Pegbelfermin in Patients With Nonalcoholic Steatohepatitis and Compensated Cirrhosis (FALCON 2): A Randomized Phase 2b Study

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

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Background & Aims: Pegbelfermin is a polyethylene 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) with compensated cirrhosis. Methods: FALCON 2 (NCT03486912) was a randomized (1:1:1:1), double-blind, placebo-controlled study. Eligible adults had biopsy-confirmed NASH and stage 4 fibrosis. Pegbelfermin (10, 20, or 40 mg) or placebo was injected subcutaneously once weekly. The primary endpoint was 1 or more stages of improvement in the NASH Clinical Research Network fibrosis score without NASH worsening at week 48; pegbelfermin dose response was assessed using a Cochran–Armitage trend test across proportions (1-sided α =.05). Additional endpoints included histologic and noninvasive measures of steatosis, fibrosis, and liver injury/inflammation. Results: Overall, 155 patients were randomized, and 154 patients received treatment. At week 48, 24% to 28% of the pegbelfermin arms had primary endpoint responses vs 31% of the placebo arm (P =.361). Nonalcoholic fatty liver disease activity score improvements were more frequent with pegbelfermin vs placebo and were driven primarily by reduced lobular inflammation. Numerically higher proportions of the pegbelfermin arms had liver stiffness (magnetic resonance elastography) and steatosis (magnetic resonance imaging-proton density fat fraction) improvements vs placebo; these differences were not statistically significant. Mean N-terminal type III collagen propeptide, alanine aminotransferase, and aspartate aminotransferase values were numerically lower in the 20- and/or 40-mg pegbelfermin arms compared with placebo. Serious adverse events were more frequent with pegbelfermin vs placebo, although none were treatment related. One patient (40-mg pegbelfermin) discontinued treatment because of a treatment-emergent adverse event (worsening ascites). Conclusions: FALCON 2 did not meet its primary endpoint of 1 or more stages of improvement in the NASH Clinical Research Network fibrosis without NASH worsening assessed via biopsy. Pegbelfermin generally was well tolerated in this advanced NASH population.

Original languageEnglish (US)
Pages (from-to)113-123.e9
JournalClinical Gastroenterology and Hepatology
Volume22
Issue number1
DOIs
StatePublished - Jan 2024

Keywords

  • Cirrhosis
  • FGF21
  • NASH

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

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