The FDA has rejected Intercept Pharmaceuticals’ obeticholic acid for nonalcoholic steatohepatitis (NASH), another disappointment for a crowded field littered with failures.
Obeticholic acid, a farnesoid X receptor agonist, was aiming to become the first drug for NASH, a potentially fatal disease characterized by fat accumulation, inflammation and fibrosis in the liver. A 1,968-patient phase 3 trial of obeticholic acid reported encouraging, if modest, results: 18–23% of treated patients experienced an improvement in fibrosis, as measured histologically on biopsy, compared with 12% of patients on placebo. On another primary endpoint, NASH resolution, there was no statistically significant difference. A 2018 FDA draft guidance on NASH recommended that sponsors consider improvement in fibrosis as one of three suggested efficacy endpoints for pivotal trials in this setting. The guidance also noted that, of the histologic features of NASH, “fibrosis is the strongest predictor of adverse clinical outcomes.”
The FDA has now rejected obeticholic acid, reportedly deciding that the drug’s predicted benefit, based on the surrogate histopathologic fibrosis endpoint, remains uncertain and does not sufficiently outweigh its risks. “On behalf of the hepatology community, we are very concerned that the agency’s apparently still evolving expectations will make it exceedingly challenging to bring innovative therapies to NASH patients with high unmet medical need,” says Intercept CEO Mark Pruzanski. Intercept will meet with the FDA to discuss next steps.
Separately, a phase 2a trial of Akero Therapeutics’ efruxifermin is offering hope. The company announced in March that its FGF21 (fibroblast growth factor 21) mimetic met its primary endpoint in this trial, reducing hepatic fat as measured by MRI. On 30 June, an exploratory efficacy analysis of end-of-treatment histological results in a subset of 40 patients whose disease responded is now bolstering enthusiasm. 48% of these patients experienced NASH resolution without worsening of fibrosis, and 48% experienced fibrosis improvement without worsening of NASH. Akero plans to start a phase 2b/3 trial of efruxifermin in 2021.
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Liver macrophages and inflammation in physiology and physiopathology of non‐alcoholic fatty liver disease
The FEBS Journal (2021)
Molecular Metabolism (2020)