口服前列腺素DP2 受体 (CRTh2) 拮抗剂Fevipiprant在低剂量吸入糖皮质激素控制不佳的过敏性哮喘中的作用
2017/12/29
摘要
目的：以低剂量吸入性糖皮质激素（ICS）控制不佳的过敏性哮喘患者为研究对象，评估口服前列腺素DP2 受体 (CRTh2) 拮抗剂fevipiprant (QAW039)的剂量相关药效和安全性。
方法：将成年患者随机分为以下3组，进行为期12周的治疗：782名患者接受fevipiprant一天一次(1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d.)或一天两次(2, 25, 75 or 150 mg b.i.d.)；139名患者接受孟鲁司特10 mg q.d；137名患者接受安慰剂作对照。所有病人都接受了吸入布地奈德治疗200 μg b.i.d。
结果：以12周时对比给药前FEV1的改变量为首要终点，Fevipiprant能够使FEV1显著提高(p=0.0035)，且其最大模型平均差异比安慰剂组高出了0.112L。在相对于安慰剂组的配对比较中，fevipiprant组效果最明显是在150 mg q.d.和75 mg b.i.d时，而fevipiprant 的q.d. 和b.i.d.组的比较差异无临床意义。 孟鲁司特在主要终点的改变上也有明显的提高。而在其它药效评估的终点中，均未发现有变化。不良反应的严重性通常是轻中度的，而且在各剂量和治疗中平均分布。
结论：在低剂量吸入糖皮质激素控制不佳的过敏性哮喘患者中，Fevipiprant通常是有效且易接受的，Fevipiprant全天总量150mg能够取得最优的效果。Fevipiprant的这种临床作用仍需合理设计临床III期试验来进一步地探究。
Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids
Eric D. Bateman, Alfredo G. Guerreros, Florian Brockhaus, et al
Abstract
Purpose：Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).
Methods:Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d.) or twice-daily (2, 25, 75 or 150 mg b.i.d.) fevipiprant (n=782), montelukast 10 mg q.d. (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d.
Results: Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d. and 75 mg b.i.d. groups, with no clinically meaningful differences between q.d. and b.i.d. Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments.
Conclusion:Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted.
目的：以低剂量吸入性糖皮质激素（ICS）控制不佳的过敏性哮喘患者为研究对象，评估口服前列腺素DP2 受体 (CRTh2) 拮抗剂fevipiprant (QAW039)的剂量相关药效和安全性。
方法：将成年患者随机分为以下3组，进行为期12周的治疗：782名患者接受fevipiprant一天一次(1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d.)或一天两次(2, 25, 75 or 150 mg b.i.d.)；139名患者接受孟鲁司特10 mg q.d；137名患者接受安慰剂作对照。所有病人都接受了吸入布地奈德治疗200 μg b.i.d。
结果：以12周时对比给药前FEV1的改变量为首要终点，Fevipiprant能够使FEV1显著提高(p=0.0035)，且其最大模型平均差异比安慰剂组高出了0.112L。在相对于安慰剂组的配对比较中，fevipiprant组效果最明显是在150 mg q.d.和75 mg b.i.d时，而fevipiprant 的q.d. 和b.i.d.组的比较差异无临床意义。 孟鲁司特在主要终点的改变上也有明显的提高。而在其它药效评估的终点中，均未发现有变化。不良反应的严重性通常是轻中度的，而且在各剂量和治疗中平均分布。
结论：在低剂量吸入糖皮质激素控制不佳的过敏性哮喘患者中，Fevipiprant通常是有效且易接受的，Fevipiprant全天总量150mg能够取得最优的效果。Fevipiprant的这种临床作用仍需合理设计临床III期试验来进一步地探究。
(复旦大学附属中山医院 呼吸科 胡湘麟 摘译 杨冬 审校)
(European Respiratory Journal 2017 50)
(European Respiratory Journal 2017 50)
Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids
Eric D. Bateman, Alfredo G. Guerreros, Florian Brockhaus, et al
Abstract
Purpose：Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).
Methods:Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d.) or twice-daily (2, 25, 75 or 150 mg b.i.d.) fevipiprant (n=782), montelukast 10 mg q.d. (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d.
Results: Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d. and 75 mg b.i.d. groups, with no clinically meaningful differences between q.d. and b.i.d. Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments.
Conclusion:Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted.
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