Study results presented at DDW offer hope for future protection from accidental gluten exposure
By Amy Ratner, Medical and Science News Analyst
Celiac disease patients who suffer symptoms and gut inflammation despite being on a gluten-free diet could get relief from both at the same time from a new drug being developed by Amgen, a study presented at Digestive Disease Week (DDW) showed.
Markku Maki, M.D., the principal investigator, detailed results of the study of AMG 714, a drug that neutralizes a molecule, called IL-15, that is believed to be a key driver in celiac disease.
“We are going from hype to hope,” Maki, a celiac disease expert and professor at the University of Tampere in Finland, told the DDW audience of mainly physicians, gastroenterologists, researchers and academics.
He noted that up to half of celiac disease patients on a gluten-free diet have intestinal damage or inflammation and a third have ongoing symptoms.
While the new Amgen results, including a separate study of AMG 714 in the treatment of refractory celiac disease – a rare but severe form which can lead to lymphoma – received the most attention at DDW, the progress of others was also noted.
In the pipeline
Ciarán Kelly, M.D., director of the Celiac Center at Beth Israel Deaconess Medical Center and a member of the Beyond Celiac Board of Directors, outlined emerging therapies in a presentation at DDW, noting that 70 percent of patients in one survey said they are interested in new treatments for celiac disease.
“The gluten-free diet is not a prescription anyone can fill,” Kelly said. He described the high burden, potential nutritional deficiencies, incomplete effectiveness, and minimal medical support related to the diet. Still, it continues to be the only treatment for celiac disease and the idea that it is all patients’ need has “stifled research, he said. Consequently, celiac disease is “poised for drug development” Kelly added.
A number of drugs are currently being investigated, Kelly explained. They work in different ways, from breaking down gluten with enzymes, to interrupting the effect of gluten on the cells lining the intestine, to preventing or interrupting the immune reaction that occurs when people with celiac disease eat gluten. Each works in the body at a different point in the process that begins when someone with celiac disease eats gluten.
Among them are Innovate Biopharmaceutical’s Larazotide Acetate, which is expected to go into phase 3 studies this year. A therapeutic vaccine that is a form of immunotherapy, NexVax 2 is also moving forward at a steady clip. Latiglutenase, another drug being developed, hit some bumps in the road in a recent trial that did not have the desired results, but researchers are still hopeful it can help celiac disease patients by degrading gluten with enzymes.
AMG 714 easing the effect of gluten
AMG 714 is an antibody that binds to IL-15, which is believed to play a key role in inflammation of the gut. The drug was originally tested for safety in patients with rheumatoid arthritis and psoriasis. Although it worked well in clinical studies related to inflammation, it was not pursued for those conditions, leading to its development as a treatment for non-responsive celiac disease.
Researchers wanted to measure the effect AMG 714 would have on patients exposed to gluten, something that often occurs in the real world despite best efforts to maintain a strict gluten free diet.
“Contamination, which can happen during food processing or packaging, during cooking and due to inadequate labeling, is known to occur very frequently, despite following a gluten-free diet,” said Francisco Leon, M.D., study director and a consultant to Amgen. The hope is that the drug will allow celiac disease patients on the gluten-free diet to experience fewer gluten-triggered consequences.
Sixty participants the clinical trial conducted in Finland were divided into two groups. One group of about 35 received a 2.5 gram gluten challenge in the form of a cookie daily for 10 weeks. Another group of seven patients was not given the challenge because they had enough damage from gluten from cross-contact in their gluten-free diet at the start of the study.
Researchers then compared the effects of AMG 714 at two dose levels, 150 milligrams (mg) and 300 mg, to a third placebo group which did not receive any medication. Patients were given the drug through subcutaneous injection six times over 12 weeks.
Urine and stool samples were collected to objectively assess gluten consumption, something that enabled researchers to more precisely interpret results, the study said.
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Subcutaneous injection: An injection in which the needle is injected just under the skin.
Randomized, double-blind placebo-controlled study: a study in which some participants are given the treatment, others are given a placebo, and neither the researchers nor the participants know which is which until the study end. The assignment of participants to treatment or placebo is done randomly. It is considered the gold standard of scientific testing for new medical interventions.
Primary endpoint: The main result that will answer the most important question being asked by a clinical trial.
Results
The randomized, double-blind, placebo-controlled phase 2a study did not meet its primary endpoint of preventing damage to the intestine in the gluten challenge group, but a decrease in intestinal inflammation was seen. Meanwhile, researchers reported a trend toward less intestinal damage in the groups that did not get the challenge. Study participants also reported fewer symptoms, especially in the group that received the larger dose of AMG 714.
Active celiac disease: celiac disease that is not responding to treatment
And none of the patients in the gluten-challenge group who took the 300 mg dose had active celiac disease at the end of the study compared to one-third of the placebo group who had did, Maki found.
“AMG 714 is the first experimental medication which has shown a reduction in the effects of gluten on gut inflammation and symptoms simultaneously,” Leon said.
The fact that the primary endpoint was not met means the drug won’t allow celiac disease patients to eat a gluten-containing diet, Leon said. “But is still shows it could help with contamination gluten as an adjunct to the gluten-free diet,” he explained.
He noted that there was a trend toward improvement in the group that did not receive the challenge but was exposed to their normal, real world exposure to gluten through cross-contact. Future studies with larger groups of patients are needed to determine the significance of this trend.
“A gluten-free diet has been the only treatment option for celiac disease patients, yet it is nearly impossible for them to avoid gluten entirely and indefinitely,” Maki said. “That is why we have been investigating medications to help prevent the consequences of hidden gluten.”
Amgen will be discussing a potential path forward for AMG 714 with regulators, said Kristen Davis, senior manager of corporate communications. Researchers emphasized that it is still in experimental stages and would not be available to patients until receiving needed approval from the U.S. Food and Drug Administration.
“AMG 714 is being studied as an adjunct to a gluten-free diet to prevent the consequences of contaminating gluten,” Davis said. “It’s important to note that this drug is being investigated for its potential to protect against modest contamination, not deliberately eating large amounts of gluten, like bread or pasta.”
AMG 714 as a treatment for refractory celiac disease showed positive results by multiple measures in a separate study also presented at DDW and is expected to move into a phase three clinical trial.
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