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Dr. Burrill B. Crohn Professor of Medicine
Chief of the Dr. Henry D. Janowitz Division of Gastroenterology
Mount Sinai Hospital
Chief, Division of Gastroenterology
Mount Sinai Health System
Director, Digestive Disease Institute
Icahn School of Medicine at Mount Sinai
New York, New York
Bruce E. Sands, MD, MS, has disclosed that he has received consulting fees from Abivax, Arena, AstraZeneca, Bacainn, Boehringer Ingelheim, Boston Pharmaceuticals, Celltrion, Genentech, Gilead Sciences, GlaxoSmithKline Index, Inotrem, Ironwood, Janssen, Kallyope, Lilly, Pfizer, Prometheus Biosciences, Prometheus Therapeutics, Surrozen, Takeda, Target RWE, USWM Enterprises, and Viela Bio and funds for research support from Theravance.
Most medications we have used to treat inflammatory bowel disease (IBD) work by suppressing the immune system, and we pay a price for that in terms of infections and, sometimes, cancers. That can make treatment daunting for some patients. Moreover, currently available therapies are not completely effective and do not work for everyone. So we are always looking for novel treatments with mechanisms of action that can diversify how we target the inflammation of IBD.
To this end, I was excited by select studies on emerging therapeutic approaches presented at the 2021 virtual Crohn’s & Colitis Congress. Although these are early‑phase trials, they arose from our improved mechanistic understanding of IBD, and they target completely novel areas of potential therapy.
Interleukin (IL)-2 is a prime T‑cell growth factor that—when administered in high doses—stimulates the immune system. In fact, high-dose IL-2 therapy is currently approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma, where stimulating T-cell proliferation leads to therapeutic benefit. However, when administered at lower doses, IL-2 does not stimulate the entire population of T-cells but selectively promotes expansion of the regulatory T-cell subset (T-regs). These cells are important regulators of the immune response by putting the brakes on T-cell activation and, subsequently, inflammatory responses.
At the 2021 virtual congress, Allegretti and colleagues presented results from a phase Ib/IIa study of low‑dose IL-2 for the treatment of moderate to severe ulcerative colitis. The rationale is that rather than directly suppressing the effector cells of inflammation, IL-2 will promote the development of T-regs that can downregulate inflammation naturally and restore balance and homeostasis to the gut.
In the dose-escalation phase, the investigators found that 14 of 16 patients who received varying doses of low-dose IL-2 had T-reg expansion. In addition, they observed some promising clinical results in terms of symptomatic responses and changes in inflammatory markers.
There were no serious adverse events in this small study population, but 1 patient developed a dose-limiting rash (a documented adverse event of IL-2 therapy). Larger studies will be needed, but hopefully the lower dose level will result in fewer adverse events than those seen in oncology, where higher doses are used.
This study provides a useful proof of principle, and I am excited by the prospect of promoting homeostasis of the immune system rather than just suppressing the immune system. Although low-dose IL-2 may or may not continue to show promise in further clinical trials, there may be other ways to promote the development of T-regs that warrant investigation for the treatment of IBD.
Genetic and physiologic studies have identified a role for endoplasmic reticulum (ER) stress in the pathogenesis of IBD. ER stress leads to protein misfolding, which subsequently promotes ileal or colonic inflammation. Tauroursodeoxycholic acid (TUDCA) is a naturally occurring bile salt that has been shown to reduce signs of ER stress in preclinical models of IBD.
In a translational phase I study, Huang and colleagues investigated the safety and efficacy of TUDCA in 12 patients with symptomatic ulcerative colitis. At the 2021 virtual congress, their abstract presented results from 9 patients who received 1 dosing regimen (2000 mg TID) of TUDCA for 6 weeks. Encouragingly, they observed a clinical response and mucosal healing in more than one half of the participants, as well as changes in bile acid profiles, as would be expected with a bile salt. There were no serious adverse events, which is consistent with expectations for this naturally occurring compound. Although this is a small phase I study, these results are impressive and promising.
Certainly, I would not recommend trying TUDCA in your practice today, but these data further highlight the important concept that there is more to treating IBD than suppressing the immune system.
The 2021 virtual Crohn’s & Colitis Congress was a great meeting for the advancement of the field of IBD, bringing important science with clinical applications forward, showing us what may be forthcoming in the treatment of our patients. Although the studies I highlighted were early-phase, shorter‑term, proof-of-concept studies, I am optimistic about the future of IBD treatment. I look forward to longer‑term data from these and other emerging therapies, and my hope is that someday these will be part of combination therapy, which is of intense interest in the field. Rather than focusing on immune suppression alone, we may want to suppress the immune system with one drug, replenish T-regs with another, and improve ER stress with yet a third drug. The hope is that if we can approach IBD from a number of angles, as is done in cancer, we will achieve higher rates of efficacy and improve safety.
Which emerging therapies presented at the 2021 virtual Crohn’s & Colitis Congress do you see as the most promising? Answer the polling question and join the discussion by posting a comment.