The U.S. Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee (PDAC) voted against Acadia Pharmaceutical’s supplemental New Drug Application (sDNA) of Nuplazid (pimavanserin) tablets for the treatment of hallucinations and delusions associated with Alzheimer’s disease psychosis by a vote of 9-3.
The negative vote came after the question, “Does the available evidence support a conclusion that pimavanserin is effective for the treatment of hallucinations and delusions in the ADP population?”
Dean Follman, Ph.D., a biostatistician with the National Institute of Allergy and Infectious Diseases, voted no. He noted, “In terms of further evidence, I’d like to see a randomized trial in ADP.” He indicated he had never seen the type of trial the company conducted, and he felt a better-designed trial would be helpful.
The size of the studies, both small, was criticized by the "no" voters. They recognized the unmet need in the field and the emotional content of the patient testimony, but they felt the data wasn’t as convincing as it should be. They also wanted a longer duration of efficacy being evaluated and a broader diversity of patients in a trial. The "yes" votes revolved around the drug already being seen as effective and safe in the Parkinson’s psychosis population and the unmet need for the drug.
Company shares popped 12% when the agency published briefing documents ahead of the meeting, although trading was halted Friday for the AdCom discussion. Nuplazid is a selective serotonin inverse agonist and antagonist that preferentially targets 5-HT2A receptors. It is the first drug approved for hallucinations and delusions associated with Parkinson’s disease psychosis. There are no approved treatments for this indication for Alzheimer’s patients.
The agency shut down the company’s first attempt at an sNDA last year, issuing a Complete Response Letter suggesting a lack of statistical significance in some of the dementia subgroups. The company then included additional data from two previous clinical trials, HARMONY and Study-019, and submitted the data with the sNDA. The FDA reported in its briefing documents that the data met the agency’s requirements to consider the drug for this indication.
The FDA did, however, point to concerns with Study-019 over “protocol deviations.” It noted some patients in the trial do not have “clear documentation that psychotic symptoms developed after AD (Alzheimer’s disease) diagnosis had been established or subjects who received exclusionary medications at the time of randomization.”
Acadia acknowledged this point, saying it had difficulties establishing the date of the Alzheimer’s diagnoses in these patients. They also stated that some patients were excluded because their psychosis was due to another psychiatric condition, for example, substance abuse or schizophrenia.
They pointed to their per-protocol analysis to evaluate those deviations, and the results favor Nuplazid. The FDA agreed they would be able to use the data from Study-019 for regulatory evaluation. The FDA also noted no key safety concerns.
“There is a great unmet need for FDA-approved medications to treat hallucinations and delusions in patients with Alzheimer’s disease,” Howard Fillit, M.D., co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF), told BioSpace. “Up to a third of the six million people with dementia develop Alzheimer’s Disease Psychosis (ADP), a devastating condition characterized by hallucinations and symptoms of psychosis that present as anxiety, aggression, and physical and verbal abuse.”
The drug brought in $115.5 million in the first quarter of this year, an 8% increase year-over-year.
The FDA has set a target action date of August 4 for its final decision. Should the agency approve the drug, it will most likely increase sales significantly. Although the FDA is not required to follow the recommendation of the advisory panel, it often does. With a mixed vote, it will be difficult to predict how the agency will fall.
