THE VERDICT WAS IN: UK-92480 had failed. Scientists at a Pfizer laboratory in Sandwich, England, had thought the compound showed promise for treating angina. But the drug never made it out of preliminary clinical trials. A single dose had only a fleeting effect on the circulation of the volunteers who took it, and multiple daily doses caused muscle aches. It appeared that UK-92480, as with so many compounds tested by the pharmaceutical industry each year, would be shelved.

But a number of men taking UK-92480 reported an unexpected side effect: improved erections. Pfizer scientists initially dismissed that result, then decided to test the compound in men with erectile dysfunction. The rest is pharmaceutical history. In 1998, the drug, renamed Viagra (sildenafil citrate), became the first oral impotence medication approved by the U.S. Food and Drug Administration.

Because of Viagra, a growing number of scientists and physicians have become intrigued by the potential of “drug repositioning”—finding new ways to use established compounds that have been tested and found safe in clinical trials. “In a sense, drug repositioning has a long history,” says David J. Sullivan Jr., an associate professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health. “But now we’re trying to take a more systematic approach rather than just relying on chance.” Sullivan is co-author, with Curtis R. Chong, an intern at Massachusetts General Hospital, of “New Uses for Old Drugs,” a widely ?cited 2007 commentary in Nature that makes the case for screening large numbers of both established and experimental human clinical compounds to detect unrecognized benefits.

The long list of drugs that have undergone a chance change of identity includes the notorious sedative thalidomide, which was pulled from the market for causing birth defects and has morphed into a treatment for leprosy complications and multiple myeloma. Iproniazid, the first modern antidepressant pill, was initially tested as a tuberculosis drug. And then there’s aspirin: Originally created to treat pain, it’s now taken by millions to reduce the risk of heart attack and stroke. All these new uses came about because physicians noticed that patients who took the drugs responded in unforeseen, favorable ways. But intentional drug repositioning is more active: a methodical hunt for any stealth benefits a known drug may offer.

“A lot of drugs have off-target effects,” says Jill Heemskerk, acting director of translational research at the National Institute of Neurological Disorders and Stroke, who oversaw an early, large-scale initiative to screen existing medicines. Those effects may be problems in terms of the medication’s intended use. A drug that hits the wrong targets may cause headaches, nausea or worse. But, Heemskerk says, “there’s also dense biological activity in drugs that screening uncovers.”

Drug repositioning—also known as repurposing or reprofiling—seeks to put that activity to work in therapeutic ways, which is something doctors do every day in clinical practice when they prescribe medications off-label—that is, for uses other than those approved by the FDA. Examples include albuterol, a bronchodilator that’s approved for treating asthma but is sometimes prescribed for patients with chronic obstructive pulmonary disease, and the anticonvulsant gabapentin, which is often prescribed for pain. Widely accepted in medical practice, off-label prescribing is not regulated by the FDA.

But the kind of repositioning gaining momentum is more systematic and may require a nod from the FDA for compounds that haven’t made it through the approval process. Even so, it is often a much faster, cheaper alternative to start-from-scratch development of a drug. “Interest in drug repositioning is growing because of the high failure rates and costs of bringing new drugs to market,” says Edward Tobinick, an assistant clinical professor of medicine at UCLA’s David Geffen School of Medicine. Tobinick is studying the effects of the arthritis drug Enbrel (etanercept) in patients with Alzheimer’s disease and other conditions.

Recycling existing medications seems like a concept tailor-made for today’s challenging economic climate, and focused efforts to find multiskilled drugs have begun to produce some unlikely linkages. There are antibiotics that may one day be used to treat neurological diseases and autoimmune disorders, heart and antifungal medications that show promise as cancer fighters, and failed ulcer drugs that could prove useful in treating type 2 diabetes. Yet while efforts in universities, clinical practices and the pharmaceutical industry are growing, several obstacles remain before drug repositioning can become a steady, mainstream source of new medications.

TO ENSURE THAT PATIENTS RECEIVE TREATMENTS THAT do the most good and the least harm, the traditional journey from laboratory to pharmacy is long and laborious. Drug developers begin by studying human or animal tissue in hopes of identifying a target—a molecule or a biological process that appears to be involved in a disease. Once a target is identified, scientists create a bioassay, or a model of the target. A bioassay can be as simple as a petri dish full of cancer cells, for instance, or enzymes that raise blood pressure. The drug developer uses the bioassay to search for substances that may have a beneficial effect on the disease. Usually a pharmaceutical company will test the bioassay against a “library” of hundreds of thousands of compounds that possess interesting biological qualities, such as low molecular weight, good solubility and atomic characteristics that make them likely to be easily metabolized.

