Commentary
Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in nonalcoholic steatohepatitis (NASH). Selonsertib is an investigational selective inhibitor of ASK1.
In order to evaluate the safety and anti-fibrotic effect of selonsertib, Stephen A. Harrison et al. conducted two randomized, double-blind, placebo-controlled, phase 3 trials in patients with NASH and bridging fibrosis (F3, STELLAR-3 trial) or compensated cirrhosis (F4, STELLAR-4 trial). Patients were randomized to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks.
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%, 12% and 13% of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14%, 13%, and 13% of patients, respectively.
Selonsertib had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. Forty-eight weeks of selonsertib monotherapy had no anti-fibrotic effect in NASH patients with stage F3 and F4 fibrosis – those most in need of treatment. Nonetheless, important lessons were learned from this and similar trials about the extent of confidence needed to progress to a phase 3 program, as we learn more about the natural history of this enigmatic disease.
