Highlights from DDW 2026
Chicago, USA, was the host city for this year’s Digestive Disease Week (DDW; 2–5 May), and approximately 13,000 attendees gathered to hear how the core theme, “Discovery at every turn”, would impact the future of gastrointestinal disease.
Kasia Moscicka, Head of Feasibility, Jessica Phillips, Associate Director of Feasibility, and Caroline Winand, Senior Site ID Specialist, formed just a small part of PSI’s delegation to this important congress. Read on for their insights, including takeaways on early treatment approaches throughout the gastroenterology therapeutic area, trial design to promote personalized medicine, and advances in imaging techniques, and how these developments will impact sponsors and the future of GI clinical trials.
You can read more about the developments this year in GI and IBD in our highlights from ECCO 2026.
Crohn’s disease (CD): Early treatment approaches, and navigating fibrostenotic Crohn’s disease (FSCD)
Optimizing outcomes through early treatment
The session, “The first five years: Optimizing early management of IBD” focused on one of the major shifts currently reshaping IBD care: The idea that the earliest phase of CD represents the most important therapeutic window.
Early intervention at diagnosis is important to fundamentally alter CD’s natural course before irreversible bowel damage develops. Data presented at DDW from a 5-year follow-up of patients with CD from the PROFILE trial [1] revealed the “top-down” approach, where advanced therapies are initiated early, proved more effective compared with the traditional “step-up” method. The “top-down” strategy is cost-effective, reduces surgeries and hospital admissions, decreases progression to structuring/penetrating disease, and “top-down” patients had reduced CRP compared with those on “step-up” regimens. Biologics, when started early, demonstrated fewer adverse effects and significant improvement in disease modification, highlighting the need to initiate effective treatment promptly.
Current therapies need to be used more effectively. In practice, most patients with CD are candidates for biologics, however undertreatment remains common, with advanced therapies introduced too late. At the same time, clinicians need to avoid overtreatment, particularly the excessive reliance on steroids.
Guidance from the American College of Gastroenterology (ACG) and American Gastroenterological Association (AGA) reflect this major paradigm change on how early CD is being evaluated and treated. While older guidance indicated the “step-up” approach, the ACG “suggests against requiring failure of conventional therapy before initiation of advanced therapy” [2], and the ACA suggests “upfront use of advanced therapy, compared with step-up therapy” [3].
For sponsors, the growing emphasis on early biologic intervention in CD may help reduce hesitancy around advanced therapies, and support trial recruitment in advanced therapy-naïve patients. Educational materials grounded in the ACG and AGA guidance could help providers frame earlier treatment (and clinical trial participation) as part of a proactive disease management strategy.
FSCD: Early identification, early treatment
Multiple presentations at DDW 2026 reflect growing recognition that fibrosis remains one of the major unmet needs in IBD.
- Lack of consensus on FSCD definitions: Identifying patients with true FSCD is challenging and requires functional assessment and cross-sectional imaging to identify strictures. Biomarkers, imaging approaches, and molecular profiling were discussed as future tools to distinguish inflammatory vs. fibrotic disease, and to help guide therapy selection
- Early disease control to prevent progression to fibrosis: Uncontrolled inflammation is a key driver of structuring disease. Early (and aggressive) biologic use, and treat-to-target strategies to handle inflammation could prevent irreversible structural bowel remodeling
- No approved anti-fibrotic therapies leaves patients with advanced strictures with surgery and endoscopic intervention as common outcomes
- Challenging trial design: The lack of a single, accepted endpoint (combined with difficulties measuring disease progression) mean that combinational endpoints remain the best option [4]
- Complex imaging needs: Continued investment in improving assessment of bowel fibrosis using advanced imaging (intestinal ultrasound and magnetic resonance enterography [MRE]) could help determine whether a structure may respond to therapy, or would require surgical intervention
With growing commercial interest in FSCD [5-7] and complicated, harder-to-treat CD phenotypes (including fistulizing disease [8] and refractory disease states), DDW 2026 reinforced the idea that FSCD is increasingly viewed not simply as a late complication, but a potentially preventable outcome if high-risk patients can be identified and treated earlier in the disease course. This suggested trajectory aligns with the congress-wide emphasis on proactive disease management in the first years following diagnosis.
