1 University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Am J Respir Crit Care Med. 2013 Dec 1;188(11):1294-302. doi: 10.1164/rccm.201212-2318OC.
IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment.
To determine efficacy and safety of brodalumab, a human anti-IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids.
Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation.
Demographics and baseline characteristics were generally balanced among groups (n = 302; n = 226 brodalumab). For the overall study population, no treatment differences were observed. Nine prespecified subgroups were examined without corrections for multiple testing. In only the high-reversibility subgroup (post-bronchodilator FEV1 improvement ≥ 20%; n = 112) was an ACQ change with nominal significance noted; ACQ responses were nominally significant in the 210-mg group (estimated treatment difference, 0.53) but not significant in the higher 280-mg group (estimated treatment difference, 0.38). Adverse events, generally balanced among groups, were most commonly asthma, upper respiratory tract infection, and injection site reaction.
Inhibition of IL-17 receptor A did not produce a treatment effect in subjects with asthma. The results of the high-reversibility subgroup analysis are of uncertain significance, requiring further study of brodalumab in this asthma subpopulation. Clinical trial registered with www.clinicaltrials.gov (NCT01199289).
IL-17 信号转导被认为与哮喘的发生和持续有关。靶向细胞因子阻断 IL-17 受体信号可能有益于哮喘的治疗。
评估布罗达卢单抗（一种人源抗 IL-17 受体 A 单克隆抗体）在接受常规吸入性皮质类固醇治疗但哮喘控制仍不理想的中重度哮喘患者中的疗效和安全性。
302 例患者被随机分配至布罗达卢单抗（140、210 或 280mg）或安慰剂组。主要终点为从基线到第 12 周时哮喘控制问卷（ACQ）评分的变化。次要终点包括 FEV1、症状评分和无症状天数。进行了预先设定的亚组分析，以确定潜在的反应亚组。分析包括接受了至少一剂研究药物的随机化受试者，采用末次观测值结转（LOCF）进行估算。
在各组（n=302；n=226 例布罗达卢单抗）中，一般人群的人口统计学和基线特征均平衡。在整个研究人群中，未观察到治疗差异。在未进行多次检验校正的情况下，对 9 个预先设定的亚组进行了检查。仅在高可逆性亚组（支气管扩张剂后 FEV1 改善≥20%；n=112）中观察到 ACQ 变化具有名义显著性；在 210mg 组中，ACQ 反应具有显著的名义差异（估计治疗差异，0.53），但在更高的 280mg 组中无显著差异（估计治疗差异，0.38）。各组之间不良反应大致平衡，最常见的是哮喘、上呼吸道感染和注射部位反应。
在哮喘患者中，抑制 IL-17 受体 A 并未产生治疗效果。高可逆性亚组分析的结果意义不确定，需要进一步研究布罗达卢单抗在该哮喘亚群中的作用。该临床试验已在 www.clinicaltrials.gov 注册（NCT01199289）。