Large-scale screening typically identifies compounds that show “druglike” activity against an assay. They kill the cancer cells, for example, or block the activity of enzymes. Chemists choose the most promising “hits” and refine the compounds by adding or subtracting atomic groups to improve their ability to bind to a target molecule while avoiding attachment to other molecules, which could cause toxicity or other problems.

Next, a compound is given to animals to collect data about dosing, pharmacodynamics (what the compound does in the body) and pharmacokinetics (what the body does to the drug). When a pharmaceutical company feels it has adequate information about a compound’s toxicity and how it is metabolized, a drug may be ready for testing in humans.

In Phase I toxicology studies, a drug developer gives increasingly large doses of the experimental compound to healthy volunteers to determine whether it’s safe. If all goes well, Phase II clinical trials measure the compound’s effects in patients who have the targeted disease or disorder. Phase III studies generate more data about the compound’s effectiveness and safety in larger groups of patients. Then the developer can seek FDA approval to sell the new drug.

Doing all of this takes a long time (often more than a decade) and is enormously expensive (about $1 billion), and very few drugs ever make it all the way through the process. What’s more, the number of treatments introduced each year is shrinking. In 1999 regulatory agencies around the world approved 46 drugs, according to Drug News and Perspectives, an industry newsletter. Since then, approvals have fallen to lows of 26 in 2004 and 31 last year. For every five drugs tested in humans, just one reaches the market. (Some estimates cite worse odds: 10 to 1.) Still, the pharmaceutical industry spent nearly $60 billion on research and development in 2007, a twenty- to thirtyfold increase over a generation ago.

Repositioning bypasses much of this process by starting with compounds that have passed Phase I studies. That includes approved drugs and compounds that were set aside after failing efficacy trials. Eliminating the need for preclinical development and human toxicology trials can shave about 40% off the cost of bringing a drug to market, according to one estimate.


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.

FINDING A NEW USE FOR A DRUG may be exciting, but that’s just the beginning if the compound is ever to be approved. “There are many hurdles in the way of drug repositioning,” says Frances Toneguzzo, director of the MGH’s corporate-sponsored research and licensing office. For a pharmaceutical company that owns the compound patent for the drug—that is, the intellectual property for the drug’s chemical composition—it’s a matter of seeking approval for a new label indication from the FDA, which probably would ask for evidence from at least one or two clinical trials.

The scenario is less straightforward for an academic researcher who discovers a novel drug application. Suppose you’re a scientist who conducts a small trial on humans and develops a theory about how to use a drug. You can publish a journal paper describing your findings, but that doesn’t guarantee that physicians will notice. And large trials will be needed to validate your idea. The best strategy may be to obtain a “use” patent for the new indication. If you own the intellectual property, you could license it to a manufacturer (most likely the one that first produced the drug) or seek funding for human testing. Yet some manufacturers aren’t interested in pursuing a new use. “Paying for trials for a new application is still a risk,” Marusina says.

If an academic scientist discovers a new way to use a drug for which the patent has expired, there may be an even greater chance that the world will never hear about it. Pharmaceutical companies have little incentive to spend on a drug they can’t sell exclusively for a significant period. (In the United States, a drug patent generally lasts 20 years, but because patents are usually obtained well before drugs are approved, the window for exclusive use may be quite a bit smaller.)

Despite such obstacles, screening drug libraries and testing failed compounds may increasingly offer an appealing end run around the lengthy, expensive process of turning molecules into medicine. But there’s still room for old-fashioned dumb luck. For a decade, MGH neurologist David Borsook was unable to find an effective treatment for a patient with pain in his hands and feet so severe that the slightest touch felt like a hot coal. Borsook became close to the patient, who had the added misfortune of developing colon cancer that metastasized to his liver. In 1997 the man agreed to undergo experimental treatment with a drug called KRN5500. Borsook accompanied him as he received his first treatment. Shortly after the infusion began, Borsook leaned over to gently touch his friend’s hand. But instead of flinching, the man said, “Do that again.” Borsook grabbed his hand and rubbed it. The pain was gone.

Although he succumbed to cancer several months later, the patient’s neuropathic pain never returned. Borsook took out a patent and has attempted to discover whether KRN5500 could be an effective pain therapy. Earlier this year, a small Phase II clinical trial showed that the drug decreased pain levels by 23% in patients with chemotherapy-induced neuropathy. Borsook sees this experience as a reminder to keep searching for serendipity in daily practice: “The keen mind can completely transform a disease condition with a single observation.”