Science Editor

In addition to the familiar stories of drugs that were developed in one indication and found success in another, such as sildenafil and thalidomide, there are regular reports of such repurposing on a smaller scale. Just last week, new data showed HIV drug Viracept (nelfinavir, Pfizer Inc.) chews up some solid tumors as well.

Right now, most repurposing arises from serendipitous discoveries. But the National Institutes of Health (NIH) is setting up a more formal process to find new indications for existing drugs, and the initiative may present both opportunities and challenges to patent holders.

An approved drug in one indication, the reasoning goes, is much more likely than a random chemical compound to have additional utility in another. And that likelihood more than makes up for the fact that someone else might already have rights to the drug. In fact, neither academia nor industry researchers necessarily view existing intellectual property as an insurmountable hurdle to drug repurposing.

New NIH Efforts

Researchers from the NIH Chemical Genomics Center (NCGC) reported in the April 28, 2011 issue of Science Translational Medicine that they have created a database, the NCGC Pharmaceutical Collection, which aims to be a "definitive collection" of all approved drugs.

For now, the new database is not yet comprehensive. With a size of slightly more than 3,300 compounds, it is not, in fact, all that big. Its importance lies in the fact that the compounds in it have been prescreened – some as far as the ultimate gold seal of FDA approval in another indication – for their potential repurposing suitability.

Christopher Austin, director of the NIH Chemical Genomics Center, said his team ultimately wants to get the number of drugs in the database up to around 7,500. That larger database, he hopes, will include all registered drugs. Some of those are in clinical trials for a new indication, "but many of them are probably not being worked on by anyone," he said.

Austin told BioWorld Insight the NCGC database will have utility "in two broad areas."

First, the database will ultimately allow "a systematic understanding of the biological effects and pathway effects of this large group of well-understood compounds." Such increased understanding, he said, should lead to "a better ability to create new molecules that will do what we want them to, and not do what we don't want them to."

After all, whether an effect is therapeutic or adverse is of no consequence to the cell it is happening in: "For a biological system, it's just an effect. We put the judgment on it saying it's good or bad," Austin said.

Second, the NCGC database will be used for straightforward repurposing, particularly for rare and neglected diseases. And Austin is not particularly worried about the fact that 20 percent of the database's compounds are still on patent.

IP: Not a Deal-Breaker . . .

Off-patent compounds are the more obvious places to look for repurposing utility, especially in rare and neglected diseases where cost issues force sometimes brutal compromises between what is needed and what is affordable.

But interestingly, patent protection is not a deal-breaker. Austin said if an assay shows that an on-patent drug might have therapeutic possibilities in a new area, the model would be to go to the company that owns the molecule and propose a collaboration.

Some companies will support work on such new indications, while some will permit such work but not support it with money or resources.

It does happen, Austin said, "that a company will say 'we really don't want you working in that space,'" out of concern for the larger franchise. But such a reaction, he added, is "rare."

"The vast majority of our collaborations have been with academic researchers or rare disease foundations," Austin said, although that may be about to change: "Just in the time since the [Science Translational Medicine] paper has been published, there has been a tremendous expression of interest from biotechnology and pharma companies."

. . . For Academia or Industry

In the private space, Charlottesville, Va.-based Biovista Inc. has built a company around repositioning drugs – though CEO Aris Persidis is not a big fan of the term "repositioning."

"We don't think of it as repositioning," he told BioWorld Insight. "We think of it as positioning. Drugs are like kitty cats: they have nine lives. And at any given time, we are only exploring one or two of them."

Biovista has a positioning program that uses a bioinformatics approach to "develop all reasonable opportunities" for a drug, Persidis said, by tracking "without bias," all biological effects of a compound. The company has collaborations with the FDA as well as pharma companies including Pfizer Inc. and Novartis AG.

But Biovista is also developing its own in-house pipeline of existing drugs for new indications, and the company puts less emphasis on the existing drugs' IP than one might expect.

Of the pipeline, "some are generics, some will soon become generics, and some are early on" in their patent protection, Persidis said.

The important thing, he said, is to pick an indication where dosing and formulation will differ from the original use in significant ways – that is, dosing regimens and routes need to be different enough that it's not just a matter of cutting the generic competitor pills in half. Such "trivial" repurposing, Persidis said, is bound to fail. But if the differences between old and new use are sufficiently large, "There is nothing that makes repurposed drugs uniquely vulnerable to off-label use."

As for drugs still under patent protection, he said, it is "absolutely" possible to get a different method of use patent on a currently marketed drug – though the new method can then only be commercialized once the composition of matter IP has expired.

In fact, this is exactly the approach start-up BioAssets Development Corp. took when it acquired a method of use patent for Amgen Inc.'s Enbrel (etanercept) in sciatica. BioAssets, whose business plan had been to expand the use of already-approved biololgics, was ultimately acquired by Cephalon Inc. for those patents, in a deal that was worth $30 million up front plus additional milestone payments.

Persidis said the story of BioAssets and Amgen shows that repurposing "can open up two sets of doors" for business development. It opens up possibilities for repurposing startups – but also for patent-holders looking to expand their franchises. It also means patent-holders "need to be even more diligent now" about understanding all of their drugs' potential applications, he said.

"If they are," Persidis said – and especially if they are willing to look past their traditional therapeutic areas – "it opens up the same possibility for the large developer as for the small virtual operation."

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