Aroxybutynin and atomoxetine (AD109) for the treatment of obstructive sleep apnea: Rationale, design and baseline characteristics of the phase 3 clinical trials

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Introduction Two key factors leading to obstructive sleep apnea (OSA) pathogenesis include relaxation of upper airway muscles at sleep onset and their insufficient reactivation during obstructive events. Medications that address this neuromuscular dysfunction by increasing upper airway tone during sleep represent a potential strategy for mitigating OSA. Methods AD109 is an investigational, once-daily oral agent taken at bedtime that combines a novel antimuscarinic, aroxybutynin (2.5 mg), with a selective norepinephrine reuptake inhibitor, atomoxetine (75 mg). LunAIRo (NCT05811247) and SynAIRgy (NCT05813275) are two ongoing, placebo-controlled 1-year and 6-month phase 3 clinical trials, respectively, investigating the efficacy and safety of AD109 to treat mild to severe OSA. Participants include adults with an apnea-hypopnea index with 4% desaturation (AHI 4 ) >5 who either refuse or fail to tolerate positive airway pressure. Participants (LunAIRo: N=660; SynAIRgy: N=646) were randomized 1:1 to receive AD109 or placebo. We hypothesize that AD109 will significantly reduce AHI 4 and symptomatic fatigue compared to placebo in people with OSA. The primary outcome for both trials is the change from baseline to Week 26 in AHI 4 in the AD109 arm versus placebo. Key Secondary outcomes include changes from baseline in oxygen desaturation index with 3% desaturation, hypoxic burden based on 4% desaturation, Patient Reported Outcome Measurement Information System (PROMIS)-Fatigue, and proportion of participants with ≥ 50% reduction in AHI 4 at Week 26. Discussion LunAIRo and SynAIRgy are fully enrolled, large Phase 3 clinical trials designed to confirm and extend our understanding of the safety and efficacy of AD109, a combination oral drug targeting the underlying neuromuscular dysfunction contributing to upper airway muscle collapse during sleep in adults with OSA.

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