The FDA’s Gastrointestinal Drugs Advisory Committee (GDAC) has recently voted against Intercept Pharmaceutical’s new drug application (NDA) for obeticholic acid (OCA) 25 mg oral tablets as a treatment for pre-cirrhotic liver fibrosis due to nonalcoholic steatohepatitis (NASH) on the basis that the benefits did not outweigh the risks. The move will significantly reduce the potential for Intercept to become the first-ever provider of NASH therapy, says GlobalData, a leading data and analytics company.

Sravani Meka, Senior Immunology Analyst at GlobalData, comments: “While extremely disappointing for Intercept and the NASH community, this vote is not entirely surprising as the briefing documents released prior to the GDAC meeting showed that the agency had numerous grievances with the filing. The main elements of concerns include side-effect profiles of OCA such as potential risks of liver injury and diabetes from the drug, and the magnitude of change seen in surrogate endpoints and the relevance of these changes in achieving meaningful clinical outcomes.”

For context, OCA failed to meet the other primary endpoint of showing significant NASH resolution with no worsening fibrosis with 25mg of OCA in the Phase 3 REGENERATE trial. The FDA stated that the “modest” efficacy that OCA offers is not enough to “justify OCA use in NASH subjects with stage 2 or 3 fibrosis” given that to qualify for the medication, patients would have to undergo a liver biopsy, which can be painful and invasive with various complications.

Meka continues: “Although this vote has narrowed OCA’s chances to get FDA approval by the target Prescription Drug User Fee Act date of June 2022, it has left the door open for OCA to potentially present more robust data in the future. However, as it currently stands, with the Phase III REGENERATE trial scheduled to reach completion in September 2025, Intercept’s OCA will not be taking the title of first-to-market therapy in NASH.”

Recall, Madrigal Pharmaceuticals recently announced plans to submit an NDA seeking accelerated approval of resmetirom (selective thyroid hormone receptor-β agonist; THR-Beta agonist) for the treatment of non-cirrhotic NASH with liver fibrosis by June 2023. The company’s announcement to file for an NDA follows positive topline results from its pivotal Phase III MAESTRO-NASH clinical trial (NCT03900429).

For context, the Phase III MAESTRO-NASH trial evaluated resmetirom (80 or 100mg) in patients with NASH and fibrosis in resolving NASH and reducing progression to cirrhosis and/or hepatic decompensation. Topline results demonstrated that both daily oral doses of resmetirom achieved both primary endpoints (improvements in NASH and liver fibrosis on liver biopsies) and potentially clinically meaningful effects compared to placebo.

Additionally, in January 2023, Madrigal presented data from a supportive analysis, conducted by central pathologists, that replicated the positive primary endpoint results using consensus reads of digitized biopsy images.

Meka concludes: “Following such positive data, unique MOA, and superior tolerability profile of Madrigal’s resmetirom, it is likely that Madrigal’s resmetirom will be the first therapy approved in NASH.”