Putting a new spin on old molecules

With the FDA focused more and more on safety, particularly in the wake of the Vioxx debacle, the pace of new drug approvals has been a bit sluggish. Add to that an increasingly challenging economy and plenty of drugs coming off patent, and you don't get the rosiest picture for pharmaceutical development.

So, in the vein of "everything old is new again," companies in the past few years have begun to explore, with increasing frequency, new uses for already approved drugs or for drugs that failed in clinical trials for reasons other than safety.

This activity, alternately called drug repositioning, drug reprofiling or drug repurposing, offers companies a chance to cut down on research expenses, increase confidence about compounds' safety and bolster their pipelines compared to doing discovery and development from ground zero.

"Drug repositioning isn't new, but it has definitely been picking up because of the tremendous dearth of productivity in the industry," says Dr. Andrew G. Reaume, president, CEO and co-founder of Melior Discovery, an Exton, Pa.-based company dedicated to uncovering new therapeutic applications for partner companies' existing drugs. "The number of new FDA approvals has continued to decline despite increases in research dollars—the 'innovation gap' that you hear people talk about in the industry. Drug repositioning is a strategy, and arguably a very cost-effective one, to help address this gap."

The business case
Th FDA approved only 19 new molecular entities last year, which was the lowest single-year total since 1983, which boasted a dismal 14 NME approvals. The second-, third- and fourth-worst years since 1983 were also this decade. Only once since the Millennium began has the FDA approved more than 30 novel molecules, and that was in 2004. Yet in the second half of the 1990s, the FDA approved more than 30 NMEs every year.

If that isn't stark enough, how about this: Over the past three full years, the FDA approved just 61 new molecular entities and novel biologics; it approved 60 in 1996 alone.

At least in 1983, as bad as that year was for new approvals, research and development costs were lower. With total R&D spending by brand-name companies being $3.2 billion in 1983 and $43 billion in 2007, according to the Pharmaceutical Research & Manufacturers of America trade association, that means the industry spent $228 million per NME approved in 1983, compared to more then $2 billion each in 2007.

So, it's little wonder that big pharma has become a bit risk-averse, even with all the billions that can be earned from just one blockbuster drug.

"People in drug discovery work very hard to find novel markers, mechanisms of action and things like that, so when a compound reaches Phase I, it's a 'woo-hoo' moment for everyone, and justifiably so," notes Dr. Kamalakar Gulukota, senior product evangelist for Westborough, Mass.-based GenomeQuest Inc., which is helping pharma companies to reposition sequences and compounds through early access to DrugBank database content. "But as we all know, most of these drugs will never go to market. It's like winning the New Hampshire primary—it doesn't mean you will be your party's candidate, much less president of the United States—except the odds are so much worse with drugs."

Robert Forrester, CFO and executive vice president of CombinatoRx Inc. in Cambridge, Mass., which looks at novel applications for drug combinations, likens drug repositioning to a race. If the traditional drug development and approval process is a 400-meter race, repurposing an approved drug is like getting a 200-meter head start.

"With new chemical entities, you just don't know what they will do in humans, but with approved drugs you already know what it does and what the side effects are, which is a huge advantage," Forrester says. "You not only know the pharmacology and toxicology, but one knows that you can actually manufacture these things. Manufacturing can be a huge hurdle to new chemical entities. With reprofiling, you can do in two or three years what might otherwise take five to 10 years, and maybe spend $10 million as opposed to something like $100 million."

Furthermore, if the repurposing effort is successful, a company can essentially extend the patent life of an existing drug, notes Lynne Gilfillan, senior director of the BioSciences Division for Menlo Park, Calif.-based SRI International, an independent, non-profit R&D organization that is now engaged in work to identify approved drugs that could also be effective against bioterrorism threats.

"Certainly, not to have to do as much work to prove safety and optimize the chemical structure is huge, because time saved means money saved," Gilfillan says. "But when you end up with a new patent, that essentially extends your market protection and broadens the audience to which you can sell the drug."

