Two-day event broadcast through live webcast
By Amy Ratner, Medical and Science News Analyst
As Columbia University put restrictions on large gatherings due to concerns about coronavirus, the Celiac Disease Center at Columbia limited attendance at its Celiac Disease Symposium and offered the event via live webcast.
Symposium presenters were permitted to attend, but some from the United States and Europe were unable to travel and instead spoke remotely. This included keynote speaker and Beyond Celiac Scientific Advisory Council member Joseph Murray, MD, who gave his talk from Minnesota. Several others presented from Italy, France and Spain.
Despite the limitation, the celiac center conducted the full two days of the symposium in a 16 hour webcast that was available for free online. The webcast broadcast both clinical and scientific sessions.
In the scientific session, celiac disease experts from around the world broadly covered topics including new treatments for celiac disease, the role of the microbiome, immune response, studies in large populations, the gluten-free diet, diagnosis and follow up care.
Here are a few newer takeaways.
A reevaluation of the gluten challenge was proposed by Daniel Leffler, MD, medical director for Takeda Pharmaceuticals and a member of the Beyond Celiac scientific advisory council, who noted distinctions between use of the challenge in clinical care of patients and in clinical trials for new treatments.
“It’s time for change in the standard of care,” Leffler said, noting that discussion of diagnosis without a biopsy, which was strongly debated during the symposium, is “not going away.”
“The biopsy is not a panacea,” he added. Leffler said that the problem with missed diagnosis in the celiac disease community will never be fixed because patients do not like the longer gluten challenge and biopsy required to diagnose celiac disease in many cases.
Leffler outlined a future standard of care for patients that could begin with baseline blood tests, followed by testing for the HLA genes related to celiac disease. Positive results would be followed by a one- to-three-day gluten challenge and subsequent Interlukin-2 (IL-2), tetramer and flow cytometry testing. A celiac disease diagnosis would be made based on positive results, while uncertain results would lead to an additional challenge and further testing.
|Interlukin-2: a type of cytokine signaling molecule in the immune system. In celiac disease, it is responsible for acute gastrointestinal symptoms when patients are exposed to gluten
One year from diagnosis, all patients would get a gluten challenge, which Leffler suggested could be “a croissant or two” followed by the IL-2 and other testing to confirm a celiac disease diagnosis. “We have so many new tools, it would be a shame not to use them,” Leffler said
In clinical research, Leffler noted that gluten challenge studies, which are designed to precipitate damage followed by treatment with a drug need to be distinguished from gluten exposure studies, which call for maintenance of the real world consumption of gluten in the gluten-free diet.
Although a gluten-free diet is currently the only treatment for celiac disease, real understanding of the intricacies of the diet seem to elude patients as well as researchers. Jocelyn Silvester, MD, director of research of the Celiac Disease Program at Boston Children’s Hospital asked the question, “Why doesn’t the gluten-free diet work?” She noted that after two years on the diet, only one third of patients have intestinal healing.
Results of Silvester’s DOGGIE Bag study show just how difficult it is to correctly connect gluten exposure on the gluten-free diet to symptoms of celiac disease. In data yet to be published, 66 percent of study participants had at least one positive result when gluten was measured in the food they ate or stool or urine. Only two participants correctly identified the food that caused them to suspect they had been exposed to gluten.
Related: More about the DOGGIE Bag study.
“The gluten-free diet is just not very good,” Silvester said, noting that she could not come up with another disease in which diet was not superseded by another treatment. She questioned what she called the “gluten-free gospel” that 20 parts per million, the standard for gluten-free labeling in the United States and Europe, is a safe level of gluten. Still, she said she is not pushing for a lower standard, but instead wonders if it’s unfair to ask patients to aim for zero gluten in their diets when that is not being asked of food manufacturers.
All participants in the DOGGIE Bag study were getting better on the diet, according to Silvester, who said that there is likely to be “background” gluten in most gluten-free diets and that individual sensitivity to gluten is “highly variable” in terms of activating the immune system, causing symptoms and intestinal damage. “My biggest worry is I don’t want the treatment to be worse than the disease,” she said. “Maybe the amount of gluten in the diet does not need to get to zero.”
Genetics play a key role in the early prediction of whether someone will develop celiac disease, with HLA genes being the strongest indicator of susceptibility, though they are not sufficient for diagnosis, said Sonia Kupfer, MD, of the University of Chicago. Some non-HLA genetic factors have small effects and might one day be used to come up with a polygenetic risk score as is being done in other diseases such breast cancer, Kupfer said. She noted this kind of score would be far off and there are questions about whether it would work in inflammatory diseases such as celiac disease. A primary goal of using genes to predict celiac disease would be disease interception in those with the highest risk, according to Kupfer.
Related: Kupfer was a panelist at the 2019 Beyond Celiac Research Symposium.
|Lipidomics: an emerging field of biomedical research which includes complex lipidome analysis. A lipidome is the comprehensive and quantitative description of a set of lipid species present in an organism.
