Following a meeting with the FDA’s Gastrointestinal Drug Advisory Committee Friday, the future of Intercept’s rare liver disease drug Ocaliva is under serious threat.
Looking to assess whether Ocaliva met its postmarketing requirements after a 2016 accelerated approval in the autoimmune disease primary biliary cholangitis (PBC), the FDA’s council of outside experts nearly unanimously rejected Intercept’s hopes for a full approval of its farnesoid X receptor agonist.
On the meeting’s first voting question, 13 experts said Intercept’s data didn’t adequately prove Ocaliva’s clinical benefit, with just one panelist voting in favor of the drug.
With regards to the second voting question on whether the medication’s overall risk-benefit profile is favorable as a second-line PBC treatment, 10 panelists voted "no," one voted "yes" and three abstained.
The experts were asked to weigh in on evidence from two Intercept post-marketing trials: the placebo controlled 747-302 study and the observational cohort trial 747-405.
Ocaliva initially won an accelerated green light in the U.S. in 2016 for PBC, a rare disease of the liver in which the bile ducts become inflamed and are slowly destroyed.
Now, following the predominantly negative votes from the adcomm—which the FDA isn’t necessarily beholden to—it looks increasingly likely that the regulator may pull Intercept’s original approval, or at least reject Intercept's bid for a full approval.
The agency has pulled accelerated approvals of multiple cancer drugs in recent years after the medicines failed to prove their worth in post-marketing studies. But, in rare diseases where treatment options are lacking, the FDA might decide to keep an accelerated approval in place when there’s no obvious harm.
The FDA is slated to make its final decision on Ocaliva’s approval status by Oct. 15, Intercept noted in a release.
Naturally, this isn’t the end result the company was hoping for.
“We are disappointed in the outcome of today’s Advisory Committee meeting and believe the vote does not accurately recognize the clinical benefit of Ocaliva as an important second-line therapy for patients living with PBC,” Paul Nitschmann, M.D., senior vice president of regulatory affairs at intercept, said in a statement.
In prep documents ahead of the committee meeting, Intercept stressed that its 405 study—which it said was designed to meet the FDA’s real-world evidence requirements—showed a “statistically and clinically meaningful treatment benefit of event-free and transplant-free survival” for Ocaliva.
As for the confirmatory 302 trial, Intercept admitted the study couldn’t be completed thanks to “recruitment and retention challenges.” The company blamed those difficulties on “multiple forms of bias in the pre-specified intent-to-treat (ITT) analysis.”
Still, the FDA’s panelists largely saw things differently, generally arguing that while Intercept’s trials pointed toward some benefit, there was also evidence of the potential for Ocaliva to cause serious patient harm.
“The ITT analysis shows a big benefit, but also evidence for potential serious harm which leads to an unfavorable benefit of harm balance for treatment indicated for early disease, even in the setting where there’s few alternatives available,” the University of North Carolina’s Til Stürmer, M.D., Ph.D., who voted no on both questions, said during Friday’s meeting.
Many others shared concerns about Ocaliva’s potential risk to patients, such as Brian Lee, M.D., from the Keck School of Medicine at the University of Southern California, who also voted ‘no’ on both questions.
“I deeply empathize with the high unmet need from the patients and the stories from the patients that we heard today, however the benefit is unconfirmed and the signal of harm with increased risk of death and liver transplant is concerning,” Lee said.
The University of Florida’s Almut Winterstein, Ph.D.—who herself cast two “no” votes—cited issues with Intercept’s real-world evidence study, including “an incomplete assessment of confounders and several reasons pointing to a lack of comparability of comparison groups and specifically disadvantages for the non-treated group.”
Chris Coffey, Ph.D., of the University of Iowa, also voted “no.” In discussing the question, he said that it’s hard to confirm 405 “reaches the level to verify benefit,” but noted that due to differing opinions about how convincing Intercept’s trials were, “I’m not sure it doesn’t show there’s no benefit.”
“It’s kind of an unfortunate case where other studies were done, and I feel like the answer that was set out to look for at the very beginning is just as unclear—perhaps at this point maybe more unclear—than it was because of the uncertainty,” Coffey explained.
Meanwhile, patient representative and PBC patient Danielle Alstat, the lone member of the panel to tender a “yes” vote for Ocaliva, said that while she found the confirmatory study 302 inconclusive, “the real world evidence for 405 does show that if [Ocaliva’s] given in the right dose for the right patient … there is a benefit that shouldn’t be ignored.”
“[A] lot of people end up dying waiting for a transplant, and if there’s an opportunity for people to be able to take a medication to be able to live a long and healthy life, I think every PBC patient now and in the future should have that opportunity,” she said.
Beyond the purview of the FDA, Intercept’s Ocaliva has struggled with efficacy and safety questions in Europe, as well.
Two weeks back, the European Commission (EC) moved to revoke the liver drug’s conditional marketing nod in PBC.
That said, Intercept—and Advanz Pharma, which picked up ex-U.S. rights to Ocaliva for $405 million in 2022—have won a reprieve after the General Court of the European Union temporarily suspended the EC’s decision.
In turn, Ocaliva will remain on the market for now to help new and existing PBC patients in EU member states, as well as those in Iceland, Liechtenstein and Norway.