Updates in Celiac Disease: Moving Forward Despite Setbacks

During the past year, numerous developments in celiac disease have been achieved by researchers in the field, whereas a number of setbacks have stalled the development of a leading drug candidate, and caused a major pediatric society to revise one of its celiac guidelines.

Spurred by the still unmet medical needs of the 7% to 30% of patients whose symptoms are inadequately controlled by a gluten-free diet, as well as the realization that even in the absence of symptoms more than 50% of patients on the diet continue to have intestinal mucosal damage and complications, efforts to develop non-dietary therapies have continued, with novel candidates entering the pipeline. Understanding of the celiac therapeutic regulatory pathway is improving in light of recent efforts by the FDA in collaboration with the celiac scientific and patient advocacy groups. Concurrently, novel tools for the detection of gluten immunogenic peptides in stool and urine are being developed for monitoring patient dietary adherence.

To provide a clearer picture of the most significant recent advancements in celiac disease, Healio Gastroenterology interviewed leading experts in the field to discuss progress in celiac prevention, therapeutics and dietary monitoring.

ESPGHAN Guideline Reversal

A recent position paper from the European Society for Pediatric Gastroenterology, Hepatology and Nutrition stated that available evidence shows age of gluten introduction has no effect on the risk for developing celiac disease in at-risk infants. This essentially reversed ESPGHAN’s 2008 recommendations — which were based only on observational studies — that initial exposure to gluten should be avoided in infants younger than 4 months and older than 7 months, and that gluten introduction should occur while the infant is still being breast-fed.

What prompted this reversal were two large randomized controlled trials published in New England Journal of Medicine — the PreventCD and CELIPREV studies — which showed that early or late gluten introduction does not influence the cumulative incidence of celiac disease during childhood. Further, a systematic review showed that breastfeeding had no preventive effect on the development of celiac disease autoimmunity or celiac disease during childhood.

These studies “suggest that, at least in small amounts, early vs. late timing of gluten introduction and breastfeeding at the time of gluten introduction doesn’t seem to make as big a difference as we thought,” Daniel Leffler, MD, MS, director of research for The Celiac Center at Beth Israel Deaconess Medical Center in Boston, told Healio Gastroenterology. “The thing worth remembering is that these studies were limited to high-risk children with a family history of celiac disease.” As the overall rate of celiac disease is much smaller, very large samples would be needed to extrapolate these findings to the general population, for whom the effects of childhood gluten exposure timing on celiac disease risk are still unclear, he said.

More recent data from the TEDDY (The Environmental Determinants of Diabetes in the Young) study group in Sweden show that the quantity of gluten exposure in childhood may be more important than timing. In a case-control study of 146 Swedish children with celiac disease and 436 controls, researchers found that genetically susceptible children who consumed more than 5 grams of gluten per day before age 2 had more than a twofold higher risk for developing celiac disease compared with those who consumed less (OR = 2.65; 95% CI, 1.7-4.13). Each additional gram of gluten consumed per day before anti-tissue transglutaminase seroconversion corresponded to a 28% increase in risk for future celiac disease.

These data “show there is a difference in celiac disease risk at least in the highest quartiles of childhood gluten exposure, so it may not matter if you add a little sooner or a little later, but if you add a lot, that may actually still precipitate celiac disease,” Leffler said.

According to an accompanying editorial by Ludvigsson and colleagues, a “slightly surprising” finding of this study is “that it is the amount from 1 year and onward that seems to be of greatest importance, and that the high consumers do not develop [celiac disease] in the first 2 years of life but later. These findings need to be confirmed in other studies before changes in feeding recommendations in Sweden ... and elsewhere are implemented,” including studies of children from lower risk countries like the U.S., they wrote.

“The story is more complicated than we thought it was, which is sort of always the case,” Leffler said. “While there’s currently no panacea for reducing childhood risk, especially in those with a family history, I think there still is an argument to be made that there may be a role for gluten timing and amount.”

Further supporting the possibility that quantity of gluten could influence the risk for developing celiac disease are more recent data from a study of its ethnic distribution, according to Benjamin Lebwohl, MD, MS, Herbert Irving Assistant Professor of Medicine and Epidemiology at the Celiac Disease Center at Columbia University Medical Center in New York City.

