Looking Ahead: How Will We Manage IBD in 2030?

Geert D’Haens, from the Inflammatory Bowel Disease Centre, reviewed some changes in clinical endpoints that are used IBD research. Endoscopy and histology endpoints are relatively recent editions to clinical trial protocols, with mucosal healing as a clinically relevant endpoint that matters to patients. He described a disconnect between drug approval trials to differentiate an active agent from placebo for a short period of time (usually 12 weeks), and patient treatment goals, which are life-long. In ulcerative colitis (UC), the Mayo score combines symptoms and endoscopy endpoints; these are usually co-primary endpoints in trials in Crohn’s disease (CD). The CDAI is used in Crohn’s disease as a clinical endpoint of remission. With centralized endoscopy reading and now the use of AI, newer endpoints include the UC Endoscopic Index of Severity (UCEIS), the Simple Endoscopic Score for CD (SES-CD), and the Endoscopic ulcer Activity Score for Evaluating CD (EASE-CD). Clinical trials may be shifting to the use of video capsule endoscopy to investigate the entire small bowel and monitor response to treatment, although intestinal ultrasound (IUS) may soon replace endoscopy as a safer, simpler, lower-cost option that provides results in real time with the same sensitivity. In addition, IBD trials are incorporating patient-reported outcomes (PROs) for symptoms that affect quality of life. The Symptoms and Impacts Questionnaires (SIQ-CD and SIQ-UC) not only ask about symptoms but also how the symptoms affect daily function. The outcome that patients want most is medication-free remission, which may one day be possible with CAR-T cell therapies. New trials are designed to treat to target (e.g., VERDICT trial in UC) and incorporate markers of inflammation severity and fibrosis (e.g., bowel wall thickness, mucosal wall enlargement with IUS in the VECTORS study of CD) to assess transmural health.

Vipul Jairath, MBChB, DPhil, from Western University, discussed the optimization of IBD clinical trial designs to generate evidence to inform clinical practice. Recruitment for IBD trials is challenging, with patients less interested in joining trials with complicated protocols and a high chance of being randomized to placebo. IBD trials are incorporating Bayesian methods using historical placebo data and asymmetrical randomization to reduce the likelihood of placebo assignment. Washout periods are being shortened or eliminated to mimic what is done in real-world clinical practice. 

While registration trials are placebo controlled, the goal in IBD research should be superiority trials that compare one or more active agents (e.g., VARSITY trial); these trials can answer clinically relevant questions (e.g., Which drug is best? Which order is best?) and will change practice. Non-inferiority trials may be sufficient for secondary endpoints. 

More trials are needed in subsets of patients that are not typically included in trials (e.g., perianal CD, ostomy, pouchitis) with inclusive recruitment of diverse populations to make findings as relevant and generalizable as possible. Pragmatic trials that are integrated into routine care may be highly relevant and efficient, but also introduce more confounders with less stringent inclusion and exclusion criteria (e.g., QUOTIENT trial). Patient-reported outcomes (PROs) are also important to include in IBD trials; CONSTRUCT was a pragmatic UC trial with a primary endpoint of “quality-adjusted survival,” or survival weighted by the Crohn’s and Colitis Questionnaire score. 

Bruce E. Sands, MD, from Icahn School of Medicine at Mount Sinai, reviewed some novel therapies and therapeutic strategies on the horizon, including early effective therapy, new targets, rational combination therapies, and precision medicine. In the absence of curative therapy, a predictive marker of therapeutic response is critically needed for the field. New agents include TL1A inhibitors (tulisokibart, duvakitug, and afimkibart) that reduce inflammation and fibrosis. Others are the JAK1 inhibitors (upadacitinib, filgotinib, tofacitinib), TYK2 inhibitors (zasocitinib), an IL-6 trans-signaling blocker (olamkicept), and anti-IL-7R monoclonal antibodies (lusvertikimab). The VEGA study kicked off combination advanced therapy with golimumab and gusekulmab, with many combination trials now ongoing. SKYLINE is a platform study in UC that will test multiple combination therapies against the component monotherapies. Bispecific antibodies are also being developed to target multiple IBD pathways; the DUET trials are examining a bi-specific antibody that targets both TNF-alpha and IL-23, compared to golimumab and guselkumab in UC and CD.

Oral therapies are also being investigated for UC, including the integrin inhibitor MORF-047 in the EMERALD study and the anti-IL-23 antibody icotrokinra in ANTHEM-UC. Apremilast, oral mufemilast, and PALI-2108 are new small molecule PDE-4 inhibitors for UC. Obefazimod is in Phase 3 trials in UC (ABTECT 1 and 2) and is thought to increase the expression of miRNA124 to normalize the immune response. Other therapeutics are being targeted to specific indications; ontunisertib targets the TGF-beta pathway to reduce transmural inflammation and fibrostenosis in CD (STENOVA trial). Cell-based therapies such as anti-CD19 CAR-T cells deplete B cells and may be beneficial in highly refractory UC.

Robert Hirten, from Icahn School of Medicine at Mount Sinai, introduced options for real-time Monitoring in IBD, to simplify surveillance without doing endoscopy. He noted that IBD and response to treatment are continuous processes, but their measurement is episodic, with sampling of isolated snapshots of disease activity. Ideally, the field needs to move to predicting flares based on signals of inflammation and autonomic dysfunction, rather than reacting to flares after the fact. Blood glucose, blood pressure and cardiac rhythms are all measured continuously as markers of disease. The same could be achieved in IBD, with measurement of changes in the autonomic nervous system and physiological signals to dampen and control inflammation. Wearable technology may be able to identify these signals to predict flares and monitor treatment response, but more studies are necessary to demonstrate the benefits and cost effectiveness of early detection.

Kenneth Croitoru, MDCM, from University of Toronto, discussed the possibility of primary prevention of IBD, or preventing the disease before it occurs. A 2022 study estimated that lifestyle modification could have prevented up to 44% of IBD cases; however, adherence in the absence of disease is historically low. Understanding the causes of IBD is the key to prevention. While there is a genetic component, environmental exposures or some initiating insult it thought to set in motion a series of molecular and cellular events that gradually build up damage until symptoms are felt. This model assumes a pre-clinical period when triggers can be targeted to prevent disease. To better understand the origins of IBD, the GEM project in Canada recruited 5000 first-degree relatives of high-risk individuals, collected baseline samples, and then contacted participants every 6 months to ask if had developed IBD. The study started in 2008; 24 participants have developed UC and 123 developed CD. The study found that fecal calprotectin was associated with future risk of disease within 2.6 years. Mannitose level as a measure of the gut barrier, antimicrobial antibodies, and gut microbiome patterns also predicted IBD, independent of other biomarkers of disease. The GEM-IRS (Integrated risk score) combines fecal calprotectin, lactulose mannitol ratio, and specific gut microbiome species to predict the risk of developing CD. Other proteomic and metabolomic markers are under investigation, and diet, fiber intake, and ultraprocessed food may be contributors. The next step is to validate predictive tools in larger populations and demonstrate causality to identify potential prevention targets. The HALT-CD study is being conducted in first-degree relatives with high calprotectin who are randomized to placebo or vedolizumab to determine whether early biologic intervention can prevent disease development. The PIONIR trial is examining a dietary intervention to prevent IBD among healthy people in GEM with elevated calprotectin.