The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study
Version of Record online: 19 JUN 2007
Alimentary Pharmacology & Therapeutics
Volume 26, Issue 5, pages 757–766, September 2007
How to Cite
PATERSON, B. M., LAMMERS, K. M., ARRIETA, M. C., FASANO, A. and MEDDINGS, J. B. (2007), The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Alimentary Pharmacology & Therapeutics, 26: 757–766. doi: 10.1111/j.1365-2036.2007.03413.x
- Issue online: 19 JUN 2007
- Version of Record online: 19 JUN 2007
- Publication data Submitted 31 May 2007 First decision 2 June 2007 Resubmitted 5 June 2007 Second decision 8 June 2007 Resubmitted 13 June 2007 Accepted 15 June 2007
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.
To determine the safety and tolerability of 12 mg doses of AT-1001 in coeliac disease subjects challenged with gluten.
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.
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).
AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.