New drugs for old

C&I Issue 3, 2013

The most recent Office of Health Economics analysis puts the cost of R&D for a new medicine at £1.2bn. High attrition rates for more complex diseases, increasingly stringent regulation and the higher cost of borrowing money have all contributed to the enormous price tag attached to developing a new drug – a process that can take as long as 15 years and has so far yielded effective treatments for only a fraction of diseases.

As a result, we are seeing an increase in drug repurposing – also known as repositioning, reprofiling, retasking, reusing or therapeutic switching. The idea is that the time and money required to develop a drug can be cut dramatically if the starting point is not a new chemical entity but a drug that is already on the market or one that has undergone some clinical testing. Knowing the reasons of potential failure of a drug, such as animal safety studies and adverse side effects, can help researchers repurpose the drug and give it a better chance of success.

There are some classic examples of successful drug repurposing, such as the erectile dysfunction drug Viagra (sildenafil), originally developed for angina, and the morning sickness drug Thalidomide, which is now used to treat leprosy and cancer of the muscles. Much repurposing in the past has been serendipitous, but with thousands of compounds approved or sitting in drug libraries, deliberate drug repurposing programmes are on the increase.

Recent activity

In May 2012, the US National Institutes of Health’s (NIH) new National Center for Advancing Translational Sciences (NCATS) launched a programme to discover therapeutic uses for existing drugs, as part of its Rescuing and Repurposing Drugs initiative. Abbott, AstraZeneca, BMS, Eli Lilly, GSK, Janssen, Pfizer and Sanofi collectively have agreed to make 58 stalled compounds available to academic researchers to investigate their repurposing potential. In June 2013, NCATS, which is also developing a comprehensive database of approved and those under investigation, plans to make around eight awards totalling $20m for this work.

‘Repurposing an already well-developed compound or drug can dramatically improve the efficiency of drug development because the “development” is starting at a much more advanced point along the 13-plus-year process,’ says Christine Colvis, programme director at the NIH. Also in the US during 2012, the Michael J. Fox Foundation made drug repositioning one of its recurring programmes.

In the UK, at the end of October 2012, the Medical Research Council announced £7m of funding for 15 research projects awarded through its collaboration with AstraZeneca, to give academic researchers free access to 22 of its mothballed compounds whose mechanisms of actions may have broader utility. This was followed, in November 2012, by the publication of a study, funded by the Alzheimer’s Society and led by King’s College London (KCL), which highlighted the huge potential in exploring available drugs for other conditions. The systematic review, led by Clive Ballard, professor of age-related diseases at King’s, identified four existing drugs and one drug class – including medicines for high blood pressure, diabetes, psoriasis and an antibiotic – that might reduce risk or slow down symptoms of Alzheimer’s (doi: 10.1038/nrd3869).

Successful drug repurposing requires a strong scientific rationale linking the causative factors of diseases to the mechanism of drug action, and this is being aided by technological advances. ‘The evolution of our understanding of the genetic basis of disease and seeing where there are opportunities for drug intervention has reduced the level of risk in R&D. In addition, better collation of clinical data to report drug side effects – both positive and negative – has provided another approach to drug repositioning based on human data,’ says John Arrowsmith, pharmaceutical executive adviser at Thomson Reuters. Paul Workman, deputy ceo of The Institute of Cancer Research, UK, which takes the repurposing route wherever possible as a quicker way to achieve benefit for patients, adds: ‘The main advance that is making drug repurposing possible is genome sequencing and gene expression profiling of infectious organisms and cancers.’


Drug repurposing is not without its challenges, however. One is access to compounds and data, which are not all freely available. Some drugs are so old that they were approved under former requirements and no one knows where the old paper files are now, points out Scott Weir, director of the Institute for Advancing Medical Innovation at the University of Kansas Medical Center, US, which is involved in The Learning Collaborative (TLC), a partnership with the NIH and The Leukemia & Lymphoma Society to develop new drug therapies for rare blood cancers. Additionally, access to pharmaceutical sponsor master files may be difficult; although the US FDA has access to such files, it is under no obligation to share them, says Weir. The quality of the data that is available is also questionable in some cases.

Moreover, many of the compounds that are repurposed have limited or no patent exclusivity remaining or are generic. ‘In these cases, the predicted return on investment is variable, which can deter some commercial entities from investing in further development,’ says Colvis. That said, options for protecting intellectual property for repositioned drugs do exist, according to Arrowsmith. They include, for example, novel drug combinations to support a new patent, orphan drug designation, or a new use patent through a change in strength, dose or route of administration, he explains.

There are other potential problems. A doctor may prescribe a drug already on pharmacy shelves for a different condition. Such practice is very difficult to police, and makes repurposing of some drugs a limited avenue for commercial companies, explains Ballard.

And reimbursement poses a particular challenge. ‘Gaining marketing authorisation may be relatively easy for a newly repurposed drug, but gaining reimbursement may prove difficult,’ says Milena Izmirlieva, analyst at IHS Global Insight. She explains that the repurposed drug may threaten the price of the original drug or vice versa. ‘Precisely this concern recently led Sanofi to withdraw Campath (alemtuzumab), a leukaemia drug, in France to avoid price pressure on Lemtrada, its new MS drug based on the same active ingredient [and which will be much more expensive],’ says Izmirlieva. Some patients have been using Campath off-label to treat their MS.

Useful partnerships

Nevertheless, drug repositioning, with its shorter timescales, can generate up to $20bn in 2012 sales, according to estimates by Thomson Reuters, which points out that there are some 2000 failed drugs sitting in drug libraries that have repurposing potential, and that the list is increasing by 150–200 compounds/ year. ‘We’re going to see more and more of this [drug repurposing],’ says Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development, Boston, US.

Although some companies are leaving R&D into repurposing to universities, where commercial return is not so important, others are aggressively engaged in drug repurposing early in the R&D life-cycle of their drug candidates. An example of the latter is Glivec (imatinib), originally marketed by Novartis for cancer of the white blood cells, but now approved for an additional eight indications and counting.

Industry is being helped significantly by academia. Weir comments that TLC considers itself a ‘middleman’, moving a compound through clinical proof of concept and generating enough data to attract a pharmaceutical partner for further development. In the case of the NCATS and MRC initiatives, the academic partner investigates the stalled corporate candidates, but the industry collaborator retains the existing rights to the compounds it has contributed. Both TLC and NCATS are also working to make academic-industry partnerships easier – NCATS with template agreements that it hopes will reduce the negotiation time that could otherwise delay research. And in Europe, the three-year Efficient Patient Recruitment for Innovative Clinical Trials of Existing Drugs to other Indications project (PONTE), which is scheduled for completion in 2013, aims to develop an IT platform that will help researchers select patients for clinical trials of repurposed drugs.

‘Every sector of the research community aspires to the same end result: improved, more effective treatments for patients,’ says Colvis. ‘It is essential that we capitalise on the strengths that each sector brings to the table to develop a more efficient path to treatments.’

Emma Dorey is a freelance writer based in Brighton, UK.

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