Nuplazid Lowers Dementia-related Psychosis Relapse Risk by Nearly 3 Times, HARMONY Study Shows

People with Alzheimer’s and other dementias treated with Nuplazid (pimavanserin) in a Phase 3 trial were almost three times less likely to have a psychosis relapse — a worsening of delusions and hallucinations — than others, HARMONY trial data show.

HARMONY met its main goal, significantly lowering the risk of a psychosis relapse by 2.8 times compared to placebo, and also found most patients unlikely to discontinue Nuplazid’s use for any reason.

Based on these findings, Arcadia Pharmaceuticals, the manufacturer of Nuplazid, plans to meet with the U.S. Food and Drug Administration early next year to discuss the possibility of extending the medicine’s use to include these patients.

If FDA approval is given, Nuplazid will be the first targeted therapy for dementia-associated psychosis.

Trial results were detailed in “HARMONY Relapse-Prevention Study: Pimavanserin Significantly Prolongs Time to Relapse of Dementia-Related Psychosis,” given by Erin Foff, MD, PhD, Acadia’s clinical director, in a late-breaking communication at the 12^th Clinical Trials on Alzheimer’s Disease (CTAD) Meeting, held Dec. 4 –7 in San Diego.

“The results presented today are an important advance for patients and caregivers who struggle with the burden of dementia-related psychosis where no FDA-approved treatment is currently available,” Jeffrey Cummings, MD, ScD, director emeritus of Cleveland Clinic Lou Ruvo Center for Brain Health, said in a press release.

“Reducing the risk of relapse of psychotic symptoms by this magnitude is an important and meaningful outcome as these are serious events which could lead to poor patient outcomes and a significant increase in caregiver burden and distress.”

An estimated 8 million people in the U.S. have dementia, and studies suggest that about 30% of them (2.4 million) also experience psychosis, commonly consisting of delusions and hallucinations.

Nuplazid — approved to treat hallucinations and delusions caused by Parkinson’s disease psychosis — is a selective serotonin inverse agonist that works by binding to serotonin receptors called 5HT2A. These receptors are associated with several mental health disorders, including psychosis, depression and schizophrenia.

Instead of activating the serotonin signaling cascade by binding to 5HT2A receptors, Nuplazid does the opposite, blocking their activity.

In trials, the medicine was found to significantly reduce the severity of psychosis without any effect on Parkinson’s motor symptoms.

HARMONY (NCT03325556) was a Phase 3, double-blind and placebo-controlled study of the safety and efficacy of Nuplazid as a preventive treatment for delusions and hallucinations associated with dementia-related psychosis in people with Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease dementia, vascular dementia, and frontotemporal dementia spectrum disorders.

It enrolled a total of 392 patients, with a mean age of 74.5. Of these people, 76% were Alzheimer’s patients with related dementia, while about 15% had Parkinson’s-related dementia, Acadia reported. Patients had symptoms of moderate-to-severe psychosis, and most were diagnosed with moderate dementia according to the MMSE mental test.

All underwent an initial 12-week open-label stabilization period, where they were given a 34 mg tablet of Nuplazid, once daily, until dementia symptoms stabilized. Individuals with difficulties tolerating the treatment at that dose were allowed to take a 20 mg tablet each day.

During this period, 61.8% of patients had a meaningful response to treatment, with a lessening in symptoms of hallucinations and delusions of 63.0% and 75.2% at weeks 8 and 12, respectively.

These patients — those who responded favorably — were eligible to enter the study’s double-blind part, where they were randomized to continue treatment with Nuplazid (either 34 mg or 20 mg daily tablets) or to switch to placebo for up to 26 weeks (six months) or until a psychosis relapse.

Relapse, or a significant worsening after stabilization, was defined as hospitalization due to dementia-related psychosis, leaving the trial due to lack of treatment efficacy, or use of off-label antipsychotic medication for dementia-related delusions or hallucinations.

The trial met its primary goal: Nuplazid significantly delayed time to relapse of dementia-related psychosis, corresponding to a 2.8-fold reduction in the risk of relapse compared to placebo.

It also met a key secondary endpoint, significantly reducing by 2.2 fold the risk of leaving the study for any reason.

Nuplazid’s use was well-tolerated over the study’s nine months. In the double-blind period, adverse events were observed in 41.0% of the patients on Nuplazid and 36.6% on placebo. Only a few were severe: 4.8% in the Nuplazid group and 3.6% in the placebo group.

No worsening in cognitive or motor symptoms was observed in Nuplazid-treated patients, and no changes in vital signs, weight, or daytime sedation were evident.

Given the treatment’s “robust” efficacy, HARMONY was stopped early in September 2019 on recommendation of its independent data monitoring committee.

“We are extremely pleased to announce the top-line results from this landmark Phase 3 study in dementia-related psychosis,” said Serge Stankovic, MD, Acadia’s president.

“The HARMONY study was designed to answer three very important questions. First, in the 12-week open-label period, pimavanserin treatment showed a meaningful reduction of the symptoms and stabilization of psychosis across all of the five clinically diagnosed subtypes evaluated,” Stankovic said.

“Second, in the 26-week double-blind period, patients on pimavanserin had a nearly three-fold reduction of risk of relapse compared to patients on placebo. And third, pimavanserin was well-tolerated by elderly patients with dementia-related psychosis,” he added.

“We look forward to discussing these results with the FDA in the first half of 2020.”

Nuplazid was designated a breakthrough therapy for the treatment of dementia-related psychosis by the FDA in 2014.

Arcadia has been evaluating the use of Nuplazid’s active ingredient, pimavanserin, in treating psychosis related to dementia, major depressive disorder, schizophrenia, and Rett syndrome.