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Feature Articles : Dec 1, 2009 (Vol. 29, No. 21)

Ireland Establishes Gastroenterology Base

Country Banks on Thematic Approach to Ensure Successful Cluster Development
  • Susan Aldridge, Ph.D.

Ireland is giving new meaning to the concept of the biotech cluster by building one that has an important therapeutic theme. Gastroenterology Ireland seeks to bring together leading academics and gastrointestinal (GI)-focused drug discovery and development, drug delivery, and medical-device companies in an initiative being fostered by Enterprise Ireland.

“The work of the Irish gastroenterology community—medical, commercial, and  academic professionals based internationally and at home—is recognized globally,” says Elaine Brennan, svp biotechnology and pharmaceuticals, Enterprise Ireland, the government agency responsible for development and promotion of the country’s business sector. “We support collaborations between industry and academia in order to develop world-class technologies, and for the future growth of the Irish indigenous life science community.”

According to Eamonn Quigley, professor of medicine at University College Cork, this initiative is more than just another biotech cluster. “In Ireland, there is a greater awareness of the commercial potential of research and the need for it to show outcomes for the public good.” 

The firms at the heart of Gastroenterology Ireland are focused mainly on GERD (gastrointestinal esophageal reflux disease), inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS) and are located in Galway, Dublin, and Cork, where they interact closely with centers of excellence in GI research such as Trinity College Dublin and the Alimentary Pharmabiotic Centre (APC) in Cork.

Galway-based Vysera Biomedical is focused on GI-related medical devices and has developed material for use in the treatment of GERD. “We wanted to introduce a softness into these devices and complement the tissue already in the GI tract by using a biomimetic approach,” explains Niall Behan, Ph.D., CTO. “No material was available with the necessary stability, so we developed our own.”

The GERD spectrum encompasses a wide range of patients, from those with sporadic reflux problems to those with chronic disease. Surgery is not always successful, and recent research has uncovered problems with proton-pump inhibitors; as a result there is potential for a device-based approach to GERD therapy.

Vysera has developed a valve that is designed to open at physiological pressures to support the faulty sphincter in GERD. “These devices look simple, but the way they function is physiological,” says Dr. Behan. Vysera’s GERD device is in preclinical development.

Crospon, also located in Galway, has developed the EndoFLIP® (endolumenal functional lumen imaging probe), a diagnostic tool for assessing the competence of the junction between the stomach and esophagus in GERD patients.

EndoFLIP measures how much the lumen opens up for a given distension, introducing the concept of distensibility as a diagnostic. “Conventionally, GI sphincters are checked with manometry, which measures pressure waves and indicates how tightly closed they are,” explains CEO John O’Dea. The EndoFLIP shows how easily the sphincter can open—and in GERD, the junction opens too easily.

GERD is a multifactorial condition, and Crospon is using the EndoFLIP to identify those patients who will benefit most from surgery. It can also be used interoperatively to titrate how tightly a gastric band should be placed. “We believe that the EndoFLIP not only helps the surgeon pick the patients who will benefit from surgery, it also makes the surgery itself easier,” adds O’Dea.

EndoFLIP is also being applied in achalasia (inability to swallow), which is usually treated by a distension balloon or cutting the muscle; the device can guide the surgery. “It provides surgeons a unique way of looking at the behavior of the esophagus as they are carrying out the surgery.”    

Drug Delivery

Sigmoid Pharma is a Dublin-based drug-delivery company tackling the issues of solubility, permeability, and stability. “Traditional drug-delivery companies tend to focus on one of these issues at a time, but in our approach, we address all three simultaneously in a single integrated technology,” comments CEO Ivan Coulter, Ph.D.

Proof-of-principle has been carried out on a hydrophobic peptide drug, and Sigmoid is now working on in-house programs in GI, transplantation, and neurodegeneration indications. The technology can also be licensed out to partners wishing to improve the formulation of marketed or pipeline drugs.

The company’s technologies include LEDDS® (liquid emulsion drug delivery system) and SmPill™ (single multiple pill), which are reportedly promising for GI conditions because most drugs are poorly water soluble and drugs are not absorbed in the colon unless they are very soluble.

