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DPP-1抑制剂brensocatib治疗支气管扩张症的2期试验
Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis


James D. Chalmers ... 呼吸系统疾病 • 2020.11.26
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• 哪种抗生素最适合与囊性纤维化无关的支气管扩张发作 • 黏液阻塞性肺疾病

支气管扩张症治疗新希望:抑制中性粒细胞弹性蛋白酶生成的抗炎药

 

高永华†#,黄妍‡#,关伟杰‡*

†郑州大学第一附属医院呼吸与危重症监护科;‡呼吸疾病国家重点实验室,呼吸疾病国家临床研究中心,广州呼吸健康研究院,广州医科大学附属第一医院

#共同第一作者;*通讯作者

 

支气管扩张症(简称支扩)是一种常见的、以中性粒细胞性炎症为主的慢性气道炎症性疾病1。患者的主要表现为慢性咳嗽、咳痰(部分患者咯大量脓痰)及反复急性加重。频繁的急性加重损害了患者的生活质量,加速肺功能的下降并增加了死亡风险2。“黏液纤毛清除障碍—气道细菌定植—中性粒细胞气道炎症—气道结构破坏”构成的恶性循环是支气管扩张症主要的病理生理机制3,这一经典学说是制定支气管扩张症的临床治疗策略的决策点。目前支气管扩张症的主要治疗策略包括:气道清理治疗(基础治疗)、抗感染治疗(长期吸入抗生素和长期口服大环内酯类药物)及黏液活化药物治疗等4。遗憾的是,既往一直缺乏直接针对抑制中性粒细胞气道炎症的治疗策略。

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摘要


背景

支气管扩张症患者频繁发作,而目前认为发作与中性粒细胞炎症相关。支气管扩张症患者基线时痰内的中性粒细胞丝氨酸蛋白酶(包括中性粒细胞弹性蛋白酶)活性和含量增加,并且发作时进一步增加。brensocatib(INS1007)是口服用药的可逆性二肽基肽酶1(DPP-1)抑制剂,而该酶的作用是激活中性粒细胞丝氨酸蛋白酶。

 

方法

在一项2期、随机、双盲、安慰剂对照试验中,我们以1∶1∶1的比例将上一年有至少2次发作的支气管扩张症患者随机分组,三组分别接受为期24周的每日1次安慰剂、10 mg brensocatib或25 mg brensocatib治疗。本试验评估了至首次发作的时间(主要终点)、发作率(次要终点)、痰中性粒细胞弹性蛋白酶活性和安全性。

 

结果

256例患者中有87例被分配接受安慰剂治疗,82例接受10 mg brensocatib治疗,87例接受25 mg brensocatib治疗。在安慰剂组、10 mg brensocatib组和25 mg brensocatib组中,至首次发作的时间的第25百分位数分别为67日、134日和96日。brensocatib治疗与安慰剂相比延长了至首次发作的时间(10 mg brensocatib vs.安慰剂的P=0.03;25 mg brensocatib vs.安慰剂的P=0.04)。与安慰剂组相比,在10 mg brensocatib组(P=0.03)和25 mg brensocatib组(P=0.046)中,校正后的发作风险比分别为0.58(95%置信区间[CI],0.35~0.95)和0.62(95% CI,0.38~0.99)。与安慰剂组相比,在10 mg组和25 mg组中,发生率比分别为0.64(95% CI,0.42~0.98)(P=0.04)和0.75(95% CI,0.50~1.13)(P=0.17)。使用两种剂量brensocatib治疗时,24周治疗期间的痰中性粒细胞弹性蛋白酶活性相对于基线降低。我们分别在10 mg和25 mg brensocatib组中观察到特别关注的牙齿和皮肤不良事件的发生率高于安慰剂组。

 

结论

在这项为期24周的试验中,brensocatib用药后支气管扩张症患者的中性粒细胞丝氨酸蛋白酶活性降低与支气管扩张症临床结局改善相关(由Insmed资助,WILLOW在ClinicalTrials.gov注册号为NCT03218917)。 





作者信息

James D. Chalmers, M.B., Ch.B., Ph.D., Charles S. Haworth, M.B., Ch.B., M.D., Mark L. Metersky, M.D., Michael R. Loebinger, B.M., B.Ch., Ph.D., Francesco Blasi, M.D., Ph.D., Oriol Sibila, M.D., Ph.D., Anne E. O’Donnell, M.D., Eugene J. Sullivan, M.D., Kevin C. Mange, M.D., M.S.C.E., Carlos Fernandez, M.D., M.P.H., Jun Zou, Ph.D., and Charles L. Daley, M.D. for the WILLOW Investigators*
From the Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee (J.D.C.), Royal Papworth Hospital NHS Foundation Trust and Department of Medicine, University of Cambridge, Cambridge (C.S.H.), and Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London (M.R.L.) — all in the United Kingdom; the University of Connecticut School of Medicine, Farmington (M.L.M.); the Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, and the Department of Pathophysiology and Transplantation, University of Milan, Milan (F.B.); the Department of Pulmonary Medicine, Respiratory Institute, Hospital Clínic–Institut d’Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, and University of Barcelona, Barcelona (O.S.); the Division of Pulmonary, Critical Care, and Sleep Medicine, Georgetown University Medical Center, Washington, DC (A.E.O.); Insmed, Bridgewater, NJ (E.J.S., K.C.M., C.F., J.Z.); and the Department of Medicine, National Jewish Health and the University of Colorado, Denver (C.L.D.). Address reprint requests to Dr. Chalmers at the Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Ninewells Ave., Dundee DD1 9SY, United Kingdom, or at jchalmers@dundee.ac.uk. *A complete list of the WILLOW Investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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