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

• Published in: Alimentary Pharmacology and Therapeutics Vol. 26; no. 5; pp. 757 - 766
• Main Authors: PATERSON, B. M., LAMMERS, K. M., ARRIETA, M. C., FASANO, A., MEDDINGS, J. B.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2007; Blackwell
• Subjects: Adult; Biological and medical sciences; Celiac Disease - diet therapy; Digestive system; Double-Blind Method; Female; Gastroenterology. Liver. Pancreas. Abdomen; Glutens - adverse effects; Humans; Male; Medical sciences; Oligopeptides - therapeutic use; Other diseases. Semiology; Pharmacology. Drug treatments; Placebos; Quality of Life; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - therapeutic use; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Vibrio cholerae; Human; Immunopathology; Pharmacokinetic pharmacodynamic relationship; Intestinal malabsorption; Toxicity; Single dose; Tolerance; Digestive diseases; Intestinal disease; Safety; Coeliac disease
• ISSN: 0269-2813; 1365-2036; 0953-0673
• DOI: 10.1111/j.1365-2036.2007.03413.x

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.