Under Fire for Risk/Efficacy Profile – Nuplazid Shows Potential for Treating Dementia-Related Psychosis

ACADIA Pharmaceuticals Inc. (NASDAQ: ACAD) announced on 9/10/18 publication of additional data from a Phase 2 single center, double-blind, placebo-controlled study to examine the safety and efficacy of pimavanserin (Nuplazid) for the treatment of psychosis in Alzheimer’s Disease Psychosis in The Journal of Prevention of Alzheimer’s Disease (JPAD). These results further demonstrate that pimavanserin may have the potential to treat dementia-related psychosis, a condition which can be present in neurodegenerative diseases such as Alzheimer’s disease, dementia with Lewy Bodies, dementia associated with Parkinson’s disease, vascular dementia and frontotemporal dementia-spectrum disorders.

The publication focused on the pre-specified analysis in the subgroup of patients who had more pronounced psychotic symptoms at baseline. In this subgroup of patients with more severe delusions and hallucinations, at the primary efficacy endpoint, pimavanserin demonstrated significant improvement relative to placebo with a similar and acceptable tolerability profile. These results were also presented recently at the Alzheimer’s Association International Conference in Chicago in July 2018. The primary results from the study were previously reported at the Clinical Trials in Alzheimer’s Disease (CTAD) conference in Boston in October 2017 and published in the Lancet Neurology in March 2018.

“The robust efficacy of pimavanserin in patients with more severe psychotic symptoms is relevant to the therapeutic benefits of pimavanserin in a patient population with Alzheimer’s disease and psychosis,” said lead investigator Clive Ballard, MBChB, MRCPsych, Pro-Vice-Chancellor and Executive Dean, University of Exeter Medical School. “These results extend and confirm the results from the primary analysis as well as results from the subgroup analysis of patients with mild dementia in the pivotal Parkinson’s disease psychosis study with pimavanserin. These findings, coupled with the results from other studies of pimavanserin, suggest a potential role for pimavanserin in treating dementia-related psychosis in patients across a range of neuropsychiatric conditions.”

Nuplazid has been under fire since CNN published an article in April of 2018 that focused on pimavanserin's side effects and questioned its efficacy. Some subsequent medical journal articles, however, have questioned the idea that pimavanserin is more dangerous than other anti-psychotics used to treat Parkinson’s Psychosis.

In an article in Neurology Today, Dr  Rajesh Pahwa said, “In my personal experience with pimavanserin, it is effective in a majority of PD [Parkinson’s] psychosis patients”. Dr Pahwa is  a professor of neurology and chief of the Parkinson & Movement Disorders Division at the University of Kansas Medical Center in Kansas City. Dr Pahwa also pointed out that US Medicare data showed a lower mortality rate associated with pimavanserin compared to another drug used off label to treat Parkinson’s Psychosis.

Specifically addressing the CNN article, Dr Pahwa said, “It is unfortunate that instead of discussing scientific data from scientific journals we are more concerned about discussing biased reporting from news channels who have no idea what PD psychosis is or the risks that it involves. Such reporting would never make it in a peer-reviewed journal,”

A separate review published in JPAD also supports the potential use of pimavanserin in other forms of neurodegenerative diseases, including dementia-related psychosis. A research group led by Jeffrey Cummings, MD, ScD, of the Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, looked at the clinical evidence that has been gathered to date that supports the potential efficacy of pimavanserin in dementia-related psychosis. “Clinical evidence is now available that supports potential efficacy of pimavanserin in dementia-related psychosis. This includes results from a sub-analysis of mildly demented patients in the Phase 3 pivotal study in patients with Parkinson’s disease psychosis, and the Phase 2 study in patients with Alzheimer’s disease. Based on the overlap in clinical presentation and pathology and the positive clinical trial results in two neurodegenerative patient populations, we think it is important to continue to evaluate pimavanserin’s effect in patients with hallucinations and delusions across a number of neurodegenerative disorders,” said Dr. Cummings.

ACADIA is currently conducting the Phase 3 HARMONY study in dementia-related psychosis. This is a randomized withdrawal study designed to evaluate the efficacy of pimavanserin in preventing relapse of psychotic symptoms in patients with dementia-related psychosis. Patients whose dementia-related hallucinations and delusions respond to 12 weeks of open-label treatment with pimavanserin are randomized, in a double-blinded manner to continue pimavanserin therapy or to placebo. The primary endpoint of this study is the average time to relapse between pimavanserin and placebo. Studies suggest that 30% of patients with dementia have psychosis, commonly consisting of hallucinations and delusions. Serious consequences have been associated with severe or persistent psychosis in patients with dementia. These consequences can impact both patients and their families. Medications that are currently used off-label to treat dementia related psychosis have been shown to impair cognition in this already impaired population.