Insmed Incorporated, 700 US Highway 202/206, Bridgewater, NJ, 08807, USA.
INSERM UMR-1100, "Research Center for Respiratory Diseases" and University of Tours, Tours, France.
Respir Res. 2023 May 17;24(1):133. doi: 10.1186/s12931-023-02444-z.
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.
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.
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.
These results suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients.
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.
Brensocatib 是一种口服、选择性、可逆的二肽基肽酶-1（DPP-1）抑制剂，负责激活中性粒细胞丝氨酸蛋白酶（NSPs），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）。在非囊性纤维化支气管扩张症（NCFBE）等慢性炎症性肺部疾病中，中性粒细胞在气道中积聚，导致过多的活性 NSPs 引起破坏性炎症和肺破坏。
24 周的 WILLOW 试验（NCT03218917）是一项在 14 个国家的 116 个地点进行的、针对 NCFBE 患者的随机、双盲、安慰剂对照、平行组试验。在这项试验中，Brensocatib 的治疗与临床结局的改善相关，包括首次加重的时间、加重频率的减少以及痰中 NE 活性的减少。对白细胞（WBC）提取物中的 NE 活性和痰中的 NE、PR3 和 CatG 活性进行了探索性分析，以进一步描述 Brensocatib 的作用，并确定潜在的相关作用。
在 Brensocatib 治疗 4 周后，WBC 提取物中的 NE 活性和痰中的 NE、PR3 和 CatG 活性呈剂量依赖性降低，治疗结束后 4 周恢复基线。Brensocatib 对 CatG 的痰活性降低最大，其次是 NE，然后是 PR3。在基线和治疗反应时，痰中的 NSPs 之间都观察到正相关，其中 NE 和 CatG 之间的相关性最强。
这些结果表明 Brensocatib 具有广泛的抗炎作用，这是其在 NCFBE 患者中观察到的临床疗效的基础。
该研究得到了所有参与中心相应伦理审查委员会的批准。该试验于 2017 年 7 月 17 日经美国食品和药物管理局批准，并在 clinicaltrials.gov 注册（NCT03218917），并经欧洲药品管理局批准，并在欧盟临床试验注册处注册（EudraCT No. 2017-002533-32）。一个独立的、外部的数据和安全监测委员会（由具有肺部专业知识的医生、有经验的评估临床安全性的统计学家以及牙周病和皮肤病学专家组成）审查了所有不良事件。
