C21-06 Estimated Reduction in Cardiovascular Risk Associated With Hypoxic Burden Improvement With AD109 in the LunAIRo and SynAIRgy Phase 3 Studies for Obstructive Sleep Apnea

Abstract Rationale Hypoxic burden (HB), a cumulative measure of the frequency, depth, and duration of oxygen desaturations during sleep, has been shown to independently predict cardiovascular morbidity and mortality. AD109, a once-daily oral medication combining a novel antimuscarinic, aroxybutynin, and a selective norepinephrine reuptake inhibitor, atomoxetine, significantly reduced HB in participants with mild-to-severe obstructive sleep apnea (OSA) in 2 randomized, placebo-controlled Phase 3 trials, SynAIRgy (NCT05813275) and LunAIRo (NCT05811247). We estimated the reduction in cardiovasular (CV) risk associated with the observed improvements in HB with AD109. Methods Hazard ratios (HRs) for incident CV events or all-cause mortality per 1-unit increase in the natural logarithm of HB at baseline were obtained from two independent cohorts free from CV disease at baseline: the Pays de la Loire Sleep Cohort, PDLL (newly-diagnosed OSA patients; N = 5385, median IQR age 60 51-69 years, 63.7% male, HB 32 13-71% min/h) and the MESA study (community-based adults; N = 1973, age 67 61-75 years, 46.4% male, HB 37.5 19.2-73.0% min/h). In both studies, risk was evaluated using fully-adjusted Cox proportional hazard models. Cohort-specific HR estimates were pooled using an inverse-variance weighted random-effects meta-analysis and used to estimate risk reduction associated with the observed HB reduction at Week 26 in AD109-treated participants (pooled trial analysis, N = 626, age 58 51-64 years, 50.5% male, HB 34.0 16.7-63.0% min/h). Analyses were performed for two estimands: the treatment policy estimand, (all randomized participants receiving treatment) and the on treatment estimand (those with ≥1 postbaseline polysomnogram while on treatment). Results In both cohorts, HB was associated with incident CV events or all-cause mortality (PDLL HR = 1.19 95% CI: 1.06-1.33, MESA HR = 1.37 95% CI: 1.18-1.60); the pooled HR derived from meta-analysis was 1.26 (95% CI: 1.10-1.45). Across the pooled LunAIRo and SynAIRgy trials, mean HB reduction with AD109 was 41.6% (95% CI: 34.7-47.8) in the treatment policy estimand and 59.6% (95% CI: 54.3-64.6) in the on treatment estimand, which corresponded to a predicted reduction in the risk of CV events or all-cause mortality of 11.9% (95% CI: 4.7-18.5) and 19.2% (95% CI: 8.2-28.8), respectively. Conclusions In participants with OSA, AD109 achieved substantial reductions in HB corresponding to an estimated 12-19% relative reduction in CV events or mortality risk, based on previously-published cohort models. This finding suggests that AD109 may have an important protective effect on cardiovascular outcomes. This abstract is funded by: Apnimed, Inc.