Select animal models of colitis and their value in predicting clinical efficacy of biological therapies in ulcerative colitis

Introduction: Advancing new therapies from discovery to development usually requires proof-of-concept in animal models to justify the costs of continuing the program. While animal models are useful for understanding the mechanism of action (MOA) of a target, limitations of many published colitis models restrict their value to predict clinical efficacy. Areas covered: The authors focused their literature search on published studies of chronic animal models used to evaluate the pre-clinical efficacy of therapeutic molecules subsequently evaluated in clinical trials for UC. The UC therapies evaluated were anti-alpha 4 beta 7, anti-IL13, anti-IL12p40, and anti-IL23p19. The models of chronic colitis evaluating these molecules were: mdra1a-/-, chronic dextran sulfate sodium (DSS), chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS), and the T cell transfer model. Expert opinion: While some models provide insight into target MOA in UC, none is consistently superior in predicting efficacy. Evaluation of multiple models, with varying mechanisms of colitis induction, is needed to understand potential drug efficacy. Additional models of greater complexity, reflecting the disease chronicity/heterogeneity seen in humans, are needed. Although helpful in prioritizing targets, animal models alone will likely not improve outcomes of UC clinical trials. Transformational changes to clinical efficacy will likely only occur when precision medicine approaches are employed.

Automated summary

This article discusses chronic animal models used to evaluate the pre-clinical efficacy of therapeutic molecules for UC, finding that none of the models are consistently superior in predicting efficacy. Evaluation of multiple models with varying colitis induction mechanisms is necessary to understand potential drug efficacy, and the development of more complex models reflecting human chronicity/heterogeneity is needed. Furthermore, transformational changes in clinical efficacy are likely to occur only when precision medicine approaches are employed.