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Abstract Background Vedolizumab (VDZ) is a gut selective, monoclonal anti-α4β7 integrin antibody approved for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD). The subcutaneous (SC) formulation of VDZ was evaluated during the Phase 3 VISIBLE 1 and 2 studies. This analysis reports hospitalisations and surgeries among patients (pts) with UC or CD treated with VDZ SC enrolled in the VISIBLE open-label extension (OLE) study. Methods Pts who participated in VISIBLE 1 or VISIBLE 2 were eligible to enrol in VISIBLE OLE (NCT02620046) and received VDZ SC 108mg every 2 weeks (Q2W) or weekly. Patients were grouped according to their scenario in VISIBLE 1/2: Pts who withdrew between week (W) 6 and W52 (Scenario 1); pts who completed 52 weeks of treatment with VDZ or placebo (Scenario 2); pts without a clinical response at W6 but who responded at W14 and were not randomised (Scenario 3). The proportions of patients who experienced UC or CD related hospitalisation and/or surgery during VISIBLE OLE were assessed by scenario and treatment received during VISIBLE 1/2. Results A total of 288 pts with UC and 458 with CD enrolled in the VISIBLE OLE. The mean (min., max.) duration of VDZ exposure during VISIBLE OLE was 1276.7 days (127, 2577 days) among pts with UC and 1110.0 days (127, 2770 days) among pts with CD. The proportions of pts who had a UC or CD related hospitalisation or surgery during VISIBLE OLE are displayed in Table 1. Across all scenarios, a total of 8.3% (24/288) of pts with UC had a related hospitalisation. In total, 3/288 pts (1.0%) with UC (from Scenarios 1 and 3) had a colectomy. No pts with UC from Scenario 2 had a colectomy. Among pts with CD, a total of 13.1% (60/458) had a related hospitalisation. A total of 19 pts (4.1%) with CD had bowel surgery. Higher rates of IBD related hospitalisations and surgeries were observed in Scenario 1, both in pts with UC and with CD. Conclusion Findings from VISIBLE OLE showed that few pts with UC and CD treated with long-term VDZ SC required IBD related hospitalisations over the course of the study. Notably, very few patients with UC or CD required colectomies or bowel surgery.

Abstract Background Long-term use of corticosteroids (CS) is a concern for patients with Crohn’s disease (CD), as prolonged use is associated with increased mortality and adverse outcomes. Upadacitinib (UPA), an oral, selective, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe CD and demonstrated CS-sparing efficacy, with a consistent safety profile through maintenance week (wk) 52.1-4 Here, we evaluated the long-term efficacy of UPA in achieving CS-free clinical and endoscopic outcomes in patients enrolled in the ongoing U-ENDURE long-term extension (LTE) study. Methods Patients who completed the U-ENDURE 52-wk maintenance study were eligible for the subsequent LTE study wherein they continued their previously assigned treatment (once daily UPA 15 mg [UPA15] or UPA 30 mg [UPA30]). Efficacy was assessed from LTE wk 0-wk48, among patients with 2 year (yr) (100 wk) of total maintenance therapy, within the overall population and in patients with baseline CS use (induction wk 0). CS-free endpoints (without CS use for ≥90 days before evaluation), included clinical remission (per stool frequency/abdominal pain score [SF/APS] and CD Activity Index [CDAI]), endoscopic response, and endoscopic remission, were evaluated using both as-observed and nonresponder imputation (NRI) methods, with NRI analysis presented in text. Safety was not evaluated here but was reported previously.3 Results Among patients with 2 yr of total maintenance therapy, 35.7% (87/244) received CS at baseline, with 13.1% (32/244) receiving CS at any time during the LTE study regardless of baseline CS use. Among patients taking baseline CS and those who received CS at any time during the LTE study (n=20), the median (range) time