Committee members said the data from the two trials submitted didn’t support efficacy of Nuplazid in Alzheimer’s patients. The PDUFA target date is Aug. 4, 2022.
The FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) have voted 9 to 3 that the evidence doesn’t support the effectiveness of Acadia Pharmaceuticals’ Nuplazid (pimavanserin) for the treatment of hallucinations and delusions associated with Alzheimer’s disease.
Although the two trials that were done showed modest efficacy, most committee members didn’t think Nuplazid met a positive endpoint. Committee members suggested an additional randomized clinical trial with patients specifically with Alzheimer’s disease psychosis would help to further the evidence.
“A randomized controlled trial that incorporates Alzheimer’s blood markers, bigger sample size, better outcome measures, would be reasonable to generate strong data to support an indication going forward,” Rajesh Narendran, M.D., committee chairperson, and attending psychiatrist and UPMC Western Psychiatric Hospital, said after the vote. He is also professor of radiology and psychiatry at the University of Pittsburgh School of Medicine.
Those who voted yes indicated their rationale was there are limited available therapies for this patient population, especially with antipsychotics currently being used off label for patients with Alzheimer’s psychosis.
Committee member Walter S. Dunn, M.D., Ph.D., voted no on whether the submitted trials support efficacy of Nuplazid in this patient population, but suggested the agency might consider a broad approach when making its decision.
“The questions before the committee are narrow and precise,” he said. “There are many factors we didn’t formally discuss such as safety and unmet clinical need. There is clearly a need in this highly vulnerable population. As a clinician, I am a proponent for having as many tools in the toolbox as possible. I trust the agency will take all these factors into consideration.”
Dunn is an assistant clinical professor at the University of California Los Angeles, director, Mood Disorders Section, and director, Interventional psychiatry at the West Los Angeles Veterans Affairs Medical Service.
Nuplazid is a selective serotonin inverse agonist and antagonist targeting 5-HT2A receptors. These receptors are thought to play an important role in neuropsychiatric disorders. The FDA approved Nuplazid in April 2016 for the treatment of patients with hallucinations and delusions associated with Parkinson’s disease psychosis. It is the only therapy approved for this indication.
“We will continue to work closely with the FDA as it completes its review of the totality of our efficacy and safety data to enable a full assessment of pimavanserin’s benefit-risk in patients with ADP,” Steve Davis, chief executive officer of Acadia, said in a press release. “We continue to believe there is substantial evidence across multiple independent clinical studies and endpoints that support the efficacy of pimavanserin in Alzheimer’s disease psychosis. There are no FDA approved treatments for this critical public health need and off-label use of multi-receptor acting antipsychotics have demonstrated poor patient outcomes, including worsening of cognition and motor function.”
In February 2022, Acadia had resubmitted its supplemental new drug application (sNDA) for Nuplazid in response to an April 2021 complete response letter from the FDA. In the first review, regulators had concluded that Study 019 was not an adequate and well-controlled study, highlighting concerns related to trial design and conduct issues.
Regulators said then that in the study, there was a lack of statistical significance in some of the subgroups of patients with dementia, and there were an insufficient number of patients in dementia subtypes. Regulatory authorities also said that it considered the phase 2 Study-019 not adequate because it was not well controlled and because protocol deviations occurred. No safety issues were raised in the response letter.
In materials released ahead of the meeting, regulators expressed several concerns. Regulators indicated that in Study 019 the magnitude of improvement observed was small — less than 2 points on a 24-point scale — and may not reflect a clinically meaningful improvement.
Regulators also expressed concern that Study 045, which was included in the submission to support the data in Alzheimer’s disease psychosis, suggests a differential response to pimavanserin across dementia subtypes. They believe it was not powered to determine an effect in the included dementia subgroups. Regulators said the Alzheimer’s and Parkinson’s disease subgroups appeared to respond differently to pimavanserin. With 123 subjects (63%), the Alzheimer’s subgroup 8 was the largest subgroup, yet the results in the Parkinson’s subgroup of 35 patients (18%) in Study 045 appeared to drive the overall study results.
Regulators indicated they don’t believe that Alzheimer’s and Parkinson’s psychosis are closely-related conditions.
After the vote, Dunn suggested the submitted trials show some evidence that pimavanserin can be effective in Alzheimer’s psychosis but further study is warranted to reach a conclusion.
“For the study 45, there are two conclusions I can make. One is that there is a different response between Alzheimer’s and Parkinson’s psychosis and that it can be very effective as a maintenance treatment for Parkinson’s disease psychosis. In the Alzheimer’s patients it would not support efficacy in the Alzheimer’s population.”