LAUSR

RATIONALE A low respiratory arousal threshold is a key endotype responsible for obstructive sleep apnea (OSA) pathogenesis. Pimavanserin is an antiserotoninergic capable of suppressing CO2-mediated arousals without affecting the respiratory motor response in animal models, and thus it holds potential for increasing arousal threshold in OSA and subsequently reducing OSA severity. OBJECTIVES We measured the effect of pimavanserin on arousal threshold (primary outcome), OSA severity, arousal index, and other OSA endotypes (secondary outcomes). METHODS 18 OSA participants were studied in a randomized, double-blind, crossover study. Patients received a single dose of placebo or pimavanserin 34 mg 4 h prior to in-lab polysomnography. Airflow was measured with an oronasal mask attached to a pneumotachograph, and ventilatory drive was recorded with an intra-esophageal EMG catheter (EMGDI). Results are presented as mean or median changes (Δ) and 95% confidence intervals (CIs). RESULTS Pimavanserin did not increase arousal threshold, nor did it decrease OSA severity or arousal index. It, however, prolonged total sleep time (Δ[CI]=39.5[‒1.2, 80.1]min). In an exploratory analysis, a subgroup of 7 patients who had ≥10% increase in arousal threshold on pimavanserin exhibited a decrease in AHI4 (hypopneas associated with 4% desaturation; Δ[CI]=5.6[3.6, 11.1]events/h) and hypoxic burden (Δ[CI]=22.3[6.6, 32.3]%min/hr). CONCLUSIONS A single dose of pimavanserin did not have a significant effect on arousal threshold or OSA severity. However, in a post hoc analysis, a subset of patients who exhibited an increase in arousal threshold on pimavanserin showed a small decrease in OSA severity. Thus, if arousal threshold could be increased with pimavanserin, perhaps with longer dosing to reach higher drug blood levels, then the desired effect on OSA severity might be achievable. Clinical trial registered with ClinicalTrials.gov (NCT04538755).