Dept of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University, Nagoya, Japan.
Dept of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.
Eur Respir J. 2022 Jun 2;59(6). doi: 10.1183/13993003.00725-2021. Print 2022 Jun.
The purinoceptor subtype P2X has been shown to have significant involvement in the cough reflex; the heterotrimer version of the purinoceptor (P2X) has been implicated in taste disturbance. The most advanced clinical candidate antagonist gefapixant has low selectivity among P2X receptors and induced taste disturbance, whereas newly developed sivopixant has high selectivity towards P2X P2X.
In a phase 2a, randomised, double-blind, placebo-controlled, crossover, multicentre study, adult patients with refractory or unexplained chronic cough received oral sivopixant 150 mg or placebo once daily for 2 weeks, followed by a 2-3-week washout period, and then crossed over to placebo or sivopixant for 2 weeks. Efficacy and safety of sivopixant were evaluated.
Of 31 randomised patients, 15 in the sivopixant-first group and 15 in the placebo-first group completed the study. After 2 weeks of treatment, the placebo-adjusted ratios of the average hourly number of coughs to baseline during daytime (primary end-point) and over 24 h (secondary end-point) were -31.6% (p=0.0546) and -30.9% (p=0.0386), respectively. Sivopixant also improved health-related quality of life. Treatment-related adverse events occurred in 12.9% and 3.2% of patients during sivopixant and placebo administration, respectively. Mild taste disturbance occurred in two patients (6.5%) during sivopixant administration.
Sivopixant reduced objective cough frequency and improved health-related quality of life, with a low incidence of taste disturbance, among patients with refractory or unexplained chronic cough.
嘌呤能受体亚型 P2X 已被证明在咳嗽反射中具有重要作用；嘌呤能受体（P2X）的三聚体形式与味觉障碍有关。最先进的临床候选拮抗剂 gefapixant 在 P2X 受体中选择性低，并引起味觉障碍，而新开发的 sivopixant 对 P2X 受体具有高选择性。
在一项 2a 期、随机、双盲、安慰剂对照、交叉、多中心研究中，难治性或原因不明的慢性咳嗽的成年患者接受口服 sivopixant 150mg 或安慰剂，每日一次，持续 2 周，然后进行 2-3 周的洗脱期，然后交叉接受安慰剂或 sivopixant 治疗 2 周。评估 sivopixant 的疗效和安全性。
31 名随机患者中，15 名进入 sivopixant 组，15 名进入安慰剂组完成了研究。治疗 2 周后，日间（主要终点）和 24 小时内（次要终点）平均每小时咳嗽次数与基线相比的安慰剂调整比值分别为-31.6%（p=0.0546）和-30.9%（p=0.0386）。Sivopixant 还改善了健康相关生活质量。在 sivopixant 和安慰剂治疗期间，分别有 12.9%和 3.2%的患者发生与治疗相关的不良事件。两名患者（6.5%）在接受 sivopixant 治疗期间出现轻度味觉障碍。
Sivopixant 可降低难治性或原因不明的慢性咳嗽患者的客观咳嗽频率，改善健康相关生活质量，且味觉障碍发生率低。
