0672 Pharmacokinetics, Efficacy, and Safety of AD109 (Aroxybutynin and Atomoxetine) in Participants with Obstructive Sleep Apnea and Obesity Taking a GLP-1

Abstract Introduction AD109, an investigational oral anti-apneic neuromuscular modulator, combines in one tablet the novel antimuscarinic aroxybutynin (2.5 mg) with the selective norepinephrine reuptake inhibitor atomoxetine (75 mg). In two phase 3 clinical trials for obstructive sleep apnea (OSA), AD109 significantly improved airway obstruction and oxygenation vs placebo. This study evaluated the pharmacokinetics (PK), efficacy, tolerability and safety of AD109 when co-administered with glucagon-like peptide-1 receptor agonists (GLP-1 RA) in participants with OSA and obesity. Methods This was an open-label, parallel-arm, 6-week phase 2 study of AD109 in participants with mild-to-severe OSA and obesity, administered either alone or while remaining on a stable maintenance dose of a GLP-1 RA (tirzepatide, semaglutide, or liraglutide). The study consisted of a screening period, 2-day single dose PK period, followed by a 6-week AD109 dosing period. Plasma PK for aroxybutynin and atomoxetine, including maximum plasma concentration (Cmax) and exposures (AUClast and AUCinf), were derived by noncompartmental analysis and evaluated using a mixed-effects model. Results Forty participants were enrolled and received AD109 (n=22) or AD109+GLP-1 RA (n=18). Geometric mean ratios (GMR; AD109+GLP-1 RA/AD109 alone [90% CI]) of aroxybutynin for Cmax, AUClast, and AUCinf were 100.6 (68.0–148.8), 142.0 (102.1–197.5), and 152.7 (111.0–210.1), respectively. GMR of atomoxetine for Cmax, AUClast, and AUCinf were 67.0 (51.0–88.1), 81.9 (57.0–117.7), and 78.2 (51.3–119.1), respectively. The proportion of participants achieving ≥50% reduction in respiratory event index based on 4% hypopnea desaturation assessed with home sleep apnea test at Week 5 in the AD109 and AD109+GLP-1 RA arms were similar (33.3% vs 29.4%, respectively). Treatment-emergent adverse events (TEAEs) were reported by 85% of participants with the majority being mild-to-moderate severity. TEAEs of dry mouth, decreased appetite, nausea, and constipation were reported with higher incidence in the AD109 alone arm. No clinically meaningful trends were detected in mean changes from baseline in lab values, physical examination variables, or vital signs. No deaths or serious TEAEs occurred. Conclusion AD109 was generally safe and well-tolerated in both treatment arms of this phase 2 trial, without large differences in PK when co-administered with GLP-1 RA. Support (if any) This study was supported by Apnimed, Inc.