Results From Trial of Pimavanserin in Patients With Dementia-Related Psychosis
ACADIA Pharmaceuticals Inc recently presented positive top-line results from its Phase 3 HARMONY study at the 12th Clinical Trials on Alzheimer’s Disease Meeting, December 4-7, 2019, in San Diego, California. HARMONY was a double-blind, placebo-controlled, relapse prevention study in 392 patients evaluating pimavanserin for the treatment of dementia-related psychosis.
Pimavanserin met the primary endpoint of the study and was stopped at the preplanned interim analysis by significantly reducing risk of relapse of psychosis by 2.8-fold compared with placebo (HR = 0.353; one-sided p=0.0023). In addition, pimavanserin met the key secondary endpoint by significantly reducing risk of discontinuation for any reason by 2.2 fold (HR = 0.452; one-sided p=0.0024).
“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,” says Jeffrey Cummings, MD, ScD, director emeritus of Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas. “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.”
The Phase 3 HARMONY study included a 12-week open-label pimavanserin treatment period prior to the randomization period of the study. In this open-label treatment period, 61.8% of eligible patients met prespecified criteria for pimavanserin treatment response at both week eight and week 12 and were subsequently randomized into the double-blind period of the study. For patients in the open-label treatment period, change from baseline to week eight and week 12 on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D) score improved by 63% and 75.2% respectively.
“We are extremely pleased to announce the top-line results from this landmark Phase 3 study in dementia-related psychosis,” says Serge Stankovic, MD, MSPH, 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. Second, in the 26-week double-blind period, patients on pimavanserin had a nearly three-fold reduction of risk of relapse compared with patients on placebo. And third, pimavanserin was well-tolerated by elderly patients with dementia-related psychosis. We look forward to discussing these results with the FDA in the first half of 2020.”
Pimavanserin was well-tolerated over the entire nine-month study duration. Patients receiving pimavanserin treatment had no worsening in cognition, as measured by the Mini-Mental State Examination (MMSE) score, from baseline and no worsening of motor symptoms, as measured by the Extrapyramidal Symptom Rating Scale A-score (ESRS-A), from baseline. In the double-blind period, low rates of adverse events were observed, 41% of patients on pimavanserin and 36.6% on placebo. Discontinuations due to adverse events were low, 2.9% for pimavanserin and 3.6% for placebo. Serious adverse events were also low, 4.8% in the pimavanserin group and 3.6% in the placebo group. One death was reported in the open-label period and one death was reported in the pimavanserin group during the double-blind period. Investigators determined neither death was related to the study drug. Additionally, pimavanserin did not result in clinically significant differences in vital signs, weight, or daytime sedation compared with placebo.
ACADIA is planning to meet with the FDA in the first half of 2020 regarding a supplemental NDA submission. The FDA previously granted Breakthrough Therapy Designation for pimavanserin for the treatment of dementia-related psychosis. Currently, no drug is approved by the FDA for the treatment of dementia-related psychosis.
About the HARMONY Study
A total of 392 patients were enrolled in the HARMONY study. The average age of patients in the study was 74.5 years. Patients had an average baseline SAPS-H+D score of 24.4, which is reflective of moderate-to-severe psychosis and an average baseline MMSE score of 16.7, which is consistent with the greatest proportion of enrolled patients having moderate dementia.
The HARMONY study included a 12-week open-label stabilization period during which patients with dementia-related psychosis were treated with pimavanserin 34 mg once daily. Dose reduction to 20 mg once daily was allowed based on tolerability within the first four weeks. Following the 12-week open-label period, patients who met prespecified criteria for treatment response were then randomized into the double-blind period of the study to continue their pimavanserin dose (34 mg or 20 mg per day) or switched to placebo and followed for up to 26 weeks or until a relapse of psychosis occurred. The primary endpoint in the study was time to relapse in the double-blind period as represented by the Kaplan-Meier curve and the hazard ratio. Pimavanserin met the primary endpoint of the study by significantly reducing the risk of relapse of psychosis by 2.8 fold compared with placebo (HR = 0.353; one-sided p=0.0023).
Relapse (psychotic exacerbation or significant worsening of dementia-related psychosis after prior stabilization) was defined in the study by one or more of the following: hospitalization due to dementia-related psychosis, significant worsening of dementia-related psychosis as measured by clinical scales and investigator impression, withdrawal from the study due to lack of efficacy, or the use of an off-label antipsychotic medication for the treatment of dementia-related delusions and/or hallucinations. All potential relapses and discontinuations in the double-blind portion of the study were adjudicated by an independent adjudication committee to determine if protocol defined relapse criteria were met.
Important Safety Information and Indication for NUPLAZID (Pimavanserin)
• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
• NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.
• Contraindication: NUPLAZID is contraindicated in patients with a history of a hypersensitivity reaction to pimavanserin or any of its components. Rash, urticaria, and reactions consistent with angioedema (eg, tongue swelling, circumoral edema, throat tightness, and dyspnea) have been reported.
• QT Interval Prolongation: NUPLAZID prolongs the QT interval.
• Adverse Reactions: The most common adverse reactions (≥2% for NUPLAZID and greater than placebo) were peripheral edema (7% vs 2%), nausea (7% vs 4%), confusional state (6% vs 3%), hallucination (5% vs 3%), constipation (4% vs 3%), and gait disturbance (2% vs <1%).
• Drug Interactions:
Indication: NUPLAZID is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.
Dosage and Administration: Recommended dose: 34 mg capsule taken orally once daily, without titration.
NUPLAZID is available as 34 mg capsules and 10 mg tablets.
Please see the full Prescribing Information including Boxed WARNING for NUPLAZID.
Source: ACADIA Pharmaceuticals Inc