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Changed Reasons Behind Failure Leaves Drugs Looking for Work

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By Anette Breindl
Science Editor

Drugs continue to fail. Most candidates that enter into the development process do not come out the other end as approved therapies. But the reasons for those failures have shifted.

Compared to a decade ago, Steven Paul told BioWorld Insight, attrition due to either safety or a lack of drug-like properties of a lead compound has been "fundamentally reduced."

Such attrition has not been eliminated. But nowadays, drugs fail more often because "they just don't work for the disease they were originally tested for" – or they are shelved despite clinical success for strategic reasons.

Chemically speaking, though, such compounds are perfectly good drugs – if they can meet their match.

Such compounds are "drugs in search of diseases," said Paul, who is at Weill Cornell Medical College as well as Third Rock Ventures, and spent almost two decades with Eli Lilly and Co. And that is the title of a paper he published, with Freda Lewis-Hall, in the May 23, 2013, issue of Science Translational Medicine.

Repurposing "has been a viable source of drugs in the past," Paul said. There have always been drugs that ended up in a different section of the pharmacy shelf than the ones their developers were eyeing during early development.

Pfizer Inc.'s Viagra (sildenafil), which is now used to treat erectile dysfunction and pulmonary arterial hypertension, started life as a potential treatment for hypertension and angina pectoris. Thalomid (thalidomide, Celgene Corp.), which was once an anti-nausea drug, and then due to a tragedy/disaster for that indication, now has a second life as a multiple myeloma treatment.

During his time at Eli Lilly, Paul worked on such drugs himself. He named chemotherapy Gemzar (gemcitabine), which was first synthesized in search of antiviral drugs, as an example. "I think every company has examples of this," he said.

But such repurposing has historically been accidental. Pfizer became aware of Viagra's potential as an erection drug because men complained (or rejoiced) about its side effects in early clinical trials.

And he believes it could become a much richer source of drugs in the future – if anyone is willing to pay for the development of repurposed drugs. And that, in turn, depends on whether anyone can figure out how to make money off of them.

One tricky issue is that drugs that have failed in one indication have done so while their patent clock is ticking, which means much less time to recoup development costs without generic competition. In extreme cases, such drugs may be without patent protection altogether. An example is cutaneous T cell lymphoma drug Targretin (bexarotene, Eisai Co.) which is coming off patent in 2016. Startup ReXceptor Inc. wants to repurpose Targretin for Alzheimer's disease.

A theoretical possibility is to protect such repurposed compounds via method-of-use patents. But such patents cannot be filed if the new method is either obvious, or has been publicly disclosed. One way for a drug to become recognized as a repurposing candidate is probably a peer-reviewed paper that pops up somewhere, and so method-of-use patents will likely not play a large role in giving patent protection to repurposed drugs. In their paper, Paul and Lewis-Hall suggested that extending data exclusivity, akin to what is the case for biosimilars, might be one solution.

The bulk of the money for repurposing is most likely to come from big pharma, for several reasons, Paul said.

He "wouldn't exclude" the possibility for some venture capital backed companies to dedicate themselves to repurposed compounds. But the late-stage clinical trials that such drugs will tend to need are at the point where small companies usually look for a deep-pocketed pharma partner: "Most VC-backed companies will not find it easy to raise that sort of money," Paul predicted.

At the same time, it is pharma which has the most incentive to get these drugs on the track to success. If the process works, a repurposed drug is a source of revenue. "Otherwise," Paul said, "these are huge sunk costs."