Safety of nelotanserin in a randomized placebo-controlled phase 2 study

Background: Nelotanserin is a highly potent and selective inverse agonist of the 5-HT2a receptor. Nelotanserin penetrates into the CNS and improves objective sleep parameters demonstrating target engagement. The safety of nelotanserin was explored in a Phase 2 study in patients with primary insomnia. Methods: This was a randomized, double-blind, placebo controlled, three-way cross-over study in patients with primary insomnia. Patients received nelotanserin doses of 10 mg and 40 mg, or placebo (PBO) at bedtime. Treatment duration was 7 days with a washout period of 7-9 days between treatments. Safety was evaluated by adverse event (AE) assessments, 12-lead ECGs, clinical laboratory results, cognitive function testing (Digit Span Test, Digit Symbol Copy Test, and Digit Symbol Coding Test), and physical exam. The safety population included subjects who received at least one dose of study drug. Results: Treatment emergent adverse events (TEAE) were similar between PBO (29.4%), 10 mg (32.1%), and 40 mg (25.9%). Eight subjects (3.5%) discontinued due to adverse events: four in the placebo arm, one in the 10 mg arm, and three in the 40 mg arm. The majority were due to increased CPK and associated with strenuous activity. The most common TEAEs considered related to study medication in ≥ 3% of subjects were somnolence (4.2-7.4%), fatigue (1.2-5.4%), and headache (1.2-3.0%). There were no notable differences between active and placebo groups and no relationship to dose. No SAEs or clinically significant changes in vital signs or ECGs were observed. No evidence of cognitive impairment, next day motor impairment or withdrawal effect was noted. Conclusion: Nelotanserin was generally well-tolerated, with a low discontinuation rate due to adverse events in this Phase 2 study in patients with primary insomnia. This safety profile supports further development for additional indications, including in patients with Dementia with Lewy Bodies.