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

Aliment Pharmacol Ther. 2007 Sep 1;26(5):757-66. doi: 10.1111/j.1365-2036.2007.03413.x.

Abstract

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-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).

Conclusions: AT-1001 is well tolerated and appears to reduce intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in coeliacs after gluten exposure.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Celiac Disease / diet therapy*
  • Double-Blind Method
  • Female
  • Glutens / adverse effects*
  • Humans
  • Male
  • Oligopeptides / therapeutic use
  • Placebos
  • Quality of Life
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / therapeutic use*

Substances

  • AT-1001
  • Oligopeptides
  • Placebos
  • Receptors, Cell Surface
  • zonula occludens toxin receptor
  • Glutens