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CLINICAL, HISTOLOGIC AND SAFETY OUTCOMES OF ZED1227 TREATMENT IN SYMPTOMATIC CELIAC DISEASE PATIENTS: RESULTS FROM THE PHASE 2B CEC-004/CEL RANDOMIZED CLINICAL TRIAL

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CLINICAL, HISTOLOGIC AND SAFETY OUTCOMES OF ZED1227 TREATMENT IN SYMPTOMATIC CELIAC DISEASE PATIENTS: RESULTS FROM THE PHASE 2B CEC-004/CEL RANDOMIZED CLINICAL TRIAL

Detlef Schuppan 1, Knut E.A. Lundin 2, Jorma Isola 3, Pekka Koskinen 4, Jari Koskenpato 5, Nigel Gilchrist 6, Michael Schumann 7, Hansjoerg Seltenreich 8, Ali Canbay 9, Øistein Hovde 10, Jochen Gerhard Klaus 11, Dominik Kralj 12, Juha Taavela 13, Heiner Wedemeyer 14, Jacek Wójtowicz 15, Michael Harrison 16, Per Martin Hellström 17, Jost Langhorst 18, Katarina Berndtsson-Blom 19, Valerie Byrnes 20, Adam Kopoń 21, Nischal Sahai 22, Mika Scheinin 23, Helga Török 24, Magdalena Andrzejewska 25, Christophe Cellier 26, Ragnar Eriksen 27, Albrecht Hoffmeister 28, Wolfgang Reindl 29, Jonas Zeitz 30, Kristina Hillen 31, Ralph Mueller 31, Ralf Mohrbacher 31, Markku Mäki 32

Affiliations

1 Medical University Mainz - Institute of Translational Immunology, Medical University Mainz ; Mainz/D, Mainz, Germany

2 Norwegian Coeliac Disease Research Centre, University of Oslo and Oslo University Hospital, Oslo, Norway

3 Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland|||Jilab, Tampere, Finland

4 Pharmasite, Malmö, Sweden

5 Aava Medical Centre, Helsinki, Finland

6 CGM Research Trust, Christchurch, New Zealand

7 Charité Berlin, Berlin, Germany

8 Coastal Digestive Health, Maroochydore QLD, Australia

9 Ruhr University Bochum, Bochum, Germany

10 Innlandet Hospital Gjoevik, Gjøvik, Norway

11 Universitätsklinikum Ulm, Ulm, Germany

12 Solmed Clinic, Zagreb, Croatia

13 Tampere University Hospital, Tampere, Finland

14 Hannover Medical School, Hannover, Germany

15 Synexus Warsaw, Warszawa, Poland

16 University of Sunshine Coast Health Clinics Sippy Downs, Sippy Downs, QLD, Australia

17 Uppsala University, Uppsala, Sweden

18 Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Germany|||University of Duisburg-Essen, Duisburg-Essen, Germany

19 Ladulaa's Clinical Studies, Borås, Sweden

20 University Hospital Galway, Galway, Ireland

21 Gastromed Torun, Torun, Poland

22 University of Sunshine Coast, Clinical Trial Centre, South Brisbane, QLD, Australia

23 CRST Oy, Turku, Finland

24 LMU University Hospital, München, Germany

25 Synexus Poznan, Poznan, Poland

26 European Georges Pompidou Hospital Dept. of Gastroenterology, Paris, France

27 Alesund Hospital, Aalesund, Norway

28 University Clinic Leipzig, Leipzig, Germany

29 University Hospital Mannheim, Mannheim, Germany

30 Hirslanden Clinic, Zürich, Switzerland

31 Dr. Falk Pharma GmbH, Freiburg, Germany

32 Tampere University Faculty of Medicine and Health Technology, Tampere, Finland

Summary

AI Generated

The phase 2b CEC-004/CEL trial of oral transglutaminase 2 inhibitor ZED1227 in celiac disease patients with residual symptoms and villous atrophy on a gluten-free diet did not meet its primary combined histology-symptom endpoint, though 50 mg once-daily significantly improved villous height to crypt depth ratio versus placebo.

397 adult celiac disease patients with residual symptoms and villous atrophy (VH:CrD ≤2.5) despite at least one year on a gluten-free diet were randomized to placebo or ZED1227 (10 mg TID, 25 mg TID, or 50 mg QD) for 12 weeks without gluten challenge.
The primary endpoint of combined improvement (≥0.4 in VH:CrD and ≥15% in CDSD symptom score) was not met: 27.1% with 10 mg TID, 16.9% with 25 mg TID, 25.3% with 50 mg QD, and 19.3% with placebo achieved the endpoint, with no significant differences between active treatment and placebo.
Mean change in VH:CrD ratio was 0.26 for 50 mg QD versus 0.12 for placebo (p<0.05, the only significant between-group difference), while 10 mg TID and 25 mg TID showed changes of 0.21 and 0.17 respectively.
Mean changes in CDSD GI total severity score were -1.20 with 50 mg QD, -0.96 with 10 mg TID, -0.95 with 25 mg TID, and -1.05 with placebo, with significant within-group improvements but no significant differences between any treatment arm and placebo.
Significant within-group improvement in both histology and symptoms in the placebo group highlighted the challenges of trials without gluten challenge in patients with heterogeneous symptoms and histology typical of partially treated celiac disease.
No notable differences in adverse events or serious adverse events were observed between study arms, no drug-related serious adverse events were reported, and the favorable safety profile of ZED1227 was confirmed with no new safety concerns.

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Abstract

Introduction

Human transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis, spurring development of the oral TG2 inhibitor ZED1227. In the phase 2a CEC-003/CEL study in CeD patients on a gluten-free diet (GFD), once-daily treatment with ZED1227 with gluten challenge (3 g/day) for 6 weeks led to significant improvement in the ratio of intestinal villous height to crypt depth (VH:CrD) versus placebo.¹ Despite adherence to a gluten-free diet, up to half of CeD patients report persistent symptoms often combined with varying degrees of small intestinal injury. Hence, potential treatments for CeD should ideally address these symptoms and improve mucosal injury.

Aims & Methods

The aim of the present study was a dose-ranging trial of ZED1227 in CeD patients with residual symptoms and villous atrophy despite a GFD. This was a double-blind, randomized, placebo-controlled phase 2b study. It enrolled adult CeD patients who had followed a GFD for at least one year and who experienced at least one moderate or severe gastrointestinal (GI) symptom in the month prior to baseline. All patients underwent an initial 5-week placebo run-in phase, followed by endoscopy and 1:1:1:1 randomization of patients with VH:CrD ≤2.5. Treatment was placebo thrice-daily (TID) or ZED1227 at doses of 10 mg TID, 25 mg TID, or 50 mg once-daily (QD) for 12 weeks. No gluten challenge was carried out. The primary endpoint was the rate of patients with both improvement by ≥ 0.4 in VH:CrD and improvement by ≥ 15% in either of two symptom scores (non-stool GI or diarrhea severity) on the celiac disease symptom diary (CDSD) from the end of the run-in phase to week 12. Key secondary endpoints included the change in VH:CrD, change in CDSD GI total severity score, and safety.

Results

A total of 397 patients were randomized to the 4 arms, of whom 92.7% completed treatment. The primary endpoint was achieved by 27.1% of patients receiving 10 mg ZED1227 TID, 16.9% for 25 mg TID, 25.3% for 50 mg QD, and 19.3% for placebo, with no significant differences between any treatment arm and placebo. The mean change in VH:CrD ratio from baseline was 0.21 for 10 mg ZED1227 TID, 0.17 for 25 mg TID, and 0.26 for 50 mg QD versus 0.12 for placebo. Within-group changes from baseline to week 12 were statistically significant within each arm, while the between-group difference in changes was significant only for 50 mg ZED1227 QD versus placebo (p<0.05). Similarly, mean changes in the CDSD GI total severity score were -0.96 with 10 mg ZED1227 TID, -0.95 with 25 mg TID, -1.20 with 50 mg QD, and -1.05 with placebo. Improvements within each arm were again statistically significant, with no significant differences between any treatment arm and placebo. There were no notable differences in the rates of adverse events or serious adverse events (SAEs) between the study arms, and no SAEs related to the study drug were reported.

Conclusion

The CEC-004/CEL study did not meet its primary endpoint of combined improvement in histology and symptoms. However, changes in the VH:CrD ratio achieved with 50 mg ZED1227 QD were statistically superior to placebo, consistent with the results of the prior CEC-003/CEL study. Significant within-group improvement from baseline to week 12 in both histologic and symptom outcomes within the placebo group underscored the challenges of clinical trials without deliberate gluten exposure in patients with the heterogeneous symptom and histology typical of partially treated CeD. The favorable safety profile of ZED1227 was confirmed, and no new safety concerns were identified.

References

1. Schuppan D, Maki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021;385(1):35-45.

Disclosure

Sponsor of the trial: Dr. Falk Pharma GmbH
Acknowledgement: This research was supported by Takeda.

Event

UEG Week Berlin 2025

Topics

Mechanisms & Personalised Medicine Small Intestine & Nutrition

Submission format

Abstract

Session

Coeliac disease: From screening to new drugs

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Re-introducing immune-tolerance to gluten: Does that work for treatment?

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Re-introducing immune-tolerance to gluten: Does that work for treatment?

Knut E.A. Lundin 1

Affiliations

1 Norwegian Coeliac Disease Research Centre, University of Oslo and Oslo University Hospital, Oslo, Norway

Summary

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Abstract

Event

UEG Week Berlin 2025

Topics

Immunology Nurses Small Intestine & Nutrition

Session

What's new in coeliac disease in 2025?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Re-introducing immune-tolerance to gluten: Does that work for treatment?

Knut E.A. Lundin

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Colm O'Morain

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GUT MICROBIOTA MODULATION AS A NOVEL THERAPEUTIC APPROACH FOR IMMUNE-CHECKPOINT INHIBITORS-RELATED DIARRHEA AND COLITIS

Irene Venturini

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

TARGETED VERSUS POPULATION-BASED SCREENING AS A PRIMARY PREVENTIVE APPROACH TOWARDS GASTRIC CANCER: INTERIM RESULTS OF THE IRISH EXPERIENCE

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TARGETED VERSUS POPULATION-BASED SCREENING AS A PRIMARY PREVENTIVE APPROACH TOWARDS GASTRIC CANCER: INTERIM RESULTS OF THE IRISH EXPERIENCE

Charlene Deane 1, Ana McKiernan 2, Donal Bailey 3, Colm Ó Sé 3, Dean Murray 4, Fiona O'Connor 3, Tom Branigan 5, Anthony Corcoran 5, Marcis Leja 6, Tatjana kofol 7, Bojan Tepes 8, Orlaith Kelly 9, Colm O'Morain 10

Affiliations

1 Connolly Hospital, Dublin, Ireland|||Beacon Hospital Research Institute, Dublin, Ireland

2 Beacon Hospital Research Institute, Dublin, Ireland

3 Irish College of General Practitioners, Dublin, Ireland

4 Royal College of Surgeons Ireland, Dublin, Ireland|||Irish College of General Practitioners, Dublin, Ireland

5 Royal College of Physicians, Ireland, Dublin, Ireland|||Irish Defence Force, Dublin, Ireland

6 University of Latvia, Riga, Latvia

7 National Institute of Public Health, Ljubljana, Slovenia

8 DC ROGASKA d.o.o., Rogaska Slatina, Slovenia

9 Royal College of Surgeons Ireland, Dublin, Ireland|||Connolly Hospital, Dublin, Ireland

10 Beacon Hospital Research Institute, Dublin, Ireland|||Trinity College Dublin - Faculty of Health Sciences, Trinity College Dublin; Dublin/IE, Dublin, Ireland

