Exciting Developments in Gluten Digestion for Celiacs — Results from Four Clinical Trials of ALV003

By: Peter Olins, PhD on December 2, 2011

A gluten-free diet alone may be insufficient for treating celiac disease. Alvine Pharmaceuticals has just released the results of its fourth clinical trial of ALV003, an enzyme which digests the gluten present in a meal. I consider this to be one of the most promising results in celiac disease research in the past year!

Background on the digestion of gluten

Gluten proteins in wheat and related grains are poorly broken down by normal human digestive enzymes, resulting in short peptide fragments that act as a trigger for celiac disease. Considerable research has been devoted to identifying additional enzymes that could be added to foods to help degrade gluten, and block the disease process.

Why is a gluten-free diet insufficient?

A strict gluten-free diet is the only current treatment for celiac disease. However, many celiac patients still have evidence of intestinal damage after years on a gluten-free diet (even if they are not experiencing any physical symptoms). Why is this? There is a very small fraction of individuals who have truly “refractory celiac disease”, which does not respond to a gluten-free diet. However, in most cases, the residual level of intestinal damage is believed to be due to one of three reasons: cross-contamination during food preparation, trace levels of gluten in processed food products or a brief lapse away from a gluten-free diet.

ALV003: a mixture of two enzymes designed to degrade dietary gluten

Regardless of the reasons for the residual intestinal damage, there is still a major need to find additional ways to protect against the effects of traces of gluten. For several years, Alvine Pharmaceuticals has been studying the use of enzymes to break down residual gluten. Their latest drug, ALV003 is a mixture of two different protease enzymes, ALV001 and ALV 002, which attack different regions within gluten proteins. ALV001 is a derivative of a naturally-occurring enzyme from barley (endopeptidase B2), and preferentially attacks glutamine amino acids, which are abundantly present in gluten. ALV002 is based on a bacterial enzyme, and is specific for proline residues, which tend to be resistant to natural human digestive enzymes. The early stages of this research were carried out at Stanford University, and included support from the Celiac Disease Research Foundation.

Early clinical trials were promising

A study published in 2010 involved pre-treating gluten with ALV003 before the gluten was consumed. Celiac patients consumed 16 g of gluten (equivalent of about 4 slices of bread) daily for three days, with or without pre-treatment with the drug. ALV003 resulted in a clear reduction of the immuno-stimulatory activity of the gluten, compared to a placebo control (Ref. 1).

This promising result prompted two Phase 1 clinical studies to assess the safety of the drug at different doses, published in September 2011 (Ref. 2). The first study involved escalating doses of enzyme alone, ranging from 100 mg to 1800 mg. All doses were well-tolerated and no serious adverse events or allergic reactions were observed. The second study involved 100 or 300 mg ALV003 together with a meal containing 1 g of gluten. Stomach contents were then tested and found to have 75% and 88% digestion of the gluten, respectively. This showed that the enzyme was working in the stomach, but only partially. The next step was to launch a Phase 2 clinical trial to try to identify an effective dose of enzyme.

Ref. 1: Tye-Din, JA et al., Clinical Immunology, 134: 289-295. The effects of ALV003 pre-digestion on immune response and symptoms in celiac disease in vivo.
Ref. 2: Siegel, M et al., Dig Ds Sci, 2011, Sep 23 [Epub ahead of print] Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating dose clinical trials.

Phase 2a study demonstrating clear clinical efficacy

The latest study, presented at the October 24, 2011 UEGW congress in Sweden showed the most exciting results (Ref. 3). The study was performed at three sites in Finland, and involved 34 celiac disease patients who had been on a gluten-free diet for a mean duration of 14 years, and had normal levels of serum anti-TG2 antibody. They were randomly assigned to two groups, and given an extra 2 g of gluten daily for six weeks. One group received 900 mg ALV003 together with the gluten, while the other group received a placebo.

The primary endpoint of this study relied on examining the cells of an intestinal endoscopy, measuring the ratio of “villous height” to “crypt depth”. This is a very sensitive measure of the effects of gluten, even more sensitive than autoantibody levels in the blood. The intestinal Vh/Cd ratio was unchanged for the group receiving the drug, but it worsened substantially in the placebo group. The difference was statistically significant. A secondary endpoint was the level of intra-epithelial lymphocytes (a measure of inflammation), and again, the drug-treated group was unchanged, but the placebo group worsened substantially.

Ref. 3: Lahdeaho, A-H et al., UEGW Congress Abstract, ALV003, a novel glutenase, attenuates gluten-induced small intestinal mucosal injury in celiac disease patients: a randomized controlled phase 2a clinical trial

What’s next? What would it take to bring ALV003 to market?

According to the clinicaltrials.gov website, Alvine Pharmaceuticals has recently completed an additional Phase 2a study to investigate different methods of administering ALV003 (these results have not been released yet). Plans to conduct a Phase 2b clinical trial in 2012 have been announced: according to comments in their recent webcast, it will be important to use a larger number of patients, in order to test if ALV003 can also block the clinical symptoms resulting from gluten consumption.

While the clearest experimental results may be seen with the relatively large amounts of gluten used in their studies so far, we believe that the most meaningful results will ultimately require measuring the benefit of ALV003 in response to lower levels of additional gluten (or none at all).

Alvine is still a long way from proving that ALV003 is sufficiently safe and effective to bring to market. Assuming that the clinical trials proceed as hoped, the company will still need to develop a consistent, cost-effective method to produce the two enzyme components in large quantities. Typically, it can be quite expensive to produce drugs composed of proteins. Fortunately, it is possible to produce the two enzyme components of ALV003 in E. coli, which is typically a cheap and efficient route for manufacturing proteins.

If we assume that the drug would be taken on a regular basis (say, with every meal), ALV003 could have huge business potential, especially since celiac disease is being increasingly diagnosed in recent years.

A word of caution. While these results look extremely promising, it’s an unfortunate fact that many drug candidates do not make it all the way through to market for a wide variety of reasons (such as safety problems, insufficient efficacy, or cost of development).

What could this mean for celiacs?

Dan Adelman, the chief medical officer of Alvine Pharmaceuticals, states that ALV003 would most likely be used in conjunction with a “gluten-free” diet. Unfortunately, the dreams of indulging oneself at a typical bakery on donuts, cakes or bread will probably remain unfulfilled. Another possibility is that, rather than taking a pill, these enzymes might be used during food processing, in order to remove traces of residual gluten. The advantage would be that food processes are typically very consistent and reliable, unlike taking a drug, which can vary from person to person. Obviously, this would add substantially to the cost of a gluten-free product.

More information. The latest clinical results haven’t yet been published in a peer-reviewed scientific journal. In the mean time, a public webcast of an October 27, 2011 presentation describing the latest results with ALV003 can be viewed on the Alvine Pharmaceuticals website. We wish Alvine the best of luck in their ground-breaking research!

Thanks to the clinical study volunteers! In addition to the scientists who performed these studies, we especially want to acknowledge the celiacs in Finland who volunteered to take the risk of an early-stage clinical trial.