Motor- and cognition-related safety of pimavanserin in patients with Parkinson's disease psychosis

Abstract

BackgroundPimavanserin, a selective 5-HT2A inverse agonist/antagonist, is the only treatment approved by the US Food and Drug Administration for hallucinations and delusions associated with Parkinson's disease (PD) psychosis.AimWe aimed to evaluate motor- and cognition-related safety in pimavanserin-treated patients with PD psychosis.MethodsThis analysis included patients with PD psychosis treated with pimavanserin 34 mg from a pooled analysis of 3 randomized, double-blind, placebo-controlled, 6-week studies [NCT00477672 (study ACP-103-012), NCT00658567 (study ACP-103-014), and NCT01174004 (study ACP-103-020)] and a subgroup of patients with PD dementia with psychosis from HARMONY (NCT03325556), a randomized discontinuation study that included a 12-week open-label period followed by a randomized double-blind period of up to 26 weeks. Motor- and cognition-related safety were examined.ResultsThe pooled analysis included 433 randomized patients (pimavanserin, 202; placebo, 231). Least squares mean (standard error [SE]) change from baseline to week 6 Unified Parkinson's Disease Rating Scale (UPDRS) II + III score was similar for pimavanserin [−2.4 (0.69)] and placebo [−2.3 (0.60)] (95% Confidence Interval [CI]:−1.9, 1.6). The change from baseline to week 6 for UPDRS II and UPDRS III scores was similar between groups. In the HARMONY open-label period, 49 patients with PD dementia with psychosis were treated with pimavanserin 34 mg, 36 of whom were randomized in the double-blind period (pimavanserin, 16; placebo, 20). In the open-label period, the mean (SE) change from baseline to week 12 (n = 39) Extra-Pyramidal Symptom Rating Scale (ESRS-A) score was −1.7 (0.74); in the double-blind period, the results were generally comparable between the pimavanserin and placebo arms. The change from baseline in Mini-Mental State Examination (MMSE) score was also comparable between pimavanserin- and placebo-treated patients in HARMONY [open-label (n = 37): mean (SE) change from baseline to week 12, 0.3 (0.66)]. Rates of motor- and cognition-related adverse events were similar between pimavanserin and placebo in both analyses.ConclusionsPimavanserin 34 mg was well tolerated and did not yield a negative impact on motor- or cognition-related function in patients with PD psychosis.

Pimavanserin: A Truly Effective Treatment for Parkinson’s Disease Psychosis? A Review of Interventions

“…Taken together, 433 patients were included in the pooled analysis. 43 The authors found that pimavanserin was well tolerated without a negative impact on motor-symptoms or cognition. Moreover, a meta-analysis 42 which included four studies comparing 417 patients with PDP treated with pimavanserin versus 263 patients with PDP treated with placebo revealed that the groups had similar scores for Unified Parkinson’s Disease Rating Scale II and III (UPDRS II and III) with a mean difference of 0.09 (95% CI–1.28, 1.46, p = 0.89).…”

“…There have been several concerns on pimavanserin’s safety. 43 A retrospective analysis of 2186 pimavanserin users and 18,212 non-users between 2015 and 2018 showed an increased risk of hospitalization at one month of treatment initiation of pimavanserin and a higher risk of death for up to one year following initiation, 44 whereas other studies did not find higher mortality or morbidity rates in pimavanserin users. 45–47 …”

“…There have been several concerns on pimavanserin's safety. 43 A retrospective analysis of 2186 pimavanserin users and 18,212 non-users between 2015 and 2018 showed an increased risk of hospitalization at one month of treatment initiation of pimavanserin and a higher risk of death for up to one year following initiation, 44 whereas other studies did not find higher mortality or morbidity rates in pimavanserin users. [45][46][47] Although concerns associated with the use of atypical antipsychotics in the elderly frail population are believed to also apply to pimavanserin, as described in labeling, postmarketing commitments were obtained to supplement preapproval safety information to better define other potential risks.…”

“…One further study 43 summarized three randomized, double-blind, placebo-controlled trials analyzing PDP patients treated with pimavanserin (NCT00477672 ( https://www.clinicaltrials.gov/ct2/show/results/NCT00477672?view=results ), NCT00658567 ( https://www.clinicaltrials.gov/ct2/show/results/NCT00658567 ), and NCT01174004 ( https://clinicaltrials.gov/ct2/show/NCT01174004 )), as well as a subgroup of patients with PD dementia and psychosis from the HARMONY trial. 41 Three studies (NCT00477672, NCT00658567, and NCT01174004) assessed motor-symptoms using the UPDRS II + III, or the Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A), which was used in the HARMONY trial.…”

Parkinson’s disease therapy: what lies ahead?

“…Notable adverse effects in studies mainly comprised headaches, constipation, edema, hallucinations, and urinary tract infections. Due to QTc prolongation in some patients, additional pharmacovigilance is required (Tariot et al 2021 ; Abler et al 2022 ; Cummings et al 2014 ; Isaacson et al 2021 ). Currently, two phase 4 studies for comparison of treatments with quetiapine or pimavanserin are recruiting in the US (NCT04373317, NCT05590637).…”