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.

项目概要 肥胖显然对哮喘有害，但我们缺乏治疗独特的肥胖哮喘表型的工具。 共病肥胖影响超过 40% 的成人哮喘患者1，并增加哮喘的严重程度、症状和症状 恶化，同时降低常规疗法的疗效。2-5 我们的长期目标是 开发针对肥胖哮喘表型气道炎症的新疗法。我们的总体目标是 转化我们的临床前和初步临床发现的下一步是确定 胰高血糖素样肽 1 受体激动剂 (GLP-1RA) 对哮喘控制以及气道和脂肪炎症的影响 患有肥胖性哮喘的成人。我们的中心假设是 GLP-1RA 改善哮喘控制并减少 肥胖性哮喘对呼吸道的直接影响导致气道炎症。生成证明- 支持 GLP-1RA 在肥胖哮喘表型和测试中的明确 3 期临床试验的概念数据 根据我们的中心假设，我们提出以下具体目标：1) 确定 GLP-1RA 对 哮喘控制和评估肥胖哮喘的耐受性，2) 确定 GLP- 的组织特异性影响 1RA 对肥胖哮喘患者气道炎症和脂肪的影响。在一项为期 12 周的双盲随机试验中， 在肥胖相关、有症状的成年受试者中口服索马鲁肽 7 mg 每日一次的安慰剂对照试验 对于没有 DMII 的哮喘，我们将测试索马鲁肽改善哮喘控制（目标 1a）的假设， 耐受（目标 1b）并减少 2 型和非 2 型气道炎症，与体重减轻无关（目标 2）。 主要临床结果将是相对于 ACQ-7 基线的变化。主要的机械结果将是 血清骨膜素相对于基线的变化。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的反应，这些标记物将用于 预先指定的亚组分析。基线时的皮下腹部脂肪和呼吸道样本 将使用 RNA 测序对治疗 5 周和 12 周进行比较，以检验 GLP-1RA 的假设 减少炎症以恢复呼吸道的稳态，与脂肪组织的变化相反 肥胖性哮喘。该提案有助于收集必要的临床、机制和耐受性 数据为 GLP-1RA 治疗哮喘的最终 III 期临床试验的设计提供信息。因此它支持 一种新型哮喘治疗方法的快速发展代表了治疗方法的范式转变 通过靶向调节上游的代谢途径对哮喘进行治疗干预 跨多个器官系统的炎症可能会改变疾病，并最终减少糖皮质激素的使用。

项目成果

Utility of nasal mucus inflammatory profile as a biomarker of nasal polyp regrowth in aspirin-exacerbated respiratory disease.

鼻粘液炎症特征作为阿司匹林加剧的呼吸道疾病中鼻息肉再生的生物标志物的效用。

• 发表时间: 2022-06
• 作者: Corey, Kristen B;Turner, Justin H;Chowdhury, Naweed I;Chandra, Rakesh K;Li, Ping;Wu, Pingsheng;Cahill, Katherine N
• 通讯作者: Cahill, Katherine N

Utility of Hypoglycemic Agents to Treat Asthma with Comorbid Obesity.

降血糖药治疗哮喘合并肥胖症的效用。

• 发表时间: 2023-03
• 影响因子: 3
• 作者: Ge, Derek;Foer, Dinah;Cahill, Katherine N
• 通讯作者: Cahill, Katherine N

Immunologic effects of aspirin desensitization and high-dose aspirin therapy in aspirin-exacerbated respiratory disease.

阿司匹林脱敏和大剂量阿司匹林治疗对阿司匹林恶化的呼吸道疾病的免疫学作用。

• 发表时间: 2021
• 作者: Cahill; Katherine N
• 通讯作者: Katherine N

Aspirin-Exacerbated Respiratory Disease: A Unique Case of Drug Hypersensitivity.

阿司匹林加剧呼吸系统疾病：药物过敏的独特案例。

• 发表时间: 2022-05
• 影响因子: 2.6
• 作者: Corey, Kristen B;Cahill, Katherine N
• 通讯作者: Cahill, Katherine N

Persistent use of dupilumab in adults with asthma or chronic rhinosinusitis with nasal polyps.

在患有哮喘或伴有鼻息肉的慢性鼻窦炎的成人中持续使用 dupilumab。

• 发表时间: 2024-03
• 作者: Corey, Kristen B;Moore, Ryan;Zuckerman, Autumn D;Littlejohn, Monica;Cahill, Katherine N
• 通讯作者: Cahill, Katherine N