By Amy Ratner, Beyond Celiac Medical and Science News Analyst

It’s hard for people who have celiac disease to give up the idea that the gluten-free diet is the only treatment they need. Bob Anderson, a gastroenterologist and leading celiac disease research scientist, completely understands this. For a long time, he says, celiac disease experts were “working on the premise that you just prescribed the gluten-free diet and everything would be just fine.”

But as researchers increasingly study celiac disease, they are finding that patients on the gluten-free diet continue to have symptoms, intestinal damage or both even when they don’t realize it. Consequently, a number of new treatments are now being studied.

Nexvax2, a therapeutic vaccine to treat celiac disease, will move into an important large, multi-nation Phase II trial next year. It’s being developed by ImmusanT, a Massachusetts biotechnology company where Dr. Anderson is the chief scientific officer. The vaccine is a form of immunotherapy, a promising approach to celiac disease that uses the body’s own immune system to treat or prevent disease.

Scientists have been seeing sustained evidence for several years that treatments other than the gluten-free diet are needed. A 2010 Mayo Clinic study found that more than a third of adults have gut damage even after following the gluten-free diet for five years. Additionally, recent research showed that 70 percent of those with celiac disease are still exposed to gluten despite their best efforts to be strictly gluten-free.

ImmusanT

Nexvax2 is designed to protect against the effect of gluten in those who have celiac disease and the gene most commonly associated with it, HLA-DQ2.5. This includes about 90 percent of celiac disease patients in the United States. ImmusanT recently reported positive results of several Phase I clinical trials, the stage in which safety of a drug is tested on a small number of patients.

The trials supported the company’s premise that Nexvax2 would target cells that react to gluten and turn off the response in those who have celiac disease and the requisite gene. The trials also investigated the safety and tolerability of the vaccine. An ongoing study is evaluating dose amounts. A Phase II trial, which will involve a larger number of study participants, is expected to begin in early 2017 in the United States, Australia, New Zealand and possibly other parts of the world.

“We are excited about the (Phase I) results and have a strong development plan looking forward to Phase II,” says Leslie Williams, ImmusanT’s president and chief executive officer. But she cautioned that it will take more studies and time before the vaccine becomes a reality. “We want people to know there is hope but not false hope because it’s still early.”

Under the company’s plan, the first Nexvax2 on the market would be used along with the gluten-free diet to protect patients when they are inadvertently exposed to gluten, for example from cross-contact when dining out. A vaccine that would allow celiac disease patients to return to a regular diet is expected to eventually follow.

ImmusanT decided to initially pursue a vaccine that works to protect against exposure while continuing on the diet after assessing what patients say they want, according to Williams. The company also evaluated the challenges of getting Food and Drug Administration (FDA) approval for the launch of a vaccine that completely negates the need for the diet and concluded that would be better as a second step.

Therapeutic vaccines

Nexvax2 falls into the newer category of therapeutic vaccines, which are designed to treat disease. It differs from vaccines for the measles, chicken pox and the flu and others, which are designed to prevent disease.

Preventative vaccines produce a new immune response in the body, Dr. Anderson explains, noting you do not have to have the flu to be protected from it. Once a patient has been given a vaccine with flu antigens, his or her immune system knows to generate a protective response if it encounters that antigen again.

As a therapeutic vaccine, Nexvax2 works in somewhat the opposite way by targeting the immune response that is already occurring in those who have celiac disease and are HLA-DQ2.5 positive. “Therapeutic vaccine is a way of reprogramming the immune system to learn not to react,” Dr. Anderson says.

Nexvax2 is also a personalized medicine, which is an innovative approach to treatment that takes into account the difference in people’s genes, environment and lifestyle. “Nexvax2 is customized to target T-cells responding to fragments of gluten bound to HLA-DQ2.5, “Dr. Anderson explains.

Rebooting the system

Nexvax2 contains three peptides, the small segments of the larger gluten protein, that cause the T-cell reaction in celiac disease that results in symptoms and intestinal damage. T-cells are white blood cells that function as the body’s disease fighting soldiers, but in the case of celiac disease are incorrectly turned on to attack when the gluten peptides are detected.

Scientists started searching for the toxic peptides that cause celiac disease more than 60 years ago. Dr. Anderson began working on the puzzle in 1998 in Oxford, England and later Australia before joining forces with Williams and bringing ImmusanT to the United States several years ago.

