Toss a complete response letter (CRL) onto two missed PDUFA dates and a few adcoms that were discussed but never actualized to get an idea of where Intercept Pharmaceuticals Inc. now stands with its NDA for obeticholic acid (OCA) to treat fibrosis due to nonalcoholic steatohepatitis (NASH).

In place of the newest PDUFA, June 26, Intercept is musing instead over the CRL it received. The FDA’s decision to issue the CRL and request for additional data is “completely unexpected and disappointing, to say the least,” Mark Pruzanski, Intercept’s president and CEO, told investors on a call Monday morning.

The New York-based company stock (NASDAQ:ICPT) dropped 39.7% to $46.70 per to close June 29.

Mark Pruzanski, president and CEO, Intercept

Based on data the FDA has reviewed, the company said, the CRL indicates the agency determined the predicted benefit of OCA based on a surrogate histopathologic endpoint remains uncertain and does not sufficiently outweigh the potential risks to support accelerated approval for the treatment of patients with liver fibrosis due to NASH.

Still, it’s not clear, Pruzanski said during the call, why the FDA’s expectations continue to evolve after years of working in lockstep to review OCA. Even the PDUFA is elusive, as the original date was March 26.

“We don’t have clarity, based on the letter, exactly what the agency is looking for,” he added.

The FDA asks Intercept to submit additional post-interim analysis efficacy and safety data from the ongoing Regenerate study to support potential accelerated approval and added that the long-term outcomes phase of the study should continue.

Intercept isn’t alone in its confusion. H.C. Wainwright and Co. analyst Ed Arce wrote Monday that the newest delay is “confounding” but what Arce does understand from the CRL is also “concerning,” noting particularly the FDA language that "the agency has determined that the predicted benefit of OCA based on a surrogate histopathologic endpoint remains uncertain and does not sufficiently outweigh the potential risks to support accelerated approval."

The FDA recommends that the company submit additional post-interim efficacy and safety from the study.

“We believe the agency's calling into question the overall risk/benefit of OCA in NASH is likely to do with the relatively weak magnitude of effect and efficacy response rate, especially in light of the well-known safety and tolerability issues,” Arce wrote.

The path leading to this day has been fraught with twists and turns. Although not on the FDA’s calendar, an adcom was tentatively scheduled in April, then tentatively moved to June 9. Intercept then said the FDA had unexpectedly postponed the meeting once again to give it time to review additional data it had requested. The agency said it would contact the company in the near future with a new proposed adcom date. Given the postponement, Intercept said the FDA’s review of the NDA likely would extend beyond the June 26 PDUFA date.

It's all mysterious to Pruzanski, who said in Monday morning’s call that “at no point during the review did the FDA communicate to us that the drug wasn’t approvable,” he said, adding, “We don’t believe this review was really fully completed based on all the available data and that this determination is premature.”

Intercept submitted an NDA for OCA in late September, asking for priority review. OCA is the only investigational therapy to meet the primary endpoint of a phase III study in patients with NASH and is the only such candidate that the FDA has designated a breakthrough therapy for NASH with fibrosis. The submission is based on positive interim analysis results from the study called Regenerate, where OCA 25 mg provided robust improvement in liver fibrosis (by ≥1 stage) without worsening of NASH at 18 months (p=0.0002 vs. placebo).

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