Summary

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Abstract

Introduction

The TOGAS consortium (TOwards GAstric cancer Screening) was established to explore effective gastric cancer screening strategies within Europe. One key method involves the detection and eradication of Helicobacter pylori (H. pylori), the leading causative agent of gastric cancer. In Western Europe, infection rates are higher among males, smokers, and individuals of lower socioeconomic status—groups that tend to engage less with preventive health services.

Aims & Methods

This pilot study aimed to determine whether targeted screening in high-risk occupational settings improves participation and outcomes compared to population-based screening via general practice.
Key outcome measures included;

Response rate
Prevalence of the infection
Treatment effectiveness

This prospective pilot study recruited individuals aged 30–34 years from January 2024 to March 2025. Participants were invited either through general practices (general population group, GP) or through two occupational screening programs (targeted group, TG) representing higher-risk, male-dominated workforces: the Irish Defence Forces and Construction Workers Health Trust. Exclusion criteria included prior H. pylori treatment or gastrectomy. All participants underwent serologic screening (BIOHIT H. pylori IgG antibody). The TG was offered initial on-site screening at their workplace; the GP group attended a local hospital. All seropositive individuals were offered confirmatory 13-C urea breath testing (Richen IR Force 200) in a local hospital. Confirmed cases were offered a 10-day regimen of PYLERA (Metronidazole/Tetracycline/Bismuth subcitrate) with Esomeprazole 40 mg BD. Eradication was assessed ≥6 weeks post-treatment. Response rates, demographics, infection prevalence, and treatment outcomes were analyzed using Mann-Whitney U and Chi² tests (significance p < 0.05).

Results

3030 individuals were invited for screening: 2824 in the GP group(GPG), 206 in the TG. Key demographics and risk factors of each group are shown in Table 1. The invitation response and participation rates were significantly higher in the TG versus the GPG (31% v’s 14%; p < 0.001, 30% v’s 14% p <0.00, respectively). H. pylori seroprevalence rates were similar between groups: 18% (11/60) in the TG, 19% (64/333) in the GPG (p<0.70). Confirmatory 13-C UBT was completed in 91% (10/11) of those who tested positive in the TG and 98% (63/64) of the GPG. Overall, ‘true’ prevalence rates based on serology & confirmatory 13-C UBT results were 10%(6/59) in the TG v’s 14% (44/325) in the GPG(p = 0.47). Treatment adherence exceeded 90% in both groups, with 100% adherence in the TG and 90% in the GPG. Among those who completed post-treatment testing (n=37), eradication was achieved in 100% of the TG (2/2) and 89% of the GPG (31/35).

Table 1 Basic Demographics by Group

	Targeted group	General population
Gender, male	97%	33%
Median age, years	31	32
Smoking status Current/previous Non-smoker	41% (24) 59% (34)	34% (137) 66% (266)
Socioeconomic status(self-rated) Higher Middle Lower Prefer not to answer	69% (40/58) 22% (13/58) 0 9% (5/58)	85% (337/397) 11% (42/397) 0% (2/397) 4% (16/397)
Family history of H.pylori infection	3% (2)	9% (36)

Conclusion

Targeted occupational screening in high-risk populations demonstrated superior response and engagement rates compared to general practice-based screening. These early results suggest this approach may be a more effective and resource-conscious strategy in low-to-intermediate risk countries and merit further evaluation in broader implementation efforts.

