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.

Narrative More than 40% of adults with asthma are obese which leads to increased asthma severity, symptom burden, healthcare utilization and reduced effectiveness of available therapies. This proposal builds on a preclinical and clinical program that indicates glucagon-like peptide-1 receptor agonists (GLP-1RA), FDA approved for the treatment of type II diabetes and obesity, will be efficacious in treating asthma. To validate the therapeutic potential of GLP-1RA in obese and non-obese asthmatics and to address the multimorbidity and polypharmacy plaguing the adult asthma population, we propose to conduct a randomized controlled clinical trial to test the hypothesis that GLP-1RA treatment improves asthma control and reduce airway inflammation.