Phase 3 SynAIRgy Data, Mechanistic Review Strengthen Scientific Foundation for Apnimed’s Oral OSA Therapy AD109

Newly published phase 3 findings and a companion mechanistic review have added to growing evidence supporting AD109, Apnimed’s investigational oral therapy for obstructive sleep apnea (OSA), as a potential pharmacologic alternative for patients who cannot tolerate or refuse positive airway pressure (PAP) therapy. Together, the publications provided both clinical and biologic validation for a neuromuscular-based treatment strategy in OSA, a field historically dominated by device-based interventions and weight-loss approaches.^1,2

The first publication, appearing in the American Journal of Respiratory and Critical Care Medicine, detailed results from the phase 3 SynAIRgy trial (NCT05813275), while the second review article, published in the American Journal of Respiratory Cell and Molecular Biology, outlined the neurophysiologic rationale underlying AD109’s mechanism of action. The publications arrive as Apnimed advances AD109 through the regulatory process, with the company noting it has already submitted a new drug application (NDA) to the FDA and expects a potential Prescription Drug User Fee Act (PDUFA) target action date in the first quarter of 2027, pending FDA acceptance for review.

“The publication of the SynAIRgy Phase 3 results, together with a companion review article on the underlying biology, provides important insights into OSA as a treatable, multifactorial disease,” Patrick J. Strollo Jr, MD, study chair of the SynAIRgy trial and vice chair of medicine for Veterans Affairs at the University of Pittsburgh School of Medicine, said in a statement.³ “These data support neuromuscular dysfunction as a key driver of disease and demonstrate that targeting this pathway can lead to meaningful improvements in objective physiologic measures, including airway obstruction and oxygenation.”

Phase 3 SynAIRgy Results

SynAIRgy was a randomized, double-blind, placebo-controlled, 26-week study evaluating AD109, a fixed-dose oral combination of aroxybutynin 2.5 mg and atomoxetine 75 mg, in adults with mild-to-severe OSA who had failed or declined PAP therapy. The study enrolled 646 participants across 69 centers in the United States and Canada, including a diverse patient population reflective of real-world sleep clinic populations. Participants were nearly evenly split by sex, with 49.3% women, and included broad representation across body mass index (BMI) classes and OSA severity ranges.

At baseline, the median apnea-hypopnea index (AHI) was 19.6 events per hour, with 35% of participants classified as mild OSA, 42% moderate, and 23% severe.

Overall, the study met its primary endpoint, showing statistically significant improvements in AHI at week 26. In the intent-to-treat analysis, AD109 achieved a model-estimated 44.1% reduction in AHI from baseline compared with a 17.6% reduction for placebo (P <.0001), corresponding to an estimated treatment difference of –4.0 events/hour (95% CI, –6.4 to –1.6; P = .001).¹

Importantly, efficacy appeared stronger among participants who remained on therapy. In supportive on-treatment analyses, AD109 reduced AHI by 55.6% from baseline versus 19.1% for placebo (P <.0001). Apnimed highlighted these findings in its accompanying press release, emphasizing that 39.6% of treated participants achieved at least a 50% reduction in AHI, while 22.3% achieved disease control defined as AHI less than 5 events/hour.³

Investigators also reported significant improvements in several oxygenation metrics linked to long-term cardiovascular and neurocognitive risk in OSA. All told, oxygen desaturation index (ODI) improved by a mean of 6.5 events/hour relative to placebo, while hypoxic burden, an increasingly recognized physiologic marker associated with cardiovascular outcomes, declined by 60.5% in on-treatment analyses.¹

More notably, the treatment effects emerged early, with improvements observed by week 4 and sustained through the 26-week study period.

Mechanistic Rationale and Neuromuscular Targeting

The companion review article contextualized these clinical findings within a broader shift in OSA pathophysiology research. Rather than viewing OSA solely as an anatomic disease related to obesity or upper airway crowding, the review emphasized that neuromuscular dysfunction plays a central role in airway collapse during sleep.²

According to the authors, sleep onset results in withdrawal of excitatory noradrenergic signaling and increased inhibitory muscarinic activity at the hypoglossal motor nucleus, which controls upper airway dilator muscles. These physiologic changes reduce airway muscle tone and predispose susceptible patients to airway collapse.

AD109 was specifically designed to target these mechanisms. Atomoxetine, a norepinephrine reuptake inhibitor, increases excitatory noradrenergic drive to upper airway motor neurons, while aroxybutynin, a selective antimuscarinic agent, reduces inhibitory signaling linked to REM-related airway collapse.²

The review authors noted that this dual-mechanism approach represents one of the first pharmacologic strategies directly targeting the neuromuscular underpinnings of OSA rather than relying exclusively on mechanical airway support.

Safety, Tolerability, and Clinical Context

Across SynAIRgy, AD109 was generally well tolerated, though adverse event (AE)–related discontinuations were more common with active treatment than placebo. Overall, 21.2% of participants receiving AD109 discontinued therapy due to AEs compared with 3.1% in the placebo arm. The most common adverse events included dry mouth, insomnia, nausea, and urinary hesitation, most of which were mild and occurred early after treatment initiation.¹

In SynAIRgy, no treatment-related serious adverse events or deaths were reported.

The findings also add to an increasingly competitive OSA treatment landscape. In recent years, the field has expanded beyond PAP therapy to include hypoglossal nerve stimulation devices and metabolic approaches such as GLP-1/GIP receptor agonists like tirzepatide, which recently became the first FDA-approved pharmacotherapy for OSA in patients with obesity.² Unlike those therapies, however, AD109 specifically targets upper airway neuromuscular dysfunction independent of body weight, potentially broadening its applicability across heterogeneous OSA populations.

“OSA is a complex and heterogeneous disease. A one-size-fits-all approach has left many people with OSA without a treatment that works for them,” Neomi Shah, MD, MPH, MSc, ATSF, chair of the Sleep and Respiratory Neurobiology Assembly at the American Thoracic Society, said in a statement.³ “Advances that connect clinical outcomes with underlying biology and explore new therapeutic approaches are essential to moving toward more personalized care. The SynAIRgy study helps move the field closer to that goal.”

REFERENCES
1. Strollo PJ Jr, 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. Published online 2026
2. Horner RL, Wellman DA, Sands SA, Azarbarzin A, Taranto-Montemurro L. Mechanisms of upper airway muscle control in sleep reveal therapeutic targets for obstructive sleep apnea. Am J Respir Cell Mol Biol. Published online 2026.
3. Apnimed Announces Publication of Phase 3 SynAIRgy Trial of AD109 for Obstructive Sleep Apnea in the American Journal of Respiratory and Critical Care Medicine. News release. Apnimed. May 18, 2026. Accessed May 18, 2026.