Lipid: a fat or fat-like substance in the blood
Renata Auricchio, MD, of the European Laboratory for the Investigation of Food Induced Disease at University Federico II in Italy, proposed that lipidomics might also play a role in the early prediction of celiac disease. “Development of celiac disease in a child from a family with a relative affected by celiac disease might be predicted long before any production of anti-TG2 antibodies or clinical symptoms,” Auricchio said via a remote connection from Italy.
A lipidomic profile of children at risk could clarify a metabolomic signature that could help predict celiac disease very early in life, she said.
The status of new treatments for celiac disease were described by researchers working on a variety of approaches. Included was a list of lessons learned from the NexVax2 vaccine study, which was unexpectedly discontinued in 2019 before completion due to results that showed the vaccine to treat celiac disease did not provide protection from gluten exposure when compared to a placebo.
|T-Cells: White blood cells that function as the body’s disease fighting soldiers and are improperly activated by gluten in those who have celiac disease.|
Robert Anderson, MD, former chief scientific officer of ImmusanT, the company that was developing Nexvax2, described how the study found a new model of celiac disease in which T-cells are rapidly activated after a gluten challenge resulting in acute symptoms of nausea and vomiting within two to four hours.
Related: Nexvax2 discontinued
Lessons resulting from the many years of work and early clinical trial successes of Nexvax2 study include evidence that the reaction to gluten is not delayed as previously thought. Also, the dominant symptoms caused by gluten in celiac disease are nausea and vomiting in one to two hours, as opposed to the diarrhea and bloating often cited.
“Nausea is the symptom we should be asking about in patients when we want to investigate compliance with the diet,” Anderson said, adding that patient reports of nausea correlated with the measure of IL-2. Nexvax2 studies also found that biopsies “rarely” show healing in celiac disease, according to Anderson, who said 90 percent of patients had negative blood tests for celiac disease antibodies and had been on the gluten-diet for more than two years. “If that is the case, it means there is a need for something better than the gluten-free diet,” he said.
Scientists working on other potential treatments currently in clinical trials described their progress. Jack A. Syage, PhD, chief executive officer of ImmunogenX, which is developing latiglutenase, said the first data in a gluten-challenge trial on urine analysis, with completion by 20 patients, is promising. Also, symptoms and quality of life show statistically and clinically significant improvements in patients with blood tests positive for celiac disease antibodies. “The [patients] who seem to suffer the most are the most responsive to latiglutenase,” Syage said.
|Interleukin-15 (IL-15): a cytokine with many biological functions essential for the maintenance and function of multiple cell types. Celiac disease studies have confirmed its role in multiple phases of the disease and expanded its impact on multiple cell types and immunological responses.|
Bioniz Therapeutics plans to move BNZ-2, a selective inhibitor of Interlukin-15 (IL-15) and Interlukin-21 (IL-21) cytokines, into a Phase 1 clinical trial, according to Nazli Azimi, PhD, chief executive officer. Pre-clinical studies have shown that the drug, which falls into a category of treatments that block the immune response to gluten, completely inhibits the pathways of both cytokines and also blunts the attack on the gut. The Phase 1 trial will enroll celiac disease patients and healthy volunteers to test the safety and tolerability of BNZ-2 and confirm whether measures of biopsies, blood test and symptoms meet study goals. The dose of the drug used in subsequent clinical trials will also be investigated.
Francisco Leon, MD, Provention chief scientific officer, reported on an upcoming Phase 2 trial of PRV-015, an anti-IL-15 antibody, with the potential to “intercept” the progression of celiac disease. “If we can prevent Type 1 diabetes, maybe we can do the same with celiac disease,” Leon said, referring to Provention’s drug candidate for prevention or delay of Type 1 diabetes in those at risk for developing the disease and interception for those newly diagnosed to preserve remaining beta cell function and reduce the need for exogenous insulin usage.
The company is planning to launch a Phase 2 study of its celiac disease drug this year, recruiting 220 adults with celiac disease who are not responding to the gluten-free diet. The study will involve six months of treatment with a weekly subcutaneous injection. The study will test three dose levels with the goal of reducing symptoms.
Related: The Celiac Disease Drug Pipeline
ZED 1227, a drug designed to block tissue transglutaminase, is being studied in a Phase 2 trial due to be completed in March, according to Detlef Schuppan, MD, a celiac disease expert at Mainz University Medical Center, Germany. The multiple dose study enrolled 160 celiac disease patients at 19 centers in Europe. Study participants who received a gluten challenge through a 3 gram cookie for six weeks were given either varying doses of the drug or a placebo. The study will measure intestinal healing as a primary goal.
An update on Takeda’s nanoparticle treatment by Ciaran Kelly, MD, director of the Celiac Center at Beth Israel Deaconess Medical Center, detailed results showing that Tak-101 prevented gluten challenge immune activation in adults with celiac disease. The study met its primary objective of preventing activation of interferon gamma producing gliadin specific cells.
“To our knowledge, this is the first clinical trial to demonstrate the induction of antigen specific immune tolerance in any autoimmune disease,” Kelly said. He noted that the nanoparticle may reduce inappropriate gluten reactivity in celiac disease and could be a pioneer for antigen-directed tolerance in autoimmunity.
Researchers expect to publish results of the study in a peer reviewed journal. Kelly noted more study is needed to determine correct dosages and additional clinical trials are needed to verify results.