“The results of this phase 2a trial support the potential use of TG2 inhibition in the treatment of celiac disease in the future,” says Professor Emeritus Markku Mäki from Tampere University who as Trial Coordinating Investigator designed the breakthrough study. Mäki was also responsible for the part of the study that was conducted in Finland.
"The results of this phase 2a trial support the potential use of TG2 inhibition in the treatment of celiac disease in the future,” says Professor Emeritus Markku Mäki from Tampere University who as Trial Coordinating Investigator designed the breakthrough study. Mäki was also responsible for the part of the study that was conducted in Finland.
The phase 2 trial was the first time this new drug candidate was tested in patients. Celiac disease can currently only be treated with a lifelong gluten-free diet.
The results of the international study were published in the prestigious New England Journal of Medicine.
Measuring the drug’s efficacy on mucosal damage
As such, gluten in the diet – meaning the prolamins in wheat, barley, and rye – does not cause problems for people with celiac disease. It is not until the small intestinal enzyme TG2 leads to the deamidation of glutamine residues in gluten peptides that enhances the stimulation of the pathogenetic mechanisms and causes mucosal inflammation and damage. Mucosal injury caused by gluten is also the cornerstone of celiac disease diagnosing globally.
Approximately 2% of Finns suffer from celiac disease.
The drug trial tested the functionality and safety of the orally taken ZED1227 molecule that inhibits the TG2 enzyme. Celiac patients received a daily gluten challenge of three grams for six weeks. The drug was tested using three different doses in three groups of patients and a fourth group that received a placebo drug.
“In our study, gluten-induced histologically measurable duodenal mucosal damage was the primary efficacy outcome measured before and after gluten exposure,” Mäki says.
“My research group at Tampere University validated the mucosal damage and inflammation indicators for the purpose of the international drug trials. Tampere University has become a world-class centre of excellence in this field,” Mäki emphasises. In Tampere, Professor Jorma Isola’s research histopathology laboratory Jilab Oy was the central laboratory used in the international study.
“In the placebo group, gluten caused structural damage to the intestinal mucosal lining, atrophy of villi and increased crypt depth,” Mäki explains. The studied drug candidate ZED1227 prevented the damage with daily doses of 50 and 100 milligrams. The lowest daily dosage of 10 milligrams was less effective but, unlike the placebo, all doses protected the intestine from gluten-induced mucosal damage.
Largest dose prevents mucosal inflammation entirely
Mucosal inflammation decreased depending on the dose and was entirely prevented with a dosage of 100 mg. Gluten caused a slight increase in liver enzymes in the placebo group, which was prevented by the studied drug candidate at all doses.
The subjects in the drug groups of the study experienced a reduction of gluten-related symptoms and an improvement in quality of life. Except for rash, which occurred in 3 patients (7.5%) in the 100 mg group, no adverse events appeared to be more common in the ZED1227 groups than in the placebo group.
The study involving 20 research centres was conducted in 7 European countries. Three Finnish centres participated:
• Tays Research Services, Pirkanmaa Hospital District, Tampere, led by Principal Investigator Marja-Leena Lähdeaho
• Clinical Research Services Turku - CRST Oy led by Principal Investigator, Emeritus Professor Mika Scheinin
• Aava Medical Centre Helsinki Kamppi led by Principal Investigator, D.Med.Sc.
Jari Koskenpato. In Finland, the researchers cooperated closely with the Finnish Coeliac Society and local patient associations.
The drug candidate was developed by the German clinical stage biotech company Zedira, and the drug trial was conducted by the German Dr. Falk Pharma company.
A randomized trial of a transglutaminase 2 inhibitor for celiac disease. Detlef Schuppan#, Markku Mäki#,* Knut E. A. Lundin, Jorma Isola, Tina Friesing-Sosnik, Juha Taavela, Alina Popp, Jari Koskenpato, Jost Langhorst, Øistein Hovde, Marja-Leena Lähdeaho, Stefano Fusco, Michael Schumann, Helga Paula Török, Juozas Kupcinskas, Yurdagül Zopf, Ansgar W. Lohse, Mika Scheinin, Karin Kull, Luc Biedermann, Valerie Byrnes, Andreas Stallmach, Jørgen Jahnsen, Jonas Zeitz, Ralf Mohrbacher, Roland Greinwald, N Engl J Med, published xxx (in print)
#Dual first authorship, Drs. Schuppan and Mäki contributed equally to this article.
Tampere University
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