Robbins Jonathan A, Sands Scott, Maganti Lata, Crumley Tami, Fox-Bosetti Sabrina, Hussain Azher, Schwartz Howard, Safirstein Beth, Ahmad Maha, Dragone Leonard, Nussbaum Jesse, Kushida Clete, Iwamoto Marian, Stoch S Aubrey
Merck & Co., Inc., Rahway, New Jersey.
Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts.
J Clin Sleep Med. 2024 Dec 1;20(12):1905-1913. doi: 10.5664/jcsm.11272.
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.
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.
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.
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.
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.
Robbins JA, Sands S, Maganti L, et al. Gefapixant as a P2X3 receptor antagonist treatment for obstructive sleep apnea: a randomized controlled trial. . 2024;20(12):1905-1913.
阻塞性睡眠呼吸暂停（OSA）是一种高度流行的疾病，会导致严重的健康后果，但治疗选择有限。对于一部分OSA患者来说，一个关键的潜在机制是呼吸的化学反射控制过敏。目前尚无针对这种内型特征的获批疗法。在此，我们确定P2X3受体拮抗剂吉法匹酯（预计可减弱颈动脉化学反射过敏）是否能降低化学反射依赖性OSA患者的OSA严重程度。
在一项随机安慰剂对照交叉研究中，24例中度至重度OSA患者（年龄39 - 68岁，非持续气道正压通气使用者），其病情对补充氧气部分有反应（化学反射依赖性OSA），接受180毫克吉法匹酯（或安慰剂）治疗，以片剂形式在睡前口服，持续7天，并通过整夜多导睡眠图进行评估。主要分析检查吉法匹酯治疗是否比安慰剂导致呼吸暂停低通气指数从基线有更大程度的降低。
吉法匹酯降低呼吸暂停低通气指数的幅度并不比安慰剂显著更大；吉法匹酯与安慰剂相比，呼吸暂停低通气指数的估计比值为0.92（90%置信区间：0.73, 1.17）。值得注意的是，夜间低氧血症有所增加（吉法匹酯与安慰剂相比，外周血氧饱和度<90%的总睡眠时间比值 = 2.08 [90%置信区间：1.53, 2.82]），这与化学反射输出减少一致。吉法匹酯常见的不良事件包括味觉丧失、味觉障碍、口腔感觉减退、恶心、嗜睡和味觉紊乱。
吉法匹酯虽然总体耐受性良好，但并未降低化学反射依赖性OSA患者的OSA严重程度。P2X3受体拮抗不太可能为OSA的治疗干预提供途径。
注册机构：ClinicalTrials.gov；名称：吉法匹酯（MK - 7264）在阻塞性睡眠呼吸暂停参与者中的安全性和耐受性（MK - 7264 - 039）；网址：https://clinicaltrials.gov/study/NCT03882801；标识符：NCT03882801。
Robbins JA, Sands S, Maganti L,等。吉法匹酯作为P2X3受体拮抗剂治疗阻塞性睡眠呼吸暂停：一项随机对照试验。. 2024;20(12):1905 - 1913。
