CELIACTODAY

People with celiac disease often dream of a day when medicine eliminates the need for a gluten-free diet.

Progress toward that goal is, in fact, being made. The prospect of swallowing a pill before downing a plate of wheat-based pasta, however, remains some way off.

In the U.S., two young companies are in the forefront of the effort to develop non-dietary treatments for celiac. Research also is underway in Europe.

The two U.S. companies are Alba Therapeutics Corp. of Baltimore, and Alvine Pharmaceuticals Inc. of San Carlos, Calif., just south of San Francisco.

Alba and Alvine both have received substantial funding from venture capital firms, which are investment companies that specialize in financing start-up businesses with unproven ideas.

Superficial Similarity

On the surface, the approaches of the two companies seem similar. Both are trying to develop a medication that could be taken orally. Both medications would be aimed at blocking the proteins contained within gluten from setting off the autoimmune reaction that causes celiac disease.

The similarities end there, however. Because, in fact, Alba and Alvine are taking very different approaches in the science behind their projects.

Neither company at this point is prepared to say that it will deliver a product that will allow people with celiac disease to consume a conventional gluten-containing diet safely.

“We do not intend to replace the gluten-free diet,” says Dr. Blake M. Paterson, Alba’s chief executive officer. “That would be like putting someone on Lipitor (the cholesterol-lowering drug) and telling them to eat steak.”

Alvine’s vice president of clinical research and development, Dr. Revati Shreeniwas, says the company’s products “may be eventually intended for use in patients to digest up to a certain amount of gluten” that may be ingested “inadvertently in the course of an attempted gluten-free diet.”

“We have products that are very potent in their ability to digest gluten,” Dr. Shreeniwas says.

However, she notes, Alvine cannot make definitive claims about its product's effectiveness, or how it might be used, until the drug completes clinical trials and obtains clearance from the U.S. Food and Drug Administration.

Alba Already in the Clinic

Of the two, Alba has made far greater headway. Its product is already in the second phase of a three-phase clinical trial process. Alba plans to apply to the FDA by “2010 or so” to begin selling the drug, Dr. Paterson says.

Alba’s approach is based on the fact that, in people with celiac disease, something seems to go awry with the mechanism that regulates the spacing between the cells that line the inner walls of the small intestine.

What seems to go wrong is that these intercellular spaces, known as tight junctions, open too widely in people with celiac. As a result, the tight junctions become more permeable. They allow large molecules of gluten proteins to slip past, and to enter the lining of the upper small intestine.

Trouble on the Inside

Once inside, the proteins stimulate the body’s immune system. In people with celiac disease, that immune response causes chronic inflammation and damages the villi, the finger-like features of the small intestine that absorb nutrients.

Over time, the damage becomes so severe that the villi no longer absorb food nutrients properly. This is what leads to the many symptoms of celiac.

Alba has developed a compound, which it calls AT-1001, that it says prevents the tight junctions from becoming too permeable. The gluten proteins cannot enter the intestinal lining, and so the auto-immune response is never triggered.

AT-1001 is based on the work of Dr. Alessio Fasano, a researcher at the University of Maryland. Dr. Fasano discovered a protein, which he named zonulin, that can be used to regulate intercellular tight junctions.

Along with Dr. Paterson, Dr. Fasano is a co-founder of Alba, and he remains one of its medical advisors.

Test Results Promising

Initial test results have been promising. In four sets of human clinical trials that Alba has completed so far, AT-1001 has proven to be safe and effective, Dr. Paterson says.

In one test, for example, volunteers were divided into two groups. One group received a dose of AT-1001, and another received a placebo. Both groups received a small dose of gluten. The autoimmune reaction was blocked in the group that received AT-1001, but not in the group that received the placebo, Alba reported.

Currently, Alba is testing whether the compound can keep celiac disease in remission when patients consume a limited amount of gluten in three meals each day for six weeks. (The amount being tested is 900 milligrams per meal, which is less than the amount of gluten in a quarter of a slice of bread.)

Aiming for Remission

Early in 2008, Alba plans to go further, and to test whether the drug can put celiac disease into remission. For that test, it will recruit two groups of adults with active celiac: ones who are newly diagnosed, and “recalcitrant” adults who are unable to follow the GF diet.

At some point, Dr. Paterson says, Alba will conduct clinical trials of the compound in children, with appropriate safeguards.

Following the “phase II” tests, Alba will start a larger “phase III” test, which is usually the final level of testing before seeking FDA approval.

Though celiac is Alba’s first target, the science behind AT-1001 has the potential to treat other diseases, as well, Dr. Paterson says. They include Crohn’s disease, Type 1 diabetes, irritable bowel syndrome, and perhaps even autism and rheumatoid arthritis, he says.

Alvine's Approach

Meanwhile, at Alvine Pharmaceuticals, researchers are working on an entirely different approach to dealing with celiac.

Alvine is developing an oral treatment that contains two kinds of specialized enzymes known as proteases. These enzymes would break down gluten proteins in the stomach and upper small intestine.

The idea is to render the proteins harmless before they progress very far into the small intestine.

The compound Alvine is developing would, in effect, deliver a "one-two punch" to gluten.

One of the proteolitic enzymes, known as EP-B2, would chop long, complex protein strands into smaller, less toxic pieces. The second enzyme, dubbed SC PEP, would dissolve the resulting protein fragments even further, rendering them essentially harmless.

Pre-Meal Medication?

In theory, someone with celiac could take Alvine's enzyme compound, which it calls ALV003, before eating a meal to protect against any gluten that is ingested unknowingly.

Based on research results so far, Dr. Shreeniwas says, the company can calculate “very precisely and quantitatively” how much gluten a dose of ALV003 would neutralize.

“This is an area of high unmet needs,” says Dr. Kirk R. Essenmacher, Alvine’s vice president of marketing and corporate & strategic development. “There is a whole spectrum of individuals with medical needs and quality-of-life needs.”

Drs. Shreeniwas and Essenmacher are both members of a new management team that Alvine has been building since July.

Trials Slated for 2008

Initially, Alvine hoped to start clinical trials in 2007. Now, those trials will begin in 2008, Dr. Shreeniwas says.

A full set of clinical trials usually takes at least four to five years to complete, and often much longer. The FDA generally accepts applications for approval only after a drug candidate has completed trials successfully.

The enzyme approach has support in the wider medical community. For instance, in a recent issue of The New England Journal of Medicine, Dr. Peter H.R. Green, director of the Celiac Disease Research Center at Columbia University in New York, wrote that enzyme therapy currently seems to hold potential to be “the most attractive alternative” to a GF diet.

Alvine’s work is based on discoveries by Chaitan S. Khosla, chairman of the chemical engineering department at Stanford University. Like many people involved in the celiac community, Dr. Khosla has a personal stake in the outcome; both his wife and son have celiac disease.

This story originally appeared in the (November, 2007 ) issue of CeliacToday.com. It was most recently updated in (October, 2009).