Aroxybutynin-Atomoxetine Reduces AHI in Obstructive Sleep Apnea

An investigational oral combination therapy improved objective measures of obstructive sleep apnea (OSA) in adults who had failed or refused positive airway pressure (PAP) therapy, according to findings from the phase 3 SynAIRgy trial published in the American Journal of Respiratory and Critical Care Medicine.

The randomized, double-blind, placebo-controlled trial evaluated aroxybutynin and atomoxetine (AD109), an investigational, once-daily-at-bedtime oral combination designed to increase upper-airway muscle tone during sleep. Participants received aroxybutynin 2.5mg/atomoxetine 37.5mg during a 1-week run-in, followed by aroxybutynin 2.5mg/atomoxetine 75mg for the remaining 25 weeks.

SynAIRgy randomized 646 adults with mild-to-severe OSA across 69 sites in the US and Canada. The primary intent-to-treat efficacy analysis included 615 participants. The primary endpoint was change from baseline to week 26 in apnea-hypopnea index (AHI). Key secondary endpoints included oxygen desaturation index (ODI), PROMIS-Fatigue T-score, hypoxic burden, PROMIS-Sleep Impairment T-score, and the proportion of participants with at least a 50% reduction in AHI.

At week 26, the estimated mean treatment difference in AHI was −4.0 events/hour with AD109 compared with placebo. This represented a model-estimated 44.1% reduction from baseline with AD109 versus 17.6% with placebo. AD109 also produced favorable changes in ODI and hypoxic burden, but the difference in PROMIS-Fatigue did not reach statistical significance in the intent-to-treat analysis.

The safety analysis included 644 participants. Adverse events occurred in 70.8% of participants receiving AD109 and 46.7% receiving placebo. Treatment discontinuation because of adverse events occurred in 21.2% and 3.1%, respectively. The most common adverse events with AD109 were dry mouth, insomnia, nausea, and urinary hesitation. No serious treatment-related adverse events were reported. The authors said AD109 may become a treatment option for patients unable to use PAP if approved, although they identified the high treatment-discontinuation rate and absence of dose reduction as trial limitations.

Source: Strollo PJ Jr, Farkas R, Taranto-Montemurro L, Cronin J, Patel SR; SynAIRgy Investigators. Aroxybutynin and atomoxetine (AD109) for obstructive sleep apnea: a randomized phase 3 trial (SynAIRgy). Am J Respir Crit Care Med. 2026;212(7):1569-1584. doi:10.1093/ajrccm/aamag215