The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment)

INTRODUCTION The expanding therapeutic armamentarium available for inflammatory bowel disease (IBD) as well as multiple compounds in clinical development inevitably raises questions as to their impact on patient outcomes at the dawn of 2022. We must be cautious in making direct efficacy comparisons between clinical trials conducted today vs 20 years ago; patients in clinical trials now are generally more refractory to treat, with multiple prior drug exposures, longer disease duration and subject to more stringent trial endpoints. Notwithstanding the aforementioned caveats, it is a reasonable assumption that we have not observed transformational efficacy with the advent of newer agents over the last 10 years. Most advanced treatments report clinical remission rates at 1 year ranging between 30% and 50%, suggesting we may have reached a therapeutic ceiling through use of single agents. Multiple pathways drive the immunemediated inflammatory process and agents effective for luminal disease may not be effective for extraintestinal manifestations or concomitant immunemediated disease (IMID), necessitating the use of additional agents. 6 Furthermore, using cumulative surgical resection rates as a surrogate for bowel damage, some studies report that these rates are similar in the prebiological versus postbiological era. Several different inflammatory pathways orchestrate the development and progression of IBD and other IMIDs, and the existence of more than one cytokine pattern is one explanation of why we may have reached a therapeutic ceiling. The concept of targeting multiplecytokines which act on shared disease pathways among IMID is well described by the reduction of entheseal inflammation in patients with IBD and concomitant psoriatic arthritis receiving the interleukin12 and interleukin23 inhibitor ustekinumab. Furthermore, Janus kinase (JAK) inhibitors, such as tofacitinib, targeting a wide range of cytokine hubs are effective in reducing the deregulated trafficking of immune effectors involving both the joints and the gut. With this in mind, the concept of advanced combination treatment (ACT) based on the use of at least two biological agents, or a biologic and a small molecule drug simultaneously, may be a promising strategy in patients with refractory IBD, in those patients at high risk of developing complications, or in patients with a concomitant uncontrolled IMID. This article will focus on the available literature on combination of advanced therapies and discuss current concepts, practical recommendations and future directions for patients with IBD.