Drug Development
References 1 Graul, AI et al. Drug News Perspect. 2010 (PMID: 20155217); 2009 (PMID: 19209296); 2008 (PMID: 18301807). 2
http://www.phrma.org/drug- development-costs-have- increased, and
http://www.phrma.org/researc h-development-process. 3 DiMasi, JA and Grabowski, HG. Manage. Decis. Econ. 28, 469-479 (2007). 4 Evaluate Pharma Alpha World Preview 2014. Evaluate Pharma report (2009). 5 Paul, SM et al. Nature Reviews Drug Discovery 9, 203-214 (March 2010) | doi:10.1038/nrd3078. 6 Cutting Edge Information. Pharmaceutical Product Relaunch: Preserving Market Share through Line Extension and New Market Entry Strategies. April 1, 2007. 7
http://ir.celgene.com/ phoenix.zhtml?c=111960&p=ir ol-newsArticle&ID= 1520733&highlight=. 8 Source: http://investors.
cephalon.com/phoenix.zhtml?c =81709&p=irol-newsArticle &ID=1485861&highlight=BDC. 9
http://www.gleevec.com: 80/index.jsp?
usertrack.filter_ap plied=true&NovaId=33501195 67064988730. 10 Lee, SJ and Wang, JYJ. J. Biol. (2009), 8:30;
doi:10.1186/jbiol134. 11 Gao, X et al. Neurology. 2011 Mar 8;76(10):863-9. 12 Pollard, SM et al (2009): Cell Stem Cell 4, 568–580, DOI 10.1016/
j.stem. 2009.03.014.
and understanding of new biology. What supports such a grand statement? Simply put, if we think of drugs not as drugs, but as reagents or probes of bio- logical function, then drugs used for repositioning have the ability to uncover new pathways and mech- anisms that would otherwise be invisible to us and to do so much faster than other tools. They can do so because of their ability to bind to targets that are not always the ones they were originally designed for. This is often called the ‘off-target’ effect, but in reality, the drugs are completely ‘on target’, binding exactly to what they are capable of binding. It is just that we may not always be fully aware of what they bind to or may not have known enough to look in the right direction and thus when an effect is later attributed to the binding of our drug to an unex- pected target, this is called ‘off target’. The impor- tant point is that a drug binds to multiple biological targets no matter how much effort has been exerted to render it as selective as it can be.
One of the most celebrated examples of this would be Imatinib, or Glevec, originally generated by rational drug design as a small molecule inhibitor that is selective for the cancer target bcr- abl, and is approved for the treatments of chronic myeloid leukaemia and gastrointestinal stromal tumours9. It is also known to inhibit c-kit, PDGF- R and NQO2, and this set of ‘off targets’ is now studied in concerted efforts to reposition Glevec in new indications including ischaemic stroke, rheumatoid arthritis, psoriasis, Crohn’s disease, type I diabetes and spondyloarthritis10. Observation of this drug binding to targets beyond that which it had originally been selected led to multiple hypotheses about its potential usefulness in other diseases, and encouraging early data have created multiple new research opportunities. Another recent example of repositioning is ibuprofen in Parkinson’s disease11. This study showed that the effect was specific to ibuprofen but not to other NSAIDs or acetaminophen, and this specificity was unexpected. The consequence here is that this unexpected observation is opening research possibilities into novel biology for Parkinson’s disease that would not have existed without repositioning.
A third compelling example is the unexpected observation that certain anti-depressant drugs are able to inhibit the growth of glioma cancer stem cells12. Since anti-depressants are believed to oper- ate mostly through neurotransmitter modulation, this observation is leading to research of potential new biology in cancer that may involve other unex- pected targets previously unidentified. The common theme in the three examples of
12
Glevec, ibuprofen and anti-depressants – and there are many others – is that the repositioning of these drugs led to unexpected observations in new dis- eases, thus contributing in a major way to current innovation in our biological understanding that we would not otherwise have.
In addition to the internal efforts of biopharma- ceutical companies, there are increasing numbers of vendors and CROs offering a variety of reposi- tioning services, including widescale in vitro bind- ing, cell line screening, protein-protein interaction studies, phenotypic screening of animal model sets and classic pathway and data mining approaches. Finding new uses for existing drugs makes com- mercial and research sense. It accelerates the devel- opment of novel products with less risk, provides further protection to embattled pipelines, has the potential for significant returns and efficiently gen- erates true innovation in our understanding of the basic biology of disease. As such, its future is assured and bright.
DDW
Dr Aris Persidis is President and co-founder of Biovista. He has also served as Senior Vice- President at Upstate/Serologicals, Managing Director and President of RHeoGene, Assistant Director, Medical School Technology Transfer Program and Assistant Professor (Adjunct) at the Entrepreneurial Center of the Wharton School of Business at the University of Pennsylvania. Dr Persidis is also a co-founder of Cellzome, in Heidelberg, Germany and participated in the founding of Anadys, San Diego, CA. He has pub- lished more than 80 papers and book chapters, has lectured at Wharton, the Columbia Business School, George Washington University and the University of Auckland Business School, and is a frequent speaker at major international meetings. He also serves as an expert evaluator for the European Union and has served on the Business Development Committee of BIO. Dr Persidis holds a First Class BSc Degree in biological chem- istry from Essex University, UK and a PhD in bio- chemistry from the University of Cambridge, UK.
Drug Discovery World Spring 2011
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