of CS use was 127.5 (2-1589) days. CS-free clinical remission was achieved at LTE wk 0 and wk 48 per SF/APS (overall population: UPA15, 71.7%, 58.9%; UPA30, 81.8%, 57.7%; patients with baseline CS use: UPA15, 71.8%, 53.8%; UPA30, 79.2%, 54.2%, NRI, Fig.1A-B) and CDAI criteria (overall population: UPA15, 74.8%, 60.7%; UPA30, 83.9%, 65.0%; patients with baseline CS use: UPA15, 74.4%, 56.4%; UPA30, 81.3%, 58.3%, NRI, Fig.1C-D). At LTE wk 48, a high fraction of UPA-treated patients achieved CS-free endoscopic response (overall population: UPA15, 48.6%; UPA30, 55.5%; patients with baseline CS use: UPA15, 38.5%; UPA30, 60.4%, NRI) and CS-free endoscopic remission (overall population: UPA15, 33.6%; UPA30, 46.0%; patients with baseline CS use: UPA15, 28.2%; UPA30, 54.2%, NRI, Fig.2). Conclusion Patients with moderate-to-severe CD who received long-term UPA maintenance treatment sustained high rates of CS-free clinical and endoscopic outcomes, suggesting that UPA may serve as an effective long-term CS-sparing therapy. References 1.RINVOQ [package insert], extended-release tablets, FDA Prescribing Information. AbbVie Inc; 2022. Accessed 1 June 2022.2. 2.RINVOQ [package insert], prolonged-release tablets. EMA Summary of Product Characteristics. AbbVie; 2022. Accessed 1 June 2022. 3.Loftus EV and Panes J et al. N Engl J Med 2023;388:1966-1980. J 4.M C Dubinsky, et al. JCC, 17; (Supp_1); 2023: i104–i106.

Abstract Background The SEQUENCE trial, in bio-exposed Crohn's disease (CD) patients, demonstrated non-inferiority for clinical remission at 24 weeks and superiority for endoscopic remission at week 48 for risankizumab (RZB) compared to ustekinumab (UST). However, this comparison has not been adequately explored in bio-naive CD patients. Our study aimed to compare the clinical effectiveness among bio-naive CD patients treated with RZB vs. UST in a real-world setting, using data from a US-based multicenter cohort. Methods This retrospective cohort study utilized data from the TriNetX US Collaborative Network, comprising sixty-eight tertiary institutions, to examine adult (≥18 years) bio-naive CD patients initiated on RZB or UST from June 17th, 2022 (FDA approval date) to October 31st, 2024. Patients with prior advanced therapy usage and those with approved rheumatologic disease indications for RZB/UST were excluded. A 1:1 propensity score matching (PSM) analysis was conducted to balance cohorts on demographics, baseline comorbidities, and indicators of CD severity, including CD phenotype, extraintestinal manifestations, concurrent corticosteroid use, hemoglobin, and body weight. Cox proportional hazards models estimated hazard ratios (HRs) in matched cohorts for one-year post-treatment composite outcomes (need for corticosteroids, hospitalizations, emergency room visits, surgeries) with a priori significance threshold of p < 0.05. Results The study sample included 1,630 bio-naive CD patients treated with RZB and 3,105 with UST. Among patients on UST, 658 (21%) were dosed every four to six weeks, after the first dose. Baseline characteristics of the PSM RZB and UST cohorts are shown in Table 1 with 1,568 patients in each cohort. After PSM (Figure 1), there were no significant differences in composite outcome (HR 1.077, p = 0.170), corticosteroid use (HR 1.099, p = 0.110), CD-related surgery (HR 1.231, p = 0.284), hospitalization (HR 0.947, p = 0.615) or ER visits (HR 1.041, p = 0.687). Additionally, no significant differences were observed in opioid use (HR 1.062, p = 0.366), switch to different advanced therapy (HR 1.097, p = 0.468) or elevated disease biomarkers, including CRP (>10mg/l, HR 1.186 p = 0.101) or fecal calprotectin (>150 µg/g; HR 1.109, p = 0.407) at 1-year follow-up. Conclusion In this real-world experience allowing for drug optimization, no difference was observed in bio naïve patients between UST and RZB as far as clinical remission and progression of CD.

