The phase 3 trial of pimavanserin in dementia-related psychosis, HARMONY, was previous halted due to positive efficacy signs at interim analysis. The drug is currently indicated for use in treating Parkinson disease-related psychosis.
Data from phase 3 of the HARMONY study (NCT03325556) suggests that patients with dementia-related psychosis (DRP) experience lower relapse risk when continuing treatment with pimavanserin (Nuplazid; Acadia).1 This positive outcome comes after the trial was halted in September 2019 at the recommendation of the independent data monitoring committee based on positive efficacy benchmarks at the pre-planned interim analysis.2
The double-blind, randomized, placebo-controlled trail evaluated relapse of psychosis as its main outcome measure, with a secondary end point analyzing time from randomization to patients’ trial discontinuation. Ultimately, treatment with the study drug reduced psychosis relapse risk by 2.8 fold compared to placebo in the double-blind period (HR, 0.35; 2-sided P = .005; 1-sided P =.0023).
Following the stopping of the trial, 41 patients withdrew for administrative reasons. Of the remaining 351 patients, 217 (61.8%) had a sustained response to pimavanserin and were then enrolled in the double-blind, randomization period. Patients were divided into treatment (n = 105) and placebo (n = 112) groups, with relapse at the time of interim analysis occurring in 12 out of 95 patients (13%) in the treatment group and 28 out of 99 patients (28%) in the placebo group (HR, 0.35 [95% CI, 0.17-0.73] P = .005).1
A total of 44 patients in the treatment arm and 35 patients in the placebo arm completed 26 weeks of the trial. Investigators also found that patients were less likely to discontinue trial when being treated with pimavanserin versus placebo, with a median duration of exposure in the double-blind phase of 17.7 weeks and 10.9 weeks, respectively.
Adverse events (AEs) were reported in 43 out of 105 patients (41%) who received pimavanserin, compared to 41 out of 112 (36.6%) of those who received placebo. The most reported AEs for those receiving treatment were headache, constipation, urinary tract infection, and asymptomatic QT prolongation. Patients mean age was 74.5 years (standard deviation [SD], 8.3) and mean duration of cognitive impairment was 4.3 years (SD, 2.8).
“The relapse prevention design of the HARMONY study mirrors exactly what we do in clinical practice. This landmark trial showed that when patients responded to pimavanserin and then continued treatment, they were almost three times less likely to develop recurrence of their hallucinations and delusions than those patients who discontinued pimavanserin treatment,” lead author, Pierre N. Tariot, MD, director, Banner Alzheimer’s Institute, said in a statement.3 “This is a substantial finding and a significant advance for a critical public health need in our field. There is no FDA approved treatment for DRP, and the majority of antipsychotics currently used off-label have equivocal efficacy and may accelerate cognitive decline.”
A total of 392 patients with different types of dementias, namely Alzheimer disease (n = 260; 66.3%), Parkinson disease (PD) dementia (n = 59; 15.1%), vascular dementia (n = 38; 9.7%), dementia with Lewy bodies (n = 28; 7.1%), and frontotemporal dementia (n = 7; 1.8%) received pimavanserin for 12 weeks during the previous open-label phase. The mean Mini-Mental State Exam score was 16.7 points (SD, 4.7).
Certain limitations were present, primarily the trial being stopped early for efficacy, limiting investigators’ ability to fully assess ongoing relapse rate or AEs and creating a median duration of exposure of 18 weeks in the pimavanserin group and 11 weeks in the placebo group, compared to the anticipated 26-weeks of the double-blind phase. Additionally, as pimavanserin is approved for treatment of PD and those with PD-related psychosis were included in the HARMONY trial, data may be skewed as a result. Patients were almost all White, investigators noted, which may not be able to accurately account for patients of different races and ethnicities.
Safety data on the use of pimavanserin in treating DRP was recently presented at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30, 2021. The data, which included pooled clinical data and the HARMONY study, suggest that patients with neurodegenerative diseases and/or neurovascular disorders receiving pimavanserin in clinical trials commonly received concomitant antidementia medication, such as acetylcholinesterase inhibitors or memantine, and that the combination was safe and tolerable.4