Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA.
The Clinical Research Center LLC, St Louis, MI, USA.
Lancet Respir Med. 2016 Oct;4(10):781-796. doi: 10.1016/S2213-2600(16)30265-X. Epub 2016 Sep 5.
In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication.
Adult patients with uncontrolled asthma, pre-bronchodilator FEV 40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061.
1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34-0·69], p<0·0001) and in the 125 mg dose group (RR 0·70 [0·51-0·95], p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 [95% CI 0·54-1·01], p=0·0609; 125 mg: RR 0·74 [0·54-1·02], p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group.
Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out.
F Hoffmann-La Roche.
在 2 期临床试验中，抗白细胞介素-13 单克隆抗体 lebrikizumab 降低了未控制的哮喘患者的恶化率并改善了 FEV，特别是在 2 型生物标志物（例如，骨桥蛋白或血嗜酸性粒细胞）浓度较高的患者中。我们进行了重复的 3 期研究，以评估 lebrikizumab 在吸入皮质激素和至少一种二线控制药物治疗后仍未控制的哮喘患者中的疗效和安全性。
患有未控制的哮喘、预支气管扩张剂 FEV 为预测值的 40-80%以及稳定背景治疗的成年患者，通过交互式语音网络应答系统随机分配（1:1:1），接受 lebrikizumab 37.5mg 或 125mg，或安慰剂皮下注射，每 4 周一次。随机分组采用筛选血清骨桥蛋白浓度、过去 12 个月内哮喘恶化史、基线哮喘药物和国家分层。主要疗效终点是生物标志物高患者（骨桥蛋白≥50ng/ml 或血嗜酸性粒细胞≥300 个/μl）在 52 周内的哮喘恶化率，采用泊松回归模型进行分析，该模型采用皮尔逊 χ校正过度分散，包括治疗组、研究前 12 个月内哮喘恶化次数、基线哮喘药物、地理区域、筛选骨桥蛋白浓度和血嗜酸性粒细胞计数等因素。这两项试验均在 ClinicalTrials.gov 上注册，LAVOLTA I，编号 NCT01867125，LAVOLTA II，编号 NCT01868061。
LAVOLTA I 中有 1081 名患者接受治疗，LAVOLTA II 中有 1067 名患者接受治疗。在 52 周内，lebrikizumab 降低了生物标志物高患者的 37.5mg 剂量组（RR 0.49 [95%CI 0.34-0.69]，p<0.0001）和 125mg 剂量组（RR 0.70 [0.51-0.95]，p=0.0232）的恶化率，与安慰剂相比。在 LAVOLTA II 中，两种剂量组的生物标志物高患者的恶化率也低于安慰剂组（37.5mg：RR 0.74 [95%CI 0.54-1.01]，p=0.0609；125mg：RR 0.74 [0.54-1.02]，p=0.0626）。两项研究合并后， lebrikizumab 组（1432 名患者中有 1125 名，79%）和安慰剂组（716 名患者中有 576 名，80%）患者发生治疗后出现不良事件（TEAE）的比例、严重不良事件（8%[115 名患者]，lebrikizumab 组；9%[65 名患者]，安慰剂组）和导致研究药物停药的不良事件（3%[49 名患者]，lebrikizumab 组；4%[31 名患者]，安慰剂组）相似。在安慰剂对照期间报告了以下严重不良事件：一例再生障碍性贫血和五例 lebrikizumab 治疗患者与嗜酸性粒细胞浓度升高相关的严重不良事件，以及安慰剂组的一例嗜酸性肺炎。
在生物标志物高的患者中， lebrikizumab 并未一致显示出对哮喘恶化的显著减少。然而，它阻断了白细胞介素-13，这一点从对白细胞介素-13 相关的药效学生物标志物的影响中可以看出，并且不能排除临床相关的变化。
F Hoffmann-La Roche。
