AD109 Yields Numerically Greater OSA Improvements in Postmenopausal Women

AD109, an investigational oral combination of aroxybutynin and atomoxetine, produced numerically greater reductions in obstructive sleep apnea (OSA) severity in postmenopausal women than in men and non-menopausal women, according to a post hoc analysis presented at the CHEST 2026 Annual Meeting in Phoenix.¹

The analysis pooled participants from the phase 3 SynAIRgy and LunAIRo trials, which enrolled adults with mild to severe OSA who were intolerant of or refused positive airway pressure therapy.¹ In the published SynAIRgy results, AD109 significantly reduced the apnea-hypopnea index (AHI) and improved oxygenation at 26 weeks versus placebo.² A pooled analysis of both trials presented earlier in 2026 showed a model-estimated 39.3% AHI reduction with AD109 versus 12.6% with placebo.³

“There’s about a 3-fold increased odds of having obstructive sleep apnea in the postmenopausal state,” said Reena Mehra, MD, head of the Division of Pulmonary, Critical Care and Sleep Medicine at the University of Washington School of Medicine and holder of the A. Bruce Montgomery, MD, American Lung Association Endowed Chair in Pulmonary and Critical Care Medicine.

Mehra, lead author of the abstract, told HCPLive the subgroup question stemmed from hormonal shifts after menopause, including declining estrogen and progesterone, along with visceral weight gain, both of which may contribute to OSA risk.

AD109 Efficacy in Postmenopausal Women With OSA

SynAIRgy (26 weeks) and LunAIRo (51 weeks) were randomized, double-blind, placebo-controlled, parallel-arm phase 3 trials of once-nightly AD109 (aroxybutynin 2.5 mg/atomoxetine 75 mg).¹˒² Investigators classified women as postmenopausal by menopause-related medical history or age ≥ 55 years and compared them with a non-menopausal cohort of men and non-menopausal women.¹ Analyses were descriptive and used the on-treatment population at week 26.¹

Of 1299 enrolled participants, 616 (47.4%) were women. The postmenopausal subgroup included 492 participants (AD109, n = 262; placebo, n = 230), and the non-menopausal cohort included 807 (AD109, n = 391; placebo, n = 416).¹ Postmenopausal women had a median age of 62 years, a median BMI of 32.5 kg/m², and a median AHI with 4% hypopnea desaturation (AHI4) of 18.5 events/hr, and 78.7% (387/492) had mild to moderate OSA.¹

In postmenopausal women, AD109 reduced AHI4 by 6.8 events/hr versus 0.7 events/hr with placebo, a geometric mean reduction of 59.6% versus 16%.¹ Response rates for ≥ 50% and ≥70% AHI4 reduction were 47.2% and 29.7% with AD109, compared with 20.2% and 8.5% with placebo, respectively¹ Hypoxic burden (HB4) fell by 69.8% with AD109 versus 20% with placebo.¹

In the non-menopausal cohort, AD109 reduced AHI4 by 5.3 events/hr versus an increase of 0.7 events/hr with placebo (geometric mean reduction, 44% vs 10.6%).¹ Response rates for ≥ 50% and ≥ 70% reduction were 33% and 18.1% with AD109 versus 18.1% and 5.3% with placebo. HB4 declined by 50.9% with AD109 versus 12.9% with placebo.¹

AD109 Tolerability and Discontinuation by Menopausal Status

Discontinuation of AD109 due to treatment-emergent adverse events was similar across subgroups, at a placebo-subtracted 17.7% in postmenopausal women and 17.5% in the non-menopausal cohort.¹ In the published SynAIRgy trial, 21.2% of participants receiving AD109 and 3.1% receiving placebo discontinued therapy due to adverse events.²

Mehra noted anticholinergic effects occurred more often among postmenopausal women but did not lead to more discontinuations in this group.

“Dry mouth and constipation were more prevalent in the postmenopausal group compared to the non-postmenopausal group,” Mehra said. “The discontinuation related to those symptoms was comparable between the two groups, so these symptoms weren’t resulting in discontinuation of AD109 in the postmenopausal women.”

Investigators described the findings as hypothesis-generating. The analysis was exploratory and post hoc, comparisons between subgroups were descriptive, and age served as a partial proxy for menopausal status.¹

“This sets the stage for us to conduct additional analyses to look into this further,” Mehra said.

Apnimed reported in May 2026 it had submitted a New Drug Application (NDA) for AD109 to the FDA, and the agent has received Fast Track designation for OSA.⁴

Editor’s note: Reported disclosures for Mehra include Amgen, JAZZ PHARMACEUTICALS, and VisionAir Solutions.

References

1. Mehra R, Aurora RN, Lee-Iannotti JK, et al. Aroxybutynin and atomoxetine (AD109) in post-menopausal women with obstructive sleep apnea. Presented at CHEST 2026; October 20, 2026; Phoenix, AZ.

2. Strollo PJ Jr, Farkas R, Taranto-Montemurro L, Cronin J, Patel SR; SynAIRgy Investigators. Aroxybutynin and atomoxetine (AD109) for obstructive sleep apnea: a randomized phase 3 trial (SynAIRgy). Am J Respir Crit Care Med. 2026;212(7):1569-1584. doi:10.1093/ajrccm/aamag215

3. AD109 effective as oral agent for obstructive sleep apnea, with Patrick John Strollo, MD. HCPLive. https://www.hcplive.com/view/ad109-effective-oral-agent-obstructive-sleep-apnea-patrick-john-strollo-md. Published May 19, 2026. Accessed October 22, 2026.

4. Apnimed. Apnimed announces publication of its phase 3 SynAIRgy trial of AD109 for obstructive sleep apnea in the American Journal of Respiratory and Critical Care Medicine. Published May 18, 2026. Accessed October 22, 2026. https://www.prnewswire.com/news-releases/apnimed-announces-publication-of-its-phase-3-synairgy-trial-of-ad109-for-obstructive-sleep-apnea-in-the-american-journal-of-respiratory-and-critical-care-medicine-302774259.html