An Update of Every Major Celiac Disease Drug, Enzyme, or Treatment in Development

Celiac.com 01/14/2019 - There are a number of new drugs in development that are designed to treat celiac disease. In addition to a possible vaccine, those drugs include enzymes and other drugs that are designed to reduce or eliminate the body’s adverse reaction to gluten through various mechanisms.

Here's a 2019 status update for every drug for treating celiac disease currently in development:

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ALV003—Created by Alvine Pharmaceuticals, is a combination of two enzymes that break down gluten before it can provoke an immune reaction. The drug is a powder to be dissolved in water and taken before meals. ALV003 passed a phase 2 clinical trial, and results were published in the June 2014 issue of Gastroenterology. Post-trial biopsies showed that ALV003 prevented intestinal damage in 34 volunteers with celiac disease, each of whom ate 2 grams of gluten per day for six weeks, in addition to taking ALV-003. Phase 2b, a 12-week trial, is now underway.
 
AN-PEP (aspergillus niger prolyl endopeptidase)—Created by DSM Food Specialties, AN-PEP is another enzyme that degrades gluten. AN-PEP is believed to work best when taken while gluten is still in the stomach. A 2013 study showed AN-PEP to be safe, but failed to show that the enzyme had any effect, so further study is under way. That study appeared in the World Journal of Gastroenterology. In a 2018 study, AN-PEP extensively degraded gluten concentrations of up to 80,000 mg/kg in rye flour, rye sourdough, and sourdough starter under specific temperatures and pH values, while leaving the microorganisms in the sourdough starter fully intact.  

ActoBiotics—Created by ActoGenX uses Lactococcus lactis as an expression system to locally secrete bio-therapeutics such as cytokines, antibodies, hormones, etc. Early pre-clinical work with a genetically altered L. lactis secreting a peptide derived from gliadin demonstrated an in vivo suppression of gluten sensitization. Specifically, Huigbregtse et al. engineered L. lactis to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and studied the induction of Ag-specific tolerance in NOD ABo DQ8 transgenic mice [34]. Although apparently not part of the ActoGenX development program, recent work by Galipeau et al. also deserves mention in this context. The group treated gluten-sensitive mice with elafin, a serine protease inhibitor, delivered by the L. lactis vector, and found normalization of inflammation, improved permeability, and maintained ZO-1 expression. There is speculation that this is due to reduced deamidation of gliadin peptide.
 
AVX176—Created by Avaxia Biologics, is an investigational oral antibody drug patented to provide "Antibody Therapy for Treatment of Diseases Associated with Gluten Intolerance." The patent, which expires on May 27 2029. AVX176 provides broad coverage for treating celiac disease using orally administered antibodies produced by Avaxia's proprietary platform technology.
 
BL-7010—by BioLineRx, is a novel co-polymer for the treatment of celiac disease, which significantly reduces the immune response triggered by gluten. This drug has been shown in mice to reduce the immune system response that leads to intestinal damage and villous atrophy in celiac disease. BL-7010 actually binds to the gluten protein, reducing the protein's toxicity.The drug, with the gluten molecule attached, then passes harmlessly through the digestive system to be expelled as stool. BL-7010 has undergone safety testing in humans and was found to be well tolerated. According to BioLineRx, testing will begin in mid-2015 to see if the drug works as expected to diminish gluten's effects on the body. However, BL-7010 is designed to protect only against gluten cross-contamination; it won't allow people with celiac disease to eat large amounts of gluten.
 
CCR9—by Chemocentryx, is a drug called vercirnon, which is also known as Traficet-EN, or CCX282B), and was originally intended for patients with moderate-to-severe Crohn's disease. CCR9 has completed one Phase 2 trial in 67 patients with celiac disease. However, despite the completion of the trial several years ago, no results relating to celiac disease have been made public or published.
 
Egg Yolk Enzyme—Little is known about efforts to develop a celiac treatment that uses egg yolk to coat gluten and allow it to pass through the body undetected, thus preventing an adverse gluten reaction in sensitive individuals. Like most other drugs being developed, this treatment would work to prevent reactions to small amounts of gluten, rather than as a cure for celiac disease. Recent news shows that the egg yolk enzyme is safe for humans.

GliadinX (Aspergillus niger)—GliadinX is a dietary supplement with the highest concentration of AN-PEP, Prolyl Endopeptidase (Aspergillus Niger), the most effective enzyme proven to break down gluten in the stomach. This high potency enzyme formulation is specifically designed to break down gliadin. GliadinX does not prevent or cure celiac disease. However, clinical research has shown that it effectively breaks down gliadin into small, harmless fragments before it can reach the small intestine.
 
INN-202 (Larazotide Acetate)—Created by Alba Therapeutics and later acquired by Innovate Pharmaceutical, and renamed INN-202, larazotide acetate works by blocking a protein that carries pieces of gluten across the gut. Results of a phase 2 trial of larazotide acetate appear in the February 2015 edition of Gastroenterology. While INN-202 may greatly reduce the symptoms of gluten exposure in celiacs, it is unlikely that a permit consumption of unlimited amounts of gluten. The U.S. Food and Drug Administration (FDA) has fast-tracked the drug. Phase III clinical trials are currently underway. Results of the trial should be available soon.

Nexvax2—Created by ImmusanT, Nexvax2 is touted as a vaccine, but works much like an allergy shot. Nexvax2 combines three proprietary peptides that elicit an immune response in celiac disease patients who carry the immune recognition gene HLA-DQ2. Similar to allergy shots, the vaccine is designed to reprogram gluten-specific T cells triggered by the patient's immune response to the protein. Nexvax2 exposes the immune system to gluten in a controlled way so that immune cells that are usually activated get turned off or eliminated. So far, Nexvax2 has completed a phase 1 trial showing it to be safe, and the company has begun Phase II trials on humans in Australia and New Zealand.

Saliva Rothia—Researchers at the Henry M. Golden School of Dental Medicine were looking at how proteins in general break down in saliva when they discovered an enzyme in a bacterium called Rothia that pulverized gluten as if it were Pac Man. That happy accident has led to a new stream of study that has moved beyond petri dishes to study the effect of the so-called ‘subtilisin,’ or protein-ingesting enzyme on the tiny digestive systems of mice. In so doing, they have found another bacterium, B. subtilis, which produces an enzyme similar to the Rothia one and is already safely consumed in Japan in a fermented soybean dish called ‘natto.’

A 2018 Boston University report concludes that “oral Rothia bacteria to gliadin digestion and pharmaceutical modification can protect Sub-A from auto-digestion as well as from acidic insults, thus rendering the usefulness of coated subtilisins as a digestive aid for gluten degradation.”
 
ZED1227—Created by Dr. Falk Pharma and Zedira recently announced the start of phase II clinical trials for the drug candidate ZED1227, a direct acting inhibitor of tissue transglutaminase. ZED1227 molecules work by targeting the dysregulated transglutaminase within the small intestine in order to suppress the immune response to gluten which drives the disease process.

Sources:

• An Update on Every Celiac Disease Drug Currently in Development
• Inside The Race for a Celiac Disease Treatment
• Promising Celiac Disease Drugs in the Pipeline
• Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials