Selonsertib misses endpoint, provides future trial design insight
BOSTON — While selonsertib did not demonstrate efficacy as a monotherapy in patients with nonalcoholic steatohepatitis-related advanced fibrosis, data from the trial provided key insights for future trial design and potential for selonsertib in combination therapy, according to data presented at The Liver Meeting 2019.
“It’s important to see what we can glean from a study of this magnitude,” Stephen A. Harrison, MD, medical director of Pinnacle Clinical Research in San Antonio, said during his presentation. “Data from these trials provide important information regarding the utility of liver biopsy and noninvasive tests as clinical trial endpoints and the natural history of NASH with advanced fibrosis.”
Selonsertib (Gilead) is a potent, selective small molecule inhibitor of ASK1 that, according to Harrison, showed beneficial effects on fibrosis regression and progression in phase 2 trials.
At a pre-planned efficacy analysis at week 48, both the STELLAR-3 trial including patients with NASH and bridging fibrosis and the STELLAR-4 trial including patients with NASH and compensated cirrhosis were stopped due to lack of efficacy, Harrison said during his presentation.
Neither the 6 mg or 18 mg dose of selonsertib led to significant improvement in the primary endpoint of improvement in fibrosis by one stage or more without worsening of NASH or the secondary endpoints of any fibrosis improvement or NASH resolution without worsening of fibrosis.
“There is an interesting phenomenon. If you put all 1,679 patients with advanced liver disease from both trials together, we can begin to draw some informative conclusions,” Harrison said. “Sixty percent of these cohorts together were female, 68% were obese, 74% were diabetic and over 80% had a [nonalcoholic fatty liver disease] score of 5 or more.”
Harrison noted that there are also some distinct differences between the bridging fibrosis population and the cirrhosis population, in which the aspartate aminotransferase/alanine aminotransferase ratio flips from less than 1 to more than 1.
“We wanted to see if we hit target engagement, despite the fact that the studies did not meet their primary endpoints,” Harrison continued.
In a post-hoc analysis of STELLAR-4 patients, the researchers found that both the 6 mg (–73 vs. –33; P = .045) and 18 mg doses (–78 vs. –33; P = .009) showed a greater reduction in the phospho-P38 area compared with placebo. Doses of 6 mg (–45 vs. 8; P = .017) and 18 mg (–63 vs. 8; P = .001) also showed a reduction in phospho-P38 nuclei.
Selonsertib was safe and well-tolerated among patients and adverse events including grade 3 and grade 4 events occurred at similar rates between both study arms and either dose.
Harrison pointed to data showing that patients with lower Enhanced Liver Fibrosis (ELF) scores at baseline were less likely to have overall disease progression and more likely to meet the primary endpoint.
“This has implications for the way we design clinical trials in the future, particularly if you’re enrolling patients with mild fibrosis and you enroll them with low ELF scores. A high percentage of those people may improve spontaneously,” he said. – by Talitha Bennett
Reference: Harrison SA. Abstract 0064. Presented at: The Liver Meeting; Nov. 7-12, 2019; Boston.
Disclosure: Harrison reports he is a consultant for 3VBio, Akero, Albereo, Axcella, Blade Therapeutics, Bristol-Myers Squibb, Cirius, Civi, CLDF, ConSynance, ContraVir, Corcept, CymaBay, Echosens, Galectin, Galmed, Gilead, HighTide, HistoIndex, Innovate, Intercept, IQVIA, Lipocine, Madrigal, Medpace, Metacrine, NGM, Novartis, Novo Nordisk, Perspectum, Pfizer, Poxel, PPD, Prometheus, Prometic and Terns; is on the speakers bureau with Alexion; and has received research support from Allergan, Axcella, Cirius, Conatus, CymaBay, Galectin, Galmed, Genfit, Gilead, HighTide, Immuron, Intercept, Madrigal, NGM, Novartis, Novo Nordisk, Pfizer, Second Genome and Tobira. This study was funded by Gilead.