Christenson Stephanie A, Hanania Nicola A, Bhatt Surya P, Bafadhel Mona, Rabe Klaus F, Vogelmeier Claus F, Papi Alberto, Singh Dave, Laws Elizabeth, Dakin Paula, Bansal Ashish, Lu Xin, Bauer Deborah, Maloney Jennifer, Robinson Lacey B, Abdulai Raolat M
Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, University of California San Francisco, San Francisco, CA, USA.
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA.
Lancet Respir Med. 2025 Aug;13(8):687-697. doi: 10.1016/S2213-2600(25)00044-X. Epub 2025 Jul 9.
A raised blood eosinophil count (≥300 cells per μL), a marker of type 2 inflammation, can identify patients with chronic obstructive pulmonary disease (COPD) with higher exacerbation risk. Dupilumab reduced exacerbations in patients with COPD and type 2 inflammation in the BOREAS trial. In this post-hoc analysis, we evaluated the predictive value and longitudinal changes in type 2 inflammatory biomarkers in patients with COPD and type 2 inflammation from the BOREAS trial who received dupilumab treatment.
BOREAS, a phase 3, multicentre, double-blind, randomised trial was conducted at 275 sites in 24 countries and included patients with COPD and type 2 inflammation (screening blood eosinophils ≥300 cells per μL). Patients were randomly assigned (1:1) to receive 300 mg of dupilumab every 2 weeks for 52 weeks or matching placebo. Randomisation was stratified by country and inhaled corticosteroid dose at baseline. This post-hoc analysis assessed blood eosinophil counts, fractional exhaled nitric oxide (FeNO), serum eotaxin-3, total plasma immunoglobulin E (IgE), and serum pulmonary and activation-regulated chemokine (PARC) concentrations in the safety population. The study was registered at ClinicalTrials.gov, NCT03930732 and is complete.
BOREAS was conducted between April 15, 2019, and May 2, 2023, and included 939 patients with COPD and type 2 inflammation. 468 patients were randomly assigned to receive 300 mg of dupilumab every 2 weeks for 52 weeks and 471 were randomly assigned to receive matching placebo. 319 (34%) participants were female and 620 (66%) were male. 657 (70%) were former smokers and 282 (30%) were current smokers. At week 52, greater median percentage reductions were observed in dupilumab versus placebo for most biomarkers (total IgE: -22·5% [IQR -30·4 to -16·5] vs -0·9% [-6·5 to 4·8]; FeNO: -28·6% [-57·1 to 0] vs -6·9% [-35·7 to 25·0]; eotaxin-3: -8·8% [-15·6 to -2·9] vs -0·4% [-5·6 to 5·0]; and PARC: -14·4% [-29·2 to 2·1] vs -0·8% [-13·9 to 17·2]). Reductions were similar across treatment groups by blood eosinophil counts. Exacerbation risk overall was reduced, with a greater magnitude of reduction in those with higher baseline blood eosinophil count (p=0·0056) and baseline FeNO (p=0·043).
Patients with COPD and type 2 inflammation who were given dupilumab showed reduced type 2 inflammatory biomarkers, with elevated blood eosinophil count and FeNO predicting greater treatment response. These findings support biomarker-driven treatment strategies to optimise therapy.
Sanofi and Regeneron Pharmaceuticals.
血液嗜酸性粒细胞计数升高（≥300个/μL）是2型炎症的标志物，可识别慢性阻塞性肺疾病（COPD）急性加重风险较高的患者。在BOREAS试验中，度普利尤单抗可减少COPD合并2型炎症患者的急性加重发作。在这项事后分析中，我们评估了来自BOREAS试验中接受度普利尤单抗治疗的COPD合并2型炎症患者中2型炎症生物标志物的预测价值和纵向变化。
BOREAS是一项3期、多中心、双盲、随机试验，在24个国家的275个地点进行，纳入了COPD合并2型炎症的患者（筛查时血液嗜酸性粒细胞≥300个/μL）。患者被随机分配（1:1）接受每2周300mg度普利尤单抗治疗52周或匹配的安慰剂。随机分组按国家和基线吸入糖皮质激素剂量进行分层。这项事后分析评估了安全人群中的血液嗜酸性粒细胞计数、呼出一氧化氮分数（FeNO）、血清嗜酸性粒细胞趋化因子-3、总血浆免疫球蛋白E（IgE）和血清肺和活化调节趋化因子（PARC）浓度。该研究已在ClinicalTrials.gov注册，编号为NCT03930732，现已完成。
BOREAS试验于2019年4月15日至2023年5月2日进行，纳入了939例COPD合并2型炎症患者。468例患者被随机分配接受每2周300mg度普利尤单抗治疗52周，471例患者被随机分配接受匹配的安慰剂。319名（34%）参与者为女性，620名（66%）为男性。657名（70%）为既往吸烟者，282名（30%）为当前吸烟者。在第52周时，度普利尤单抗组与安慰剂组相比，大多数生物标志物的中位数降低百分比更大（总IgE：-22.5%[IQR -30.4至-16.5]对-0.9%[-6.5至4.8]；FeNO：-28.6%[-57.1至0]对-6.9%[-35.7至25.0]；嗜酸性粒细胞趋化因子-3：-8.8%[-15.6至-2.9]对-0.4%[-5.6至5.0]；PARC：-14.4%[-29.2至2.1]对-0.8%[-13.9至17.2]）。各治疗组血液嗜酸性粒细胞计数的降低情况相似。总体急性加重风险降低，基线血液嗜酸性粒细胞计数较高者（p = 0.0056）和基线FeNO较高者（p = 0.043）降低幅度更大。
接受度普利尤单抗治疗的COPD合并2型炎症患者的2型炎症生物标志物降低，血液嗜酸性粒细胞计数和FeNO升高预示着更好的治疗反应。这些发现支持基于生物标志物的治疗策略以优化治疗。
赛诺菲和再生元制药公司。
