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Beyond Biopsy and Gluten-Free Diet

Emerging Diagnostics and Therapies for Celiac Disease

Issue: April 2015

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The prevalence of celiac disease in the United States has more than doubled during the past 2 decades and currently affects approximately 2 million Americans and 3.5 million Europeans, according to recent estimates. However, most individuals with celiac disease remain undiagnosed, and for those who receive a diagnosis, notoriously difficult lifelong adherence to a gluten-free diet remains the only effective treatment.

According to experts interviewed by Healio Gastroenterology, celiac disease research has reached an interesting moment in light of recent advances in diagnostic tools and several promising emerging therapies that are currently under development.

Diagnostic Process Debate

Although there has been a true increase in background undiagnosed celiac disease during the past 20 years, much of the rise in prevalence can be attributed to the rate of diagnosis, which has risen 15-fold in that same time period, according to Joseph A. Murray, MD, from the Mayo Clinic in Rochester, Minnesota.

Joseph A. Murray

“There has been a dramatic increase in the rate of diagnosis of celiac disease in the United States,” Murray said, which “reached a plateau in about 2004 and has stayed at this high level — much higher than it was before.”

In a recent review, Murray and co-author Steffen Husby, MD, from Odense University Hospital in Denmark, credited better clinical awareness and tests for these advances in diagnosis rates. The traditional reliance on histological analysis of duodenal biopsy samples for diagnosis has been reduced by highly accurate celiac-specific serological analyses — primarily, tests for tissue transglutaminase 2 (tTG2) immunoglobulin (Ig) A and endomysial IgA antibodies, both of which have demonstrated greater than 90% sensitivity and specificity, they wrote. Thus, a debate has ensued during the past decade surrounding the circumstances in which a biopsy can be omitted for the diagnosis of celiac disease.

The most recent guideline recommendations from the American College of Gastroenterology and the British Society of Gastroenterology, both of which Murray co-wrote, include utilizing symptoms, celiac antibodies, human leukocyte antigen (HLA)-based genetic tests and biopsy histology for diagnosis. Both guidelines “affirmed the value of biopsy for the confirmation of the diagnosis of celiac disease in adults,” Murray said, whereas the 2012 guideline from European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommended “that in certain restricted circumstances a duodenal biopsy could be avoided in European children.” These circumstances involve very specific requirements, including tTG2 IgA antibody levels of more than 10 times the upper limit of normal, a positive endomysial IgA antibody test, a positive genetic HLA test and objective improvement on a gluten-free diet.

Murray and the ACG guideline co-authors “felt we were not ready for avoidance of a biopsy diagnosis [in children],” he said. In their review, he and Husby wrote that because the ESPGHAN guideline places “considerable demands on the quality of anti-tTG2 antibody analysis … the evidence base for this strategy needs further strengthening.” However, they considered a possible “central truth … that maybe not everybody needs a biopsy to make the diagnosis,” he said. “There is a degree of flux that is going on. The big problem [is that] people are not reading the [ESPGHAN] guidelines in detail and are applying them inaccurately and incorrectly to a much larger population.”

Daniel A. Leffler

Daniel A. Leffler, MD, MS, director of clinical research at The Celiac Center at Beth Israel Deaconess Medical Center in Boston, said that although the ESPGHAN guideline is reasonable, as “invasive procedures in children are something to be avoided whenever possible,” it does not negate the utility of diagnostic biopsy, especially in adults. “Endoscopy is one of the safest invasive procedures we do. Risks are miniscule, it’s a quick procedure, and it provides not only diagnostic information but can be helpful in follow-up.”

Repeat endoscopy performed routinely for some celiac patients with persistent symptoms “is a perfectly reasonable thing to do,” he said, “but the yield of that is much lower if you don’t have the original biopsy to compare it to, and since you don’t know who is not going to respond years down the road, not having that irretrievable information is a problem.” There also is some evidence that having a diagnostic biopsy leads to better long-term adherence to a gluten-free diet, as the results are “much less abstract” than a blood test result, Leffler added.

Anthony J. DiMarino Jr., MD, chair of the division of gastroenterology and hepatology and director of the Celiac Center at Jefferson University Hospital in Philadelphia, said a biopsy is valuable for its ability to provide a concrete diagnosis. “The biopsy is the gold standard,” for both diagnostic and prognostic purposes. “I view the other diagnostics as adjuncts, [and] I can see in certain cases where if biopsy was not easily accessible, and if the celiac antibodies are high and the patient was HLA-DQ2 or HLA-DQ8 positive, then you could make a presumptive diagnosis.”

