New enzyme may protect celiacs from gluten-induced mucosal injury

By Lorraine L. Janeczko

NEW YORK (Reuters Health) - Celiac patients treated with a gluten-specific enzyme may be less exposed to gluten and its potential damaging effects, according to a phase 2 study from Finland.

In what the authors call the first study to find that a non-dietary treatment may benefit celiac disease patients, they say the gluten-specific protease ALV003 was "able to attenuate gluten-induced injury to the small intestinal mucosa in celiac disease patients."

The finding was reported online April 29 in Gastroenterology; the press embargo was lifted last week.

ALV003 is a mixture of two recombinant gluten-specific proteases given orally.

"This study suggests that ALV003 works by degrading low levels of gluten that remain undigested in the intestine. Based on this study, no significant 'cons' were noted. However, the amount of gluten that the study patients received is relatively little compared with how much gluten the average American ingests on a daily basis. Further studies are needed, and the cost of this potential treatment could be a 'pro ' or a 'con,' but is unknown," said Dr. Sheila E. Crowe of the University of California, San Diego in La Jolla, in an email to Reuters Health.

"I expect that additional trials will be needed in a larger sample size; and ideally, studies conducted in North America will be needed. Trials that test protection by ALV003 glutenase with larger amounts of gluten in the test diet might also be needed," said Dr. Crowe, who was not involved in the study but wrote the accompanying editorial.

Dr. Marja-Leena Lahdeaho of the University of Tampere, Finland, and colleagues conducted their randomized in adults ages 18 to 75 with biopsy-proven celiac disease. All had adhered to a gluten-free diet for at least a year, with minimal or no symptoms, and were transglutaminase 2-immunoglobulin A (TG2-IgA)-negative.

First, the authors administered three different doses of gluten (1.5, 3, and 6 grams) in three daily doses for six weeks. Based on patient tolerance and histologic results, they selected 2 grams as the optimal daily gluten dose.

They randomized patients to receive oral treatment with either ALV003 or placebo, and everyone directly involved in the study was blinded. Participants took either 900 mg of ALV003 (n=20) or a placebo (n=21) once daily at a major meal for six weeks. At the same meal, all participants ate baked breadcrumbs containing 2 grams of gluten (roughly half the gluten found in a standard slice of bread in the United States, according to the American Gastroenterological Association). The researchers instructed all participants to otherwise maintain their usual gluten-free diet.

They collected duodenal biopsies at baseline and after the gluten challenge and measured the villus height-to-crypt-depth ratios and the intraepithelial lymphocyte densities.

After the gluten challenge, biopsies from the placebo group showed mucosal injury (the mean villus height-to-crypt-depth ratio changed from 2.8 before the challenge to 2.0 after; P=0.0007; the CD3+ intraepithelial lymphocytes density changed from 61 to 91 cells/mm after the challenge; P=0.0003).

They found no significant mucosal deterioration in biopsies from the ALV003 group, though.

Morphologic changes and CD3+ intraepithelial lymphocyte counts between the groups differed significantly from baseline to week 6 (P=0.0133 and P=0.0123, respectively), but differences in symptoms between the groups were non-significant.

"This agent might be helpful in permitting patients with celiac disease to ingest small amounts of gluten without incurring an immune response that causes symptoms and damage to the intestine. Even the most strictly gluten-free patients are often exposed to gluten when eating out of their homes and while traveling. Also, some patients who are careful to avoid gluten can have persistent symptoms and have intestinal biopsies that are not completely healed may benefit from this treatment," said Dr. Crowe.

"Many celiac disease patients do not return to complete wellness on a gluten-free diet and this may be due to continued exposure to small amounts of gluten, unintentionally or otherwise. Given the difficulties of staying completely gluten free, an adjunctive treatment that could ameliorate the clinical effects of exposure to gluten would be a welcome addition to managing patients with celiac disease," she said.

Dr. Tanvi Dhere of Emory University in Atlanta, Georgia, said in an email, "The use of adjunct endopeptidases to treat celiac disease is intriguing. The study adds to the growing body of literature on the use of endopeptidases in the management of celiac disease. Such treatments may eventually be offered to those patients who don't fully respond to a standard gluten-free diet," she said.

"ALV003 appears to be well tolerated, but prior to the medication's launch into clinical use, further larger-scale more powered studies with longer-term data are required. If the medication were to be commercially available, concerns of cost and who will be eligible will arise," said Dr. Dhere, who was not involved in the study.

The corresponding author was unable to comment by deadline.

Alvine Pharmaceuticals, Inc., of San Carlos, California, sponsored the study.

SOURCE: http://bit.ly/1kVMNPC

Gastroenterology 2014.

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