafermin). All SAEs were unrelated to drug. [Table presented] Conclusion: In patients with NASH, aldafermin therapy resulted in statistically significant reduction in LFC and robust improvement in fibrosis and NASH histology compared with PBO. A greater proportion of patients treated with aldafermin achieved both histological endpoints of fibrosis improvement and NASH resolution compared to PBO. Aldafermin 1 mg maintained a durable response for 24 weeks with a favorable tolerability and safety profile.