Born Again
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Mauricio Alejo
A key development in the movement toward systematic drug repositioning happened during the 1990s, when several firms—including MicroSource Discovery Systems and Prestwick Chemical—began selling libraries of pharmaceutical products. The market for these libraries included drug developers who might use an existing medication as a starting point and then alter its molecular structure to produce a new drug designed to treat a different condition. Or a chemist who had developed a bioassay might use a sample of a drug with known effects to test whether the assay worked. But today many laboratories that purchase libraries from MicroSource and Prestwick are interested in drug repurposing.
The 2,000 or so samples in these libraries are packaged in vessels called microtiter plates, which are dotted with a grid of depressions, or wells, that contain a small amount of a drug prepared in a solvent. Microtiter plates are designed for high-throughput screening, a technology that combines robotics, data processing and other advanced technologies that can rapidly test drug compounds against bioassays. It has become an essential tool in identifying new drug candidates—and for screening existing drugs for new uses.
By early 2001, Heemskerk at NINDS had learned that some academic researchers were compiling drug libraries to screen for new uses. A colleague reminded Heemskerk that clinicians often discovered alternative applications by chance, so it seemed natural to push the serendipity. NINDS worked with MicroSource to develop its own library of 1,040 marketed drugs, focusing on medications for conditions affecting the central nervous system. With funding from several disease associations, the institute gave copies of the library to 26 investigators who had developed assays for such disorders as amyotrophic lateral sclerosis and Huntington’s disease.
The project yielded a number of surprising hits. One of the most promising assays revealed that certain antibiotics may be useful in treating neurodegenerative conditions. Follow-up research has shown that ceftriaxone, a cephalosporin commonly used to treat meningitis, slows the loss of neurons and muscle strength in mice bred to have ALS. Merit E. Cudkowicz, a neurologist at the MassGeneral Institute for Neurodegenerative Disease, suspects that ceftriaxone may work by lowering levels of the neurotransmitter glutamate, which can be toxic to neurons. Cudkowicz is overseeing Phases I through III of a clinical trial of the drug that will include as many as 600 ALS patients at 60 sites in the United States and Canada.
Meanwhile, neurosurgeon Robert M. Friedlander and his colleagues at Boston’s Brigham and Women’s Hospital are studying 16 drugs also identified by the NINDS screen. Their goal is to find a compound that can protect mitochondria, the organelles that generate energy in neurons and all other cells. Such a drug could block a pathway that destroys neurons not only in ALS and Huntington’s disease but also in stroke and other neurological conditions. Friedlander’s team recently found that methazolamide, a drug used for treating glaucoma, protected neurons against stroke-induced damage in mice—a discovery that would have been difficult to imagine without a screening effort.
Some pharmaceutical companies have taken an interest in drug repositioning as a strategy to help them recoup drug development costs. In a few cases, they’ve found new applications for drugs currently on the market. Evista (raloxifene), first approved for osteoporosis, was later approved for breast cancer prevention. And Gleevec (imatinib), initially developed for chronic myeloid leukemia, was subsequently approved for treating gastrointestinal stromal tumors.
So far, however, pharmaceutical companies have shown little enthusiasm for mining their inventories of compounds. “It takes a lot of digging to find out what happened to compounds that were discontinued some years ago,” says Kate Marusina, manager of research facilitation and industry alliance at the University of California, Davis.
Marusina directs the Clinical and Translational Sciences Awards Pharmaceutical Assets Portal, a pilot project she hopes will serve as a matchmaker between pharmaceutical companies with compounds that could have hidden potential and university scientists willing to study those molecules. “Drugs that are shelved but were once in use represent a tremendous asset,” says Marusina. “They’re the low-hanging fruit.”
Pfizer now wants to reposition compounds at every stage of its product pipeline. In 2007 the company established an Indications Discovery Unit, which has a mandate to look for new ways to use every drug Pfizer has produced—more than 1,000 in all. Don Frail, chief scientific officer of IDU, says seven candidates so far have a strong chance of reaching human trials.
