I am an avid reader of Living Without and they published an interesting article in their latest issue. Basically, the FDA is working on a pill that will help break down the amino acids into smaller fragments, it should pass through our bodies without harming us. Sounds like science fiction but in the US, the pill is in Phase 2 trials and other countries like Finland, Hungary, and Australia are working on similar drugs.
Below is the article from Living Without Dec/Jan 2011 Issue
By Christine Boyd
A Celiac Pill
Treatment for celiac disease is the gluten-free diet. There may be another way.
Celiac Pill
When Izzie Simon* was diagnosed with celiac disease during her freshman year of college, she took the news hard. Treatment for the condition—a lifetime of strict adherence to the gluten-free diet—meant giving up much more than pizza, pasta and the bun off her burger.
“Most of the food on campus was off-limits. Gluten was everywhere! I was totally overwhelmed and unsure how I would manage at school,” says Simon.
A university dietitian helped arrange for a selection of gluten-free cereals, yogurt, plain chicken and veggies for Simon in the main cafeteria but she still felt she was missing out. Her options were bland and limited. She knew college presented a special set of challenges—but she suspected the diet would always be socially inconvenient. Would there ever be another way to treat celiac disease?
Doctors began using the gluten-free diet to manage celiac disease in the 1950s. A Dutch physician noted that the wheat shortage during World War II appeared to benefit children with celiac disease and the gluten-free diet was born shortly thereafter.
Still the cornerstone of celiac disease treatment, the gluten-free diet doesn’t win popularity awards with patients like Simon. Many celiac experts are dissatisfied with the diet, as well. It’s not only challenging to follow, it may not be sufficient, they warn.
“There’s growing evidence in the medical literature and in clinical experience that if a repeat endoscopy is performed, many adults on the gluten-free diet have persistent damage to the small intestine,” reports Alessio Fasano, MD, medical director of the University of Maryland Center for Celiac Research.
A 2007 study found that some degree of intestinal damage was observed in approximately 25 percent of children and over 80 percent of adults with celiac disease when follow-up biopsies were performed.
One reason is that inadvertent gluten exposure is common. Despite best efforts, many celiacs on a gluten-free diet are still exposed to a minimal amount of gluten every day, typically via cross contamination, says Fasano. Exposure often happens outside the household. While it may not be enough to trigger symptoms, it’s enough to cause damage, cautions Fasano.
Intestinal damage may persist for other reasons. A patient’s age at diagnosis, the duration of gluten exposure and possibly even genetic factors may contribute to how well the body responds to the gluten-free diet, say researchers in a 2010 study from the Mayo Clinic.
Fortunately, the call for alternatives to the gluten-free diet hasn’t gone unanswered. Various drug and vaccine-based therapies have been studied over the years, with several recently entering clinical trials, a key stage in the development of any new treatment.
Promising Treatments
Simon regularly browses the websites of several celiac organizations. When one posted an ad for a clinical trial needing subjects, she jumped at the chance to participate. The trial was a six-week study with the investigational drug Larazotide Acetate. Simon completed the preliminary information but didn’t qualify because she lived too far from the nearest research site. Still, she was encouraged, “It’s exciting to realize that research into an alternative treatment is really happening.”
Larazotide Acetate is one of the potential non-dietary treatments for celiac disease. Formulated as a capsule, Larazotide Acetate is thought to work by closing tight junctions and thereby reducing the permeability or leakiness of the intestine. A “leaky gut” may contribute to celiac disease by allowing gluten to slip deeper into the intestine where it can trigger an immune response.
“Larazotide Acetate should [close tight junctions and] decrease traffic in the gut,” explains Fasano, who discovered the drug and helped launch Alba Therapeutics, the Baltimore-based pharmaceutical company currently running the clinical trials.
Also creating buzz is ALV003, being developed by Alvine Pharmaceuticals. Like Larazotide Acetate, ALV003 is a capsule designed to prevent an immune response to gluten but it uses a different mechanism.
“No humans fully digest gluten,” explains Daniel C. Adelman, MD, senior vice president of development and chief medical officer of Alvine Pharmaceuticals, located in San Carlos, California. “When we eat gluten, we digest it down to a protein comprised of about 33 amino acids.” But that large a protein can be immunogenic—capable of stimulating an immune response in those with celiac disease. ALV003 chops up the gluten protein further than the digestive system does naturally, with the hope of rendering it harmless.
