In top-line results from the pivotal phase 3 HARMONY (NCT03325556) study, treatment with pimavanserin vs placebo (Nuplazid, Acadia Pharmaceuticals, San Diego, CA) reduced risk of psychotic relapse by 2.8 fold (HR = 0.353; one-sided P = .0023) for people with dementia-related psychosis (DRP). People treated with pimavanserin were 2.2 times less likely to discontinue the study medication compared with those treated with placebo (HR = 0.452; one-sided P= .0024). This finding met the predetermined primary endpoint; as a result, the study was terminated early for efficacy.
In an initial open-label period, 61.8% of participants responded to treatment at weeks 8 and 12 and were then randomized into the double-blind placebo-controlled portion of the trial. During the open-label period, participants had a 63.0% and 75.2% improvment in the Scale for Assessment of Positive Symptoms Hallucinations and Dementia subtests (SAPS-HD) at weeks 8 and 12, respectively. Treatment response was seen across multiple subtypes of PDR, including Alzheimer’s disease, dementia with Lewy bodies (DLB), Parkinson’s disease (PD) dementia, vascular dementia, and frontotemporal dementia (FTD).
No worsening of cognition was seen on the Mini-Mental State Examination (MMSE). No worsening of motor symptoms as measured by the Extrapyramidal Symptom Rating Scale A (ESRS-A) were seen. The rate of serious adverse events was low for both pimavanserin treatment (4.8%) and placebo (3.6%); overall adverse events occurred in 41% of people treated with pimavanserin compared with 36.5% of those treated with placebo. In those treated with pimavanserin vs placebo, headache (9.5% vs 4.5%) and urinary tract infection (6.7% vs 3.6%) were more common. A single death occurred in each phase of the trial; these 2 deaths were not considered as treatment related.
“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,” said Jeffrey Cummings, MD, ScD, Director Emeritus of Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and member of the Practical Neurology editorial board. “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.”
“We are extremely pleased to announce the top-line results from this landmark phase 3 study in DRP,” said Serge Stankovic, MD, MSPH, president of Acadia Pharmaceuticals. “The HARMONY study was designed to answer 3 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 5 clinically diagnosed subtypes evaluated. Second, in the 26-week double-blind period, (participants) on pimavanserin had a nearly threefold reduction of risk of relapse compared with placebo. And third, pimavanserin was well-tolerated by elderly patients with DPR. We look forward to discussing these results with the FDA in the first half of 2020.”
The HARMONY study included a 12-week open-label stabilization period during which participants with DPR were treated with pimavanserin 34 mg once daily for 4 weeks, which could then be reduced to 20 mg if clinically warranted. After the open-label period, participants who responded to treatment were randomly assigned to continue on pimavanserin or be switched to placebo for up to 26 weeks or until DPR relapse occurred. Participants were mean age 74.5 years with an average baseline 24.4 SAPS-H+D score, reflective of moderate-to-severe psychosis and an average baseline 16.7 MMSE score, consistent with moderate dementia.
These results were presented today at the 12th Annual Clinical Trials in Alzheimer Disease conference taking place in San Diego, CA, December 4-7, 2019.
Ilana E. Green; Andrew M. Southerland, MD, MSc; and Bradford B. Worrall, MD, MSc
Olivia Reese; Rimas V. Lukas, MD; and Katherine S. Carroll, MD
James Geyer, MD; and Thomas Patton, MD