CHICAGO – Larazotide acetate, a first-in-class oral medication developed specifically to treat celiac disease, reduced both gastrointestinal and non-GI symptoms in patients who were symptomatic despite being on a gluten-free diet in a 74-site, randomized, double-blind phase II study.

"Safety and tolerability were comparable to placebo, setting this drug up, we believe, for phase III trials," Dr. Joseph A. Murray said at the annual Digestive Disease Week.

The study included 342 adult patients with celiac disease who had been on a gluten-free diet (GFD) for at least 12 months and continued on the GFD throughout the 12-week treatment period. Thus, this was a study of larazotide as an adjunct to the GFD, not as an alternative to it.

A GFD is of well-established efficacy as the sole proven therapy for celiac disease. However, the diet can be challenging. Surveys indicate 70% of celiac disease patients on a GFD experience recurrent symptoms due to inadvertent exposure or lapses in the strict adherence required. Thus, there is a significant unmet need for an effective pharmacologic therapy for this common disease, observed Dr. Murray, professor of medicine at the Mayo Clinic in Rochester, Minn.

Study participants were randomized to 12 weeks of double-blind treatment with larazotide at 0.5, 1, or 2 mg three times daily or to placebo. The study provided a successful opportunity to validate a new instrument designed for evaluation of celiac disease symptoms both in clinical trials and in daily practice. The instrument, known as the Celiac Disease Patient Reported Outcome (CeD PRO), entails daily assessment of symptoms in three key domains: abdominal symptoms such as cramping, bloating, and pain; diarrhea and loose stools; and the non-GI symptoms of headache and tiredness, which figure prominently in the disease but aren’t included in the older Celiac Disease Gastrointestinal Symptom Rating Scale.

Patients in the larazotide 0.5-mg t.i.d. group showed a significant 26% reduction in the average weekly number of CeD PRO symptomatic days, compared with placebo-treated controls. Twenty-nine percent of patients in the larazotide 0.5-mg group also achieved at least a 50% decrease from baseline in the weekly average CeD PRO abdominal symptom domain scores for at least 6 of the 12 weeks of treatment, significantly greater than the 14% rate with placebo. In addition, the larazotide 0.5-mg t.i.d. group had a 31% increase in the average number of CeD PRO days with minimal or no symptoms, compared with controls. Moreover, patients on the lowest dose of larazotide showed a significant reduction in CeD PRO non-GI symptoms, the only study arm to do so.

Of note, patients on the two higher doses of larazotide didn’t significantly outperform the control group in any of these study endpoints, although favorable trends were seen.

No changes in serially measured levels of anti–tissue transglutaminase antibodies or anti–deaminated gliadin antibodies were seen in any treatment arm.

Larazotide is an oral peptide that prevents the opening of epithelial tight junctions in the small bowel, an event that occurs in response to gluten exposure and inflammatory cytokines in patients with celiac disease. When these tight junctions are open inappropriately, the result is increased intestinal permeability and inflammation.

One audience member expressed reservations about the finding that only the lowest tested dose in a dose-ranging study proved effective.

"I’m troubled by drugs that don’t show a dose-response curve. This positive result could just be the play of chance," he cautioned.

Dr. Murray replied that he believes the consistency of the positive results with the 0.5-mg dose across multiple endpoints reduces that likelihood. Also, the lowest tested dose was the one that was effective in all the prior challenge studies. In any case, he added, the larger patient numbers planned for the phase III trials will sort out this issue.

Dr. Benjamin Lebwohl was enthusiastic about the larazotide results.

"It’s a very exciting time in the celiac disease community. Larazotide is one of several nondietary treatments currently in the pipeline," noted Dr. Lebwohl of the celiac disease center at Columbia University, New York.

The time is at hand, he added, to think big in terms of celiac disease research questions.

"Is it possible to prevent celiac disease in those individuals at increased risk? And among those individuals who come to us having been diagnosed with celiac disease, can we stop it in its tracks? Can we tolerize patients to gluten, allowing them to eat gluten either intermittently or even resume a full gluten-containing diet? Will there be a cure for celiac disease?" Dr. Lebwohl asked.

The study was supported by Alba Therapeutics. Dr. Murray reported serving as a consultant to or on the advisory boards of nearly a dozen pharmaceutical companies, Alba not among them. Dr. Lebwohl reported having no financial conflicts.

bjancin@frontlinemedcom.com

Larazotide eased symptoms in phase II celiac trial