Investigational Agent Prevents Gluten Toxicity in Patients With Celiac Disease

Martha Kerr

May 23, 2008

May 23, 2008 (San Diego, California) – A novel compound in phase 2 trials announced here at Digestive Disease Week 2008 shows excellent safety and signs of efficacy in preventing gluten toxicity in patients with celiac disease.

AT-1001 (Alba Therapeutics) reduces intestinal barrier dysfunction, promoting tighter cell-to-cell junction in the small intestine and thereby reducing permeability. The drug promotes proinflammatory cytokine production and in theory should promote luminal healing and reduce the risk for gastrointestinal cancer, principal investigator Daniel A. Leffler, MD, clinical research director of the Celiac Disease Center at Beth Israel Deaconess Medical Center in Boston, Massachusetts, told meeting attendees.

AT-1001 "significantly reduced gastrointestinal symptoms on gluten challenge" in a phase 2a study of 86 patients with biopsy-proven disease, Dr. Leffler announced. There were no serious adverse events and the overall adverse rate was no higher than in the placebo group of the study.

Patients were randomized to 1 of 7 treatment groups: gluten plus AT-1001 at 0.25 mg, 1 mg, 4 mg, or 8 mg; gluten plus AT-1001 placebo; gluten placebo plus AT-1001 8 mg; or gluten placebo plus AT-1001 placebo. All AT-1001 was taken three times a day, and gluten 800 mg was taken twice a day. After the 14-day treatment period, patients were followed for another 21 days.

Dr. Leffler's team measured change in intestinal permeability using the urinary lactulose/mannitol ratio (LAMA). They also assessed disease symptoms, quality-of-life measures, nitrate/nitrite urinary excretion, anti-t-transglutaminase (anti-tTG) titers, serum cytokines, and peripheral blood cell-surface markers of celiac disease.

AT-1001 showed a significant effect in preventing an increase in intestinal permeability on day 21 compared with day 7, but not on day 7 compared with baseline. "We were surprised to see this," Dr. Leffler said.

After the 14-day treatment period, 71% of the patients in the gluten plus AT-1001 placebo group reported symptoms, compared with 17% of patients in the gluten placebo plus AT-1001 placebo group (P = .001), and 21% of patients in the gluten plus active AT-1001 groups (P = .008). Patients on the 4 mg and 8 mg doses had better protection from gluten toxicity than patients on the 2 lower doses.

There was no difference between drug and placebo in differential sugar absorption. Intestinal permeability was slightly better with active treatment during the gluten challenge.

"Celiac disease affects about 1% of the population, but by far the bulk of the disease is undiagnosed," moderator Peter H. Green, MD, director of the Celiac Disease Center at Columbia Presbyterian-New York Hospital, said in introductory remarks before Dr. Leffler's presentation.

"The reason for the low diagnosis rate is physician education. Physicians are not getting the information, and this is often driven by drug companies. Our patients often know more about celiac disease that we do," Dr. Green noted.

"In Europe, there is more education and there are [screening programs]. Here, the pharmaceutical industry provides the bulk of postgraduate education programs, and there are currently no drugs for the treatment of celiac disease."

"There are only 5 celiac disease centers in this country," Dr. Green noted. He and Dr. Leffler are the directors of 2 of the 5. "In contrast, there is an inflammatory bowel disease center at every major tertiary hospital."

At least 20% to 30% of patients do not or can not adhere to a strict gluten-free diet," Dr. Leffler commented. "It is difficult to get and it is socially restrictive. We need something beyond just a gluten-free diet for our patients."

"Diet is obviously safe, so what we had to do was come up with a drug that is assafe as diet," Dr. Leffler told Medscape Gastroenterology. "Our safety data [with AT-1001] are quite reasonable...and there is no systemic absorption or detectable serum levels of the drug."

"Despite methodological difficulties in assessing the effects of brief gluten exposure, the results suggest a protective effect of AT-1001 that warrants further investigation," Dr. Leffler said. "What we are doing now is running another 2b study to definitely establish efficacy."

Dr. Leffler received a research grant from Alba Therapeutics, Corp. Dr. Green is on the advisory boards of a number of pharmaceutical companies, including Salix, Alba, and Prometheus Laboratories.

Digestive Disease Week (DDW) 2008: Abstract 585. Presented May 20, 2008.


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