Materials and methods for the treatment of celiac disease
Inventors
Fasano, Alessio • Paterson, Blake
Assignees
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Publication Number
US-9279807-B2
Publication Date
2016-03-08
Expiration Date
Abstract
The present invention provides materials and methods for the treatment of celiac disease. In addition, the present invention provides materials and methods of monitoring the treatment of a subject having celiac disease.
Core Innovation
The invention relates to materials and methods for celiac disease treatment and monitoring centered on zonulin inhibition. It provides an orally administered zonulin receptor antagonist, Larazotide acetate (AT-1001; SEQ ID NO:15 octapeptide), intended to block gliadin-induced tight-junction disassembly and persistent intestinal permeability, including downstream immune activation.
A key aspect is luminal duodenal delivery by an oral dosage capsule comprising enteric-coated multiparticulate beads. The beads are stable in gastric fluid but unstable in intestinal fluid so as to release the peptide at the duodenum.
The peptide is administered at least three times daily prior to a meal to block persistent intestinal permeability and immune activation. The disclosed monitoring approach uses cytokine biomarkers, including IL-6, IL-8, and IL-10, to indicate severity changes between samples and to reflect immune activation.
Claims Coverage
Two independent claims are provided. Both claims focus on administering Larazotide acetate (SEQ ID NO:15) via an oral enteric-coated multiparticulate capsule formulated for duodenal release to block persistent intestinal permeability and immune activation in celiac patients on a gluten-free diet. Across both independent claims, the main inventive features include duodenal luminal delivery, enteric-coated multiparticulate beads with gastric stability and intestinal instability, and dosing at least three times daily prior to meals, with one claim additionally requiring a treatment duration and a quantitative capsule peptide range.
Duodenal luminal administration of Larazotide acetate to block intestinal permeability and immune activation
Administering to the luminal surface of the duodenum of the patient a peptide having the amino acid sequence of SEQ ID NO:15 (Larazotide Acetate), administered at least three times daily prior to a meal so as to block persistent intestinal permeability and immune activation in a celiac patient on a gluten-free diet.
Oral enteric-coated multiparticulate capsule for gastric-stable and intestinal-unstable release to the duodenum
Administering an oral dosage capsule comprising enteric-coated multiparticulate beads that are stable in gastric fluid but unstable in intestinal fluid so as to release peptide at the duodenum.
At-least-two-weeks dosing with quantified Larazotide acetate per capsule and meal timing
Administering for a period of at least two weeks an oral dosage capsule comprising enteric-coated beads containing from 0.25 mg to 8 mg of Larazotide acetate, formulated for delivery to the duodenum, administered at least three times daily about 15 minutes prior to a meal, wherein the capsule comprises enteric-coated multiparticulate beads that are stable in gastric fluid but unstable in intestinal fluid so as to release peptide in the duodenum.
The independent claims collectively cover treating celiac disease on a gluten-free diet by administering SEQ ID NO:15 (Larazotide acetate) for duodenal luminal delivery using an oral enteric-coated multiparticulate capsule with gastric-stable and intestinal-unstable release, with dosing at least three times daily prior to meals. One independent claim further specifies a treatment period of at least two weeks, a peptide amount range of 0.25 mg to 8 mg, and administration about 15 minutes prior to meals.
Stated Advantages
Blocks persistent intestinal permeability.
Blocks immune activation.
Preserves barrier function.
Associated with reduced gastrointestinal adverse event frequency, including reduced diarrhea.
Documented Applications
Treatment of celiac disease in a celiac patient on a gluten-free diet using oral administration of Larazotide acetate to the duodenum to block persistent intestinal permeability and immune activation.
Monitoring of severity changes using cytokine biomarkers such as IL-6, IL-8, and IL-10 between samples in the context of the described treatment approach and gluten challenge.
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