Mechanisms of upper airway muscle control in sleep reveal therapeutic targets for obstructive sleep apnea

Obstructive sleep apnea (OSA) is the most prevalent sleep-related breathing disorder and is associated with cardiovascular, metabolic, neurocognitive, and mortality risk. OSA arises from recurrent upper airway collapse during sleep, producing intermittent hypoxia and sleep fragmentation. While anatomical vulnerability contributes to airway instability, a key determinant of OSA pathophysiology is the sleep-related reduction in upper airway neuromuscular activity that occurs at the wake-sleep transition. Despite this central role, no approved pharmacologic therapies have targeted the neuromuscular mechanisms underlying airway collapse. This review summarizes the biological basis of upper airway neuromuscular dysfunction in OSA, integrating insights from preclinical models of hypoglossal motor control with clinical evidence supporting neuromodulatory treatment strategies. We focus on AD109, an investigational oral therapy combining a norepinephrine reuptake inhibitor (atomoxetine) with an antimuscarinic agent (aroxybutynin), designed to counteract sleep-related withdrawal of excitatory noradrenergic drive and rapid eye movement (REM)-related muscarinic inhibition at the hypoglossal motor nucleus. Early phase clinical studies demonstrated rapid and substantial improvements in airway collapsibility and apnea-hypopnea index, providing proof of concept for this approach. Results from large phase 3 trials confirm that targeting neuromuscular dysfunction can produce reductions in airway obstruction and meaningful improvements in oxygenation, including hypoxic burden, a metric closely linked to OSA-related sequelae. Symptomatic patients also experienced improvements in fatigue, sleepiness, and snoring versus placebo. Together, these findings support neuromuscular dysfunction as a tractable therapeutic target in OSA and highlight the potential of pharmacologic strategies to address both the physiological consequences of intermittent hypoxia and patient-relevant outcomes across a broad and heterogeneous OSA population.