The resubmission includes additional data from the phase 2 Study -019 and the pivotal phase 3 HARMONY study, which showed a significant 2.8-fold reduction in the risk of relapse of psychosis.
After being issued a complete response letter (CRL) by the FDA in April 2021, Acadia Pharmaceuticals has resubmitted its supplemental new drug application (sNDA) for pimavanserin (Nuplazid) to treat hallucinations and delusions associated with dementia-related psychosis (DRP).1
In the CRL, the FDA stated it could not approve the drug in its present form because of a lack of statistical evidence in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes.2 Furthermore, the agency also believed that the phase 2 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 protocol deviations occurred.
The resubmission by Acadia included additional analyses from Study -019 and the pivotal phase 3 HARMONY study (NCT03325556), the study for which was the sNDA was originally accepted for in July 2020. According to the company, the newly added data is intended to address the concerns raised in the CRL.1
At the time of the issued CRL, Steve Davis, chief executive officer of Acadia, said in a statement that the company "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."2
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 (PD) psychosis by the FDA in April 2016. It remains one of the only few FDA-approved medications to treat patients with this condition.
In HARMONY, pimavanserin met its primary end point, demonstrating a significant reduction in the risk of relapse of psychosis by 2.8-fold compared to placebo (HR, 0.353; one-side P = .0023). The double-blind, placebo-controlled trial included 392 patients with various dementia subtypes, including Alzheimer disease (AD), PD dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia.3
Those included were initially enrolled in an open-label stabilization period where they received 34-mg pimavanserin once daily for 12 weeks. In September 2019, an independent data monitoring committee recommended the study be halted, citing positive efficacy benchmarks at the pre-planned interim analysis.4 Following the stopping of the trial, 41 patients withdrew for administrative reasons, of the remaining 351 patients, 217 (61.8%) met the sustained treatment response criteria at week 8 and 12 and proceeded to the double-blind period.
Patients were divided into treatment (n = 105) and placebo (n = 112) groups, with relapse at the time of interim analysis occurring in 12 out of 95 patients (13%) in the treatment group and 28 out of 99 patients (28%) in the placebo group (HR, 0.35 [95% CI, 0.17-0.73] P = .005).A total of 44 patients in the treatment arm and 35 patients in the placebo arm completed 26 weeks of the trial. Investigators also found that patients were less likely to discontinue trial when being treated with pimavanserin versus placebo, with a median duration of exposure in the double-blind phase of 17.7 weeks and 10.9 weeks, respectively.5
In total, 43 of 105 pimavanserin-treated patients reported adverse events (AEs), compared with 41 out of 112 (36.6%) of those who received placebo. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation were among the most common AEs.
At the 2021 American Academy of Neurology annual meeting, held April 17-22, Clive Ballard, MD, presented a literature review on multiple studies of pimavanserin, including HARMONY, that indicated no negative impacts on cognitive function in patients with neurodegenerative diseases treated with the medication compared to those on placebo. Ballard and colleagues found that the Mini-Mental Status Scale (MMSE) score least squares mean (LSMO) change from baseline to week 12 was –0.25 (SE, 0.42) in study 019 and 0.0 (SE, 0.57) in study 032, and similar to placebo in both. LSMO change from baseline to week 8 was 1.2 (SE, 0.21; n = 132) for pimavanserin and 0.5 (SE, 0.21; n = 128) for placebo in the interim analysis of study 046.6
Ballard, professor, age-related diseases, and pro-vice-chancellor and executive dean, University of Exeter Medical School, sat down with NeurologyLive® following his presentation to discuss his results and the effectiveness of pimavanserin to treat psychosis in patients with PD and other forms of dementia.