(T-129) A prototype mechanistic systems pharmacology model of Type 2 interventions in eosinophilic esophagitis

Lu Huang, PhD – Associate Director, Bristol Myers Squibb; Peijin Zhang, MD, PhD – Director, Bristol Myers Squibb; Claudia de Oliveira, MD – Clinical Development Program Lead, Bristol Myers Squibb; Brian Schmidt, PhD – Executive Director, Bristol Myers Squibb; Panagiota Foteinou, PhD – Director, Bristol Myers Squibb

Objectives: Eosinophilic esophagitis (EoE) is a class of type 2 inflammatory diseases characterized by increased eosinophil infiltration in the esophagus. Studies on the immunological basis of these diseases have indicated the aberrant production of the prototypical type 2 cytokines (IL-4, IL-5, and IL-13) contributes to enhanced peripheral and tissue eosinophilia. Consequently, multiple therapies targeting selective factors within the multi-faceted type 2 inflammatory network are under investigation. Dupilumab has emerged as the first FDA-approved biologic targeting IL-4/IL-13 pathways for the treatment of multiple type 2-driven indications including EoE. To better understand the exposure-response relationship of Type 2 interventions in disease-targeted tissues, a human quantitative systems pharmacology (QSP) model has been developed.

Methods: The proposed QSP model consists of four (4) biological compartments: subcutaneous, peripheral, bone marrow, blood, and the esophagus. Type 2 interventions such as dupilumab, administered subcutaneously and biodistributed amongst all four compartments, exerts its pharmacodynamic activity by binding to IL-4Rα on eosinophils, fibroblasts, and epithelial cells; thereby inhibiting IL-4 signaling via the type I receptor (heterodimer of IL-4Rα and the common γ-chain) and both IL-4 and IL-13 signaling via the type II receptor (heterodimer of IL-4Rα and IL-13Rα1). Such molecular interactions are explicitly considered in the model and linked to downstream signaling and clinical (biomarker) responses such as Eotaxin, Periostin and TARC. The model also describes the critical role of IL-5 in the development of eosinophils in the bone marrow before recruitment into the esophagus. During the model development phase, published clinical datasets were used to parameterize and validate the model, including pharmacokinetic (PK) and pharmacodynamic (PD) data from dupilumab and other published interventional studies such as mepolizumab (anti-IL5) in EoE patients. Based on these studies, a virtual population [1] was developed to capture the clinical (PD) variability as seen in EoE (trial) patients and predict target engagement biomarkers.

Results: A mechanistic QSP model for Type 2-driven EoE has been built and calibrated to relevant clinical data. The model successfully recapitulates the clinical variability as observed in EoE patients treated with type 2 biologics. Further, this model was applied to understand the tissue exposure-response relationship – difficult to experimentally dissect – and crucial to optimizing new therapies.

Conclusions: A robust multiscale QSP strategy has been successfully implemented to capture key aspects of Type 2 inflammation in eosinophilic disorders. The proposed work is expected to help understand better the complex tissue PK/PD relationship of biological therapies in type-2 driven eosinophilic disorders including the complicated crosstalk between different cell types and disease biomarkers.

Citations: [1] Cheng et al. AAPS J. 2017;19(4):1002-1016. doi:10.1208/s12248-017-0100-x