Ocaliva fails NASH trial just as Intercept charts path toward FDA application

The path to a potential nonalcoholic steatohepatitis (NASH) drug approval just got bumpier for Intercept Pharmaceuticals.

The company’s obeticholic acid (OCA) has failed to top placebo at improving liver scarring among patients with compensated NASH-related cirrhosis in a phase 3 trial, Intercept said Friday. The drug is currently marketed as a biliary cirrhosis treatment under the brand name Ocaliva.

The failure of the trial, dubbed Reverse, adds an extra wrinkle to Intercept’s planned FDA filing for OCA in patients with less advanced liver fibrosis, or scarring, caused by NASH. That filing centers around a second analysis of another phase 3 trial called Regenerate.

Intercept was quick to distance Regenerate from the fresh Reverse flop. The company said it remains on track to resubmit its application for OCA in NASH-caused liver fibrosis by the end of the year, a plan that’s unaffected by the new efficacy results in Reverse.

In an August note, RBC Capital Markets analysts put Ocaliva’s U.S. sales estimates in pre-cirrhotic NASH patients at $567 million in 2027 and $226 million in more advanced patients.

Reverse was one of the two trials Intercept launched with the hope to expand Ocaliva to different populations in NASH. The trial was designed to evaluate whether the drug could help patients with compensated cirrhosis achieve at least one stage of histological improvement in fibrosis with no worsening of NASH after 18 months of treatment.

By that time, 11.1% of patients who took 10 mg of OCA once daily and 11.9% of subjects who later titrated to 25 mg of OCA achieved that goal. The drug’s performance wasn’t significantly better than the 9.9% recorded in the placebo group, so the trial missed its primary endpoint. But Intercept said a positive impact on liver stiffness was noted in the OCA arms.

Hitting statistical significance for histological improvement in compensated cirrhosis has proven to be “an extremely high bar” in clinical trials, Intercept’s R&D chief M. Michelle Berrey, M.D., said in a statement. The negative readout “underscores the importance of treating liver fibrosis due to NASH before it progresses to cirrhosis,” she added.

Pre-cirrhotic liver fibrosis is the indication Intercept intends to pursue with its upcoming FDA filing. Back in 2020, the FDA rejected Intercept’s application for an accelerated approval in NASH based on a histopathologic analysis of the successful Regenerate trial.

Intercept recently re-analyzed Regenerate using a central consensus reading of liver biopsies across the trial, instead of relying on an individual pathologist’s own interpretation. In the new analysis, 22.4% of patients with milder scarring (compared with those in Reverse) who took OCA at 25 mg achieved at least one stage of fibrosis improvement without worsening of NASH at month 18, versus 9.6% for placebo. The company also provided a longer safety follow-up of the patients, offering a median of 42 months of exposure to the drug compared with 15 months in the previous analysis.

In July, Intercept had a “very productive” meeting with the FDA, during which the agency “acknowledged the vast amount of data that we’ve been collecting especially on the safety front over the last couple of years,” Berrey said during an investor call in early August. And now Intercept has a “clear path forward” for a resubmission, she said.

At that time, Intercept already stated that applications will be separate based on the two NASH trials and that the current Reverse readout wouldn’t affect the firm’s plan for a refiling based on Regenerate.

Meanwhile, other companies are trying to crack NASH, which still doesn’t have an FDA-approved drug after numerous failures. Axcella Therapeutics just disclosed an early look at phase 2b data, showing a high dose of its twice-daily AXA1125 might be able to improve liver stiffness. 

Akero Thepraeutics, with an equity investment from Pfizer, just reported positive midphase data for its efruxifermin. After 24 weeks, around 40% of pre-cirrhotic patients on efruxifermin experienced a one stage or more improvement in fibrosis without worsening of NASH, compared to 20% of those in the control arm. 

Alnylam and partner Regeneron are running a phase 2 program for their RNA interference therapy. And Novo Nordisk, whose star semaglutide has recently failed in a phase 2, just paid $70 million upfront to purchase Ventus Therapeutics’ VENT-01 in several cardiometabolic diseases, including NASH.