The U.S. Food and Drug Administration has delivered a significant blow to NASH drug development by rejecting Intercept Pharmaceuticals' obeticholic acid, triggering industry-wide implications for the treatment of non-alcoholic steatohepatitis (NASH). The decision sent Intercept's shares plummeting by more than 40% on the Nasdaq stock exchange.
Regulatory Setback and FDA Requirements
The FDA issued a Complete Response Letter (CRL) for obeticholic acid, citing uncertainties about the drug's predicted benefits based on surrogate endpoints. The agency has requested additional safety and efficacy data from the ongoing REGENERATE study, specifically calling for the continuation of the long-term outcomes phase to support potential accelerated approval.
The rejection came after two extensions of what was initially planned as a six-month expedited review. The FDA had postponed an expert advisory committee meeting due to the COVID-19 pandemic but proceeded with its decision without convening the panel.
Industry Impact and Company Response
Intercept's CEO Mark Pruzanski strongly criticized the FDA's decision, highlighting a lack of communication regarding the drug's ineligibility for accelerated approval. "The FDA has progressively increased the complexity of the histologic endpoints, creating a very high bar that only [obeticholic acid] has so far met in a pivotal phase 3 study," Pruzanski stated.
The company expressed particular concern about the FDA's "evolving expectations," which they believe could significantly impede the development of innovative therapies for NASH patients with high unmet medical needs. Intercept plans to meet with the FDA to discuss potential pathways forward.
Safety Considerations and Market Implications
The rejection raises important safety considerations, as obeticholic acid has previously shown liver damage risks in its approved indication for primary biliary cholangitis (PBC). The current PBC label recommends reduced dosing for patients with severe liver impairment, suggesting the FDA may be seeking treatments with better safety profiles.
Competitive Landscape Shifts
The FDA's decision has created ripple effects across the NASH drug development landscape. While competitors like Genfit have already faced setbacks with their candidate elafibranor's phase 3 trial failure, French biotech Inventiva has emerged as a potential contender with their drug lanifibranor, which recently demonstrated positive results in a phase 2b trial.
The rejection sets a precedent for higher regulatory standards in NASH drug development, potentially affecting the timeline and requirements for other companies working on treatments for this condition. Inventiva plans to meet with regulators in the fourth quarter, targeting a potential 2025 launch pending successful phase 3 trials.
