With NASH Drug Rejected, Intercept CEO Lambasts FDA’s Evolving Guidelines

by Sangeeta Chakraborty
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By Sangeeta Chakraborty, Ph.D.

In a complete response letter, the FDA handed an outright rejection to Intercept’s fatty liver drug, obeticholic acid (OCA), much to the ire of its top brass.


Intercept Pharmaceuticals had been a long time investor in the development and commercialization of novel therapeutics for the treatment of progressive non-viral liver diseases. OCA is one of its potential flagship drugs touted as a breakthrough therapy for the treatment of fibrosis in patients with non-alcoholic steatohepatitis (NASH).

NASH, an advanced and severe form of non-alcoholic fatty liver disease (NAFLD) is characterized by scarring and fibrosis of liver tissue. NAFLD starts with a buildup of fat in the liver due to preexisting obesity, high sugar diet, physical inactivity, and diabetes. This eventually causes inflammation, damage and impairs liver function giving rise to NASH. Symptoms are not readily apparent until the late stages.

Primary treatments include lifestyle changes and dietary management, with some cases requiring pharmacological interventions. Farnesoid X receptor regulates hepatic metabolism, and NAFLD has been reported to have abnormal FXR activity. OCA is a first-in-class selective FXR agonist with anticholestatic and hepato-protective properties. Currently, OCA is registered for the treatment of primary biliary cholangitis. However, clinical trials are underway to determine OCA’s benefits in NASH.



The currently ongoing Phase 3 REGENERATE trial, a randomized, double-blind, placebo-controlled study, evaluates the efficacy of OCA in reducing liver fibrosis in 2480 NASH patients with two primary endpoints:

  1. Do patients treated with OCA achieve improvement of liver fibrosis without worsening their NASH, or achieve resolution without worsening liver fibrosis?
  2. Does OCA improve survival by reducing mortality from any or liver-related cause?

In February 2019, Intercept had announced the first set of REGENERATE study results obtained from the planned 18-month interim analysis, and based on the positive data, it was hopeful that OCA would become the first approved drug for those living with fibrosis due to NASH.

In one of the main goals of the study, NASH patients who were taking once-daily OCA 25 mg showed improvement in their liver fibrosis without any worsening of the disease. Although it aided in the resolution of symptoms, it missed the overall intended primary objective due to a lack of statistical significance. As per the FDA, the study was required to meet one of the two primary endpoints. Later in April, Intercept reported additional positive data on the robust efficacy of OCA across several biochemical and histologic parameters and submitted it for accelerated approval by September. However, prior to the NDA filing, Intercept and the FDA agreed on an amended clinical trial design where attaining just one of the two primary endpoints would be enough to expedite approval.

An independent advisory panel of experts was supposed to convene earlier this year to examine the interim analysis of the trial, but it was postponed to June 9th because of the COVID-19 pandemic. However, Intercept reports that the rescheduled meeting never took place. Meanwhile, as per the Agency’s request, additional data were submitted to enable a favorable decision, which unfortunately culminated in a rejection notice.

In a complete response letter, the FDA stated that it does not support the accelerated approval of OCA for patients with NASH based on the data that they reviewed to date. It further elaborated that it finds the predicted benefit of the drug uncertain, based on a surrogate histologic endpoint and that the benefits do not outweigh the drug’s potential risks. However, Intercept is asked to submit additional long-term safety and efficacy data from the trial to continue to support possible approval in the future.

“At no point during the review did the FDA communicate that OCA was not approvable on an accelerated basis, and 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,” Intercept’s CEO Mark Pruzanski said in a statement.

Expressing his concerns, he further condemned the Agency’s “apparently still evolving expectations [that] will make it exceedingly challenging to bring innovative therapies to NASH patients with a high unmet medical need.”

Pruzanski said the immediate next step is scheduling a meeting with the FDA to discuss the rejection letter.

Editor: Rajaneesh K. Gopinath, Ph.D.

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