Late-breaking research in IBD

Nurulamin Noor, MD, PhD, from Cambridge University Hospitals NHS Foundation Trust, presented the 5-year follow-up data from the PROFILE trial that compared early “top down” therapy to “step-up” therapy among patients with Crohn’s disease (CD). The trial was designed to determine whether the use of anti-TNF therapy early after diagnosis could modify the course of CD. Two weeks after diagnosis, patients with symptomatic, endoscopically active disease were randomized 1:1 to top down therapy with anti-TNF or step up therapy for 48 weeks, then moved to the local standard of care. The 48-week efficacy data has been published, and demonstrated greater efficacy and cost-effectiveness of the top down approach. This long-term follow-up analysis sought to assess progression and disease course. Compared with the step up group, patients in the top down group required fewer hospitalizations and surgeries and had a longer time to surgery, as well as a lower risk of progression starting at year 1 that continued to decrease through 5 years. There was also an early and sustained normalization of inflammatory markers in the top down group. Almost all patients continued maintenance therapy, and a very small number de-escalated therapy. There was no difference in adverse events between the groups. 

Christopher Ma, from the University of Calgary, reported the 50-week results from the phase 2 ARTEMIS-UC study of the anti-TL1A tulisokibart in patients with moderate-to-severe active ulcerative colitis (UC). TL-1A is an emerging target in IBD, and acts as an amplifier of fibrotic pathways and inflammation. Tulisokibart binds TL-1A to block receptor activation, and downregulates fibroblast activation and inflammation. Induction with intravenous tulisokibart was associated with significant improvement in clinical remission compared to placebo out to 50 weeks. The current analysis evaluated symptomatic relief and changes in stool frequency and rectal bleeding, as well as a composite endpoint of disease clearance that includes symptomatic remission and mucosal clearing and histologic remission based on endoscopy. Disease clearance, a marker of deep and multilayered disease control, is emerging as a new trial endpoint. Baseline demographics were well balanced between the treatment arms and represented significant burden of disease, with 70% having severe endoscopic disease activity and many patients with previous exposure to one or more advanced therapies. Patients who received tulisokibart had normalization of stool frequency, normalization of rectal bleeding, and symptom remission that was sustained from week 12 through week 50 of maintenance. Disease clearance was achieved in 33-40% of patients at 50 weeks, and in 50% of patients naïve to advanced therapy. Endoscopic scores and pancolitis also improved and were maintained. By week 50, disease clearance was achieved in 47% of patients with severe baseline endoscopic disease (Mayo score 3) and 46% of patients with pancolitis at baseline.

Maarten Pruijt, MD, PhD, from Amsterdam UMC Locatie VUmc, presented results from the INSIGHT study, suggesting that early intestinal ultrasound combined with fecal calprotectin is a predictor of endoscopic recurrence after ileocecal resection in CD. Endoscopic recurrence occurs in 70% of patients with CD 12 months after ileocecal resection, and current guidelines recommend a follow-up endoscopy 6-12 months after surgery. Fecal calprotectin and intestinal ultrasound (IUS) are each good predictors of recurrence, with sensitivities of 70% and 82% and specificities of 69% and 88%, respectively. This multicenter, international, prospective study asked whether these two markers combined could more accurately predict endoscopic recurrence 6 months after surgery. Central readers were used for IUS and endoscopy of the proximal colon, anastomosis, and neo-terminal ileum. The study included 112 patients, with a median age of 34 years and disease duration of 8 years; 25% had penetrating disease, 30% were active smokers, 40% had a previous resection, and 40% had previous advanced treatment. By 6 months after surgery, 49 patients had Rutgeerts 2b or higher endoscopic recurrence. The combination of fecal calprotectin and IUS had a sensitivity of 94% and specificity of 81% for predicting recurrence. Bowel thickness on IUS of 2 mm or greater in the neo-terminal ileum was the strongest predictor of recurrence by 6 months. Previous use of one or more advanced therapy was a risk factor for recurrence. An algorithm was developed to recommend closer monitoring and early intervention or escalation of treatment in high-risk patients, and delay of endoscopy in low-risk patients.

Laurent Peyrin-Biroulet, from University de Lorraine, presented week 24 results from the phase 3 multicenter FUZION study of guselkumab for perianal fistulizing CD, a severe and complex manifestation seen in 25% of patients. The presence of perianal fistula at diagnosis predicts a worse course, is associated with worse symptoms, and impacts quality of life. Medical surgical management is available, but durable fistula healing remains challenging. Guselkumab is an IL-23 inhibitor that has been shown safe and effective for endoscopic healing in CD. FUZION was a double-blind treat-through study that included 286 patients with at least one active draining fistula, active CD, and inadequate response to therapy. Patients were randomized 2:2:1 to two different doses of subcutaneous guselkumab or placebo. Treatment continued for 12 weeks, after which non-responders could proceed to surgery with antibiotics. The primary endpoint was fistula remission confirmed clinically and radiologically at 24 weeks. One quarter of patients had more than one fistula and 30% were naïve to biologic therapy. At week 24, 28% of patients who received either dose of guselkumab achieved fistula remission compared to 10% in the placebo group. Fistula response was achieved by 50% of treated patients versus 5% with placebo. A statistically significant improvement in clinically assessed fistula response was reached by week 12, suggesting that setons could be removed at that time point. No new safety signals were seen. 

Dr. Peyrin-Biroulet also shared open-label extension results from a phase 2 trial of mufemilast, an oral PDE4 inhibitor, in patients with moderate-to-severe UC. Mufemilast was approved in China in 2025 as an optimized version of apremilast that targets multiple inflammatory pathways and has an additional impact on fibrosis. Patients were randomized to either 60 mg or 45 mg BID mufemilast or placebo for 12 weeks of treatment, then moved to an open-label extension with 60 mg mufemilast BID out to 24 weeks. At baseline, a large number of patients had pancolitis. Discontinuations were higher in the placebo group, suggesting an early signal of efficacy; these patients entered the open-label phase early and went on to complete the trial. Clinical remission was seen at weeks 12 and 24, with a 43% treatment effect of the higher dose of mufemilast compared to placebo. Endoscopic improvement was seen in 66% of patients, with a rescue effect when placebo patients were moved to the open-label extension. Similar patterns of response were seen in biologic naïve and exposed patient subgroups. No severe infections or malignancy were reported. The trial also included 17 patients with TB, who did not experience any serious AEs. Headache, dizziness, and nausea were common adverse events that improved as treatment continued. Data has been collected out to 1 year of exposure with no concerning safety signals.