The odd couple

FRAMINGHAM (09/24/2003) - While almost everyone in the drug industry is looking for ways to speed new drugs to market, CombinatoRx Inc. has taken a particularly pragmatic approach: Rather than looking for new drugs, it is searching for novel combinations of existing drugs with synergistic effects.

"Doctors try drugs together all the time," says Alex Borisy, CombinatoRx's CEO and co-founder. But he estimates that only 1 percent or so of all possible combinations have been tried. The CombinatoRx solution? Develop a platform that allows systematic testing of drug pairs.

The three-year-old company, based in Boston, has already put three drug combinations into clinical trials and plans to push forward two more within the next couple of years. Because all of these compounds have already been tested for safety in humans, and many are actually approved somewhere in the world, this approach should cut development time. Some of the drugs' patents have expired, while others are still owned by someone else. "Where we have to, we do a partnership," Borisy says.

Getting started wasn't easy, however. For one thing, they had to track down and assemble the compound collection. "It was a mammoth undertaking," says co-founder Brent Stockwell, a Whitehead Institute Center for Genome Research fellow. They also faced the problem of how to perform the studies. "No one has ever built a platform to look at combination effects," Borisy says. "We had to invent it."

CombinatoRx starts, as most high-throughput screening labs do, by selecting cell lines that are good models for particular diseases. A specific assay might, for example, use a type of cell that produces molecules related to inflammation.

But here's the twist: Rather than just throwing many individual drugs against the screen to see which ones knock out the pro-inflammatory molecules, CombinatoRx uses a 6 x 6 matrix that lets its researchers evaluate 36 different dosing configurations for many pairs of compounds. "It's completely different from all other high-throughput screening," Borisy says.

All the tools, including the robotics and informatics, had to be specially adjusted to work on this system. The data-management tools were a particular problem. "We tried using existing packages, but we had to transition away from it," Borisy says. "Ultimately, we had to build it ourselves."

The company has a set of 2,000 existing compounds, providing a pool of about 2 million pairwise combinations for investigation. If it chooses the right assays, the "platform and the power of empiricism" point them to synergistic pairs, Borisy says. Animal studies and other tools are also used to validate these effects. CombinatoRx's most advanced combinations are for cancer and rheumatoid arthritis, and the company also has projects involving respiratory, metabolic, and infectious diseases.

Combo Special

Several bizarre combinations are coming out of the company's work. A recent paper published in Proceedings of the National Academy of Sciences describes three candidate tandems that emerged from screening 120,000 different drug combinations (Borisy, A.A. et al. "Systematic discovery of multicomponent therapeutics." PNAS 100, 7977-7982; 2003).

For example, one anticancer coupling includes an antipsychotic (chlorpromazine) and an antiparasitic (pentamidine). "When he saw it, a world-leading oncologist said, 'Who the heck would have put these together?'" Borisy recalls.

Another combination, which paired an unusually low dose of a steroid with an antiplatelet, seems to suppress TNF-alpha (tumor necrosis factor alpha), an important immune system molecule. In the third example, a pain reliever enhanced the activity of an antifungal drug. Together, these two drugs appear to combat a drug-resistant version of the common fungal infection Candida albicans.

The company has already attracted a healthy $60 million in funding, thanks in part to a highly respected group of Harvard and MIT chemists among the founders and executives, including Michael Foley, vice president of chemical technologies at Infinity Pharmaceuticals Inc. Stockwell and Curtis Keith, another founder, are former students of Harvard Chemistry Chair Stuart Schreiber. Stockwell is now making his own mark in the field of chemical genomics by using compounds to probe biological function. Keith, renowned for his work in multicomponent (or multiple-agent) chemical genetics, is CombinatoRx's vice president of research.

Their work using individual drugs as probes led the scientists to think combinations might be even more useful. "These are all highly complex redundant networks," Stockwell says. "Often, you need to knock out not one but multiple proteins."

Borisy also once worked in Schreiber's lab. Now he's making a name for himself in the business world. The debutant CEO was recently named Ernst & Young's Biopharmaceutical New England Entrepreneur of the Year.

Like many other researchers, scientists at CombinatoRx are also interested in understanding drug mechanisms. But they don't let that get in the way of success. "We like to draw pretty pictures about mechanisms as much as anyone," Borisy says. "But let's face it -- there is so much that we don't know about how these drugs work."

The approach does reveal such information, and if CombinatoRx uncovers new disease mechanisms, it can patent the targets and find partners to develop them. However, Borisy has little interest in traditional drug discovery and development right now. "We are busy enough unmasking the hidden potential of drugs that are already available," he says.

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