Evaluate pimavanserin’s impact on cognitive measures in patients with neuropsychiatric manifestations of NDD.

Neuropsychiatric symptoms, including psychosis, are common among patients with dementia and are associated with poorer clinical outcomes. No therapies are approved in the United States for treating dementia-related psychosis (DRP). Off-label antipsychotic use is associated with significant adverse outcomes, including accelerated cognitive decline.

Cognitive function measured by Mini-Mental State Examination (MMSE) was a prespecified safety outcome in 3 parallel-arm, double-blind studies (019, 032, 046) comparing pimavanserin 34mg with placebo, and the phase 3 randomized withdrawal study, HARMONY, which included a 12-week open-label phase followed by a randomized, double-blind period. Studies enrolled patients with neuropsychiatric manifestations of NDD (N=697 receiving pimavanserin, 622 of whom had DRP). Cognition-related treatment-emergent adverse events (TEAEs) were examined across studies using 14 Preferred Terms.

In 019 and 032, the MMSE score least squares (LS) mean (SE) change from baseline (CFB) to week 12 was -0.25 (0.42) and 0.0 (0.57), respectively, and similar to placebo. In the 046 interim analysis, the LS mean (SE) CFB to week 8 was 1.2 (0.21; n=132) for pimavanserin and 0.5 (0.21; n=128) for placebo. In HARMONY, mean (SE) CFB to week 12 was 1.0 (0.22; n=245). During the HARMONY double-blind period, mean MMSE score with pimavanserin did not decline and was similar to placebo. Patients exposed to pimavanserin for the 9-month study duration (n=46) had a mean (SE) CFB of 1.2 (0.51). Confusional state and memory impairment were the only cognition-related TEAEs reported; they occurred infrequently and/or at rates similar to placebo.

Across studies, mean MMSE score changes in pimavanserin-treated patients with NDD were small and were similar to placebo. Cognition-related TEAEs were reported infrequently. Overall, pimavanserin did not have a negative impact on cognitive function with up to 9 months of treatment.