Cathepsin C (dipeptidyl peptidase 1) inhibition in adults with bronchiectasis: AIRLEAF, a phase II randomised, double-blind, placebo-controlled, dose-finding study.

Cathepsin C (CatC; dipeptidyl peptidase 1) activates NSPs during neutrophil maturation.

组织蛋白酶C（CatC；二肽基肽酶1）在中性粒细胞成熟过程中激活NSPs。

CatC inhibitors can potentially reduce neutrophil-mediated lung damage.

CatC 抑制剂有可能减少中性粒细胞介导的肺损伤。

This phase II, randomised, double-blind, placebo-controlledtrial (AIRLEAF®; clinicaltrials.gov identifier NCT05238675) evaluated efficacy, safety and optimal dosing of BI 1291583, a novel, reversible CatC inhibitor, in adults with bronchiectasis.

这项第二阶段、随机、双盲、安慰剂对照试验（AIRLEAF®；临床试验注册号 NCT05238675）评估了一种新型可逆 CatC 抑制剂 BI 1291583 在成人支气管扩张症患者中的疗效、安全性和最佳剂量。

Methods

In total, 322 participants were randomised (2:1:1:2) to receive one of three oral doses of BI 1291583 (1 mg/2.5 mg/5 mg) or placebo for 24-48 weeks.

总共，322名参与者被随机分配（2:1:1:2）接受三种口服剂量的BI 1291583（1毫克/2.5毫克/5毫克）或安慰剂，为期24-48周。

A multiple comparison procedure and modelling approach was used to demonstrate a nonflat dose-response curve based on the time to first pulmonary exacerbation up to week 48.

使用多重比较程序和建模方法来展示基于首次肺部恶化的发生时间（至第48周）的非平坦剂量-反应曲线。

In addition, efficacy of individual BI 1291583 doses was evaluated based on the frequency of exacerbations, severe exacerbations (fatal or leading to hospitalisation and/or intravenous antibiotic administration), lung function and quality of life.

此外，根据发作频率、严重发作（导致死亡或住院和/或静脉抗生素给药）、肺功能和生活质量评估了个体BI 1291583剂量的疗效。

Results

A significant dose-dependent benefit of BI 1291583 over placebo was established based on time to first exacerbation (shape: maximum effect curve 1; adjusted p=0.0448).

基于首次发作时间，确定了BI 1291583与安慰剂相比具有显著的剂量依赖性益处（形状：最大效应曲线1；调整后的p=0.0448）。

Treatment with BI 1291583 5 mg and 2.5 mg numerically reduced the risk of an exacerbation compared with placebo (hazard ratio(95% CI) 0.71 (0.48 to 1.05) and 0.66 (0.40 to 1.08), respectively; both p>0.05).

与安慰剂相比，BI 1291583 5 mg 和 2.5 mg 在数值上降低了急性加重的风险（风险比（95% 置信区间）分别为 0.71（0.48 至 1.05）和 0.66（0.40 至 1.08），两者 p>0.05）。

BI 1291583 2.5 mg showed numerically better efficacy compared with 5 mg across several end-points; 1 mg was similar to placebo.

在多个终点上，BI 1291583 2.5 mg 的疗效在数值上优于 5 mg；1 mg 与安慰剂相似。

The safety profile of BI 1291583 was similar to placebo.

BI 1291583的安全性特征与安慰剂相似。

Conclusions

Treatment with BI 1291583 resulted in a reduction in the risk of experiencing an exacerbation in adults with bronchiectasis.

BI 1291583治疗导致成年支气管扩张患者经历加重的风险降低。