ARCHIVED - A New Use for an Old Drug

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February 07, 2007— Ottawa, Ontario

People with heart block (a type of disorder where the heart beats too slowly) or asthma use it. It is known under more than 100 brand names, including Aleudrin and Isuprel. Now, it may be used as a simple eye drop to help prevent cataract, the leading cause of blindness throughout the world. It's called isoproterenol, and NRC scientists have found a new use for this old drug – a new use with North American and Western European market potential of more than $8 billion in annual sales.

A scene as it might be viewed by a person with cataract. Credit: National Eye Institute, National Institutes of Health.
A scene as it might be viewed by a person with cataract. Credit: National Eye Institute, National Institutes of Health.

They have found that isoproterenol can inhibit glycation, a series of reactions where sugars damage proteins, nucleic acids and lipids, and is one of the major causes of cataract. The damage accumulates with aging, but is also hastened by diabetes and smoking, both high risk factors for cataract.

People with diabetes are 60% more likely to develop cataracts and tend to develop them at a younger age. It is estimated that delaying cataract formation by ten years could reduce the prevalence of cataracts by 45%. This would have a huge impact on the quality of life of people with diabetes and substantially lower costs to our health-care system. Currently in Canada, cataract surgery is one of five areas where federal and provincial/territorial governments are working together to shorten wait times. Preventing the development of cataracts could cut those wait times drastically, even potentially eliminating them altogether.

Normal vision. Credit: National Eye Institute, National Institutes of Health.
Normal vision. Credit: National Eye Institute, National Institutes of Health.

Dr. Yasuo Konishi and his colleagues from the NRC Biotechnology Research Institute (NRC-BRI) screened more than 2,000 existing drugs, looking for compounds that could inhibit glycation. They discovered epinephrines such as isoproterenol are potent anti-glycation agents.

Discovering a new molecule, says Dr. Konishi, is a long and costly process. But, he says, "Finding new applications for existing drugs is both low risk and high reward." That's why some two-thirds of drugs approved by the American Food and Drug Administration between 1989 and 2000 were for repositioned drugs – 674 drugs, compared to 361 drugs approved as new molecular entities.

The big advantage? Faster development times of 3-12 years, compared to 10-17 years for drug development "from scratch". Partly this is because of the lower risk of repositioned drugs, since their safety profiles and how they act in the body – how they are absorbed, distributed and eliminated – are well known. This also means that companies working on repositioning drugs have less trouble raising venture capital.

So far, Dr. Konishi and his team have tested a prodrug (a drug which is converted into its active form once in the body) form of isoproterenol called D-isoproterenol dipivalate, which has demonstrated significant delays in the development of cataract in rats. The team is now looking eagerly to the next stage, clinical trials in humans.

NRC-BRI Business Development Officer Daniel Desmarteaux is equally excited about the potential for licensing this new development to a company and continuing the process toward its eventual use in humans.

Eye diagram. Credit: National Eye Institute, National Institutes of Health.
Eye diagram. Credit: National Eye Institute, National Institutes of Health.

In 2005, Dr. Konishi won first prize in the NRC Business Case Challenge for his presentation of the commercial potential of isoproterenol for preventing cataract. Now, the business consultant who helped him develop his business case, Mark Adam, has started a new company, called AgaPharm, to hasten its commercialization. "It's a very young company, still at the start-up phase. But we have a committed person who wants to develop the product," says Mr. Desmarteaux. "We strongly believe that our eye drop will replace surgery as the treatment of choice for diabetic cataracts," says Mr. Adam, who says there are currently 5.5 million people in the United States suffering from diabetic cataracts and an additional 8 million in Western Europe.

AgaPharm has been actively presenting the product in several business conferences and was recently selected as a finalist in Canada's Top 10 Life Sciences Companies Competition. It is currently negotiating funding to complete pre-clinical trial and launch clinical trials.

Dr. Konishi believes that these trials can move quickly, proceeding through the early stages within three-to-four years, with another four-to-six years for the larger, phase III trials – which means that an effective way to prevent the leading cause of blindness in adults could be less than a generation away.

A short primer on cataracts

A cataract is a clouding of the lens, the part of the eye responsible for focusing light and producing clear sharp images. The lens is mostly made of water and protein. Sometimes, some of the protein can clump together and cloud a small area of the lens. This reduces the sharpness of the image that reaches the retina. Over time, the clumps of protein can grow larger, clouding more of the lens and making it harder to see.

Cataracts are primarily related to age, usually affecting vision after age 60. But diseases such as diabetes, lifestyle factors such as smoking and prolonged exposure to sunlight can also lead to cataracts.

There is no prescription drug available to prevent or delay the onset of cataract and the only way of treating them is by surgically removing the lens and replacing it with a clear implant once the cataract interferes sufficiently with vision.

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