By Amy Ratner, Beyond Celiac Medical and Science News Analyst

What condition can have no symptoms but left untreated can lead to serious consequences, including death?

High cholesterol might to come mind.

But celiac disease should, too, says Francisco Leon, MD, chief medical officer and chief executive officer of Celimmune, a company developing a drug to treat celiac disease that does not respond to the gluten-free diet.

“We are all so into the culture of symptoms,” Dr. Leon laments. “People who think they are not sick, in fact, may be sick even if they don’t have obvious symptoms.”

This has become abundantly clear to Dr. Leon in his work on AMG 714, a drug that neutralizes a molecule, called IL-15, that is believed to be a key driver in celiac disease. Celimmune, a clinical development stage immunotherapy company, is currently conducting Phase II clinical trials to evaluate AMG 714 as treatment for non-responsive and refractory celiac disease.

Non-responsive celiac disease

Non-responsive celiac disease is defined as continuing to have persistent symptoms, elevated antibodies or small intestinal damage even after following a strict gluten-free diet for six to 12 months.

Dr. Leon says that patients sometimes don’t respond to the gluten-free diet because of conditions unrelated to celiac disease, including bacterial overgrowth and lactose intolerance, but even when these are excluded, a seemingly strict gluten-free diet can inadvertently include enough gluten to trigger symptoms or damage.

A 2007 study by the gastroenterology department at Beth Israel Deaconess Medical Center, Boston, found that 36 percent of patients with non-responsive celiac disease were inadvertently consuming gluten.

“We often find that an underlying cause is the inability of a patient to improve the gut because they are still being exposed to contaminating gluten,” Dr. Leon says. “Most patients would improve with absolute zero exposure to gluten, but it’s almost impossible to completely avoid it.”

In recent years, endoscopy and biopsy studies have shown that non-responsive celiac disease includes a larger group of patients than previously thought. While current scientific literature indicates that about 30 percent of patients have non-responsive celiac disease, Dr. Leon says there is evidence the number is closer to 50 percent when those who don’t have symptoms but continue to have damage to the intestine, called mucosal atrophy, are included.

“When we use the rule of thumb that 50 percent of all patients on a gluten-free diet continue to have disease activity and call them non-responsive, it is based on a composite of symptoms, antibodies and biopsy results,” he says.

Celiac disease patients may become so accustomed to low level symptoms that they see them as normal, says Ashleigh Palmer, Celimmune’s executive chairman. But the biopsy and antibody tests provide researchers with better tools than in the past to identify those who are not recovering as well as thought.

Non-responsive celiac disease is common in both children and adults. AMG 714 will initially be studied in adults. If its safety and effectiveness is proven, it would then be investigated for the treatment of children.

AMG 714 is an antibody that binds to IL-15, which is believed to play a key role in inflammation of the gut. It has previously been tested for safety in patients with rheumatoid arthritis and psoriasis. It worked well in clinical studies regarding inflammation in arthritis, leading to the idea that it might work in relationship to non-responsive celiac disease.

The drug could also play a critical role in the treatment of refractory celiac disease, a rare but severe form of the disease.

Refractory celiac disease

Refractory celiac disease is marked by a lack of response to a strict gluten-free diet after six to 12 months, with symptoms, intestinal damage and an abnormal population of white blood cells in the gut.

These cells, called abnormal intraepithelial lymphocytes, are unique immune cells found in the lining of the small intestine. Their presence is the distinguishing and disturbing characteristic of refractory celiac disease because they can be the beginning of cancer.

A patient is classified as having refractory celiac disease Type I or II based on the proportion and characteristics of the intraepithelial lymphocytes. For diagnosis, the cells are counted by a flow cytometer, an instrument that analyzes the chemical and physical properties of particles. Patients with less than 20 percent of the abnormal lymphocytes have Type I refractory celiac disease, and those with more than 20 percent, Type II.

About 1 in 100 celiac disease patients have Type I and 1 in 200 have Type II.

Refractory celiac disease is believed to be independent of gluten since the gluten-free diet is not effective in preventing the lymphocytes from increasing.

