Introduction

Ozanimod (OZA) was efficacious and well tolerated over 52 wk in pts with moderately to severely active ulcerative colitis (UC) in the phase 3 True North (TN) study (NCT02435992). Previous interim analyses of the ongoing TN open-label extension (OLE; NCT02531126) through OLE Week (W) 142 demonstrated long-term efficacy and safety of ~4 y of continuous OZA treatment.

Aims & Methods

The efficacy and safety of OZA were assessed for an additional year in pts who completed OLE W190 (~5 y of continuous OZA) or discontinued the OLE by data cutoff (January 10, 2024). Clinical responders after 52 wk of continuous OZA treatment (0.92 mg/d) who subsequently entered the OLE were included. Symptomatic response and symptomatic remission were evaluated from OLE W5 through OLE W190. Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at OLE W46, W94, W142, and W190. Treatment-emergent adverse events (TEAEs) were monitored during TN and the OLE through data cutoff. Laboratory abnormalities, including absolute lymphocyte count (ALC) reductions, were repeatedly assessed during the OLE through data cutoff.

Results

In all, 131 W52 clinical responders entered the OLE. At data cutoff, 75/131 pts (57.3%) had completed OLE W190; the most common reasons for discontinuation up to OLE W190 included withdrawal by pt (19/131 pts, 14.5%) and lack of efficacy (15/131 pts, 11.5%). Symptomatic response was maintained in the OLE, with 76/77 pts (98.7%) and 62/63 pts (98.4%) achieving the endpoint at OLE W142 and OLE W190, respectively, in the observed case (OC) analysis (76/131 pts [58.0%] and 62/131 pts [47.3%], respectively, in the nonresponder imputation [NRI] analysis). Similar patterns were observed for symptomatic remission, with 68/77 pts (88.3%) and 54/63 pts (85.7%) achieving the endpoint at OLE W142 and OLE W190, respectively, in the OC analysis (68/131 pts [51.9%] and 54/131 pts [41.2%], respectively, in the NRI analysis). Clinical remission, clinical response, endoscopic improvement, and CS-free remission were also maintained over an additional year in the OLE (Table). There were no new cases of bradycardia, third-degree atrioventricular block, infection (including serious infection and herpes zoster), macular edema, or malignancy, and no new discontinuations due to TEAEs with an additional year in the OLE. ALC <200 cells/µl was observed in 8/131 pts (6.1%); however, none of these pts developed serious or opportunistic infections during the OLE. No serious hepatic events occurred.

Conclusion

OZA efficacy was sustained for a total of ~5 y of continuous treatment in TN and the OLE. No new safety concerns were observed. These findings suggest that OZA is a durable, safe, and tolerable therapy for pts with UC for up to 5 y.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, and Alexandra Stafford, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.
JOL: received consulting and/or speaker fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Engitix, Ferring, Galapagos, Gilead, GlaxoSmithKline, Janssen, MSD, Napp, Orchard Therapeutics, Pfizer, Shire, and Takeda; received investigator-led research grants from AbbVie, Gilead, and Takeda.
SD: received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor.
DCW: received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, and Takeda.
KM: received speaker fees from AbbVie, EA Pharma, Eli Lilly, Gilead, Janssen, Kissei, Mitsubishi Tanabe, Mochida, Pfizer, and Takeda; received research grants from AbbVie, JIMRO, Mochida, Nippon Kayaku, and Zeria.
ID: served as a speaker, consultant, and advisory board member for AbbVie, Altman, Athos, Celltrion, Celgene/Bristol Myers Squibb, Eli Lilly, Ferring, Gilead, Galapagos, Iterative Scopes, Janssen, Pfizer, Roche/Genentech, Sangamo, Sublimity, Sandoz, Takeda, and Prometheus; shareholder of Gutreat and Harp Diagnostics.
BSB: consultant for Bristol Myers Squibb and Pfizer; received grant support from Merck and Gilead.
LER: consultant and/or advisory board member for Bristol Myers Squibb, Fresenius Kabi USA, Geneoscopy, Janssen, Roivant Sciences, and Takeda.
DM, NRS, AP, MD, HW, DW, MTO, and AJ: employees and/or shareholders of Bristol Myers Squibb
RKC: consulted for AbbVie, Adiso, Bristol Myers Squibb, Fresenius Kabi, Fzata, Janssen, Magellan Health, Option Care Health, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, Sebela, and Takeda; received grant support from Janssen; scientific co-director of the CorEvitas Registry; executive committee member of the IBD Education Group.