However, he said, there is the possibility that these patients may question their diagnosis years down the road, possibly due to misinterpreting their improved symptoms after adhering to a gluten-free diet, in which case a biopsy would be required anyway because a confirmatory antibody test result would be normal at that point. An initial biopsy diagnosis could pre-empt this by providing “confirmation” and “closure” to such patients, DiMarino said.

The diagnostic criteria debate aside, the overall rate of diagnosis remains low in the United States, at about 15% of cases compared with 50% or more in many European countries, Leffler said. “There are so many different ways celiac disease can present — from growth failure, to hair loss, rashes, fatigue, GI symptoms — that unless we keep a very low threshold for testing, and test regularly, we are going to be missing it a fair number of times.” The currently available serology tests are 95% accurate, in general, he said, but “the problem is we just don’t use them enough.”

Furthermore, Leffler said, all of the guidelines recommend routine follow-up of patients with celiac disease, “just like any other chronic disorder, and while primary care might be failing in making the initial diagnosis, we are not doing a great job as GIs in monitoring these patients, and especially as we get new therapies that can treat people more effectively, we should begin to take follow-up of our celiac patients seriously.”

Drug Development

Experts said it has long been assumed that a gluten-free diet was a sufficient treatment with the exception of patients with refractory celiac disease, who are exceedingly rare. However, adherence to a gluten-free diet is incredibly difficult in the gluten-rich environment of Western societies, and mounting data supports this. According to study data published in the journal Appetite in 2013, more than 70% of patients with celiac disease surveyed in England reported intentional or inadvertent nonadherence to their gluten-free diet.

Anthony J. DiMarino Jr.

“Almost all studies show that you are lucky if 50% of [patients] are anywhere near where they need to be in regard to the amount of gluten that is felt to be safe,” which is often regarded to be 50 mg, DiMarino said.

Leffler agreed that adherence is a persistent problem. “There’s no such thing as a gluten-free diet — that’s a misnomer. The best you can do is a very low gluten-containing diet,” he said. “Even what is allowed by the FDA to be labeled ‘gluten-free’ is really just less than 20 parts per million, and there’s good research now that shows those products occasionally have significantly more gluten due to batch-to-batch variations. So even people doing the best they can … are still getting exposed to gluten regularly, and just convincing them to work harder is probably not the best solution to the problem.”

Thus, “we have moved to a point where there is general agreement, at least among the celiac disease community, that there is a great need for new adjuvant medical therapies,” Leffler said.

According to Murray, there are five categories of patients with celiac disease for whom there is an unmet medical need:

• patients with recurring symptoms despite their best effort to be gluten-free;
• patients who would like to alleviate the burden of gluten-free diet;
• patients who lack intestinal healing and require a therapy to induce healing;
• patients who would like to avoid bad symptoms resulting from occasional gluten exposure; and
• rare patients with refractory celiac disease who have the poorest outcomes.

The aim, Murray said, is to develop adjunctive and alternative treatments for these patients, with the ultimate goal of developing a “holy grail” of celiac disease treatments, or “a passport to eating gluten with impunity.”

Tight-Junction Regulator Peptide

Larazotide acetate (formerly AT-1001, Alba Therapeutics) has the potential to become the first approved medical therapy for celiac disease and has been granted fast track designation from the FDA for this indication, according to a press release from the manufacturer. It is an investigational, first-in-class tight-junction regulator peptide that works directly on the small intestine luminal surface to prevent intestinal epithelial tight junctions from opening, “thus reducing the inflammatory process in response to gluten.” Positive results from a phase 2b trial were announced by the manufacturer in February 2014 and are currently in press in Gastroenterology.

Larazotide is “a new drug in a new category, which appears to prevent tight junction dysregulation that occurs in response to gluten, so it interrupts the effect that gluten has on tight junctions in the intestine and, by doing so, it prevents them from becoming leaky,” Murray said. “Even with the highest doses, we’ve never been able to detect it in the circulation, so it’s a topically active drug, and it probably only works for 2 or 3 hours after administration. It’s specifically given before meals as a way to interrupt the acute response to gluten exposure with a meal.”

In preliminary gluten challenge studies, Murray said, the drug “seemed to ameliorate or prevent the symptoms induced by gluten challenges at lower doses.” The most recent phase 2b trial was a double blind, placebo-controlled, real-life study in patients that continued to adhere to a gluten-free diet.

This trial assessed the safety and efficacy of larazotide acetate in 342 patients with celiac disease who have persistent symptoms despite adhering to a gluten-free diet. After a 4-week placebo run-in, patients were randomly assigned to placebo or 0.5 mg, 1 mg or 2 mg larazotide acetate three times daily for 12 weeks, followed by a 4-week placebo run-out. Compared with placebo, patients in the 0.5-mg group had significant improvement overall and in individual symptom parameters as assessed by the celiac disease gastrointestinal symptom rating scale, and safety was comparable to placebo.

“In addition to the GI symptoms getting better, the patients also had significant improvement of headache and fatigue,” Murray said. “So there was significant improvement of both GI and non-GI symptoms on the lowest dose.”

Data on the safety profile of larazotide is especially promising, DiMarino said. It “seems to have virtually no side effects,” because it works at the surface of the intestinal lumen rather than systemically. “All of the toxicology studies have been incredibly favorable, which is especially important in drug development.”

This study was the first successful trial of a novel therapeutic agent targeting tight junction regulation in patients with celiac disease who have persistent symptoms despite adherence to a gluten-free diet, the researchers concluded, and the manufacturer has announced plans for phase 3 clinical trials are currently underway.

Gluten-Specific Proteases

ALV003 (Alvine Pharmaceuticals) is an oral combination of two gluten-specific proteases (a cysteine protease and a prolyl endopeptidase) shown to degrade gluten in vitro, thus diminishing its immunogenicity, according to a press release from the manufacturer. It also has received fast track designation from the FDA and is currently being studied in a phase 2b trial.

Results from a previous phase 2a 6-week gluten challenge study presented at the 2012 Digestive Diseases Week meeting showed that ALV003 could diminish gluten-induced intestinal mucosal injury in well-controlled patients with celiac disease on a gluten-free diet. Biopsies from the placebo group (n = 18) showed evidence of mucosal injury after gluten challenge (mean villus height-to-crypt depth ratio changed from 2.8 to 2; P = .0007; and density of CD3+ intraepithelial lymphocytes changed from 61 cells/mm to 91 cells/mm; P = .0003), whereas no significant mucosal deterioration was observed in biopsies from the ALV003 group (n = 16). “Interestingly, there were no statistically significant differences in symptoms between groups,” Murray and colleagues wrote in a review.

The current phase 2b clinical study, CeliAction, aims to determine the safety and efficacy of ALV003 at different dose levels over 12 weeks in approximately 500 patients from the United States, Canada and Europe, who have persistent symptoms despite being on a gluten-free diet. The manufacturer announced that the first patient was dosed in the CeliAction study in October 2013, and by Leffler’s estimates the results will be available in 6 months to a year.

Immunotherapy

There are many other promising drug candidates for celiac disease in the research and development pipeline, experts said, although none as far along in development as larazotide acetate or ALV003.

Nexvax2 (ImmusanT) is the first therapeutic vaccine for celiac disease, which combines three proprietary peptides that elicit an immune response in HLA-DQ2–positive celiac patients, according to a press release from the manufacturer.

The mechanism of Nexvax2, Murray said, is to “induce immune tolerance by injecting gliadin peptide into the skin — not under the skin, but into the skin. Now that could be a ‘passport to eating gluten with impunity’ if it works; theoretically it could make a person tolerant to gluten again.”

In December, the manufacturer announced positive phase 1b results demonstrating safety, tolerability and relevant bioactivity, and plans for phase 2b trials to commence in 2015.

An immunotherapy such as Nexvax2 is among the more intriguing candidates in the pipeline, Leffler said, as restoring tolerance to gluten would “basically be a sort of a cure for celiac disease.” Currently, however, it is “probably the furthest from reality.”

‘Completely Unmet Medical Need’

According to Leffler, “we have moved in recent years from not really understanding much about the unmet medical need in celiac disease to now understanding that there is actually a great, completely unmet medical need. The treatment is burdensome and if that weren’t enough, it doesn’t work as effectively as we once thought,” considering the large number of patients with persistent symptoms and lack of intestinal healing.

“Outside the celiac disease world, for industry, for regulatory bodies, this is still an argument we are actively trying to make, but we’ve come a long way in a relatively small number of years. There are actually a lot of things coming down the pipeline that work in different ways,” Leffler said, and with larazotide and ALV003 “neck and neck” in terms of development, we could “potentially see something on the market in the next few years in a best-case scenario.” – by Adam Leitenberger