Background The systematic review and meta-analysis (SRMA) evaluates the safety and effectiveness of combining biologics and/or small molecules in treating refractory inflammatory bowel diseases (IBD).Methods Our 2022 SRMA identified 13 studies published until November 3, 2020. An updated systematic search was completed from May 2020 through January 31, 2024. Random-effects inverse variance model was used to calculate pooled estimates for adverse events (AEs) and clinical and endoscopic-radiologic response/remission rates in IBD patients.Results Twenty-seven eligible studies had 619 patients and 631 therapeutic trials (TTs). Upadacitinib (UPA) + vedolizumab (VDZ) and tofacitinib (Tofa) + anti-TNF (aTNF) had the lowest AEs rate (0%, 2 TTs) and (9.2%, 33 TTs), respectively. Higher AE rates were seen in natalizumab (NAT) + aTNF (92.3%, 52 TTs) and aTNF + guselkumab (63.4%, 71 TTs). No serious AEs (SAEs) were observed in NAT + aTNF (52 TTs), Tofa + ustekinumab (UST) (23 TTs), and UPA + VDZ (2 TTs). The highest rate of SAEs was observed in UPA + UST (23%, 17 TTs). UPA + UST and UPA + VDZ had 100% clinical response rates and the highest clinical remission rates (83.3%, 12 TTs) and (100%, 2 TTs), respectively. High clinical response rates were also seen in Tofa + aTNF (82.7%, 34 TTs), UST + aTNF (82.1%, 63 TTs), and VDZ + UST (82.0%, 71 TTs).Conclusions Combining biologics and/or small molecules may be effective for IBD patients who fail to achieve remission with monotherapy; however, safety profiles need to be carefully considered prior to implementing these strategies in clinical practice.

Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation1,2. Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

BACKGROUND & AIMS:Interventional clinical trials in acute severe ulcerative colitis (ASUC) are characterized by substantial heterogeneity due to a lack of consensus in several key areas of trial design-this impedes clinical research efforts to identify novel therapies. The objective of this initiative was to achieve the first consensus and provide clear position statements on ASUC trial design. METHODS:A modified Delphi consensus approach was employed with a panel of 20 clinicians with international representation and expertise in ASUC trial design and delivery. Agreement was defined as at least 75% of participants voting as "agree" with each statement. RESULTS:In total, 30 statements achieved consensus and were approved. Statements centred on proposing suitable eligibility criteria (disease extent, disease severity, prior therapy exposure), optimizing trial design (randomization, stratification, corticosteroid handling, timing of assessments), and recommending primary and secondary endpoints alongside defining key efficacy outcomes (clinical and endoscopic response and remission, treatment failure, quality of life). CONCLUSIONS:The expansion of drugs to treat moderate-severe ulcerative colitis over the past decade, particularly the rapidly acting Janus kinase inhibitors, is promising and has reignited the interest in identifying suitable therapeutic candidates for ASUC. Clinical trials in this high-risk population are challenging to conduct and this consensus provides a framework for future trials to advance drug development.

Background Tamuzimod (VTX002) is a selective sphingosine 1-phosphate receptor 1 modulator in development for ulcerative colitis. We aimed to assess the safety and efficacy of tamuzimod in patients with moderately-to-severely active ulcerative colitis. Methods This double-blind, randomised, placebo-controlled, phase 2 induction trial was conducted at 122 centres across 15 countries in Asia, Europe, and North America. Patients aged 18-80 years with a modified Mayo score (MMS) of 4-9 and an inadequate response or a loss of response, or intolerance to one or more approved ulcerative colitis therapies were randomly assigned (1:1:1) to once-daily oral tamuzimod (60 mg or 30 mg) or placebo for 13 weeks. Randomisation was stratified by previous advanced therapy, baseline corticosteroid, and baseline MMS. The primary endpoint was clinical remission (defined as an MMS stool frequency subscore of <= 1, rectal bleeding subscore of 0, and endoscopic subscore <= 