PATINA - Precision Administration of Treatment in Neutrophilic severe Asthma

项目摘要 重度哮喘占哮喘相关发病率的比例不成比例。 多种生物疗法现在变得可用，靶向嗜酸性粒细胞或2型- 驱动性哮喘然而，SARP的数据表明，>60%的患者患有严重哮喘， 具有嗜中性粒细胞表型（SANP），如通过诱导痰分化所定义的。这些 患者的发病率过高，目前还没有有效的治疗方法， 嗜酸性炎症。我们最近完成的一项研究表明， 肥大细胞与伊马替尼（一种KIT干细胞因子信号传导抑制剂）在 具有嗜酸性表型的患者。此外，我们发现血清类胰蛋白酶的降低 可以识别出最有可能对这种治疗产生反应的患者。此外，我们还表明， 在严重哮喘中，尽管积极的皮质类固醇治疗（通常减少 炎性类二十烷酸）这些患者继续产生促炎性类二十烷酸 和低亲解析类二十烷酸。这是由我们发现的持续升高， 呼出气冷凝液中的LTB 4（一种强效中性粒细胞化学引诱物）。最后，IL-6 与非2型哮喘、胰岛素抵抗和CD 4 + T细胞TH 17偏移有关。 细胞IL 6受体多态性与哮喘风险相关，高IL 6 与肺功能降低和加重增加相关，即使在 严重的哮喘我们假设以下一组主要假设，并在每种情况下，我们列出 严重哮喘表型及其表型标记物（PM），我们的主要候选者 2个月时的反应标志物（RM）（括号中为我们的次要RM），以及目标 干预（TI）。我们的假设是：1）血清IL-6（PM）水平高的SANP患者， C-反应蛋白（TH 17细胞，胰岛素抵抗）（RM）下降，将确定那些更有可能 抗IL 6治疗后改善（TI）; 2）SANP伴高呼出LTB 4（PM）， LTB 4（尿半胱氨酰白三烯）（RM）将确定那些更有可能改善5- 脂氧合酶抑制剂（5-L0 i）（其阻断促炎性类二十烷酸的产生）; 3） 重度哮喘伴痰中性粒细胞（PM）增加，血清类胰蛋白酶（痰 上清液类胰蛋白酶）（RM）将确定哮喘患者更有可能改善后， KIT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 我们的RM阈值，用于识别对靶向药物有较高反应可能性的患者 疗法我们拥有一支经验丰富的成人和儿童哮喘试验专家团队， 生物标志物的开发，这些生物标志物背后的机制，以及适应性试验设计 和综合分析，这将大大增强PRECISE网络的实力。

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.