Novel Oral Therapy Shows Promise in Celiac Disease

ZED1227, a potential therapeutic transglutaminase 2 inhibitor, reduced mucosal damage from gluten in celiac disease patients, a randomized proof-of-concept trial found.

At week 6, the difference in villus height-to-crypt depth average ratio, a measurement of intestinal injury, was significant at three different dosages of ZED1227 (10 mg, 50 mg, and 100 mg) compared to placebo, reported Detlef Schuppan, MD, PhD, from the Johannes Gutenberg University in Mainz, Germany, and colleagues, writing in the New England Journal of Medicine.

“As a proof of concept, this is an exciting example of how targeted therapy could be used to treat autoimmune disease — especially if there are advancements in identifying antigens underlying disease-associated immune responses in other immune-mediated diseases,” Joanna M. Melia, MD, from Johns Hopkins University in Baltimore, who was not involved in the research, told MedPage Today.

Affecting up to 2% of the world’s population, celiac disease causes small intestinal inflammation, generally due to an autoimmune response in people with predisposed genotypes (HLA-DQ2 or HLA-DQ8) after ingesting gluten. Maintaining a strict gluten-free diet is difficult and has been the only method of preventing symptoms, but symptoms arise even with a strict diet, leaving patients with an unmet need, according to Schuppan and co-authors.

Prior research found that ZED1227 prevents transglutaminase 2, stopping symptom flare-ups in patients, and a phase I trial found that it was safe, with no drug-related adverse events.

“An absence of mucosal damage is a critical criterion to ensure the long-term health of a patient, and this clinical trial in celiac disease meets this important endpoint,” wrote Bana Jabri, MD, PhD, of the University of Chicago, in an accompanying editorial.

“ZED1227 is the first nondietary treatment that has preliminarily shown the capacity to prevent mucosal damage in persons with celiac disease,” she said, describing the results as encouraging, but added that long-term efficacy data are needed.

The phase II, double-blind randomized proof-of-concept trial involved 163 participants and was conducted at 20 centers across seven countries in Europe from May 2018 to February 2020.

Adults (ages 18 to 65) were eligible if they had controlled biopsy-confirmed celiac disease, had been diagnosed at least 1 year prior, and were adhering to a daily gluten-free diet were included. Participants were required to be positive for predisposed celiac disease genotypes, test negative for transglutaminase 2 IgA, eat a maximum of 3 g of gluten a day, and have an average villus-to-crypt ratio of ≥1.5.

Reduction of mucosal damage by gluten was the primary endpoint. Secondary endpoints focused on the Celiac Symptom Index score, density of CD3+ intraepithelial lymphocytes, as well as scores from the Celiac Disease Questionnaire.

Participants were randomized to one of three dosages of ZED1227 or placebo. Efficacy results were reported for 159 participants, with duodenal biopsy samples taken for 142 participants. Demographics were similar across groups, with the exception of the 10 mg group having more women.

Compared to placebo, the change in the mean ratio of villus height-to-crypt depth from baseline to week 6 was 0.44 for the ZED1227 10 mg group (95% CI 0.15-0.73), 0.49 for the 50 mg group (95% CI 0.20-0.77), and 0.48 for the 100 mg group (95% CI 0.20-0.77).

There was an increase in intraepithelial lymphocyte density, which helps measure mucosal inflammation, from baseline in the 10 mg group, 50 mg group, and placebo group that was not observed in the 100 mg group, with the authors noting “the increase was attenuated by ZED1227 dose-dependently.”

About 80% of patients who received at least one dose of treatment or placebo experienced adverse events, which included nausea, vomiting, diarrhea, abdominal pain, and headache. Adverse events related to the study drug occurred in 50% of the 100 mg group, 46% of the 50 mg group, and 34% of the 10 mg group, while 55% of the placebo group experienced adverse events. No adverse events appeared to be more common in the intervention group versus placebo group, except for rash, which occurred in three patients, the authors said.

Schuppan told MedPage Today that research starting later this year will assess the ZED1227’s efficacy in a real-world setting.

“Based on the promising results of this study, we have planned a phase IIb/III clinical study treating patients with celiac disease that do not respond completely to a gluten-free diet,” he said, adding they plan to test different doses and dose regimens of the drug versus placebo.

Schuppan added that after the next study, he hopes ZED1227 will be available for celiac patients who require “neutralization” of minor-to-moderate gluten amounts from ill-defined foods or for patients with a high-gluten sensitivity.

Limitations of the study included its small size and that it only included participants of European descent. Several patients were lost to follow-up and data were lacking in cross-country comparisons.

Jabri also noted that since ZED1227 was given just 30 minutes prior to the consumption of gluten, gastrointestinal adverse effects “are more complex to decipher.”

“To me, there could be more to the biology here,” said Melia, who also encouraged long-term studies. “This may not be the end of gluten avoidance in celiac patients, but this drug could help those who continue to have refractory disease.”