Aroxybutynin and Atomoxetine (AD109) Reduces Obstructive Sleep Apnea Budren in Phase 3 SynAIRgy

Combination aroxybutynin and atomoxetine (AD109) provided statistically significant improvement to apnea-hypopnea index (AHI) scores in patients with obstructive sleep apnea (OSA) across multiple weight classes, according to findings from the phase 3 SynAIRgy trial.1

The 26-week trial data, presented during late-breaking data sessions at the American College of Chest Physicians (CHEST) 2025 Annual Meeting in Chicago, IL, this week, suggest the combined regimen of two proven OSA treatments may provide a broad benefit to the growing patient population. Prior research into oral AD109 supported Apnimed’s plans to submit a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for the combination drug in early 2026.2

How do aroxybutynin and atomoxetine function in treating OSA?

Aroxybutynin is an antimuscarinic with a newer clinical profile than agents like oxybutynin. However, it has been hypothesized to result in fewer adverse events than the latter, such as urinary side effects — a common treatment issue among men with OSA.3

Atomoxetine (Strattera) is a norepinephrine reuptake inhibitor (SNRI) approved by the FDA to for the treatment of attention-deficit hyperactivity disorder (ADHD). Investigators hypothesized that a lower dose of atomoxetine, in combination with an antimuscarinic, may assist in keeping upper airway muscles active yet more relaxed during sleep.

What were the results of the phase 3 SynAIRgy trial?

Investigators led by Patrick J. Strollo, MD, professor of medicine and clinical & translational science in the Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine at the University of Pittsburgh, assessed the efficacy and safety of oral aroxybutynin 2.5 mg plus atomoxetine 75 mg in patients with OSA.1

SyAIRgy was a designed randomized, double-blind, placebo-controlled, parallel-arm phase 3 trial comparing AD109 versus placebo in adults with mild-to-severe OSA over 26 weeks. Patients met inclusion criteria if they were intolerant to or refused positive airway pressure (PAP) therapy. They additionally were at a baseline AHI ≥5 (AHI4), a PROMIS-Fatigue raw score ≥17 (indicating high limitation due to fatigue), and with a body mass index (BMI) of 18 – 40 kg/m2 for males and 18.5 - 42 kg/m2 for females.

A total of 639 participants were randomized to either AD109 (n = 319) or placebo (n = 320). Strollo and colleagues sought efficacy endpoints in the intention-to-treat (ITT) set for all randomized participants receiving ≥1 dose of medication, and modified ITT (mITT) for all participants having ≥1 post-baseline polysomnography on treatment).

The final assessment included 539 participants who completed the trial (84.6%). In the mITT cohort (AD109, 260; placebo, 296), AHI4 events per hour were reduced from a median 19.3 (IQR, 12.7 – 28.7) at baseline to 10.6 (IQR, 5.3 – 20.0) at week 26 among the AD109 arm. Comparatively, the placebo arm decreased only from 19.2 (IQR, 12.9 – 29.1) to 18.0 (IQR, 9.2 – 30.5) in 26 weeks.

Additionally among the mITT cohort, the AD109 arm reported a 55.6% improved AHI4 versus placebo at 26 weeks (P <.0001).

Among the ITT cohort (AD109, 302; placebo, 313), the treatment arm reported a significantly improved AHI4 at week 26 (-3.3; IQR, -5.1 to -1.5) versus placebo (0.7; IQR, -1.0 to 2.4; P = .001).

Investigators additionally observed significant improvements in key secondary endpoints including change in oxygen desaturation index (ODI) as well as relative change in hypoxic burden. PROMIS-Fatigue and sleep impairment scores significantly improved among the mITT cohort to receive AD109 versus placebo.

At least 1 adverse event was reported by 232 (71.4%) of all participants in the AD109 arm, versus 151 (47.3%) of the placebo. The most common adverse events were dry mouth, insomnia, nausea, urinary hesitation, constipation and somnolence — each occurring in ≥5% of all participants. No serious treatment-related adverse events were observed.

“AD109 led to clinically meaningful and statistically significant improvement in AHI4 compared to placebo,” Strollo and colleagues concluded. “Overall, AD109 was well-tolerated. This phase 3 trial demonstrates that AD109 provides therapeutic benefit for participants with mild-to-severe OSA across a range of weight classes.”

References

1. Stroller PJ, Farkas R, Taranto L, Cronin JW, et al. The SynAIRgy Trial: A 26-Week Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Aroxybutynin and Atomoxetine (AD109) in Obstructive Sleep Apnea. Poster presented at: CHEST Annual Meeting 2025. Chicago, IL. October 19 – 22, 2025.
2. Positive Phase 3 Data for Oral OSA Medication AD109, FDA Clears First Blood Test for Alzheimer Disease, DHE Autoinjector Treatment Approved for Migraine. NeurologyLive. Published online May 24, 2025. https://www.neurologylive.com/view/positive-phase-3-data-oral-osa-medication-ad109-fda-clears-first-blood-test-alzheimers-dhe-autoinjector-treatment-approved-migraine
3. Rosenberg R, Abaluck B, Thein S. Combination of atomoxetine with the novel antimuscarinic aroxybutynin improves mild to moderate OSA. J Clin Sleep Med. 2022;18(12):2837-2844. doi:10.5664/jcsm.10250