Two companies are moving forward with a non-diet treatment to treat celiac disease.

By Steven P. Galante
Editor

Celiacs often dream of the day when medicine will deliver them from the gluten-free diet.

Progress towards realizing this dream is, in fact, happening. The prospect of swallowing a pill before swallowing a plate of wheat-based pasta, however, remains a bit remote.

Two companies in the United States are taking center stage for their efforts to develop a non-diet treatment for celiacs. Research is also being carried out in Europe.

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

Alba and Alvine have both received substantial funding from venture capital firms, which are investment firms specializing in starting up companies betting on unproven ideas.

Superficial Similarities

On the surface, the approach of the two companies seems similar. The two are trying to develop an oral drug. Both drugs should tend to prevent the proteins contained within the gluten from initiating an autoimmune reaction causing celiac disease.

The similarities end here though. In fact Alba and Alvine take totally different scientific approaches in their projects.

Neither company, at this point, is ready to say they will deliver a product that allows celiacs to safely consume a normal gluten-containing diet.

“We have no intention of replacing the gluten-free diet,” says Dr. Blake Paterson, executive chef at Alba. “It would be like giving a person Lipitor (a cholesterol-lowering drug) and telling them to eat steak.”

Vice President of Clinical Research and Development at Alvine, Dr. Revati Shreeniwas, says the company’s products will “eventually serve people to digest up to a certain amount of gluten” that might be ingested” inadvertently as part of a gluten-free diet”.

“We have products with very high potential for their ability to digest gluten,” says Dr. Shreeniwas.

However, she notes, Alvine cannot make definitive publicity about the effectiveness of its products, or how they should be used, until clinical trials are completed and the Food and Drug Administration (FDA) in the United States will not have given its approval.

Alba already in Clinical Trials

Of the two companies, Alba is the one that has come the furthest. Its product is already in the second phase of the three-phase testing process. Alba plans to apply to the FDA “in approximately 2010” for permission to begin selling the drug, Dr. Paterson says.

Alba’s approach is based on the fact that in celiacs something seems to be wrong with the mechanism that regulates the space between the cells that make up the wall of the small intestine.

What seems to go wrong is that these intercellular spaces, which are called tight junctions, open up too wide in celiacs. The result is that the tight junctions become more permeable, allowing large molecules like gluten proteins to squeeze between the cells and into the wall of the small intestine.

Interior Problems

Once inside, the proteins stimulate the body’s immune system. In celiacs, this immune response causes chronic inflammation and damages the villi, those finger-like projections on the surface of the wall of the small intestine, which absorb nutrients.

Over time, this damage becomes so severe that the villi can no longer absorb nutrients properly. This is what causes many symptoms of celiac disease.

Alba has developed a compound, called AT-1001, which can prevent tight junctions from becoming too permeable. Since gluten proteins cannot penetrate the intestinal wall, the immune response is never initiated.

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

Dr. Fasano is co-founder with Dr. Paterson of the Alba company, and remains one of the medical advisors.

Test Results Are Promising

Initial test results are promising. Through four human clinical trials completed to date, AT-1001 has proven its safety and efficacy, says Dr. Paterson.

In one test, for example, volunteers were divided into two groups. One group received a dose of AT-1000 and another received a placebo. Both groups received a dose of gluten. The autoimmune reaction was blocked in the group that received AT-1001 but not in the group that received a placebo, reports Alba.

Alba is currently conducting trials to determine if the drug is able to keep celiacs in remission while consuming a limited amount of gluten for three meals a day over a six-week period. (The amount of gluten is 900 milligrams per meal, which is less than the amount of gluten in a quarter slice of bread).

Forgiveness as a Goal

In early 2008, Alba wanted to go further to test whether the drug could keep celiacs in remission. For this test, she will recruit two groups of adults with active celiac disease: a group of newly diagnosed celiacs and a group of “recalcitrant” celiacs who are not able to follow a gluten-free diet.

At that point, Dr. Paterson says, Alba will conduct clinical trials of the drug in children, with appropriate safety measures.

After “Phase II” testing, Alba will begin extensive “Phase III” testing, which is usually the final phase before seeking FDA approval.

Although celiac disease is Alba’s primary target, the science behind AT-1001 has treatment potential for other diseases as well, says Dr. Paterson. For example Crohn’s disease, type 1 diabetes, irritable bowel syndrome and possibly also autism and rheumatoid arthritis, he says.

Alvine’s approach

Meanwhile at Alvine, researchers are working on an entirely different approach to celiac disease.

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

The idea is to render the proteins harmless before they make it further into the small intestine.

The compound in development at Alvine should, in effect, provide “two assaults in one” against gluten.

One of the two proteolytic enzymes, called EP-B2, would be able to split the complex gluten proteins into smaller, less toxic fragments. The second enzyme, named SC PEP, would be able to quickly detoxify the residual oligopeptides, products of the digestion of EP-B2, ultimately rendering them essentially harmless.

Medication Before Meal?

In theory, a celiac could take an Alvine enzyme compound called ALV003 before a meal to protect against any inadvertently ingested gluten.

Based on the results of research conducted to date, says Dr. Shreeniwas, the company can calculate “very precisely and quantitatively” how much gluten a dose of ALV003 is able to neutralize.

“This is a segment where the needs are great,” says Dr. Kirk Essenmacher, vice president of marketing and strategic development at Alvine. “There is a whole range of individuals with medical needs who are waiting for a better quality of life”.

Drs Shreeniwas and Essenmacher are the two members of the new administrative team formed at Alvine since July.

Trials Registered for 2008

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

The full range of trials usually takes at least four years and often more. The FDA generally accepts applications for approval only after the drug candidate has successfully completed trials.

In the medical community, the enzymatic approach is supported by a large majority. For example, in a recent issue of The New England Journal of Medicine , Dr. Peter HR Green, director of the Celiac Disease Research Center at Columbia University , New York, wrote that enzyme therapy seems, currently hold the potential to be “the most appealing alternative” to the gluten-free diet.

Alvine’s work is based on findings made by Chaitan S. Khosla , Director of Studies in the Department of Chemical Engineering at Stanford University. Like many people involved in the celiac community, Dr. Khosla has a personal interest in the outcome of this research; indeed, both his wife and son are celiacs.