The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: A proof of concept study

Alba Therapeutics Corporation, Baltimore, MD 21201, USA.
Alimentary Pharmacology & Therapeutics (Impact Factor: 5.48). 10/2007; 26(5):757-66. DOI: 10.1111/j.1365-2036.2007.03413.x
Source: PubMed

ABSTRACT 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-gamma 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.

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Available from: Alessio Fasano, Oct 06, 2014
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    • "In a pilot study, AT-1001 was well tolerated with no increase in adverse events compared to placebo, the majority of adverse events being GI disorders, mostly frequenty diarrhoea [231]. A trend to reduce intestinal barrier permeability, IFN-production and GI symptoms after acute gluten exposure was observed although this must be confirmed. "
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    • "When the integrity of the tj system is compromised as in CD, a paracellular leak and an inappropriate immune response to environmental antigens develops [74]. The possibility to use the synthetic peptide inhibitor of zonulin receptor AT-1001 to recover intestinal permeability was explored in a Phase I clinical trial [75]. The objective of this study was to establish the safety and tolerability of oral AT-1001 in CD patients in remission challenged with a single dose of gluten. "
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