Elevated Poster Presentation International Celiac Disease Symposium 2026

Clinical, histologic and safety outcomes of ZED1227 treatment in symptomatic celiac disease patients: results from the phase 2b CEC-004/CEL randomized clinical trial (143152)

Detlef Schuppan 1 2 , Knut Lundin 3 , Jorma Isola 4 5 , Pekka Koskinen 6 , Jari Koskenpato 7 , Nigel Gilchrist 8 , Michael Schumann 9 , Hans Seltenreich 10 , Ali Canbay 11 , Øistein Hovde 12 , Jochen Klaus 13 , Dominik Kralj 14 , Juha Taavela 15 , Heiner Wedemeyer 16 , Jacek Wojtowicz 17 , Michael Harrison 18 , Per Hellström 19 , Jost Langhorst 20 21 , Katarina Berndtsson-Blom 22 , Valerie Byrnes 23 , Adam Kopoń 24 , Nischal Sahai 25 , Mika Scheinin 26 , Helga-Paula Török 27 , Magdalena Andrzejewska 28 , Christophe Cellier 29 , Ragnar Eriksen 30 , Albrecht Hoffmeister 31 , Wolfgang Reindl 32 , Jonas Zeitz 33 , Kristina Hillen 34 , Ralph Müller 35 , Ralf Mohrbacher 35 , Markku Mäki 36
  1. Institute of Translational Immunology, Medical University Mainz, Mainz, Germany
  2. Division of Gastroenterology and Celiac Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  3. Gastroenterology, Norwegian Coeliac Disease Research Centre, University of Oslo and Oslo University Hospital, Oslo, Norway
  4. Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  5. Jilab, Tampere, Finland
  6. Pharmasite, Malmö, Sweden
  7. Gastroenterologists K1B, Aava Medical Centre, Helsinki, Finland
  8. CGM Research Trust, Christchurch, New Zealand
  9. Department of Gastroenterology, Charité Berlin, Berlin, Germany
  10. Gastroenterogy Unit, Coastal Digestive Health, Maroochydore QLD, Australia
  11. Department of Medicine, Ruhr University Bochum, Bochum, Germany
  12. Head of the Gastroenterological section, Innlandet Hospital Gjoevik, Gjøvik, Norway
  13. Department of Internal Medicine I, Universitätsklinikum Ulm, Ulm, Germany
  14. Solmed Clinic, Zagreb, Croatia
  15. StudyCor Oy, Tampere University Hospital, Tampere, Finland
  16. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
  17. Synexus Warsaw, Warszawa, Poland
  18. University of Sunshine Coast Health Clinics Sippy Downs, Sippy Downs, QLD, Australia
  19. Specialmedicine / Gastroenterology, Uppsala University, Uppsala, Sweden
  20. Department for Internal and Integrative Medicine, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Germany
  21. Department of Integrative Medicine, University of Duisburg-Essen, DuisburgEssen, Germany
  22. Ladulaa's Clinical Studies, Borås, Sweden
  23. Department of Gastroenterology, University Hospital Galway, Galway, Ireland
  24. Gastromed Torun, Torun, Poland
  25. Clinical Trial Centre, University of Sunshine Coast, South Brisbane, QLD, Australia
  26. CRST Oy, Turku, Finland
  27. Department of Medicine II, LMU University Hospital, München, Germany
  28. Synexus Poznan, Poznan, Poland
  29. Dept. of Gastroenterology, European Georges Pompidou Hospital, Paris, France
  30. Department of Gastroenterology, Alesund Hospital, Aalesund, Norway
  31. Gastroenterology Division, University Clinic Leipzig, Leipzig, Germany
  32. II. Medical Clinic, University Hospital Mannheim, Mannheim, Germany
  33. GastroZentrum Hirslanden, Hirslanden Clinic, Zürich, Switzerland
  34. Clinical Research, Dr. Falk Pharma GmbH, Freiburg, Germany
  35. Clinical Research, Dr. Falk Pharma GmbH, Freiburg, Germany
  36. Celiac Disease Research Center, Tampere University Faculty of Medicine and Health Technology, Tampere, Finland

Background: Human transglutaminase 2 (TG2) is key in celiac disease (CeD) pathogenesis and target of the oral TG2 inhibitor ZED1227. In the phase2a CEC-003/CEL study, ZED1227 improved intestinal histology during gluten-challenge. However, despite a gluten-free diet (GFD) up to half of patients continue to experience symptoms and persistent villous atrophy, highlighting need for additional treatments.

Aim: To evaluate the efficacy and safety of ZED1227 in CeD patients with residual symptoms and villous atrophy despite adherence to a GFD.

Methods: CEC-004/CEL was a double-blind, randomized, placebo-controlled phase2b trial. Adults with CeD on a GFD for ≥1 year and ≥1 moderate-to-severe gastrointestinal symptom underwent a 5-week placebo run-in. Patients with a villous height-to-crypt depth ratio (VH:CrD) ≤2.5 were randomized (1:1:1:1) to placebo 3x daily (TID), ZED1227 10mg TID, ZED1227 25mg TID, or ZED1227 50mg once daily (QD) for 12 weeks. No gluten challenge was performed. The primary endpoint was patients achieving both ≥0.4 improvement in VH:CrD and ≥15% improvement in either non-stool gastrointestinal symptoms or diarrhea severity on the Celiac Disease Symptom Diary (CDSD).

Results: Among 397 randomized patients, 92.7% completed treatment. The primary endpoint was achieved by 27.1%, 16.9%, 25.3%, and 19.3% of patients receiving ZED1227 10mg TID, 25mg TID, 50mg QD, and placebo, respectively, with no significant differences versus placebo. Mean VH:CrD changes were 0.21, 0.17, and 0.26 with ZED1227 versus 0.12 with placebo; only 50mg QD was significantly superior to placebo (p<0.05). CDSD GI total severity scores improved significantly within all groups, without significant between-group differences. Safety profiles were comparable across groups, with no treatment-related serious adverse events.

Conclusions: Although the primary endpoint was not met, ZED1227 50mg QD produced a significant histologic benefit versus placebo and showed a favorable safety profile, consistent with previous findings. Placebo-group improvements highlight challenges evaluating therapies in partially treated CeD without gluten exposure.

  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