A selective oral transglutaminase 2 inhibitor, dubbed ZED1227, reduced gluten-induced duodenal mucosal injury in patients with celiac disease, according to findings from the preliminary CEC-3 trial published in the New England Journal of Medicine.
Intestinal transglutaminase 2 is an enzyme responsible for modifying immunogenic gluten peptides by way of deamidation, resulting in the generation of immunogenic T-cell antigens and subsequent activation of inflammatory T-cells that are reactive to gluten. ZED1227 is an oral transglutaminase 2 inhibitor that prevents formation of deamidated gluten as well as the early steps of gluten-induced T-cell activation.
Researchers recently tested the efficacy and safety of a 6-week treatment with ZED1227 in a proof-of-concept trial. In the study, adult patients with well-controlled celiac disease were randomly assigned to receive either 10 mg ZED1227 (n=41), 50 mg ZED1227 (n=41), 100 mg ZED1227 (n=39), or placebo (n=38).
Participants in the trial took their assigned treatment every morning after ≥6 hours of fasting. Approximately 30 minutes later, participants then underwent a daily, prebreakfast gluten challenge that entailed consuming a biscuit containing 3 grams of gluten. Participants were instructed to continue adherence to a strict gluten-free diet throughout the 6-week study period.
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All 3 dose levels of ZED1227 attenuated gluten-induced duodenal mucosal injury, the primary endpoint assessed using the ratio of villus height to crypt depth. In the group that received 10 mg ZED1227, the estimated difference from placebo in the change in the average ratio of villus height to crypt depth was 0.44 (95% CI, 0.15-0.73; P =.001) from baseline to week 6. Additionally, the estimated difference from placebo in this measurement was 0.49 (95% CI, 0.20-0.77; P <.001) in the 50-mg group and 0.48 (95% CI, 0.20-0.77; P <.001) in the 100-mg group.
The researchers also compared the treatment groups with placebo in terms of intraepithelial lymphocyte density. 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) for the group that received 10 mg ZED1227, −4.2 cells per 100 epithelial cells (95% CI, −8.9 to 0.6) for the 50-mg ZED1227 group, and −9.6 cells per 100 epithelial cells (95% CI, −14.4 to −4.8) for the 100-mg treatment group.
All groups demonstrated an increase in the Celiac Symptom Index score over the 6-week study. An assessment comparing scores with placebo favored all ZED1227 dose levels.
Headache, nausea, diarrhea, vomiting, and abdominal pain were the most common adverse events across all dose groups. Rash was reported in 8% of patients who received 100 mg ZED1227.
Limitations of the study included the loss of patients to the follow-up as well as the study’s short duration. The researchers also note that the study’s controlled protocol for gluten ingestion could limit the findings across real-world conditions.
The researchers explained that, “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.” As such, the therapy holds promise in the prevention of “the deamidation of gluten peptides in the small intestinal mucosa and thus abolishes the immunogenic process.”
Disclosure: This clinical trial was supported by Dr. Falk Pharma. Please see the original reference for a full list of authors’ disclosures.
Reference
Schuppan D, Mäki M, Lundin KEA, et al, for the CEC-3 Trial Group. A randomized trial of a transglutaminase 2 inhibitor for celiac disease. N Engl J Med. 2021;385(1):35-45. doi:10.1056/NEJMoa2032441
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