A82-04 Aroxybutynin And Atomoxetine (AD109) In Obstructive Sleep Apnea

Rationale

Obstructive sleep apnea (OSA) is a chronic disease with no FDA-approved oral pharmacologic options. AD109 is an investigational fixed-dose oral anti-apneic neuromuscular modulator, combining the novel antimuscarinic, aroxybutynin (2.5 mg), with the selective norepinephrine reuptake inhibitor, atomoxetine (75 mg) in one tablet. We conducted two Phase 3 trials, SynAIRgy and LunAIRo, to evaluate the efficacy, safety, and tolerability of AD109 in OSA, representing one of the largest clinical development efforts for an OSA pharmacotherapy.

Study Design Including Participants

SynAIRgy (NCT05813275; 26-weeks) and LunAIRo (NCT05811247; 51-weeks) were randomized, double-blind, placebo (PBO)-controlled, parallel-arm trials of AD109 in adults with mild-to-severe OSA, who were intolerant to, or refused positive airway pressure (PAP) therapy. Key inclusion criteria required an apnea-hypopnea index >5 events/hr (AHI4; 4% hypopnea desaturation) and body mass indexes of 18.5-40 kg/m2 (males) / 18.5-42 kg/m2 (females). Pooled primary efficacy at Week 26 was analyzed in the treatment policy estimand (randomized and received ≥1 treatment dose) with supportive analyses in the on-treatment estimand (≥1 post-baseline on-treatment polysomnogram).

Key Existing Data and/or Data Trends

In the Phase 2b MARIPOSA trial, AD109 significantly improved AHI4 in adults with mild-to-severe OSA over 4 weeks. In both Phase 3 trials, AD109 met the primary endpoint of significantly reducing AHI4. AD109 improved oxygenation metrics. Treatment-emergent adverse events (TEAEs) were predominantly mild.

Results

A total of 1299 participants were randomized 1:1 to receive AD109 (n = 648) or placebo (n = 651); 82.3% (1063/1292) of participants who received treatment completed the trials. Many participants had baseline mild-moderate OSA (73.5%). In the treatment policy estimand (AD109: n = 626; PBO: n = 639), AD109 reduced AHI4 (LS mean difference [95%CI]: −4.0 [−5.6, −2.5]; p < 0.0001), representing a model-estimated 39.3% reduction from baseline (vs 12.6% [PBO]; p < 0.0001). In the on-treatment estimand (AD109: n = 500; PBO: n = 589), AD109 reduced AHI4 (−6.2 [−7.8, −4.6]; p < 0.0001), representing a model-estimated 51.6% reduction from baseline (vs 13.3% [PBO]; p < 0.0001). 39.0% achieved an AHI4 reduction ≥50% with AD109 (vs 18.8% [PBO]; p < 0.0001). More participants receiving AD109 (22.6%) achieved OSA disease control (AHI4<5; vs 8.3% [PBO]; p < 0.0001). AD109 reduced hypoxic burden by 59.6% from baseline (vs 14.9% [PBO]; p < 0.0001). In participants with baseline excessive daytime sleepiness (ESS≥10; AD109: n = 280; PBO: n = 294), AD109 improved PROMIS-Fatigue and PROMIS-Sleep Impairment T-scores vs PBO (p = 0.0071; p = 0.0137, respectively). TEAEs leading to treatment discontinuation by Week 26 was 25.0% (163/653) in participants receiving AD109 and 6.7% (43/646) receiving PBO. 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. No AD109-related serious TEAEs were identified.

Significance of Study

Despite the efficacy of PAP therapy, a substantial unmet need in OSA exists due to poor adherence and limited use of alternative therapies. AD109, with a first-in-class mechanism of action, seeks to address this unmet need by targeting neuromuscular dysfunction. Two Phase 3 trials demonstrated statistically significant and clinically responsive improvements in airway obstruction and oxygenation.

Results

suggest a therapeutic benefit across patients with mild-to-severe OSA. Pooled analyses support observed improvements over multiple domains of OSA treatment responses, including airway obstruction, oxygenation, and symptomatology. AD109 may represent a transformative shift in OSA treatment, potentially offering a simple pharmacological option for untreated or under-treated patients, if approved.

Results from High-Profile Phase II or Phase III Clinical Trials

Following successful completion of Apnimed’s Phase 3 program in OSA, SynAIRgy results are under peer review with AJRCCM. LunAIRo results alongside a comprehensive pooled analysis are being finalized for subsequent publication. These positive outcomes will be submitted in an NDA to the U.S. FDA, a pivotal step in expanding the OSA treatment landscape.

This abstract is funded by: