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UP-FRONT VEDOLIZUMAB VERSUS CONVENTIONAL TREATMENT FOR CHECKPOINT INHIBITOR INDUCED COLITIS – VEICO: AN OPEN LABEL RANDOMIZED CLINICAL TRIAL

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Introduction

Immune checkpoint inhibitor (ICI) mediated enterocolitis (IMC) may lead to treatment discontinuation. Corticosteroids for IMC is associated with serious side effects and might affect cancer progression in addition to preclude continued ICI treatment. We hypothesized that vedolizumab, a gut selective α4β7 integrin inhibitor, is effective as a first-line treatment and investigated whether vedolizumab reduces corticosteroid exposure and facilitate ICI resumption.

Aims & Methods

We conducted a single center, open-label, explorative phase 2 trial including patients treated with ICI who developed IMC. Patients were randomized 1:1 ratio to receive vedolizumab (300 mg) or standard treatment with corticosteroids, with infliximab used as recue therapy for corticosteroid failure. The primary outcome was cumulative corticosteroid dose at week 30. Key secondary outcomes included cumulative corticosteroid dose at week 10, corticosteroid free remission at week 10 and ICI resumption rates.

Results

Twenty-two patients received vedolizumab, and 19 patients received standard treatment. At week 10, the mean cumulative corticosteroid use was significantly lower in the vedolizumab arm (1157 mg vs. 2207 mg). By week 30, the mean corticosteroid use remained lower but not statistically significant (1378 mg vs. 2390 mg, estimated difference 1012 mg, 95% CI -229 to 2253, p=0.107), Among patients with less severe IMC, who did not need corticosteroids during screening, vedolizumab-treated patients used in average 1729 mg less corticosteroid (95% CI 631 to 2827). Corticosteroid-free remission at weeks 2 and 10 was more common with vedolizumab. Seven patients (33.3%) in the vedolizumab group resumed with ICI compared to three (16.7%) in the standard arm. In patients with severe colitis, who required upfront corticosteroid treatment, a trend towards longer hospitalization in the vedolizumab arm was observed.

Conclusion

For patients with less severe colitis, not needing corticosteroids during screening, vedolizumab may be a viable corticosteroid-sparing option, enabling faster remission and ICI resumption.

Disclosure

The study was funded by Aage og Johanne Louis-Hansens Fond, National Research grants. Takeda Pharma provided the study drug vedolizumab.

UP-FRONT VEDOLIZUMAB VERSUS CONVENTIONAL TREATMENT FOR CHECKPOINT INHIBITOR INDUCED COLITIS – VEICO: AN OPEN LABEL RANDOMIZED CLINICAL TRIAL

Emilie Kristine Dahl 1, Jacob Wium Bjerrum 2, Katrine Risager Christensen 2, Anita Bilde Wozniak 2, Johan Fremberg Ilvemark 2, Milos Mathias Koch 3, Paul Blanche 3, Nicolai Ditzel Vad 4, Marco Donia 2, Inge Marie Svane 2, Jacob Seidelin 2

1 Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

2 Copenhagen University Hospital, Herlev, Denmark

3 Copenhagen University, Copenhagen, Denmark

4 Copenhagen University Hospital, North Zealand, Denmark

Event

UEG Week Berlin 2025

Topics

Gut Microbiota IBD Immunology Mechanisms & Personalised Medicine

Submission format

Late-Breaking Abstract

Session

Late-breaking trials in IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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The treatment

Judith Wellens 1

1 University Hospitals Leuven, Leuven, Belgium

Event

UEG Week Berlin 2025

Topics

IBD Primary Care

Session

When IBD and IBS experts collaborate for optimal diagnosis and treatment of IBD with IBS-like symptoms

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

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Introduction

Current therapies for inflammatory bowel disease (IBD) suppress inflammation rather than inhibiting underlying microbial drivers. Treatment failures of frontline interventions, including corticosteroids, can lead to dose escalation and risk of adverse effects.^1,2 Bacteria with pro-inflammatory potential, like adherent-invasive Escherichia coli (AIEC), have been postulated as a possible microbial driver in Crohn’s disease (CD), however, targeting these bacteria with precision in IBD remains challenging.^3,4 Most antibiotics have broad-spectrum activity and disturb the background microbiome, which may exacerbate inflammation.⁵ Attention has shifted towards bacteriophages, yet their underlying mechanisms of treating IBD, and how they may work as an adjunctive therapy, remains elusive.