1, excluding friability) at week 13. Adverse events and laboratory abnormalities were assessed for safety. Efficacy and safety analyses included all randomly assigned patients who received at least one study dose, with the efficacy analysis restricted to patients with a baseline MMS of 5-9 based on regulatory feedback. The study was registered with ClinicalTrials.gov, NCT05156125, and EudraCT, 2021-003050-23. Findings Between Nov 4, 2021, and Aug 30, 2023, 367 patients were screened, and 213 (mean age 406 years [SD 142]; 116 [54%] males and 97 [46%] females) were randomly assigned to tamuzimod 60 mg (n=70), tamuzimod 30 mg (n=73), or placebo (n=70). Two in the tamuzimod 30 mg group and two in the tamuzimod 60 mg group with baseline modified Mayo score of 4 were excluded from the efficacy analysis. At week 13, clinical remission was reached by 19 (28%) of 68 patients receiving tamuzimod 60 mg, 17 (24%) of 71 patients receiving tamuzimod 30 mg, and eight (11%) of 70 patients receiving placebo (risk difference 165% [95% CI 32 to 294], p=0018, for tamuzimod 60 mg vs placebo and 125% [-02 to 249], p=0041, for tamuzimod 30 mg vs placebo). Treatment-emergent adverse events occurred in 33 (47%) of 70 patients receiving tamuzimod 60 mg, 34 (47%) of 73 patients receiving tamuzimod 30 mg, and 24 (34%) of 70 patients receiving placebo. Most adverse events were mild or moderate. The most frequently reported treatment-emergent adverse events (in >= 5% of in any treatment group) were upper respiratory tract infection (six [9%] of 70 patients in the tamuzimod 60 mg group, one [1%] of 73 in the tamuzimod 30 mg group, and one [1%] of 70 in the placebo group), anaemia (three [3%], four [5%], and six [9%]), and headache (four [6%], five [7%], and two [3%]). No adverse events of atrioventricular block, bradycardia, macular oedema, severe or opportunistic infections, malignancies, or deaths occurred. Interpretation Induction therapy with tamuzimod was effective and well tolerated in patients with ulcerative colitis. These results and the favourable risk-benefit profile of tamuzimod collectively support the continued clinical development of tamuzimod for the treatment of moderately-to-severely active ulcerative colitis. Funding Ventyx Biosciences. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Abstract Background Obefazimod is an oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC across 4 clinical studies: two placebo-controlled Phase 2 induction trials, and two subsequent open-label maintenance (OLM) studies [2, 3]. Here we report an integrated safety analysis of those studies in the UC clinical program. Methods Exposure-adjusted incidence rates (EAIRs per patients-years [PY]) of treatment emergent adverse events (TEAEs) were examined among patients from the induction trials (NCT03093259, NCT03760003), and the OLM studies (NCT03368118, NCT04023396). Patients received one of three obefazimod doses (25mg, 50mg or 100mg QD) or placebo during induction, and all patients received 50 mg QD during OLM studies. Results Demographics and disease characteristics were similar among treatment groups. Exposure for all obefazimod-treated patients (N=274) was 440.1 PY including induction and maintenance periods. EAIR of TEAEs per PY was 1.40 in obefazimod-treated patients and 2.40 in placebo-treated patients (N=73), with TEAEs occurring in 78.5% and 47.9% of patients, respectively (Table 1). The most common TEAEs (EAIR per PY ≥ 0.05) in all obefazimod-treated patients included headache, Covid-19, ulcerative colitis, nasopharyngitis, and nausea. For each of these TEAEs, the incidence per PY was numerically lower in the group of all obefazimod-treated patients relative to placebo. Conclusion This integrated safety analysis of the 4 completed studies in the obefazimod UC clinical program indicates that exposure-adjusted incidence rates of TEAEs were generally numerically lower among patients treated with obefazimod relative to placebo. Integrated safety data further support a favorable safety and tolerability profile. References 1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697 2. Vermeire S, et al. Gastroenterology 2021; 160: 2595-2598 3. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.

