作者: Kelly, Ciaran P ; Wang, Chao ; Bachir, Natalie M ; DiMarino, Anthony ; Bercik, Premysl ; Leffler, Daniel A ; Fedorak, Richard N ; Murray, Joseph A ; Rasmussen, Henrik ; Perrow, Wendy ; Green, Peter H R

BACKGROUND & AIMS:

Celiac disease (CeD) is a prevalent autoimmune condition. Recurrent signs and symptoms are common despite treatment with a gluten-free diet (GFD), yet no approved or proven nondietary treatment is available.

METHODS:

In this multicenter, randomized, double-blind, placebo-controlled study, we assessed larazotide acetate 0.5, 1, or 2 mg 3 times daily to relieve ongoing symptoms in 342 adults with CeD who had been on a GFD for 12 months or longer and maintained their current GFD during the study. The study included a 4-week placebo run-in, 12 weeks of treatment, and a 4-week placebo run-out phase. The primary end point was the difference in average on-treatment Celiac Disease Gastrointestinal Symptom Rating Scale score.

RESULTS:

The primary end point was met with the 0.5-mg dose of larazotide acetate, with fewer symptoms compared with placebo by modified intention to treat (n = 340) (analysis of covariance, P = .022; mixed model for repeated measures, P = .005). The 0.5-mg dose showed an effect on exploratory end points including a 26% decrease in celiac disease patient-reported outcome symptomatic days (P = .017), a 31% increase in improved symptom days (P = .034), a 50% or more reduction from baseline of the weekly average abdominal pain score for 6 or more of 12 weeks of treatment (P = .022), and a decrease in the nongastrointestinal symptoms of headache and tiredness (P = .010). The 1- and 2-mg doses were no different than placebo for any end point. Safety was comparable with placebo.

CONCLUSIONS:

Larazotide acetate 0.5 mg reduced signs and symptoms in CeD patients on a GFD better than a GFD alone. Although results were mixed, this study was a successful trial of a novel therapeutic agent targeting tight junction regulation in patients with CeD who are symptomatic despite a GFD. Clinicaltrials.gov: NCT01396213.

2012-10-01·The American journal of gastroenterology1区 · 医学

A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease During Gluten Challenge

1区 · 医学

Article

作者: J A Murray ; L A Arterburn ; H Z Abdallah ; Daniel Alexander Leffler ; L A Harris ; B M Paterson ; Ciaran Patrick Kelly ; F Leon ; A M Colatrella ; Z H Lan

OBJECTIVES:

In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1-mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease.

METHODS:

In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG.

RESULTS:

LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge-placebo arm compared with the placebo-placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection.

CONCLUSIONS:

LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge.

2012-05-01·Peptides3区 · 医学

Larazotide acetate regulates epithelial tight junctions in vitro and in vivo

3区 · 医学

Article

作者: Sefik S. Alkan ; Shobha Gopalakrishnan ; Blake M. Paterson ; Elena F. Verdu ; Malarvizhi Durai ; Robert Somerville ; Amir P. Tamiz ; Mark Ginski ; Kelly Kitchens ; Niranjan B. Pandey ; Joseph A. Murray

Tight junctions (TJs) control paracellular permeability and apical-basolateral polarity of epithelial cells, and can be regulated by exogenous and endogenous stimuli. Dysregulated permeability is associated with pathological conditions, such as celiac disease and inflammatory bowel disease. Herein we studied the mechanism by which larazotide acetate, an 8-mer peptide and TJ regulator, inhibits the cellular changes elicited by gliadin fragments, AT-1002, and cytokines. Previously, we demonstrated that AT-1002, a 6-mer peptide derived from the Vibrio cholerae zonula occludens toxin ZOT, caused several biochemical changes in IEC6 and Caco-2 cells resulting in decreased transepithelial electrical resistance (TEER) and increased TJ permeability. In this study, larazotide acetate inhibited the redistribution and rearrangement of zonula occludens-1 (ZO-1) and actin caused by AT-1002 and gliadin fragments in Caco-2 and IEC6 cells. Functionally, larazotide acetate inhibited the AT-1002-induced TEER reduction and TJ opening in Caco-2 cells. Additionally, larazotide acetate inhibited the translocation of a gliadin 13-mer peptide, which has been implicated in celiac disease, across Caco-2 cell monolayers. Further, apically applied larazotide acetate inhibited the increase in TJ permeability elicited by basolaterally applied cytokines. Finally, when tested in vivo in gliadin-sensitized HLA-HCD4/DQ8 double transgenic mice, larazotide acetate inhibited gliadin-induced macrophage accumulation in the intestine and preserved normal TJ structure. Taken together, our data suggest that larazotide acetate inhibits changes elicited by AT-1002, gliadin, and cytokines in epithelial cells and preserves TJ structure and function in vitro and in vivo.

