Safety and efficacy of astegolimab for COPD with frequent exacerbations regardless of baseline blood eosinophil counts (ALIENTO and ARNASA): randomised, double-blind, placebo-controlled, phase 2b and 3 trials.

We aimed to assess the efficacy and safety of astegolimab, an anti-ST2 human IgG2 monoclonal antibody, which were evaluated in two COPD pivotal trials.

我们旨在评估抗-ST2人IgG2单克隆抗体astegolimab的疗效和安全性，该药物在两项COPD关键试验中进行了评估。

Methods

In two randomised, double-blind, placebo-controlledtrials (phase 2b ALIENTO and phase 3 ARNASA), current or former smokers with COPD and a history of frequent exacerbations, irrespective of baseline blood eosinophils, were randomly assigned (1:1:1; stratification by smoking status and region) to receive subcutaneous astegolimab 476 mg every 2 weeks, every 4 weeks, or placebo, alongside optimised inhaled maintenance therapy over 52 weeks.

在两项随机、双盲、安慰剂对照试验（2b期的ALIENTO试验和3期的ARNASA试验）中，无论基线血液嗜酸性粒细胞水平如何，患有COPD且有频繁加重病史的当前或前吸烟者被随机分配（1:1:1；按吸烟状态和地区分层）接受每两周一次或每四周一次皮下注射476 mg的astegolimab，或安慰剂，同时接受优化的吸入维持治疗，为期52周。

The primary endpoint (analysed in participants receiving one or more doses) was annualised rate of moderate or severe exacerbations.

主要终点（分析对象为接受一次或多次剂量的参与者）是中度或重度加重的年化率。

Missing data were considered similar to data from other participants in the same treatment group with the same baseline characteristics.

缺失数据被视为与同一治疗组中具有相同基线特征的其他参与者的数据相似。

The trials were registered with ClinicalTrials.gov (NCT05037929 and NCT05595642).

这些试验已在ClinicalTrials.gov上注册（NCT05037929和NCT05595642）。

Results

In ALIENTO, 1301 participants (astegolimab every 2 weeks, n=433; astegolimab every 4 weeks, n=437; and placebo, n=431) initiated treatment between Oct 5, 2021, and Feb 19, 2024.

在ALIENTO研究中，1301名参与者（每两周一次astegolimab，n=433；每四周一次astegolimab，n=437；安慰剂，n=431）在2021年10月5日至2024年2月19日期间开始治疗。

In ARNASA, 1375 participants (astegolimab every 2 weeks, n=459; astegolimab every 4 weeks, n=459; and placebo, n=457) initiated treatment between Jan 9, 2023, and June 25, 2024.

在ARNASA研究中，1375名参与者（每两周一次astegolimab，n=459；每四周一次astegolimab，n=459；安慰剂，n=457）在2023年1月9日至2024年6月25日期间开始治疗。

Adjusted rate ratios versus placebo for the primary endpoint were 0·85 (95% CI 0·72-1·00; p=0·049) for astegolimab every 2 weeks and 0·93 (0·79-1·10; p=0·38) for astegolimab every 4 weeks in ALIENTO, and 0·85 (0·72-1·01; p=0·068) for astegolimab every 2 weeks and 0·82 (0·70-0·98; p=0·024) for astegolimab every 4 weeks in ARNASA.

在ALIENTO研究中，与安慰剂相比，每两周一次的astegolimab调整后的率比为0.85（95%置信区间0.72-1.00；p=0.049），每四周一次的astegolimab调整后的率比为0.93（0.79-1.10；p=0.38）；在ARNASA研究中，每两周一次的astegolimab调整后的率比为0.85（0.72-1.01；p=0.068），每四周一次的astegolimab调整后的率比为0.82（0.70-0.98；p=0.024）。

Adverse events were balanced between treatments, with most participants experiencing one or more adverse events (1093 [84·0%] of 1301 participants in ALIENTO and 1176 [85·5%] of 1375 in ARNASA).

不良事件在各治疗组之间分布均衡，大多数参与者经历了一个或多个不良事件（ALIENTO研究中1301名参与者中有1093名[84.0%]，ARNASA研究中1375名参与者中有1176名[85.5%]）。

The most common non-COPD adverse eventwas nasopharyngitis in ALIENTO and upper respiratory chest infection in ARNASA.

在ALIENTO中，最常见的非COPD不良事件是鼻咽炎，在ARNASA中则是上呼吸道胸腔感染。

Deaths occurred in 40 (3·1%) of 1301 participants in ALIENTO and in 44 (3·2%) of 1375 participants in ARNASA, and were balanced across treatment groups.

ALIENTO的1301名参与者中有40人（3.1%）死亡，ARNASA的1375名参与者中有44人（3.2%）死亡，且两组治疗之间的死亡率是均衡的。

Across both trials, a total of three deaths (0·1%) were considered to be related to treatment by investigators.

在这两项试验中，研究者认为共有三例死亡（0.1%）与治疗相关。

interpretation

In ALIENTO, astegolimab every 2 weeks was associated with a lower annual rate of exacerbations versus placebo in patients with COPD and a history of frequent exacerbations.

在ALIENTO研究中，每两周使用一次astegolimab与安慰剂相比，在有频繁加重病史的慢性阻塞性肺疾病（COPD）患者中，每年加重率较低。

In ARNASA, these findings did not meet statistical significance.

在ARNASA研究中，这些发现未达到统计学意义。

Together, these findings suggest a role for targeting the ST2/IL-33 pathway to reduce the frequency of COPD exacerbations in patients with limited treatment options.

综合这些发现，提示针对ST2/IL-33通路可能有助于减少有限治疗选择的慢性阻塞性肺疾病（COPD）患者急性加重的频率。

funding

Genentech, a member of the Roche Group, and F Hoffmann-La Roche.

罗氏集团成员基因泰克公司以及F霍夫曼-拉罗奇公司。