Pimavanserin Efficacy for Dementia-Related Psychosis Leads to Early Discontinuation of Pivotal Phase 3 Trial

  • Alzheimer Disease
  • Corticobasal degeneration
  • Dementia
  • Frontotemporal dementia
  • Lewy body dementia
  • Parkinson disease
  • Parkinson disease psychosis
  • Pimavanserin

In the phase 3 HARMONY trial (NCT03325556), treatment of dementia-related psychosis with pimavanserin (Nuplazid; Acadia Pharmaceuticals, San Diego, CA) was superior to placebo for treatment of dementia-related psychosis (P < .0033). The trial is now ended because this marks early achievement of the primary endpoint and prespecified stopping criteria.

After receiving pimavanserin for 12 weeks on an open-label basis, participants were randomly assigned to receive placebo or continue on pimavanserin on a double-blind basis. Time to relapse was significantly less for those who continued pimavanserin vs being switched to placebo. 
Participants in the trial have dementia-related psychosis related to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), Parkinson’s disease (PD) dementia; vascular dementia, and frontotemporal dementia spectrum disorders. 

“With no approved treatment options available today for dementia-related psychosis, the pimavanserin study results represent a meaningful advance that will potentially bring us a much-needed therapy for this debilitating disease,” said Jeffrey Cummings, MD, ScD, director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health and editorial board member of Practical Neurology. 

The starting dose of pimavanserin in the 12-week prerandomization phase was 34 mg/day, which could be reduced to 20 mg/day during the first 4 weeks, if clinically appropriate. Participants who met prespecified criteria for treatment response continued into the randomized double-blind phase and were followed for 26 weeks or until a relapse occurred. Relapse was defined as dementia-related psychosis, worsening of dementia-related symptoms on clinical scales, withdrawal from the study due to lack of efficacy, or use of an off-label antipsychotic medication to treat dementia-related delusions and/or hallucinations. 

Pimavanserin is a selective serotonin inverse agonist and antagonist that targets 5-HT2A receptors. These receptors are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders. In vitro, pimavanserin demonstrated no binding affinity for dopamine (including D2), histamine, muscarinic, or adrenergic receptors

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