Dr Sanjay Patel

An investigational oral combination therapy halved airway obstruction in adults with obstructive sleep apnoea who had failed or refused CPAP, pooled phase III data show, signalling a potential new treatment option beyond positive airway pressure therapy.

Presenting late-breaking pooled results from the SynAIRgy and LunAIRo trials at the American Thoracic Society International Conference 2026, Dr Sanjay Patel, sleep physician and Professor of Medicine at the University of Pittsburgh Medical Center, said AD109 produced clinically meaningful improvements across mild-to-severe OSA.

The pooled analysis combined data from more than 1300 adults across the two randomised, double-blind phase III trials conducted in the US and Canada. Results from the 646-patient SynAIRgy trial were simultaneously published in the American Journal of Respiratory and Critical Care Medicine.

Participants had a median age of 58 years, median BMI of 32 and median apnoea-hypopnoea index of about 20 events per hour. About one-third had mild disease, 42% moderate OSA and one-quarter severe OSA.

AD109 combines aroxybutynin, the R-enantiomer of oxybutynin, with the norepinephrine reuptake inhibitor atomoxetine, targeting upper airway muscle dysfunction during sleep.

Key pooled findings at 26 weeks included:

• 52% reduction in AHI with AD109 versus 13% with placebo
• 39% of treated patients achieved at least 50% AHI reduction versus 19% for placebo
• 23% achieved disease resolution (AHI below 5) versus 8% for placebo
• 48% improved by at least one disease severity category versus 29% for placebo
• Hypoxic burden fell 41% in intention-to-treat analysis and nearly 60% in on-treatment analysis
• Loud snoring reduced by almost 70% versus placebo

The published SynAIRgy paper reported a 44.1% model-estimated AHI reduction in the intention-to-treat analysis versus 17.6% with placebo, with larger reductions in on-treatment analyses.

Beyond AHI: the hypoxic burden argument

Investigators argued OSA assessment requires a broader framework than AHI alone. Dr Patel said hypoxic burden, which integrates both the frequency and severity of oxygen desaturation, may better reflect cardiovascular risk and long-term disease burden than AHI, which measures interruption frequency but not oxygenation impact.

AD109 significantly reduced both apnoea and hypopnoea indices, suggesting it may convert complete obstructive apnoeas into partial obstructions, potentially producing larger gains in oxygenation even when respiratory events persist.

Professor Patrick Strollo

Professor Patrick Strollo, professor of medicine at the University of Pittsburgh School of Medicine, said modelling based on cohort data suggested the 59.6% on-treatment reduction in hypoxic burden could correspond to approximately 20% lower cardiovascular risk over seven years. However, the published paper noted these findings should be interpreted cautiously, as formal hierarchical testing stopped earlier in the sequence after PROMIS-Fatigue failed to reach statistical significance in the intention-to-treat analysis.

Delegates questioned whether projected cardiovascular benefits could be offset by modest increases in blood pressure and heart rate seen with atomoxetine. Investigators reported systolic blood pressure increases of roughly 1.5 mmHg alongside small increases in heart rate.

No major adverse cardiovascular events occurred among AD109-treated patients across the two trials, compared with five in placebo-treated participants, although the studies excluded patients with significant cardiovascular disease and were not powered for cardiovascular outcomes.

Safety and tolerability

Common adverse events included dry mouth, insomnia, nausea and urinary hesitation. About one in five participants in SynAIRgy discontinued because of adverse events, mostly during the first month. The paper suggested adverse effects were generally mild, reversible and clustered early after treatment initiation.

Discussion at the ATS session highlighted unresolved questions around longer-term cognitive safety and chronic anticholinergic exposure. Dr Patel acknowledged emerging epidemiological signals around dementia risk warranted discussion with patients as part of shared decision-making.

The treatment effect appeared broadly consistent across age, sex, race and symptom subgroups, though patients with BMI below 30 derived greater benefit than those with obesity. Investigators noted about one-third of AD109 trial participants were not obese, a finding that may prove relevant following recent approval of tirzepatide for obesity-related sleep apnoea.