References

1. Teo CH, Ng CJ, Booth A, White A. Barriers and facilitators to health screening in men: A systematic review. Soc Sci Med. 2016 Sep;165:168-176. doi: 10.1016/j.socscimed.2016.07.023. Epub 2016 Aug 1. PMID: 27511617. 5.
2. Lou L, Wang L, Zhang Y, et al. Sex difference in incidence of gastric cancer: an international comparative study based on the Global Burden of Disease Study 2017.BMJ Open 2020;10:e033323. doi: 10.1136/bmjopen-2019-033323
3. Salmani H, Ahmadi M, Shahrokhi N. The Impact of Mobile Health on Cancer Screening: A Systematic Review. Cancer Informatics. 2020;19. doi:10.1177/1176935120954191
4. CSO. (2023, May 30). Employment, Occupation, Industry and Commuting - CSO -Central Statistics Office. https://www.cso.ie/en/releasesandpublications/ep/pcpsr/censusofpopulation2022- summaryresults/employmentoccupationindustryandcommuting/

Disclosure

Dr. Deane reports receipt of research funding support from EU4 Health grant GA number: 101101252. Receipt of 13-C Urea Breath Test bags for this study was provided for by Richen - Dr Deane was the winner of the Richen Global Research Competition 2023

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Endoscopy Stomach & H. Pylori

Submission format

Abstract

Session

Targeting gastric cancer: How to proceed

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Re-introducing immune-tolerance to gluten: Does that work for treatment?

Knut E.A. Lundin

TARGETED VERSUS POPULATION-BASED SCREENING AS A PRIMARY PREVENTIVE APPROACH TOWARDS GASTRIC CANCER: INTERIM RESULTS OF THE IRISH EXPERIENCE

Colm O'Morain

Whole diet interventions for IBS

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VISCERAL OSTEOPATHY IN TREATING REFRACTORY IRRITABLE BOWEL SYNDROME: RESULTS OF A FRENCH NATIONAL MULTICENTRE RANDOMISED CONTROLLED TRIAL

Robert Benamouzig

Transglutaminase inhibition in CeD

Detlef Schuppan

GUT MICROBIOTA MODULATION AS A NOVEL THERAPEUTIC APPROACH FOR IMMUNE-CHECKPOINT INHIBITORS-RELATED DIARRHEA AND COLITIS

Irene Venturini

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

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Whole diet interventions for IBS

Heidi Staudacher 1

Affiliations

1 The University of Queensland, Melbourne, Australia

Summary

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Abstract

Event

UEG Week Berlin 2025

Topics

IBD Neurogastroenterology & Motility Primary Care

Session

Diet and disorders of gut-brain interaction: From IBS to IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Re-introducing immune-tolerance to gluten: Does that work for treatment?

Knut E.A. Lundin

TARGETED VERSUS POPULATION-BASED SCREENING AS A PRIMARY PREVENTIVE APPROACH TOWARDS GASTRIC CANCER: INTERIM RESULTS OF THE IRISH EXPERIENCE

Colm O'Morain

Whole diet interventions for IBS

Heidi Staudacher

VISCERAL OSTEOPATHY IN TREATING REFRACTORY IRRITABLE BOWEL SYNDROME: RESULTS OF A FRENCH NATIONAL MULTICENTRE RANDOMISED CONTROLLED TRIAL

Robert Benamouzig

Transglutaminase inhibition in CeD

Detlef Schuppan

GUT MICROBIOTA MODULATION AS A NOVEL THERAPEUTIC APPROACH FOR IMMUNE-CHECKPOINT INHIBITORS-RELATED DIARRHEA AND COLITIS

Irene Venturini

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

VISCERAL OSTEOPATHY IN TREATING REFRACTORY IRRITABLE BOWEL SYNDROME: RESULTS OF A FRENCH NATIONAL MULTICENTRE RANDOMISED CONTROLLED TRIAL

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

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VISCERAL OSTEOPATHY IN TREATING REFRACTORY IRRITABLE BOWEL SYNDROME: RESULTS OF A FRENCH NATIONAL MULTICENTRE RANDOMISED CONTROLLED TRIAL

