A79-16 Aroxybutynin and Atomoxetine (AD109) in Obstructive Sleep Apnea: A Pooled Analysis of the SynAIRgy and LunAIRo Phase 3 Trials

Rationale

AD109, an investigational oral anti-apneic neuromuscular modulator, combines the novel antimuscarinic, aroxybutynin (2.5 mg), with the selective norepinephrine reuptake inhibitor, atomoxetine (75 mg) in one tablet. In two phase 3 trials representing the largest clinical development program conducted for an obstructive sleep apnea (OSA) pharmacotherapy, AD109 significantly improved airway obstruction and oxygenation vs placebo (PBO). We performed a pooled analysis of the phase 3 trials of AD109 in OSA.

Methods

SynAIRgy (NCT05813275; 26-week) and LunAIRo (NCT05811247; 51-week) were randomized, double-blind, PBO-controlled, parallel-arm trials of AD109 in adults with mild-to-severe OSA who failed or refused positive airway pressure therapy. Key inclusion criteria required an apnea-hypopnea index >5 (AHI4; 4% hypopnea desaturation), Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue raw score ≥17, and body mass index 18.5-40 kg/m2 for males / 18.5-42 kg/m2 for females. Efficacy assessments for the primary endpoint were performed in the treatment policy estimand (all randomized and received ≥1 dose of study medication) at Week 26. Safety and tolerability of AD109 was assessed throughout the duration of each trial.

Results

Of 1,299 randomized participants (AD109: n = 648; PBO: n = 651), 1,063 (81.8%) completed the trials. Baseline OSA severity was mild in 36.2%, moderate in 37.3%, and severe in 26.5% of participants. In the treatment policy estimand (AD109: n = 626; PBO: n = 639), AD109 reduced AHI4 (LS mean [95% CI]; events/hr) by − 3.7 [−4.8, −2.5] vs 0.4 [−0.8, 1.5] (p < 0.0001), representing a model-estimated 39.3% reduction from baseline (vs 12.6% with PBO; p < 0.0001). AD109 reduced AHI4 by ≥ 50% in 28.3% of participants (vs 17.7% with PBO; p < 0.0001); a higher proportion of participants receiving AD109 achieved disease control (AHI4<5; p < 0.0001). AD109 exhibited greater relative reduction in hypoxic burden (41.6% vs 9.9%; p < 0.0001). In participants with baseline excessive daytime sleepiness (ESS≥10; AD109: n = 348; PBO: n = 316), AD109 improved PROMIS-Fatigue and PROMIS-Sleep Impairment T-scores (p = 0.044 and p = 0.048, respectively). Treatment was discontinued by Week 26 in 227 (35.2%) participants randomized to AD109 and 100 (15.5%) to PBO. Treatment-emergent adverse events (TEAEs) were predominantly mild, with ≥1 TEAE reported by 500 (76.6%) participants on AD109 and 370 (57.3%) on PBO. The most common TEAEs were dry mouth, insomnia, nausea, urinary hesitation, somnolence, and constipation.

Conclusions

AD109 led to statistically significant and clinically meaningful improvement of OSA vs PBO and was well-tolerated. The analyses indicate AD109 provides therapeutic benefit for participants with mild-to-severe disease across a range of weight classes.

This abstract is funded by: Apnimed, Inc.