Members who voted no expressed that they would have liked to have seen results from an additional randomized controlled trial.
In a meeting of the FDA’s Psychopharmacologic Drugs Advisory Committee (AdComm) to review pimavanserin (Nuplazid; Acadia Pharmaceuticals) ahead of the agency’s pending decision on the drug's treatment of Alzheimer disease (AD) psychosis, the committee voted in opposition to the drug's efficacy for the treatment of hallucinations and delusions in patients with AD psychosis.1 The PDUFA date for the therapy’s supplemental new drug application (sNDA) is August 4, 2022.
Among 12 voting members, 3 voted 'yes' and 9 voted 'no' in answering the question, "Does available evidence support a conclusion that pimavanserin is effective for the treatment of hallucinations and delusions in the AD [psychosis] population?"
Some committee members expressed their wants of an additional randomized controlled trial, including a withdrawal trial, better representation across ethnicity and race, and a longer duration of efficacy assessed. Among those who voted "yes," members expressed the great unmet need in this population and that there are no known safety concerns with the drug, which is already available for a similar indication in Parkinson disease.
The vote casts further doubt on Acadia's chances of a positive decision come August 4, when the FDA will decide the fate of the brand's resubmitted supplemental NDA.
“We appreciate our ongoing engagement with the FDA and look forward to a productive discussion on the clinical evidence supporting the positive benefit-risk profile for pimavanserin as a treatment for ADP at the upcoming Advisory Committee meeting,” Steve Davis, chief executive officer, Acadia, said in a statement when the AdComm meeting was annnounced.2
This decision on the selective serotonin inverse agonist and antagonist preferentially targeting 5HT2A receptors follows an up-and-down journey to this point. It was originally approved for the treatment of Parkinson disease psychosis in April 2016. It would then be submitted to the FDA in an sNDA in July 2020 for the treatment of AD psychosis, but in April 2021, the FDA issued a complete response letter to Acadia for pimavanserin regarding the treatment for hallucinations and delusions associated with dementia-related psychosis.3
Following the review, the FDA determined that the drug could not be approved in its present form, citing mainly a lack of statistical evidence in some of the subgroups of dementia and insufficient numbers of patients with certain less common dementia subtypes. The agency also stated in the CRL that it considers the phase 2 AD psychosis Study-019 (NCT02035553), a supportive study in the sNDA filing, to be not adequate nor well-controlled, noting that it was single center in nature and lacked 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,” Davis said in a statement at the time.3 "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.”
Shortly after the CRL, in August 2021, NeurologyLive® inquired Jeffrey L. Cummings, MD, ScD, professor of brain science, and director, Chambers-Grundy Center for Transformative Neuroscience, University of Nevada–Las Vegas, and a coinvestigator of the HARMONY trial, about the potential need for more data on pimavanserin. “Yes, I think we will need to investigate more about how each of the dementias themselves responds to pimavanserin. We do have data already on Parkinson disease psychosis because pimavanserin is approved for Parkinson disease psychosis, but we need additional data on Alzheimer disease, vascular dementia, dementia with Lewy bodies, and Frontotemporal dementia. Those are all dementias that are more uncommon—except for Alzheimer disease, of course. So, we need additional data on these other dementia states,” Cummings said at the time.
In February 2022, Acadia resubmitted its sNDA, this time including additional analyses from Study -019 and the pivotal phase 3 HARMONY study (NCT03325556), the study which originally accepted supported the July 2020 submission. According to the company, the newly added data were aimed at addressing the FDA’s concerns.4
In the HARMONY study, pimavanserin met its primary end point in showing a significant 2.8-fold reduction in the risk of psychosis relapse compared with 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.5 Those included were initially enrolled in an open-label stabilization period where they received 12 weeks of treatment with 34-mg pimavanserin.
An independent data monitoring committee recommended the study be halted n September 2019, citing positive efficacy benchmarks at the preplanned interim analysis.6 At this point, 41 patients withdrew for administrative reasons with 351 patients remaining. Of those, 217 (61.8%) met the sustained treatment response criteria at week 8 and 12 and proceeded to the double-blind period. These were assigned to treatment (n = 105) and placebo (n = 112) groups, with relapse at the time of interim analysis being reported by 12 of 95 patients (13%) in the treatment group and 28 of 99 (28%) in the placebo group (HR, 0.35; 95% CI, 0.17-0.73; P = .005).4,5
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.7 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.