Glucagon-Like Peptide-1 Receptor Agonist Treatment in Adult, Obesity-Related, Symptomatic Asthma

胰高血糖素样肽 1 受体激动剂治疗成人肥胖相关症状性哮喘

• 批准号: 10609049
• 负责人: Gordon R Bernard
• 金额: $ 158.37万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609049
• 关键词: Abdomen; Address; Adipose tissue; Adolescent; Adult; Adult asthma; Adverse event; Agonist; Allergens; Anti-Inflammatory Agents; Asthma; Biological Markers; Biopsy; Body Weight decreased; Body mass index; Clinical; Clinical Data; Collection; Data; Development; Disease; Double-Blind Method; Effectiveness; Exhalation; FDA approved; Formulation; GLP-I receptor; Glucocorticoids; Goals; Homeostasis; Hormones; Inflammasome; Inflammation; Inhalation; Insulin Resistance; Interleukin-13; Interleukin-5; Interleukins; Link; Lung; Lymphoid Cell; Measures; Mediating; Mediator; Metabolic Pathway; Modeling; Mucous body substance; Mus; Nasal Epithelium; Nitric Oxide; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Oral; Outcome; Pathway Analysis; Pathway interactions; Peptides; Phase III Clinical Trials; Phenotype; Polypharmacy; Population; Prediabetes syndrome; Quality of life; Questionnaires; Randomized Controlled Clinical Trials; Respiratory System; Role; Safety; Sampling; Serum; Severities; Specific qualifier value; Sputum; Subgroup; Symptoms; System; TSLP gene; Testing; Therapeutic; Therapeutic Intervention; Thinness; Tissues; Translating; Viral; adult obesity; airway epithelium; airway inflammation; airway remodeling; asthma exacerbation; asthmatic; asthmatic patient; bariatric surgery; biomarker performance; body system; cohort; comorbidity; conventional therapy; design; differential expression; efficacy evaluation; eosinophil; glucagon-like peptide 1; granulocyte; health care service utilization; heart function; improved; insight; insulin sensitivity; methacholine; multiple chronic conditions; neuroprotection; neutrophil; novel; novel therapeutics; obese person; obesity-associated asthma; periostin; pre-clinical; predicting response; primary outcome; programs; pulmonary function; randomized placebo controlled trial; secondary outcome; small molecule; subcutaneous; tool; transcriptome sequencing

Project Summary Obesity is clearly detrimental in asthma, yet we lack tools to treat the unique obese asthma phenotype. Comorbid obesity impacts >40% of adult asthmatics1 and increases asthma severity, symptoms and exacerbations while simultaneously reducing the efficacy of conventional therapies.2-5 Our long-term goal is to develop novel treatments for airway inflammation in the obese asthma phenotype. Our overall objective, which is the next step in translating our preclinical and preliminary clinical findings, is to determine the impact of glucagon-like peptide-1 receptor agonists (GLP-1RA) on asthma control and airway and adipose inflammation in adults with obese asthma. Our central hypothesis is that GLP-1RA improve asthma control and reduce airway inflammation due to direct effects on the respiratory tract in obese asthma. To generate the proof-of- concept data to support definitive phase 3 clinical trials of GLP-1RA in the obese asthma phenotype and test our central hypothesis, we propose the following specific aims: 1) Determine the efficacy of GLP-1RA on asthma control and assess tolerability in obese asthma and 2) Determine the tissue-specific impact of GLP- 1RA on inflammation in the airway and adipose in obese asthma. In a 12-week double-blind, randomized, placebo-controlled trial of oral semaglutide 7 mg once daily in adult subjects with obesity-related, symptomatic asthma without DMII, we will test the hypotheses that semaglutide improves asthma control (aim 1a), is tolerated (aim 1b) and reduces type-2 and non-type 2 airway inflammation independent of weight loss (aim 2). The primary clinical outcome will be change from baseline in ACQ-7. The primary mechanistic outcome will be change from baseline in serum periostin. Because insulin resistance is variable in obesity and baseline blood eosinophil counts are often predictive of response to asthma therapeutics, these markers will be used for prespecified subgroup analyses. Subcutaneous abdominal adipose and respiratory tract samples at baseline and 5 and 12 weeks of therapy will be compared using RNA sequencing to test the hypothesis that GLP-1RA reduce inflammation to restore homeostasis in the respiratory tract opposite to changes in adipose tissue in obese asthma. This proposal facilitates the collection of the necessary clinical, mechanistic, and tolerability data to inform the design of a definitive phase III clinical trial of a GLP-1RA in asthma. It thereby supports the rapid development of a novel therapeutic class for asthma and represents a paradigm shift in the approach to therapeutic intervention in asthma through the targeting of a metabolic pathway which regulates upstream inflammation across multiple organ systems, may be disease modifying, and ultimately glucocorticoid sparing.

项目摘要 肥胖显然对哮喘有害，但我们缺乏治疗独特肥胖哮喘表型的工具。 合并症肥胖症> 40％的成人哮喘患者1，并增加哮喘的严重程度，症状和 加重，同时降低常规疗法的功效。2-5我们的长期目标是 开发肥胖哮喘表型中气道炎症的新型治疗方法。我们的整体目标 是翻译我们的临床前和初步临床发现的下一步是确定 哮喘控制和气道和脂肪炎症的胰高血糖素样肽-1受体激动剂（GLP-1RA） 在肥胖哮喘的成年人中。我们的中心假设是GLP-1RA改善了哮喘控制并减少 气道炎症是由于对肥胖哮喘中呼吸道的直接影响引起的。生成 - 概念数据以支持肥胖哮喘表型中GLP-1RA的最终阶段3期临床试验和测试 我们的中心假设，我们提出以下特定目的：1）确定GLP-1RA的功效 哮喘控制和评估肥胖哮喘的耐受性和2）确定GLP的组织特异性影响 1RA在气道中发炎，肥胖哮喘中的脂肪。在12周的双盲，随机的 在患有肥胖相关的成年受试者中，每天一次口服半卢比的安慰剂对照试验 没有DMII的哮喘，我们将测试Semaglutide改善哮喘控制（AIM 1A）的假设 耐受性（AIM 1B）并减少2型和非型气道炎症，而与体重减轻无关（AIM 2）。 主要的临床结果将是ACQ-7中的基线变化。主要的机械结果将是 从血清骨膜素中的基线变化。因为肥胖和基线血液中的胰岛素抵抗是可变的 嗜酸性粒细胞计数通常可以预测对哮喘治疗剂的反应，这些标记将用于 预先指定的亚组分析。基线时皮下腹部脂肪和呼吸道样品 将使用RNA测序比较5周和12周的治疗，以检验GLP-1RA的假设 减少炎症以恢复与脂肪组织变化相反的呼吸道中的稳态 肥胖哮喘。该建议促进了必要的临床，机械和耐受性的收集 数据以告知哮喘中GLP-1RA的确定性III期临床试验的设计。因此，它支持 快速发展哮喘的新型治疗类别，代表了该方法的范式转变 通过对上游调节的代谢途径的靶向对哮喘的治疗干预 多个器官系统之间的炎症可能是疾病改变，最终是糖皮质激素的损害。