Introduction

The options for treating chronic inflammatory bowel disease (IBD) with biologics and small molecules (advanced therapies (AT)) have expanded considerably in recent years with the approval of new targeted drugs, some of which have novel mechanisms of action. Direct comparison of effectiveness in the real world is not easy. Therapy persistence measures the willingness of physicians and patients to continue treatment and is therefore a long-term indicator of the effectiveness and safety of a therapy.

Aims & Methods

The aim is to indirectly compare the treatment persistence of different ATs (adalimumab (ADA), infliximab (IFX), vedolizumab (VDZ), IL-12/23 and IL-23 inhibitors (IL-12/23) and JAK inhibitors (JAKi)) stratified by Crohn's disease (CD) and ulcerative colitis (UC).
The TARGET register collects data on the effectiveness and safety of ATs in IBD patients throughout Germany and is designed as a prospective, indication-stratified (CD and UC), multicentre, non-interventional cohort. Data are currently being collected after weekly follow-up during the induction phase and then every 6 months during maintenance therapy. In this analysis, data from 807 patients who were enrolled between November 2019 and December 2023 and followed in the TARGET registry for at least 12 months were analysed up to the cut-off date of 31 December 2024. Treatment persistence was calculated up to 5 years and compared using Kaplan-Meier (KM) curves (log-rank test).

Results

In patients with CD, there were 610 treatment courses with a newly started AT: 198 ADA, 161 IFX, 89 VDZ, 147 IL12/23 (140 UST, 7 RISA), 15 JAKi (1 TOFA, 14 UPA) with a mean observation period of 38, 38, 31, 31 and 9 months. The treatment groups differed in terms of disease duration and the proportion of biologic-experienced patients: both were lowest in the anti-TNF group (Table 1). The persistence rates at 5 years were 79.8% for ADA, 82.0% for IFX, 74.2% for VDZ, 85.7% for IL-12/23 and 100% for JAKi and were not statistically different (p=0.167).
In patients with UC, there were 339 treatment courses with newly initiated AT: 45 ADA, 102 IFX, 111 VDZ, 47 IL12/23 (46 UST, 1 MIRI), 34 JAKi (8 TOFA, 10 FIL, 16 UPA) with a mean observation period of 33, 35, 34, 23 and 16 months. The treatment groups differed in the proportion of patients with prior biologic exposure, which was lowest in the anti-TNF group (Table 1). The persistence rates at 5 years were 66.7% for ADA, 78.4% for IFX, 70.3% for VDZ, 59.6% for IL-12/23 and 91.2% for JAKi. IFX was statistically superior to IL-12/23 (p=0.014).

Conclusion

All patients showed high AT persistence rates of approximately 60-80% up to 5 years, with only minor differences between the different lines of therapy in this current analysis.

Disclosure

PE has received personal fees from: AbbVie, BMS, Galapagos, Janssen, and Amgen, outside the submitted work.
WM has received consulting fees from: AbbVie, Advanz, Amgen, Biogen, Bristol-Myers Squibb, Ferring, Fresenius Kabi, Galapagos, Hexal, Janssen, and Takeda, outside the submitted work. Fees for lectures and further education from: AbbVie, alanta health service, Bristol-Myers Squibb, Galapagos, Janssen, Pfizer, Takeda, and Tillotts, outside the submitted work. He is an active member of the following public law bodies: Advisory Commission of the Examination Office for the Saarland, the State Committee of Physicians and Health Insurance Companies and the Extended State Committee, and an employee in a company belonging to Alanta health group GmbH, Hamburg, Germany, outside the submitted work. Shares, other fees from: AbbVie outside the submitted work.
UT has served as a consultant for Ferring, Abbvie, Janssen-Cilag, Falk-Foundation outside the submitted work.
BB has served as a consultant or advisory board member for Abbvie, MSD, Shire, Ferring, Takeda, Movetis, Shield Therapeutics, Pfizer, Biogen, Janssen, Hexal, Cellgene, Allergan, Galapagos, Arena, BMS, Merckle, Falk and Celltrion outside the submitted work.
SS has served as a consultant or advisory board member for AbbVie, Amgen, Arena, Bristol Myers Squibb, Biogen, Celltrion, Celgene, Ferring, Fresenius, Galapagos, Gilead, HIKMA, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal, Takeda, Theravance and UCB outside the submitted work.
SPD, EG, FHE, MvdO, SFS and TW have no relevant financial or non-financial interests to disclose.

Introduction

Biologic and small-molecule therapies are widely used for ulcerative colitis (UC), but their comparative effectiveness in TNF-exposed patients remains unclear.

Aims & Methods

This study evaluates the clinical and biomarker responses to Vedolizumab, Tofacitinib, and Ustekinumab over 12 months, adjusting for baseline differences using Inverse Probability of Treatment Weighting (IPTW). A multicenter retrospective cohort of TNF-exposed UC patients treated with Vedolizumab (n = 260), Tofacitinib (n = 149), or Ustekinumab (n = 193) was analyzed. Clinical outcomes, including Partial Mayo Score (pMayo), clinical remission, and biomarker response (CRP, ESR, fecal calprotectin), were assessed at baseline (T0), 8 weeks (T1), 24 weeks (T2), and 52 weeks (T3). IPTW balanced baseline characteristics, and longitudinal changes were analyzed using a repeated-measures general linear model (GLM) with post-hoc corrections for multiple comparisons.

Results

Before IPTW, significant baseline differences existed, with Tofacitinib patients being younger (p < 0.001), more frequently female (p = 0.003), and having higher fecal calprotectin levels (p = 0.005). After IPTW, covariate balance was achieved (SMD < 0.10). pMayo scores significantly declined in all treatment groups over time (p < 0.001, η² = 0.469), with no significant main effect of therapy (p = 0.329). A minor time-by-therapy interaction (p = 0.036, η² = 0.026) indicated slight response variations but lacked clinical significance. Before IPTW, Tofacitinib showed superior pMayo improvement versus Ustekinumab (p = 0.008), but this difference lost significance post-IPTW, suggesting baseline confounding. At 52 weeks, clinical remission was highest with Tofacitinib (57%), followed by Vedolizumab (40%) and Ustekinumab (22%) (p = 0.003). Biomarker remission favored Vedolizumab (48.8%) over Tofacitinib (19.5%) and Ustekinumab (21.2%) (p = 0.002). Adverse events were rare but more frequent with Vedolizumab (p < 0.001).

Conclusion

Over 12 months, all therapies significantly improved clinical and biomarker outcomes, with no significant differences in overall pMayo reduction post-IPTW. Tofacitinib achieved the highest clinical remission, while Vedolizumab demonstrated superior biomarker response. These findings highlight the need for individualized treatment selection in TNF-exposed UC patients.

Introduction

Colorectal pinch biopsies may result in substantial histological artifacts in the form of tissue fragmentation, haemorrhage and large quantities of Muscularis Mucosa (MM) in the biopsy. Current digital Quality Control (QC) approaches on colorectal Whole Slide Images (WSIs) focus on laboratorial discrepancies and overlook quantifying the presence of such features that either confound or are irrelevant to routine scorings. Identifying these features can therefore aid in excluding inadequate slides or provide visual cues to guide histological assessment of inflammatory bowel disease (IBD). Accordingly, we built a deep learning system to identify muscularis mucosa (MM), blood, and tissue fragmentation in WSIs to streamline colorectal sample QC and the pathologist assessment process.

Aims & Methods

We trained Convolutional Neural Network (CNN) segmentation models for H&E images of bowel biopsies using 52 manually annotated WSIs, with 26 training WSIs (161 biopsy sections) and 26 testing WSIs (184 biopsy sections), developing clear-cut annotations for these features using a human-in-the-loop training paradigm. We exported 5,241 image-annotation training pairs (256*256 pixels) for MM and 3,743 for blood, applying augmentations before training a UNet++ CNN with an 80:20 split (training:validation). We implemented custom spatial postprocessing pipelines to harmonise predictions and improve overall accuracy.

Results

Our AI models accurately distinguished MM and blood in WSIs despite their similar appearance, and we quantified these relative to total tissue content in 129 patients with IBD. The MM model provided a useful visual reference for the identification of crypt shortfall and sample orientation, while the blood model helped identify sampling damage by flagging slides with high laminal blood content. We found MM accounted for 11.6% ± 10.9% of the biopsy section area across 594 WSIs. A significant presence of blood was also observed, primarily located in the lamina propria. We introduced a tissue fragmentation score and quantified it across 317 biopsies to determine areas of tissue which were damaged and showed its effectiveness as a metric for identifying degraded tissue sections.

Conclusion

Our tissue biopsy evaluation models accurately delineate MM and blood and quantify tissue fragmentation. By assessing key biopsy features often overlooked by other QC systems, our pipeline has the potential to offer valuable guidance, including re-cut recommendations, to enhance the evaluation of sample adequacy in IBD.

Disclosure

RL/DW/AM/PA/PW and CL are employees at Perspectum Ltd. EF and RG are consultants for Perspectum Ltd. All other co-authors have no conflicts of interest to declare relevant to this work.