학술논문
Integrated systems modeling of severe asthma: Exploration of IL‐33/ST2 antagonism
Document Type
Report
Author
Source
CPT: Pharmacometrics & Systems Pharmacology. September 2022, Vol. 11 Issue 9, p1268, 10 p.
Subject
Language
English
Abstract
Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? The IL‐33/ST2 pathway contributes to activation of immune cells and may contribute to asthma exacerbation. Phase II trials of anti‐IL‐33 [...]
: Asthma is a complex, heterogeneous disease with a high unmet medical need, despite therapies targeting a multitude of pathways. The ability to quantitatively integrate preclinical and clinical data on these pathways could aid in the development and testing of novel targets and therapeutics. In this work, we develop a computational model of asthma biology, including key cell types and mediators, and create a virtual population capturing clinical heterogeneity. The simulated responses to therapies targeting IL‐13, IL‐4Rα, IL‐5, IgE, and TSLP demonstrate agreement with clinical endpoints and biomarkers of type 2 (T2) inflammation, including blood eosinophils, FEV1, IgE, and FeNO. We use the model to explore the potential benefit of targeting the IL‐33 pathway with anti‐IL‐33 and anti‐ST2. Model predictions are compared with data on blood eosinophils, FeNO, and FEV1 from recent anti‐IL‐33 and anti‐ST2 trials and used to interpret trial results based on pathway biology and pharmacology. Results of sensitivity analyses on the contributions of IL‐33 to the predicted biomarker changes suggest that anti‐ST2 therapy reduces circulating blood eosinophil levels primarily through its impact on eosinophil progenitor maturation and IL‐5‐dependent survival, and induces changes in FeNO and FEV1 through its effect on immune cells involved in T2 cytokine production. Finally, we also investigate the impact of ST2 genetics on the conferred benefit of anti‐ST2. The model includes representation of a wide array of biologic mechanisms and interventions that will provide mechanistic insight and support clinical program design for a wide range of novel therapies during drug development.
: Asthma is a complex, heterogeneous disease with a high unmet medical need, despite therapies targeting a multitude of pathways. The ability to quantitatively integrate preclinical and clinical data on these pathways could aid in the development and testing of novel targets and therapeutics. In this work, we develop a computational model of asthma biology, including key cell types and mediators, and create a virtual population capturing clinical heterogeneity. The simulated responses to therapies targeting IL‐13, IL‐4Rα, IL‐5, IgE, and TSLP demonstrate agreement with clinical endpoints and biomarkers of type 2 (T2) inflammation, including blood eosinophils, FEV1, IgE, and FeNO. We use the model to explore the potential benefit of targeting the IL‐33 pathway with anti‐IL‐33 and anti‐ST2. Model predictions are compared with data on blood eosinophils, FeNO, and FEV1 from recent anti‐IL‐33 and anti‐ST2 trials and used to interpret trial results based on pathway biology and pharmacology. Results of sensitivity analyses on the contributions of IL‐33 to the predicted biomarker changes suggest that anti‐ST2 therapy reduces circulating blood eosinophil levels primarily through its impact on eosinophil progenitor maturation and IL‐5‐dependent survival, and induces changes in FeNO and FEV1 through its effect on immune cells involved in T2 cytokine production. Finally, we also investigate the impact of ST2 genetics on the conferred benefit of anti‐ST2. The model includes representation of a wide array of biologic mechanisms and interventions that will provide mechanistic insight and support clinical program design for a wide range of novel therapies during drug development.