Williams compares the way Nexvax2 would work to rebooting a computer. “Hopefully by delivering the peptides, the patient is protected if they do get exposed to small amounts of gluten because you are rebooting the immune system so it doesn’t go on the attack,” she says.

The premise behind Nexvax2 is that if a small amount of the vaccine is given initially as an injection and gradually increased with booster shots, the immune system will build up resistance without any negative effects. “That’s the driving hypothesis,” Dr. Anderson says.

“That’s the plan and that is what our trials are designed to test,” Williams notes.

In the longest clinical trial done so far, 39 participants who were following a gluten-free diet were given twice weekly doses of Nexvax2 or a placebo for eight weeks. After the first dose, T-cells were activated in those who received Nexvax2. When the treatment ended, T-cells were no longer activated by Nexvax2.

Additionally, T-cells were not activated in study participants who received Nexvax2 when they ate gluten for three days. But those who received the placebo showed a T-cell response after a gluten challenge. The effects of gluten on symptoms and treatment with Nexvax2 compared to placebo will be assessed in detail in future studies. As part of the trial, biopsies were collected from 14 participants who received Nexvax2 or the placebo treatment and no changes were seen in either group over the eight-weeks of treatment. Researchers were looking to determine that Nexvax2 does not damage the gut.

The results of this study show, for the first time, that a very specific, targeted immunotherapy using the parts of the gluten protein that trigger response can reprogram the immune system of those who have celiac disease so that the body no longer attacks itself, William says.

The vaccine targets only the part of the immune system that causes the damaging reaction in the gut, which then leads to celiac disease complications throughout the body. This is appealing because the immune system in celiac disease is otherwise essentially normal. Unlike immunotherapy treatments for cancer, rheumatoid arthritis and inflammatory bowel disease, Nexvax2 does not suppress the whole immune system. “These work, but there is a cost involved in treating the disease because they make people more prone to infection,” Dr. Anderson says. As studies of Nexvax2 progress, researchers will monitor immune responses unrelated to the gut to be sure no other part of the immune system is being affected.

A little pinch

Like allergy vaccines, which are also therapeutic and targeted, Nexvax2 would be given as an injection into the skin using a very small micro needle. “It’s almost like taking your finger nails and giving yourself a little pinch,” Williams says.

In an early Phase I clinical trial, study participants who received Nexvax2 initially experienced symptoms similar to those caused by eating gluten. Researchers wanted to see symptoms with early dosing because it indicated that the vaccine was hitting the intended target.

“Not only did it hit the target, but it implied we had proven the CD4 T-cell is the cell in the immune system that is responsible for what people experience when they eat gluten. It was a very significant advance in the field of celiac disease research,” Dr. Anderson says.

But he adds that it’s clear patients don’t want symptoms and subsequent trials will look for dosing schedules to avoid them, with a goal of having no side effects. Future trials will also address the question of how long protection from the vaccine would last.

Going slow to go fast

ImmusanT is initially seeking FDA approval of a vaccine for adults, followed by a treatment for children. “It would be very powerful to relieve some of the burden of celiac disease in children,” Dr. Anderson says.

Overall, Williams says ImmusanT is “going slow to go fast” to help ensure the success of Nexvax2. The company is looking to involve patients and physicians in an ongoing way.

One of the challenges the company faces goes back to the patient perspective that the diet is the only treatment needed, even as the scientific community recognizes the need for something better. Beyond Celiac also recognizes this challenge and has made it a top priority to inform patients about evidence of the need for treatment beyond the diet. This commitment is reflected in the name change made by the organization earlier this year. Using its Research Opt-In, Beyond Celiac shares research and medical news as well as information about opportunities to participate in research with patients and their families.

Dr. Anderson says evidence of the need for new treatments comes from research that shows biopsies taken from patients who have been on the gluten-free diet for a long time demonstrate significant levels of intestinal damage. “Part of the enlightenment from work conducted in the past four to five years is that unless you look, you don’t realize your intestine is still significantly damaged even when you think you are on a gluten-free diet,” he explains.

Still, he is wary of criticizing the diet because it’s all that’s available. “But is the diet 100 percent the answer? No,” he says. “It’s probably 50 percent of the answer on a good day.”

A number of drug development companies are working on new treatments for celiac disease. This is the first in a series that will take a close look at the progress they are making.