Research ArticleSelonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials
Graphical abstract
Introduction
Non-alcoholic steatohepatitis (NASH), a progressive form of non-alcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis, hepatocyte injury, and inflammation, is estimated to have a worldwide prevalence between 1.5% and 6.5%.1 The natural history of NASH is variable, but approximately one-third of patients will progress to cirrhosis with the attendant risks of hepatic decompensation, hepatocellular carcinoma (HCC), and premature mortality.2 The prevalence of cirrhosis resulting from NASH has risen dramatically in recent decades, and will soon overtake viral hepatitis as the leading indication for liver transplantation.[3], [4], [5] Thus far, no pharmacologic therapies have been approved for the treatment of NASH. Although weight loss may be effective, it has proven difficult to achieve and sustain, and antifibrotic effects in patients with advanced fibrosis appear limited.6 As fibrosis is the primary determinant of clinical disease progression in patients with NASH, there is a clear unmet medical need for new therapies with antifibrotic effects, particularly for patients with bridging fibrosis and cirrhosis.[7], [8], [9], [10]
Selonsertib is an oral, once daily inhibitor of apoptosis signal-regulating kinase 1 (ASK1). When activated by oxidative stress, ASK1 signals through the mitogen-activated protein kinase pathway terminating in the effector kinases p38 and c-Jun N-terminal kinase, which mediate proinflammatory and pro-fibrotic changes in the liver.[11], [12], [13], [14], [15] The ASK1 pathway, as indicated by hepatic expression of phosphorylated p-38 (p-p38), is upregulated in patients with NASH and correlates with the stage of liver fibrosis.15 In pre-clinical models of NASH and liver fibrosis, ASK1 inhibition has demonstrated antifibrotic effects.14 Moreover, in a 24-week, phase II study in patients with NASH and stage 2 or 3 liver fibrosis, 43% of those receiving selonsertib 18 mg and 30% of those receiving selonsertib 6 mg experienced a reduction of at least 1 stage in hepatic fibrosis, compared with 20% of patients receiving an inactive therapy (simtuzumab).16 Hepatic expression of p-p38 was reduced in this trial in a dose-dependent fashion, supporting the pharmacodynamic activity of selonsertib.
Based on this mechanistic rationale, pre-clinical data, and promising phase II data, we conducted the STELLAR-3 and STELLAR-4 phase III trials to evaluate whether ASK1 inhibition with selonsertib could cause fibrosis regression and reduce clinical disease progression in patients with bridging fibrosis or compensated cirrhosis due to NASH.
Section snippets
Patients
Eligible patients were 18 to 70 years of age with a histologic diagnosis of NASH (defined as a NAFLD activity score [NAS] of ≥3 with at least each of grade 1 steatosis, hepatocellular ballooning, and lobular inflammation). The STELLAR-3 trial (NCT03053050) enrolled patients with bridging fibrosis (F3 fibrosis according to the NASH Clinical Research Network [CRN] classification) and the STELLAR-4 trial (NCT03053063) enrolled patients with compensated cirrhosis (F4 fibrosis). An historical liver
Baseline characteristics
For the STELLAR-3 trial, 2,250 patients were screened between January 31, 2017 and March 17, 2018, at sites in 26 countries in Europe, North America, South America, Asia, and the Pacific region. Of these, 808 patients with bridging fibrosis (F3) were randomized and 802 began treatment (Fig. S1). For the STELLAR-4 trial, 2,154 patients were screened between January 30, 2017 and January 23, 2018 at sites in 21 countries in Europe, North America, Asia, and the Pacific region. Of these, 883
Discussion
In these 2 large, randomized, placebo-controlled, phase III studies in patients with bridging fibrosis or compensated cirrhosis due to NASH, treatment for 48 weeks with the ASK1 inhibitor selonsertib demonstrated potent activity against the target, but was not associated with regression of fibrosis or a reduction in liver-related clinical events. This lack of efficacy was confirmed by all methods of assessment including histology and serum markers of fibrosis and liver injury. Moreover,
Financial support
This study was funded by Gilead Sciences.
Authors' contributions
Study Concept and Design: C. Stephen Djedjos, G. Mani Subramanian, Robert P. Myers. Acquisition of Data: Stephen A. Harrison, Vincent Wai-Sun Wong, Takeshi Okanoue, Natalie Bzowej, Raj Vuppalanchi, Ziad Younes, Anita Kohli, Shiv Sarin, Stephen H. Caldwell, Naim Alkhouri, Mitchell L. Shiffman, Nadege Gunn, Aasim Sheikh, Quentin M. Anstee, Manuel Romero Gomez, Michael Trauner, Zachary Goodman, Eric J. Lawitz, Zobair Younossi. Analysis and Interpretation of Data: Catherine Jia, Yanni Zhu, C.
Role of the sponsor
The studies were designed and conducted according to protocol by the sponsor (Gilead Sciences) in collaboration with the principal investigators. The sponsor collected the data, monitored study conduct, and performed statistical analyses.
Writing assistance
The initial draft of the manuscript was prepared by a professional writer (David McNeel) employed by the sponsor; subsequent drafts incorporated input from all authors.
Conflict of interest
Dr. Harrison consults for, advises, and has received grants from, and owns stock in Galectin, GENFIT, and Madrigal. He consults for, advises, and has received grants from Axcella, Cirius, CymaBay, Galmed, Gilead, HighTide, Intercept, NGM, Novartis, Novo Nordisk, and Pfizer. He consults for, advises, and owns stock in Akero and Metacrine. He consults for and advises 3V Bio, Albireo, Blade, Bristol-Myers Squibb, CLDF, ContraVir, Consynance, Corcept, Echosens, Gelesis, HistoIndex, Innovate, IQVIA,
Acknowledgements
We thank the patients and their families, as well as the investigators and site personnel.
The manuscript was drafted by David McNeel and editorial assistance was provided by Sandra Chen, both of Gilead Sciences.
References (24)
- et al.
Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States
Gastroenterology
(2015) - et al.
Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease
Gastroenterology
(2009) - et al.
Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury
Toxicol Appl Pharmacol
(2015) - 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) - et al.
Characterization of ASK1 signaling in human NASH liver and human hepatic stellate cells
J Hepatol
(2018) - et al.
Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis
Gastroenterology
(2018) - et al.
The conundrum of cryptogenic cirrhosis: adverse outcomes without treatment options
J Hepatol
(2018) - et al.
Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes
Hepatology
(2016) - 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) - et al.
Increasing incidence of nonalcoholic steatohepatitis as an indication for liver transplantation in Australia and New Zealand
Liver Transpl
(2019)
NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances
Am J Gastroenterol
The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials
Hepatology
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Author names in bold designate shared co-first authorship
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STELLAR-3 and STELLAR-4 investigators listed in the online supplementary information.