UPDATED: FDA's internal review of Acadia's Parkinson's drug raises safety, benefit concerns

Acadia's regulatory and research crew will face some tough questions come Tuesday's FDA advisory committee review of its Parkinson's antipsychotic drug pimavanserin ($ACAD), but a scan of the agency's internal review document issued today suggests that the door is still open to a possible approval.

The long-delayed FDA assessment acknowledges that the 34-mg dose of pimavanserin (Nuplazid) did significantly improve symptoms of Parkinson's. But regulators clearly red-flagged their safety concerns, noting a distinct increase in the number of deaths as well as adverse events among the patients taking the drug compared to the control arm of the study--even if there was no obvious clue what was triggering those events.

Because of the safety issues, the agency in particular wants to have a discussion with the outside experts about the questionable meaningfulness of the clinical benefit of the drug.

"While the applicant will present evidence that the treatment effect represents a clinically meaningful change," writes Mitchell Mathis, director of the division of psychiatry products, "the Division's medical officer will present his interpretation of the same data and reach a different conclusion." 

None of that seemed to spook investors, though. Acadia's shares shot up 25% in early trading on Monday.

Analysts have pegged 2020 revenue from Nuplazid at $1.4 billion, making this one of the top drug prospects up for review this year. The FDA has designated the therapy as a "breakthrough" drug warranting a quick response from regulators.

"Serious adverse events (AEs) occurred in 16/202 (7.9%) patients taking pimavanserin 34 mg versus 8/231 (3.5%) placebo-treated patients" in the studies, noted the FDA review. And it was also clear to the regulators that the rate of AEs increased with the dosage of the drug. But that's also not necessarily damning. This is a patient population, after all, that suffers a high mortality rate, as well as adverse events. The regulators were also unable to explain the differences.

States the FDA: "As with the disproportionate increase of serious adverse events in the pimavanserin 34 mg daily group compared to the placebo group, there is no obvious unifying pathophysiologic process or unique adverse event that drives or dominates this disproportion."

Side effects and increased mortality rates among Parkinson's patients taking antipsychotic meds is common, though, as a new study from investigators at the University of Pennsylvania has just pointed out. Looking over VA records on some 15,000 Parkinson's patients, the researchers found that patients starting on the drugs were twice as likely to die over the next 6 months compared to a similar patient group who stayed off drugs.

Another concern San Diego-based Acadia will face on Tuesday: The review noted that the agency only has one positive trial to consider in making a decision on the drug, even though it typically would require at least two positive studies. That, also, was not presented as a deal killer by the FDA reviewers.

Like many other FDA reviews, the regulators in this case wanted to highlight the weaknesses in Acadia's case. But they accomplished that without sounding the kind of alarm that usually signals an odds-on rejection by the outside experts. This review will center on a risk/benefit analysis where there is no obvious outcome. And that should make Tuesday's panel review all the more interesting, as Acadia has a lot riding on the vote.

- here's the review (PDF)