Pimavanserin Significantly Reduces Risk of Relapse of Dementia-related Psychosis: Results From the Double-Blind Phase of the HARMONY Study

Patients with dementia often experience dementia-related psychosis (DRP), which is associated with adverse outcomes and has no approved therapy in the US. Pimavanserin is a selective serotonin inverse agonist/antagonist at 5-HT2A receptors approved for treating hallucinations and delusions associated with Parkinson's disease psychosis. We studied pimavanserin use for treating hallucinations and delusion in patients with DRP.

HARMONY was a randomized, placebo-controlled, phase 3 relapse-prevention study. Patients with moderate-to-severe psychosis associated with Alzheimer’s disease dementia, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia were eligible to enroll and received open-label (OL) pimavanserin for 12 weeks. Patients with a sustained response at weeks 8 and 12 were randomized 1:1 to continue pimavanserin or receive placebo for up to 26 weeks in the double-blind (DB) period. The primary endpoint was time from randomization to relapse of DRP.

392 patients enrolled. 217 (61.8%) eligible patients experienced a sustained response and were randomized. The study stopped early for superior efficacy when a prespecified interim analysis revealed >2.8-fold reduction in relapse risk with pimavanserin (hazard ratio: 0.353; 95% CI: 0.172, 0.727; 1-sided P=0.0023). Adverse event rates were low and balanced (OL: 36.2%; DB: 41.0% pimavanserin, 36.6% placebo). No negative trends for worsening in cognition (Mini-Mental State Examination) or motor function (Extrapyramidal Symptoms Rating Scale-A) were observed.

The HARMONY study demonstrated a robust decrease in hallucinations and delusions and significant maintenance of efficacy with pimavanserin treatment in DRP. Pimavanserin was well tolerated by this elderly population over the study duration.