Aims & Methods

We aimed to assess whether and how phage therapy, specific for a CD-associated bacterium, reduces colitis severity using gnotobiotic mouse models.
In vitro kill curves and biofilm challenges were used to identify lytic phage candidates. Adult germ-free C57BL/6 mice were colonized with altered Schaedler-flora (ASF) and E. coli NRG857c (NRG), a CD-associated isolate. After 3 weeks, mice were treated with an NRG-specific lytic phage (1x10⁹ PFU/dose; daily or TIW) or vehicle (PBS) for 2 weeks (n=6/group) and then exposed to 1 cycle of dextran sulfate sodium (2%; DSS) in drinking water. PBS-treated mice (n=6) not exposed to DSS served as controls. Phage treatment was also tested in a spontaneous model of colitis using C57BL/6NTac-Il10^em8Tac (IL-10^-/-) mice, treated weekly. Mice were monitored daily for weight, stool consistency, and occult blood. Fecal contents were cultured to determine bacterial load, and the expression of NRG fimS was quantified using qPCR as an assessment of virulence. At endpoint, colon tissues were collected for histological and immunohistochemistry analysis to quantify colitis severity and NRG infiltration, respectively. Additional C57BL/6 mice were colonized and treated as previously described. During colitis induction, mice received a low-dose of budesonide (2μg/day)⁶ (n=5) or vehicle (n=5) until endpoint. Mice were monitored daily for disease activity and colon tissues were collected for histological analysis. HPLC was used to determine active budesonide levels.

Results

HER259 was identified as a lytic phage against CD-associated AIEC NRG. In ASF and NRG colonized mice, HER259 reduced clinical symptoms (p< 0.001, p< 0.001) and histological scores (p< 0.0001, p< 0.001) in chemical induced and spontaneous colitis, respectively. A 1-log reduction in NRG bacterial load was observed in HER259-treated mice (p< 0.001). Reisolated NRG exhibited a reduced FimS ON/OFF ratio (p-value < 0.01). Immunohistochemistry revealed reduced infiltration of NRG into the lamina propria following HER259 treatment, with greater accumulation in the epithelium. HER259 treatment increased the efficacy of a sub-therapeutic dosing regimen of budesonide (p< 0.001), which was independent of microbial-based drug metabolism as determined by HPLC.

Conclusion

Our results demonstrate that lytic phage targeting a CD-associated bacterium attenuates colitis in two gnotobiotic mouse models. The intervention did not lead to complete eradication of the disease-driving agent, but instead modulated bacterial virulence mechanisms and enhanced responses to corticosteroid therapy. The data suggests that alternative mechanisms should be considered when translating phage therapy to treat IBD in clinical trials.

References

1. Yan, Y. et al. Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability. Cell Rep Med 4, 101153 (2023).
2. Nagayama, M., Gogokhia, L. & Longman, R. S. Precision microbiota therapy for IBD: premise and promise. Gut Microbes 17, 2489067 (2025).
3. Darfeuille-Michaud, A. et al. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127, 412–421 (2004).
4. A, D.-M. et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology 115, 1405–1413 (1998).
5. Nelson, R. L., Suda, K. J. & Evans, C. T. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev 3, (2017).
6. Bercik, P. et al. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139, (2010).

