The FDA cited a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.
The FDA has issued a complete response letter (CRL) for the supplemental new drug application (sNDA) for pimavanserin (Nuplazid; Acadia Pharmaceuticals), a treatment for hallucinations and delusions associated with dementia-related psychosis. Following review of the application, it was determined that the drug cannot be approved in its present form.1
A lack of statistical evidence in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes was cited as lack of substantial evidence of effectiveness to support approval. The agency also stated in the CRL that it considers the phase 2 Alzheimer disease (AD) psychosis study –019, a supportive study in the sNDA filing, to not be adequate and well controlled, citing that it was a single center study with no type 1 error control of secondary end points in which certain protocol deviations occurred.
"Acadia stands behind the robustly positive results from the pivotal Phase 3 HARMONY study and the prospectively agreed trial design and criteria for establishing efficacy in DRP. Over the entire course of the review, the Division did not raise any concerns regarding the agreed upon study design, including the issues raised in the CRL,” Steve Davis, chief executive officer, Acadia, said in a statement. "We will immediately request a Type A meeting to work with the FDA to address the CRL and determine an expeditious path forward for the approval of pimavanserin in DRP.”
Pimavanserin, a selective serotonin inverse agonist and antagonist preferentially targeting 5HT2A receptors, was approved for the treatment of hallucinations and delusions associated with Parkinson disease psychosis by the FDA in April 2016.
This news comes just a month after Acadia announced that the FDA had identified deficiencies precluding the labeling and post-marketing requirements for the therapy, a notification which was deemed not reflective of its final decision on the information under review. It did not specify the deficiencies identified by the FDA at the time, though Acadia announced its intent to work with the agency to ascertain the deficiencies’ roots and resolve them.2
The supplemental new drug application (sNDA) for pimavanserin was originally accepted by the agency in July 2020 and is supported by the results of the phase 3 HARMONY study (NCT03325556). Pimavanserin met the primary end point in HARMONY, demonstrating a significant reduction in the risk of relapse of psychosis by 2.8-fold compared to placebo (hazard ratio [HR], 0.353; one-sided P = .0023).3
HARMONY, a double-blind, placebo-controlled trial, contained 392 patients (mean age, 74.5 years) and evaluated the safety and efficacy of pimavanserin for the treatment of hallucinations and delusions associated with dementia-related psychosis in patients with various dementia subtypes, including AD, PD dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia. Those included were initially enrolled in an open-label stabilization period where they received 34-mg pimavanserin once daily for 12 weeks. All told, 61.8% met the sustained treatment response criteria at week 8 and 12 and proceeded to the double-blind period. Patients then were randomly assigned to receive either 34-mg or 20-mg daily pimavanserin or placebo for up to 26 weeks or until relapse occurred. The trial was originally halted in September 2019 after an interim efficacy analysis identified a statistically significant effect on DRP.4
Additionally, data from the phase 2 study in patients with Alzheimer disease (AD) psychosis and the phase 3 study in patients with Parkinson disease (PD) psychosis, both of which also met their primary end points, were also included in the sNDA.
In December 2020, Acadia announced that the FDA gave the OK to a prior approval supplement application for updating the prescribing information for pimavanserin. The labeling update provides instructions for the sprinkling of the capsule contents onto both food and liquids for dosing and administration. The capsules, which can be swallowed whole, can be emptied over 15 mL of applesauce, yogurt, pudding, or a liquid nutritional supplement for patients with Parkinson disease who face difficulty in swallowing—a challenge that occurs for this population at a rate that is 3 times greater than in healthy elderly people.5