A novel oral medication for obstructive sleep apnea (OSA) has advanced to Phase III clinical trials, offering potential relief for millions of patients who cannot tolerate continuous positive airway pressure (CPAP) therapy. AD109, developed by Apnimed, combines aroxybutynin and atomoxetine to target key neurological pathways that activate upper airway dilator muscles during sleep.
Phase III SynAIRgy Trial Design
The ongoing SynAIRgy trial (NCT05813275) is enrolling approximately 640 participants with OSA who either decline or cannot tolerate CPAP treatment. Led by Patrick J. Strollo Jr., MD, at the University of Pittsburgh, the randomized, controlled study assigns participants 1:1 to either AD109 or placebo for a 26-week treatment period.
Eligible patients must have an apnea-hypopnea index (AHI-4) greater than 5 and body mass index less than 42 kg/m² for women and less than 40 kg/m² for men. The primary endpoint measures response rate, defined as at least a 50% reduction in AHI4 over 26 weeks using polysomnography.
Promising Phase II Results
The Phase II MARIPOSA trial (NCT05071612) demonstrated statistically significant improvements in both objective and subjective outcomes. The study included 211 patients (41% female) with a median age of 55 years and BMI of 32.2 kg/m² who were randomized to AD109, atomoxetine alone, or placebo.
Treatment with AD109 at the 2.5mg/75mg dose reduced AHI4 from a median of 20.5 to 10.8 events per hour (P <0.001 vs placebo). Notably, 77% of patients with mild OSA (AHI 10-15) achieved scores below 10, while 42% of those with moderate OSA (AHI 15-30) reached this threshold. Only 7% of severe cases (AHI >30) achieved the target.
Among all participants who completed the study, 41% achieved an AHI below 10 when treated with AD109, 44% had greater than 50% reduction from baseline, and 15% experienced an 80% or greater reduction. Atomoxetine monotherapy did not improve daytime OSA symptoms and significantly worsened nighttime sleep quality.
Mechanism and Clinical Benefits
AD109 represents a first-in-class once-daily medication that targets neurological pathways controlling upper airway muscles. Aroxybutynin, typically used for overactive bladder, is combined with atomoxetine, an ADHD medication, to address the different muscle behaviors during REM and non-REM sleep phases.
Patients treated with AD109 demonstrated statistically significant improvements versus placebo in PROMIS-Fatigue scores, a measure of daytime functioning (P <0.05). The treatment also showed trends toward statistical significance on scales measuring sleep impairment and sleep disturbance.
Safety Profile and Limitations
The MARIPOSA trial found AD109 to be safe and well-tolerated, with no serious adverse events and no unexpected side effects. The most common adverse events were dry mouth, insomnia, and nausea.
However, critics note limitations in the current data. Douglas Kirsch, MD, medical director of sleep medicine at Atrium Health, emphasized the importance of oxygen saturation measurements: "There's a big difference between somebody who has a minimum oxygen saturation of 89% and went from an AHI of 20 to 12... What you really want to talk about is how much or how long does that oxygen get low?"
Personalized Treatment Approach
According to study coauthor Dr. Erin Elliott, the medication addresses one component of OSA's complex pathophysiology. "These drugs can really work as they help with upper airway dilation, and they need this drug combination because muscles are different in REM sleep versus non-REM sleep," Elliott explained.
The treatment may be most effective when combined with other interventions. "These drugs in combination with an appliance would be awesome. We must start tailoring treatments based on phenotypes and not a one-treatment-fits-all philosophy," Elliott noted.
Ongoing Research
Beyond SynAIRgy, AD109 is being evaluated in the LunAIRo study, a randomized, double-blind, placebo-controlled, 1-year parallel-arm study enrolling at least 640 participants with mild to severe OSA across clinical centers in the United States.
Paula Schweitzer, PhD, director of Research at St. Luke's Sleep Medicine and Research Center, highlighted the medication's potential impact: "For those who cannot tolerate current treatments, AD109 has the potential to be a convenient, oral pill that could improve people's quality of life both at night and during the day."
