National Heart and Lung Institute, Imperial College London, London, UK.
Imperial Clinical Trials Unit, Imperial College London, London, UK.
Thorax. 2022 Oct;77(10):950-959. doi: 10.1136/thoraxjnl-2021-217429. Epub 2021 Oct 29.
The chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesised that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.
Atopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomised to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 3 weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.
Six subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant-treated and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0-14 (difference 3.0 (95% CI -29.0 to 17.0), p=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo-treated but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events or drug-related withdrawals.
Timapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.
趋化因子受体同源分子表达在辅助性 T 细胞 2 型（CRTH2）上的拮抗剂替马匹坦在 2 期研究中改善了肺功能和哮喘控制，并有证据表明减少了恶化。我们旨在评估替马匹坦是否减轻或预防实验性鼻病毒（RV）感染引起的哮喘恶化。我们还假设替马匹坦会抑制 RV 诱导的 2 型炎症，从而改善抗病毒免疫反应。
在维持吸入皮质类固醇的部分控制哮喘的特应性患者中，随机分配到替马匹坦（n=22）或安慰剂（n=22）组，并在 3 周后用 RV-A16 进行挑战。主要终点是感染后 14 天内的累积下呼吸道症状评分。在上呼吸道症状、肺活量、气道高反应性、呼出气一氧化氮、RV-A16 病毒载量和上下气道样本中的可溶性介质以及支气管活检中的 CRTH2 染色之前和期间进行了评估。
6 名受试者退出研究，8 名未感染；在 16 名接受替马匹坦治疗和 14 名接受安慰剂治疗且成功感染的受试者中评估了结果。在治疗组之间，在临床恶化严重程度方面没有差异，包括累积下呼吸道症状评分 0-14 天（差异 3.0（95%CI-29.0 至 17.0），p=0.78）、病毒载量、抗病毒免疫反应，或 RV-A16 诱导的气道炎症，除了在支气管活检中，在安慰剂治疗组而不是替马匹坦治疗组中，CRTH2 染色在 RV-A16 感染期间增加。替马匹坦具有良好的安全性，无死亡、严重不良事件或与药物相关的停药。
替马匹坦治疗对部分控制哮喘中 RV-A16 感染引起的临床病理变化影响不大。