Experts highlighted TL1A, a member of the TNF superfamily, as a promising therapeutic target in FSCD given its role in amplifying mucosal inflammation and fibrotic pathways. This aligns with findings presented at DDW suggesting that anti-TNF therapies may be more effective at limiting stricture progression than IL-12/23 inhibitors. TL1A-directed therapies may have the potential to inhibit fibroblast activation and reduce fibrosis progression.
Preventing fibrosis through earlier and aggressive inflammatory control, developing therapies to directly target fibrotic pathways, and using biomarkers and imaging to identify high-risk patients earlier will drive more precision-based trials, early-intervention studies, and greater competition for advanced therapy-naïve patients.
Modernizing trial design paradigms
One of the biggest draws at this year’s DDW was a session on future perspectives in IBD management, “Looking ahead: How will we manage IBD in 2030”.
Innovations in placebo strategy
Dr. Vipul Jairath outlined the key considerations in modern trial design strategies – in particular, the use of Bayesian design to improve analytical outcomes. An early (and important) example is the secukinumab trial, where the primary endpoint was informed by Bayesian statistics and historical placebo information to strengthen findings and reduce the need for an extensive placebo arm [9], with Teva and Sanofi’s RELIEVE-UCCD trial serving as a modern example and featuring Bayesian design accommodating new cohorts over time [10, 11].
Strategies to minimize placebo use include:
- Asymmetrical randomization ratios
- Active comparator arms
- Bayesian design
- Historical or external controls
- Shared placebo arms (trials under a Master Protocol)
Platform trials are under Master Protocols, and are geared toward reducing placebo by sharing control arms, while also featuring flexible addition and removal of treatment arms [12]. Spyre’s SKYLINE-UC [13], Mirador’s ASCEND-IBD [14], and Janssen’s MACARONI-23 [15] are all poised to deliver promising results from platform trials.
High placebo exposure can make enrollment more difficult, increase dropout rates, and lengthen study timelines. Placebo will likely remain in early-phase trials (where safety is paramount), but late-phase trials may require superiority to approved drugs, or perhaps non-inferiority to an active comparator for induction endpoints and superiority for maintenance endpoints.
Making combination trials viable
Dr. Bruce Sands outlined how combination therapy is being increasingly explored to improve efficacy – through potential synergy or additivity across different pathways [16, 17].
- From escalation to synergy: Combination therapies are no longer rescue therapy for refractory disease
- Mechanism-driven pairing is replacing empirical stacking: Rational pairing of mechanisms for biological complementarity (e.g., anti-cytokine + anti-trafficking, systemic + gut restricted) rather than additive effects
- Safety is the limiting factor: Even individually safe drugs may behave unpredictably in combination
- PK and exposure are crucial: Thinking beyond route of administration and dosing optimization to system-level exposure design
- The implications on trial design and logistics are significant: Sponsors must rethink their clinical development; complex factorial or adaptive designs can be more efficient to test multiple combinations, however, will come under greater regulatory scrutiny. Finding the right population is key, and partnering with a CRO able to overcome any logistical barriers could define a clinical development campaign
The competitive edge will come from selecting the right mechanistic combinations early, designing for safety (and the ability to pivot if needed) intelligently, and proving durable disease modification rather than incremental response gains that do not translate to meaningful impact to patients.
Treatment optimization
Suboptimal care remains a critical problem in IBD, characterized by poor adherence to standards, inappropriate dosing, prolonged steroid use, and missed preventative care opportunities. Many patients encounter a therapeutic ceiling due to non-optimized therapies and frequent switching between medications, which generally focus on treating symptoms rather than the underlying disease. This reactive response requires patients to “earn” therapy alternatives through disease progression and loss of response, leading to increased healthcare costs and subpar outcomes.
In Dr. David Rubin’s engaging session on clinical care takeaways in the optimization of treatment of patients with IBD, 9 pearls of wisdom were covered:
- Treat patients early, choosing a therapy that matches the disease activity and prognosis
- Choose the first line therapy wisely to avoid ineffective cycling. The prognosis should guide the therapy as much as the disease activity
- Avoid corticosteroids – which are often tapered too long. If the new therapy is working, stop the corticosteroids
- Treat to target with continuous assessment and adjustment until the target is reached, and commence monitoring
- Develop an approach to non-response and anticipate non-response with proactive disease monitoring. Evaluate serum concentration, recapture attenuation – shortening the interval is better than increasing the dose, and consider switching therapy class
- Combine therapies where safe and rational, with mechanism-based or time-based combinations to target multiple facets for increased synergy
- Adjust the patient. Treat the patient with GLP-1 (or similar) drugs to improve the patient’s weight and metabolic profile, however careful monitoring is recommended, especially in terms of inflammatory and gut profile. An appendectomy is associated with reduced advanced therapy escalation
- Focus on the patient’s diet to augment biological effectiveness, and supplement with dietary therapeutics
- Treat the patient that is in front of you – solving the patient’s actual issues is better than best intentions with their disease
These principles reinforce the need to design trials and clinical development strategies around generating stronger evidence of disease-modifying impact rather than symptom control.
