Nuplazid Heads to the FDA for New Indication for Dementia-Related Psychosis


The drug, previously approved for Parkinson disease psychosis, received breakthrough therapy designation for this new indication.

Jeffrey Cummings, MD, ScD

Jeffrey Cummings, MD, ScD

A supplemental new drug application has been submitted to the FDA for an additional indication for pimavanserin (Nuplazid; Acadia), this time for the treatment of delusions and hallucinations associated with dementia-related psychosis.1

The Acadia Pharmaceuticals drug was previously approved in 2016 for a similar indication in Parkinson disease psychosis — the first therapy to address this debilitating symptom of the movement disorder.2

“This is an important step forward for the approximately 2.4 million people in the US who suffer from dementia-related hallucinations and delusions, representing a large unmet need with currently no approved treatment options,” said Steve Davis, Acadia’s chief executive order, in a statement.1

The application is supported by results from the phase 3 HARMONY study, which evaluated the safety and efficacy of pimavanserin for the treatment of hallucinations and delusions associated with dementia-related psychosis in patients with various dementia subtypes, including Alzheimer disease, Parkinson disease dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia. Overall, 392 patients (mean age, 74.5 years) were enrolled in the study, which assessed time to relapse, defined as a significant worsening of psychosis symptoms after stabilization leading to hospitalization, significant clinical deterioration, study withdrawal, or use of an off-label antipsychotic, during the 26-week double-blind treatment period.

Patients were initially enrolled in an open-label stabilization period where they received 34 mg pimavanserin once daily for 12 weeks. Ultimately 61.8% of patients met the sustained treatment response criteria at week 8 and 12, after which they entered the double-blind period. There, patients were randomly assigned to receive either 34 mg or 20 mg daily pimavanserin or placebo for up to 26 weeks or until relapse occurred.

The study ultimately met its primary endpoint and was stopped early at its preplanned interim analysis after showing a 2.8-fold significant reduction in risk of relapse of psychosis compared with placebo (hazard ratio 0.353; one-sided P = .0023).

Notably, the drug, a selective serotonin inverse agonist and antagonist preferentially targeting 5HT2A receptors, was well-tolerated and was not associated with a decline in cognition as measured by Mini-Mental State Examination scores or onset or worsening of extrapyramidal symptoms. Overall, 41% of patients taking pimavanserin experienced adverse events compared with 36.6% on placebo. Discontinuations in the treatment group were 2.9%, and 4.8% had serious adverse events.

“If it's approved, this will be the first drug for any neuropsychiatric syndrome in any dementia disorder. I think that signals a real point of progress,” trial investigator Jeffrey Cummings, MD, ScD, director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health and vice chair of the department of brain health at the University of Nevada Las Vegas, told NeurologyLive in a previous interview.


1. Acadia Pharmaceuticals submits supplemental new drug application to U.S. FDA for Nuplazid® (pimavanserin) for the treatment of hallucinations and delusions associated with dementia-related psychosis. News release. Acadia Pharmaceuticals. June 15, 2020.

2. Acadia Pharmaceuticals announces pivotal phase 3 HARMONY trial stopped early for positive efficacy as pimavanserin meets the primary endpoint in patients with dementia-related psychosis. News release. Acadia Pharmaceuticals. September 9, 2019.

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