With the release by the FDA of briefing documents Friday, any lingering investor frets eased about the fate of Acadia Pharmaceuticals Inc.'s Nuplazid (pimavanserin) for psychosis associated with Parkinson's disease (PDP) at Tuesday's advisory panel. U.S. regulators seemed happy with the 5HT2a inverse agonist's efficacy as well as safety, making no mention of a black-box warning, though the truth won't be known until members of the Psychopharmacologic Drugs Advisory Committee cast their votes on three questions and the full agency decides.

"While investors generally view pimavanserin's (pim) clinical data favorably, FDA panels conjure up fear of the unknown, which for Acadia appears to be a slightly more salient investment controversy, given prior new drug application [NDA] filing setbacks and the fact that phase III data were generated about three years ago," analyst Paul Matteis with Leerink pointed out earlier this month. Further due diligence by his group "has re-affirmed our confidence in FDA approval, especially as we benchmark pimavanserin's risk/benefit off the fact that quetiapine [Seroquel, Astrazeneca plc] is widely prescribed in PDP, despite a lack of efficacy data, motor side effects, greater QTc prolongation and a black-box warning against elevated mortality risk in the elderly," he wrote in the March 1 research report. Still, he predicted a similar warning for Nuplazid, "consistent with the FDA's tendency toward class labeling" in central nervous system disorders, though the cautionary black box would only be "modestly impactful to the pace of the launch, and relatively less important to pim's value proposition in Parkinson's or to PDP peak sales."

Briefing documents address the mortality concerns at various junctures in the 20 pages of material, but they go easy on pimavanserin, pointing out that "PDP has been associated with nursing home placement, which itself has been associated with increased morbidity and mortality for these patients; therefore, a drug to prevent psychosis in this population without worsening motor function would, indeed, represent an important treatment advance."

In any case, the warning is looking less likely now. Cowen and Co. analyst Ritu Baral last week – also ahead of the briefing documents – sounded optimistic. "We note pimavanserin has received breakthrough designation from the FDA in the fall of 2014, and as such has very likely had extensive, regular dialogue with the FDA on efficacy and safety over about the last 18 months," she said. "We think the company likely is aware of points of concern for the agency, and has likely been able to extensively prepare for their discussion" at the advisory committee meeting.

All currently approved antipsychotics have a black-box warning about increased mortality in dementia patients, but they also all work – unlike pimavanserin – at least partially through dopaminergic mechanisms. "The mechanism of the increased mortality is unclear," Baral wrote in her report. "In fact, the evidence for the warning comes from an FDA meta-analysis which has never been published," and most of the experts she consulted "believe the increased mortality signal is an artifact. Of those that do think it may be real, many believe it may be related to a dopaminergic mechanism (and therefore should not extend to pima) while others believe it is related to sedation and related respiratory depression (and therefore applicable to pima). Any panel discussion on the meta-analysis may be enlightening."

H.C. Wainwright analyst Andrew Fein in a March 1 report said the black-box issue has "become a point for the panel to belabor and [we] anticipate discussion on the labeling requirements, given the potential for layering of Nuplazid to existing atypical antipsychotics." But since no approved therapies exist for the indication, and Nuplazid has no effect on motor symptoms while offering a much better safety profile overall, the warning likely would not affect uptake of the drug if approved, in his view.

J.P. Morgan analyst Cory Kasimov expressed a slightly more nuanced opinion, saying the "safety profile of Nuplazid doesn't really jump out in a negative way – indeed it seems clean other than the QTc signal, which we would expect to be a (non-boxed) warning," he wrote in a March 17 alert to investors. "While the FDA could include a black-box warning for use in elderly patients with dementia, given [that] Nuplazid falls into the antipsychotic class, whether the drug deserves one is a likely point of discussion during the panel." Although the drug could be successful in PDP even with a black-box warning, "the commercial potential of Nuplazid could be larger than expected without it," he noted. San Diego-based Acadia submitted its NDA last September, after delays that troubled some on Wall Street but also gave the company time to do extensive market research, put in place a disease-awareness program, and build a strong team, CEO Stephen Davis said at the time. (See BioWorld Today, Sept. 4, 2015.)