Selonsertib (Gilead) is a small molecule that inhibits apoptosis signal-regulating kinase 1 (ASK1). ASK1 has been shown to promote inflammation, apoptosis, and fibrosis in settings of oxidative stress. Non-alcoholic steatohepatitis (NASH) increases oxidative stress and ASK1 activation, so by inhibiting ASK1, selonsertib has been shown to decrease inflammation and fibrosis in patients with NASH.
Selonsertib’s failure to show a ≥1 stage improvement in fibrosis without worsening of NASH in both F3 and F4 patients has left Gilead relying on a combination approach with cilofexor and firsocostat. The failure to show a benefit in both patient populations is concerning and could be indicative of a mechanistic flaw. Selonsertib is an inhibitor of ASK1. Despite preclinical evidence linking apoptosis with NASH, it is possible that this mechanism is not sufficient alone without treating the underlying cause of fibrosis. Cilofexor, a nonsteroidal farnesoid X receptor (FXR) agonist, targets liver fibrosis, while firsocostat, an acetyl-CoA carboxylase (ACC) inhibitor, blocks fatty acid synthesis. The combined effects of these therapies could impact earlier changes that contribute to apoptosis and fibrosis. If successful, this could provide a strong marketing opportunity for Gilead, though currently this is speculative given the failure of the Phase III STELLAR 3 and STELLAR 4 trials in F3 and F4 NASH patients, respectively.
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