A pill that blocks the enzyme the causes a reaction to gluten in celiac disease meets study goals
By Amy Ratner, Director Scientific Affairs
A new drug being investigated to treat celiac disease reduced intestinal damage in patients undergoing a gluten challenge, early results reported in a new study found.
ZED1227 is designed to block transglutaminase 2 (tTG), an enzyme that reacts with fragments of gluten. This reaction makes the fragments more recognizable to the cells that cause destruction of the nutrient-absorbing villi in those who have celiac disease.
After a six-week clinical trial during which about 160 study participants ate a cookie containing three grams of gluten each morning, researchers found that those who then took varying doses of ZED1227 had a greater reduction in intestinal damage compared to study participants who were given a placebo. Researchers call the amount of the gluten challenge “moderate.”
Damage to the intestine was measured through the villus height-to-crypt depth average ratio in biopsy samples, according to the study published in the New England Journal of Medicine. This measurement was the main goal of the study, called the primary endpoint.
“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,” the authors wrote. “The endpoint was achieved at all three dose levels of ZED1227.”
ZED1227 is intended to prevent the immune response that drives celiac disease by blocking tTG.
ZED1227 was given daily as a pill to three study groups of about 40 participants each. One group received 10 milligrams(mg), a second, 50 mg, and a third 100 mg. All participants continued their gluten-free diet with the exception of the gluten challenge that was part of the study.
A decrease in the villus height to crypt depth is a sign of damage from gluten. Over the six weeks of the trial, the gluten challenge decreased the ratio of the villus height to crypt depth by about -.61 in the group that got the placebo, according to the study. In the 50 mg and 100 mg treatment groups, ZED1227 prevented this deterioration, the study says, with an estimated change of -.12 and -.13 respectively. The drug was slightly less effective in the 10 mg group, where the ratio was -.17. “As compared with the placebo, all three dose levels of ZED1227 significantly prevented a decrease in the ratio of villus height to crypt depth,” the study says.
All study participants reported an increase in symptoms at six weeks compared to when they started the study, though the increase was greater in the placebo group. Meanwhile, all patients getting ZED1227 reported an increase in quality of life. Those in the placebo group, who had the gluten challenge but not the drug, reported a decrease in quality of life. Patient symptoms and quality of life, as well as a measure of inflammation in the intestine, were secondary goals, or endpoints, of the study.
Patients in the placebo group and study participants getting 10 or 50 mg of the drug had an increase in the measure of inflammation, though the increase was smaller the greater the dose ZED1227. Inflammation was not seen in the 100 mg group.
Adverse effects occurred in about 80 percent of study participants who received at least one dose of ZED1227 or the placebo. The most common adverse effects across all groups were headache, nausea, diarrhea, vomiting, and abdominal pain. Additionally, three patients receiving the highest dose of the drug reported getting a rash. Researchers classified adverse effects according to whether they were related to the gluten challenge or potentially to the drug or placebo themselves. They concluded that 34 percent in the 10 mg group, 46 percent in the 50 mg group, 55 in the 100 mg and placebo groups, fell into this category.
The authors noted that the incidence and severity of adverse effects were similar in the treatment and placebo groups.
Detlef Schuppan, MD, director of the Institute of Translational Immunology and Celiac and Small Intestinal Diseases at the University of Mainz in Germany, and Markku Maki, MD, professor emeritus, University of Tampere in Finland, led the study. Research was done at 20 centers in seven European countries. All study participants had been diagnosed for at least a year and were following a gluten-free diet. At the start of the study, they had negative TTG blood test results and biopsies that showed an acceptable villus height to crypt ratio.
Intestinal damage is an objective marker of gluten-induced celiac disease activity and can be measured quantitatively, the study authors wrote. And the gluten challenge produces statistically and clinically significant but reversible deterioration that allows the effectiveness of a treatment to be assessed, they noted.
Study limitations included the loss of some study participants for follow-up, the short time the study was conducted and the controlled gluten-challenge versus real-life gluten consumption on a gluten-free diet, largely from inadvertent gluten exposure.
The study was funded by Dr. Falk Pharma, a company that specializes in the development of drugs used in gastroenterology. Zedira, a clinical-stage bio-tech company with a focus on celiac disease and transglutaminase, is also involved in development of the drug. The project was also funded by the German Federal Ministry of Education and Research.
Based on results of the phase 2a, proof of concept study, researchers plan to launch a larger study in a real-world setting. Study authors pointed to inadequacy of the gluten-free diet, currently the only treatment for celiac disease. They note that “only 50 percent of patients have mucosal recovery” and often do not have negative results in blood test for celiac disease even one year after diagnosis. “Moreover, many patients with celiac disease report having symptoms despite adherence to the gluten-free diet,” they wrote. “There is an unmet medical need for an effective treatment adjunct to a strict gluten-free diet.”
“I am very happy about the success of our therapeutic approach that addresses a mechanism that is highly disease specific and based on our prior research,” Schuppan said. “An oral drug for celiac disease is urgently needed, since many patients do not heal despite the gluten free diet.”
In an editorial published in the same issue of NEJM, Bana Jabri, MD, director of research at the University of Chicago Celiac Disease Center, noted that ZED1227 is the first nondietary treatment that has preliminarily shown the capacity to prevent mucosal damage in persons with celiac disease.
“Although this trial is very encouraging, whether treatment with ZED1227, and more generally transglutaminase 2 inhibition, in patients with celiac disease will be efficient in real life and during long-term gluten exposure remains to be determined, “she wrote.
You can read more about the study here.