Gilead’s selonsertib flunks another NASH phase 3

Gilead’s NASH candidate selonsertib has disappointed in yet another phase 3 trial. This time, two different doses of the drug did worse than placebo at reducing scarring in patients with bridging fibrosis—also called stage 3 fibrosis—from nonalcoholic steatohepatitis (NASH). 

The phase 3 STELLAR-3 study enrolled more than 800 patients with NASH-related bridging fibrosis—so-called because the scarring "bridges" liver lobules and the central veins of the liver. The patients were randomized to receive one of two doses of the ASK1 inhibitor selonsertib or placebo once a day. After 48 weeks, the investigators looked at how many patients had an improvement in fibrosis of at least one stage—that is, how many patients’ scarring reduced to stage 2 or even stage 1 fibrosis—without any worsening of NASH. 

The numbers were bleak. Of the 322 patients who received the higher dose of selonsertib, only 9% achieved this improvement, as measured against the NASH Clinical Research network classification. The lower dose fared a little better, with 12% of the 321 patients achieving a ≥ 1-stage improvement in fibrosis. But both doses were outperformed by placebo, which improved fibrosis in 13% of 159 patients. 

Gilead is now working to wrap up the trial "in a manner consistent with the best interests of each patient," it said in a statement. It had been slated to run for five times as long: 240 weeks. 

The news comes after selonsertib failed a different phase 3 study testing it in nearly 900 patients with NASH-linked cirrhosis, or stage 4 fibrosis. Though the higher dose did slightly better than placebo—14% vs. 13% —it didn’t statistically outperform placebo. The lower dose did worse than placebo. That trial met the same fate as STELLAR-3. 

"While we had hoped for different outcomes from the STELLAR program, we remain focused and committed to developing highly effective treatments for patients living with advanced fibrosis due to NASH. We are actively exploring the STELLAR data and will work with external collaborators like PathAI and insitro, to further our understanding of this complex disease and advance our development programs," said Gilead Chief Scientific Officer and Head of R&D John McHutchison, M.D., in the statement. 

Gilead and insitro struck a three-year deal to discover and develop up to five drug targets for NASH just last week. The Big Pharma paid up $15 million upfront, but with $200 million in milestones for each of the targets, insitro could pick up more than $1 billion in total. 

McHutschison also offered hope in Gilead’s other NASH programs: "We believe that effective therapy for NASH will ultimately require a combination approach that targets distinct pathways involved in the pathogenesis of this disease. In this regard, we look forward to data from the Phase 2 ATLAS combination trial of selonsertib, cilofexor and firsocostat in patients with advanced fibrosis due to NASH, which will be available later this year," he said.

Gilead picked up cilofexor and firsocostat from Phenex Pharmaceuticals and Nimbus Therapeutics respectively. Earlier this month, Gilead reported that the combination of the two saw improvements in hepatic steatosis, liver stiffness, liver biochemistry and serum fibrosis markers in a small, 20-patient study.

by Amirah Al Idrus

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