Pimavanserin Under Scrutiny for Reported Deaths in Parkinson's Patients

APRIL 10, 2018
Kevin Kunzmann
FDA, Acadia, Nuplazid, pimavanserin, deaths, adverse eventsAcadia Pharmaceutical’s antipsychotic therapy pimavanserin (Nuplazid) is facing public scrutiny and fiscal uncertainty after a report from CNN Monday detailed the deaths of more than 700 patients prescribed the therapy for Parkinson’s disease (PD) since June 2016.

Combined statistics from the nonprofit health care organization Institute for Safe Medication Practices (ISMP) as well as the US Food and Drug Administration (FDA) Averse Events Reporting System (FAERS) indicate there has been 741 adverse events (AEs) reported as deaths in patients treated with Nuplazid, as of Tuesday.

Pimavanserin is an antagonist at serotonin 5-HT 2A receptor, with a novel mechanism that allows it to behave as a selective inverse agonist of the receptor without significant affinity or activity at dopamine receptors — contrary to the mechanism of other receptors. When it was approved to treat hallucinations and delusions associated with psychosis experienced by patients, the FDA Center for Drug Evaluation and Research’s Director of the Division of Psychiatry Products Mitchell Mathis, MD, said Nuplazid “represents an important treatment” for patients of PD who experience such symptoms.

It was approved on the strength of a six-week clinical trial involving 199 patients, in which pimavanserin showed superior efficacy in decreasing hallucination and delusion frequency and/or severity in PD patients — without worsening primary motor symptoms.

Similar to other approved uncommon antipsychotic therapies, Nuplazid was given a Boxed Warning which indicates an increased risk of death associated with its use for treated older patients with dementia-related psychosis.

ISMP argued in its November 2017 report that, despite this warning, FDA had not done its due diligence when judging pimavanserin for its current market indication. The organization called its clinical evidence for benefits outweighing risks “limited,” and wrote the FDA had relied on a single trial indicating minimal treatment effect — without consideration to its invalid symptoms measurement scale or failed preceding trials attempting to show its clinical benefit.

They added the FDA’s medical reviewer had previously recommended against approval to the deciding committee that voted 12-2 in favor of approving its new drug application (NDA).

“He noted that although other psychiatric drugs were often approved on limited evidence of benefit, in the case of pimavanserin treatment more than doubled the risk of death and/or serious adverse events in its pivotal trial,” the organization wrote.

Among the 244 deaths reported to the FDA between Nuplazid’s launch and March 2017 were hundreds more AEs, ISMP reported. According to their tally, another 487 counts (21.8%)  of hallucination, 333 counts (14.9%) of drug ineffectiveness, and 258 counts (11.5%) of confusional state comprised the most frequently-reported AE list with death (10.9%).

When the organization shared these preliminary results with Acadia, the pharmaceutical company responded that large volume of AE reports was due to increased contact between physicians and consumers through a drug-distributing specialty pharmacy network, as well as a company patient support program.

A response provided by Acadia to CNN’s reporting stated that, since the therapy’s approval, the company has conducted another 2 controlled clinical studies in more than 300 combined patients with AD whose overall mean age was 82.5 years. They state that there was no reported difference in deaths between elderly patients with dementia treated with either pimavanserin or placebo (4 deaths each).

The FDA provided a response to the report in which they could not identify a specific safety issue “that is not already adequately described in the product labeling,” referring to its Boxed Warning indication. They also noted that most AE and death-related cases reported thus far involve elderly patients with advanced-stage PD, who already suffered from multiple conditions that require other life-threatening therapies.

As of Monday afternoon, Acadia’s stock had dropped 25%, and the company has released no public statement on the critical reports. The state of the PD therapy market is already a struggling one, as clinicians have recently detailed the hurdles of initiating clinical trials for prospective PD drugs.

While pimavanserin’s future for treating psychosis in patients with PD remains foggy, its prospect as a general antipsychotic drug remains considered. It is currently being researched for the treatment of Alzheimer’s disease — a condition which often relies on multi-indication use of drugs for other psychiatric or mental illnesses.

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