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.).
N Engl J Med. 2020 Nov 26;383(22):2127-2137. doi: 10.1056/NEJMoa2021713. Epub 2020 Sep 7.
Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.
In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed.
Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo.
In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).
支气管扩张症患者经常发生加重，这些加重被认为与中性粒细胞炎症有关。基线时支气管扩张症患者的痰液中中性粒细胞丝氨酸蛋白酶（包括中性粒细胞弹性蛋白酶）的活性和数量增加，在加重期间进一步增加。布伦索替布（INS1007）是一种口服可逆的二肽基肽酶 1（DPP-1）抑制剂，DPP-1 是一种负责激活中性粒细胞丝氨酸蛋白酶的酶。
在一项 2 期、随机、双盲、安慰剂对照试验中，我们以 1:1:1 的比例随机分配过去 1 年内至少发生过 2 次加重的支气管扩张症患者接受安慰剂、10mg 布伦索替布或 25mg 布伦索替布每日 1 次，共 24 周。评估首次加重的时间（主要终点）、加重的发生率（次要终点）、痰中性粒细胞弹性蛋白酶活性和安全性。
在 256 名患者中，87 名患者被分配接受安慰剂，82 名患者接受 10mg 布伦索替布，87 名患者接受 25mg 布伦索替布。安慰剂组首次加重的第 25 百分位数时间为 67 天，10mg 布伦索替布组为 134 天，25mg 布伦索替布组为 96 天。与安慰剂相比，布伦索替布治疗延长了首次加重的时间（10mg 布伦索替布与安慰剂相比，P=0.03；25mg 布伦索替布与安慰剂相比，P=0.04）。与安慰剂相比，布伦索替布与安慰剂相比，10mg 组的加重发生率的校正风险比为 0.58（95%置信区间[CI]，0.35 至 0.95；P=0.03），25mg 组为 0.62（95%CI，0.38 至 0.99；P=0.046）。10mg 组与安慰剂相比，发病率比为 0.64（95%CI，0.42 至 0.98；P=0.04），25mg 组与安慰剂相比，发病率比为 0.75（95%CI，0.50 至 1.13；P=0.17）。在两种布伦索替布剂量下，痰中性粒细胞弹性蛋白酶活性在 24 周治疗期间均从基线水平下降。与安慰剂相比，10mg 和 25mg 布伦索替布剂量的牙齿和皮肤不良事件的发生率分别较高。
在这项为期 24 周的试验中，支气管扩张症患者中性粒细胞丝氨酸蛋白酶活性的降低与支气管扩张症临床结局的改善相关。（由 Insmed 资助；WILLOW 临床试验.gov 编号，NCT03218917）。
