Pimavanserin for the Treatment of Alzheimer’s Disease Psychosis: An Evaluation of the Clinical Importance of Efficacy Results

Alzheimer’s disease psychosis (ADP) is a common and serious condition with substantial unmet need for safe and effective treatments. Pimavanserin is approved in the US to treat Parkinson’s disease hallucinations and delusions. This post-hoc analysis of randomized, double-blind, placebo-controlled, phase 2 trial of nursing-home-residents with ADP evaluated the efficacy of pimavanserin by improvements (least squares mean change) in the Neuropsychiatric Inventory–Nursing Home Version Psychosis Score (NPI-NH PS). The clinical significance of the primary endpoint was assessed using responder analyses (≥ 30% and ≥ 50%); numbers needed to treat (NNT); cumulative response (0-100% improvement); All Patients and Severe Psychosis (NPI-NH PS ≥ 12) subgroups were evaluated; improvements in hallucinations and delusions by NPI-NH-PS frequency (3 or 4 points) and severity (2 or 3 points); and ≥ 50% responder analysis at earlier timepoints (weeks 2 and 4). Among 345 patients screened, 181 patients were randomized to pimavanserin (n = 90) and placebo (n = 91). Patients were elderly (mean age: 86 years) and frail (baseline mean NPI-NH PS scores of 9.5 and 10 for pimavanserin and placebo, respectively). Pimavanserin significantly improved NPI-NH PS relative to placebo (−3.76 versus −1.93, respectively; p = 0.0451). In responder analyses, pimavanserin demonstrated a significantly greater reduction in NPI-NH PS versus placebo at both the ≥ 30% ( p = 0.0159) and ≥ 50% ( p = 0.0240) thresholds with NNTs of 6 and 7, respectively. Furthermore, pimavanserin demonstrated significantly earlier reductions in NPI-NH PS compared with placebo for the ≥ 30% ( p = 0.0336) and ≥ 50% ( p = 0.0044) thresholds. The cumulative response analysis demonstrated significantly greater efficacy of pimavanserin for All Patients ( p = 0.052) and Severe Psychosis ( p = 0.004), and Severe Patients versus All Patients demonstrated a greater reduction in NPI-NH PS (p = 0.011; effect size = 0.73). Pimavanserin also demonstrated numerically greater improvements for the frequency and severity of delusions and hallucinations. Responder analyses at earlier timepoints demonstrated significantly greater response rates with pimavanserin versus placebo at week 2 (p = 0.016) but not 4 (p = 0.051). These findings support pimavanserin as safe and effective in a population of nursing-home-resident patients with ADP.