Repurposing Drugs — Tackling the Why and How
The process of bringing a novel drug into the market is both expensive and time-consuming, estimated to last about a decade and costing over 2.5 billion US dollars, as evaluated by Tufts Center for the Study of Drug Development. With generic drugs threatening the viability of pharmaceutical innovation, and the ever increasing complexity of pre-clinical testing, companies are now looking for quicker and more cost-effective methods of drug development. Drug repurposing is the process of taking an existing drug with a clearly defined and approved use in one condition, and applying it to a different condition. For example, The International Journal of Oncology published a study in 2003 examining the chemotherapeutic effects of the quinolone antibiotic ciprofloxacin, which is commonly used to treat bacterial infections, when targeting hormone resistant prostate cancer. These effects were associated with cell cycle arrest and apoptosis.
In the field of oncology, which presents a unique set of challenges due to an overall success rate of a mere 9.6% from phase I to approval, repurposing drugs to use in combination therapies could show promising results. Increasing evidence shows that combination therapies are preferred over single agents, particularly when targeting advanced neoplastic lesions. We are now cognizant of the large number of cancer-inducing DNA mutations, and the role that tumor microenvironments play in the growth and spread of cancer. That, along with the advent of immunotherapies in the form of checkpoint inhibitors and monoclonal antibodies mean that cancer therapy is becoming more diverse and more complex. In order to target multiple malfunctioning cellular machineries, we can consider exploring combinations of therapies. Repurposing the array of drugs that are approved for non-cancer indications, with available preclinical and clinical safety data could therefore lead to more effective therapy — in theory. While drug repurposing certainly leads to faster development and reduced costs, there have been limited evidence based reports of successful repurposing of drugs as anticancer agents. The reasons for this are multifactorial. It is erroneous to assume that failure rates for a repurposed drug would be any different from a new drug. When evaluating repurposed drugs, we also have to consider the dosage required for anticancer activity, and what constitutes as an acceptable toxicity for cancer therapy versus the indication that the drug was originally intended for.
A large majority of drugs possess off-target effects that could cause therapeutic benefits (Nature 2009, 462:175–81). So by screening through existing, updated scientific databases, it is possible to identify drugs that are able to recognize specific targets. This approach was used in the treatment of small-cell lung cancer by identifying tricyclic antidepressants (imipramine and clomipramine). Another effective strategy is assume that drugs with similar side-effect profiles also have similar targets. (Science 2008, 321:263–66). Epidemiology studies can be used to conduct meta-analyses that determine associations between use of drugs and specific outcomes. In 2005, the BMJ published a case-control study that first suggested a possibly reduced cancer risk in diabetic patients treated with metformin (BMJ 2005, 330:1304–05). Another example is the paper published in Lancet, which suggested the beneficial effects of aspirin on overall mortality are mainly through reductions in cancer deaths (Lancet 2011, 377:31–41).
Some ways to promote drug repurposing:
Companies could be incentivized to invest in the research that goes into repurposing of drugs by providing them longer market exclusivity. Chemical agents that were ineffective and abandoned, but met the safety parameters can be systematically assessed by teams from varying therapeutic domains. A particularly promising solution is presented by public-private institutions that allocate time and resources for research into compounds that have been shelved to identify potential new targets. (Nat Rev Drug Discov 2011, 10:397) To make phase III trials of repurposed drugs affordable, a dedicated budget can be allocated by central funding bodies, particularly to not-for-profit foundations that are currently investing in this research. We have enough success stories in the past from viagra originally intended to treat high blood pressure and angina, to the teratogenic thalidomide being used as therapy for leprosy and multiple myeloma — drug repurposing need not be a last resort to compensate for a drug discovery pipeline that is threatening to dry up.
Sonia Rebecca Menezes
Department of Clinical Pharmacology
Advanced Center for Treatment, Research and Education in Cancer