“We wanted to know whether patients in the United States from various ethnicities and ancestries had varying risks of celiac disease,” Lebwohl said. Therefore, he and his colleagues analyzed duodenal biopsy specimens from a large pathology database and calculated the prevalence of intestinal villous atrophy among different ethnicities, which were determined by a name-based algorithm. Their notable findings were that patients from the northern Punjab region of India had the highest prevalence of celiac disease (3.08%), while Hispanics and East Asians had lower rates than other Americans, and Jewish individuals had similar rates compared with other Americans.

“The findings regarding Punjabi Americans were surprising until we learned about all of the work coming out of India, and we then found that actually it’s very much congruent with the literature,” Lebwohl said. “It seems that whatever it is about coming from that area, that risk tends to carry to the U.S., It might not be due to genetics because, in fact, we know that the rate of the main celiac disease risk gene in Northern India is similar to that in the south and to that in the U.S. in general. However, we do know that people in northern India eat wheat in quantities that are far greater than elsewhere in India, raising the possibility that, once again, quantity of gluten ingestion, perhaps early in life, could play a role in the risk of celiac disease.”

Despite these new clues about possible triggers of celiac disease, in a recent commentary by the leadership of the North American Society for the Study of Celiac Disease, Joseph A. Murray, MD, of the Mayo Clinic in Rochester, Minn., and colleagues characterized the findings of the PreventCD and CELIPREV studies and the subsequent ESPGHAN guideline reversal as a “back to the drawing board” moment for the celiac disease community, and called for refocused research efforts on environmental factors beyond infant feeding, such as intrauterine and perinatal exposures, drug exposure, infections and the microbiome.

“One of the lessons from the reversal of the ESPGHAN guidelines in early feeding is that we have to be careful about making proclamations about what people should do until we have robust data, because sometimes we get the answer wrong,” Murray said in an interview with Healio Gastroenterology.

Although this setback may be frustrating to parents who wish to reduce their children’s risk for celiac disease, the community should also recognize that “several promising research developments in the treatment of celiac disease have occurred in recent years,” Murray and colleagues wrote in the NASSCD commentary. “The mainstay of treatment remains a strict gluten-free diet, but multiple non-dietary therapies are in various phases of testing. These include pretreatment of gluten prior to ingestion, intraluminal digestion of gluten during meals, enhancement of intestinal tight junctions, inhibition of transglutaminase, and other mechanisms.”

Although a non-dietary therapy for celiac disease has yet to be approved by the FDA, the past year saw a major advancement in the community’s understanding of the celiac regulatory pathway following the 2015 FDA Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT) meeting, which experts agreed should increase the confidence of stakeholders in the drug development effort.

Regulatory Pathway

A “major step forward” in therapeutic development for celiac disease occurred in the form of the GREAT Meeting in March 2015, according to Leffler and co-author Sonia Kupfer, MD. This focused in part on “defining target populations for pharmacologic therapies, defining clinical benefit in celiac disease clinical trials, and measuring clinical benefit in celiac clinical trials to support marketing approval,” Leffler and Kupfer wrote in an AGA Perspectives article summarizing the meeting.

“In many ways I think the GREAT meeting ... was sort of a culmination, where we got to the point of recognizing what a fairly well developed celiac drug development pathway looks like,” at least for adjunctive therapies, Leffler said. Generally, this involves a gluten-challenge study followed by a real-life trial, with symptom improvement serving as the primary endpoint.

However, the best way to measure clinical benefit in celiac clinical trials is a “difficult issue,” Leffler wrote, and GREAT participants debated the roles of patient-reported outcomes, histologic assessment and serologic tests.

“We now have the tools to show that patients can benefit symptomatically from a treatment, and we know what these trials look like,” Leffler said.

Two patient reported outcomes for celiac disease have since been created according to the FDA guidance, respectively developed by Alvine and Alba.

“The FDA were really great partners in this, and have been really engaged in seeing celiac disease therapeutics move forward. We have made huge progress in the more than 5 years of patient reported outcome development that have been done, which I think will stand the test of time and will be tools for the wider celiac community to use going forward,” Leffler said.

Drug Pipeline

Proteases and Peptides

With a clearer regulatory pathway in place, drug development efforts in celiac disease have continued to advance during the past year, despite some notable setbacks.

Following a phase 2b trial, latiglutenase (formerly ALV-003, Alvine), an oral combination of two recombinant gluten-specific proteases that degrades gluten proteins, was acquired by ImmunogenX along with Alvine’s other non-cash assets. The company renamed the candidate to IMGX-003 and plans to continue its development, according to a press release.

Although the results are not yet published, it is public knowledge that the phase 2b real-life trial of latiglutenase failed to meet its primary endpoints, according to Leffler. “This basically led to the dissolution of the company and [latiglutenase] as a therapeutic modality ... in the near-term,” he said. “So that was disappointing ... because the enzyme does have clear biological activity. The readout from the gluten challenge study was quite clear that it does degrade gluten and protect against gluten exposure, but for whatever reason when used in more of a real-life [setting], ... it was no better than placebo,” possibly due to a high placebo response in the trial’s control arm, he said.

Larazotide acetate (INN-202, Innovate), belonging to a new class of drugs called tight junction regulators, is an oral peptide that has been shown to improve clinical symptoms of celiac disease in multiple clinical trials. The most recent, a phase 2 randomized controlled trial led by Leffler, showed superior symptom improvement achieved with a 0.5 mg dose of larazotide acetate plus a gluten-free diet vs. a gluten-free diet alone.

According to a press release from Innovate Biopharmaceuticals announcing the acquisition of larazotide acetate from Alba, the agent has “the potential to become the first approved medicine to treat celiac disease, and has been granted ‘Fast Track’ designation from the FDA.” In the release, the company announced plans to begin the first phase 3 clinical trials in celiac disease late this year.

Vaccine

More recently, ImmusanT presented its latest phase 1 data on Nexvax2, an investigational vaccine that aims to protect individuals with celiac disease from the effects of gluten exposure. It is an “epitope-specific immuno-therapy that consists of an injectable formulation of three peptides with epitopes recognized by gluten-reactive CD4+ T cells to target and render these cells unresponsive to gluten,” according to a company press release.

In this double blind, crossover, placebo-controlled study, researchers randomly assigned 59 patients to receive 16 doses of either Nexvax2 or placebo twice weekly for 8 weeks. Then patients underwent a 3-day gluten challenge and were assessed for T-cell response.

“It appears based on the data that were presented that, first of all, the vaccine does have biologic effects; the kinds of immune cells that were designed to be stimulated by this vaccine were actually detectable in patients’ blood samples,” Lebwohl said. “It also appears that the vaccine was well tolerated.”

The researchers observed T-cell activation after the first dose, and after the final dose, comparable plasma cytokines and GI symptoms were observed between groups, “suggesting the induction of antigenic nonresponsiveness to Nexvax2 administration,” according to the press release. Moreover, a gluten challenge after treatment showed most of the patients in the treatment group did not reproduce the increased T-cell responses seen after the first dose, and more patients in the treatment group completed the gluten challenge vs. the placebo group.

“The results of this study demonstrate for the first time that an antigen-specific immunotherapy using peptides can induce antigen-specific unresponsiveness to dominant epitopes for gluten-reactive CD4+ T cells,” Bob Anderson, PhD, ImmusanT’s chief scientific officer, said in the press release.

“We do not yet know whether the vaccine has a significant clinical effect on patients’ ability to tolerate gluten, as these trials were not designed to do that,” Lebwohl said. A phase 2 study to determine the optimum dose and efficacy threshold is the next step, which their presenter said is planned for next year, he added.

Previously, the company announced results from a gluten-challenge study that found adults and children with celiac disease have similar immune responses to gluten. Researchers analyzed T-cell responses to gluten using blood samples from 41 children and four adults with celiac disease who underwent a 3-day gluten challenge, and found 73% of the children had gluten-specific T-cell responses that recognized the same peptides that were immunogenic to adults with celiac disease.

In addition to the intraluminal therapies and immunotherapies, the development of immunomodulators and biologics for more severe celiac disease continued to advance during the past year.

IL-15 Antagonists

Celimmune recently announced the initiation of two phase 2 clinical trials of AMG-714, an anti–interleukin-15 (IL-15) antibody, in refractory celiac disease type two and in nonresponsive celiac disease.