BACKGROUND:Endoscopy is essential for measuring luminal disease activity in Crohn's disease. Existing indices for evaluating endoscopic Crohn's disease activity are only modestly correlated with clinical disease activity, contain items with ambiguous definitions and poor interobserver reliability, and do not have validated thresholds for defining clinically relevant changes. To address these issues, we conducted a multiphase study to develop and validate a novel endoscopic index for Crohn's disease. METHODS:Paired baseline and post-induction ileocolonoscopy videos from a phase 3b adalimumab trial (NCT00348283) and phase 2 risankizumab trial (NCT02031276) were assessed by multiple central readers using candidate endoscopic items with face validity derived using modified RAND/UCLA appropriateness methods. The four readers were masked to all clinical information, including treatment assignment and patient symptom scores. A total of 112 and 99 paired ileocolonoscopy videos with treatment assignment were available from the adalimumab trial and risankizumab trial, respectively; after the four readers assessed the 112 videos, two readers then reassessed 44 post-treatment videos to assess inter-rater reliability in index development. Items with acceptable inter-rater reliability (with an intraclass correlation coefficient [ICC] of ≥0·41) and responsiveness (win probability [WinP], the probability that a patient receiving active treatment has a better endoscopy score than a patient receiving placebo, of ≥0·56) were included as covariables in regression for model building with internal validation with bootstrapping. External validation was conducted using the paired videos from the risankizumab trial. FINDINGS:Ten endoscopic items met ICC and WinP thresholds and were considered for novel index development. They included items from the SES-CD (presence and size of ulcers, extent of ulcerated surface, and extent of affected surface) and CDEIS (percentage of surface involved by Crohn's disease, percentage of ulcerated surface, deep ulceration, and superficial ulceration) and exploratory items (presence of Crohn's disease-related lesions, Crohn's disease-related lesion severity, and Crohn's disease-related lesion involvement). The final model, Endoscopic ulcer Activity Score for Evaluating CD (EASE-CD), included the presence and size of ulcerations measured on an ordinal scale of 0 (none), 1 (ulcers <5 mm), 2 (ulcers between 5 mm and 20 mm), and 3 (ulcers >20 mm); the presence or absence of deep ulcerations measured dichotomously, with 0 for absent and 1 for present; and the proportion of ulcerated surface area, expressed as a continuous proportion from 0-1, with each item evaluated and averaged across visualised bowel segments. The total score ranges from 0-100 with higher scores indicating greater endoscopic activity. The r2 and optimism adjusted r2 of EASE-CD in internal validation were 0·608 and 0·554, and the index was well calibrated with a slope of 0·983. In external validation, the adjusted r2 was 0·565 and the calibration slope was 0·997. EASE-CD also demonstrated substantial inter-rater reliability (ICC 0·798 [95% CI 0·711-0·836]) and a large degree of responsiveness (WinP 0·769 [95% CI 0·658-0·851], p<0·001) in external validation. A 10-point reduction in EASE-CD had 82·4% specificity (95% CI 78·6-86·0) and 69·9% sensitivity (63·3-76·4) for endoscopic response, defined by at least 50% reduction in SES-CD or CDEIS. Ulcer-free endoscopic remission results in EASE-CD score of 0. INTERPRETATION:EASE-CD is a novel, internally and externally validated continuous measure of endoscopic ulcer activity in Crohn's disease that is reliable and responsive to treatment. FUNDING:None.

Abstract Background In the phase 2, double-blind, placebo-controlled, multicenter ARTEMIS-UC trial, 12 weeks of induction treatment with the anti-tumor necrosis factor-like cytokine 1A (TL1A) monoclonal antibody tulisokibart led to significant rates of clinical remission, endoscopic improvement and mucosal healing, and improvement in patient-reported outcome (PRO) measures and disease surrogate biomarkers in patients with moderately to severely active ulcerative colitis (UC).1 This post-hoc analysis from ARTEMIS-UC examined the time course of improvement from baseline in patient-reported symptoms (PRO-2 score [combined Mayo stool frequency and rectal bleeding subscores]) and biomarkers (fecal calprotectin and high-sensitivity C-reactive protein [hs-CRP]) with tulisokibart. Methods Adults with moderately to severely active UC were randomized 1:1 to receive i.v. placebo or tulisokibart (1000 mg on Day 1 and 500 mg at Weeks 2, 6, and 10). The study population consisted of 2 cohorts based on a genetic diagnostic test (Dx) assessing likelihood for responding to anti-TL1A treatment. Cohort 1 included participants stratified by Dx results while Cohort 2 included only Dx positive participants. Cohort 1 is the population used in this post-hoc analysis. Participants recorded stool frequency and rectal bleeding scores daily using an e-diary. Fecal calprotectin was assessed at baseline and Weeks 6 and 12, and hs-CRP was assessed at baseline and Weeks 2, 6, 10, and 12. Symptomatic response was defined as a reduction from baseline in PRO-2 score ≥ 1 point. A mixed model repeated measures approach was used to compare tulikisobart to placebo for the difference in PRO-2 score for the first 14 days of treatment and the fold change from baseline in fecal calprotectin and hs-CRP at each timepoint. Results Among 135 randomized participants in Cohort 1, 60/67 (89.6%) receiving placebo and 68/68 (100%) receiving tulisokibart completed the 12-week induction period. The numerical difference in improvement of PRO-2 started as early as Day 2 and achieved significant improvement with tulisokibart compared to placebo at Day 9, with a sustained improvement persisting from the latter part of Week 2 through Week 12 (Figure 1, Table 1). Significant improvements with tulikisobart compared to placebo in fecal calprotectin and hs-CRP were observed by Weeks 6 and 2 (the first time point when these biomarkers were measured), respectively, which were maintained through Week 12 (Table 1). Conclusion In patients with moderately to severely active UC, induction with tulisokibart led to early and sustained improvement in patient-reported outcomes. Induction with tulisokibart also led to early and persistent improvement in biomarkers. References 1. Sands BE, et al. N Engl J Med 2024;391:1119-29.

