Effects of the DPP-1 inhibitor HSK31858 in adults with bronchiectasis in China (SAVE-BE): a phase 2, multicentre, double-blind, randomised, placebo-controlled trial.

HSK31858 is a novel reversible inhibitor of DPP-1.

HSK31858是一种新型的DPP-1可逆抑制剂。

We aimed to assess the efficacy and safety of HSK31858 in decreasing the frequency of bronchiectasis exacerbations among adults with bronchiectasis.

我们旨在评估HSK31858在减少成人支气管扩张症患者急性加重频率方面的疗效和安全性。

Methods

SAVE-BE was a phase 2, double-blind, randomised, placebo-controlledtrial in 25 tertiary centres in China.

SAVE-BE是一项在中国25个三级中心进行的2期、双盲、随机、安慰剂对照试验。

Participants were aged 18 years or older with a physician diagnosis of bronchiectasis, according to chest high-resolution CT showing bronchial dilatation and compatible respiratory symptoms, and at least two exacerbations within 12 months before screening.

参与者年龄在18岁或以上，根据胸部高分辨率CT显示支气管扩张和符合的呼吸系统症状，以及在筛选前12个月内至少有两次加重，被诊断为支气管扩张症的医生诊断。

Participants were randomly assigned (1:1:1) via a central interactive web-response system to receive 20 mg HSK31858, 40 mg HSK31858, or placebo, orally, once daily for 24 weeks.

参与者通过中央互动网络响应系统随机分配（1:1:1），接受20毫克HSK31858、40毫克HSK31858或安慰剂，口服，每日一次，为期24周。

Randomisation was stratified by exacerbation frequency in the previous year (less than three vs three or more annually) and study investigators and participants were masked to group assignment for analysis of study outcomes.

随机分组按前一年加重频率进行分层（每年少于三次与三次或更多），研究调查员和参与者对分组分配进行分析时被蒙蔽。

The primary endpoint was the annualised exacerbation frequency over 24 weeks, assessed in the full analysis set.

主要终点是24周内年化加重频率，在完整分析集中进行评估。

Safety was monitored throughout the study.

研究期间持续监测了安全性。

This trial is registered with ClinicalTrials.gov, NCT05601778.

该试验已在ClinicalTrials.gov注册，注册号为NCT05601778。

Results

Between Dec 6, 2022, and March 31, 2024, 292 patients were screened, 226 of whom were enrolled and randomly assigned (75 to the 20 mg HSK31858 group, 76 to the 40 mg HSK31858 group, and 75 to the placebo group. 74 patients received 20 mg HSK31858, 75 received 40 mg HSK31858, and 75 received placebo and were included in the full analysis set.

在2022年12月6日至2024年3月31日期间，共有292名患者接受了筛查，其中226名患者被纳入并随机分配（20 mg HSK31858组75人，40 mg HSK31858组76人，安慰剂组75人。74名患者接受了20 mg HSK31858，75名患者接受了40 mg HSK31858，75名患者接受了安慰剂，并被纳入全分析集。

In the full analysis set, 136 (61%) participants were female and 88 (39%) were male.

在全分析集中，136名（61%）参与者为女性，88名（39%）为男性。

The mean annualised frequency of exacerbations was 1·00 per person-year (SD 1·44) in the 20 mg HSK31858 group, 0·75 per person-year (1·37) in the 40 mg HSK31858 group, and 1·88 per person-year (1·97) in the placebo group.

在20毫克HSK31858组中，急性加重的平均年化频率为每人年1.00次（标准差1.44），在40毫克HSK31858组中为每人年0.75次（标准差1.37），在安慰剂组中为每人年1.88次（标准差1.97）。

The least-squares mean frequency of exacerbations was 1·05 per person-year (95% CI 0·73-1·51) in the 20 mg HSK31858 group, 0·83 per person-year (0·55-1·25) in the 40 mg HSK31858 group, and 2·01 per person-year (1·53-2·63) in the placebo group.

急性加重的最小二乘平均频率在20毫克HSK31858组为每人年1.05次（95%置信区间0.73-1.51），在40毫克HSK31858组为每人年0.83次（95%置信区间0.55-1.25），在安慰剂组为每人年2.01次（95%置信区间1.53-2.63）。

The incidencerate ratio compared with placebo was 0·52 (95% CI 0·34-0·80; p=0·0031) for the 20 mg HSK31858 group and 0·41 (0·26-0·66; p=0·0002) for the 40 mg HSK31858 group.

与安慰剂相比，20 mg HSK31858组的发病率比率为0.52（95%置信区间0.34-0.80；p=0.0031），40 mg HSK31858组的发病率为0.41（95%置信区间0.26-0.66；p=0.0002）。

The incidenceof adverse events was similar across the three groups.

三个组别中不良事件的发生率相似。

Neither HSK31858 dose was associated with an increased incidenceof adverse events of special interest (eg, hyperkeratosis, gingivitis, or life-threatening infections).

HSK31858的剂量与特殊关注不良事件（例如，角化过度、牙龈炎或危及生命的感染）的发生率增加无关。

interpretation

Both HSK31858 doses improved clinical outcomes in adults with bronchiectasis, significantly reducing the exacerbation frequency compared with placebo.

两种剂量的HSK31858均改善了支气管扩张症成人的临床结果，与安慰剂相比显著降低了急性加重的频率。

The development of new drugs targeted at amelioration of neutrophilic inflammation (eg, via suppression of DPP-1 activity) might lead to new options for hindering the progression of bronchiectasis.

针对中性粒细胞炎症改善的新药开发（例如，通过抑制DPP-1活性）可能会为延缓支气管扩张症进展带来新的治疗选择。

funding

Haisco.

海斯科。