Trials must be able to support rapid (de)escalation and treat-to-target approaches, and data generated should reflect real-world complexity. Regulators, payers, and clinicians will increasingly judge therapies on how well they perform within adaptive, personalized treatment pathways rather than fixed-line algorithms.
What’s new in…
Eosinophilic esophagitis (EoE)
Diagnosis of EoE has surged over the past decade in the US (primarily based on emergency department visits claims data), underscoring the need for innovative solutions and heightened awareness.
While food elimination and elemental diets can be effective in achieving remission in patients with EoE, these approaches can be difficult to sustain long-term and may not be appropriate for all patients. Strict dietary restriction can negatively affect quality of life and social functioning, and has been associated with nutritional deficiencies and disordered eating in some patients [18]. In those not responding to diet modification, treatment is initially using proton pump inhibitors (PPIs), then topical steroids, and then biologics. Further challenges in treating patients with EoE include:
- PPIs are only effective in around half of patients
- Disease recurrence is common, with approximately 60% of patients relapsing within a year despite treatment
- 15% of patients starting biologics require esophageal dilation within a year
- Clinical remission does not align with histological improvement, leading to false assumptions about patient recovery
The recommendation to approach EoE as an allergic GI disease was a big talking point at DDW 2026. Epithelial cytokines are predicted to be the next molecule to impact the EoE. The discovery of elevated TSLP, IL-33, and IL-25 in EoE patient biopsies (released from the epithelium in response to environmental insults, these cytokines drive T2 inflammation and the structural changes characteristic of EoE) calls for further exploration into the genetic mechanisms behind epithelial-driven inflammation, and sponsor investment into novel therapies at this early stage of clinical development.
CAR-T
A multidisciplinary approach and better infrastructure are required to fully implement CAR-T therapies for GI diseases – a distinct approach from current use in oncology. CAR-T offers an innovative path to reconstruct immune responses (inducing durable, long-term remission), however heightened toxicity, early infection risks, and unproven endoscopic evidence of effect make this therapy risky. The main CAR-T strategy currently under investigation targets B-cells via BCMA [19], but it, alongside other CAR-T strategies in GI, is at a very early proof-of-concept stage.
While CAR-T therapy’s success in oncology is well established, its application in non-cancer indications, including gastrointestinal diseases, is an exciting frontier. Early preclinical and clinical studies suggest the potential to modulate pathogenic immune responses or fibrosis, offering real promise, but careful optimization of safety and targeting will be key to realizing its full clinical impact.
Intestinal ultrasound (IUS)
This year’s DDW showcased particularly strong research and data from advanced imaging methods in IBD. The INSIGHT trial highlighted the predictive value of early IUS combined with fecal calprotectin in CD [20]. Evaluation at 3 months was able to predict outcomes at 6 months, demonstrating IUS as a reliable, non-invasive monitoring tool, performing comparably (both sensitivity and specificity) to CT and MRE.
IUS will become the go-to diagnostic and monitoring tool in IBD management, potentially completely replacing endoscopy. Safety, speed, cost-effectiveness, environmental savings, ease of use, patient-friendliness, and real-time readouts enable prompt clinical decisions and data gathering. While limitations (reduced efficacy in overweight patients or those with proctitis) exist, IUS is rapidly becoming part of both clinical trials and real-world practice.
AI
Integrating AI can help rapidly distinguish between UC and CD: Sequencing the gut microbiome shows enrichment and depletion of certain microorganisms (most evident in patients with CD), and viruses been detected using an AI multi-kingdom machine learning approach [21]. This approach could become clinically validated for routine diagnosis and monitoring.
Developed by J&J, the Continuous Mucosal Endoscopic Score (CMES) [22] offers a dynamic and more sensitive measure of disease severity compared with the traditional Mayo score (MES). CMES captures signals across the colon, correlates to other clinical measures of disease, and if used in trials could prove useful in reducing the needed sample sizes for clinical power.
