Tags

Type your tag names separated by a space and hit enter

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.JH

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.

Authors+Show Affiliations

Pinnacle Clinical Research, San Antonio, TX, USA. Electronic address: sharrison@pinnacleresearch.com.Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China.Saiseikai Suita Hospital, Suita City, Osaka, Japan.Oschner Medical Center, New Orleans, LA, USA.Indiana University School of Medicine, Indianapolis, IN, USA.Gastro One, Germantown, TN, USA.The Institute for Liver Health, Chandler, AZ, USA.Institute of Liver and Biliary Sciences, New Delhi, India.University of Virginia, Charlottesville, VA, USA.Texas Liver Institute, University of Texas Health San Antonio, TX, USA.Liver Institute of Virginia, Bon Secours Mercy Health, Richmond, VA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Gilead Sciences, Inc., Foster City, CA, USA.Pinnacle Clinical Research, Austin, TX, USA.GI Specialists of Georgia, Marietta, GA, USA.Institute 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.Hospital Universitario Virgen del Rocio, Sevilla, Spain.Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria.Inova Fairfax Hospital, Falls Church, VA, USA.Texas Liver Institute, University of Texas Health San Antonio, TX, USA.Inova Fairfax Hospital, Falls Church, VA, USA.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32147362

Citation

Harrison, Stephen A., et al. "Selonsertib for Patients With Bridging Fibrosis or Compensated Cirrhosis Due to NASH: Results From Randomized Phase III STELLAR Trials." Journal of Hepatology, vol. 73, no. 1, 2020, pp. 26-39.
Harrison SA, Wong VW, Okanoue T, et al. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. J Hepatol. 2020;73(1):26-39.
Harrison, S. A., Wong, V. W., Okanoue, T., Bzowej, N., Vuppalanchi, R., Younes, Z., Kohli, A., Sarin, S., Caldwell, S. H., Alkhouri, N., Shiffman, M. L., Camargo, M., Li, G., Kersey, K., Jia, C., Zhu, Y., Djedjos, C. S., Subramanian, G. M., Myers, R. P., ... Younossi, Z. (2020). Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. Journal of Hepatology, 73(1), 26-39. https://doi.org/10.1016/j.jhep.2020.02.027
Harrison SA, et al. Selonsertib for Patients With Bridging Fibrosis or Compensated Cirrhosis Due to NASH: Results From Randomized Phase III STELLAR Trials. J Hepatol. 2020;73(1):26-39. PubMed PMID: 32147362.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials. AU - Harrison,Stephen A, AU - Wong,Vincent Wai-Sun, AU - Okanoue,Takeshi, AU - Bzowej,Natalie, AU - Vuppalanchi,Raj, AU - Younes,Ziad, AU - Kohli,Anita, AU - Sarin,Shiv, AU - Caldwell,Stephen H, AU - Alkhouri,Naim, AU - Shiffman,Mitchell L, AU - Camargo,Marianne, AU - Li,Georgia, AU - Kersey,Kathryn, AU - Jia,Catherine, AU - Zhu,Yanni, AU - Djedjos,C Stephen, AU - Subramanian,G Mani, AU - Myers,Robert P, AU - Gunn,Nadege, AU - Sheikh,Aasim, AU - Anstee,Quentin M, AU - Romero-Gomez,Manuel, AU - Trauner,Michael, AU - Goodman,Zachary, AU - Lawitz,Eric J, AU - Younossi,Zobair, AU - ,, Y1 - 2020/03/06/ PY - 2019/10/17/received PY - 2020/01/28/revised PY - 2020/02/16/accepted PY - 2020/3/10/pubmed PY - 2020/3/10/medline PY - 2020/3/10/entrez KW - Cirrhosis KW - Fibrosis KW - NAFLD KW - Steatohepatitis KW - Therapy KW - Treatment SP - 26 EP - 39 JF - Journal of hepatology JO - J. Hepatol. VL - 73 IS - 1 N2 - 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. SN - 1600-0641 UR - https://www.unboundmedicine.com/medline/citation/32147362/Selonsertib_for_patients_with_bridging_fibrosis_or_compensated_cirrhosis_due_to_NASH:_Results_from_randomized_phase_III_STELLAR_trials_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-8278(20)30126-4 DB - PRIME DP - Unbound Medicine ER -