A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease

Abstract

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. METHODSIn 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). RESULTSOf 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 duodenalbiopsy 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. CONCLUSIONSIn this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.

Compliance to a Gluten-Free Diet in Swedish Children with Type 1 Diabetes and Celiac Disease

“…This support could, for example, be more frequent visits with a dietician who specializes in the specific challenges that comes with monitoring both T1D and CD simultaneously. These results may also suggest children with both T1D and CD as a group suitable for trying promising new treatments like transglutaminase 2 inhibitors [40].…”

Injection of prototypic celiac anti-transglutaminase 2 antibodies in mice does not cause enteropathy

“…Recent observations from the above mentioned animal model [ 36 ] and from a clinical trial with a TG2 inhibitor [ 37 ] support the notion that TG2 is engaged in the pathogenesis of celiac disease, and that the catalytic activity of the enzyme is involved. The antibodies that celiac disease patients make against TG2, as is the case for the 14E06 antibody, do not interfere with the catalytic activity of TG2 [ 17 ].…”

Tissue Transglutaminase but Not Microbial Transglutaminase Is Inhibited by Exogenous Oxidative Substances in Celiac Disease

“…The in vitro data obtained in our study show that both molecules PX12 and L-cystine are potent inhibitors of TG2. Further research concerning inhibition of TG2 by oxidative molecules is clearly needed, and could augment the portfolio of therapy candidates in CD apart from competitive inhibitors [33]. Role of intra/extracellular TG2 and mTG within CD pathogenesis.…”