Taken all together, the advantages of drug repositioning, while they don't guarantee success, point to a burgeoning market for making old drugs do new tricks, Reaume says. "Three years ago when our company officially started up, there was only one annual drug repurposing meeting," he notes, "This year, we're attending or sponsoring four of them in just the next few months."

Technologies and strategies
One of the reasons drug repositioning hasn't taken off as a major business strategy until the past few years, despite the obvious value it brings, is because the technology is only now getting to the point where it is viable for companies to really dig into their stockpile of failed drugs to look for new applications. In the past, drug repositioning has mostly been accidental, points out Tom Barnes, senior vice president of discovery for Ore Pharmaceuticals of Gaithersburg, Md.—formerly Gene Logic Inc.—which identifies new uses for stalled or failed drug compounds provided by pharmaceutical partners and identifies new uses for drug compounds acquired from the public domain.

"People have always done it, though the one people so often point to is Viagra, which was a cardiovascular drug that didn't perform that well. But people noticed it had an interesting effect that could make it useful for erectile dysfunction," Barnes says. "What is new is the ability to do this systematically. We've reached a level of conviction that if you look at molecules systematically with current technology, you will find enough useful, hidden properties to make that effort rewarding, instead of having to find repurposing opportunities serendipitously through off-target effects or novelty around the target area."

The potential for mining is great, Ore Pharmaceuticals has noted, given that more than 2,000 compounds are sitting idle at big drug companies after failing in Phase II or Phase III trials, and the industry shelving another 150 to 200 drugs at those stages each year.

Melior Discovery approaches the repositioning challenge from a different angle, using a discovery platform that multiplexes animal disease models to uncover new indications for existing pharmaceutical compounds. By integrating multiple in vivo models, the company reports it reduces the number of personnel, test subjects and amount of compound required to conduct the screens. The result is an increase in efficiency and a reduction in the overall cost compared to approaches that run assays separately.

Pharma researchers are also getting help from GenomeQuest, which has an exclusive license to distribute DrugBank database content ahead of public distribution so that companies are better positioned to pursue repositioning efforts. GenomeQuest helps fund the database, and in return, it gets IND information exclusively for its own efforts and information on marketed drugs six months in advance of when they release on the DrugBank site.

"We aim to break down barriers between various silos of knowledge in companies, particularly between the chemistry and biology teams," Gulukota says. "If these silos had more knowledge about each other's work and their data were more coordinated, they could reach repositioning hypotheses earlier and perhaps more quickly notice when what seems like a side effect, for example, might actually be a clue to an alternate indication."

CombinatoRx, for its part, "takes reprofiling to the logical conclusion, which is to look at all approved drugs in the world as combinations—two-, three- or even four-way—to see if we can uncover synergies or novel mechanisms of action," Forrester says. "One of the advantages of this is that compared to traditional reprofiling, we get strong intellectual property because we can get full 20-year composition of matter patents."

What stands in the way
For all its value, drug repurposing is far from a slam-dunk affair. For one thing, the science of repositioning is inexact. Yes, you can spend less than you would on a from-the-ground-up approach, but you have to screen broadly to find a novel action and that means figuring out the trade-off between effort and expense.

If you're extremely thorough in your screening, Barnes notes, you might get a good hit rate, but spend a fortune; if you run just a few data points across many assays, you'll save money, but get a much lower hit rate.

Also, as Reaume notes, even though the risk profile is lessened with drug repositioning, you still might fail to have clinical efficacy in clinical trials, and you might find safety concerns along the way, particularly if you are exploring a compound that failed in trials rather than an already approved one.

Forrester adds there can be internal resistance in a company from marketing teams that are very protective of their brands and worry if anyone mucks around finding new indications for a currently marketed drug, they might uncover new side effects or otherwise blemish the brand.

Also, the scientific culture in an organization may lead to resistance, notes Gilfillan. "In a strong research culture, it might be viewed as 'more scientific' to find a biological target and then look for agents for that target, and repositioning might be viewed as something that inhibits explorations that lead to increased understanding about disease pathways."