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The study presented at the 2021 AAN Meeting follows the complete response letter issued by the FDA to Acadia Pharmaceuticals due to deficiencies in their sNDA.
New data shows patients with neurodegenerative diseases (NDD) treated with pimavanserin (Nuplazid) did not experience negative impacts on cognitive function with up to 9 months of treatment compared to placebo.
These findings were presented at the 2021 American Academy of Neurology (AAN) Annual Meeting, April 17-22, by Clive Ballard, MD, professor, age-related diseases, and pro-vice-chancellor and executive dean, University of Exeter Medical School. Ballard and colleagues sought to evaluate pimavanserin’s impact on cognition in patients with neuropsychiatric manifestations of NDD across multiple studies.
“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,” Ballard and colleagues wrote in the abstract.
The researchers analyzed cognitive function via the Mini-Mental State Examination (MMSE) that was an outcome in 3 parallel-arm, double-blind studies (019, 032, 046) that compared 34 mg of pimavanserin with placebo as well as the phase 3 randomized withdrawal HARMONY study. This study consisted of a 12-week open label phase followed by a randomized, double-blind period. There were 697 patients receiving pimavanserin across all studies, and 622 had DRP. Cognition related treatment-emergent adverse events (TEAEs) were also analyzed.
Ballard and colleagues found that the MMSE score least squares mean (LSMO change from baseline to week 12 was –0.25 (standard error [SE], 0.42) in study 019 and 0.0 (SE, 0.57) in study 032, and similar to placebo in both. LSM change from baseline to week 8 was 1.2 (SE, 0.21; n = 132) for pimavanserin and 0.5 (SE, 0.21; n = 128) for placebo in the interim analysis of study 046.
In the HARMONY study, the mean change from baseline to week 12 was 1.0 (SE, 0.22; n = 145). During the double-blind period, mean MMSE score with pimavanserin treatment did not decline and was similar to placebo. Patients treated with pimavanserin for the whole 9 months of the study (n = 46) had a mean change from baseline of 1.2 (SE, 0.51).
The researchers also found that confusion and memory impairment were the only cognition-related TEAEs reported. These TEAEs were infrequent and occurred 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,” Ballard and colleagues concluded.
Pimavanserin, a selective serotonin inverse agonist and antagonist preferentially targeting 5HT2A receptors, was previously approved for the treatment of hallucinations and delusions associated with Parkinson disease psychosis in April 2016.
In April 2021, the FDA issued a complete response letter to Acadia Pharmaceuticals due to deficiencies in their supplemental new drug application (sNDA) filing for pimavanserin for the treatment of DRP.
The FDA stated that the treatment cannot be accepted with the sNDA in its current form, citing a lack of statistical significance in some of the subgroups of dementia, and insufficient numbers of patients with certain less common dementia subtypes as lack of substantial evidence of effectiveness to support approval.