Pimavanserin lowers relapse risk in patients with dementia-related psychosis
In a phase 3 trial of pimavanserin that came to a premature halt for efficacy, patients with dementia-related psychosis who continued the treatment had a lower risk for relapse than those who were switched to placebo, researchers reported.
Pimavanserin (Nuplazia, Acadia Pharmaceuticals) is an oral 5-HT2A inverse agonist and antagonist that was previously approved by the FDA to treat psychosis related to Parkinson’s disease.
In April, the FDA issued a complete response letter to the manufacturer for a supplemental new drug application that sought approval of pimavanserin for patients with dementia-related psychosis. In the letter, the FDA stated that it could not approve the application for several reasons, including a lack of statistical significance among certain dementia subgroups and insufficient numbers of patients with certain less common dementia subtypes.
An FDA-approved treatment for dementia-related psychosis would fill “a huge unmet need,” Pierre N. Tariot, MD, a clinician, researcher and director of the Banner Alzheimer’s Institute in Phoenix, told Healio Primary Care. “It is a tough issue to live with, both for the patient and for care partners. We need better ways to help these folks.”
For the HARMONY trial, Tariot and colleagues analyzed results from 392 older adults who met the criteria for dementia and clinical criteria for either Parkinson’s disease dementia, dementia with Lewy bodies, possible or probable Alzheimer’s disease, frontotemporal dementia or vascular dementia. The adults received open-label pimavanserin for 12 weeks. For the first 4 weeks, patients received one 34 mg dose of pimavanserin daily. If a patient experienced adverse events, his or her once-daily dose dropped to 20 mg. A patient’s dose at the end of week 4 remained fixed until the end of the 12-week open-label phase.
Participants who had a 30% or more reduction in Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions (SAPS-H+D) score — in which a higher score suggests greater psychosis — and a Clinical Global Impression–Improvement score of 1 (“very much improved”) or 2 (“much improved”) at weeks 8 and 12 were then randomly assigned in a 1:1 ratio to continue receiving pimavanserin or switch to placebo at their last open-label dose for up to 26 weeks.
The primary endpoint was a psychosis relapse, which the researchers defined as a SAPS-H+D score that was at least 30% higher than the first test and a Clinical Global Impression–Improvement score of 6 (“much worse”) or 7 (“very much worse”), hospital admittance for dementia-related psychosis, stopping the treatment or withdrawal from the trial for lack of efficacy, or utilization of antipsychotic agents for dementia-related psychosis.
The researchers reported that 41 patients withdrew from the trial for administrative reasons because the trial was stopped early for efficacy. Of the 351 patients who remained, 217 (61.8%) had a sustained response and were randomly assigned to continue pimavanserin (n = 105) or switch to placebo (n = 112).
After randomization, 35 participants in the pimavanserin group and 31 in the placebo group were withdrawn for administrative reasons. In addition, 26 participants in the pimavanserin group and 46 in the placebo group discontinued treatment due to relapse, adverse events or other reasons.
Of the remaining participants, Tariot and colleagues reported that a relapse occurred in 13% of participants in the pimavanserin cohort and 28% of participants in the placebo cohort (HR = 0.35; 95% CI, 0.17-0.73). During the 26-week, double-blind phase, adverse events occurred in 41% of patients who received pimavanserin and 36.6% who received placebo. Adverse events among the pimavanserin cohort included headache, constipation, urinary tract infection and asymptomatic QT prolongation.
Tariot noted that this is the first time that pimavanserin had been tested in patients with psychosis due to one or more dementias.
“I confess I was gratified and relieved to see such a clear signal of efficacy, such that the trial was stopped early for efficacy,” he said.
The trial revealed several “important results,” Steve Davis, CEO of Acadia Pharmaceuticals, told Healio Primary Care.
“In the 26-week, double-blind period, patients on pimavanserin had a nearly threefold reduction of risk of psychosis relapse compared to patients on placebo [and] pimavanserin was well-tolerated by elderly patients with [dementia-related psychosis],” Davis said.
An Acadia Pharmaceuticals spokesperson told Healio Primary Care that the company “looks forward to working with the FDA to identify a path to potentially bring pimavanserin to patients with dementia-related psychosis” and intends to provide an update on its future plans for the drug in early August.