Background

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, which has shown increased expression in patients with chronic obstructive pulmonary disease (COPD) compared with healthy individuals. We aimed to assess the efficacy and safety of tezepelumab in patients with moderate to very severe COPD despite receiving triple inhaled therapy.

Methods

COURSE was a double-blind, randomised, placebo-controlled, phase 2a trial across 90 sites in ten countries in Asia, Europe, and North America. Eligible participants were aged 40–80 years, had moderate to very severe airflow limitation, were receiving triple inhaled maintenance therapy, and had at least two moderate to severe COPD exacerbations in the 12 months before enrolment. Patients were randomly assigned (1:1) to receive tezepelumab 420 mg or placebo subcutaneously every 4 weeks for up to 52 weeks. Randomisation was stratified by geographical region and by number of exacerbations in the 12 months before enrolment. Participants, investigators, site staff, and the study sponsor were masked to treatment assignment. The primary endpoint was the annualised rate of moderate or severe COPD exacerbations over 52 weeks. A prespecified subgroup analysis assessed the primary endpoint in patients grouped by baseline blood eosinophil counts (BECs). Efficacy and safety were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04039113 (completed).

Findings

Between July 30, 2019, and Oct 4, 2022, 333 patients (mean age 67·2 years [SD 7·0]; 145 [44%] female and 188 [56%] male; 293 [88%] White, 34 [10%] Asian, and four [1%] Black or African American) were randomly assigned and treated with tezepelumab (n=165) or placebo (n=168). The annualised rate of moderate or severe COPD exacerbations over 52 weeks was 1·75 for tezepelumab versus 2·11 for placebo (rate ratio 0·83 [90% CI 0·64–1·06]; p=0·10 [one-sided]; the primary endpoint was not met). In prespecified subgroup analyses, the annualised rate of moderate or severe COPD exacerbations over 52 weeks was 2·04 with tezepelumab versus 1·71 with placebo (rate ratio 1·19 [95% CI 0·75–1·90]) in patients with a baseline BEC of less than 150 cells per μL, 1·64 versus 2·47 (0·66 [0·42–1·04]) in patients with a baseline BEC of 150 cells per μL to less than 300 cells per μL, and 1·20 versus 2·24 (0·54 [0·25–1·15]) in patients with a baseline BEC of 300 cells per μL or higher. Adverse events occurred in 133 (81%) of 165 patients in the tezepelumab group and 126 (75%) of 168 patients in the placebo group. Serious adverse events occurred in 49 (30%) patients in the tezepelumab group and 50 (30%) patients in the placebo group. Five patients died while receiving study treatment: two in the tezepelumab group and three in the placebo group. No deaths were determined to be causally related to study treatment by investigator assessment.

Interpretation

A significant reduction was not observed in the annualised rate of moderate or severe COPD exacerbations with tezepelumab versus placebo. Further studies are required to evaluate the efficacy of tezepelumab in patients with moderate to very severe COPD, particularly in patients with a baseline BEC of 150 cells per μL or higher. Tezepelumab was well tolerated, with no safety concerns identified.

Funding

AstraZeneca and Amgen.

中文翻译：

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tezepelumab 与安慰剂在成人中度至极重度慢性阻塞性肺疾病 （COURSE） 中的疗效和安全性：一项随机、安慰剂对照、2a 期试验

 背景

Tezepelumab 是一种人单克隆抗体，可阻断胸腺基质淋巴细胞生成素，与健康个体相比，该蛋白在慢性阻塞性肺病 （COPD） 患者中的表达增加。我们旨在评估 tezepelumab 在接受三联吸入治疗后的中度至极重度 COPD 患者中的疗效和安全性。

 方法

COURSE 是一项双盲、随机、安慰剂对照的 2a 期试验，在亚洲、欧洲和北美 10 个国家/地区的 90 个地点进行。符合条件的参与者年龄在 40-80 岁之间，有中度至非常严重的气流受限，正在接受三重吸入维持治疗，并且在入组前 12 个月内至少有两次中度至重度 COPD 恶化。患者被随机分配 （1：1） 接受 tezepelumab 420 mg 或安慰剂皮下注射，每 4 周一次，持续长达 52 周。随机分组按地理区域和入组前 12 个月内的恶化次数进行分层。参与者、研究人员、现场工作人员和研究申办者对治疗分配不知情。主要终点是 52 周内中度或重度 COPD 恶化的年化率。预先指定的亚组分析评估了按基线血嗜酸性粒细胞计数 （BEC） 分组的患者的主要终点。对所有接受至少一剂研究药物的患者进行了疗效和安全性评估。此试用版已在 ClinicalTrials.gov， NCT04039113 注册（已完成）。

 发现

在 2019 年 7 月 30 日至 2022 年 10 月 4 日期间，333 名患者（平均年龄 67·2 岁 [SD 7·0];145 名 [44%] 女性和 188 名 [56%] 男性;293 名 [88%] 白人，34 名 [10%] 亚裔和 4 名 [1%] 黑人或非裔美国人）被随机分配并接受 tezepelumab （n=165） 或安慰剂 （n=168） 治疗。tezepelumab 在 52 周内中度或重度 COPD 恶化的年化发生率为 1·75，安慰剂组为 2·11（比率比 0·83 [90% CI 0·64–1·06];p=0·10 [单侧];未达到主要终点）。在预先设定的亚组分析中，基线 BEC 低于 150 个细胞/μL 的患者，tezepelumab 在 52 周内中度或重度 COPD 恶化的年化率为 2·04，而安慰剂组为 1·71（比率比 1·19 [95% CI 0·75–1·90]），基线 BEC 为 150 个细胞/μL 的患者为 1·64 vs 2·47 （0·66 [0·42–1·04]）在基线 BEC 为 300 个细胞/μL 或更高的患者中，每 μL 细胞数为 1·20 与 2·24 （0·54 [0·25–1·15]）。tezepelumab 组的 165 名患者中有 133 名 （81%） 发生不良事件，安慰剂组的 168 名患者中有 126 名 （75%） 发生不良事件。tezepelumab 组有 49 名 （30%） 患者发生严重不良事件，安慰剂组有 50 名 （30%） 患者发生严重不良事件。5 例患者在接受研究治疗期间死亡：2 例在 tezepelumab 组，3 例在安慰剂组。研究者评估未确定死亡与研究治疗有因果关系。

 解释

与安慰剂相比，tezepelumab 的中度或重度 COPD 恶化的年化发生率未观察到显著降低。需要进一步的研究来评估 tezepelumab 对中度至极重度 COPD 患者的疗效，尤其是基线 BEC 为 150 个细胞/μL 或更高的患者。Tezepelumab 耐受性良好，未发现安全性问题。

 资金

 阿斯利康和安进。