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.
“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.
Translating Potential Into Practice
“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,” Bana Jabri, MD, of the University of Chicago, wrote in an accompanying editorial.
The primary endpoint of no mucosal damage is “especially notable because it was achieved under a controlled gluten challenge, albeit with a relatively moderate amount of gluten (a regular diet contains 12 g of gluten daily, whereas the challenge involved 3 g daily) and for a short period of time,” Jabri said. The reduction of disease-associated symptoms and apparent improvement in quality of life with 100-mg dose added value to the findings, she said.
Future research areas include whether cross-reactive T cells, which were not analyzed in the current study, might “expand and become pathogenic after a long-term gluten challenge,” Jabri noted.
However, “ZED1227 is the first nondietary treatment that has preliminarily shown the capacity to prevent mucosal damage in persons with celiac disease,” she said.
“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,” Jabri concluded.
Need for Data on Dosing Consistency
“Celiac disease affects up to 2% of the population in many countries, and the main therapy of celiac disease is avoidance of gluten,” Kim Isaacs, MD, of the University of North Carolina, Chapel Hill, said in an interview. “This is challenging due to the ubiquitous nature of gluten in many food products,” she said. “Restrictive eating also affects social interaction which is often focused around food,” she added. “Availability of an oral therapy that is effective to treat celiac in the face of gluten exposure will have a profound impact on patients in terms of liberalization of dietary intake.”
Overall, “the changes in the villus height to crypt depth was similar between all the active treatment groups, whereas there was a dose-dependent reduction in transepithelial lymphocyte density,” Isaacs noted. “The symptom improvement was greatest in the 100-mg group, suggesting that symptoms may be related to a greater extent to the lymphocyte density than the minimal differences in villus height to crypt depth ratios seen in the active treatment groups,” she said.
Potential barriers to the use of the treatment include cost because “this will need to be a daily long-term therapy,” said Isaacs. “Compliance is a potential barrier as well,” she said. “This study looks at daily administration of the transglutaminase 2 inhibitor and shows a benefit, but it is not clear whether missing doses of the medication will have a prolonged impact on efficacy,” she emphasized. Consequently, long-term efficacy studies are needed, Isaacs said. Other research questions to answer include whether patients will become refractory to the beneficial effects over time, the effect of missing doses, and whether patients would lose all the benefits of the therapy if dosing is not consistent, she emphasized.
The study was funded by Falk Pharma. The researchers, as well as Jabri and Isaacs, had no financial conflicts to disclose. Isaacs is on the editorial advisory board of GI & Hepatology News.
This article originally appeared on MDedge.com , part of the Medscape Professional Network.
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