K. Gadkar, S. Sukumaran, M. Rodrigo, C. Stokes, H. Scheerens, S. Ramanujan; Genentech, South San Francisco, CA
BACKGROUND: Asthma is a chronic inflammatory disease of the airways involving numerous underlying immunological and stromal pathways. Various treatments in development target activities or proteins in these pathways, and show differential impact on clinical outcomes and pathway biomarkers. Although specific molecular pathways are being characterized more thoroughly, the understanding of the linkage between the different pathways as well as the functional clinical outcomes is still very limited.
METHODS: We have developed a mechanism-based systems model representing different cellular and soluble contributors to asthma, including (1) innate immune, adaptive immune, and airway resident cells (2) soluble proteins such as IL5, IL13, IL4, and IgE and (3) other measurements such as FeNO and FEV1. Mechanistic pathways in the model were identified based on in vitro and in vivo literature, and parameters were calibrated based on clinical data. Measurements from a total of 50 clinical studies ranging from large randomized controlled trials to small observational studies were methodically catalogued into a data-repository.
RESULTS: The model was calibrated to and was found to successfully describe the clinical measurements for different patient severities and for interventions such as anti-IgE, anti-IL5, and anti-IL13.
CONCLUSION: The model will be useful to elucidate biological pathways underlying observed effects of the different interventions as well as to explore and predict the impact of additional interventional strategies for which little to no clinical data is available.