Objective: To examine the clinical profile of nelotanserin, a novel agent in development for the treatment of Lewy body dementia.

Background: Although not FDA-approved for the treatment of dementia, atypical antipsychotics such as quetiapine and clozapine are currently most commonly used in patients with behavioral disturbances. The utility of atypical antipsychotics in dementia is thought to be related to their affinity to the 5HT2A receptor. Quetiapine has been associated with a risk of QTc prolongation and clozapine use requires monitoring due to the risk of serious blood dyscrasias. All atypical antipsychotics carry a black box warning for use in dementia, and have been linked to an increased risk of mortality. There remains a significant unmet need for safer drugs in this population. Nelotanserin is a highly potent and selective 5HT2A inverse agonist currently in development for the treatment of behavioral disturbances in Lewy body dementia. There has been no evidence in any nelotanserin clinical trial to date suggesting an increased risk of QTc prolongation or need for blood monitoring. Nelotanserin may represents a meaningful advance in the treatment of behavioral disturbances in dementia.

Methods: Nelotanserin has been evaluated in five phase 1 studies and two phase 2 studies to date encompassing 792 subjects receiving active drug. We present cardiovascular data from the first-in-human phase 1 study and the two phase 2 studies. The phase 2 studies were conducted in patients with primary insomnia. Cardiovascular measurements were assessed by monitoring adverse events and 12-lead electrocardiogram (ECG) recordings.

Results: Nelotanserin was not associated with any clinically relevant changes from baseline on ECG parameters measured. There was no evidence of adverse events suggesting proarrhythmic risks, and no clinically relevant changes were observed with nelotanserin in QTcF intervals.

Conclusions: The absence of QTc prolongation differentiates nelotanserin from other drugs of the same class – including pimavanserin, a 5HT2A inverse agonist developed to address Parkinson’s disease psychosis. Pimavanserin was reported to increase the QTcB interval by 7.3 ms from baseline in its published phase 3 study. Nelotanserin has the potential to be an impactful new treatment based on its unique clinical profile.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/examining-the-clinical-profile-of-nelotanserin-a-novel-agent-in-development-for-lewy-body-dementia/