FDA Advisory Committee Votes Down Pimavanserin's Efficacy in AD Psychosis Ahead of PDUFA
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
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.
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"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
In February 2022,
In the HARMONY study,
An independent data monitoring committee
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.
REFERENCES
1. June 17, 2022, Meeting of the Psychopharmacologic Drugs Advisory Committee Meeting Announcement. FDA website. June 17, 2022. Accessed June 17, 2022. https://www.fda.gov/advisory-committees/advisory-committee-calendar/june-17-2022-meeting-psychopharmacologic-drugs-advisory-committee-meeting-announcement-06172022
2. Acadia Pharmaceuticals Announces FDA Advisory Committee Meeting to Review Resubmission of Supplemental New Drug Application for NUPLAZID® (pimavanserin) for the Treatment of Alzheimer’s Disease Psychosis Scheduled for June 17, 2022. News release. May 2, 2022. Accessed June 17, 2022. https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-fda-advisory-committee-meeting-to-review-resubmission-of-supplemental-new-drug-application-for-nuplazid-pimavanserin-for-the-treatment-of-alzheimers-d/
3. Acadia Pharmaceuticals Receives Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Pimavanserin for the Treatment of Hallucinations and Delusions Associated with Dementia-Related Psychosis. April 5, 2021. Accessed June 17, 2022. https://www.businesswire.com/news/home/20210405005229/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Dementia-Related-Psychosis
4. Acadia Pharmaceuticals announces resubmission of supplemental new drug application to US FDA for Nuplazid (pimavanserin) to treat Alzheimer disease psychsosis. News release. Acadia Pharmaceuticals. February 16, 2022. Accessed June 17, 2022. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-resubmission-supplemental-new
5. Foff EP, Devanand DP, Ballard C, McEvoy B, Stankovic S. HARMONY: response to Pimavanserin in the 12-week, open-label treatment phase. Presented virtually at AAIC 2020. Poster 4543
6. Acadia Pharmaceuticals Announces Pivotal Phase 3 HARMONY Trial Stopped Early for Positive Efficacy as Pimavanserin Meets the Primary Endpoint in Patients with Dementia-Related Psychosis. News release. Acadia Pharmaceuticals. September 9, 2019. Accessed June 17, 2022. biospace.com/article/releases/acadia-pharmaceuticals-announces-pivotal-phase-3-harmony-trial-stopped-early-for-positive-efficacy-as-pimavanserin-meets-the-primary-endpoint-in-patients-with-dementia-related-psychosis/
7. Tariot P, Cummings JL, Soto-Martin ME, et al. Trial of Pimavanserin in Dementia-Related Psychosis. N Engl J Med. 2021;385:309-319. doi: 10.1056/NEJMoa2034634
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