FDA Panel Votes on Obeticholic Acid for Pre-Cirrhotic Fibrosis Due to NASH

The Food and Drug Administration’s (FDA) Gastrointestinal Drugs Advisory Committee voted 12 “no” and 2 “yes” (with 2 abstentions) on whether the available data supported the approval of obeticholic acid (OCA), a farnesoid X receptor agonist, for the treatment of pre-cirrhotic fibrosis due to nonalcoholic steatohepatitis (NASH).

The panel also voted 15 to 1 to defer approval of OCA for this indication until additional clinical outcome data from the REGENERATE trial (ClinicalTrials.gov Identifier: NCT02548351) was submitted and reviewed.

The New Drug Application (NDA) submission included 2 interim analyses from the double-blind, placebo-controlled phase 3 REGENERATE trial, which enrolled patients with biopsy-proven stage 2 or 3 liver fibrosis due to NASH. Participants were randomly assigned to receive OCA 10mg (n=312), OCA 25mg (n=308), or placebo (n=311) orally once daily for 18 months. The coprimary endpoints were the proportion of patients achieving at least 1 stage of liver fibrosis improvement with no worsening of NASH; or the proportion of patients achieving NASH resolution with no worsening of liver fibrosis.

Results showed OCA 25mg was found to be superior to placebo on the primary endpoint of improvement in fibrosis and no worsening of NASH; across different analyses, the estimated risk difference ranged from 8.6% to 12.8%. However, neither OCA 10mg or 25mg were superior to placebo on the primary endpoint of resolution of NASH and no worsening of fibrosis.

The most common treatment-emergent adverse event reported was pruritus. The OCA 25mg group was observed to have higher rates of biliary events, including gallstones. An analysis of safety data showed a higher number of adjudicated hepatic adverse events for OCA 25mg, which was of substantial concern to the committee. Treatment with OCA was also associated with elevation in LDL-C and worsening of glycemic control.

Commenting on the vote, Jerry Durso, President and CEO of Intercept said, “We are disappointed in the outcome of today’s meeting. 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.”

According to the FDA, NITs lack the accuracy to identify patients with NASH with stage 2/3 fibrosis. Liver biopsy, which carries morbidity risk, would therefore be required to diagnose, stage, and grade NASH. In the briefing document, the panel also noted “significant challenges and uncertainties” with mitigating the risks of drug-induced liver injury (DILI) in clinical practice. “Given the lack of predictability for the timing of DILI emergence, and the potential that cholelithiasis may heighten the DILI risk, FDA is concerned that any DILI risk mitigation plan will fall short, and moderate to severe DILI is likely to occur at the same frequency, or possibly at a higher frequently, in the postmarket setting.”

Although not bound to the committee’s recommendations, the FDA does take them into consideration when making decisions on approval. A regulatory decision is expected on June 22, 2023.

Obeticholic acid is currently approved under the brand name Ocaliva for the treatment of adult patients with primary biliary cholangitis without cirrhosis or with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA.