Precision medicine and therapeutic innovation: Clinical trial highlights from ECCO’26

NORDTREAT (NCT05180175) was a randomized, multicenter, biomarker-strategy trial evaluating whether a protein-signature–guided “top-down” approach to treatment (anti-TNF ± immunomodulator) improves outcomes vs standard stepwise care in newly diagnosed adults with IBD.

Among 313 enrolled patients, 157 were randomized to the biomarker-access arm; 24 (15%) were identified as high-risk and received top-down therapy. In the non-access arm (n=156), 29 (19%) were retrospectively found to be high-risk, with 55% receiving advanced therapy after a median of 15 days.

At Week 52, the primary endpoint, corticosteroid-free clinical and endoscopic remission, was achieved in 42% (10/24) of patients receiving top-down therapy vs 27% (8/29) with standard care (absolute difference 15%; 95%CI -11-41, p=0.26). Endoscopic remission rates were comparable (53% vs 53%, p=0.99). Median cumulative steroid exposure was numerically lower with top-down (1232mg) than standard care (1651mg). Serious adverse events (SAEs) were similar, with 7 vs 13 hospitalizations in the top-down and standard care groups, respectively; there was one death after colectomy in the standard care group. Post-hoc analyses showed higher rates of achieving the primary endpoint in Crohn’s disease (CD; 50% vs 11%; p=0.09), but not in ulcerative colitis (36% vs 35%; p=0.97).

GUIDE-IBD was a multicentre, randomized trial evaluating whether biomarker-informed therapy guidance improves outcomes in patients starting anti-TNF therapy for IBD. 103 adult patients were assigned to molecular medicine care (MMC), provided with molecular reports (including mRNA-based biomarkers) at weeks 2, 14, 26 and 52, or to best care (BC). At Week 52, Comprehensive Disease Control was achieved significantly more often with MMC than BC (43% vs 23%, respectively), with an odds ratio of 2.53 (95%-CI: 1.09-5.86, p=0.031). Secondary outcomes, including steroid-free, clinical, and endoscopic remission, also favoured MMC. More therapy changes and dose adjustments occurred in the biomarker-guided arm. Overall, biomarker-informed management improved anti-TNF treatment outcomes compared with standard care.

Ulcerative colitis

Ulcerative colitis research featured prominently at this year’s meeting, reflecting an expanding treatment landscape spanning orally administered pathway inhibitors, advanced biologics, and long-term safety and durability data for established agents. Several pivotal trials presented at ECCO’26 evaluated novel mechanisms such as IL-23 pathway blockade, integrin targeting in paediatric populations, and microRNA-modulating therapies. In addition, long-term extension studies offered valuable real-world insights into the sustained efficacy and safety of current advanced therapies. Together, these findings highlight meaningful progress toward more individualized and durable disease control for patients with moderate-to-severe UC.

• ANTHEM-UC (NCT06049017), a Phase 2b randomized, double-blind, placebo-controlled trial, evaluated icotrokinra, an oral IL-23 receptor blocker, in adults with moderate-to-severe ulcerative colitis. Participants were randomized (1:1:1:1) to once-daily icotrokinra 100mg, 200mg, 400mg, or placebo.

At Week 12, all icotrokinra doses reduced inflammatory biomarkers (serum C-reactive protein and fecal calprotectin). All groups except placebo had markedly lower serum IL-23 pathway biomarkers (IL-22, IL-17A, and IL-17F), with greater reductions at the 200mg and 400mg doses of icotrokinra. Gene-expression analysis of colonic biopsies showed that all icotrokinra doses markedly dampened IL-23–driven inflammation in tissue relative to baseline and shifted the tissue transcriptome toward a healthy profile. Attenuation of systemic and tissue inflammation was sustained through Week 28.

• KEPLER (NCT04779307) was a Phase 3 trial assessing intravenous vedolizumab, an α₄β₇ integrin antagonist, in children and adolescents (ages 2–17) with moderately to severely active ulcerative colitis who had failed conventional therapies.

A total of 121 patients were enrolled (120 treated); following initial induction, 93 entered maintenance and were randomized 1:1 to weight-based low- or high-dose vedolizumab every 8 weeks. At Week 54, 47.3% (44/93) achieved clinical remission, with similar rates across dosing groups. Clinical remission occurred in 34.7% (42/121) at Week 14, and sustained remission at Week 54 was achieved by 29.0% (27/93). Remission rates were comparable across weight, age, anti-TNF exposure, and baseline steroid use. Immunogenicity was low; 5.8% (7/120) had anti-vedolizumab antibodies and 3.3% (4/120) had neutralizing antibodies.

