A novel oral inhibitor of transglutaminase 2 appears to block gluten-induced mucosal damage in patients with celiac disease at three different doses, based on proof-of-concept trial data from 132 patients.
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“Currently, no drug therapy reliably prevents the effects of dietary gluten or has been approved by regulators to treat celiac disease,” which remains an unmet need in these patients, many of whom struggle with symptoms even when they adhere to a gluten-free diet, wrote Detlef Schuppan, MD, of Johannes Gutenberg University of Mainz (Germany) and colleagues.
Celiac disease is driven in part by the enzyme transglutaminase 2, and a transglutaminase 2 inhibitor known as ZED1227 has been tested safely in phase 1 trials, they reported.
“ZED1227 targets the intestinal mucosa predominantly and thereby mediates protection; thus, it is unaffected by the complexity of the food matrix and is less dependent on the timing of ingestion of gluten-containing food,” the researchers explained.
In a study published in the New England Journal of Medicine, the researchers assessed the safety and efficacy of three dose levels of ZED1227. Adults with controlled celiac disease were randomized to doses of 10 mg (41 patients), 50 mg (41 patients), and 100 mg (41 patients), and 40 patients received a placebo. Of these, 35, 39, 28, and 30 patients, respectively, had sufficient duodenal biopsy samples for analysis.
Patients underwent a daily gluten challenge of 3 g for 6 weeks. At the end of 6 weeks, the primary study endpoint of attenuation of gluten-induced mucosal damage was measured by the ratio of villus height to crypt depth.
Patients in all three treatment groups showed significant attenuation of mucosal damage. The change in the average ratio of villus height to crypt depth compared to placebo in the 10-mg, 50-mg, and 100-mg groups was 0.44, 0.49, and 0.48, respectively, with P values equal to .001 in the 10-mg group and less than .001 in the 50-mg and 100-mg groups.
Adverse events were similar across all treatment groups and the placebo group, with the exception of a rash in three patients in the 100-mg group. A total of 74 patients reported adverse events, and the most common were headache, nausea, diarrhea, vomiting, and abdominal pain. The investigators determined that from 34% to 55% of the adverse events across groups were related to the study drug or placebo.
Two patients developed serious adverse events that were deemed related to the study drug or placebo; one patient in the 50-mg group developed migraine with aura, and one placebo patient developed ventricular extrasystoles. The patients recovered after discontinuing the drug or placebo.
Secondary endpoints included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score. Estimated changes in intraepithelial lymphocyte density, compared with placebo, were –2.7 cells per 100 epithelial cells in the 10-mg group, −4.2 cells per 100 epithelial cells in the 50-mg group, and −9.6 cells per 100 epithelial cells in the 100-mg group. Compared with those of patients taking placebo, the 6-week changes in Celiac Symptom Index scores and Celiac Disease Questionnaire scores suggested slight improvements in symptoms and quality of life for the 100-mg dose.
The study findings were limited by several factors including missing data and loss of several patients to follow-up, as well as the short trial duration and use of controlled gluten ingestion, the researchers noted. Larger studies involving real-world conditions of minor gluten ingestion are needed to support the preliminary signs of safety and efficacy, they said.
Study strengths include high levels of patient adherence to the treatment and the gluten challenge, they said. “Future studies of ZED1227 in more patients are needed to provide additional evidence of the safety and efficacy of the drug, potentially in real-life conditions with minor gluten ingestion,” they concluded.