For the 2 million Americans suffering from rheumatoid arthritis, the best cure is also a curse. Anti-inflammatory steroids dramatically reduce the agonizing pain, but they also cause nasty side effects like diabetes and high blood pressure. Chemists at pharmaceutical and biotech companies have long sought the perfect cure - a steroid that cuts inflammation without the downsides. So far, no luck.
Enter Alexis Borisy, the 32-year-old CEO of Boston biotech CombinatoRx, with a novel suggestion: Why not deploy two chemicals to attack the disease from different directions? Using a new drug development process known as combination high-throughput screening, CombinatoRx mixes millions of pairs of existing drugs in search of unexpected synergies - the rare case where one plus one equals three. The process has revealed several promising leads in the quest to treat rheumatoid arthritis. One, currently in human trials, combines a common steroid with an "enhancer molecule," targeting the inflammation without introducing the toxicity.
And arthritis is just the beginning. CombinatoRx has several cocktails in preclinical trials, including remedies for asthma and psoriasis. The company's best hope, a combination of two unlikely ingredients to treat certain types of cancer, is even further down the pipeline, in Phase I and II human trials. "Who would have ever put together an antibiotic and a sedative to create an anticancer drug?" Borisy says, reveling in the unexpectedness of it all.
One reason complex diseases like cancer have proven so resistant to medication is that they have no single cause. Instead, they occur as the result of several gene mutations accumulating over decades. This makes finding a single treatment - the Big Pharma magic bullet approach - near impossible. By enlisting a mix of drugs to mount a multi-front assault, CombinatoRx offers new hope.
The notion of combining medications isn't new. Physicians battle cancer with an array of chemotherapy treatments, and AIDS with multidrug cocktails. But those mélanges arose when doctors blended medicines already used for cancer and AIDS. With the help of a MiniTrak workstation robot, CombinatoRx mixes unrelated drugs on an unprecedented scale. The patent-pending process - developed by Borisy and three colleagues in 1998 - combines 2,000 or so well-known drugs in every which way (A with B, A with C, B with C, and so on).
Why hasn't anyone tried this before? It's only recently that the technologies have been available to do such data-intensive screening. Of course, all major pharmaceutical firms already use robotics for high-speed scouting of potential drug treatments. It's a relatively straightforward process to analyze the interactions of a single chemical and a single protein. By contrast, searching out unexpected interactions among 2,000 disparate compounds yields nearly 2 million possibilities for any one disease. Three- and four-part combinations, which Borisy hopes to try, will produce between 1 billion and 600 billion possible combinations.
Pairing up drugs is just step one of the CombinatoRx process. Looking for cocktails that attack a cell on multiple fronts means examining the reactions of an entire diseased cell - without necessarily knowing what's being affected inside. Then each concoction has to be examined at various doses and ratios. If screening drugs separately is like trying out keys in a lock, combination screening is like trying to crack a safe with random numbers.
For now, CombinatoRx is developing treatments derived only from drugs whose patents have expired. But the real value of combination high-throughput screening will come if and when CombinatoRx licenses the process, unlocking Big Pharma's massive libraries of patented medicines. Leading firms are finding diminishing returns from within their own R&D labs. They're desperately seeking new avenues for drug development. Venture capitalists have showered CombinatoRx with $90 million in funding - a bet that the company's screening process could reveal a gold mine within the stables of patented drugs.
Peter Lansbury, cofounder of Harvard Medical School's Laboratory for Drug Discovery in Neurodegeneration, says CombinatoRx's process could represent "a really important change in the way drugs are developed."
CombinatoRx isn't blowing its VC money on a lavish office for its CEO. Borisy works in modest digs, on the ground floor of Boston University's Biosquare complex; his desk is flanked by a Muppet-sized plastic Yoda doll and his 2003 Ernst & Young New England Entrepreneur of the Year trophy. The juxtaposition says a lot about Borisy, a charismatic science geek who discovered a knack for business after dropping out of Harvard's chemistry program in 1995 to consult for the drug industry.
CombinatoRx's cancer treatment emerged from that first test. Consisting of an antipsychotic and an antibiotic mixed in precise ratios, the cocktail prevents the spread of tumors by simultaneously targeting two points in the mechanism that cancer cells use to divide. In lab tests, the treatment has proven to be as effective as the best-selling chemotherapy agent paclitaxel (Taxol), showing 97 percent effectiveness in blocking the proliferation of colorectal cancer cells, with similar results for other types of cancer.
Despite the early success, Borisy has his skeptics. They ask questions like, What's to prevent doctors from simply prescribing two drugs separately, instead of the combined cocktail? Can CombinatoRx really obtain defensible patents on combinations of preexisting drugs? And wouldn't paired drugs have unpredictable toxic side effects? "If I'm at the FDA, I'm going to ask, Why wouldn't toxicity be synergistic? Why wouldn't adverse effects be synergistic?" says Harvard's Lansbury.
Borisy swats away such objections. All synergies are rare events, which means the chance of finding a successful combination that's also toxic is vanishingly small. "If you find one of those, you don't pursue it," he says. As for doctors mixing their own cocktail prescriptions for patients, Borisy notes that CombinatoRx potions contain precise ratios. Prescribing uncalibrated doses separately simply wouldn't be as effective. Finally, CombinatoRx has already demonstrated its process to be patentable. Borisy and company own a patent on the multiple-tumor drug, retaining broad rights to a "pharmaceutical composition" that's effective against cancer. CombinatoRx may have trouble enforcing such a patent, but $90 million in venture funding should buy the company at least a small team of lawyers.
No matter the ultimate fate of CombinatoRx, Borisy has revealed a new resource for the treatment of complex diseases: Big Pharma drug libraries. Major firms will surely continue trying to make expensive new treatments. But one of them is bound to start pairing up its drugs just to see what happens. After all, two shots are better than one - even when firing magic bullets.
Chris Mooney (moonecc@yahoo.com) is a freelance writer in Washington, DC.
credit Illustration by Joost Korngold/Renascent