Abstract Background Risankizumab (RZB), a high-affinity humanised IgG1 monoclonal antibody targeting interleukin-23 p19, has shown sustained efficacy and an acceptable safety profile for patients (pts) with ulcerative colitis (UC).1 This interim analysis reports efficacy data at week (wk) 0 and wk 96, as well as safety data of the COMMAND (NCT03398135) open-label extension (OLE). Methods The COMMAND OLE enrolled pts who completed 52-wks maintenance dosing in the COMMAND substudies or entered directly from the induction study.1 All pts received RZB180 subcutaneous (SC) starting at OLE wk 0, except pts who had prior rescue therapy (single RZB 1200 mg intravenous [IV] dose then RZB360 Q8w) who continued RZB360 in the OLE. The OLE was not designed to compare RZB180 and RZB360 groups. The data cut-off date for this interim analysis was as of June 30, 2024. Efficacy endpoints assessed were clinical remission (CR) per AMS, clinical response per AMS, endoscopic improvement, endoscopic remission, and corticosteroid-free CR per Partial AMS up to wk 96. Data are reported as observed prior to RZB rescue therapy during OLE. The safety analysis also includes pts who directly entered the OLE from induction; presented as events/100 pt years (E/100 PY). Results Of the pts who entered the OLE (RZB180, N = 701; RZB360, N = 302), approximately 40% of pts had the opportunity to reach OLE wk 96 as of the cut-off date. At OLE wk 0 and 96, a similar proportion of patients in the RZB180 group achieved clinical and endoscopic outcomes (Figure 1A). In the RZB360 group, the percent of pts achieving clinical and endoscopic endpoints increased from OLE wk 0 through OLE wk 96 (Figure 1B). Similar rates of serious AEs, severe AEs, and AEs leading to discontinuation of study drug were reported in the RZB180 group and the RZB360 group with no new safety risks identified (Table 1). Conclusion In this interim analysis of the OLE, a sustained benefit was observed with long-term RZB treatment up to 96 wks. The long-term safety profile for RZB remains consistent and supports the long-term use. References 1. Louis E et al. JAMA 2024;332(11):881-897

INTRODUCTION: Patients with ulcerative colitis (UC) and prior biologic failure may have reduced or delayed efficacy with subsequent advanced therapies. This analysis evaluated the efficacy and safety of ozanimod during the True North (TN) study and its open-label extension (OLE) in biologic-exposed patients with UC. METHODS: TN was a randomized, placebo-controlled 52-week trial (10-week induction, 42-week maintenance period). Eligible patients could enter the OLE. Clinical outcomes were assessed at TN week (W) 10 and W52 and OLE W46 and W94. Symptomatic efficacy was evaluated through induction and in the OLE until W94. Safety was assessed. RESULTS: This analysis included 376 biologic-exposed patients. In the placebo-controlled cohort, more ozanimod-treated patients achieved clinical response than placebo at W10 regardless of the number or type of prior biologics; patients who used 1 vs ≥2 prior biologics achieved higher efficacy rates. Efficacy rates were higher at W52 than W10 and were similar across subgroups regardless of the number or type of prior biologics. Significantly greater proportions of ozanimod vs placebo patients achieved symptomatic response by W5 ( P = 0.0173) and symptomatic remission by W10 ( P = 0.0207). Among biologic-exposed TN W10 ozanimod nonresponders who entered the OLE, 61% achieved symptomatic response with an extra 10 weeks of ozanimod treatment. Ozanimod efficacy was durable for ∼3 years of continuous treatment in biologic-exposed W52 clinical responders who entered the OLE. No new safety signals were observed. DISCUSSION: Ozanimod was effective and safe in biologic-exposed patients with UC, but these patients may require more time to respond to treatment. Clinical trial registry website and trial numbers: ClinicalTrials.gov, numbers NCT02435992 and NCT02531126.