Fabien Wuestenberghs 1, Jean Marc Sabate 1, Pauline Jouet 2, Francois Mion 3, Mathias Vidon 4, Thierry PICHE 5, Marie Napoléon 3, Sabine Roman 3, Heithem Soliman 6, Mourad Benallaoua 1, Michel Bouchoucha 1, Robert Benamouzig 1

Affiliations

1 APHP, Avicenne Hospital, Sorbonne Paris Nord University, Bobigny, France

2 APHP, Ambroise Paré Hospital, Boulogne-Billancourt, France

3 Hospices Civils de Lyon, Lyon, France

4 Créteil Intercommunal Hospital, Créteil, France

5 CHU de Nice, Nice Cedex 3, France

6 AP-HP, Louis Mourier Hospital, Paris Cité University, Colombes, France

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Abstract

Introduction

Irritable bowel syndrome (IBS), which affects between 5 and 10% of the population according to the Rome III or IV diagnostic criteria, manifests as chronic abdominal pain associated with altered bowel transit. Moderate or severe IBS significantly impair the quality of life of patients, who are often dissatisfied with conventional treatments. In search of more effective solutions, many are turning to complementary and alternative approaches, such as hypnotherapy, whose effectiveness is well-established. Among these approaches, osteopathy, adopted by nearly 40% of patients in France, attracts growing interest. Single-centre studies with small sample sizes (30 to 40 patients) have reported promising but miscellaneous results, suggesting an improvement in symptoms and an effect on rectal sensitivity (1), or a transient effect on the severity of IBS (2).

Aims & Methods

Our study aims to evaluate the efficacy of visceral osteopathy on the severity of IBS symptoms in a French multicentre study. The trial, conducted as part of the 2015 National Hospital Clinical Research Program (PHRCN-PHRC-15-294), included adult patients suffering from IBS according to Rome III criteria and with moderate or severe IBS (IBS-SSS of 175 to 500 points at baseline). Patients were randomised into two groups: one with visceral osteopathy (three sessions performed over one month, two weeks apart) and one with placebo manipulation performed by the same osteopaths. Clinical characteristics (age, gender, BMI, IBS subtype according to bowel movements), anxiety (Spielberger State-Trait Anxiety Inventory, STAI-1 and STAI-2) and depression (Beck Depression Inventory or BDI II) levels, quality of life (IBS-QOL, ranging from 0 to 100, with 100 corresponding to the best quality of life), and IBS severity (IBS-SSS) were recorded. The primary objective of the study was the improvement in the IBS-SSS severity score at 2 months (1 month after the end of osteopathy). The effects on anxiety and depression levels as well as on quality of life were secondary objectives. The number of subjects to be included was calculated at 210 patients.

Results

Six centres included a total of 156 patients* (78 per group): mean age of 46 (± 15) years, 73% of women, 60% with IBS-C, 17% with IBS-D, 15% with IBS-M, and 8% with IBS-U. The mean IBS-SSS severity score was 336 (± 66) points (27.1% moderate severity and 72.9% severe with IBS-SSS > 300), with no difference between the two groups. Before inclusion, 61% of patients felt that osteopathy would be effective for their condition. At 2 months, the absolute decrease in the severity score (primary endpoint) was similar in both groups (52.4 ± 97.6 vs. 48.6 ± 98.9 points, p-value = 0.975), suggesting a placebo effect, as were the state-trait anxiety levels and quality of life (secondary endpoints).
* The monitoring committee terminated the study after a futility analysis on the first 156 patients because the study message could not be changed by including additional patients out of a planned total of 210.

Conclusion

In this first randomised multicentre study, visceral osteopathy was no more effective than a placebo manipulation in improving the severity of IBS, psychological comorbidities, or quality of life.

