Traditional drug discovery relies on the identification of a target, typically an enzyme or receptor, where it is hoped that binding to the target will elicit a desired biological response. Hundreds of thousands of compounds are tested for target binding through high throughput screening. However, this approach has typically taken 10-15 years with a cost of about $1.3 billion per successful drug launch. These enormous costs are due to high attrition rates of preclinical candidates because of lack of efficacy or unexpected safety concerns in clinical trials.
Fluorescent images of human neuronal cells, typically used in screening for new drugs.
PharmaKure’s solution to this development challenge is to screen molecules that have already been through some degree of clinical development in order to discover novel activities in other diseases. This ‘repositioning’ of existing or old drugs for new targets has the following advantages:
The drugs may be known to exert a biological response in humans. This response may be beneficial for additional conditions. For example, studies of patients taking cholesterol lowering statin drugs revealed an unexpected link between cholesterol levels and Alzheimer’s disease, with patients on statins having a lower risk of Alzheimer’s disease.
Such molecules are already usually known to be bioactive, have a known safety profile, be bioavailable and have FDA approval for use in humans. Indeed most drugs cannot cross the blood-brain barrier, which is often problematic for development of a drug for neurodegeneration.
Many of the steps in drug development, such as determining ADMET properties and phase I clinical trials, have already been undertaken, hence reducing drug development costs, accelerating timelines development and improving chances of success.
Fonseca, A., Resende, R., Oliveira, C. R., and Pereira, C. M. F. (2009) Cholesterol and statins in Alzheimer’s disease: Current controversies, Experimental Neurology 223, 282-293.
The drug repositioning or repurposing strategy has already led to several blockbuster drugs, for example, Viagra, which was initially intended to treat pulmonary hypertension, but has since been used to treat erectile dysfunction; and Rogaine which was intended to treat high blood pressure has been subsequently repositioned for treatment of hair loss and promotion of hair re-growth. Up to 2011, 34 reports were published where groups screened libraries of FDA approved drugs against various whole cell or target assays. None were for Alzheimer’s disease. Each screen identified at least one compound with a novel bioactivity.
In addition, rather than seeing if compounds bind to a single target, one of our strategies is to measure activities in cell culture. This gives a much larger range of targets, thus increasing the chances of success.
Ekins, S., and Williams, A. J. (2011) Finding Promiscuous Old Drugs for New Uses, Pharm. Res. 28, 1785-1791.