Verapamil is a drug with a long history of use in cardiovascular conditions. First approved by the US Food and Drug Administration in 1981, it has been widely used in the treatment of problems such as angina, hypertension, and arrhythmia.
The drug's cardiovascular activity is mediated by blockade of calcium channels, which results in effects on cardiac function as well as on vasodilation. However, it can also exert gastrointestinal effects, which, in cardiovascular patients, are considered an unwanted side effect. Dublin-based AGI Therapeutics, which specializes in repurposing old drugs for gastrointestinal indications, has found a way of separating these two activities and is focusing on one of them as a novel drug mechanism.
Verapamil exists as a racemic mixture of two stereoisomers, which have differing activity profiles. AGI's intellectual property is based on an unexpected finding: The R-isomer, which is biologically less active, displays greater selectivity for intestinal tissue than it does for cardiovascular tissue, whereas the S-isomer is equally active against both.
This concept is captured in AGI's lead drug, Rezular, which contains arverapamil, a single enantiomer moiety of verapamil. Unlike the currently available commercial forms of racemic verapamil, Rezular shows a dominant activity in the gastrointestinal tract without the traditional cardiovascular actions of the racemic drug. AGI has shown that Rezular is a triple-action intestinal regulator, a first-in-class mechanism, and it is developing the drug as a new mode of action for treating diarrhea-predominant irritable bowel syndrome (IBS). It is due to report data from a Phase III trial of the drug later this year.
"That will be the key for them. If that goes well, the prospect of a significant commercialization agreement with a pharmaceutical partner would be very much on the cards," says Jack Gorman, analyst at Davy Stockbrokers in Dublin.
AGI was set up in 2003 by a team of former Elan executives led by CEO John Devane, and it raised €42.5 million ($65 million US) in a dual IPO on the Irish Stock Exchange in Dublin and on London's Alternative Investment Market in February 2006. It is following a low-risk drug development strategy, based on compounds with known safety profiles. In addition to the IBS program, it has four other clinical development programs: gastroesophageal reflux disease, gastroparesis, ulcerative colitis, and chemotherapy-induced diarrhea.
"Our products address real areas of unmet medical need," says CEO John Devane. "While up to 10 to 20% of the population can suffer from IBS, there are currently few safe and effective therapeutic options available to these patients."
"The efficacy and safety of Rezular in IBS patients has already been established in our Phase II trial," says Devane. Yet that compound, and the rest of AGI's pipeline, are as yet underappreciated in the market, says Gorman. The company, which reported €30.9 million ($47.8 million US) in cash at the end of 2007, is valued at around €85 million ($131.4 million US) at present. "At current levels I would certainly believe there's a disconnect between what the market is valuing AGI at and the potential we would see in the pipeline."