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European Biopharmaceutical Review

Drugs in Search of Diseases

Critical of conventional drug discovery and development methodology, Duncan McHale and Albert B Seymour at Pfizer Global Research and Development look at a reverse approach that identifies opportunities earlier in the process

The traditional approach to drug discovery and development is to start with a specific disease, identify a target based on knowledge of the biology, and screen a compound library for a chemical which will interact appropriately with the target, resulting in the expression of a desired effect. The chemical is then tested for efficacy in animal models of disease, for toxicology preclinically, and ultimately for toleration and pharmacokinetics in humans.

At least two thirds of compounds die at this stage before we can establish if our target selection was correct in treating the human disease. The attrition in this forward testing approach of unprecedented mechanisms can be as high as 49 in 50 compounds tested. In this article, we propose a reverse approach to drug discovery and development once chemical tractability and pharmacological tolerability of a particular mechanism have been established.

PHARMACOLOGICALLY TOLERANT GENE

Recent publications have analysed how the intersection of the proportion of the human genome that is tractable to chemical intervention, and the number of drug targets that are relevant to human disease may be as few as 600-1,500 (1). The final subset not considered in this analysis is those where pharmacological intervention would be tolerated – the pharmacologically tolerant genome. This is a difficult parameter to estimate, as our willingness to tolerate adverse effects of drugs varies considerably depending on the disease being treated and the seriousness of the adverse event. Even if we are optimistic, our ability to tolerate pharmacological intervention of these targets may reduce the total number of tractable targets by up to a half.

This ever diminishing number highlights the need to ensure that all potential diseases which could be treated by a new mechanism of action are identified once the safety of this mechanism has been established. This tactic of identifying new indications for proven drugs has been used with great success in the past, meeting significant areas of medical need and adding billions of dollars to the commercial value of products.

A survey conducted in 1998 demonstrated that 40 per cent of blockbuster drug sales were from alternative indications (2). Good examples include gabapentin, originally developed as an anti-epileptic medication, with subsequently proven efficacy in neuropathic pain, and sildenafil, developed for erectile dysfunction and subsequently demonstrated to offer a major advance in the treatment of primary pulmonary hypertension. Many of these alternative indications result from data generated in small-scale investigator-initiated studies postapproval, or from serendipitous case reports of unexpected benefits. The challenge is how to systematically identify and evaluate these opportunities earlier in the drug development and approval process.


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Dr Duncan McHale graduated from Medical School at the University of Newcastle-Upon-Tyne in 1991 and initially trained in internal medicine and clinical genetics. He obtained a Wellcome Trust Research Fellowship in 1996 and was awarded a PhD in Molecular Genetics from the University of Leeds in 2000. He joined Pfizer in 1999 as a Clinical Project Manager within the Clinical Pharmacogenomics Group. In his current role as European Head of Clinical Pharmacogenomics, he provides genetics expertise to Pfizer’s drug discovery and clinical development programmes within Europe and Japan. He is Chair of the EFPIA pharmacogenetics and pharmacogenomics ad hoc group, and is a co-author of the recent papers written by the cross-industry Pharmacogenetics Working Group.

Albert B Seymour is the Director of Pharmacogenomics at Pfizer Global Research and Development. Since joining Pfizer in 1997, he has been studying the role that human genomic variation plays in both disease pathogenesis and drug response, with a major emphasis in oncology and inflammation. Albert received his BA in Biology from the University of Delaware, his MS in Molecular Biology from The Johns Hopkins University, studying the molecular genetics of pancreatic cancer, and was awarded his PhD in Human Genetics by The University of Pittsburgh. Albert has authored numerous publications in the area of human genetics and pharmacogenomics.

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Dr Duncan McHale
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Albert B Seymour
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