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

Published:March 05, 2020DOI:


      • Selonsertib was safe and inhibited its target (ASK1) but did not lead to fibrosis regression or reduce disease progression in NASH.
      • Improvement in liver fibrosis on biopsy was associated with improvement only in other histologic features.
      • Improvements in ELF score and liver stiffness by transient elastography correlated with a variety of clinical parameters.

      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.


      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.


      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.


      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

      Graphical abstract


      Linked Article

      • STELLAR 3 and STELLAR 4: Lessons from the fall of Icarus
        Journal of HepatologyVol. 73Issue 1
        • Preview
          When planes crash or experience a near miss, the United States Federal Aviation Authority has a longstanding policy that mandates a review that “will ensure that all of the facts, conditions, and circumstances leading to an event are recorded and evaluated, and that action is taken to prevent similar events to the extent practical and feasible.” Safety and efficacy of air travel is immeasurably better for it.
        • Full-Text
        • PDF
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Younossi Z.M.
        • Koenig A.B.
        • Abdelatif D.
        • Fazel Y.
        • Henry L.
        • Wymer M.
        Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes.
        Hepatology. 2016; 64: 73-84
        • Kabbany M.N.
        • Conjeevaram Selvakumar P.K.
        • Watt K.
        • Lopez R.
        • Akras Z.
        • Zein N.
        • et al.
        Prevalence of nonalcoholic steatohepatitis-associated cirrhosis in the United States: an analysis of National Health and Nutrition Examination Survey data.
        Am J Gastroenterol. 2017; 112: 581-587
        • Calzadilla-Bertot L.
        • Jeffrey G.P.
        • Jacques B.
        • McCaughan G.
        • Crawford M.
        • Angus P.
        • et al.
        Increasing incidence of nonalcoholic steatohepatitis as an indication for liver transplantation in Australia and New Zealand.
        Liver Transpl. 2019; 25: 25-34
        • Wong R.J.
        • Aguilar M.
        • Cheung R.
        • Perumpail R.B.
        • Harrison S.A.
        • Younossi Z.M.
        • et al.
        Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.
        Gastroenterology. 2015; 148: 547-555
        • Noureddin M.
        • Vipani A.
        • Bresee C.
        • Todo T.
        • Kim I.K.
        • Alkhouri N.
        • et al.
        NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances.
        Am J Gastroenterol. 2018; 113: 1649-1659
        • Mathurin P.
        • Hollebecque A.
        • Arnalsteen L.
        • Buob D.
        • Leteurte E.
        • Caiazzo R.
        • et al.
        Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease.
        Gastroenterology. 2009; 137: 532-540
        • Sanyal A.J.
        • Harrison S.A.
        • Ratziu V.
        • Abdelmalek M.F.
        • Diehl A.M.
        • Caldwell S.
        • et al.
        The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.
        Hepatology. 2019; 70: 1913-1927
        • Ekstedt M.
        • Hagström H.
        • Nasr P.
        • Fredrikson M.
        • Stål P.
        • Kechagias S.
        • et al.
        Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
        Hepatology. 2015; 61: 1547-1554
        • Angulo P.
        • Kleiner D.E.
        • Dam-Larsen S.
        • Adams L.A.
        • Bjornsson E.S.
        • Charatcharoenwitthaya P.
        • et al.
        Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2015; 149: 389-397
        • Dulai P.S.
        • Singh S.
        • Patel J.
        • Soni M.
        • Prokop L.J.
        • Younossi Z.
        • et al.
        Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis.
        Hepatology. 2017; 65: 1557-1565
        • Ichijo H.
        • Nishida E.
        • Irie K.
        • ten Dijke P.
        • Saitoh M.
        • Moriguchi T.
        • et al.
        Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways.
        Science. 1997; 275: 90-94
        • Yamamoto E.
        • Dong Y.F.
        • Kataoka K.
        • Yamashita T.
        • Tokutomi Y.
        • Matsuba S.
        • et al.
        Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition.
        Hypertension. 2008; 52: 573-580
        • Xie Y.
        • Ramachandran A.
        • Breckenridge D.G.
        • Liles J.T.
        • Lebofsky M.
        • Farhood A.
        • et al.
        Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury.
        Toxicol Appl Pharmacol. 2015; 286: 1-9
        • Budas G.
        • Karnik S.
        • Jonnson T.
        • Shafizadeh T.
        • Watkins S.
        • Breckenridge D.
        • et al.
        Reduction of liver steatosis and fibrosis with an ASK1 inhibitor in a murine model of NASH is accomplished by improvements in cholesterol, bile acid and lipid metabolism.
        J Hepatol. 2016; 64: S170
        • Budas G.
        • Wu F.
        • Turner S.
        • Zagorska A.
        • Li L.
        • Breckenridge D.
        Characterization of ASK1 signaling in human NASH liver and human hepatic stellate cells.
        J Hepatol. 2018; 68: S351
        • Loomba R.
        • Lawitz E.
        • Mantry P.S.
        • Jayakumar S.
        • Caldwell S.H.
        • Arnold H.
        • et al.
        The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial.
        Hepatology. 2018; 67: 549-559
        • Harrison S.A.
        • Abdelmalek M.F.
        • Caldwell S.
        • Shiffman M.L.
        • Diehl A.M.
        • Ghalib R.
        • et al.
        Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis.
        Gastroenterology. 2018; 155: 1140-1153
        • Anstee Q.M.
        • Lawitz E.J.
        • Alkhouri N.
        • Wong V.W.
        • Romero-Gomez M.
        • Okanoue T.
        • et al.
        Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials.
        Hepatology. 2019; 70: 1521-1530
        • Anstee Q.M.
        • Trauner M.
        • Lawitz E.J.
        • Bzowej N.
        • Vuppalanchi R.
        • Younes Z.
        • et al.
        Validation of histologic and noninvasive measures of fibrosis as surrogate endpoints of disease progression in patients with nonalcoholic steatohepatitis (NASH).
        Hepatology. 2019; 70: 1-1476
        • Morton V.
        • Torgerson D.J.
        Effect of regression to the mean on decision making in health care.
        BMJ. 2003; 326: 1083-1084
        • Younossi Z.
        • Stepanova M.
        • Sanyal A.J.
        • Harrison S.A.
        • Ratziu V.
        • Abdelmalek M.F.
        • et al.
        The conundrum of cryptogenic cirrhosis: adverse outcomes without treatment options.
        J Hepatol. 2018; 69: 1365-1370
        • Bhala N.
        • Angulo P.
        • van der Poorten D.
        • Lee E.
        • Hui J.M.
        • Saracco G.
        • et al.
        The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study.
        Hepatology. 2011; 54: 1208-1216
        • Targher G.
        • Day C.P.
        • Bonora E.
        Current concepts: risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.
        N Engl J Med. 2010; 363: 1341-1350
        • Sanyal A.J.
        • Van Natta M.
        • Lazo M.
        • Dasarthy S.
        • Loomba R.
        • Diehl A.M.
        • et al.
        A prospective longitudinal study of clinical outcomes in adults with nonalcoholic fatty liver disease.
        Hepatology. 2019; 70: 1-1476