Treatment-emergent adverse events (TEAEs) occurred in 85.8% (103/120) of patients; 12.5% were related to vedolizumab (15/120) and 4.2% (5/120) were serious and related to vedolizumab. Seven patients discontinued due to adverse events (AEs), mainly UC worsening or infection.

• Obefazimod is an oral small molecule, designed to enhance the expression of microRNA-124. The ABTECT-1 (NCT05507203) and ABTECT-2 (NCT05507216) Phase 3 randomized, double-blind, placebo-controlled induction trials evaluated obefazimod in 1,272 patients with moderate-to-severe UC. Patients were randomized 2:1:1 to obefazimod 50mg, 25mg, or placebo once daily for 8 weeks.

At Week 8, both obefazimod doses produced substantially greater improvements in disease-specific quality of life compared with placebo, with mean IBDQ scores of 161.9 (50mg) and 159.2 (25mg) vs 135.7 with placebo (110.8, 110.8, and 109.7 at baseline, respectively; Obe-50:Δ25.97 and Obe-25:Δ22.33, p<0.0001). A meaningful within-patient change in IBDQ total score occurred in 60.9% (50mg) and 56.9% (25mg) of patients receiving obefazimod vs 39.8% with placebo (Obe-50:Δ21.20 and Obe-25:Δ17.07, p<0.0001). IBDQ remission in patients without IBDQ remission at baseline was also higher in obefazimod treatment groups 50mg (36.7%) and 25mg (33.2%) vs placebo (19.6%) (Obe-50:Δ17.13 and Obe-25:Δ13.56, p<0.001). Improvements in overall quality of life were similarly superior with obefazimod, with both EQ-5D-5L index and VAS scores increasing significantly vs placebo.

Long-term data underscored the sustained effectiveness and safety of two approved advanced therapies, risankizumab (an IL-23 inhibitor) and upadactinib, in moderate-to-severe ulcerative colitis.

• In the COMMAND (NCT03398135) open-label extension study, patients with moderate-to-severe UC who completed prior risankizumab induction and/or maintenance entered a long-term extension to assess the efficacy and safety of risankizumab. The interim analysis reports findings through 96 weeks (~3 years of total maintenance therapy with risankizumab). All patients received subcutaneous risankizumab 180 mg in the extension, except a subset who continued prior rescue dosing (1200mg intravenous dose then 360 mg every 8 weeks). Efficacy was sustained for all endpoints from the start of the extension through Week 96, with sustained clinical and endoscopic benefits observed in patients receiving long-term maintenance therapy; efficacy was numerically lower in patients with prior inadequate response to advanced therapy. Safety outcomes, including any AEs, severe adverse events, and SAEs, were similar across long-term risankizumab groups, and no new safety risks were identified.
• U-ACTIVATE (NCT03006068) is an ongoing long-term extension study investigating the efficacy and safety of upadacitinib for moderate-to-severe UC. Patients who responded to 8 weeks of high-dose induction and completed maintenance with upadactinib 15mg, 30mg, or placebo, were followed for an additional 192 weeks (~5 years in total), with nonremitters eligible for dose escalation. At Week 192, most patients in both dose groups maintained clinical remission (>69%) and among those in remission at the start of the extension, >80% maintained clinical remission for both doses. Across doses, most patients achieved endoscopic improvement (>80%) and maintained this at Week 192. Endoscopic remission was achieved by >50% of patients at Week 192 across doses, with 54% (15mg) and 80% (30mg) of initial remitters maintaining remission long-term. TEAE rates were similar between doses and consistent with prior analyses.

Crohn’s disease

In Crohn’s disease, ECCO’26 featured a diverse set of clinical investigations spanning complex phenotypes, paediatric care, and real-world comparative effectiveness. Particular emphasis was placed on the performance of ustekinumab, an IL-12/23 inhibitor in challenging disease presentations such as fistulizing perianal CD. Two long-term extension programmes highlighted sustained clinical, endoscopic, and symptomatic improvement with selective IL-23 blockade over multiple years of follow-up. These data provide confidence in the durability and safety of newer biologic classes and reinforce their role in long-term disease control, even in patients who initially failed to achieve early endoscopic response.