“If you can degrade gluten into smaller fragments, fewer than nine amino acids in length, you can destroy its immunogenic potential,” says Adelman.
Both ALV003 and Larazotide Acetate are being studied as companions to the gluten-free diet. They’re not likely to replace the diet any time soon.
“ Inadvertent gluten exposure is common despite best efforts.”
“The current plan is for ALV003 to be taken in conjunction with the gluten-free diet to reduce the risk of intestinal injury from cross-contamination inherent in a gluten-free diet,” says Adelman.
Hope for a Cure
Although two of the most promising treatments for celiac disease–ALV003 and Larazotide Acetate—won’t eliminate the need for the gluten-free diet in the near term, research into a cure for the disease is moving ahead.
Australian researchers just completed the first clinical trial on a peptide-based vaccine known as Nexvax2, which exposes the immune system to very specific, small amounts of gluten fragments (peptides) with the idea that repeated small exposures will help induce the immune system to once again tolerate gluten. It’s a concept not unlike allergy shots.
“The long-term ambition of Nexvax2 is to replace the need for the gluten-free diet and to prevent celiac disease,” says Bob Anderson, PhD, director of Nexpep, the biotechnology company that developed Nexvax2 and is running the clinical trial. “Data from early laboratory studies, including animal studies, indicate these are realistic objectives.”
Animal-based research is proving important in the push for a vaccine. “A major milestone is the successful development of a relevant mouse model of celiac disease—a mouse model that reproduces key features of the human disease,” explains Bana Jabri, MD, PhD, co-director of the University of Chicago Digestive Disease Research Core Center and leader of the team responsible for the mouse model. “Because it’s impossible to control for all variables when studying human subjects, it can be very difficult to establish cause-effect relationships and understand why treatments work or don’t work.”
The mouse model can help by reducing many of the variables. It also allows researchers to identify, test and optimize new therapeutic avenues before moving on to humans.
“Not having a mouse model for celiac disease was a barrier,” says Jabri, who’s encouraged that a vaccine for celiac disease is now within reach.
Slow But Steady
“Studies always take longer to complete than patients would like,” says Adelman. After the clinical portion of the study is over—the part Simon volunteered for—the data are then analyzed and peer reviewed, typically at major medical association meetings. The results are often published in medical journals and then may be disseminated to the public.
In an effort to improve access, the FDA recently mandated that clinicaltrials.gov, a widely used registry of federally and privately supported clinical trials, report the results of studies on its website. But because the rule is relatively new, few results are currently available. They will be in the future, says Adelman.
While Larazotide Acetate, ALV003, and Nexvax2 are all moving forward, none has advanced beyond what is known as Phase 2. Clinical trials generally involve three stages of testing. Phase 1 typically tests for safety in a small sample of healthy individuals. Phase 2 continues to look at safety but may also begin to test for efficacy, this time with individuals who have the disease of interest, such as celiac disease. Here roughly 20 percent of drugs tested make it to market—it’s a long shot. Phase 3 trials are larger studies that need to show the investigational treatment is better than existing treatment and that it’s safe. After successful completion of Phase 3, an application for FDA marketing approval can be submitted.
Larazotide Acetate has a leg up when the time comes for submission to FDA. It’s been granted fast-track status, a designation allowing for speedier review by FDA when no drug exists on the market for the medical condition. Without fast track, FDA review may take a year or longer.
For now, more testing with Larazotide Acetate is planned. The team at Alba is working on another Phase 2b clinical study, reports Francisco Leon, MD, PhD, chief medical officer at Alba Therapeutics. Phase 2 studies are sometimes divided into 2a and 2b. Phase 2a tends to focus on dose (how much drug should be given), while 2b is designed to test efficacy (how well the drug works at the given dose).
Larazotide Acetate won’t be available at your local drug store any time soon but there’s cause for optimism.
“There’s a real possibility that in the next 10 to 15 years, we will be able to offer celiac disease patients an alternate treatment for the gluten-free diet,” says Jabri. “We can even dream today of being able to identify a preventive cure for individuals at high risk of developing celiac disease. This is something we wouldn’t have said even five years ago. There’s been lots of progress.”
Wider Application
So far, all the treatments in clinical trials are being tested on individuals officially diagnosed with celiac disease. No one with gluten sensitivity has been included.