AMG-714 is a fully human immunoglobulin monoclonal antibody that binds to IL-15, which is believed to be responsible for generating aberrant and malignant intraepithelial lymphocytes in refractory celiac disease type two, according to a press release. The agent was well tolerated by healthy participants and patients with rheumatoid arthritis or psoriasis in four prior clinical studies.

“IL-15, in general, is a very interesting target for refractory celiac disease,” Murray said. “It’s involved in probably several of the pro-inflammatory processes within the intestine, and it seems to have an especially important role in patients with refractory celiac disease, so it makes for a very good target.” An open-label phase 1 trial of another IL-15 pathway antagonist called Hu-Mik Beta-1 (an anti-IL-2/IL-15R Beta [CD122] antibody that blocks the action of IL-15) is also currently underway at Mayo Clinic, “in cooperation with University of Chicago and the National Cancer Institute,” Murray said. “Blocking IL-15 has a lot of promise for those rare patients with refractory celiac disease.”

Thus, two phase 2a, randomized, double blind, placebo-controlled, parallel group trials of AMG-714 in both refractory celiac disease type two and nonresponsive celiac disease are currently recruiting, with primary completion expected in 2017. Additionally, new safety data on AMG-714 was recently presented at Digestive Disease Week.

“This was a secondary analysis of AMG-714 in patients with psoriasis, and the specific goal of this analysis was to see the specific kind of blockade that this drug does, and to determine whether it appears to be a target suppressor of secretion of IL-15 without having downstream effects on the immune system that could lead the patient to be susceptible to unforeseen infections,” Lebwohl said.

This study showed the drug was able to neutralize IL-15 in vivo in humans without decreasing circulating natural killer cells or impairing their response to stimuli other than IL-15, which is consistent with “the lack of infectious or any other safety signals in the approximately 200 AMG-714-treated patients studied to date in clinical trials,” the researchers wrote.

“This was not a celiac disease trial, but because this is becoming a potentially relevant drug for celiac disease, this study is important in that it provides some indirect safety data that is reassuring,” Lebwohl said.

A number of other potential therapies for celiac disease continue to advance in early development and are expected to report data in coming months and years.

Novel Monitoring Tools

Despite ongoing drug development, the gluten-free diet remains the only available treatment option for patients. A major challenge in dietary therapy is the ability to assess adherence to treatment and monitor patients for gluten exposure, “as there is no practical tool available for routine use,” Leffler wrote in a review article. However, recent “reports of the successful use of antibodies to detect gluten immunogenic peptides in stool and development of tests for urine represent a paradigm shift away from traditional dietician-based approaches.”

ELISA (laboratory-based) and lateral flow (point of care, potentially over-the-counter) tests have been developed by Biomedal SL in Spain to detect gluten in stool. These assays have been shown to detect gliadin 33-mer equivalent immunogenic peptidic epitopes in human feces with high sensitivity using the last generation of monoclonal antibodies to detect gluten in food, clinically validated to react with the most immunogenic gluten peptides. Gluten-derived peptide detection also correlated with the amount of gluten intake and with symptoms.

According to Leffler, “looking at gluten in stool as a measure of dietary adherence and gluten exposure, a direct measure which we really haven’t had before, is exciting.”

Although the stool gluten ELISA test is already available in some European countries, clinical trials in the U.S. and Canada are still ongoing.

Similarly, Biomedal has developed methods, including a lateral flow test, for the detection of gluten immunogenic peptides in urine, which was evaluated in a clinical trial presented at UEG Week 2015 and later published in Gut.

In this trial, researchers tested urine samples from 76 healthy individuals and 58 patients with celiac disease. They collected the samples at different time points during which participants were subjected to different dietary conditions. Gluten immunogenic peptides were detected with high sensitivity at levels as low as 50 mg of gluten. Further, urinary gluten correlated with mucosal damage in celiac patients.

Patients who had gluten in their urine also had mucosal atrophy with a correlation of approximately 90%; similarly, the absence of gluten in urine correlated highly with an absence of atrophy.

Although the presence of gluten in stool was somewhat expected, its presence in urine is more surprising, and has interesting implications, according to Leffler. “Not only is it making its way through the intestine, ... it’s getting into the blood, through the liver, and getting excreted by the kidneys. So that’s interesting, because it gives us ... a more responsive measure of gluten exposure.”