• USTAP (NCT04496063) was a double-blind, placebo-controlled, multicenter trial, investigating ustekinumab for active draining fistulizing perianal CD. Thirty-two patients were randomized 1:1 to placebo or ustekinumab (6mg/kg IV at baseline, then 90mg SC every 8 weeks). At Week 12, placebo non-responders could switch to ustekinumab, while ustekinumab non-responders could be intensified.

At Week 12, combined clinical and radiologic remission occurred in 62% of ustekinumab-treated patients vs 25% with placebo. Clinical remission rates were 69% vs 31%, and radiologic remission 87.5% vs 75%, respectively. At Week 48, treatment persistence from randomization was 56% (9/16) with ustekinumab and 12.5% (2/16) with placebo; 9/16 placebo patients switched to ustekinumab in the open-label phase. Combined remission at Week 48 was 7/16 (50%) in the placebo-ustekinumab arm and 5/16 (31%) in the ustekinumab arm. AEs and SAEs were comparable across groups, with 2 placebo-treated patients discontinuing the study at Week 6. The study was discontinued in June 2024, due to slow recruitment.

• UNITI Jr (NCT04673357) evaluated ustekinumab in children and adolescents (ages ≥2 – <18 years) with moderate-to-severe Crohn’s disease. All 101 participants received open-label IV ustekinumab induction. At Week 8, 97 were randomized 1:1 to blinded maintenance dosing every 8- or 12-weeks for a duration of 44 weeks, stratified by weight and induction response.

At Week 8, clinical remission (PCDAI ≤10) occurred in 46.5% (47/101) of participants. Among Week-8 responders, 68.1% (32/47) maintained remission through Week 52. Clinical response at Week 8 was 84.2% (85/101); among these, Week-52 clinical remission and corticosteroid-free remission were 54.1% [95%CI: 43.6%-64.3%] and 52.9% [95% CI: 42.4%-63.2%], respectively. Safety was comparable between groups. SAEs occurred in 16.8% (17/101) of participants and serious infections occurred in 5.9%.

• The ENEIDA registry study compared the durability and effectiveness of upadacitinib and risankizumab in 562 Crohn’s disease patients after anti-TNF failure. Both therapies were effective and showed good overall treatment durability, with Week-24 persistence of 59% for upadacitinib vs 72% for risankizumab in second-line, and 40% vs 76% in third-line, respectively. Baseline disease severity was associated with relapse, while third-line treatment discontinuation was more likely with upadacitinib. Adverse events were more frequent with upadacitinib (28% vs 10% with risankizumab), most commonly acne, but therapy was still maintained in 81% of upadacitinib and 91% of risankizumab patients experiencing AEs, supporting both agents as viable options in this difficult-to-treat population.

Long-term data underscored the sustained effectiveness and safety of two approved advanced therapies, mirikizumab, a selective IL-23p19 monoclonal antibody, and risankizumab in Crohn’s disease.

• In the ongoing 3-year VIVID-2 extension study (NCT04232553), mirikizumab maintained high levels of efficacy among Week-52 endoscopic non-responders who received reinduction then continued maintenance. By Week 152, 78.8%/62.0% (observed cases [OCs] and modified nonresponder imputation [mNRI], respectively) had achieved Crohn’s Disease Activity Index (CDAI) remission and 76.1%/59.9% (OC/mNRI) had achieved corticosteroid-free CDAI remission. In addition, 62.5%/48.0% (OC/mNRI) achieved bowel urgency (BU) clinically meaningful improvement (CMI), and 46.9%/36.7% (OC/mNRI) achieved BU remission. Of patients who achieved the specified endpoint at Week 52, there were high maintenance rates of CDAI and BU remission at Week 152, with some patients who didn’t meet the endpoint at Week 52 gaining remission over time. Inflammatory biomarkers continued to improve, and the safety profile remained consistent with earlier phases.
• In the SEQUENCE trial (NCT04524611) risankizumab was evaluated for durability of effectiveness through Week 148 in patients with moderate-to-severe CD who had previously failed anti-TNF therapy. Patients who achieved clinical remission by Week 8 demonstrated high long-term maintenance of key outcomes: 98.5% achieved CDAI remission and 88.1% maintained stool frequency/abdominal pain score remission at Week 148. Of patients who achieved endoscopic improvements at Week 24, 84.7% and 78.2% maintained endoscopic response and remission, respectively, and 67.3% maintained mucosal healing at Week 148.