The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT‐1001 in coeliac disease subjects: a proof of concept study
BM Paterson, KM Lammers, MC Arrieta… - Alimentary …, 2007 - Wiley Online Library
Alimentary pharmacology & therapeutics, 2007•Wiley Online Library
Background Lifelong adherence to a strict gluten‐free diet is the cornerstone of coeliac
disease treatment. Elucidation of disease pathogenesis has created opportunities for novel
therapeutic approaches to coeliac disease. AT‐1001 is an inhibitor of paracellular
permeability whose structure is derived from a protein secreted by Vibrio cholerae. Aim To
determine the safety and tolerability of 12 mg doses of AT‐1001 in coeliac disease subjects
challenged with gluten. Methods An in‐patient, double‐blind, randomized placebo …
disease treatment. Elucidation of disease pathogenesis has created opportunities for novel
therapeutic approaches to coeliac disease. AT‐1001 is an inhibitor of paracellular
permeability whose structure is derived from a protein secreted by Vibrio cholerae. Aim To
determine the safety and tolerability of 12 mg doses of AT‐1001 in coeliac disease subjects
challenged with gluten. Methods An in‐patient, double‐blind, randomized placebo …
Summary
Background
Lifelong adherence to a strict gluten‐free diet is the cornerstone of coeliac disease treatment. Elucidation of disease pathogenesis has created opportunities for novel therapeutic approaches to coeliac disease. AT‐1001 is an inhibitor of paracellular permeability whose structure is derived from a protein secreted by Vibrio cholerae.
Aim
To determine the safety and tolerability of 12 mg doses of AT‐1001 in coeliac disease subjects challenged with gluten.
Methods
An in‐patient, double‐blind, randomized placebo‐controlled safety study utilizing intestinal permeability, measured via fractional excretions of lactulose and mannitol, as an exploratory measure of drug efficacy.
Results
Compared to placebo, no increase in adverse events occurred in patients exposed to AT‐1001. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while none was seen in the AT‐1001 group. Interferon‐γ levels increased in four of seven patients (57%) of the placebo group, but only in four of 14 patients (29%) of the AT‐1001 group. Gastrointestinal symptoms were more frequently detected in the placebo group when compared to the AT‐1001 group (P = 0.018).
Conclusions
AT‐1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.
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