“When testing a drug in clinical trials, the patient population under study needs to be well defined,” says Adelman. Celiac disease has specific criteria used for confirming both the diagnosis and a response to treatment but gluten sensitivity currently lacks that specificity.
“Not all physicians have come to an agreement that gluten sensitivity is real,” says Adelman. “Although we can’t ignore the increasing numbers of patients that truly feel better when they avoid gluten, it’s not yet a well-defined condition. Until then, it will be difficult to develop a treatment or test existing therapies in clinical trials.”
Although the treatments are currently focused exclusively on celiac disease, their target audience may eventually be expanded. The gluten-sensitive population is one natural application, says Fasano. There may be others, as well. In fact, a treatment for celiac disease may open the floodgates.
“Celiac disease is a test case for many autoimmune and allergic conditions,” says Anderson. As the only autoimmune condition that can be ‘turned off’ or sent into remission via the gluten-free diet, it’s long been hoped that celiac disease would provide important clues to stopping the autoimmune process.
Experimental Treatments
Happy with the Diet
Not everyone is on board with the need for a non-dietary treatment for celiac disease. Many are satisfied with the gluten-free diet, including veteran celiac Kate Smyth.
The selection and quality of gluten-free products is better than ever, says Smyth, noting that this market could take a hit if a non-dietary treatment becomes available. She also says dining out is much easier today, with many restaurants now offering gluten-free menus. “There are only a few times a year I find it truly challenging to be gluten free.”
Smyth worries that an alternate treatment for celiac disease may hurt much of the recent progress in celiac awareness.
“When I was diagnosed ten years ago, no one had heard of celiac disease. That’s all changed now. Everyone knows someone with celiac—a friend, teacher or neighbor. A treatment or pill for celiac disease could put it in a similar category as a condition like lactose intolerance. People might not take it seriously any more.”
The potential for unpleasant or even dangerous side effects from a drug treatment dampens the enthusiasm of others. There are few, if any, side effects to controlling a condition exclusively through diet, they argue.
Although no safety concerns with Larazotide Acetate or ALV003 have been reported to date in clinical trials, the drugs haven’t been studied in large populations yet. Approximately 500 people have taken Larazotide Acetate, not enough subjects to see rare or long-term adverse effects. If such effects are to occur, they should be captured in larger Phase 3 studies, after the drug hits the market in Phase 4 safety surveillance studies or in patient registries.
A Safety Net
A major goal in developing a non-dietary treatment is to improve the quality of life for celiacs and their families, says Fasano.
Simon thinks an alternative treatment will make a big difference in her life. Having a dietary restriction can be isolating, she says. She doesn’t always join friends when they go out, not wanting to risk getting sick. If a treatment like Larazotide Acetate were available, she’d have a lot more peace of mind about eating out. Those who prepare food for her would benefit, too, she says. Friends hesitate to send her care packages, not confident about what she can safely eat.
“When you don’t do gluten free every day at every meal, it’s challenging to do it perfectly. Having a treatment would simplify things for them,” she says.
But what excites Simon most about an alternative treatment is that traveling, something she loves to do, would be more manageable.
“It would be a safety net for those unavoidable situations when you’re traveling and you can’t control everything,” she says. “And that would be a dream come true.”
Medical writer Christine Boyd lives in Baltimore.
About Clinical Trials
Clinical trials are conducted in phases, each with a different purpose.
Phase 1 Researchers test an experimental drug or treatment in a small group of people (20 to 80) for the first time to evaluate its safety, determine a dosage range, and identify side effects.
Phase 2 The treatment is given to a larger group of people (100 to 300) to see if it’s effective and to further evaluate its safety.
Phase 3 The treatment is given to large groups of people (1,000 to 3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely.
Phase 4 Post-marketing studies delineate additional information, including the drug’s risks, benefits and optimal use.
Source: clinicaltrials.gov
For additional information about celiac disease and the gluten-free diet, contact these organizations.
American Celiac Disease Alliance
Celiac Disease Foundation
Celiac Sprue Association
Gluten Intolerance Group
National Foundation for Celiac Awareness
In the Know
To learn more about non-dietary treatments for celiac disease, check out these websites.
Alba Therapeutics
Alvine Pharmaceuticals
Food and Drug Administration
Nexpep
University of Chicago Celiac Disease Center
University of Maryland Center for Celiac Disease Research
Drinkin' & Ridin' 