ZED1227 prevents increased mucosal injury in celiac disease
Transglutaminase 2 inhibitor ZED1227 decreased intestinal mucosal injury among patients with celiac disease, according to research published in The New England Journal of Medicine.
“The only available treatment for celiac disease is lifelong adherence to a strict gluten-free diet, a diet that is difficult to maintain. ... Moreover, many patients with celiac disease report having persistent symptoms despite adherence to the gluten-free diet. Thus, there is an unmet medical need for an effective treatment adjunct to a strict gluten-free diet,” Detlef Schuppan, MD, PhD, Johannes Gutenberg University, and colleagues wrote. “ZED1227 inhibits transglutaminase 2 with high specificity and prevents the formation of deamidated gluten and, putatively, the initial steps of gluten-induced T-cell activation. Our phase 1 clinical studies ... did not show drug-related adverse effects or signs of drug toxicity.”
In a phase 2, proof-of-concept trial, researchers assessed the safety and efficacy of ZED1227 in the treatment of well-controlled celiac disease. Patients underwent a daily gluten challenge (3 g/day) and received either ZED1227 10 mg (n = 41), 50 mg (n = 41), 100 mg (n = 39) or placebo (n = 38) for 6 weeks. Researchers followed up with patients at week 2, week 4, week 6 and week 10. The primary endpoint was attenuated gluten-induced mucosal damage measured by the ratio of villus height to crypt depth.
Compared with placebo, the estimated difference of the mean change in gluten-induced mucosal damage was 0.44 (95% CI, 0.15-0.73) in the ZED1227 10 mg group, 0.49 (95% CI, 0.2-0.77) in the ZED1227 50 mg group and 0.48 (95% CI, 0.2-0.77) in the ZED1227 100 mg group. The estimated difference in intraepithelial lymphocyte density was –2.7 cells per 100 epithelial cells (95% CI, –7.6-2.2) in the 10 mg group, –4.2 cells per 100 epithelial cells (95% CI, –8.9-0.6) 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. Researchers noted adverse events in 78% of patients who received at least one dose of ZED1227 or placebo.
“The ratio of villus height to crypt depth is widely considered to be the most objective and valid primary endpoint in clinical studies for therapies for celiac disease and the endpoint was achieved at all three dose levels of ZED1227. The benefits across multiple endpoints were most pronounced for the 50 mg and 100 mg doses,” Schuppan and colleagues concluded. “Improved patient-reported outcomes across the dose groups need to be confirmed in a larger study.”