FDA Rejects NDA for Fatty Liver Disease Therapy

The FDA has issued a complete response letter (CRL) for the new drug application (NDA) for obeticholic acid (OCA) to treat patients with pre-cirrhotic fibrosis due to nonalcoholic steatohepatitis (NASH).

NASH is a progressive liver disease caused by excessive fat accumulation in the liver that leads to inflammation and liver injury. Progressive liver scarring (fibrosis) can lead to cirrhosis, liver failure, cancer, and death. Developed by Intercept Pharmaceuticals, obeticholic acid is a farnesoid X receptor (FXR) agonist. FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways.

Last month, an FDA advisory committee voted no on the question of whether the efficacy and safety presented outweigh the risks. In its CRL, the FDA indicated that any resubmission of an NDA for OCA in NASH would require data on long-term outcomes.

This is the second complete response letter for OCA. Intercept had resubmitted an NDA in December 2022, after the FDA issued CRL in June 2020. At issue was Intercept’s use of a surrogate endpoint. The agency wanted to see additional post-interim analysis efficacy and safety data.

Related: FDA Accepts Application for NASH Drug

The company has decided to discontinue all NASH-related research and restructured to focus on rare and serious liver diseases. R&D will now focus on a fixed-dose combination of OCA and bezafibrate to treat patients with primary biliary cholangitis (PBC), a chronic disease that affects the bile ducts in the liver.

Jerry Durso

“We remain committed to the liver community and will continue to advance our leadership in rare and serious liver diseases where Intercept has deep expertise and a recognized dedication to therapeutic innovation,” Jerry Durso, president and chief executive officer of Intercept, said in a press release.

The first phase 2 interim analysis for the OCA-bezafibrate combination was presented recently at the 2023 European Association for the Study of the Liver Congress. The analysis show that the combination as effective in normalizing multiple biochemical markers associated with primary biliary cholangitis-induced liver damage. Two ongoing phase 2 studies are exploring a range of therapeutic doses for the combination, with planned interim analyses from both studies expected to be completed in 2023.

Additionally, company executives said an ongoing phase 2a study of INT-787, a next-generation farnesoid X receptor (FXR) agonist, seeks to establish a proof-of-concept in severe alcohol-associated hepatitis.