Treatment of patients with the rare disease eosinophilic granulomatosis with polyangiitis (EGPA) with mepolizumab, a monoclonal antibody to interleukin-5 (IL-5) that reduces blood eosinophil counts, as an add-on therapy to glucocorticoid treatment, results in more accrued weeks in remission, reductions in glucocorticoid use and reductions in relapse rate. However, treatment response varies across a continuum. Therefore, to investigate if large genetic effects could identify responders, the impact of genetic variants on efficacy in EGPA subjects taking mepolizumab and glucocorticoids was assessed in this post hoc study. Using linear regression and a negative binomial model, genetic variant association with three endpoints (accrued duration of remission, average oral glucocorticoid dose, and frequency of relapse) was tested in 61 EGPA subjects dosed with mepolizumab from MIRRA, a phase 3 trial. Candidate gene and genome-wide approaches were used. The candidate gene analysis was designed to investigate drug target effects with eight gene regions selected that were focused on the intersection of the glucocorticoid response (steroidal response) and IL-5 response mechanisms and recognizing potential overlap between EGPA and severe eosinophilic asthma diseases for which mepolizumab is used. The sample size was insufficient to enable testing of rare variants for effects. No genetic variant from either the candidate gene analysis or the GWAS associated with any endpoint. Thresholds to declare significance were p < 0.0008 (candidate variant) and p < 2.5 × 10^–8 (genome-wide) analyses. Large genetic effects on mepolizumab-treatment response were not identified which could help differentiate responders from non-responders.

美泊珠单抗是一种减少白细胞介素5（IL-5）的单克隆抗体，可减少血液嗜酸性粒细胞计数，作为糖皮质激素治疗的附加疗法，可以治疗多血管炎（EGPA）罕见疾病嗜酸性粒细胞肉芽肿病（EGPA）在缓解方面，减少了糖皮质激素的使用并降低了复发率。但是，治疗反应在整个连续过程中有所不同。因此，为调查大的遗传效应是否能识别应答者，在这项事后研究中评估了遗传变异对服用美泊利珠单抗和糖皮质激素的EGPA受试者疗效的影响。使用线性回归和负二项式模型，遗传变异与三个终点（应计缓解时间，平均口服糖皮质激素剂量，和复发频率）在61位EGPA受试者中进行了测试，该受试者接受了来自MIRRA的美泊利单抗，这是一项3期试验。使用候选基因和全基因组方法。候选基因分析旨在研究药物靶点作用，其中选择了八个基因区域，这些区域专注于糖皮质激素应答（类固醇应答）和IL-5应答机制的相交部分，并识别了EGPA与严重的嗜酸性粒细胞性哮喘疾病（美泊珠单抗）之间存在潜在的重叠用来。样本数量不足以测试稀有变体的效果。候选基因分析或GWAS的任何终点均无遗传变异。声明重要性的阈值是 候选基因分析旨在研究药物靶点作用，其中选择了八个基因区域，这些区域专注于糖皮质激素应答（类固醇应答）和IL-5应答机制的相交部分，并识别了EGPA与严重的嗜酸性粒细胞性哮喘疾病（美泊珠单抗）之间存在潜在的重叠用来。样本数量不足以测试稀有变体的效果。候选基因分析或GWAS的任何终点均无遗传变异。声明重要性的阈值是 候选基因分析旨在研究药物靶点作用，其中选择了八个基因区域，这些区域专注于糖皮质激素应答（类固醇应答）和IL-5应答机制的相交部分，并识别了EGPA与严重的嗜酸性粒细胞性哮喘疾病（美泊珠单抗）之间存在潜在的重叠用来。样本数量不足以测试稀有变体的效果。候选基因分析或GWAS的任何终点均无遗传变异。声明重要性的阈值是p  <0.0008（候选变体）和p  <2.5×10 ^–8（全基因组范围）分析。未鉴定出对美泊利珠单抗治疗反应有较大的遗传效应，这可能有助于区分反应者和非反应者。