CHICAGO — A novel drug designed for the treatment of celiac disease reduced both gastrointestinal (GI) and non-GI symptoms in people inadvertently exposed to gluten in a randomized placebo-controlled trial.
Larazotide acetate, a first-in-class oral peptide, "met the study's primary end point of a reduction in GI symptoms," said Joseph Murray, MD, from the Mayo Clinic in Rochester, Minnesota.
"This study is the first large therapeutic trial in celiac disease to meet its primary end point of reducing signs and symptoms, and is the first successful trial of a novel class of agents targeting tight-junction regulation," the investigators write in their abstract.
Dr. Murray presented the results from the study as a late-breaking abstract here at Digestive Disease Week 2014.
Epithelial tight junctions control paracellular permeability, which is increased in celiac disease. The permeability is partly the result of an inflammatory immune response to the entrance of gluten peptides into the intestinal lamina propria through these tight junctions.
Larazotide acetate prevents tight-junction opening and reduces gluten uptake, inhibiting gluten- and cytokine-induced intestinal permeability and inflammation in vivo.
An Adjunct to Diet
The prevalence of celiac disease could be as high as 7%, although only about one-third of those patients have been formally diagnosed. The disease, which is triggered by the ingestion of gluten, is managed with a gluten-free diet; however, symptoms often recur as a result of inadvertent exposure to gluten or nonadherence to the diet.
"Up to 70% of individuals report being exposed to gluten deliberately or inadvertently, which causes not only GI-related symptoms, but also headache and tiredness," Dr. Murray reported.
This randomized, parallel, double-blind, placebo-controlled, multicenter trial was conducted at 74 sites in North America. The aim was to evaluate the effect of larazotide acetate on GI signs and symptoms in patients with celiac disease.
"These subjects had been on a gluten-free diet for a median of 5 years, so the disease and its treatment were stable. We wanted a real-life setting to evaluate this drug as an adjunct to a gluten-free diet," said Dr. Murray.
The 342 patients had maintained a gluten-free diet for at least 12 months. They were randomized to placebo or to 1 of 3 doses of larazotide acetate 3 times daily: 0.5 mg, 1.0 mg, or 2.0 mg. The 20-week study had a 4-week placebo run-in, a 12-week treatment phase, and a 4-week placebo run-out.
The primary end point was improvement in the GI symptoms of digestion, indigestion, and abdominal pain (including cramping, pain, bloating, gas, nausea, and stools), measured with the Gastrointestinal Symptom Rating Scale (GSRS) for celiac disease. The non-GI symptoms of headache and tiredness were evaluated using patient-reported outcomes.
There was a significant difference in the reduction in GI symptoms between the larazotide acetate 0.5 mg group and the placebo group in the modified intention-to-treat analysis (P = .022) and the per protocol analysis (P = .005).
"The end point of reduction in GI symptoms was met and sustained during the active phase of the study, but only the lowest dose was effective. The higher doses had no effect," Dr. Murray reported. He added that this finding is consistent with clinical challenges in previous studies.
Patients in the 0.5 mg group were significantly more likely than those in the placebo group to report a reduction in headache and tiredness (P = .010). They were also more likely to report a significant improvement in several exploratory measures.
There was a 26% decrease in the number of days in which patients reported severe symptoms (P = .017) and a 31% increase in the number of days patients reported no or very few symptoms (P = .034). In addition, 28% of patients reported a reduction in symptoms of at least 50% for at least 6 of the 12 weeks (P = .022).
Total GSRS score was significantly better in the 0.5 mg group than in the placebo group in the modified intention-to-treat analysis (P = .017) and the per protocol analysis (P = .004).
There were no increases in antibody titers to gluten (IgA or IgG) at any dose of the drug. Treatment-emergent adverse events were no different in the 2 groups, and no serious adverse events were reported.
Larazotide acetate 0.5 mg has the potential to be the first pharmacologic treatment for celiac disease and warrants investigation in phase 3 clinical trials, Dr. Murray concluded. According to an industry news release, the drug has been granted Fast Track status by the US Food and Drug Administration.
"This was a fairly large study, with a placebo control and randomized design, so this is very interesting," said David Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk.
"The findings suggest that larazotide acetate has the potential to be an exciting option for patients with celiac disease who may not be as compliant with a gluten-free diet or who are unknowingly exposed to gluten," he told Medscape Medical News.
This study was funded by Alba Therapeutics. Dr. Murray reports financial relationships with Alvine, Enteromedics, Flamentara, Ironwood Pharmaceuticals, Vysera, Iralnd, Torax Medical, AMAG, Enterohealth, Bioline Rx, and GSK.
Digestive Disease Week (DDW) 2014. Abstract 929f. Presented May 7, 2014.
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Cite this: Novel Drug for Celiac Disease Reduces GI and Non-GI Symptoms - Medscape - May 07, 2014.