背景:Brensocatib是一种口头的,选择性,二肽基肽酶-1(DPP-1)的可逆抑制剂,负责激活中性粒细胞丝氨酸蛋白酶(NSP),包括中性粒细胞弹性蛋白酶(NE),蛋白酶3(PR3),和组织蛋白酶G(CatG)。在慢性炎症性肺病中,例如非囊性纤维化支气管扩张(NCFBE),嗜中性粒细胞在气道中积聚,导致过量的活性NSP,其引起破坏性炎症和肺破坏。
方法:为期24周的WILLOW试验(NCT03218917)是一项随机试验,双盲,安慰剂对照,在14个国家的116个地点进行的NCFBE患者的平行组试验。在这次审判中,brensocatib治疗与临床结局的改善相关,包括首次加重的时间,恶化频率降低和痰中NE活性降低。白细胞(WBC)提取物和NE中NE活性的探索性分析,进行了痰中的PR3和CatG活性,以进一步表征brensocatib的作用并确定潜在的相关作用。
结果:NE,Brensocatib治疗四周后,痰中PR3和CatG活性降低,WBC提取物中NE活性以剂量依赖性方式降低,治疗结束后四周恢复到基线。Brensocatib使CatG的痰液活动减少最大,其次是NE,然后是PR3。在基线和对治疗的反应中观察到痰NSP之间的正相关。痰NSP与NE和CatG的相关性最强。
结论:这些结果表明,在NCFBE患者中观察到的Brensocatib具有广泛的抗炎作用。
背景:该研究得到了所有参与中心的相应伦理审查委员会的批准。该试验获得了美国食品和药物管理局的批准,并于2017年7月17日在clinicaltrials.gov(NCT03218917)注册,并获得了欧洲药品管理局的批准,并在欧盟临床试验注册(EudraCTNo.2017-002533-32)。一个独立的,外部数据和安全监测委员会(由具有肺部专业知识的医生组成,在临床安全性评估方面经验丰富的统计学家,和牙周病和皮肤病学专家)审查了所有不良事件。
BACKGROUND: Brensocatib is an oral, selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), responsible for activating neutrophil serine proteases (NSPs) including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG). In chronic inflammatory lung diseases such as non-cystic fibrosis bronchiectasis (NCFBE), neutrophils accumulate in the airways resulting in excess active NSPs that cause damaging inflammation and lung destruction.
METHODS: The 24-week WILLOW
trial (NCT03218917) was a randomized, double-blind, placebo-controlled, parallel-group
trial in patients with NCFBE conducted at 116 sites across 14 countries. In this
trial, treatment with brensocatib was associated with improvements in clinical outcomes including time to first exacerbation, reduction in exacerbation frequency and a reduction in NE activity in sputum. An exploratory analysis of NE activity in white blood cell (WBC) extracts and NE, PR3 and CatG activity in sputum was conducted to further characterize brensocatib\'s effect and identify potential correlated effects.
RESULTS: NE, PR3 and CatG activities were reduced in sputum and NE activity was reduced in WBC extracts in a dose-dependent manner after four weeks of brensocatib treatment, with a return to baseline four weeks after the end of treatment. Brensocatib produced the greatest reduction in the sputum activity of CatG, followed by NE and then PR3. Positive correlations among the sputum NSPs were observed both at baseline and in response to treatment, with the strongest correlation among the sputum NSPs for NE and CatG.
CONCLUSIONS: These results suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients.
BACKGROUND: The
study was approved by the corresponding ethical review boards of all participating centers. The
trial was approved by the Food and Drug Administration and registered at clinicaltrials.gov (NCT03218917) on July 17, 2017 and approved by the European Medicines Agency and registered at the European Union Clinical trials Register (EudraCT No. 2017-002533-32). An independent, external data and safety monitoring committee (comprising physicians with pulmonary expertise, a statistician experienced in the evaluation of clinical safety, and experts in periodontal disease and dermatology) reviewed all adverse events.