The Food and Drug Administration’s Gastrointestinal Drugs Advisory Committee has voted against the accelerated approval of Intercept Pharmaceuticals’ obeticholic acid (OCA) for treatment of nonalcoholic steatohepatitis (NASH) with stage 2 or 3 fibrosis.
This is the second time that Intercept has sought FDA approval for OCA in treating NASH.
The committee voted 12 to 2 (with 2 abstentions) that the benefits of OCA did not outweigh the risks to this patient population. While OCA showed a modest benefit of improving fibrosis in NASH patients, safety concerns included increased risk for drug-induced liver injury (DILI), cholelithiasis, pruritus, dyslipidemia, and dysglycemia.
Committee members were most concerned with the increased risk for DILI in patients taking OCA. Intercept said that frequent monitoring for DILI in such a large eligible population – an estimated 6-8 million individuals taking the drug to treat the condition – would be difficult.
“Typically, in clinical practice, NASH patients are followed every 6-12 months, so more frequent monitoring would be a substantial change and may not be achievable outside of the clinical trial setting,” according to a briefing document released before the committee meeting.
The FDA estimates that 16.8 million U.S. adults have NASH, with 5.7 million having NASH with advanced fibrosis, according to briefing documents. NASH is the second leading cause of liver transplants in the United States and is the. There are currently no FDA-approved therapies to treat NASH.
OCA, sold under the commercial name Ocaliva, was first approved in 2016 to treat primary biliary cholangitis, and is prescribed at up to 10 mg per day. Intercept proposed that OCA be given in daily 25-mg doses in the treatment of precirrhotic fibrosis attributable to NASH.
In 2019, Intercept initially filed for a new drug application (NDA) for OCA for the treatment of precirrhotic fibrosis attributable to NASH but were issued a Complete Response Letter after the FDA determined that the medication had an “unfavorable risk benefit-risk assessment.” Intercept resubmitted an NDA for OCA in December 2022, including two 18-month analyses from a phase 3 study, REGENERATE (Randomized Global Phase 3 Study to Evaluate the Impact on NASH with Fibrosis of Obeticholic Acid Treatment). In the study, which included data from 931 patients, OCA 25 mg outperformed placebo in improving fibrosis with no worsening of NASH over 18 months, one of two primary endpoints of the clinical trial. The estimated risk difference ranged from 8.6 to 12.8 across different analyses, which the FDA categorized as a “modest treatment effect.”
There was no significant difference between OCA 25 mg and placebo in NASH resolution with no worsening fibrosis. Both endpoints were surrogate endpoints, meaning that they were “reasonably likely to predict clinical benefit.” The FDA noted that it is not known if a decrease in fibrosis stage would lead to clinically meaningful outcomes, such as reduction in liver-related events.
The committee members voted 15-1 to defer approval until clinical outcome data is submitted and reviewed. The FDA has set a target decision date regarding the accelerated approval of OCA for NASH for June 22, 2023.
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