项与 Alba Therapeutics Corp. 相关的新闻（医药）

2007-09-19

·BioSpace

Alba Therapeutics Corporation Announces Phase IIb Clinical Trial for Oral AT-1001 for the Treatment of Celiac Disease

BALTIMORE, Sept. 19 /PRNewswire/ -- Alba Therapeutics Corporation today announced that it has dosed its first patient in a six-week Phase IIb trial with oral AT-1001, an inhibitor of gastrointestinal barrier dysfunction, for the maintenance of remission in patients with Celiac Disease (CD). The multi-center, double-blind, placebo-controlled, dose ranging study will evaluate the efficacy, safety and tolerability of AT-1001 in CD subjects during a six-week gluten challenge, while also testing components of a Celiac Disease activity rating index, a new patient-reported outcomes instrument. "This is Alba's fifth human trial with AT-1001 and highlights our efforts to develop paradigms for the treatment of CD and for the assessment of activity in this neglected disease" stated Dr. Blake Paterson, CEO of Alba. "Since there is no effective treatment for CD and no validated means of measuring disease progression, the successful completion of this study will be a tremendous step forward for Celiac patients." About Celiac Disease Celiac Disease ("CD") is a T-cell mediated auto-immune disease that occurs in genetically susceptible individuals and is characterized by small intestinal inflammation, injury and intolerance to gluten. According to the National Institutes of Health, CD affects approximately 3 million Americans. The only current treatment for CD is complete elimination of gluten from the diet, which results in remission for some patients. About AT-1001 AT-1001 is an inhibitor of barrier dysfunction that has been shown to block intestinal permeability and the genesis of some autoimmune diseases, either as a result of reduction of antigen presentation to the body's immune system, or through some unknown inhibitory, direct effect on gastrointestinal associated lymphoid tissue. AT-1001 is orally formulated, has been granted "Fast Track" designation by the U.S. Food and Drug Administration for the treatment of Celiac Disease, and is also being evaluated for the treatment of Type 1 Diabetes and Crohn's Disease. Results of the Company's first study in celiac patients are available online at: About Alba Alba Therapeutics Corporation is a privately held, clinical-stage biopharmaceutical company based in Baltimore, Maryland. Alba is dedicated to development and commercialization of disease-modifying therapeutics to treat autoimmune and inflammatory disease, drug delivery agents and mucosal vaccine adjuvants by exploiting its technology to regulate the assembly and disassembly of tight junctions in cell barriers throughout the body. Contact: Bernard McDonald, PhD Phone: 410-319-0780 E-mail: info@albatherapeutics.com Web site: Alba Therapeutics Corporation CONTACT: Bernard McDonald, PhD of Alba Therapeutics Corporation,+1-410-319-0780 Web site:

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2005-10-26

·BioSpace

Alba Therapeutics Corporation Announces Completion Of First Human Trial For AT-1001 And FDA "Fast Track" Designation

BALTIMORE, Oct. 26 /PRNewswire/ -- Alba Therapeutics Corporation ("Alba") today announced successful completion of its first Phase I trial for the drug candidate AT-1001, and that the FDA has granted "Fast Track" designation to AT-1001 for treatment of Celiac Disease (CD). "We are pleased to have concluded our first human study of oral AT-1001 and delighted that the FDA has granted fast track status to AT-1001. These two events are important additional milestones in our efforts to help those suffering from CD, a disease for which there is no effective treatment," said Blake Paterson, MD, President and CEO of Alba. Alba plans to begin a proof of concept study demonstrating efficacy of AT-1001 in celiac patients within the next few months. Fast track process is designed to facilitate development and expedite the review of new drugs with the potential to address significant unmet medical needs for the treatment of serious or life-threatening conditions. Potential fast track benefits include FDA input into development, submitting new drug applications in sections rather than all at once and the option of requesting Accelerated Approval. About Celiac Disease Celiac Disease is a T-cell mediated auto-immune disease that occurs in genetically susceptible individuals and is characterized by small intestinal inflammation, injury and intolerance to gluten. Gluten is a mixture of proteins found in common food grains such as wheat, rye and barley. According to the NIH, CD affects approximately 3 million Americans, although the diagnosis is rarely made. The only treatment for CD is complete elimination of gluten from the diet, which results in remission for some patients. About Zonulin Zonulin is an endogenous signaling protein that transiently and reversibly opens the tight junctions ("tj") between the cells of epithelial and endothelial tissues such as the intestinal mucosa, blood brain barrier and pulmonary epithelia. Discovered by Alba co-founder Dr. Alessio Fasano, zonulin appears to be involved in many disease states in which leakage occurs via paracellular transport across epithelial and endothelial tight junctions (tj), and thus may play an important potential role in the treatment of auto-immune diseases. About Alba Alba Therapeutics Corporation is a privately held biopharmaceutical company based in Baltimore, Maryland. Alba is dedicated to commercializing disease-modifying therapeutics and drug delivery adjuvants based on the zonulin pathway. Alba's lead molecule, AT-1001, is targeted towards the treatment of Celiac Disease and Type 1 Diabetes. Contact: Dr. Blake Paterson Alba Therapeutics Corporation 410-522-8708 Alba Therapeutics Corporation CONTACT: Dr. Blake Paterson of Alba Therapeutics Corporation,+1-410-522-8708 Web site:

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