Continued treatment with the atypical antipsychotic pimavanserin (Nuplazid) reduces risk for recurring delusions and hallucinations related to dementia, new data reveal.
Phase 3 results from the HARMONY study show patients with dementia who stayed on pimavanserin had a lower psychosis relapse risk than those who switched to placebo — and did so without some of the side effects associated with current treatment options.
“These encouraging results add to the evidence that suggest pimavanserin could eventually become a therapeutic option for treatment of severe dementia-related psychosis,” study investigator Pierre Tariot, MD, director of the Banner Alzheimer’s Institute in Phoenix, Arizona, told Medscape Medical News.
The findings were published online today in The New England Journal of Medicine.
Topline Results Confirmed
Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT2A receptors, which are thought to play an important role in psychosis, schizophrenia, depression, and other neuropsychiatric disorders.
The US Food and Drug Administration (FDA) approved pimavanserin for the treatment of hallucinations and delusions associated with Parkinson-related psychosis in 2016. However, the drug is not yet approved for dementia-related psychosis.
The HARMONY trial was a double-blind, placebo-controlled, relapse prevention study involving patients with dementia related to Alzheimer’s disease, Parkinson’s disease, Lewy body disease, frontotemporal degeneration, or vascular disease.
During the initial 12-week open-label treatment period, 217 of 351 patients (62%) had a sustained reduction in psychosis symptoms while taking pimavanserin (34 mg once daily) and were then randomly assigned to continue taking pimavanserin (105 patients) or switch to placebo (112 patients) for 26 weeks.
The trial was stopped at the interim analysis when it became clear that the frequency of psychosis relapse was significantly lower in the pimavanserin group than in the placebo group (13% vs 28%; hazard ratio [HR], 0.35; 95% CI, 0.17 – 0.73; P = .005).
Pimavanserin also met the key secondary endpoint by significantly reducing risk for discontinuation for any reason, which occurred in 21 participants (22%) in the pimavanserin group vs 38 participants (38%) in the placebo group (HR, 0.45; 95% CI, 0.26 – 0.79; P = .005).
These findings confirm the topline study results previously reported by Medscape Medical News.
Help vs Hurt
The mean prolongation of the corrected QT interval, calculated with the use of Fridericia’s formula (QTcF), in patients who were exposed to pimavanserin in the open-label phase was 5.4 milliseconds, which was “consistent with the current labeling of the drug,” the investigators write.
“We were gratified to see that a substantial majority of people were helped without being hurt. Our current options are older antipsychotic drugs, which are just so toxic,” Tariot said in a statement.
He told Medscape Medical News that because a head-to-head comparison study has not yet been conducted, he can only speculate on the findings.
“However, a significant difference so far seems to be that pimavanserin has not been associated with cognitive impairment in comparison with placebo, unlike what has been reported with many other antipsychotics in trials in persons with dementia,” said Tariot.
“This is not a miracle drug, but these results suggest the potential of a future, new therapeutic tool in our toolbox,” he added.
The author of an accompanying editorial notes that the study “represents a step forward given the unique mechanism of action of pimavanserin that distinguishes it from currently used agents for this purpose.”
The data show a “longer sustained reduction in psychotic symptoms with pimavanserin than with placebo in patients with several types of dementia, no significant liability for extrapyramidal symptoms, and an acceptable side-effect profile,” Joseph Friedman, MD, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, writes.
Commenting on the findings for Medscape Medical News, Timothy Sullivan, MD, chair of psychiatry and behavioral sciences at Staten Island University Hospital, New York City, noted that psychosis in dementia is not a rare occurrence.
“It occurs at a significant and generally underreported rate, and so is a common clinical problem,” said Sullivan, who was not involved with the research.
“The findings of this study are persuasive,” he added.
Sullivan noted that the decreased risk for relapse in the treated group was significant, there was a very low incidence of side effects, and the side effects that did occur “were relatively less concerning, which is really important.”
Until now, the pharmacologic “toolbox” that psychiatrists have available to treat psychosis in patients with dementia has been “quite limited,” said Sullivan.
“We are always trying to figure out what’s the least of the evils that we may choose from,” he said. The available agents aggravate symptoms, particularly Parkinson’s symptoms, aggravate cognitive impairment in dementia, and increase risk for cerebrovascular events, Sullivan noted.
In this study, the fact that two thirds of the patients had an initial response is “pretty good and better than we get with many antidepressants,” Sullivan said. “And the fact that the response was sustained, at least through 26 weeks and without much in the way of adverse reactions, is very encouraging.”
The study was funded by Acadia Pharmaceuticals Inc. Disclosures for the study authors and editorial writer are listed with the original article. Sullivan has disclosed no relevant financial relationships.