Larazotide Acetate in Patients With Coeliac Disease Undergoing a Gluten Challenge

A Randomised Placebo-controlled Study

C. P. Kelly; P. H. R. Green; J. A. Murray; A. DiMarino; A. Colatrella; D. A. Leffler; T. Alexander; R. Arsenescu; F. Leon; J. G. Jiang; L. A. Arterburner; B. M. Paterson; R. N. Fedorak


Aliment Pharmacol Ther. 2013;37(2):252-262. 

In This Article

Abstract and Introduction


Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten-free diet (GFD), which is difficult for many patients. Larazotide acetate is a first-in-class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae.

Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge.

Methods This exploratory, double-blind, randomised, placebo-controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run-in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose-to-mannitol (LAMA) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale (GSRS) and anti-transglutaminase antibody levels.

Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1-mg limited gluten-induced symptoms measured by GSRS (P = 0.002 vs. placebo). Mean ratio of anti-tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 (P = 0.010), 3.88 (P = 0.005) and 7.72 (P = 0.025) in the larazotide acetate 1-, 4-, and 8-mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups.

Conclusions Larazotide acetate reduced gluten-induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.


Coeliac disease is an autoimmune disorder triggered by the ingestion of gluten by genetically susceptible individuals. Patients with coeliac disease frequently present with gastrointestinal symptoms such as diarrhoea, abdominal pain and bloating, and may also experience extra-intestinal signs such as iron deficiency anaemia, dermatitis, osteoporosis, infertility and neurological complications.[1–3] Serious complications include intestinal adenocarcinoma and non-Hodgkin's lymphoma, which may develop due to chronic inflammation and chronic stimulation of intestinal lymphocytes.[4,5]

Currently, the only management option for coeliac disease is a gluten-free diet (GFD). Adherence to this highly restrictive diet is difficult due to the pervasiveness of gluten in foods. The estimated inadvertent exposure to gluten despite adherence to a GFD ranges from several milligrams up to 2 g per day.[6,7] Exposure to even these small amounts can trigger signs and symptoms and cause histological changes including intestinal villous atrophy and increased intraepithelial lymphocytes.[8,9] Consequently, many patients, even if they follow the GFD, do not attain full relief from symptoms, nor do they experience complete mucosal healing even after long-term maintenance of a GFD.[10,11] Failure to heal is associated with excess morbidity and perhaps mortality.[12] A GFD alone, therefore, is not sufficient to fully control the disease in many patients.[13]

Gene pairs encoding the HLA molecules DQ2 or DQ8 and environmental exposure to the gluten antigen are required, but not sufficient for the development of coeliac disease.[14] In addition, tight junction opening may contribute to disease development and/or persistence.[15] Patients with coeliac disease have altered tight junction morphology and higher intestinal permeability compared with healthy controls.[16–18] Gluten triggers the opening of tight junctions, which may result in enhanced paracellular gluten transport and immunological exposure to luminal antigens in the lamina propria.[19] This is believed to be a factor in the increased secretion of inflammatory cytokines leading to prolonged opening of tight junctions, thus perpetuating a self-amplifying inflammation loop.[20,21]

Larazotide acetate is a first-in-class, 8-amino acid, synthetic peptide that in vitro prevents the opening of tight junctions induced by multiple stimuli, including cytokines, bacterial antigens and gluten fragments.[22,23] In a transgenic mouse model of gluten-sensitive enteropathy, larazotide acetate reduced the transport of a marker protein across the intestinal epithelium, preserved intestinal tight junction structure and reduced macrophage count in the lamina propria.[22] In a Phase 1 clinical trial of patients with coeliac disease, larazotide acetate blocked the gluten-induced increase in intestinal permeability and alleviated gastrointestinal symptoms.[24] In a dose-ranging, randomised, placebo-controlled study, some doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity during a gluten challenge.[25] Here, we report the results of a separate and larger, exploratory, dose-ranging study in which we evaluated the clinical efficacy and tolerability of larazotide acetate in patients with coeliac disease who have been observing a GFD. The study was also conducted to gain additional experience in the use of clinical outcome measures and gluten challenge in a randomised, placebo-controlled study of a pharmacological therapy in patients with coeliac disease.