The US FDA has rejected Intercept’s obeticholic acid for fibrosis due to nonalcoholic steatohepatitis (NASH), another setback for an indication beset with failures.
NASH is a form of liver disease that is marked by excessive fat accumulation, inflammation and cellular damage in the liver. It affects 3–12% of adults in the US and can lead to cirrhosis, liver cancer and liver failure, but there are as yet no approved drugs for the indication. Dozens of agents are in various stages of development for this disease, chasing disease-modifying activity and a projected US$15 billion market.
Intercept’s obeticholic acid, a farnesoid X receptor (FXR) agonist, had been positioned for a first approval for this setting. In a 1,968-patient phase III trial of the drug, the primary end points were fibrosis improvement with no worsening of NASH, or NASH resolution with no worsening of fibrosis. It succeeded on the fibrosis front, with 18–23% of patients experiencing an improvement versus 12% on placebo, the company reported in The Lancet last year. But the trial missed on NASH resolution, with only 11–12% of treated patients experiencing improvement compared with 8% of placebo recipients.
The drug’s side effects include pruritus and elevated LDL cholesterol levels. The FDA approved obeticholic acid for primary biliary cholangitis in 2016, but with a black box warning that incorrect dosing can lead to fatal liver failure.
According a press release from Intercept, the FDA did not approve the drug for NASH because “the predicted benefit of [obeticholic acid] based on a surrogate histopathologic end point remains uncertain and does not sufficiently outweigh the potential risks.”
Intercept remains committed to the drug. “We strongly believe that the totality of data submitted to date both meet the requirements of the Agency’s own guidance and clearly support the positive benefit–risk profile of [obeticholic acid],” said Intercept CEO Mark Pruzanski.
Nature Reviews Drug Discovery 19, 501 (2020)