Phase 2 study of fazpilodemab, a FGFR1/Klothoβ agonist, in metabolic dysfunction-associated steatohepatitis (MASH).

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited treatment options. Fazpilodemab, a bispecific antibody targeting fibroblast growth factor receptor 1 (FGFR1) and Klotho β (KLB), showed promising trends in liver health markers in type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease.

METHODS

This Phase 2 randomized study evaluated the efficacy, safety, and pharmacokinetics of fazpilodemab in patients with MASH and hepatic steatosis. Patients were randomized to receive fazpilodemab or placebo subcutaneously every 2 weeks for 52 weeks. The primary endpoint was MASH resolution without fibrosis worsening at Week 52. Secondary endpoints included histological improvement from baseline (≥2 points reduction in MAS with ≥ 1-point reduction in either lobular inflammation or hepatocellular ballooning and no worsening of fibrosis stage), fibrosis improvement from baseline (≥1 MASH CRN fibrosis stage) and no worsening of steatohepatitis (no increase in MAS for ballooning, inflammation, or steatosis), and changes in hepatic fat fraction. Safety, PK, and immunogenicity were also assessed.

RESULTS

A total of 46 patients (fazpilodemab 50 mg [n=11], 75 mg [n=11], or 100 mg [n=11]; and placebo [n=13]) were enrolled, of whom 23 had Week 52 or early termination biopsy. The proportion of patients achieving resolution of MASH without worsening of fibrosis was 37.5% (3/8) in the 50 mg arm, 14.3% (1/7) in the 75 mg arm, and 33.3% (2/6) in the 100 mg arm, compared to 16.7% (1/6) in the placebo arm. For the secondary endpoints, improvements in liver histology and fibrosis were numerically higher in fazpilodemab-treated patients; transient improvements in hepatic fat fraction were observed. Fazpilodemab was adequately tolerated, with no new safety signals identified.

CONCLUSIONS

While the study was prematurely terminated, fazpilodemab demonstrated a safety profile consistent with previous studies. No definite conclusion could be drawn regarding the preliminary fazpilodemab efficacy profile due to the limited sample size and early dropouts.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT04171765 IMPACT AND IMPLICATIONS: Dual targeting of FGFR1 and Klotho β (KLB) with fazpilodemab demonstrated preliminary signals in liver histology and steatosis reduction alongside a favorable safety profile in patients with MASH. Although early trial termination precludes definitive efficacy conclusions, these findings support FGFR1 agonism as a viable strategy for future drug development in metabolic liver disease.