“Our technique makes the drug soluble,” says Dr. Coulter. “It is a technology that allows the activity of a drug locally in the GI tract to be optimized or, by tweaking the formulation, the absorption to be maximized.”

Sigmoid’s lead product, a colon-specific, nonsystemic, poorly soluble drug for the treatment of ulcerative colitis, is scheduled to complete a Phase II study by mid-2010.

Merrion Pharmaceuticals is dedicated to creating oral versions of injectable drugs, improving patient comfort and convenience, and making the drugs more widely applicable. The technologies making this possible are GIPET® (gastrointestinal permeation enhancement technology), which improves the delivery of poorly permeable drugs, and GIRES™ (gastrointestinal retention system), which increases retention time in the stomach, allowing controlled release.

Inflammation plays a key role in IBD and ulcerative colitis (UC). Opsona, a spinoff from Trinity College Dublin, is focused on therapies that deal with inflammation by targeting the innate immune system. Toll-like receptors are the first recognition point, sensing invaders and signaling to the inflammatory cascade.

Opsona is interested in developing small molecules targeting the inflammasome. It is developing a prodrug, OPN-501, which is activated only in the anaerobic conditions of the colon and is potentially applicable to Crohn’s disease and UC.

Meanwhile, Pharmatrin, another Trinity spin-off, is developing small molecule immunomodulatory compounds for the treatment of inflammatory bowel disease. It is interested in immunomodulatory compounds and has been working on autoimmune disease models. “There is a wealth of experience in gastroenterology at Trinity College,” reports managing director Neil Frankish, Ph.D. 

Although the company’s lead compound, now being developed by medicinal chemistry, is not itself a natural product, the program began through the investigation of secondary metabolites used in Taiwanese folk medicine. The compound shows low toxicity, high bioavailability, high water solubility, and a good half life, according to Dr. Frankish.

Academic Collaborations

University College Cork is the location of the Alimentary Pharmabiotic Centre (APC), whose mission is to investigate gastrointestinal science in its broadest sense. Key interests include the link between gut health and psychiatry, the metagenomics of  gut flora, the relationship between the immune system and the gut, and mining gut flora for biomarkers and drugs.

GlaxoSmithKline, one of APC’s industrial partners, is currently pursuing a number of new targets discovered by its researchers at the center. Professor Fergus Shanahan, APC’s director, says that big pharma is beginning to show a real interest in gut flora and its impact on health in areas such as diabetes.

Work on germ-free (lacking gut flora) animals has been particularly revealing, he adds. These animals have poor immunity and are susceptible to stress. Studies have shown that healthy gut flora is essential for development of the immune system.

Studies of gut microflora were crude in the past, but now molecular approaches such as metagenomics allow for microflora fingerprinting and monitoring of how the community of gut microbes varies between individuals and throughout the lifespan.

“Childhood and old age are the critical times for establishing and maintaining  healthy gut microflora,” says Prof. Shanahan. “If you know the molecular basis for the health of the microbiome of the gut, you can do something about it.”

There are many practical outcomes from these studies. For instance, gut microbes are important in metabolism, and they also produce bioactives such as short chain fatty acids that have anticancer properties and play a role in cardiovascular health.

The APC’s second industrial partner, Alimentary Health, was founded in 1999 from research into probiotics at University College Cork. “The breadth of knowledge there gave us a great platform to build from,” explains Jennifer Roper, Ph.D., IP and clinical trials director. The company is developing therapeutic commensal gut bacteria (probiotics) for general wellness and GI therapeutics—namely for UC, Crohn’s disease, IBS, and C. difficile infection.

Alimentary Health’s flagship product Align®, a capsule containing Bifantis®, a probiotic in the form of dried live bacteria, is being marketed by Procter & Gamble for maintaining a healthy digestive system. The company is also conducting research  into pharmaceutical treatments for IBS and other inflammatory conditions.

Alimentary Health’s collaborations with APC are focused on the mechanisms and mode of action of probiotics. It is building a strain bank for GI applications, focusing on chronic inflammatory disease. It is also looking at the components of the bacteria, including thuricin, a narrow-spectrum antibacterial product that is being developed for treating C. difficile.