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ClinicalThought: New Data from ECCO 2022
ECCO 2022: New Agents and an Expanding Treatment Landscape for Crohn Disease and Ulcerative Colitis

Released: May 13, 2022

Expiration: May 12, 2023

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In the past year—nearly 25 years after the approval of the first anti–tumor necrosis factor (TNF) biologic therapy for inflammatory bowel disease (IBD)—we have seen an acceleration in the development and approval of both biologics and small-molecule inhibitors for patients with IBD. First was ozanimod, a small-molecule inhibitor approved less than 1 year ago for ulcerative colitis (UC). Next came upadacitinib, another small-molecule inhibitor approved for UC in March 2022. In addition, we anticipate a third new therapy—the first of the anti-P19/interleukin (IL)-23 biologics—to be approved soon for Crohn disease. With these new approvals, the treatment landscape of IBD becomes more complex, and healthcare professionals must choose among more drug classes while deciphering how to best position each agent for each patient. This growing complexity was reflected in new data presented at the 17th Congress of the European Crohn’s and Colitis Organisation (ECCO 2022).

The Ascendence of Small Molecules
In the earliest days of treatment for IBD, small molecules were the only option—classically, the 5-aminosalicylates, corticosteroids, and immunomodulators. Now, we are seeing a resurgence of small-molecule inhibitors and, along with them, a distinct set of pros and cons.

Among the pros of small molecules is the convenience of oral dosing. Most patients with IBD are in the prime of their lives (the median age at diagnosis is 30 years), so these are active people who largely prefer oral dosing of medications. It is my sense that receiving treatment parenterally also reminds some patients of how sick they have been with IBD.

Whereas biologics have exquisite specificity with clear adverse event profiles and few off-target effects, small molecules can have numerous potential off-target effects that must be discussed with patients. For example, tofacitinib, a JAK inhibitor, now carries a black box warning based on recent data showing an excess of mortality, major adverse cardiovascular events, cancers, and thrombosis compared with anti-TNF therapy in patients with rheumatoid arthritis aged 50 years or older with 1 or more cardiovascular risk factors. The FDA also has applied this warning to our patients with UC, thereby positioning tofacitinib as a later line of therapy, certainly after failure of biologics—chiefly anti-TNF therapy. Likewise, upadacitinib, another JAK inhibitor, is positioned after anti-TNF failure due to a black box warning for an increased risk of serious infections, malignancy, major adverse cardiovascular events, thrombosis, and death. This is unfortunate in light of new results from a Bayesian network meta-analysis presented at ECCO 2022 showing that upadacitinib is more efficacious than other UC therapies for inducing and maintaining clinical and endoscopic outcomes. Even ozanimod, an S1P receptor modulator with what I would consider a manageable safety profile, has risks that may include delayed cardiac conduction, hypertension, macular edema, and drug interactions. The safety of this class in pregnancy also is not known—an important issue for our young female patients with UC.

So, these small molecules will be woven into our armamentarium in different ways based on the risk–benefit profiles of each agent, including the labeling that is conferred.

New Biologics
At ECCO 2022, we saw new data on several anti-P19/IL-23 antibodies in IBD, including mirikizumab, risankizumab, and guselkumab. These antibodies all are raised against the P19 subunit of IL-23, so they are specific for IL-23. By contrast, ustekinumab blocks IL-12 and IL-23. Although it is counterintuitive that blocking 1 cytokine rather than 2 cytokines could be better, this does seem to be the case. 

With mirikizumab, we saw the first phase III data for an anti-P19 biologic in patients with UC. By Week 12, there were significant improvements in clinical remission vs placebo. Also, new phase III data suggest that risankizumab might be one of the safest and most effective biologics for patients with Crohn disease. Also in Crohn disease, guselkumab demonstrated durable safety and efficacy in the phase II GALAXI-I trial. Finally, we also saw interesting results from the phase IIa VEGA study combining guselkumab with an anti-TNF, golimumab, in patients with UC. The combination therapy showed an additive efficacy vs either agent as monotherapy with no new safety signals.

With new biologics, we are seeing the development of more effective agents that have improved safety profiles relative to TNF inhibition. How these compare with anti-TNFs, which are available as biosimilars and therefore cheaper, will need to be determined to better understand how we will be sequencing these agents in the future.

Conclusion
It is a very exciting time in the treatment of IBD—but rapid evolution brings complexity around clinical decisions. We will ultimately need more data and updated guidance on how to choose the right agents for the right individuals.

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