Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials

J Hepatol. 2020 Jul;73(1):26-39. doi: 10.1016/j.jhep.2020.02.027. Epub 2020 Mar 6.

Abstract

Background & aims: Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH.

Methods: We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events.

Results: Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups.

Conclusions: Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH.

Lay summary: Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients.

Trial registration details: Clinicaltrials.gov numbers NCT03053050 and NCT03053063.

Keywords: Cirrhosis; Fibrosis; NAFLD; Steatohepatitis; Therapy; Treatment.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides* / administration & dosage
  • Benzamides* / adverse effects
  • Biopsy / methods
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Monitoring / methods
  • Female
  • Humans
  • Imidazoles* / administration & dosage
  • Imidazoles* / adverse effects
  • Liver / pathology*
  • Liver Cirrhosis* / drug therapy
  • Liver Cirrhosis* / etiology
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease* / complications
  • Non-alcoholic Fatty Liver Disease* / diagnosis
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Pyridines* / administration & dosage
  • Pyridines* / adverse effects
  • Treatment Outcome

Substances

  • Benzamides
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • MAP Kinase Kinase Kinase 5
  • selonsertib

Associated data

  • ClinicalTrials.gov/NCT03053050
  • ClinicalTrials.gov/NCT03053063