Despite concerns amid reports of deaths and serious adverse events, the FDA has confirmed the safety profile of the therapy has remained consistent.
The FDA has released a statement reiterating its stance on the safety of pimavanserin (Nuplazid, Acadia Pharmaceuticals) for the treatment of hallucinations and delusions due to Parkinson disease psychosis.
Since the therapy was approved for this indication in April 2016, the agency reviewed all available data from postmarketing reports of deaths and serious adverse events (SAEs) reported with the use of the drug. “After a thorough review, FDA’s conclusion remains unchanged that the drug’s benefits outweigh its risks for patients with hallucinations and delusions of Parkinson’s disease psychosis,” the agency concluded.1
The FDA stated that overall, the data were consistent with the safety data included in the controlled clinical trials of pimavanserin for Parkinson disease psychosis which were submitted with the new drug application (NDA). This data comprised of 25 clinical studies, including a phase 3 trial, all of which totaled more than 1200 patients.
The phase III trial, Study 020, included 105 patients given pimavanserin 34 mg compared to 94 on placebo, of which 89 and 87 patients completed the trial, respectively. The trial revealed a change in Symptoms Adapted for Parkinson's Disease (SAPS-PD) scale score improvement of ≥3 points for 65.3% of those on the therapy compared to 42.2% on placebo (P = .002), a ≥5 point score improvement of 53.7% compared to 33.3%, respectively (P = .005), and a complete response in 13.7% compared to 1.1% (P = .001).2
In the FDA’s advisory committee report on the therapy, it was reported that 58.5% of patients exposed to the therapy in clinical trials in doses of 8.5 mg, 17 mg, and 34 mg experienced treatment-emergent AEs compared to 61% of those given placebo.3 Over the course of 10 years of follow-up, there were 62 reported deaths. The report’s summary of safety concluded that the therapy was well tolerated and the overall AEs were similar to placebo, and that although there was an observed imbalance in SAEs and deaths, there was “no unifying pathophysiologic process” and it was “consistent with risk factors associated with [Parkinson disease] psychosis and medical comorbidities.
The data reviewed included information submitted to the FDA Adverse Event Reporting System (FAERS), drug utilization data, safety data from the pimavanserin NDA, the sponsor’s Periodic Adverse Drug Experience Reports, the sponsor’s analysis of fatal adverse event reports with pimavanserin, and published medical literature.
The therapy, along with others in the antipsychotic class, has a Boxed Warning regarding the increased risk of death in the elderly with dementia-related psychosis associated with their use. The agency noted that in the FAERS reports which included a cause of death, often the submissions did not provide enough data to assess cause and effect of the drug, and overall, there was no pattern which suggested a drug effect.
“In assessing the reports of deaths, FDA considered that patients with Parkinson’s disease psychosis, for whom [pimavanserin] is indicated, have a higher mortality (death) rate due to their older age, advanced Parkinson’s disease, and other medical conditions. Moreover, [pimavanserin] is primarily distributed through a patient support program and a specialty pharmacy network, which increases the likelihood that deaths will be reported to the manufacturer,” the agency said.
1. FDA analysis finds no new or unexpected safety risks associated with Nuplazid (pimavanserin), a medication to treat the hallucinations and delusions of Parkinson’s disease psychosis [press release]. Bethesda, MD: FDA; Published September 20, 2018. fda.gov/Drugs/DrugSafety/ucm621160.htm. Accessed September 24, 2018.
2. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson’s disease
psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540. doi: 10.1016/S0140-6736(13)62106-6.
3. Monahan M, Isaacson S, Stankovic S, Demos G, Ballard C. Psychopharmacologic Drugs Advisory Committee of the FDA. FDA website. fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/psychopharmacologicdrugsadvisorycommittee/ucm493998.pdf. Published March 29, 2016. Accessed September 24, 2018.