The microbiome
Increasingly recognized as affecting drug availability and effectiveness, the microbiome was also a hot topic – particularly with a growing belief that the FDA may eventually require microbiome panels during trials to determine drug bioavailability. Bioaccumulation by gut bacteria can modify drug availability and metabolism, impacting PK, adverse effects, and overall drug response (e.g., 5-ASA [23]). Patients with IBD experience disruption in their microbiomes, complicating treatment efficacy.
Final thoughts
Development in GI continues at a rapid pace. The push for new agents and new modalities remains strong. DDW 2026 reinforced a clear direction of travel:
- Early intervention is the dominant paradigm
- Placebo is under pressure
- New imaging modalities are gaining traction
- FSCD and complicated Crohn’s disease are rising in priority
- Combination therapy is gaining clinical momentum
For sponsors, this translates into tougher enrollment in late-line populations, and a greater need for biomarker-driven strategy and demonstration of long-term (pragmatic) impact, not just induction efficacy.
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Abbreviations
5-ASA, 5-aminosalicylic acid;
ACG, American College of Gastroenterology;
AGA, American Gastroenterological Association;
BCMA, B-cell maturation antigen;
CAR-T, Chimeric Antigen Receptor T-cell;
CD, Crohn’s disease;
CMES, Continuous Mucosal Endoscopic Score;
CT, computed tomography;
DDW, Digestive Disease Week;
ECCO, European Crohn’s and Colitis Organisation;
EoE, eosinophilic esophagitis;
FDA, Food and Drug Administration;
FSCD, fibrostenotic Crohn’s disease;
GI, gastrointestinal;
GLP-1, glucagon-like peptide-1;
IBD, inflammatory bowel disease;
IL, interleukin;
IUS, intestinal ultrasound;
MES, Mayo Endoscopic Score;
MRE, magnetic resonance enterography;
PK, pharmacokinetics;
T2, type 2 inflammation;
TL1A, Tumor necrosis factor-like ligand 1A;
, Tumor necrosis factor;
TSLP, Thymic Stromal Lymphopoietin;
UC, ulcerative colitis.
References
1. Noor, N.M., et al., A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): a multicentre, open-label randomised controlled trial. Lancet Gastroenterol Hepatol, 2024. 9(5): p. 415–427.
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7. Rieder, F., et al., DOP100 RXC008, a first-in-class gastrointestinal restricted pan-ROCK inhibitor developed for treatment of intestinal fibrosis shows GI restriction and tolerability: Results from the phase 1 program in healthy participants. Journal of Crohn’s and Colitis, 2025. 19(Supplement_1): p. i266–i266.
8. National Institutes of Health. A Study of Guselkumab in Participants With Fistulizing, Perianal Crohn’s Disease (FUZION CD) (NCT05347095). 2026. Accessed May 2026. Available from: https://clinicaltrials.gov/study/NCT05347095.
9. Hueber, W., et al., Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut, 2012. 61(12): p. 1693–700.
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11. Reinisch, W., et al., OP41 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active ulcerative colitis: Results from a phase 2b, randomised, double-blind, placebo-controlled, dose-ranging, basket trial (RELIEVE UCCD). Journal of Crohn’s and Colitis, 2025. 19(Supplement_1): p. i79–i80.
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15. National Institutes of Health. A Study of Guselkumab in Pediatric Participants With Moderately to Severely Active Crohn’s Disease (MACARONI-23) (NCT05923073). 2026. Accessed May 2026. Available from: https://clinicaltrials.gov/study/NCT05923073.
16. Digestive Disease Week 2026, Better Together: New Combination Therapy Improves Outcomes In The Most Difficult-To-Treat Patients With IBD. 2026.
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19. National Institutes of Health. BCMA-CD19 cCAR T for the Treatment of Refractory Inflammatory Bowel Disease (IBD) (NCT07544160). 2026. Accessed May 2026. Available from: https://clinicaltrials.gov/study/NCT07544160.
20. National Institutes of Health. Prediction and Close Monitoring of Postoperative Recurrence by Intestinal Ultrasound After Ileocecal Resection in Crohn’s Disease Patients (INSIGHT) (NCT05713409). 2026. Accessed May 2026. Available from: https://clinicaltrials.gov/study/NCT05713409.
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