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Clinical Trial
. 2024;98(1):265-274.
doi: 10.3233/JAD-231167.

Safety Profile of Pimavanserin Therapy in Elderly Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study

Gus Alva  1 , Wiesław J Cubała  2 , Ana Berrio  3 , Bruce Coate  3 , Victor Abler  3 , Sanjeev Pathak  3
Affiliations
Clinical Trial

Safety Profile of Pimavanserin Therapy in Elderly Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study

Gus Alva et al. J Alzheimers Dis. 2024.

Abstract

Background: Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, is the only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Further expanding knowledge of the safety profile of pimavanserin in PDP and neurodegenerative diseases (NDD) such as Alzheimer's disease is of great interest for informing its use in patients with PDP (with or without dementia), given this population is highly sensitive to adverse effects following antipsychotic use.

Objective: This trial evaluated the effects of pimavanserin compared to placebo in frail older adults and elderly patients with neuropsychiatric symptoms related to NDD, such as hallucinations and delusions, to better understand the safety of pimavanserin in this population.

Methods: This was a phase 3b, 8-week treatment (study duration of up to 16 weeks), multicenter, randomized, double-blind, placebo-controlled, two-arm parallel-group trial (NCT03575052). The primary endpoint was safety and tolerability, measured by treatment-emergent adverse events (TEAEs). Secondary safety endpoints were change from baseline in motor and cognitive function; exploratory endpoints included suicidality, sleep quality, and neuropsychiatric symptoms.

Results: Incidences of TEAEs were similar between treatment groups; 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%), and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%). Pimavanserin did not impact motor- or cognitive-related function.

Conclusions: Pimavanserin was well tolerated and not associated with motor or cognitive impairment. Together, these findings highlight the manageable and generally favorable safety profile of pimavanserin in patients with NDD, contributing to our knowledge on the safety of pimavanserin as it generalizes to patients with PDP.

Keywords: Alzheimer’s disease; elderly patients; neurodegenerative diseases; neuropsychiatric symptoms; pimavanserin; safety.

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Conflict of interest statement

GA: Research support from Accera, Allergan, Axovant, Eisai, Neurotrope, Genentech, Intra Cellular, Janssen, Lundbeck, Neurim, Novartis, Otsuka, Roche, Suven, and Trans Tech. Speakers Bureau and Consultant for Acadia, Alkermes, Allergan, Avanir, Janssen, Lundbeck, Merck, Nestle, Otsuka, Sunovion, Takeda, and Vanda. WJC: Received grants from Acadia, Alkermes, Allergan, Angelini, Auspex Pharmaceuticals, BMS, Celon, Cephalon, Cortexyme, Ferrier, Forest Laboratories, GedeonRichter, GW Pharmaceuticals, HMNC Brain Health, IntraCellular Therapies, Janssen, KCR, Lilly, Lundbeck, Minerva, MSD, NIH, Novartis, Orion, Otsuka, Sanofi, and Servier; received honoraria from Adamed, Angelini, AstraZeneca, Bristol Myers Squibb, Celon, GSK, Janssen, KRKA, Lekam, Lundbeck, Minerva, NeuroCog, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, and Zentiva; served on advisory boards for Angelini, Celon (terminated), Douglas Pharmaceuticals, Janssen, MSD, Novartis, and Sanofi.

VA, AB, SP, and BC: employees of ACADIA Pharmaceuticals Inc. (San Diego, CA, USA) at the time of the study.

Figures

Fig. 1
Fig. 1
The (A) study design and (B) patient disposition of the trial. aSubjects who enrolled in the open-label extension study did not complete the safety follow-up period. bIn the pimavanserin group, one patient was discontinued from the study due to an adverse event and died 4 days after the early termination visit and 4 days after stopping study drug. LAR, legally acceptable representative; R, randomization; QD, once daily.
Fig. 2
Fig. 2
CGI-I score throughout the study period. aLSM from MMRM with fixed categorical effects of region, planned treatment, visit, treatment-by-visit interaction, and fixed continuous covariates of baseline CGI-severity score and baseline CGI-severity score-by-visit interaction. CGI-I, Clinical Global Impression-Improvement; LSM, least square means; MMRM, mixed-effects model repeated measures.
Fig. 3
Fig. 3
Total score change from baseline on the SDI. aLSM from MMRM with fixed categorical effects of region, planned treatment, visit, treatment-by-visit interaction, and fixed continuous covariates of baseline SDI score and baseline SDI score-by-visit interaction. LSM, least square means; MMRM, mixed-effects model repeated measures; SDI, Sleep Disorders Inventory.
See this image and copyright information in PMC

References

    1. Kitten AK, Hallowell SA, Saklad SR, Evoy KE (2018) Pimavanserin: A novel drug approved to treat Parkinson’s disease psychosis. Innov Clin Neurosci 15, 16–22. - PMC - PubMed
    1. Yunusa I, El Helou ML, Alsahali S (2020) Pimavanserin: A novel anti psychotic with potentials to address an unmet need of older adults with dementia-related psychosis. Front Pharmacol 11, 87. - PMC - PubMed
    1. FDA, FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease, https://www.fda.gov/news-events/press-announcements/fda-approves-first-d..., Accessed June 14.
    1. Hacksell U, Burstein ES, McFarland K, Mills RG, Williams H (2014) On the discovery and development of pimavanserin: A novel drug candidate for parkinson’s psychosis. Neurochem Res 39, 2008–2017. - PMC - PubMed
    1. Vanover KE, Weiner DM, Makhay M, Veinbergs I, Gardell LR, Lameh J, Del Tredici AL, Piu F, Schiffer HH, Ott TR, Burstein ES, Uldam AK, Thygesen MB, Schlienger N, Andersson CM, Son TY, Harvey SC, Powell SB, Geyer MA, Tolf BR, Brann MR, Davis RE (2006) Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phen ylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist, J Pharmacol Exp Ther 317, 910–918. - PubMed

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