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Abstract Details |
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Selonsertib for Patients With Bridging Fibrosis or Compensated Cirrhosis Due to NASH: Results From Randomized Phase III STELLAR Trials |
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Hepatol. 2020 Jul;73(1):26-39. doi: 10.1016/j.jhep.2020.02.027. Epub 2020 Mar 6.
Stephen A Harrison 1, Vincent Wai-Sun Wong 2, Takeshi Okanoue 3, Natalie Bzowej 4, Raj Vuppalanchi 5, Ziad Younes 6, Anita Kohli 7, Shiv Sarin 8, Stephen H Caldwell 9, Naim Alkhouri 10, Mitchell L Shiffman 11, Marianne Camargo 12, Georgia Li 12, Kathryn Kersey 12, Catherine Jia 12, Yanni Zhu 12, C Stephen Djedjos 12, G Mani Subramanian 12, Robert P Myers 12, Nadege Gunn 13, Aasim Sheikh 14, Quentin M Anstee 15, Manuel Romero-Gomez 16, Michael Trauner 17, Zachary Goodman 18, Eric J Lawitz 10, Zobair Younossi 18, STELLAR-3 and STELLAR-4 Investigators
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Author information
- 1Pinnacle Clinical Research, San Antonio, TX, USA. Electronic address: sharrison@pinnacleresearch.com.
- 2Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.
- 3Saiseikai Suita Hospital, Suita City, Osaka, Japan.
- 4Oschner Medical Center, New Orleans, LA, USA.
- 5Indiana University School of Medicine, Indianapolis, IN, USA.
- 6Gastro One, Germantown, TN, USA.
- 7The Institute for Liver Health, Chandler, AZ, USA.
- 8Institute of Liver and Biliary Sciences, New Delhi, India.
- 9University of Virginia, Charlottesville, VA, USA.
- 10Texas Liver Institute, University of Texas Health San Antonio, TX, USA.
- 11Liver Institute of Virginia, Bon Secours Mercy Health, Richmond, VA, USA.
- 12Gilead Sciences, Inc., Foster City, CA, USA.
- 13Pinnacle Clinical Research, Austin, TX, USA.
- 14GI Specialists of Georgia, Marietta, GA, USA.
- 15Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK & Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
- 16Hospital Universitario Virgen del Rocio, Sevilla, Spain.
- 17Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria.
- 18Inova Fairfax Hospital, Falls Church, VA, USA.
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.
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