# A Novel Pharmacological Therapy for Obstructive Sleep Apnea

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $675,424

## Abstract

PROJECT SUMMARY/ABSTRACT
Obstructive sleep apnea (OSA) is a highly prevalent disorder with numerous deleterious effects on
neurocognitive function and cardiovascular health. However, the leading treatment, continuous positive airway
pressure (CPAP), is poorly tolerated by many individuals. Thus, the development new treatment strategies are
critically needed. A pharmacological therapy for OSA remains elusive.
A key contributor to OSA is reduced pharyngeal dilator muscle tone and responsiveness during sleep. Animal
studies support the view that two mechanisms are responsible: a loss of noradrenergic drive and muscarinic
inhibition to the hypoglossal motor pool. Accordingly, in a small study in human patients with OSA, we
administered a novel combination of existing agents—a noradrenergic reuptake inhibitor atomoxetine plus an
antimuscarinic oxybutynin—on a single night, and found a reduction in OSA severity by ~75%, by far the most
powerful effect of any pharmacological intervention observed previously. Our current proposal leverages our
preliminary findings to make major headway on pharmacological therapy for OSA.
In Aim 1, we seek to demonstrate the repeated-dose efficacy and tolerance of atomoxetine-plus-oxybutynin in a
randomized, placebo-controlled, crossover study in 48 male and female patients with OSA for 1 month. We will
assess effects on OSA severity (apnea-hypopnea index, primary outcome), nocturnal oxygenation, the frequency
of arousals from sleep, sleepiness and disease-specific quality of life. Adherence to therapy and adverse events
will also be carefully monitored. In Aim 2, we will investigate the mechanisms by which atomoxetine and
oxybutynin improve OSA severity, alone and in combination. Using gold-standard “deep phenotyping”
mechanistic studies, we will test the hypotheses that both agents increase muscle responsiveness, separately
and synergistically, and that oxybutynin counterbalances the effect of atomoxetine to increase arousability.
These results will have key implications for the ongoing development of this pharmacological approach. In Aim
3, we will use both deep phenotyping and non-invasive (clinically-applicable) methods to determine which patient
phenotypes respond best to atomoxetine and oxybutynin. Preliminary data strongly suggested that patients with
less-severe collapsibility exhibit a greater response to therapy, and that this can be detected with a surrogate
measurement from a routine clinical sleep study. This personalized medicine approach will provide the scientific
knowledge needed to progress towards larger studies in selected patients.
Overall, our proposal is expected to demonstrate that a combination of agents has the potential to treat OSA
through reinstatement of muscle responsiveness during sleep. If judiciously administered, this intervention could
provide many patients with an effective alternative to CPAP. Such results are of major importance because they
have great potential to improve the quali...

## Key facts

- **NIH application ID:** 10445052
- **Project number:** 5R01HL146697-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Scott A Sands
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $675,424
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445052

## Citation

> US National Institutes of Health, RePORTER application 10445052, A Novel Pharmacological Therapy for Obstructive Sleep Apnea (5R01HL146697-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10445052. Licensed CC0.

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