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Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial
Jonathan A Robbins1, Scott Sands2, Lata Maganti1
1Merck & Co., Inc., Rahway, New Jersey.
Study Objectives:
Obstructive sleep apnea (OSA) is a highly prevalent disorder with serious health consequences but limited therapeutic options. For a subset of those with OSA, a key underlying mechanism is hypersensitive chemoreflex control of breathing. There is no approved therapy that targets this endotypic trait. Here we determine whether the P2X3 receptor antagonist gefapixant, which is predicted to attenuate hypersensitive carotid chemoreflexes, reduces OSA severity in patients with chemoreflex-dependent OSA.
Methods:
In a randomized placebo-controlled crossover study, 24 patients with moderate-to-severe OSA (aged 39-68 years, non-continuous positive airway pressure users) whose disorder was partially responsive to supplemental oxygen (chemoreflex-dependent OSA) were treated with gefapixant 180 mg (or placebo) administered as tablets taken orally before bedtime for 7 days and assessed via overnight polysomnography. The primary analysis examined whether gefapixant treatment resulted in a greater reduction in the apnea-hypopnea index from baseline than placebo.
Results:
Gefapixant did not lower the apnea-hypopnea index significantly more than placebo; the estimated ratio of the apnea-hypopnea index on gefapixant vs placebo was 0.92 (90% confidence interval: 0.73, 1.17). Notably, nocturnal hypoxemia was increased (ratio of total sleep time with saturated peripheral oxygen < 90% on gefapixant vs placebo = 2.08 [90% confidence interval: 1.53, 2.82]), consistent with reduced chemoreflex output. Commonly reported adverse events with gefapixant included ageusia, dysgeusia, oral hypoaesthesia, nausea, somnolence, and taste disorders.
Conclusions:
Gefapixant, while generally well tolerated, did not reduce OSA severity in patients with chemoreflex-dependent OSA. P2X3 receptor antagonism is unlikely to provide an avenue for therapeutic intervention in OSA.
Clinical Trial Registration:
Registry: ClinicalTrials.gov; Name: Safety and Tolerability of Gefapixant (MK-7264) in Participants with Obstructive Sleep Apnea (MK-7264-039); URL: https://clinicaltrials.gov/study/NCT03882801; Identifier: NCT03882801.
Citation:
Robbins JA, Sands S, Maganti L, et al. Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med. 2024;20(12):1905-1913.
Insights
Gefapixant did not reduce obstructive sleep apnea (OSA) severity in patients with hypersensitive chemoreflexes. The P2X3 receptor antagonist also increased nocturnal hypoxemia, suggesting it
Area of Science:
- Sleep Medicine
- Respiratory Physiology
- Pharmacology
Background:
- Obstructive sleep apnea (OSA) is a prevalent disorder with limited treatment options.
- Hypersensitive chemoreflex control of breathing is a key mechanism in a subset of OSA patients.
- Currently, no approved therapies target this specific endotypic trait.
Purpose of the Study:
- To investigate if the P2X3 receptor antagonist gefapixant can reduce OSA severity.
- To determine if gefapixant attenuates hypersensitive carotid chemoreflexes in patients with chemoreflex-dependent OSA.
Main Methods:
- A randomized, placebo-controlled, crossover study involving 24 patients with moderate-to-severe OSA.
- Patients received gefapixant 180 mg or placebo orally before bedtime for 7 days.
- Overnight polysomnography was used to assess the apnea-hypopnea index (AHI).
Main Results:
- Gefapixant did not significantly reduce the AHI compared to placebo (ratio 0.92).
- Nocturnal hypoxemia increased significantly with gefapixant use (ratio 2.08).
- Common adverse events included taste disturbances and nausea.
Conclusions:
- Gefapixant did not demonstrate efficacy in reducing OSA severity in patients with chemoreflex-dependent OSA.
- P2X3 receptor antagonism is unlikely to be a viable therapeutic strategy for OSA.
- Gefapixant was generally well-tolerated but did not offer clinical benefit for OSA severity.
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