References

(1) Attali et al. Treatment of refractory irritable bowel syndrome with visceral osteopathy: Short-term and long-term results of a randomized trial. Journal of Digestive Diseases 2013; 14; 654–661. doi: 10.1111/1751-2980.12098
(2) Florance et al. Osteopathy improves the severity of irritable bowel syndrome: a pilot randomized sham-controlled study. European Journal of Gastroenterology & Hepatology 2012 ; 24 (8) : p 944-949. DOI: 10.1097/MEG.0b013e3283543eb7

Disclosure

Nothing to disclose

Event

UEG Week Berlin 2025

Topics

Neurogastroenterology & Motility Colorectal

Submission format

Abstract

Session

Lower GI motility I

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Re-introducing immune-tolerance to gluten: Does that work for treatment?

Knut E.A. Lundin

TARGETED VERSUS POPULATION-BASED SCREENING AS A PRIMARY PREVENTIVE APPROACH TOWARDS GASTRIC CANCER: INTERIM RESULTS OF THE IRISH EXPERIENCE

Colm O'Morain

Whole diet interventions for IBS

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VISCERAL OSTEOPATHY IN TREATING REFRACTORY IRRITABLE BOWEL SYNDROME: RESULTS OF A FRENCH NATIONAL MULTICENTRE RANDOMISED CONTROLLED TRIAL

Robert Benamouzig

Transglutaminase inhibition in CeD

Detlef Schuppan

GUT MICROBIOTA MODULATION AS A NOVEL THERAPEUTIC APPROACH FOR IMMUNE-CHECKPOINT INHIBITORS-RELATED DIARRHEA AND COLITIS

Irene Venturini

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

Transglutaminase inhibition in CeD

Detlef Schuppan 1

Affiliations

1 Medical University Mainz - Institute of Translational Immunology, Medical University Mainz ; Mainz/D, Mainz, Germany

Summary

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Abstract

Event

UEG Week Berlin 2025

Topics

Immunology Nurses Small Intestine & Nutrition

Session

What's new in coeliac disease in 2025?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Re-introducing immune-tolerance to gluten: Does that work for treatment?

Knut E.A. Lundin

TARGETED VERSUS POPULATION-BASED SCREENING AS A PRIMARY PREVENTIVE APPROACH TOWARDS GASTRIC CANCER: INTERIM RESULTS OF THE IRISH EXPERIENCE

Colm O'Morain

Whole diet interventions for IBS

Heidi Staudacher

VISCERAL OSTEOPATHY IN TREATING REFRACTORY IRRITABLE BOWEL SYNDROME: RESULTS OF A FRENCH NATIONAL MULTICENTRE RANDOMISED CONTROLLED TRIAL

Robert Benamouzig

Transglutaminase inhibition in CeD

Detlef Schuppan

GUT MICROBIOTA MODULATION AS A NOVEL THERAPEUTIC APPROACH FOR IMMUNE-CHECKPOINT INHIBITORS-RELATED DIARRHEA AND COLITIS

Irene Venturini

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

GUT MICROBIOTA MODULATION AS A NOVEL THERAPEUTIC APPROACH FOR IMMUNE-CHECKPOINT INHIBITORS-RELATED DIARRHEA AND COLITIS

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GUT MICROBIOTA MODULATION AS A NOVEL THERAPEUTIC APPROACH FOR IMMUNE-CHECKPOINT INHIBITORS-RELATED DIARRHEA AND COLITIS

Serena Porcari 1, Franziska Deutschbein 1, William Fusco 1, Andrea Severino 1, Debora Rondinella 1, Irene Venturini 1, Antonio Di Sabatino 2, Marco Vincenzo Lenti 2, Ettore D'Argento 1, Emilio Bria 1, Giovanni Schinzari 1, Eleonora Palluzzi 1, Olga Martelli 1, Mariagrazia Distefano 1, Carolina Maria Sassu 1, Serena Maria Boccia 1, Laura Vertechy 1, Ida Paris 1, Roberto Iacovelli 1, Chiara Ciccarese 1, Francesca Romana Ponziani 1, Claudia Marchetti 3, Giampaolo Tortora 1, Antonio Gasbarrini 1, Giovanni Cammarota 1, Gianluca Ianiro 1

