1 Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, United Kingdom.
2 Innovative Medicines and Early Development, IMED RIA, AstraZeneca, Mölndal, Sweden.
Am J Respir Crit Care Med. 2017 Nov 15;196(10):1255-1263. doi: 10.1164/rccm.201704-0769OC.
Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough.
XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough.
XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomized, placebo-controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough, and patient-reported outcomes.
XEN-D0501 was more efficacious and 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. In vivo XEN-D0501 completely inhibited capsaicin-induced cough, whereas 100 times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline, XEN-D0501, -19.3 ± 16.4) coughs; placebo, -1.8 ± 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7 ± 16.9 coughs/h; placebo, 0.4 ± 13.7 coughs/h; P = 0.41).
XEN-D0501 demonstrated superior efficacy and potency in preclinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registered with www.clinicaltrialsregister.eu (2014-000306-36).
吸入辣椒素后咳嗽反应增强是慢性咳嗽患者的特征，辣椒素是瞬时受体电位香草酸 1（TRPV1）激动剂。然而，先前的研究显示，尽管 TRPV1 拮抗剂（SB-705498）可降低辣椒素诱发的咳嗽，但并未改善慢性咳嗽患者的自发性咳嗽频率。
本研究旨在比较 XEN-D0501（一种有效的 TRPV1 拮抗剂）和 SB-705498 在临床前研究中的疗效，以确定其是否具有改善的疗效特征，从而支持进一步开展 XEN-D0501 治疗难治性慢性咳嗽的临床试验。
本研究采用感觉神经激活测定法对 XEN-D0501 和 SB-705498 进行了分析，并在豚鼠体内评估了它们对辣椒素诱导的咳嗽的效力。20 例难治性慢性咳嗽患者参与了一项双盲、随机、安慰剂对照交叉研究，评估了 14 天 XEN-D0501（口服，每天 2 次，4mg）与安慰剂对清醒时咳嗽频率（主要终点）、辣椒素诱发的咳嗽和患者报告的结果的影响。
XEN-D0501 抑制豚鼠和人离体迷走神经辣椒素诱导的去极化作用的效力比 SB-705498 高 1000 倍，作用更有效。体内，XEN-D0501 完全抑制了辣椒素诱导的咳嗽，而 SB-705498 则需要 100 倍的剂量才能达到相同的效果。在患者中，XEN-D0501 显著降低了辣椒素引起的最大咳嗽反应（XEN-D0501 组从基线的平均变化，-19.3±16.4 次咳嗽；安慰剂组，-1.8±5.8 次咳嗽；P<0.0001），但对自发性清醒时咳嗽频率无影响（XEN-D0501 组从基线的平均变化，6.7±16.9 次咳嗽/小时；安慰剂组，0.4±13.7 次咳嗽/小时；P=0.41）。
XEN-D0501 在辣椒素挑战的临床前和临床研究中显示出更好的疗效和效力；尽管药效学特征有所改善，但自发性咳嗽频率并未改善，这排除了 TRPV1 作为难治性咳嗽的有效治疗靶点。临床试验在 www.clinicaltrialsregister.eu（2014-000306-36）注册。