BACKGROUND:Healing in Crohn's disease is complex and difficult to measure due to incongruencies between clinical symptoms and disease states. Mucosal healing (MH) and transmural healing (TH) are increasingly used to measure clinical improvement in Crohn's disease, but definitions of MH and TH can vary across studies, and their relationship to long-term outcomes is not clear. To address this knowledge gap, we performed a systematic literature review (SLR) to examine studies measuring MH and TH in Crohn's disease. METHODS:Database records from 2012 to 2022 were searched for real-world evidence and interventional studies that reported the association of MH or TH with clinical, economic, or quality of life outcomes of adult patients with Crohn's disease. RESULTS:A total of 46 studies were identified in the systematic literature review, representing a combined patient population of 5530. Outcomes of patients with MH were reported by 39 studies; of these, 14 used validated scales for endoscopic assessment. Thirteen studies reported outcomes of patients with TH. Among studies that examined the outcomes of patients with and without MH or TH, patients with healing generally experienced improved clinical outcomes and reduced healthcare resource utilization, including fewer hospitalizations and surgeries and improved rates of clinical remission. This was especially true for patients with TH. CONCLUSIONS:Mucosal and transmural healing are associated with positive long-term outcomes for adult patients with Crohn's disease. The adoption of standardized measures and less invasive assessment tools will maximize the benefits of patient monitoring.

Abstract Background Duvakitug is a human IgG1 monoclonal antibody that inhibits TL1A binding to DR3, a key driver of inflammation and fibrosis. In comparison, it has less binding selectivity for DcR3, which regulates excess TL1A, maintaining homeostasis. Duvakitug has demonstrated reduced inflammation and fibrosis in colitis animal models.1 Few data are available for the potential of anti-TL1A therapies in Crohn’s disease (CD). A phase 2b induction basket trial (NCT05499130)2 assessed the efficacy, safety and tolerability of duvakitug in adults with moderately to severely active ulcerative colitis and CD. Methods RELIEVE UCCD was a randomised, placebo (PBO)-controlled, double-blind induction study. The CD cohort comprised of adults with moderately to severely active disease with documented inadequate response, loss of response or intolerance to conventional and/or advanced therapies (ATs). Patients were randomised to receive subcutaneously a 2250 mg loading dose of duvakitug or PBO, followed by either duvakitug 450 mg, 900 mg or PBO (1:1:1; stratified by prior AT) every 2 weeks.2 Primary endpoint was endoscopic response (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) at week 14. Safety and tolerability were assessed by adverse event (AE) reporting and laboratory monitoring. Results In total, 138 patients with CD were randomised, treated and included in the analysis (n=46 per arm). Demographics and baseline characteristics were similar across arms (Table 1). Both duvakitug doses achieved the primary endpoint (26% [450 mg], 48% [900 mg] versus 13% [PBO]; PBO-adjusted rates: 13% [450 mg], 35% [900 mg]) with statistically significant endoscopic responses based on the prespecified Bayesian analysis, with a >0.90 posterior probability that each duvakitug dose is superior to PBO. Duvakitug treatment effect was observed in both AT-experienced and -naïve patients (Table 2). AE incidence was similar for duvakitug 900 mg (43%) and PBO (48%), and lower than duvakitug 450 mg (67%). Incidences of AEs leading to discontinuation were 2% each for duvakitug 900 mg and PBO, and 9% for duvakitug 450 mg. Conclusion These are the first data reported for a double-blind, randomised, PBO-controlled induction study of an anti-TL1A antibody in patients with CD. Duvakitug demonstrated statistically significant and clinically meaningful endoscopic response versus PBO with no emergent safety signals observed. These results support further development of duvakitug as a treatment option for patients with moderately to severely active CD. Funding Duvakitug is being developed in partnership between Teva and Sanofi. References 1. Clarke AW, et al. MAbs. 2018;10:664–77. 2. Reinisch W, et al. 19th Congress of European Crohn’s and Colitis Organization (ECCO) 2024; 21–24 February 2024; Stockholm, Sweden. Abstract P998.