Affiliations

1 Fondazione Policlinico Universitario 'A.Gemelli' - IRCCS, Roma, Italy

2 IRCCS Policlinico S. Matteo, Pavia, Italy

3 Fondazione Policlinico Universitario 'A.Gemelli' - IRCCS, Roma, Italy|||Università Cattolica del Sacro cuore, Roma, Italy

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Abstract

Introduction

Immune checkpoint inhibitors (ICIs) have marked a breakthrough in the management of a wide range of cancer types, leading to increased overall survival. However, this treatment is frequently associated with the onset of various immune-related adverse events (irAEs), including ICI-related diarrhea and colitis.¹ Current recommendations for patients with diarrhea or colitis grade 2 or higher (graded via CTCAE)² include the discontinuation of ICI and administration of immune suppressants (e.g. steroids or biologics), which may lead to worse outcomes in these patients.³Therefore, alternative therapeutic strategies to manage irAEs are needed. The gut microbiota plays a pivotal role in the onset of gastrointestinal irAEs, but the role of its therapeutic modulation on these disorders is mostly unknown. ^4,5

Aims & Methods

Our aim was to evaluate the efficacy and safety of therapeutic microbiome modulation for gastrointestinal irAEs in cancer patients. We enrolled cancer patients affected by ICI-related diarrhea/colitis referred to our Microbiome Clinic from January 2023 to March 2025. After clinical evaluation, patients were stratified according to severity of diarrhea (graded via CTCAE)² and then received a microbiome-modulating therapy. Patients were followed-up for at least 8 week after the initiation of therapy. We collected data about patient demographics (age and gender), patient’s overall health status as assessed by the the Charlson Comorbidity Index (CCI)⁶, type of cancer, oncological therapy and its suspension, time in weeks from initiation of cancer therapy to onset of diarrhea, severity of diarrhea (graded via CTCAE)², time in weeks until resolution of diarrhea and resumption of oncological therapy

Results

We enrolled 42 patients in the study period (8 males, 34 females, mean age 58,3 years-old, mean CCI-index 5.8). All patients were treated with ICI (Pembrolizumab: n=25 , Dostarlimab: n=4, Nivolumab: n=4; Atezolizumab: n=3; Novulumab and Ipilumab: n=2, Cemiplimab: n=2; Mogamulizumab: n=1; Pertuzumab: n=1). Ten patients experienced G1 diarrhea (23,8%), 16 (38,1) G2, 15 (35,7%) G3 and one G4 (2,4%). As indicated by current European Guidelines³, 30 patients (71,4%) had to interrupt ICI due to diarrhea. Multi-strain probiotics were administered to 27 (64.3% ) patients, rifaximin to 22 (52,4%). Overall, 21 patients (50%) needed therapy with systemic steroids. Seven patients who experienced ICI-related colitis refractory to steroids and biologics were successfully treated with FMT. Twenty-eight patients (66.7% ) had a resolution of the diarrhea (G0) and 11 patients (26.2%) had diarrhea G1 at a mean time of 8 weeks. Upon resolution of diarrhea, nine of the 30 patients who had interrupted ICI (30%) were able to resume the treatment. None of the patients experienced any adverse event related to gut microbiota modulation as defined by CTCAE².

Conclusion

Therapeutic modulation of gut microbiota appears to be a promising safe and effective approach for treating ICI-related diarrhea and colitis. However, these preliminary findings need confirmation through more consolidated and well-designed studies.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009
3. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
5. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.01235
6. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Gut Microbiota Immunology Mechanisms & Personalised Medicine Colorectal

Submission format

Abstract

Session

Oncobiome

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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