New drug may reduce gluten-induced duodenal mucosal damage in celiac disease: NEJM

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. It was 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.With this background,a team of researchers 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.

Taking a step forward, rescent research published in New England Journal of Medicine has shown that treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.

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.

In a proof-of-concept trial, researchers 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 put forth some key facts.

· 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.

For full article follow link: DOI: 10.1056/NEJMoa2032441

Source: New England Journal of Medicine