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 trial suggested diagnostic criteria for the disease may be too strict, leaving many patients with early-stage disease undiagnosed and untreated.
Celiac disease is a T-cell-mediated autoimmune disorder that is characterized by small intestinal inflammation, injury, and intolerance to gluten found in wheat, rye, and barley products. It affects about 3 million people in the United States. The small intestine primarily is affected, but the disorder is associated with a 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 being developed by Alba Therapeutics Corp. in Baltimore.
Dr. Daniel Leffler and his colleagues—from 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. They 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.
The primary end point was intestinal permeability, as measured by the urinary lactulose/mannitol ratio. None of the the 69 patients who completed the study met the primary outcome in the 14-day study period. In ad hoc analyses, however, permeability was significantly improved by day 21, said 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.
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. Twenty 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 so avoid inflammation and symptoms. After treatment, there was no significant difference in symptom profiles, but 10 patients had a decrease in fecal fat levels, indicating increased gluten tolerance.
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 indicating that celiac disease damage occurs gradually with clinical symptoms appearing well before histologic damage.
He 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 and randomized them 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, whereas symptoms, antigluten antibodies, and mucosal inflammation were all significantly reduced in those who restricted gluten.
He urged more studies before changing diagnostic criteria, but urged considering celiac disease in all symptomatic patients and a trial of dietary restriction.