Pimavanserin Safe in Elderly Patients With Neurodegenerative Disease-Related Neuropsychiatric Symptoms

Gustavo Alva, MD, DFAPA

Findings from a large-scale, placebo-controlled, phase 3 trial, pimavanserin (Nuplazid; Acadia Pharmaceuticals), an FDA-approved medication for Parkinson disease (PD) psychosis, was well tolerated in a cohort of patients with neuropsychiatric symptoms related to neurodegenerative diseases. Presented at the 2023 Alzheimer’s Association International Conference (AAIC), held June 16-20, in Amsterdam, Netherlands, the agent did not show an impact on cognitive decline or motor dysfunction.¹

The primary outcome of the multicenter, parallel-group study was safety, with 730 total individuals included, split evenly between pimavanserin and placebo. Over an 8-week treatment period, the incidence of treatment-emergent adverse events (TEAEs) were similar between groups, with 30.4% and 29.3% of those on active and placebo, respectively, reporting at least 1 TEAE. Among the 1.8% of patients who reported serious TEAEs, 2.0% were in the pimavanserin group and 1.5% were on placebo.

Led by Gustavo Alva, MD, DFAPA, Distinguished Fellow of the American Psychiatry Association, pimavanserin was assessed in doses of 34 mg in a cohort of frail adults and elderly patients with neuropsychiatric symptoms related to neurodegenerative disorders. Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, has been FDA-approved as a therapy to treat hallucinations and delusions association with PD psychosis since 2016. In late 2022, it was denied as a potential agent for the treatment of hallucinations and delusions in patients with Alzheimer disease (AD) psychosis, the second complete response letter the agent received.²

READ MORE: Donanemab Demonstrates Slowing of Alzheimer Disease Progression in Phase 3 TRAILBLAZER-ALZ 2 Trial

In the study, TEAEs leading to discontinuation occurred in 2.6% of pimavanserin-treated individuals and 2.3% of those on placebo. Urinary tract infection (pimavanserin: 6.4%; placebo: 4.1%) and headache (pimavanserin: 2.0%; placebo: 3.8%) were among the most common TEAEs observed. Mortality because of TEAEs was similar between the groups (0.5% in each).1

Secondary outcomes of the study, which included changes in motor, conducted using the Extrapyramidal Symptom Rating Scale-Abbreviated, and cognition, using the Mini-Mental State Examination, were not impacted through pimavanserin. Changes in Clinical Global Impression-Improvement, an exploratory end point, were improved in pimavanserin-treated patients (least square mean [LSM], ­–0.2 [SE, 0.07]; P = .0140) at 8 weeks. Similar benefits were observed in sleep function, as assessed through the Sleep Disorders Inventory (LSM, –0.3 [SE, 0.06]; P <.00001) in comparison with placebo. No differences were observed across other measures of suicidality, collected using the Columbia-Suicide Severity Rating Scale and Global Clinician Assessment of Suicidality, as well as the 5-level version of EQ-5D.

Pimavanserin, an atypical antipsychotic, has been shown to be among the safest agents to treat patients with PD psychosis. According to a systematic review and network meta-analysis published earlier this year, pimavanserin (standardized mean differences [SMD], –4.81; 95% CI, –5.39 to –4.24) and clozapine (SMD, –4.25; 95% CI, –5.24 to –3.26) were the top rated to improve symptoms relative to placebo. Other agents included in the analysis were quetiapine, olanzapine, ziprasidone, and risperidone.³

More recently, at the 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana, data from a pilot study suggested pimavanserin may be a beneficial therapy for individuals with post-traumatic stress disorder (PTSD)-associated insomnia. In a small cohort of 6 adult veterans assessed over a period of 6 weeks, preliminary analyses revealed a greater trend toward improvement on subjective measures of insomnia compared with objective sleep measures.

Currently, an investigator initiated, placebo-controlled trial (NCT05441280) assessing the effect of the therapy in patients with PTSD-associated insomnia is being planned. The preliminary study, which has not begun recruitment, is expected to include 60 veterans with insomnia and PTSD who will be followed for an 8-week treatment period.

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REFERENCES
1. Alva G, Cubala WJ, Berrio A, et al, Safety profile of pimavanserin therapy in elderly patients with neurodegenerative disease-related neuropsychiatric symptoms: a phase 3b study. Presented at: AAIC 2023; July 16-20; Amsterdam, Netherlands. Abstract 76487
2. Acadia Pharmaceuticals Receives Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Pimavanserin for the Treatment of Hallucinations and Delusions Associated with Alzheimer’s Disease Psychosis. Acadia Pharmaceuticals. August 4, 2022. July 16, 2023 https://www.businesswire.com/news/home/20220804006095/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Alzheimer%E2%80%99s-Disease-Psychosis
3. Yunusa I, Rashid N, Rajagopalan K, et al. Comparative efficacy, safety, and acceptability of pimavanserin and other atypical antipsychotics for Parkinson’s disease psychosis: systematic review and network meta-analysis. J Geriatr Psychiatry Neurol. Published online January 31, 2023. doi:10.1177/08919887231154933
4. Jones M, Agrawal R, Sharafkhaneh A, et al. Pimavanserin 34 mg at bedtime for insomnia in veterans with post-traumatic stress disorder: open-label case series. Presented at: 2023 SLEEP Annual Meeting; June 3-7; Indianapolis, Indiana. Abstract 0357
5. Pimavanserin for insomnia in veterans with PTSD (PIP-II). Clinicaltrials.gov. Updated April 12, 2023. Accessed July 16, 2023. https://clinicaltrials.gov/ct2/show/NCT05441280