Drug development: Teaching old pills new tricks

Exploding research costs and falling sales: there seems to be no cure for the pharma industry’s two big afflictions. But it may have found a way to both cut costs and open up new markets: repurposing drugs already approved for treatment of one disease or those that failed to gain approval in the late stages of development. Alas, this is not as easy as it sounds—mostly for legal reasons.

Finding new uses for old or failed drugs is on average 40% cheaper than inventing a new drug from scratch: it allows to skip the early stages of development. Since coming up with a new drug can cost more than $1 billion, such savings are nothing to sneeze at. Repurposing also trims the risk of failure because new drugs hit a dead end mostly during the early stages of development.

In 2007, a report in Nature, a science journal, counted 41 drugs that have found new uses. But there should be many more, experts say. This is why America’s National Institutes of Health, the country’s biggest government agency financing drug research, and the Medical Research Council, its British counterpart, each have launched new grant programmes. Worth $20m and £10m ($15m) respectively, they are meant to allow university researchers analyse failed drugs from big pharma firms such as Pfizer, AstraZeneca and Eli Lilly and see whether they can be repurposed.

Yet such schemes are not enough, as work by Grant Churchill, a researcher at Oxford University, shows. In a recent paper in Nature Communications, another science journal, he describes how he and his colleagues looked for a drug to treat bipolar disorder, which causes uncontrollable mood swings. Instead of developing a new compound, they tested a library of known ones and found that ebselen, a drug first developed to treat stroke, was a candidate. Their claim, based on animal tests, is that ebselen is as good as and much safer than lithium, currently considered the best treatment for bipolar disorder.

But this was where things hit a hurdle that is hard to overcome. Universities do not have the money to further develop promising drug candidates that need to be tested on a large scale. Expensive human trials are usually carried out by pharma firms, which own the patent for a drug and thus can hope to make their money back. But in the case of many repurposed drugs, like ebselen, the patent has expired. Filing for a new one, which is possible, is not of much help: patients could simply buy versions of the drug which are already available from other makers.

One way of solving this problem would be to change the patent system, for instance by extending the length of patent protection, but this could hamper innovation in other ways. A better solution, argues Benjamin Roin, a law professor at Harvard University, is to have regulators grant the drugmaker that has repurposed the drug some exclusivity and thus time to recover research costs: it is rare that a drug is used in the same form and the same dosage for two different diseases; regulators could wait a few years before they allow other firms to offer the drug for the new purpose. If old drugs can learn new tricks, regulators should do so, too.

First published on economist.com.


  1. Singh et al., A safe lithium mimetic for bipolar disorder, Nature Communications2013.
  2. DiMasi et al., The price of innovation: new estimates of drug development costs, Journal of Health Education2003.
  3. Chong & Sullivan, New uses for old drugs, Nature2007.
  4. Roin, Unpatentable Drugs and the Standards of Patentability, Texas Law Review2009.

Image credit: The Economist

Cancer drugs: Refusing to die

Suicide is a part of life. Whenever any of the 100 trillion or so cells that make up the human body malfunction, which happens all the time even in healthy tissue, they are programmed to provoke their own death. The mechanism hinges on a protein called TRAIL, which is produced by the damaged cell and binds to receptors on its surface, causing inflammation. That is a signal for the immune system to sweep in and, through a process called apoptosis, break down the damaged cell and recycle its parts to feed healthy ones. If this self-destruct is subverted, however, the result is a tumour.

When TRAIL’s tumour-suppressing ability was first discovered in 1995 researchers hoped that by discriminating between cancer cells and healthy ones, TRAIL would do away with the debilitating side-effects associated with traditional treatments like radio- and chemotherapy. These are good at destroying tumours but also cause lots of collateral damage. Unfortunately, it turned out that simply injecting a synthetic version of the molecule into the patient’s body provoked only a limited immune response in a handful of cancers.

That, says Joshua Allen from the Pennsylvania State Cancer Institute, was because people assumed that cancer’s subversion of TRAIL consisted merely in halting the molecule’s production within the cell. It turns out, however, that cancerous cells also suppress their TRAIL receptors, so no amount of synthetic TRAIL sloshing about would ever be enough. What you need, Dr Allen reasoned, is something to reboot the TRAIL-producing pathway within cells as well as to unblock their TRAIL receptors. Only then would the immune system be spurred into action.

So he and his colleagues sifted through a library of molecules maintained by America’s National Cancer Institute and found a molecule, called TIC10, whose biochemistry seemed to fit the bill. When enough of these molecules accumulate in a cancer cell, they activate a protein called FOXO3a. This binds to DNA and flips on many biological pathways, including those involved in the TRAIL mechanism that lead to the immune-system alerting inflammation.

