PATINA - Precision Administration of Treatment in Neutrophilic severe Asthma

项目摘要 在与哮喘相关的发病率中，严重哮喘占不成比例的比例。 现在，针对嗜酸性粒细胞或2型的多种生物疗法正在变得可用。 引发哮喘。然而，SARP的数据显示，60%的患者患有严重哮喘 中性粒细胞表型(SANP)，根据诱导痰的差异来定义。这些 患者的发病率过高，目前还没有有效针对 中性粒细胞炎症。我们最近完成了一项研究，在该研究中，我们证明了 肥大细胞使用伊马替尼(KIT中干细胞因子信号转导的抑制剂)对 中性粒细胞表型的患者。此外，我们发现血清类胰蛋白酶的降低 可以确定最有可能对这种治疗有反应的患者。此外，我们已经证明了 在严重哮喘中，尽管进行了积极的皮质类固醇治疗(通常会减少 炎性二十烷类)这些患者继续精心设计促炎二十烷类化合物 和低分辨率的二十烷类化合物。这一点从我们发现的持续升高的 呼气冷凝液中的LTB4(一种有效的中性粒细胞趋化剂)。最后，IL-6 与非2型哮喘、胰岛素抵抗和CD4+TH17失衡有关 细胞。白介素6受体基因多态性与哮喘风险相关，高白介素6受体与哮喘风险相关。 与肺功能降低和加重有关，即使在一组 严重的哮喘患者。我们假设了以下一组基本假设，在每种情况下我们都列出了 重症哮喘表型及其表型标志物(S)(PM)，我们的首要候选 2个月的响应标记(RM)(在括号中为我们的二次RMS)，以及目标 干预(TI)。我们的假设是：在有以下情况的受试者中：1)SANP伴高血清IL-6(PM)， -C反应蛋白(TH17细胞，胰岛素抵抗)(RM)的下降将更有可能识别这些 在抗IL6治疗后改善(TI)；2)SANP合并高呼气LTB4(PM)，呼气量下降 尿半胱氨酰白三烯(Rm)将确定那些更有可能改善的5- 脂氧合酶抑制物(5-LOI)(可抑制促炎二十烷类物质的产生)；3) 严重哮喘伴痰中性粒细胞(PM)升高，血清类胰蛋白酶(痰)下降 上清液类胰酶(Rm)将确定哮喘患者在接受治疗后更有可能好转 试剂盒抑制剂(TI)。我们的适应性研究设计和治疗方法将使我们能够定义 识别对靶向应答可能性较高的患者的我们的RM的阈值 心理治疗。我们有一支经验丰富的成人和儿童哮喘试验团队，专家 生物标记物的发展，这些生物标记物背后的机制，以及适应性试验设计 和综合分析，这将为精确的网络增加显著的力量。

Project Summary Severe asthma accounts for a disproportionate share of the morbidity associated with asthma. Multiple biological therapies are now becoming available that target eosinophilic or Type 2- driven asthma. However, data from SARP indicate that >60% of patients have severe asthma with a neutrophilic phenotype (SANP), as defined by induced sputum differentials. These patients experience excess morbidity, and there are currently no therapies that effectively target neutrophilic inflammation. We recently completed a study wherein we showed that targeting mast cells with imatinib (an inhibitor of stem-cell factor signaling at KIT) was most effective in patients with a neutrophilic phenotype. Further, we found that reductions in serum tryptase could identify patients most likely to respond to this treatment. Additionally, we have shown that in severe asthma, despite aggressive corticosteroid therapy (which normally reduces inflammatory eicosanoids) these patients continue to elaborate pro-inflammatory eicosanoids and low-pro-resolving eicosanoids. This is indicated by our discovery of persistent elevation of LTB4 (which is a potent neutrophil chemoattractant) in exhaled breath condensate. Lastly, IL-6 has been associated with non-Type 2 asthma, insulin resistance, and TH17 skewing of CD4+ cells. IL6 receptor polymorphisms have been associated with asthma risk, and high IL6 has been associated with reduced lung function and increased exacerbations, even in a cohort of severe asthmatics. We posit the following set of primary hypotheses and in each case we list the severe asthma phenotype and its phenotype marker(s) (PM), our primary candidate response marker at 2 months (RM) (in parentheses our secondary RMs), and the targeted intervention (TI). Our hypotheses are that in subjects with : 1) SANP with high serum IL6 (PM), a fall in—C-reactive protein (TH17 cells, insulin resistance ) (RM), will identify those more likely to improve after anti-IL6 therapy (TI); 2) SANP with high exhaled LTB4 (PM), a fall in exhaled LTB4 (urinary cysteinyl leukotrienes) (RM) will identify those more likely to improve with a 5- lipoxygenase inhibitor (5-LOi) (that blocks production of pro-inflammatory eicosanoids); 3) Severe asthma with increased sputum neutrophils (PM), a fall in serum tryptase (sputum supernatant tryptase) (RM) will identify asthmatics more likely to improve after treatment with a KIT inhibitor (TI). Our adaptive study design and treatment approach will allow us to define the threshold values of our RM that identify patients with a higher likelihood of response to targeted therapy. We have a team of seasoned trialists in adult and pediatric asthma, experts in biomarker development, the mechanisms behind these biomarkers, and adaptive trial design and integrative analyses, which will add significant strength to a PRECISE network.