Even more interesting, he said, is the question that is then raised.

“What is gluten doing in our blood? It’s a complicated protein, it’s not even clear it should be there, but it may actually shed a light on some of these weird gluten-related ... symptoms that people describe. So I think this is raising a whole new line of questioning,” Leffler said. “Nobody would have thought to look for gluten in the blood — I certainly wouldn’t have thought it would have been there in measurable quantities. So I think that’s an emerging area that people are just starting to look at.”

According to Murray, these stool and urine tests will be “very useful” for identifying recent contamination of the diet with gluten in patients with celiac disease. “Obviously when you’re working collaboratively with the patient, we tend to believe them when they tell you they’re gluten free, but often people can be inadvertently exposed to gluten, and having some way to test that would be very helpful.” They could also be useful in clinical trials, although more data on their sensitivity is needed, he added.

“We really are in need of better biomarkers, ways to monitor adherence to the gluten-free diet, and both stool and urine tests offer potentially promising tools in our arsenal,” Lebwohl said. “Issues we have to look out for include the matter of collection — we all know that it’s easier to collect urine than stool — and also the issue of timing. Ideally, I would be interested in knowing whether someone has been exposed to gluten in recent weeks as opposed to being exposed to gluten in the past day or two. It’s very possible that a patient could change his or her diet in the day or two leading up to an appointment, but if we had a way to monitor gluten exposure the way we monitor blood sugar control in diabetes with hemoglobin a1c, it would be a big advance.”

“Further development of these tools for patient use has the potential to revolutionize how patients approach the gluten-free diet as they can confirm whether gluten exposure has occurred,” Leffler wrote in a review. “Point-of-care tools may radically alter how the gluten-free diet is managed while alternative or adjunct treatments to a gluten-free diet are developed.”

The experts interviewed seemed confident that in the coming years the first of these alternative or adjunct therapies will become available. Fortunately, they all agreed that the community’s awareness of the significant unmet medical needs of celiac patients has been steadily increasing.

“We’re more and more building the case that there is a lot more that needs to be done to improve the health related outcomes and quality of life in patients with celiac disease,” Leffler said. – by Adam Leitenberger

• References:
• Aronsson CA, et al. Clin Gastroenterol Hepatol. 2016;doi:10.1016/j.cgh.2015.09.030.
• Comino I, et al. Am J Clin Nutr. 2012;doi:10.3945/ajcn.111.026708.
• Gorski K, et al. Abstract #847. Presented at: Digestive Disease Week; May 21-24, 2016; San Diego.
• ImmunogenX. Immunogenx Acquires The Assets Of Alvine Pharmaceuticals.; 2016. Available at: http://www.businesswire.com/news/home/20160315006846/en/ImmunogenX-Acquires-Assets-Alvine-Pharmaceuticals. Accessed June 15, 2016.
• ImmusanT. Immusant Reports Nexvax2 Phase 1 Data In Patients With Celiac Disease.; 2016. Available at: http://www.immusant.com/docs/ImmusanT%20DDW%20Data%20Release%20FINAL%205.24.16.pdf. Accessed June 15, 2016.
• Krigel A, et al. Clin Gastroenterol Hepatol. 2016;doi:10.1016/j.cgh.2016.04.032.
• Kupfer S, Leffler DA. A GREAT Day for Celiac Disease. AGA Perspectives. June/July 2015. http://www.gastro.org/news_items/2015/7/17/a-great-day-for-celiac-disease.
• Leffler DA, et al. Gastroenterol. 2015;doi:10.1053/j.gastro.2015.02.008.
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• For more information:
• Benjamin Lebwohl, MD, MS, can be reached at bl114@cumc.columbia.edu.
• Daniel Leffler, MD, can be reached at dleffler@bidmc.harvard.edu.
• Joseph Murray, MD, can be reached at Murray.Joseph@mayo.edu.

Disclosures: Lebwohl reports no relevant financial disclosures. Leffler reports he has received consulting fees and/or research support from Alba Pharmaceuticals, ImmunosanT, Ferring, Pfizer and Innova Diagnostics. Murray reports he has been a consultant to Alvine, GlaxoSmithKline, Glenmark and The Israeli Company, and has received grants (to the Mayo Clinic) from Alba.