Editorial: biologics in inflammatory bowel disease—time for direct comparisons

Inflammatory bowel disease (IBD) is entering an era in which multiple biologics with novel mechanisms of action are now or will soon be available.¹ As the number of targeted biologic agents increases, comparative effectiveness studies will be essential to help clinicians determine how to best position these medications. Meanwhile, in an effort to compare the efficacy of biologic treatments in the absence of head-to-head data, the literature has started to overflow with network meta-analyses which allow indirect comparisons between drugs.^2–4

In a recent issue of Alimentary Pharmacology and Therapeutics, Cholapranee et al. performed a systematic review and network meta-analysis examining differences in mucosal healing rates during induction and maintenance therapy between available biologic agents using data from clinical trials.⁵ This is an important question since mucosal healing, which should more accurately be termed endoscopic healing, is becoming the preferred treatment target in IBD. The authors found that anti-tumor necrosis factor (anti-TNF) biologics were more likely to achieve mucosal healing than placebo in Crohn’s disease (CD) and both anti-TNFs and vedolizumab had higher rates of mucosal healing compared to placebo in ulcerative colitis (UC). Next, pairwise comparisons between different biologic agents suggested some possible differences in efficacy. In CD, there were insufficient data to compare induction therapies but there was a trend toward superiority of combination therapy (infliximab and azathioprine) over azathioprine monotherapy for mucosal healing in maintenance. Combining data from UC trials, infliximab and combination therapy appeared to be superior to adalimumab with a trend toward higher efficacy compared to golimumab and vedolizumab at inducing mucosal healing during induction. No biologic was clearly superior for maintenance of mucosal healing in UC, although there was a trend toward vedolizumab outperforming adalimumab and golimumab.

The authors should be commended for conducting a thorough literature review, providing a systematic overview of the mucosal healing efficacy of biologics, and applying a rigorous network meta-analysis methodology to provide a measure of comparative effectiveness. However, the results should be interpreted with caution and how these data should impact clinical practice is still unclear. First, the amount of available data on mucosal healing from clinical trials is limited. Second, as the authors note, we need to be mindful of heterogeneity in the study populations with earlier trials with infliximab including more biologic naive patients which may bias results. In addition, issues around pharmacokinetics may influence comparisons across drugs, which may not have been optimally dosed in the original clinical trial. This may be particularly applicable for adalimumab in UC for which there is an ongoing trial investigating a higher dose regimen for induction of remission (NCT02065622). Further, although efforts have been made for a consensus definition of mucosal healing, the optimal definition remains to be determined and validated in prospective studies.^6,7 Last, the optimal time-point to measure mucosal healing for biologics is also unclear, as the time to achieve mucosal healing likely may vary depending on a medication’s mode of delivery or mechanism of action.

Interestingly, this study also highlights the overall modest rate of mucosal healing that we are able to achieve with our current biologic therapies. For example, the pooled rates for mucosal healing in induction and maintenance in CD were 29% and 28%, respectively. Pooled mucosal healing rates in UC were 45% for induction trials and 33% in maintenance. There is a significant gap to be closed in order to get more patients to what we believe is our best therapeutic endpoint. This will likely require significant advances in therapeutic strategies including new therapy combinations, early effective intervention, and precision medicine approaches for selecting the right drug for the right patient.

To conclude, although network meta-analyses offer some insight into comparative effectiveness of agents, ultimately direct head-to-head trials are needed to change and guide clinical practice. Along this line, the results of two ongoing studies in UC, one directly comparing adalimumab to vedolizumab and another etrolizumab to infliximab, are eagerly awaited (NCT02497469 and NCT02136069). The time for direct comparison studies is now.