Highlight
- AD109, a fixed oral combination of aroxybutynin 2.5 mg and atomoxetine 75 mg, targets neuromuscular dysfunction in obstructive sleep apnea (OSA).
- The SynAIRgy trial is a randomized, double-blind, placebo-controlled phase 3 study involving 646 adults with mild-to-severe OSA intolerant to positive airway pressure (PAP) therapy.
- AD109 significantly reduced the apnea-hypopnea index (AHI) and improved oxygenation metrics at 26 weeks compared to placebo.
- Adverse events were more frequent with AD109 but included primarily mild symptoms such as dry mouth, nausea, insomnia, and urinary hesitation, without serious treatment-related safety concerns.
Study Background and Disease Burden
Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder characterized by repetitive upper airway obstruction during sleep, leading to intermittent hypoxia, fragmented sleep, and excessive daytime fatigue. OSA significantly increases the risks of cardiovascular disease, neurocognitive impairment, metabolic dysfunction, and mortality. The current gold standard treatment, positive airway pressure (PAP) therapy, effectively reduces airway collapse but faces widespread limitation due to low patient adherence and tolerance issues. Approximately 30-50% of OSA patients cannot sustain PAP therapy due to discomfort, claustrophobia, or inconvenience. This unmet clinical need has spurred the search for alternative treatment modalities, including pharmacologic agents that target the neuromuscular control of the upper airway.
AD109, a fixed-dose oral combination of aroxybutynin—a muscarinic receptor antagonist—and atomoxetine—a norepinephrine reuptake inhibitor—was developed to enhance upper airway muscle tone during sleep. Previous mechanistic studies indicated that modulating upper airway neuromuscular control could reduce airway collapsibility. However, robust clinical evidence from large randomized controlled trials was lacking.
Study Design
The SynAIRgy trial was a 26-week, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial conducted across 69 sites. The study enrolled 646 adult participants with mild to severe OSA (median baseline AHI 19.6 events/hour), all of whom were either intolerant to or refused PAP therapy. The study population was diverse with a median age of 58 years, equal gender distribution (49.3% female), and median body mass index (BMI) of 32.4 kg/m².
Participants were randomized to receive AD109 (2.5 mg aroxybutynin combined with 75 mg atomoxetine) or placebo once daily for 26 weeks. The primary efficacy endpoint was the change in apnea-hypopnea index (AHI) from baseline to week 26. Secondary endpoints included oxygen desaturation index (ODI), hypoxic burden (HB), Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue and Sleep Impairment T-scores, and the proportion of participants with a ≥50% reduction in AHI.
Key Findings
Efficacy Outcomes
At 26 weeks, AD109 showed a statistically significant improvement in AHI compared to placebo. The mean treatment difference was -4.0 events/hour (95% confidence interval [CI], -6.4 to -1.6; P=0.001), corresponding to a model-estimated reduction of 44.1% versus 17.6% in placebo (P<0.0001). This AHI reduction was observed across the spectrum of OSA severity (mild to severe) and in a population unable to tolerate standard PAP therapy.
Significant improvements in oxygenation were also noted with AD109. The oxygen desaturation index (ODI) and hypoxic burden (the cumulative exposure to hypoxia during sleep) showed favorable reductions, indicating better nocturnal oxygenation. However, PROMIS-Fatigue scores did not differ significantly between groups, suggesting symptom improvement in daytime fatigue may require further investigation or longer treatment duration.
Safety and Tolerability
Adverse events leading to treatment discontinuation occurred in 21.2% of participants receiving AD109 compared to 3.1% receiving placebo. The most common side effects reported were dry mouth, nausea, insomnia, and urinary hesitation. Notably, no serious treatment-related adverse events were reported, supporting an acceptable safety profile. The adverse events were largely consistent with the known pharmacologic actions of the component drugs. Given the chronic nature of OSA treatment, tolerability will be an important consideration for clinicians.
Expert Commentary
The SynAIRgy trial fills a critical gap in OSA therapeutics by providing high-quality evidence for a non-PAP pharmacologic option, addressing the significant challenge of PAP intolerance. The mechanistic rationale for combining a muscarinic antagonist with a norepinephrine reuptake inhibitor is to enhance upper airway muscle tone during sleep, thereby reducing airway collapsibility. These results align with emerging concepts that neuromotor control is a viable target for OSA treatment alongside traditional mechanical therapies.
Limitations include the relatively modest absolute reduction in AHI, which, while statistically robust, may not fully normalize breathing disturbances in severe OSA cases. The absence of significant fatigue improvement raises questions about translating physiological improvements to clinical symptoms. Future research may explore optimizing dosing, combination with other modalities, or identifying patient subgroups most likely to benefit based on endotype profiling.
Conclusion
AD109, an oral combination of aroxybutynin and atomoxetine, demonstrated significant reductions in airway obstruction and improved oxygenation in patients with mild-to-severe obstructive sleep apnea who are unable or unwilling to use PAP therapy. The therapy was generally well tolerated with manageable side effects. AD109 represents a promising alternative treatment option expanding the armamentarium for OSA management particularly for PAP-intolerant patients. Further post-marketing and real-world studies are warranted to assess long-term effectiveness, quality of life benefits, and integration into clinical practice.
Funding and Clinical Trial Registration
The SynAIRgy trial was supported by the sponsors involved in drug development and conducted across multiple international centers. The trial is registered at ClinicalTrials.gov under the identifier NCT05813275.
References
1. Strollo PJ, Farkas R, Taranto-Montemurro L, et al. Aroxybutynin and atomoxetine (AD109) for obstructive sleep apnea: a randomized phase 3 trial (SynAIRgy). Am J Respir Crit Care Med. 2026 Jul 1;212(7):1569-1584. PMID: 42148495.
2. Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013 Apr 15;188(8):996-1004.
3. Kapur VK, Auckley DH, Chowdhuri S, et al. Clinical Practice Guideline for Diagnostic Testing for Adult Obstructive Sleep Apnea: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017 Mar 15;13(3):479-504.
