Evaluate motor function changes in patients with neuropsychiatric symptoms (NPS) of neurodegenerative disease (NDD) treated with pimavanserin.

NPS of NDD, such as dementia-related psychosis (DRP), are commonly treated with off-label antipsychotics. These have substantial safety concerns, including worsening motor function and extrapyramidal symptoms, primarily due to their activity as dopamine receptor-blocking agents. Pimavanserin is a selective serotonin 5-HT_2A receptor inverse agonist/antagonist.

Motor function was evaluated using the Unified Parkinson’s Disease Rating Scale Part III (UPDRS) or Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) in 2 double-blind, parallel-group studies (019, 046) and in the HARMONY randomized withdrawal study, which included an open-label period followed by a randomized double-blind period. Patients had neuropsychiatric manifestations of NDD (N=626 receiving pimavanserin), including DRP (N=562 receiving pimavanserin). Motor-related treatment-emergent adverse events (TEAEs) were examined based on 71 Preferred Terms.

In 019, mean (SE) UPDRS change from baseline (CFB) to week 12 was similar for pimavanserin (-1.0 [0.96]; n=41) and placebo (-0.5 [1.20]; n=44). In the HARMONY open-label period, the mean (SE) ESRS-A CFB to week 12 was minimal (-0.7 [0.17]; n=244), with a trend toward improved motor function. During the double-blind period, mean CFB in total ESRS-A was small and similar in the 2 treatment groups at all time points. In the 046 interim analysis, least squares mean ESRS-A CFB to week 8 was similar for pimavanserin (-0.3 [0.37]; n=132) and placebo (-0.6 [0.37]; n=130). In each study, individual motor-related TEAEs in pimavanserin patients were reported at rates ≤2.2%; rates were similar to placebo.

Mean changes in motor function were minimal in pimavanserin-treated patients and were similar to placebo. In pimavanserin-treated patients, motor-related TEAEs were reported infrequently and at similar rates to placebo. Pimavanserin did not have a negative impact on motor function in this aggregated dataset of frail, vulnerable patients.