JOIN USTeaching old drugs new tricks
In 2010, Grant Churchill’s group at the University of Oxford, UK, was looking for ways to treat bipolar disorder without using lithium — a drug that often works well, but is plagued with side effects. So Grant asked the physician, Justyn Thomas, to screen all of the 450 compounds in the US National Institutes of Health Clinical Collection, a library of drugs that had passed safety tests in humans but, for various reasons, had never reached the market.
Justyn pipetted a few drops of each compound into Petri dishes filled with bacteria that had been genetically engineered to manufacture the human enzyme suppressed by lithium — and eventually got a hit. A compound originally intended for people who had experienced a stroke also damped production of the enzyme, suggesting that it might give patients the same benefits as lithium. After experiments in mice showed that the drug, ebselen, could get through the chemical barrier that protects the brain — something only a few compounds can do — Grant’s group did a small-scale trial and found that ebselen could be used safely in healthy volunteers.
The University of Oxford has now teamed up with a pharmaceutical company to run clinical trials of ebselen for bipolar disorder. The researchers are able to skip the phase I safety trials, because the drug had already passed them, and are going straight to phase II: testing the drug’s efficacy against bipolar disorder. Grant is well aware that ebselen could fail this trial or the larger, more stringent ones needed to test whether the drug works better than lithium.
Such stories are becoming more and more common: taking drugs that have been developed for one disorder and ‘repositioning’ them to tackle another is an increasingly important strategy for researchers in industry and academia alike. Partly, this is the result of advances in technology. These include big data analytics that can now uncover molecular similarities between diseases; computational models that can predict which compounds might take advantage of those similarities; and high-throughput screening systems that can quickly test many drugs against different cell lines.
But for the pharmaceutical industry, the real impetus is economics. Getting a drug to market currently takes 13–15 years and between $2 billion and $3 billion on an average, and the costs are going up — even though the number of drugs approved every year per dollar spent on development has remained flat or decreased for most of the past decade.
The 3,000 or so drugs that have been approved by at least one country therefore represent a vast untapped resource if they can be used against another condition — as do the thousands more that stalled in clinical trials.
Many of them, like ebselen, can probably skip the phase I trials and pose a substantially lower risk of producing dramatic side effects in later phases — thereby slashing those development costs compared with completely new compounds. “My feeling is that the proportion of drugs that in theory could be repositioned is probably around 75%,” says Bernard Munos, a senior fellow at FasterCures, a drug-development advocacy organisation in Washington DC.
The easiest target for repositioning is generic drugs. They have been on the market for years, their safety profiles are well-known, and they are easy and cheap to obtain for clinical trials because their original patents have expired. And, if they involve new formulations or applications to new disorders, they can still be covered by patents or be granted 3 years of market exclusivity by the US Food and Drug Administration (FDA).
Biovista, for example, starts by automatically scanning through all the publicly available information on generic compounds, from scientific papers and patents to the database of adverse events compiled by the FDA. Then it creates a kind of cellular social network, mapping all the connections that it has found between drugs, molecular pathways, genes and other biologically relevant entities. The thinking is that the more connections that a drug has in common with a disease, the more likely it is to be a good candidate for repositioning.
Another source of knowledge is what doctors see in the clinic. “Every drug that’s been around for some years has about 20 off-label uses, two-thirds of which are started by practicing physicians,” says Moshe Rogosnitzky, who heads one of the first academic centres for drug repositioning, established last year at Ariel University in Israel. “But the other doctors don’t know about them, because clinicians have a hard time publishing their results.”
Failed but not forgotten
Another favourite target is the long list of failed drugs. Most of them pass phase I trials, but do not get past phase II because they don’t have the same effect in humans that they had in animals. “Still, there are not many compounds that have some biological activity and are safe in humans, so for heaven’s sake let’s try to do something else with them,” says Gregory Petsko, a neuroscientist at Weill Cornell Medical College in New York city. The problem is that, apart from really old ones like ebselen, they tend to be locked in the industry’s drawers.
“Sometimes, companies make official announcements when they abandon a molecule, but in most cases they don’t,” says Hermann Mucke, a biochemist who in 2000 founded the Vienna-based firm HM Pharma Consultancy, which now makes a business from hunting through discontinued compounds. When they feel there may be room for repositioning, Hermann and his staff approach the owner of the drug and try to strike a deal that will allow them to do further tests and development — and share in any profits that result. They are also creating a database of drugs that have been approved but are no longer manufactured, and of drugs that have been abandoned during development. “We are developing it for our own use,” he says. “But if we can find investors, we would like to turn it into a public resource.”
In the absence of such a public resource, both the UK Medical Research Council (MRC) and National Center for Advancing Translational Sciences (NCATS) have struck deals with major pharmaceutical companies, convincing them to pick some abandoned compounds from their pipelines and release enough information for academic groups to work out whether repositioning might be feasible. “There’s a lot of research that could be done but is not happening, simply because academic people are not aware of what pharmaceutical companies are doing,” says Christine Colvis, who heads the NCATS drug-repurposing effort.
Although the MRC programme officially aims to help researchers to understand the biology of diseases, many of the groups that it funds end up doing interesting repositioning work, too. The NCATS programme has drawn criticism, however. “It’s good that some groups have had access to some drugs, but that leaves out the vast majority of us,” says Gregory. “And there’s no guarantee that the compounds in those lists were really the most interesting ones.” In the end, says Atul Butte, a bioinformatician at the University of California, San Francisco, drug repositioning is a complement to the discovery of new molecules, rather than an alternative. “We just need more of both,” he says. “In modern medicine, we’re becoming better at figuring out that each disease is actually 5 or 10 different ones. There are simply not enough companies out there to develop new drugs to treat them all.