A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease.

Abstract

BACKGROUND:

In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.

METHODS:

In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).

RESULTS:

Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.

CONCLUSIONS:

In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).

• Authors: Detlef Schuppan, Markku Mäki, Knut E A Lundin, Jorma Isola, Tina Friesing-Sosnik, Juha Taavela, Alina Popp, Jari Koskenpato, Jost Langhorst, Øistein Hovde, Marja-Leena Lähdeaho, Stefano Fusco, Michael Schumann, Helga P Török, Juozas Kupcinskas, Yurdagül Zopf, Ansgar W Lohse, Mika Scheinin, Karin Kull, Luc Biedermann, Valerie Byrnes, Andreas Stallmach, Jørgen Jahnsen, Jonas Zeitz, Ralf Mohrbacher, Roland Greinwald, CEC-3 Trial Group
• Journal: The New England journal of medicine (N Engl J Med) Vol. 385 Issue 1 Pg. 35-45 (07 01 2021) ISSN: 1533-4406 [Electronic] United States
• PMID: 34192430 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Massachusetts Medical Society.

Chemical References

• Imidazoles
• Pyridines
• ZED1227
• Glutens
• Protein Glutamine gamma Glutamyltransferase 2
• Transglutaminases
• GTP-Binding Proteins

Topics

• Administration, Oral
• Adult
• Celiac Disease (drug therapy, pathology)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Duodenum (immunology, pathology)
• Female
• GTP-Binding Proteins (antagonists & inhibitors)
• Glutens (administration & dosage, adverse effects)
• Humans
• Imidazoles (administration & dosage, adverse effects)
• Intestinal Mucosa (immunology, pathology)
• Lymphocyte Count
• Male
• Middle Aged
• Proof of Concept Study
• Protein Glutamine gamma Glutamyltransferase 2
• Pyridines (administration & dosage, adverse effects)
• Quality of Life
• Severity of Illness Index
• Transglutaminases (antagonists & inhibitors)