Prof. Schuppan, MD, PhD

NEJM: First Effective Non-Dietary Treatment of Celiac Disease Interview with:

Prof. Schuppan, MD, PhD

Prof. Schuppan, MD, PhD

Prof. Dr. D. Schuppan, MD, PhD
Professor of Medicine
Director Institute of Translational Immunology
University Medical Center of the Johannes Gutenberg University
Consultant Gastroenterologist and Hepatologist
Director Celiac and Small Intestinal Disease Center
Director Center for Food Intolerances and Autoimmunity
Director Liver Fibrosis and Metabolism Research
Research Center for Immune Therapy (FZI)
Mainz Project for Chemical Allergology (MPCA)
Mainz, Germany

Professor of Medicine, Division of Gastroenterology
Beth Israel Deaconess Medical Center
Harvard Medical School Boston, MA 02215 What is the background for this study?

Response: Celiac disease (CeD) is a common intestinal inflammatory disease that affects about 1% of most wheat consuming populations worldwide. CeD is caused by the ingestion of gluten containing foods, such as wheat, spelt, rye and barley, that activate small intestinal inflammatory T cells.

The only current therapy is the rigorous avoidance of even traces of gluten in the daily diet, which is difficult and a social and psychological burden.

We previously identified the body’s own enzyme tissue transglutaminase (TG2) as the CeD autoantigen. Moreover, TG2 drives celiac disease pathogenesis by enzymatically modifying dietary gluten peptides that makes them more immunogenic.

We therefore developed an oral small molecule (ZED1227) that specifically inhibits TG2 activity in the intestine.

While this should attenuate CeD in patients exposed to dietary gluten, it was unclear if  it could prevent gluten induced intestinal inflammation and damage. What should readers take away from your report?

Response: In this phase 2a clinical study, 160 celiac disease volunteers in remission, i.e., with a healed intestine after a longterm gluten free diet were included and challenged with a low dose of daily gluten sufficient to induce moderate intestinal damage for 6 weeks.

Patients received either one of 3 escalating doses of the ZED1227 as a pill or placebo.

ZED1227 prevented intestinal damage, as measured by villous atrophy, vs placebo at all 3 doses, with a visible dose-response.

It also improved several secondary endpoints, including patient well-being.

Our study suggests that this is the first effective non-dietary treatment of CeD.
Moreover, it is highly targeted to CeD, being based on a celiac disease-specific mechanism of action. What recommendations do you have for future research as a result of this study? 

Response: Based on the promising results of this study, we have planned a phase 2b (3) clinical study treating patients with celiac disease that does not respond completely to the gluten free diet. In this population of high need we will test different doses and dose regimens of ZED1227 vs placebo.

This setting will also allow us to test the drug’s efficacy in a more real life scenario.

The study is to start in autumn of 2021.

We hope that ZED1227 will be generally available to patients with celiac disease who need to “neutralize” minor to moderate amounts of gluten in ill-defined foods, or to patients with complicated (highly gluten sensitive) celiac disease, after a successful completion of these follow up studies.

 No special disclosures. No commercial involvement from my side.


A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease

Detlef Schuppan, M.D., Ph.D., Markku Mäki, M.D., Ph.D., Knut E.A. Lundin, M.D., Ph.D., Jorma Isola, M.D., Ph.D., Tina Friesing-Sosnik, M.D., Juha Taavela, M.D., Ph.D., Alina Popp, M.D., Ph.D., Jari Koskenpato, M.D., Jost Langhorst, M.D., Øistein Hovde, M.D., Ph.D., Marja-Leena Lähdeaho, M.D., Ph.D., Stefano Fusco, M.D.,  for the CEC-3 Trial Group*July 1, 2021
N Engl J Med 2021; 385:35-45
DOI: 10.1056/NEJMoa2032441



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Last Updated on July 1, 2021 by Marie Benz MD FAAD