Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Stage 3 Fibrosis (FALCON 1): A Randomized Phase 2b Study

Rohit Loomba, Arun J. Sanyal, Atsushi Nakajima, Brent A. Neuschwander-Tetri, Zachary D. Goodman, Stephen A. Harrison, Eric J. Lawitz, Nadege Gunn, Kento Imajo, Natarajan Ravendhran, Takemi Akahane, Bradly Boone, Masayuki Yamaguchi, Arkendu Chatterjee, Giridhar S. Tirucherai, Diane E. Shevell, Shuyan Du, Edgar D. Charles, Manal F. Abdelmalek

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background & Aims: Pegbelfermin is a polyethlene glycol–conjugated analog of human fibroblast growth factor 21, a nonmitogenic hormone that regulates energy metabolism. This phase 2b study evaluated 48-week pegbelfermin treatment in patients with nonalcoholic steatohepatitis (NASH) and stage 3 (bridging) fibrosis. Methods: The FALCON 1 study (NCT03486899) was a multicenter, randomized (1:1:1:1), double-blind, placebo-controlled study. Patients with biopsy-confirmed NASH and stage 3 fibrosis (N = 197) received weekly subcutaneous pegbelfermin (10, 20, or 40 mg) or placebo injections for 48 weeks. The week 24 primary endpoint was a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening; pegbelfermin dose response was assessed using a Cochran-Armitage trend test across proportions (1-sided α = 0.05). Secondary/exploratory endpoints included histological and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. Results: At week 24, the primary endpoint was met by 14% (placebo) vs 24%–31% (pegbelfermin arms); statistical significance was not reached due to lack of pegbelfermin dose response (P =.134). At weeks 24 and 48, more patients who received pegbelfermin had ≥30% relative reductions in hepatic fat fraction (magnetic resonance imaging-proton density fat fraction) vs placebo, although no differences reached statistical significance. In the pegbelfermin arms, improvements in liver fibrosis (magnetic resonance elastography and N-terminal type III collagen propeptide) and liver injury/inflammation (alanine aminotransferase, aspartate aminotransferase) were observed vs placebo. Adverse events occurred at similar frequencies across arms. No treatment-related serious adverse events were observed. Conclusions: The FALCON 1 study did not meet its primary endpoint; a ≥1-point decrease in fibrosis score without NASH worsening or NASH improvement without fibrosis worsening assessed via biopsy. Pegbelfermin was generally well tolerated during 48 weeks of treatment.

Original languageEnglish (US)
Pages (from-to)102-112.e9
JournalClinical Gastroenterology and Hepatology
Volume22
Issue number1
DOIs
StatePublished - Jan 2024

Keywords

  • Bridging Fibrosis
  • FGF21
  • NASH

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

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