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: 5.73). 10/2007; 26(5):757-66. DOI: 10.1111/j.1365-2036.2007.03413.x
Source: PubMed


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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    • "Patients were instructed to report any symptom experienced during the challenge, which was graded for severity according to the WHO toxicity grading scale as mild (grade 1), moderate (grade 2), severe (grade 3) and life threatening (grade 4) [15]. We used a 2.5 g protein dose for the challenge, corresponding approximately to one slice of bread and to the dose used by others [16-18] for “proof of the concept” challenge studies. "
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    ABSTRACT: Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and ex-vivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD. We performed a single blind, cross-over study involving 12 CD patients who had been on a GFD for at least 12 months, challenged on day 0, 14 and 28 with a single fixed dose of 2.5 grams of the following (random order): Tm, rice (as reference atoxic protein) and Amygluten (as reference toxic protein) dispersed in a gluten-free pudding. The primary end-point of the study was the change in intestinal permeability, as assessed by changes in the urinary lactulose/rhamnose ratio (L/R ratio) measured by High Pressure Liquid Chromatography. We also assessed the occurrence of adverse gastrointestinal events, graded for intensity and duration according to the WHO scale. Variables were expressed as mean ± SD; paired t-test and χ2 test were used as appropriate. The urinary L/R ratio did not change significantly upon challenge with the 3 cereals, and was 0.055 ± 0.026 for Tm Vs 0.058 ± 0.035 for rice (p = 0.6736) and Vs 0.063 ± 0.054 with Amygluten (p = 0.6071). Adverse gastrointestinal events were 8 for Tm, Vs 11 for rice (p = 0.6321) and Vs 31 for Amygluten p = 0.0016), and, in all cases events were graded as “mild” or “moderate” with TM and rice, and as “severe” or “disabling” in 4 cases during Amygluten. No definite conclusion can be drawn on the safety of Tm, based on no change in urinary L/R because even Amygluten, a toxic wheat protein, did not cause a significant change in urinary L/R indicating low sensitivity of this methodology in studies on acute toxicity. Tm was, however, well tolerated by all patients providing the rationale for further investigation on the safety of this cereal for CD patients. Trial registration EudraCT-AIFA n2008-000697-20
    BMC Gastroenterology 05/2013; 13(1):92. DOI:10.1186/1471-230X-13-92 · 2.37 Impact Factor
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    • "No increase in adverse events was recorded among patients exposed to larazotide acetate as compared to placebo. Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, while no changes were seen in the Larazotide acetate group [39]. After gluten exposure, IFN-γ levels increased in 4 out of 7 patients (57.1%) of the placebo-group, but only in 4 out of 14 patients (28.6%) of the larazotide group. "
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    ABSTRACT: Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Gluten is a protein component in wheat and other cereals like rye and barley. At present, the only available treatment is a strict gluten-free diet. Recent advances have increased our understanding of the molecular basis for this disorder. Last decade has seen new scientific developments in this disease and led to the formulation of new concepts of pathophysiology that offer possible targets for new treatments or interventions integrative to the gluten-free diet.
    Clinical and Developmental Immunology 10/2012; 2012(9):959061. DOI:10.1155/2012/959061 · 2.93 Impact Factor
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    • "Another possible therapeutic alternative that is currently pursued is a vaccine that contains a mixture of immunodominant peptides that trigger the immune response and are supposed to retrain the immune system of HLA-DQ2 positive CD subjects to tolerate gluten [24,30]. Furthermore, an inhibitor of paracellular permeability (AT-1001, larazotide acetate) has been shown to reduce the intestinal barrier dysfunction, production of pro-inflammatory cytokines, and GI symptoms in CD individuals after gluten exposure [31,32]. Moreover, attempts have been made to degrade toxic gluten sequences during sourdough fermentation with selected lactobacilli strains [33]. "
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    ABSTRACT: Coeliac disease (CD) is a common and complex disorder of the small intestine caused by intolerance to wheat gluten and related edible cereals like barley and rye. Peptides originating from incomplete gliadin digestion activate the lamina propria infiltrating T cells to release proinflammatory cytokines, which in turn cause profound tissue remodelling of the small intestinal wall. There is no cure for CD except refraining from consuming gluten-containing products. Phage from a random oligomer display library were enriched by repeated pannings against immobilised gliadin proteins. Phage from the final panning round were plated, individual plaques picked, incubated with host bacteria, amplified to a population size of 1011 to 1012 and purified. DNA was isolated from 1000 purified phage populations and the region covering the 36 bp oligonucleotide insert from which the displayed peptides were translated, was sequenced. Altogether more than 150 different peptide-encoding sequences were identified, many of which were repeatedly isolated under various experimental conditions. Amplified phage populations, each expressing a single peptide, were tested first in pools and then one by one for their ability to inhibit binding of human anti-gliadin antibodies in ELISA assays. These experiments showed that several of the different peptide-expressing phage tested inhibited the interaction between gliadin and anti-gliadin antibodies. Finally, four different peptide-encoding sequences were selected for further analysis, and the corresponding 12-mer peptides were synthesised in vitro. By ELISA assays it was demonstrated that several of the peptides inhibited the interaction between gliadin molecules and serum anti-gliadin antibodies. Moreover, ELISA competition experiments as well as dot-blot and western blot revealed that the different peptides interacted with different molecular sites of gliadin. We believe that several of the isolated and characterised gliadin-binding peptides described here could provide valuable tools for researchers in the field of CD by facilitating studies on localisation and uptake of various gliadin peptides in the small intestine. In future work, the potential of these peptides to detoxify gluten will be investigated.
    BMC Biotechnology 02/2011; 11(16):16. DOI:10.1186/1472-6750-11-16 · 2.03 Impact Factor
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