Introduction


introduction I


n the Introduction to the Summer 2011 edition of Drug Discovery World reference was made to a statement by Dr Janet Woodcock of the FDA in which she anticipated that the total of novel drugs which would be approved by the FDA in 2011 was likely to exceed the 21 cleared in 2010. Figures now available show that her anticipation was correct in that 30 new treatments were approved in 2011 representing a seven-year high. In quoting this figure, Bloomberg News suggests that companies have responded to the regulators demand for better safety data and have also avoided last minute requests for more data. In the same article the point is made that higher approval rates will, to some extent, compensate for the rash of patent expirations which are due in the next year or so. It was stated that at least 21 medicines with a combined revenue of $11.5 billion will come off patent in 2012.


So, there can be no let up in the process of discovering and developing new medicines and, as always, our contributors have produced suggestions for making that process more effective. One author postulates that a dramatic rethink is called for and that consideration should be given to what he calls an ‘evolutionary disease management approach’. This would involve revisiting the basics of biology which, he suggests, might have been forgotten among the many significant scientific and technological advances that have been made in the past few decades. This may, in turn, lead to radical shifts in practices ‘to get us to a world only dreamt of before’.


In a more immediate timeframe the authors of another of our articles point out that two of the most important factors to be considered in attempts to improve the drug discovery/development process are attrition rates and timelines. These authors have created a simultaneous visualisation of these two factors into a funnel diagram from which turnaround time and percentage progression can be viewed at a glance. It is claimed that this tool overcomes the risks of either going too fast in the wrong direction or producing the highest quality too slowly. There is discussion of the issues involved including the ‘people aspects’ of successful deployment and suggestions as to possible future developments.


There is acknowledgement in another article that high throughput screens (HTS), despite their universal usage, have produced low hit rates and there have been high attrition rates among lead candidates which have emerged from these screens. HTS libraries typically comprise ‘drug-like’ molecules which tend to be large and lipophilic and which need to be chemically modified before they are seen as realistic development candidates. Unfortunately these modifications tend to reduce their ‘drug-likeness’, often resulting in poor absorption, distribution and metabolism characteristics. In the last decade, with the objective of improving this situation, Fragment-Based Drug Discovery (FBDD) has emerged as a complementary strategy to HTS. This technique allows a much larger chemical space to be explored by screening a relatively low number of diverse fragments. It yields hits that can be optimised into lead candidates without losing ‘drug- likeness’. As is pointed out by our authors, the success of the screen ultimately depends on the design of the fragment library and they discuss the main factors which need to be considered in that regard. In another article it is stated that, until recently, HTS and High Content Imaging (HCI) ‘have been considered as two separate worlds sharing only some borders’. HCI assays were introduced more than a decade ago but,


Drug Discovery World Winter 2011/12


although they are recognised as prod- ucing physiologically relevant results, until recently it was not possible to carry them out in high throughput. This is no longer the case although, as is discussed by our authors, improve- ments still need to be made to enable them to be used to their full potential in hit identification.


Stem cells are generally recognised as having potential applications in most of the stages of drug discovery from


target identification through to toxicology studies. The cells can be propagated for prolonged periods of time, cryopreserved and differentiated to physiologically relevant cell types and in these respects they offer advantages over, for example, recombinant cell lines and primary cells. However, as is pointed out in one of our articles, for the full potential of stem cells to be realised, methods for their differentiation need to be improved. The techniques now available are discussed as are potential further developments.


There is increasing interest in drug discovery laboratories in installing simple small-scale benchtop automation to take care of technically challenging or repetitive processes. There are obvious benefits in labour savings, better quality data, etc. A report in this edition of DDW indicates that interest is greatest in various emerging applications of sample preparation and recent advances in instrument developments are discussed. Finally, in an article from the US, there is an observation that in recent years ‘drug discovery has found a new home in academia’. Pharmaceutical companies have entered into various collaborative arrangements with academic laboratories to increase their research capabilities and thus feed their drug discovery pipelines. An example is HTS where an academic facility not only provides a fee-for-service facility but also acts as a ‘critical collaborative partner’. The article suggests that, rather than competing with one another, academic laboratories such as those involved in HTS and related activities, should form consortia. This would not only increase their chances of survival in the current challenging economic climate but would also allow them to make a greater contribution to the drug discovery landscape and ultimately to the well-being of patients.


Dr Roger Brimblecombe PhD, DSc, FRCPath, FIBiol 7


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