FDA Committee Votes Against Risk-Benefit Profile of OCA 25 mg for NASH


The June 22, 2023 PDUFA date for obeticholic acid 25 mg oral tablets for the treatment of precirrhotic liver fibrosis appears to be in jeopardy after a May 23, 2023 meeting of the FDA's Gastrointestinal Drugs Advisory Committee.

Credit: US Food and Drug Administration

Credit: US Food and Drug Administration

The potential for the medical community to see the first approved therapy for nonalcoholic steatohepatitis (NASH) in June 2023 was dealt a significant blow in the US Food and Drug Administration’s May 19, 2023, Gastrointestinal Drugs Advisory Committee meeting, which concluded with returning a pair of negative votes related to the New Drug Application (NDA) for obeticholic acid (OCA) 25 mg oral tablets for the treatment of precirrhotic liver fibrosis.

The meeting, which occurred just more than a month before the agent’s PDUFA Target Action Date of June 22, 2023, concluded with more than two-thirds of the committee voting against the risk-benefit profile of the agent and 15 of the 16 committee members voting to defer approval until further clinical outcomes data is submitted and reviewed.

“We are disappointed in the outcome of today’s meeting,” said Jerry Durso, President and Chief Executive Officer of Intercept.2 “We continue to disagree with the FDA on certain characterizations of OCA’s efficacy and safety in pre-cirrhotic fibrosis due to NASH and the role of non-invasive tests (NITs), as discussed in today's meeting. The robust body of evidence provided by Intercept was underscored by public testimony from the liver community, who supported OCA as an option to address the urgent treatment need in NASH and the use of NITs to manage this devastating disease in clinical practice."

The New Drug Application (NDA) for OCA 25 mg oral tablets is based on the data from the phase 3 REGENERATE trial. An ongoing phase 3, double-blind, placebo-controlled, randomized clinical trial compared OCA 10 mg and OCA 25 mg daily to placebo therapy, Intercept Pharmaceuticals filed data from an interim analysis as part of their NDA. In this interim analysis, which detailed the effects of use on surrogate endpoints at month 18, 22.4% of those using OCA 25 mg met the trial’s primary endpoint of achieving at least 1 stage of fibrosis improvement without worsening of NASH on liver biopsy relative to 9.6% of the trial’s placebo arm (P <.0001).3

When asked, “Given the available efficacy and safety data, do the benefits of OCA 25 mg outweigh the risks in NASH patients with Stage 2 or 3 fibrosis?”,12 of the FDA committee members voted “no”, with 2 abstentions and 2 voting “yes”. Following this vote, committee members were asked, at present, if they would recommend approval under the accelerated pathway based on current available data or defer approval until further clinical outcomes data can be submitted and reviewed, 15 of the 16 committee members voted in favor of deferral.1

“I voted no for a couple of reasons. Although I acknowledge the applicant has met the primary endpoint for efficacy, and I would like to be very optimistic that this will translate ultimately into clinical benefit, I remain concerned a drug like this will remain restricted to prescription only by experts who are willing to take the necessary steps that are required to mitigate risks,” explained Jacquelyn Maher, MD, chief of gastroenterology at the Zuckerberg San Francisco General Hospital and program director of UCSF Liver Center, when explaining her vote against the risk-benefit profile.1 “I also am concerned at the high prevalence of biliary disease in this population is going to raise the potential for drug-induced liver injury.”

In their release, the company noted it will be hosting a conference call on Monday, May 22, 2023, from 8:30-9:00 AM ET to discuss the advisory committee meeting. According to the company’s release, Intercept expects the REGENERATE trial to continue.2


  1. “May 19, 2023 Meeting of the Gastrointestinal Drugs Advisory Committee (GIDAC)" YouTube, uploaded by U.S. Food and Drug Administration, May 29, 2023, https://www.youtube.com/live/iZZveut3cd8?feature=share
  2. Intercept announces outcome of FDA Advisory Committee meeting for Obeticholic acid as a treatment for pre-cirrhotic fibrosis due to Nash. Intercept Pharmaceuticals, Inc. May 19, 2023. Accessed May 19, 2023. https://ir.interceptpharma.com/news-releases/news-release-details/intercept-announces-outcome-fda-advisory-committee-meeting.
  3. Intercept announces positive data in fibrosis due to Nash from a new analysis of its phase 3 regenerate study of Obeticholic acid (OCA). Intercept Pharmaceuticals, Inc. July 7, 2022. Accessed May 19, 2023. https://ir.interceptpharma.com/news-releases/news-release-details/intercept-announces-positive-data-fibrosis-due-nash-new-analysis.
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