Genentech, Inc., South San Francisco, CA, USA.
University of Leicester and Glenfield Hospital, Leicester, UK.
Clin Exp Allergy. 2020 Dec;50(12):1342-1351. doi: 10.1111/cea.13731. Epub 2020 Oct 4.
The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling.
To report safety and efficacy results from enrolled participants with available data from CLAVIER.
We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm of basement membrane (cells/mm ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling.
There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies.
CONCLUSIONS & CLINICAL RELEVANCE: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling.
NCT02099656.
抗白细胞介素 13（IL-13）单克隆抗体 lebrikizumab 可改善中重度未控制哮喘患者的肺功能，但尚不清楚其对气道炎症和重塑的影响。CLAVIER 旨在评估 lebrikizumab 对嗜酸性粒细胞炎症和重塑的影响。
报告 CLAVIER 入组患者的安全性和有效性结果。
我们对未控制哮喘患者进行支气管镜检查，在 lebrikizumab（n=31）或安慰剂（n=33）随机双盲治疗 12 周前后进行。主要终点为气道基底膜下嗜酸性粒细胞每毫米上皮下细胞数（细胞/mm）的相对变化。预先设定的次要和探索性终点包括 IL-13 相关生物标志物的变化和气道重塑的测量。
基线时组织嗜酸性粒细胞存在不平衡，且治疗组之间的变异性较大。lebrikizumab 治疗后，平均调整后上皮下嗜酸性粒细胞/mm 无明显变化（95%CI，-82.5%，97.5%）。与先前观察到的一样，lebrikizumab 治疗后 FEV 增加。此外，lebrikizumab 治疗后基底膜下胶原厚度减少 21.5%（95%CI，-32.9%，-10.2%），支气管组织中呼出气一氧化氮分数、CCL26 和 SERPINB2 mRNA 表达也降低。Lebrikizumab 耐受性良好，安全性与其他 lebrikizumab 哮喘研究一致。
我们没有观察到 lebrikizumab 治疗与组织嗜酸性粒细胞数量减少相关。然而，在预先设定的探索性分析中，lebrikizumab 治疗与基底膜下纤维化程度降低相关，纤维化是气道重塑的特征，同时也改善了肺功能，并降低了支气管组织中关键的药效学生物标志物。这些结果强调了白细胞介素 13 在气道病理生物学中的重要性，并表明中和白细胞介素 13 可能减少哮喘气道重塑。
NCT02099656。
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