Novel Therapies in Inflammatory Bowel Disease: An Evaluation of the Evidence

Abstract

The introduction of anti-tumor necrosis factor (anti-TNF) therapies for both Crohn’s disease (CD) and ulcerative colitis (UC) was a landmark in the management of these debilitating diseases. For a substantial proportion of patients, anti-TNF therapies have reduced relapse rates and allowed mucosal healing and, as a result, improved long-term outcomes. However, research into novel therapies for inflammatory bowel diseases (IBD) has been challenging and positive early trials have not always translated to proof of efficacy and safety in late-phase studies. As an alternative to targeting inflammation through cytokines (e.g., TNF), reducing the ability of lymphocytes to generate an inflammatory response is now a therapeutic reality with the availability of the integrin inhibitors. The “gut-selective” vedolizumab is now an established treatment option for UC and CD either before, or after, anti-TNF therapy. Other agents in development that target lymphocyte adhesion include novel anti-integrin and anti-mucosal vascular addressin cell adhesion molecule-1 (anti-MadCAM-1) agents, or target lymphocyte trafficking (e.g. anti-sphingosine 1-phosphate therapies). In addition however, there are novel ways of reducing inflammation by targeting downstream signaling (e.g., Janus kinase inhibitors), the use of antisense oligonucleotides to transforming growth factor-β, or by targeting novel cytokines such as interleukin-12/23 or interleukin-6 that have been implicated in the pathogenesis of IBD. The introduction of a novel formulation of budesonide (budesonide MMX) for UC illustrates that for patients with mild IBD there is also a need for novel therapies and agents in development, include other second-generation corticosteroids that are associated with reduced systemic delivery and approaches to enhance the mucosal barrier or alter the microbiota. Many new and effective therapies are in development for IBD and, if positive in late phase trials, are anticipated to be available within the next decade. Having a number of different agents available will allow the clinician to offer the best therapies for an individual patient. This will likely have huge implications not only for patients and clinicians, but for society as a whole.