“The concept is that refractory celiac disease is almost a different disease, or it’s a disease on top of a disease,” Dr. Leon says. “It’s a complication of celiac disease.”

Patients with Type II have a greater than 50 percent chance of the abnormal lymphocytes spreading outside the gut, causing a full-blown lymphoma, which has a poor prognosis and high mortality.

“Type I is milder, and it has been shown that with steroids you can control the disease,” according to Dr. Leon. “But with Type II you need something more powerful to prevent the cells from invading the body. If that happens, the patient has a 50 percent chance of dying.”

He describes a process of damage, repair, damage, repair that occurs when a patient with celiac disease consumes gluten. “If you don’t take care of that process, it could eventually lead to cancer,” he said, noting that a similar mechanism, with different triggers, is at work in colon and skin cancers.

Most cases of both types of refractory celiac disease occur in older patients who are not diagnosed until later in life. Typically, they suffer symptoms for many years until severe pain develops and abnormalities such as severe anemia are discovered. Finally, celiac disease is pinpointed as the cause. Refractory celiac disease only appears in patients who have not been on a gluten-free diet or have not followed the diet correctly for decades, Dr. Leon says.

“If there is a significant number of patients who are not aware they are being continually exposed to gluten, and they are constantly getting damage from that exposure at either the symptomatic or asymptomatic level, over many years they can transition to refractory celiac disease,” Palmer explains. “That is of great concern.” The concern has grown as it’s become clear how nearly impossible it is for patients to be completely gluten-free.

Clinical trials

One of the clinical trials being conducted by Celimmune specifically targets refractory celiac disease Type II. The study, which lasts 20 weeks and is being conducted in the United States, France, Holland, England and Spain, is enrolling 24 patients with a confirmed diagnosis of refractory celiac disease Type II. The first participant began receiving a bi-weekly intravenous infusion of AMG 714 in April. All study participants will have intestinal biopsies before and after treatment and will maintain a strict gluten-free diet.

Dr. Leon says some patients with refractory celiac disease Type II have lymphoma in the gut for five to 10 years, and it still does not spread to the rest of the body. Others have a much quicker progression. Studies being done by Celimmune are looking at factors that might help explain what triggers the cancer growth. Biomarkers in the gut and blood are being collected.

“One of our goals is to see if we can correlate the parameters with the clinical course of the disease,” Dr. Leon says.

Celimmune’s second clinical trial, which also lasts 20 weeks, is being done in Finland and investigates non-responsive celiac disease. The first of 63 participants began receiving AMG 714 in April. The study includes both patients who have intestinal damage despite being on the gluten-free diet and those who are well controlled on the diet.

The first group will stay on the gluten-free diet, with the study determining how the drug affects them. In the second group, the study will evaluate how well the drug reduces the effects of gluten during a controlled gluten challenge.

The trials are designed to determine how AMG 714 would be used by patients, including whether it would replace the gluten-free diet or be added to it, Dr. Leon says.

Celimmune will have data from both trials on a broad range of gluten exposure because the company is measuring gluten consumption with new urine and stool tests offered by Biomedal, a Spanish company. The tests will be used to determine if study participants are truly on a strict gluten-free diet and to monitor the gluten challenge.

Patients’ role in new treatments

Dr. Leon says the AMG 714 clinical trials are an important milestone for the company and an exciting step toward finding much-needed treatment options for celiac disease.

He credits celiac disease patients who have participated in research for making an increase in studies and research publication possible. These studies have resulted in better understanding of the role of symptoms in evaluating responsiveness to the gluten-free diet.

And he called on more patients to become a part of the search for new treatments. You can do that through the Beyond Celiac Research Opt-In here. When you register for the Research Opt-In you will receive regular news and updates about advances in research and medicine, including announcements with opportunities for how to get involved in clinical trials and other studies.

“The importance of patients participating in research can’t be emphasized enough,” Dr. Leon says. “Research to understand the cause of the disease, to understand the cause of unresponsiveness and to test potential therapies requires active participation.”