SAN DIEGO — Two new therapeutic approaches to celiac disease modestly improved patients' gluten tolerance, based on the results of early studies reported at a press briefing at the annual Digestive Disease Week.
The results of a third small trial indicated that the diagnostic criteria for celiac disease may be too strict, leaving many patients with early-stage disease undiagnosed and untreated.
Celiac disease is a T-cell-mediated autoimmune disorder characterized by small intestinal inflammation, injury, and intolerance to gluten found in wheat, rye, and barley products. Celiac disease affects about 6.5 million people worldwide and 3 million people in the United States. The small intestine primarily is affected, but the disorder is associated with a wide range of other systemic effects including malnutrition, bone mineral loss, anemia, and delayed growth. Treatment is limited to a gluten-free diet, but dietary adherence is difficult and response to diet is poor in up to 30% of patients.
Results were presented from a phase IIb study of larazotide acetate (AT-1001), a novel oral drug that inhibits intestinal barrier dysfunction and is being developed by Baltimore-based Alba Therapeutics Corp. Dr. Daniel Leffler and his colleagues—from the Beth Israel Deaconess Medical Center, Boston; the Mayo Clinic, Rochester, Minn.; and the South Hills Endoscopy Center in Pittsburgh—reported on 86 patients who had biopsy-proven celiac disease and were in remission for at least 6 months. Subjects were randomized to one of seven treatment arms, including placebo and various doses of the active drug, with or without a gluten challenge, for 14 days. The drug was taken three times daily with meals.
The primary end point was intestinal permeability, as measured by the urinary lactulose/mannitol ratio. Among the 69 patients who completed the study, the primary outcome was not met in the 14-day study period. In ad hoc analyses, however, permeability was significantly improved by day 21, reported Dr. Leffler of the divisions of clinical nutrition and gastroenterology.
Alba aims to launch a larger phase II study, and planning for phase III has already begun, he said. The drug was well tolerated and undetectable in serum, making it a potentially safe addition or alternative to a gluten-free diet, said Dr. Leffler.
Working with Alvine Pharmaceuticals Inc., Dr. Peter Watson, of the Belfast City (Ireland) Hospital Trust performed a double-blind crossover study of another therapeutic designed to aid gluten digestion.
For the study, 20 celiac disease patients were randomly assigned to receive 5 g of gluten pretreated with a combination of enzymes or 5 g of untreated enzymes. The enzymes, prolyl endopeptidase and endopeptidase-B2, were synthesized from microorganisms and barley. The enzymes hypothetically could help celiac disease patients fully digest gluten and thus avoid inflammation and symptoms, said Dr. Watson.
After treatment, there was no significant difference in symptom profiles, but 10 patients had a decrease in fecal fat levels, indicating increased gluten tolerance.
Dr. Peter H. Green, director of the celiac disease center at Columbia University, New York, hailed the two studies, saying that they indicated a potential for patients to have a treatment besides diet, which is notoriously difficult to follow. “It's very exciting for [researchers] and patients that the pharmaceutical industry has started to study this,” he said.
Currently, the diagnosis of celiac disease is confirmed by a biopsy showing small bowel mucosal villous atrophy with crypt hyperplasia (Marsh III).
But Dr. Markku Mäki of the University of Tampere (Finland) presented results of a randomized, prospective study that indicate damage from celiac disease occurs gradually, with clinical symptoms appearing well before histologic damage.
Dr. Mäki and his colleagues at Tampere and the University of Helsinki identified 23 patients out of 145 consecutive cases who had only intraepithelial lymphocytosis with or without crypt hyperplasia. These 23 patients were randomized either to a gluten-free diet or a normal diet. A year later, clinical, serologic, and histologic exams were repeated. Villous architecture had deteriorated, and symptoms and antibody titers were unchanged in the normal diet group.
Symptoms, antigluten antibodies, and mucosal inflammation were all significantly reduced in those who restricted gluten, Dr. Mäki said.
Dr. Mäki urged more studies before changing diagnostic criteria, but recommended considering celiac disease in all symptomatic patients and a trial of dietary restriction.
Dr. Green said that until a serum-based diagnostic test was available, intestinal biopsies were likely to remain the diagnostic standard.
Fewer than 5% of Americans with celiac disease have been diagnosed, Dr. Green estimated. “We're all looking for an easier way [than biopsy] to diagnose this disorder.”
'It's very exciting for [researchers] and patients that the pharmaceutical industry has started to study this.' DR. GREEN