Faculty Collaboration Database

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

Date

03/10/2020

Pubmed ID

32147362

DOI

10.1016/j.jhep.2020.02.027

Scopus ID

2-s2.0-85082566789 (requires institutional sign-in at Scopus site)   461 Citations

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.

Author List

Harrison SA, Wong VW, Okanoue T, Bzowej N, Vuppalanchi R, Younes Z, Kohli A, Sarin S, Caldwell SH, Alkhouri N, Shiffman ML, Camargo M, Li G, Kersey K, Jia C, Zhu Y, Djedjos CS, Subramanian GM, Myers RP, Gunn N, Sheikh A, Anstee QM, Romero-Gomez M, Trauner M, Goodman Z, Lawitz EJ, Younossi Z, STELLAR-3, STELLAR-4 Investigators

Author

Kia Saeian MD Interim Chief, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Benzamides
Biopsy
Disease Progression
Dose-Response Relationship, Drug
Double-Blind Method
Drug Monitoring
Female
Humans
Imidazoles
Liver
Liver Cirrhosis
MAP Kinase Kinase Kinase 5
Male
Middle Aged
Non-alcoholic Fatty Liver Disease
Protein Kinase Inhibitors
Pyridines
Treatment Outcome