As Dr Allen and his colleagues report in Science Translational Medicine, tests in mice with brain tumours confirmed the biochemical hunch. Murine subject given TIC10 lived twice as long as those that received no treatment. The drug also worked for lymphoma, as well as breast, colon and lung cancers. And it did not seem to cause the wasting side-effects typically associated with chemotherapy, suggesting that it can indeed tell cancer cells from healthy ones. As an added bonus, TIC10 is small compared to TRAIL, and cheaper to concoct than the complex protein is.

Last year Dr Allen secured a $1.3m grant from Pennsylvania’s department of health to begin clinical trials. These will be carried out in collaboration with Oncoceutics, a drug company. Nine out of ten promising molecules which work in mice fail in humans, so “Cure for cancer” headlines must wait. If TIC10 does live up to its promise, though, it would make one killer app.

First published on economist.com.

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The value of medicine


Drug discovery is a long, arduous and expensive process. Is it worth it?

“One minute I was looking at death. The next, I was looking at my whole life in front of me,” said Suzan McNamara, a patient suffering from chronic myeloid leukaemia (CML), a nasty form of blood cancer. She had just heard that she would be receiving doses of imatinib, a drug that had shown remarkable recovery among patients of this cancer. Four decades of research was needed to make this drug, and to enable such a moment for a cancer patient. It is Ms McNamara’s story and that of many others like her that could possibly justify billions of dollars and years of efforts put into discovering drugs.

CML causes unregulated growth of white blood cells leading to pain, debilitating illness, and, before imatinib was discovered, all too often, death. The only options for treatment, before the drug therapy became common, were a bone marrow transplant, which is very risky, or daily infusions of interferon, an artificial way of boosting a patient’s immune system that has severe side-effects.

The process of discovering a drug like imatinib, commercially known as Gleevec, is a long one. First pharmacologists pick apart the workings of the disease and find a pathway that can be targeted. Then chemists design molecules or use readymade libraries of molecules to block (or, occasionally, activate) that pathway. Typically, of the 5000 molecules that showed promise at this first step, on average, only five are deemed safe enough to undergo human trials. Then, after three to six years of clinical testing, only one of those five molecules may become a drug. Finding a drug is literally like looking for a needle in a haystack. All considered, the success rate is 0.02% and it requires more than a decade worth of research at an average cost of $1 billion.

But imatinib was worth it. It was the first drug that could precisely target cancerous molecules. The science that underpins the achievement began with a discovery in 1960. Two researchers at the University of Pennsylvania found that cancerous cells possessed a particularly small chromosome (number 22 out of the 23 chromosomes that make up human DNA), and this was proposed as the cause of unregulated growth. This was the first time that cancer was linked to a genetic abnormality.

How that abnormality led to cancer remained a mystery until new techniques to visualise segments of this chromosome were found in 1973. Then Janet Rowley, of the University of Chicago, showed that the small size of chromosome 22 was due to an exchange of one of its large segments with a small fragment from chromosome 9. The alien material on chromosome 22 now led to the production of a cancer-causing protein. This rogue protein, an enzyme, was involved in the regulation of cell growth. Dr Rowley postulated that blocking this enzyme should stop cancerous cells.

The charge to find the blocking agent was taken up by medicinal chemist Nicholas Lydon, of Novartis, and oncologist Brian Druker, then of the Dana-Faber Cancer Institute in Boston. They needed to find a molecule that will selectively block the rogue enzyme and leave hundreds of useful ones alone. Following the iterations of the drug discovery process, the team took eight years of efforts to find imatinib. In Phase II clinical trials nearly every patient who took the drug felt surprisingly better in a short period of time, which led to a fast-tracked approval for the molecule from the Food and Drug Administration in 2001.

Imatinib was also approved for treatment of gastrointestinal stromal tumours and other forms of leukaemia, too. Earlier this year, Dr Rowley, Dr Lydon and Dr Druker received the prestigious $650,000 Japan Prize given for outstanding achievements that advance the frontiers of knowledge. “Their work shocked the world of clinical medicine”, the prize citation said. Times have changed drastically from early 20th century when patients depended on good fortune, as drugs were often only found serendipitously.

Ms McNamara was diagnosed with CML in 1998. By the time she received imatinib through a clinical trial in January 2000, her condition had become quite severe. “I was basically on my last limb,” she recalls. Before imatinib was discovered, only three out of five CML patients survived for more than five years after diagnosis. But a 2011 study showed that even eight years after diagnosis, only 1% of CML-related deaths occur among patients using the wonder drug.

With her health restored to normal, Ms McNamara went on to get a PhD in leukaemia research. Quite early in her studies she realised she may not be the one to cure leukaemia herself, but she said, “I might publish one paper that has one key for the next person to go a step further. That’s important”.

Drug discovery is a long, arduous, and expensive endeavour, but it is a process that is being continuously refined to produce results faster and more cheaply. Researchers consider themselves fortunate if they witness the successful launch of a drug in their lifetime, but extraordinary stories of patients motivate them to keep improving this process and searching for that elusive molecule.

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