Abstract Background Obefazimod is an investigational, oral, once-daily (QD), small molecule which enhances expression of microRNA-124 and demonstrated efficacy and safety in patients with moderately to severely active ulcerative colitis (UC) in a placebo-controlled, Phase 2b induction trial and the subsequent 96-week open-label maintenance (OLM) study [1, 2]. Here, we report proportions of patients that met endoscopic, histologic and combined histologic-endoscopic outcomes at the end of the induction trial (baseline of OLM), Weeks 48 (W48) and 96 (W96) of the OLM study. Methods Patients received obefazimod 25mg, 50mg or 100mg once daily (QD) or placebo during induction and could enter the optional 96-week OLM study irrespective of their clinical response to receive obefazimod 50mg QD. Rectal or sigmoidal biopsies were collected during endoscopy at OLM baseline, W48 and W96 to evaluate treatment effect on histopathology scores using the Geboes score. Endoscopic improvement (endoscopic sub-score ≤1), endoscopic remission (endoscopic sub-score = 0), histologic improvement (Geboes histologic score ≤3.1), histologic remission (Geboes histologic score <2.0), histo-endoscopic mucosal improvement (HEMI, Geboes histologic score ≤ 3.1 and endoscopic improvement) and histo-endoscopic mucosal remission (HEMR, Geboes histologic score <2.0 and endoscopic remission) were evaluated using as observed analysis (i.e. only patients with both endoscopic and histologic outcome for each endpoint) and non-responder imputation (NRI) for patients missing either endoscopy data and/or histology data. Results There were 217 patients that completed the induction trial and entered OLM. In a data-as-observed analysis, the proportions of patients achieving endoscopic improvement increased from 49% at OLM baseline to 73% at W48, and 78% at W96. The proportion of patients achieving histologic improvement rose from 59% at OLM baseline to 85% at W48, and 89% at W96; 39% achieved HEMI at OLM baseline, and increased to 69% at W48, and 74% at W96 (Table 1). Similar trends were observed for remission endpoints as well as in the NRI analysis. Conclusion In this Phase 2b OLM study, patients with moderately to severely active UC treated with obefazimod experienced clinically meaningful improvements in endoscopic, histologic, and combined histologic-endoscopic outcomes with proportions of patients meeting these endpoints consistently increasing from OLM baseline through W96. These data suggest sustained and progressive therapeutic benefits over time. References 1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-16972. 2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.

Abstract Background The combined achievement of endoscopic and histologic remission is an emerging therapeutic target in ulcerative colitis (UC) and is associated with lower clinical relapse rates and reduced corticosteroid use.1,2 Here, we present endoscopic and histologic outcomes following maintenance treatment with subcutaneous (SC) infliximab (IFX) using data from the LIBERTY-UC study.3 Methods In the LIBERTY-UC study,3 patients (pts) received induction doses of IFX 5 mg/kg via intravenous infusion at Weeks (W) 0, 2 and 6. Clinical responders at W10 were randomised 2:1 to receive either IFX SC every other week or a placebo (PBO) during maintenance therapy. All pts randomised at W10 were included in this post hoc analysis. Endoscopic and histologic assessments were performed at screening, W8, W22 and W54 (centrally evaluated). Endoscopic improvement (Mayo endoscopic subscore [MES] ≤1), endoscopic normalisation (MES=0), histologic remission (Robarts Histopathology Index [RHI] <3 without neutrophils in the epithelium or lamina propria) and the combination of histologic remission and endoscopic normalisation were assessed. Non-responder imputation was used for pts who underwent dose adjustment or had missing data. Data were analysed descriptively with nominal p-values. Results Baseline characteristics were similar between IFX SC and PBO groups, with 48.6% and 53.5% of pts having severe disease (MES=3); and mean histologic activity (RHI) of 17.0 and 