PATINA - Precision Administration of Treatment in Neutrophilic severe Asthma

PATINA - 中性粒细胞性严重哮喘的精准治疗

• 批准号: 10454802
• 负责人: Elliot Israel
• 金额: $ 43.43万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454802
• 关键词: Adrenal Cortex Hormones; Adult asthma; Advisory Committees; Aftercare; Algorithms; Arachidonate 5-Lipoxygenase; Area; Asthma; Biochemical; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biology; C-reactive protein; CCL3 gene; CD4 Positive T Lymphocytes; Cells; Cellular biology; Chemotactic Factors; Childhood; Childhood Asthma; Clinical Research; Data; Eicosanoids; Environment; Exhalation; Futility; Future; Genetic Polymorphism; Genomics; IL6 gene; Imatinib; Immunobiology; Industry; Inflammation; Inflammatory; Insulin Resistance; Interleukin 6 Receptor; Interleukin-6; Intervention; Knowledge; Letters; Leukotriene B4; Lipoxygenase Inhibitors; Methodology; Morbidity - disease rate; Mus; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Placebos; Population; Production; Publishing; Recording of previous events; Request for Proposals; Research Design; Risk; Running; Seasons; Serum; Signal Transduction; Single-Blind Study; Specific qualifier value; Sputum; Stem Cell Factor; Target Populations; Testing; Therapeutic; Therapeutic Intervention; Translational Research; Tryptase; Urine; Work; arm; asthmatic; base; biomarker development; biomarker discovery; biomarker validation; candidate marker; cohort; cysteinyl-leukotriene; design; effective therapy; experience; falls; genomic RNA; improved; inhibitor; innovation; macrophage; mast cell; neutrophil; phenotypic biomarker; predictive marker; pulmonary function; recruit; responders and non-responders; response; response biomarker; targeted treatment; treatment arm; trial design; urinary

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.

项目概要 严重哮喘在哮喘相关发病率中所占比例过高。 现在有多种针对嗜酸性粒细胞或 2 型细胞的生物疗法可供使用 驱动性哮喘。然而，SARP 的数据表明，>60% 的患者患有严重哮喘 具有中性粒细胞表型 (SANP)，如诱导痰差异所定义。这些 患者发病率过高，目前尚无有效针对的治疗方法 中性粒细胞炎症。我们最近完成了一项研究，其中我们表明目标 使用伊马替尼（KIT 干细胞因子信号传导抑制剂）治疗肥大细胞最有效 具有中性粒细胞表型的患者。此外，我们发现血清类胰蛋白酶降低 可以识别最有可能对这种治疗产生反应的患者。此外，我们还证明了 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 炎症类二十烷酸）这些患者继续制造促炎类二十烷酸 和低促溶解类二十烷酸。我们发现持续升高表明了这一点 呼出气冷凝液中的 LTB4（一种有效的中性粒细胞化学引诱剂）。最后，IL-6 与非 2 型哮喘、胰岛素抵抗和 CD4+ 的 TH17 偏向有关 细胞。 IL6 受体多态性与哮喘风险相关，高 IL6 与哮喘风险相关 与肺功能下降和病情加重有关，即使在一组 严重哮喘患者。我们提出以下一组主要假设，并在每种情况下列出 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 (RM) 时的反应标记（括号中是我们的次要 RM），以及目标 干预（TI）。我们的假设是，在患有以下情况的受试者中：1) SANP 血清 IL6 (PM) 高， C反应蛋白（TH17细胞，胰岛素抵抗）（RM）的下降，将识别那些更有可能 抗IL6治疗（TI）后改善； 2) SANP 呼出 LTB4 (PM) 较高，呼出气体下降 LTB4（尿半胱氨酰白三烯）（RM）将识别那些更有可能通过 5- 脂氧合酶抑制剂 (5-LOi)（阻止促炎类二十烷酸的产生）； 3） 严重哮喘伴有痰中性粒细胞 (PM) 增加、血清类胰蛋白酶下降（痰 上清液类胰蛋白酶）（RM）将识别哮喘患者在接受治疗后更有可能改善 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 阈值可识别对目标药物有较高反应可能性的患者 治疗。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，这将为精确网络增添显着的力量。