TARGETED PHAGE INTERVENTION IMPROVES BACTERIAL-DRIVEN COLITIS AND RESPONSE TO TOPICAL CORTICOSTEROIDS BY ATTENUATING VIRULENCE OF CROHN’S DISEASE-ASSOCIATED BACTERIA

Kyle Jackson 1, Heather Galipeau 2, Amber Hann 2, Marco Constante 2, Megan Zangara 3, Alexandra Fuentas 2, Chiko Shimbori 2, Premysl Bercik 2, Brian Coombes 3, Zeinab Hosseinidoust 1, Elena Verdu 2

1 McMaster University, Hamilton, Canada|||Farncombe Family Digestive Health Research Institute, Hamilton, Canada

2 Farncombe Family Digestive Health Research Institute, Hamilton, Canada

3 McMaster University, Hamilton, Canada

Event

UEG Week Berlin 2025

Topics

Gut Microbiota IBD

Submission format

Abstract

Session

New tales of the gut microbiome: From profiling to new therapies

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Getting to the bottom of Crohn´s: Gastroenterologist vs surgeon perspective

Gianluca Pellino 1, Iago Rodríguez-Lago 2

1 Hospital Universitari Vall d’Hebron, Barcelona, Spain

2 Hospital Universitario de Galdakao, Bilbao, Spain

Event

UEG Postgraduate Teaching Programme Berlin 2025

Session

The Crohn´s disease journey

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

UEG Presentation

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LINERIXIBAT SIGNIFICANTLY IMPROVES CHOLESTATIC PRURITUS IN PRIMARY BILIARY CHOLANGITIS: RESULTS OF THE PIVOTAL PHASE 3 GLISTEN TRIAL

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Introduction

Cholestatic pruritus is common, debilitating and undertreated in patients with primary biliary cholangitis (PBC). Here, we describe the results of GLISTEN (NCT04950127), a Phase 3 study investigating the efficacy and safety of the ileal bile acid transporter inhibitor linerixibat for pruritus in PBC.

Aims & Methods

In this double-blind, randomised, placebo-controlled study, patients with PBC and moderate-to-severe pruritus received oral linerixibat 40 mg or placebo twice daily. Pruritus severity and pruritus-related sleep interference were assessed using a 0–10 numerical rating scale. The primary endpoint was change from baseline in worst itch over 24 weeks. Secondary endpoints included: at Week 2, change in worst itch; over 24 weeks, change in sleep interference; at Week 24, proportion of responders (≥ 2-, ≥ 3-, ≥ 4-point reduction in worst itch) and analysis of responses to 2 patient global impression items (itch severity and change). Safety endpoints included adverse event (AE) reporting.

Results

238 patients were randomised; 95% were female, itch severity was mean (standard deviation [SD]) 7.34 (1.54), 52% had alkaline phosphatase < 1.67 times upper limit of normal, and 47% were receiving stable therapy for pruritus. Pruritus improvement over 24 weeks was significantly greater with linerixibat than placebo: least-squares (LS) mean change -2.86 versus -2.15, adjusted mean difference -0.72; p = 0.001. At Week 24, the observed mean (SD) difference from baseline in pruritus was -3.66 (2.50) with linerixibat and -2.82 (2.32) with placebo. The effect of linerixibat was rapid and superior to placebo at Week 2: LS mean change -1.78 versus -1.07, adjusted mean difference -0.71; p < 0.001. Linerixibat also significantly improved pruritus-related sleep interference over 24 weeks versus placebo: LS mean change ‑2.77 versus -2.24, adjusted mean difference -0.53; p = 0.024. At Week 24, more patients on linerixibat than placebo achieved a ≥ 2-point (68% vs 64%), ≥ 3-point (56% vs 43%) or ≥ 4-point (41% vs 29%) reduction in pruritus and a higher proportion of linerixibat than placebo-treated patients reported their pruritus was very much improved (55% vs 37%) or absent (21% vs 9%). AEs reported more frequently with linerixibat than placebo were predominantly gastrointestinal (GI), including diarrhoea (61% vs 18% of patients) and abdominal pain (18% vs 3% of patients); 4% of patients in the linerixibat group discontinued treatment due to diarrhoea.

Conclusion

In patients with PBC and moderate-to-severe pruritus, linerixibat rapidly and significantly improved pruritus and pruritus-related sleep interference versus placebo. While GI AEs were more common with linerixibat than placebo, they rarely led to treatment discontinuation.

Disclosure

Funded by GSK. Various authors declare conflicts of interest as consultants, employee, recipients of grants and stockholders. These will be reported in full during the presentation.