Background: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). It is known that non-serious treatment-emergent adverse events (TEAEs) may not lead to UC drug discontinuation but can affect treatment tolerability. Objectives: This post hoc analysis evaluated the incidence of specific, common, non-serious TEAEs reported in the etrasimod UC clinical programme and the characteristics of affected patients. Design: Data included patients from the Placebo-controlled UC cohort (phase II OASIS, and phase III ELEVATE UC 52 and ELEVATE UC 12 trials) receiving QD etrasimod (2 or 1 mg) or placebo. Methods: Proportions and incidence rates (IRs; the number of patients with a TEAE divided by the total exposure in patient-years (PYs), per 100 PY) of Headache, Pyrexia, Nausea and Dizziness TEAEs were reported. Changes in heart rate among patients with Dizziness TEAEs were also evaluated. Results: Among 943 patients (etrasimod 2 mg, N = 577 (276.7 PY); etrasimod 1 mg, N = 52 (11.4 PY); placebo, N = 314 (115.1 PY)), 48, 34, 27 and 21 patients experienced events of Headache, Pyrexia, Nausea and Dizziness, respectively. All events were non-serious; one patient treated with etrasimod was discontinued due to a Pyrexia TEAE. Numerically, IRs of Headache and Dizziness TEAEs were higher, and Nausea slightly higher, with etrasimod versus placebo (13.45 vs 8.63 per 100 PY, 6.52 vs 1.69 and 7.18 vs 5.13 per 100 PY, respectively); IRs were similar for Pyrexia. The duration of most TEAEs was 1–10 days. Conclusion: In the etrasimod UC clinical programme, all Headache, Pyrexia, Nausea and Dizziness events were non-serious. Headache and Dizziness were more frequent, and Nausea slightly more frequent, among patients receiving etrasimod versus placebo. The post hoc nature of this analysis is a limitation. These results reiterate the favourable safety profile and tolerability of etrasimod. Trial registration: ClinicalTrials.gov: NCT02447302; NCT03945188; NCT03996369.

Abstract Background and Aims Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal dysplasia and colorectal cancer compared to the general population. Although the use of surveillance protocols has improved the ability to detect dysplasia, some lesions are still missed at colonoscopy. This study aims to determine the rate of dysplastic lesions that are undetected at colonoscopies in IBD patients undergoing colectomy and to identify factors associated with missed dysplasia. Methods Patients who had received a total or subtotal colectomy at Mayo Clinic (Rochester, Minnesota), between January 2003 and December 2022, and had a complete colonoscopy within 5 years before surgery were retrospectively enrolled. Data abstracted included demographic information, disease-related data, colonoscopy and pathology reports, and surgery pathology reports. Colonoscopy and surgery findings were compared, and patients were divided into 3 groups: no dysplasia at both, detected dysplasia, and undetected dysplasia. Results Among 1320 IBD patients undergoing colectomy, 5.4% had undetected dysplastic lesions identified only at surgery. Factors independently associated with dysplasia detection were endoscopic remission or mild endoscopic disease activity (odds ratio [OR], 2.326; P = .0081; 95% CI, 1.246-4.342), prior dysplasia detection (OR, 1.876; P = .0491; 95% CI, 1.002-3.511), colonoscopy performed for surveillance (OR, 2.380; P = .0048; 95% CI, 1.302-4.350), and longer disease duration at surgery (OR, 1.039; P = .0085; 95% CI, 1.010-1.070). Conclusions Clinicians should be aware of the risk of missing dysplastic lesions, especially when endoscopic disease activity is moderate/severe, and not only for longstanding disease. Efforts should be made to obtain endoscopic remission to make the “invisible” visible.