Anti-fibrotics in inflammatory bowel diseases: Challenges and successes

Stricture formation leading to obstruction in Crohn's disease (CD) remains one of the largest unmet needs in the field of inflammatory bowel diseases (IBD). Despite this need no selective anti-stricture drug has been approved for use in CD patients. This contrasts with other fibrotic diseases, such as in the lung, liver or kidney, where multiple drug development programs crossed the starting line and two anti-fibrotics are now being approved for pulmonary fibrosis. Strictures are composed of a mix of inflammation, excessive deposition of extracellular matrix (ECM) and smooth muscle hyperplasia, likely all ultimately being responsible for the luminal narrowing driving patient symptoms. Our understanding of the pathogenesis of stricturing CD has evolved and indicates a multifactorial process involving immune and non-immune cells and their soluble mediators. This understanding has rendered target pathways for anti-stricture drug development. Significant progress was made in creating consensus definitions and tools to enable clinical trials with two clinical development programs having been conceived to date. In this chapter, we discuss stricture pathogenesis with a focus on the pathways being tested in clinical trials, and clinical trial endpoints developed for this indication.