Nuplazid ‘Encouraging’ in Lowering Dementia-related Psychosis Risk, HARMONY Trial Finds

[Editor’s note: This story, published on Dec. 10, was updated on Dec. 16 with additional details provided by Acadia Pharmaceuticals.]

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, Acadia 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 12th Clinical Trials on Alzheimer’s Disease (CTAD) Meeting, held Dec. 4–7 in San Diego.

Foff called the results “very encouraging,” a much-needed alternative to the off-label treatment now used.

“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, 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,” Cummings added.

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

“Untreated, psychosis leads to significant adverse outcomes — higher rates of morbidity, mortality, increased utilization of care,” Foff said in a webcast that accompanied the announcement of trial results.

According to this cognitive neurologist, treatment options available for dementia-related psychosis are “inadequate.” 

“Right now, we reach out off-label for typical and atypical antipsychotics and these drugs have low-to-modest efficacy, depending on the trial, and a whole host of negative effects,” Foff said.

Antipsychotics’ side effects include the risk of worsening cognitive decline, tardive dyskinesia (uncontrolled, involuntary movements), and sedation, which can lead to falls.

Nuplazid and HARMONY’s results detailed

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 — the five most common forms of dementia-related psychosis.

The trial did not focus specifically on Alzheimer’s psychosis because in clinical practice “it can be really difficult to tell one subtype apart from another,” Foff said.

Different types can look quite alike, both clinically and even sharing the same disease-causing effects.

Many of the trial participants were also suspected of having mixed conditions.

Still, “one of the important features is that we manage the symptoms of psychosis the same regardless of the underlying disease subtype,” Foff said. The only exception is dementia with Lewy bodies, where antipsychotics are usually avoided.

HARMONY enrolled a total of 392 elderly patients, with a mean age of 74.5. Of these, 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 dementia-related psychosis, and most were diagnosed with moderate dementia according to investigators’ opinion and 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.

Less than 10% of the patients needed to reduce their Nuplazid dose, which “speaks to the tolerability of the 34 mg dose in this population,” Foff said.

Results from the open-label period showed that Nuplazid led to a meaningful reduction in symptoms and a “durable stabilization of psychosis,” he added.

Of the patients enrolled, 61.8% become stable, with a substantial lessening in psychotic symptoms, including hallucinations and delusions, of 63.0% and 75.2% at weeks 8 and 12, respectively.

“This was higher than we anticipated, which was very encouraging,” Foff said.

Of note, 70 patients (19.9%) failed to respond positively to treatment at week 8 and were asked to leave. As such, data at 12 weeks’ use includes responders only, 217 people or 61.8% of the initial trial group.

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 be switched to placebo for up to 26 weeks (six months) or until a psychosis relapse.

Relapse, or a significant worsening after stabilization, was defined as one or more of the following: significant worsening of symptoms as measured by clinical scales and investigator impression, hospitalization due to dementia-related psychosis, leaving the trial due to lack of treatment efficacy, or needing to use off-label antipsychotic medication for dementia-related delusions or hallucinations.

The trial’s primary goal, or endpoint, was time to relapse. In agreement with the FDA, such endpoint and relapse criteria were chosen because they are “clinically meaningful,” Foff said.

“It’s meaningful to us if a patient who is previously stabilized has a recurrence of their symptoms,” she added.

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 times the risk of patients leaving the study for any reason

These results specifically reflected such an “overwhelming positive efficacy” that HARMONY was stopped early in September 2019, on recommendation of its data monitoring committee.

Nuplazid’s use also appeared to be safe, with an overall rate of adverse events “quite low” despite multiple conditions this patient population typically has. In the trial, half of those enrolled had five or more comorbidities.

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.

Two deaths were reported — one in the open-label and one in the double-blind period in the Nuplazid group, but none was considered related to treatment. 

Most common side effects included headaches (9.5% vs 4.5%) and urinary tract infection (6.7% vs 3.6%) on Nuplazid versus placebo-treated individuals.

Importantly, there were no higher rates of agitation and aggression on Nuplazid, and no negative effects on motor function.

Unlike with conventional antipsychotics, no worsening in cognition was observed over nine months in Nuplazid-treated patients, and no changes in vital signs, weight, or daytime sedation were evident.

Request for approval expected

“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.”

According to Stankovic, Acadia’s request for broader Nuplazid’s use will include supportive data from two other trials where the therapy proved beneficial, as well as safety data collected over the years. The two trials are a Phase 2 trial  (NCT02035553) specifically in patients with Alzheimer’s disease psychosis, and a Phase 3 study in those with Parkinson’s disease psychosis (either NCT01174004, which supported the application that led to its FDA approval for these patients, or Nuplazid’s first Phase 3 trial NCT00658567).

Nuplazid was designated a breakthrough therapy for dementia-related psychosis by the FDA in 2017.

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