Dupilumab for chronic obstructive pulmonary disease with type 2 inflammation: a pooled analysis of two phase 3, randomised, double-blind, placebo-controlled trials.

We aimed to characterise the efficacy and safety of dupilumab in patients with COPD and type 2 inflammation.

我们的目标是描述 dupilumab 在患有 COPD 和 2 型炎症的患者中的疗效和安全性。

Methods

For this pooled analysis, we pooled and analysed data from all patients in the intention-to-treatpopulations of the phase 3, randomised, double-blind, placebo-controlledBOREAS and NOTUS trials, which comprised 206 hospitals and clinics in BOREAS and 217 in NOTUS in 38 countries across Europe, Asia, North America, South America, Africa, and Australia.

在这项汇总分析中，我们汇总并分析了来自意向治疗人群的数据，这些数据来自第三阶段、随机、双盲、安慰剂对照的BOREAS和NOTUS试验，这些试验包括了BOREAS的206家医院和诊所以及NOTUS的217家，遍布欧洲、亚洲、北美、南美、非洲和澳大利亚的38个国家。

Eligible patients were current or former smokers with 10 pack-years or more of smoking history, were aged 40-85 years, had physician-diagnosed COPD for at least 12 months before randomisation, had a post-bronchodilator FEV1/forced vital capacity (FVC) ratio of less than 0·7, had a post-bronchodilator percentage predicted FEV1 of 30-70%, had documented evidence of two moderate or one severe exacerbations of COPD in the previous year (at least one exacerbation had to have occurred on triple therapy), and had blood eosinophil counts 300 cells per μL or more during screening.

符合条件的患者是目前或以前的吸烟者，吸烟史至少有10包年，年龄在40-85岁之间，在随机分组前至少12个月被诊断为COPD，使用支气管扩张剂后FEV1/用力肺活量（FVC）比率小于0.7，使用支气管扩张剂后FEV1的预测百分比为30-70%，在过去的12个月中有两次中度或一次重度COPD加重的记录（至少一次加重必须在三联疗法下发生），并且在筛查期间血液嗜酸性粒细胞计数为300个细胞/μL或更多。

Patients had to have symptomatic COPD and a reported chronic productive cough for at least 3 months in the previous year.

患者必须有症状性慢性阻塞性肺疾病（COPD）和过去一年中至少3个月的慢性咳嗽伴有痰液分泌。

Key exclusion criteria were history of asthma, pulmonary disease other than COPD, or other diagnosed pulmonary or systemic disease associated with elevated blood eosinophil.

主要排除标准包括哮喘病史、除慢性阻塞性肺疾病（COPD）以外的肺部疾病或其他与血液嗜酸性粒细胞升高相关的肺部或系统性疾病。

In both trials, eligible patients were randomly assigned (1:1) via block randomisation with block size 4 to receive subcutaneous dupilumab 300 mg or matching placebo once every 2 weeks for 52 weeks, alongside established background therapy with inhaled corticosteroids, a long-acting β2-agonist, and a long-acting muscarinic antagonist.

在这两项试验中，符合条件的患者通过块随机化（1:1）被随机分配，每个块大小为4，接受每两周一次皮下注射300毫克度普利尤单抗或匹配安慰剂，为期52周，同时接受吸入皮质类固醇、长效β2激动剂和长效毒蕈碱拮抗剂的背景治疗。

The primary endpoint was the annualised rate of moderate or severe exacerbations over 52 weeks.

主要终点是52周内中度或重度急性发作的年化率。

Results

1874 patients were randomly assigned in BOREAS and NOTUS from May 9, 2019, to May 23, 2023; 938 (50·1%) were randomly assigned to the dupilumab groups and 936 (49·9%) were randomly assigned to the placebo groups.

从2019年5月9日至2023年5月23日，共有1874名患者在BOREAS和NOTUS研究中随机分配；其中938名（50.1%）被随机分配到dupilumab组，936名（49.9%）被随机分配到安慰剂组。

Mean age across both groups was 65·1 years (SD 8·2). 622 (33·2%) of 1874 patients were female and 1252 (66·8%) were male. 1628 (86·9%) patients were White, 719 (38·4%) were from Eastern Europe, and 1316 (70·2%) were former smokers.

两组患者的平均年龄为65.1岁（标准差8.2）。在1874名患者中，622名（33.2%）为女性，1252名（66.8%）为男性。1628名（86.9%）患者为白人，719名（38.4%）来自东欧，1316名（70.2%）为前吸烟者。

During the 52-week treatment period, 559 moderate or severe exacerbations were reported in 338 (36·0%) of 938 patients in the dupilumab group and 774 exacerbations were reported in 394 (42·1%) of 936 patients in the placebo group.

在52周的治疗期间，共有338名（36.0%）的938名患者在dupilumab组报告了559次中度或重度加重，而在安慰剂组的936名患者中有394名（42.1%）报告了774次加重。

There was a reduction in the annualised rate of moderate or severe exacerbations compared with placebo (annualised exacerbation rate 0·794 in the dupilumab group and 1·156 in the placebo group; incidencerate ratio 0·687, 95% CI 0·595-0·793; p<0·0001).

与安慰剂相比，中度或重度加重的年化率有所降低（dupilumab组的年化加重率为0.794，安慰剂组为1.156；发生率比为0.687，95%置信区间为0.595-0.793；p<0.0001）。

In the dupilumab group, the time to first severe exacerbation was longer than in the placebo group (0·611, 0·409-0·912; p=0·016).

在度普利尤单抗组中，首次严重发作的时间比安慰剂组更长（0·611，95% 置信区间0·409-0·912；p=0·016）。

However, there was no reduction in the annualised rate of severe exacerbations (annualised exacerbation rate 0·084 in the dupilumab group and 0·124 in the placebo group; 0·674, 0·438-1·037; p=0·073).

然而，严重发作的年化率并没有降低（度普利尤单抗组的年化发作率为0·084，安慰剂组为0·124；0·674，95% 置信区间0·438-1·037；p=0·073）。

Treatment-emergent adverse events, serious adverse events, adverse events that led to permanent treatment discontinuation, and adverse events that led to death were similar between the two groups.

两组间出现的治疗相关不良事件、严重不良事件、导致永久性治疗中断的不良事件以及导致死亡的不良事件相似。

interpretation

Dupilumab, as an add-on to standard triple therapy, reduced the annualised rate of moderate or severe exacerbations compared with placebo, highlighting its potential for personalised treatment approaches in patients with COPD with specific clinical endotypes.

作为标准三联疗法的附加治疗，杜普利尤单抗降低了与安慰剂相比的中度或重度加重的年化率，突显了其在具有特定临床表型的COPD患者个性化治疗方法中的潜力。

funding

Sanofi and Regeneron Pharmaceuticals.

赛诺菲和再生元制药公司。