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,” Dr. 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,” Dr. 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,” Dr. 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,” Dr. 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 Dr. 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, Dr. 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 Dr. Falk Pharma. The researchers, as well as Dr. Jabri and Dr. Isaacs, had no financial conflicts to disclose. Dr. Isaacs is on the editorial advisory board of GI & Hepatology News.