SAN DIEGO—Of the roughly eight million individuals in the United States living with dementia, research suggests that some 30 percent of those patients suffer from psychosis. Dementia-related psychosis includes that seen in Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease, vascular dementia and frontotemporal dementia.
ACADIA Pharmaceuticals is advancing pimavanserin, a candidate it hopes will provide a treatment for such patients. The company recently announced that the drug met its primary endpoint in the HARMONY study, which was stopped at the pre-planned interim analysis due to having significantly reduced risk of relapse of psychosis by 2.8-fold compared to placebo. Pimavanserin also met the key secondary endpoint by significantly reducing risk of discontinuation for any reason by 2.2-fold. Top-line results from the HARMONY study were presented at the 12th Clinical Trials on Alzheimer’s Disease meeting held in December.
The Phase 3 HARMONY study was a double-blind, placebo-controlled, relapse prevention study in 392 patients, meant to assess the safety and efficacy of pimavanserin as a treatment for delusions and hallucinations associated with dementia-related psychosis. Pimavanserin is a selective serotonin inverse agonist and antagonist that preferentially targets 5-HT2A, which is implicated in psychosis, schizophrenia, depression and other neuropsychiatric disorders. The drug was approved in April 2016 by the U.S. Food and Drug Administration for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis under the name Nuplazid.
“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 Dr. Jeffrey Cummings, 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 study included a 12-week open-label pimavanserin treatment period prior to randomization, during which 61.8 percent of eligible patients met pre-specified criteria for pimavanserin treatment response at weeks eight and 12, and were randomized into the double-blind portion of the study. In the open-label period, patient 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 63.0 percent and 75.2 percent, respectively.
Pimavanserin was well tolerated, with no further loss of cognition and no worsening of motor symptoms. Adverse events were seen at a rate of 41 percent in the double-blind period, with discontinuations due to adverse events of only 2.9 percent and serious adverse events of only 4.8 percent. One death was reported in the open-label period, and one death in the pimavanserin group during the double-blind period; investigators determined that neither was related to pimavanserin.
“We are extremely pleased to announce the top-line results from this landmark Phase 3 study in dementia-related psychosis,” commented ACADIA’s president, Dr. Serge Stankovic. “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 threefold reduction of risk of relapse compared to 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.”
ACADIA intends to meet with the FDA regarding a supplemental NDA submission. While pimavanserin has received Breakthrough Therapy Designation for the treatment of dementia-related psychosis, no drugs have yet been approved for that indication.
In a webcast of ACADIA Pharmaceuticals’ presentation by CEO Stephen Davis at the 38th Annual J.P. Morgan Conference, Davis noted that in 2019, the company saw a 50-percent increase of pimavanserin sales growth year over year compared to 2018. He also pointed out that of the company’s four late-stage programs, three feature pimavanserin: dementia-related psychosis, major depressive disorder (adjunctive therapy) and negative symptoms of schizophrenia.
“These three indications, in addition to [Parkinson’s disease psychosis], represent a potential 35-fold increase in the number of treated patients,” Davis remarked in the presentation, adding that dementia-related psychosis, major depressive disorder (with pimavanserin solely as an adjunctive therapy) and negative symptoms of schizophrenia represent market opportunities that are 10, 20 and five times the size of the Parkinson’s disease psychosis market, respectively.
ACADIA is advancing pimavanserin through trials in all three of those indications, with results from its Phase 3 CLARITY-2 trial in major depressive disorder expected in the fourth quarter of 2020 and a second pivotal study in schizophrenia slated to begin this summer.