18.0, respectively (Table). At W8, half of the pts achieved endoscopic improvement in both groups (IFX SC: 53.1%; PBO: 50.0%). From W22 onwards, the difference in rates of endoscopic improvement between the two groups was statistically significant (50.7% vs 34.0%; p=0.0011) up to W54 (43.9% vs 22.2%; p<0.0001). Similar findings were observed for histologic remission. Endoscopic normalisation rate in the IFX SC group increased with continued treatment (23.8% at W8, 26.9% at W22 and 32.7% at W54), while it declined in the PBO group (21.5% at W8, 18.8% at W22 and 11.1% at W54). Furthermore, a greater proportion of pts in the IFX SC group achieved combined histologic remission and endoscopic normalisation compared to the PBO group from W22 up to W54 (22.1% vs 16.7% at W22; p=0.2072; 27.9% vs 11.1% at W54; p<0.0001) (Figure). Conclusion Maintenance treatment with IFX SC resulted in significantly greater improvements in endoscopic and histologic outcomes at W54 compared to PBO. Endoscopic improvements were observed as early as W8, along with enhancements in stringent endpoints such as endoscopic normalisation and the combined endpoint of histologic remission and endoscopic normalisation over time, supporting the sustained benefit of a maintenance therapy with IFX SC. References 1. Yoon H, et al. Gastroenterology. 2020;159(4):1262-1257.e7. 2. Bryant RV, et al. Gut. 2016;65(3):408-414. 3. Hanauer SB, et al. Gastroenterology. 2024;167(5):919-933.

Abstract Background VIVID-2 (NCT04232553) is an ongoing open-label long-term extension study of efficacy and safety of mirikizumab (MIRI), a selective interleukin-23p19 inhibitor, in patients with moderately to severely active Crohn’s disease (CD). We present efficacy and safety results from patients randomised to MIRI in the phase 3 VIVID-1 study (NCT03926130) who received MIRI for a second year in VIVID-2, with or without reinduction. Methods In VIVID-1, the MIRI group received induction with 900 mg intravenously (IV) at weeks (W) 0, 4, and 8, then 300 mg subcutaneously (SC) every 4W. Week 52 endoscopic responders (≥50% reduction from baseline in Simple Endoscopic Score for CD [SES-CD]) continued the same MIRI SC dosing in VIVID-2. Endoscopic non-responders received reinduction with MIRI IV at the start of VIVID-2 followed by SC dosing (IV-SC) as described. Outcomes at W104 of MIRI treatment included endoscopic response and endoscopic remission (SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1 for any individual variable). The cutoff date was 02 August 2024; VIVID-2 patients entered after 01 August 2023 were excluded from this interim analysis. Safety was assessed from the first dose in VIVID-2 through the cutoff date. Discontinuations or missing data were handled using modified nonresponder imputation (mNRI) and observed cases (OCs). Results Among MIRI endoscopic responders (N=251) who continued MIRI SC, 81.8% (mNRI)/87.6% (OC) maintained endoscopic response at W104 (Fig. 1A). At W104, endoscopic remission was maintained by 72.5% (mNRI)/78.6% (OC) of the 137 patients also in endoscopic remission at W52 and gained by a further 33.3% (mNRI)/35.4% (OC) of the 112 patients not in endoscopic remission at W52 (Fig. 1A). Among MIRI endoscopic nonresponders (N=179) who received reinduction with MIRI IV at the start of VIVID-2 followed by MIRI SC, 30.9% (mNRI)/36.1% (OC) gained endoscopic response; 12.1% (mNRI)/13.7% (OC) of the 174 patients not in endoscopic remission at W52 gained endoscopic remission at W104 (Fig. 1B). Treatment-emergent adverse events (AEs) were reported in 64.3% (MIRI SC) and 65.3% (MIRI IV-SC) of patients, and serious AEs were reported in 6.8% (MIRI SC) and 9.0% (MIRI IV-SC) of patients (Table 1). Conclusion In VIVID-2, high maintenance rates of endoscopic response and endoscopic remission were observed in patients with moderately to severely active CD who were endoscopic responders at 1 year, with additional patients gaining endoscopic remission in year 2 of MIRI treatment. Over 30% of endoscopic nonresponders at 1 year gained endoscopic response with MIRI reinduction. Overall, safety was consistent with the known MIRI safety profile.