英国Ninewells医院James D. Chalmers团队研究了DPP-1抑制剂Brensocatib治疗支气管扩张症的疗效与安全性。该项研究成果发表在2025年4月24日出版的《新英格兰医学杂志》上。

在支气管扩张中，中性粒细胞炎症与加重和疾病进展的风险增加有关。Brensocatib是一种口服，可逆的二肽基肽酶1 （DPP-1）抑制剂，靶向中性粒细胞丝氨酸蛋白酶，中性粒细胞炎症的关键介质。

在一项临床3期双盲试验中，课题组随机分配支气管扩张患者（成人1:1:1比例，青少年2:2:1比例）接受brensocatib （10 mg或25 mg，每天一次）或安慰剂治疗。主要终点是52周期间确诊肺恶化的年化率。次要终点（按等级测试顺序列出）为52周期间至首次加重的时间；第52周无恶化的患者百分比；1秒内用力呼气量（FEV1）的变化；严重恶化的年化率；生活质量的改变。

共有1721名患者（1680名成人和41名青少年）接受随机分组，接受brensocatib或安慰剂。10 mg brensocatib组肺恶化的年化率为1.02，25 mg brensocatib组为1.04，安慰剂组为1.29 （brensocatib与安慰剂的比率比，10 mg brensocatib组为0.79，25 mg brensocatib组为0.81）。到第一次加重时间的风险比为0.81（95% CI, 0.70 ~ 0.95；调整P=0.02），10 mg剂量为0.83（95% CI, 0.70 ~ 0.97；调整P=0.04），剂量为25mg。

在每个brensocatib组中，48.5%的患者在第52周仍无恶化，而安慰剂组为40.3%（比率比，10mg剂量为1.20，25mg剂量为1.18）。在第52周，FEV1在10mg剂量组下降了50ml， 25mg剂量组下降了24ml，安慰剂组下降了62ml（与安慰剂的最小二乘平均差值，10mg剂量组下降了11ml， 25mg剂量组下降了38ml）。除了brensocatib的角化过度发生率较高外，各组不良事件的发生率相似。

研究结果表明，在支气管扩张患者中，每日一次brensocatib治疗（10 mg或25 mg）导致肺恶化的年化率低于安慰剂，并且25mg brensocatib剂量的FEV1下降低于安慰剂。

附：英文原文

Title: Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis

Author: James D. Chalmers, Pierre-Régis Burgel, Charles L. Daley, Anthony De Soyza, Charles S. Haworth, David Mauger, Michael R. Loebinger, Pamela J. McShane, Felix C. Ringshausen, Francesco Blasi, Michal Shteinberg, Kevin Mange, Ariel Teper, Carlos Fernandez, Migdalia Zambrano, Chunpeng Fan, Xiangmin Zhang, Mark L. Metersky

Issue&Volume: 2025-04-24

Abstract:

BACKGROUND

In bronchiectasis, neutrophilic inflammation is associated with an increased risk of exacerbations and disease progression. Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), targets neutrophil serine proteases, key mediators of neutrophilic inflammation.

METHODS

In a phase 3, double-blind trial, we randomly assigned patients with bronchiectasis (in a 1:1:1 ratio for adults and a 2:2:1 ratio for adolescents) to receive brensocatib (10 mg or 25 mg once per day) or placebo. The primary end point was the annualized rate of adjudicated pulmonary exacerbations over a 52-week period. The secondary end points, listed in hierarchical testing order, were the time to the first exacerbation during the 52-week period; the percentage of patients remaining exacerbation-free at week 52; the change in forced expiratory volume in 1 second (FEV1); the annualized rate of severe exacerbations; and change in quality of life.

RESULTS

A total of 1721 patients (1680 adults and 41 adolescents) underwent randomization and received brensocatib or placebo. The annualized rate of pulmonary exacerbations was 1.02 in the 10-mg brensocatib group, 1.04 in the 25-mg brensocatib group, and 1.29 in the placebo group (rate ratio, brensocatib vs. placebo, 0.79 [95% confidence interval {CI}, 0.68 to 0.92; adjusted P=0.004] with the 10-mg dose and 0.81 [95% CI, 0.69 to 0.94; adjusted P=0.005] with the 25-mg dose). The hazard ratio for the time to the first exacerbation was 0.81 (95% CI, 0.70 to 0.95; adjusted P=0.02) with the 10-mg dose and 0.83 (95% CI, 0.70 to 0.97; adjusted P=0.04) with the 25-mg dose. In each brensocatib group, 48.5% of patients remained exacerbation-free at week 52, as compared with 40.3% in the placebo group (rate ratio, 1.20 [95% CI, 1.06 to 1.37; adjusted P=0.02] with the 10-mg dose and 1.18 [95% CI, 1.04 to 1.34; adjusted P=0.04] with the 25-mg dose). At week 52, FEV1 had declined by 50 ml with the 10-mg dose, 24 ml with the 25-mg dose, and 62 ml with placebo (least-squares mean difference vs. placebo, 11 ml [95% CI, 14 to 37; adjusted P=0.38] with the 10-mg dose and 38 ml [95% CI, 11 to 65; adjusted P=0.04] with the 25-mg dose). The incidence of adverse events was similar across groups, except for a higher incidence of hyperkeratosis with brensocatib.

CONCLUSIONS

Among patients with bronchiectasis, once-daily treatment with brensocatib (10 mg or 25 mg) led to a lower annualized rate of pulmonary exacerbations than placebo, and the decline in FEV1 was less with the 25-mg dose of brensocatib than with placebo.

DOI: NJ202504243921605

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2411664