A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease

Detlef Schuppan ¹, Markku Mäki ¹, Knut E A Lundin ¹

¹From the Institute of Translational Immunology and Celiac Center, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz (D.S., T.F.-S.), the Department of Internal and Integrative Medicine, Sozialstiftung Bamberg, Bamberg (J.L.), the Department of Integrative Medicine, University of Duisburg-Essen, Duisburg-Essen (J.L.), the Division of Gastroenterology, Hepatology, and Infectious Diseases, Department of Internal Medicine I, University Hospital Tübingen, Tübingen (S.F.), the Department of Gastroenterology, Infectious Diseases, and Rheumatology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Berlin (M. Schumann), the Department of Medicine II, University Hospital, Ludwig Maximilians University, Munich (H.P.T.), the Department of Medicine 1, Hector Center for Nutrition, Exercise, and Sports, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen (Y.Z.), the Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg (A.W.L.), the Department of Internal Medicine IV, University Hospital, Friedrich-Schiller University Jena, Jena (A.S.), and Dr. Falk Pharma, Freiburg (R.M., R.G.) - all in Germany; the Division of Gastroenterology and Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (D.S.); the Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital (M.M., A.P., M.-L.L.), the Faculty of Medicine and Health Technology, Tampere University (J.I., J.T.), Jilab (J.I.), and the Department of Pediatrics, Tampere University Hospital (M.-L.L.), Tampere, the Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä (J.T.), Lääkärikeskus Aava Helsinki Kamppi, Helsinki (J. Koskenpato), and Clinical Research Services Turku, Turku (M. Scheinin) - all in Finland; Oslo University Hospital, Rikshospitalet, and Stiftelsen K.G. Jebsen Celiac Disease Research Center, University of Oslo, Oslo (K.E.A.L.), the Medical Department, Innlandet Hospital Trust, Gjøvik (O.H.), and Akershus University Hospital, Lørenskog (J.J.) - all in Norway; the University of Medicine and Pharmacy "Carol Davila" and the National Institute for Mother and Child Health "Alessandrescu-Rusescu," Bucharest, Romania (A.P.); the Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania (J. Kupcinskas); the Department of Gastroenterology, Internal Medicine Clinic, Tartu University Hospital, Tartu, Estonia (K.K.); the Department of Gastroenterology and Hepatology, University Hospital Zurich (L.B., J.Z.), and the Swiss Celiac Center, Center of Gastroenterology, Clinic Hirslanden (J.Z.) - both in Zurich, Switzerland; and University College Hospital Galway, Galway, Ireland (V.B.).

⁰From the Institute of Translational Immunology and Celiac Center, Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz (D.S., T.F.-S.), the Department of Internal and Integrative Medicine, Sozialstiftung Bamberg, Bamberg (J.L.), the Department of Integrative Medicine, University of Duisburg-Essen, Duisburg-Essen (J.L.), the Division of Gastroenterology, Hepatology, and Infectious Diseases, Department of Internal Medicine I, University Hospital Tübingen, Tübingen (S.F.), the Department of Gastroenterology, Infectious Diseases, and Rheumatology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Berlin (M. Schumann), the Department of Medicine II, University Hospital, Ludwig Maximilians University, Munich (H.P.T.), the Department of Medicine 1, Hector Center for Nutrition, Exercise, and Sports, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen (Y.Z.), the Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg (A.W.L.), the Department of Internal Medicine IV, University Hospital, Friedrich-Schiller University Jena, Jena (A.S.), and Dr. Falk Pharma, Freiburg (R.M., R.G.) - all in Germany; the Division of Gastroenterology and Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston (D.S.); the Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital (M.M., A.P., M.-L.L.), the Faculty of Medicine and Health Technology, Tampere University (J.I., J.T.), Jilab (J.I.), and the Department of Pediatrics, Tampere University Hospital (M.-L.L.), Tampere, the Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä (J.T.), Lääkärikeskus Aava Helsinki Kamppi, Helsinki (J. Koskenpato), and Clinical Research Services Turku, Turku (M. Scheinin) - all in Finland; Oslo University Hospital, Rikshospitalet, and Stiftelsen K.G. Jebsen Celiac Disease Research Center, University of Oslo, Oslo (K.E.A.L.), the Medical Department, Innlandet Hospital Trust, Gjøvik (O.H.), and Akershus University Hospital, Lørenskog (J.J.) - all in Norway; the University of Medicine and Pharmacy "Carol Davila" and the National Institute for Mother and Child Health "Alessandrescu-Rusescu," Bucharest, Romania (A.P.); the Gastroenterology Department and Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania (J. Kupcinskas); the Department of Gastroenterology, Internal Medicine Clinic, Tartu University Hospital, Tartu, Estonia (K.K.); the Department of Gastroenterology and Hepatology, University Hospital Zurich (L.B., J.Z.), and the Swiss Celiac Center, Center of Gastroenterology, Clinic Hirslanden (J.Z.) - both in Zurich, Switzerland; and University College Hospital Galway, Galway, Ireland (V.B.).

The New England Journal of Medicine +

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June 30, 2021

View abstract on PubMed

Summary

ZED1227, a transglutaminase 2 inhibitor, reduced gluten-induced duodenal damage in celiac disease patients. This oral medication shows promise for treating celiac disease by mitigating intestinal injury.

Area Of Science

Gastroenterology
Immunology
Pharmacology

Background

Celiac disease involves transglutaminase 2 (TG2) deamidating gluten peptides, enhancing T-cell stimulation and causing mucosal injury.
TG2 inhibition presents a potential therapeutic strategy for managing celiac disease.

Purpose Of The Study

To evaluate the efficacy and safety of ZED1227, an oral TG2 inhibitor, in a proof-of-concept trial.
To assess the impact of ZED1227 on gluten-induced duodenal mucosal damage and patient-reported outcomes in celiac disease.

Main Methods

A 6-week, double-blind, placebo-controlled trial involving adults with celiac disease undergoing daily gluten challenge.
Patients received ZED1227 at three dose levels (10mg, 50mg, 100mg) or placebo.
Primary endpoint: attenuation of gluten-induced mucosal damage (villus height to crypt depth ratio); secondary endpoints: intraepithelial lymphocyte density, symptom scores, and quality of life.

Main Results

ZED1227 treatment at all doses significantly attenuated gluten-induced duodenal mucosal injury compared to placebo.
A dose-dependent reduction in intraepithelial lymphocyte density was observed, particularly with the 100mg dose.
The 100mg dose of ZED1227 showed potential improvements in symptom and quality-of-life scores.
Adverse events were generally mild and similar across groups, with rash noted in 8% of the 100mg group.

Conclusions

ZED1227 effectively reduced gluten-induced duodenal mucosal damage in patients with celiac disease.
The study supports ZED1227 as a potential therapeutic agent for celiac disease, warranting further investigation.