TABLE OF CONTENTS
LIST OF TABLES
LIST OF FIGURES
GLOSSARY AND ABBREVIATIONS
EXECUTIVE SUMMARY
CHAPTER 1 INTRODUCTION
1.1 Introduction and definition
1.1.1 Genetic variation
1.2 Background to pharmacogenomics
1.2.1 Genetic selection
1.2.2 Drug metabolism
1.2.3 Disease taxonomy
1.2.4 Drug target polymorphism

CHAPTER 2 MOLECULAR ADVANCES AND APPLICATIONS OF PHARMACOGENETICS
2.1 Transition to pharmacogenomics
2.1.1 Molecular characterisation of genetic variants
2.1.2 Differential screening
2.2 The genetics of drug response and toxicity
2.2.1 Drug metabolism
2.2.1.1 Cytochrome P450 family
2.2.1.2 Alcohol and aldehyde dehydrogenase
2.2.1.3 Glucose-6-phosphate dehydrogenase
2.2.1.4 Acetyltransferase
2.2.2 Polymorphism of drug targets and pathways determining response and toxicity
2.2.3 Disease redefinition using genetics and its impact on therapeutic targeting

CHAPTER 3 THERAPEUTIC APPLICATIONS
3.1 Cancer
3.1.1 Thiopurine S-methyltransferase deficiency
3.1.2 Dihydropyrimidine dehydrogenase deficiency
3.1.3 Cyclophosphamide metabolism
3.1.4 Ataxia telangiectasia
3.1.5 Novel cancer therapies
3.2 CNS pharmacogenomics
3.2.1 ApoE and Alzheimer's disease
3.2.2 Anaesthesia
3.2.2.1 Succinylcholine sensitivity
3.2.2.2 Malignant hyperthermia
3.2.3 Cytochrome P450 effects and psychotropic drugs
3.2.4 Clozapine and 5-HT receptors
3.2.5 Migraine
3.3 Cardiovascular pharmacogenomics
3.3.1 Debrisoquine
3.3.2 N-acetylation polymorphism: procainamide and hydralazine
3.3.3 Cholesterol ester transfer protein
3.3.3.1 Long Q-T syndrome
3.3.3.2 Anticoagulation
3.4 Infectious diseases
3.4.1 Identification of pathogens
3.4.2 Drug resistance
3.4.3 Choosing therapy to manage escape variants
3.4.4 Identifying vaccine responders and non-responders

CHAPTER 4 PRACTICAL AND STRATEGIC IMPLICATIONS
4.1 Practical issues and future challenges
4.2 Candidate genes - pharmacogenomics using genes known to contribute to biotransformation or response
4.3 Systematic association strategies in pharmacogenomics
4.3.1 Practical issues utilising differential expression for pharmacogenomics

CHAPTER 5 FUTURE DEVELOPMENTS
5.1 Pharmacogenomics: why change?
5.1.1 Forces behind change
5.1.1.1 The pharmaceutical industry
5.1.1.2 Healthcare providers and clinical practice
5.1.2 Role of diagnostics in increasing market size and competitiveness
5.1.3 Market forces - the consumer
5.1.4 Early intervention
5.2 Technology developments
5.2.1 Methods for the detection of SNP polymorphisms
5.2.2 Polymorphic site recognition assays
5.2.3 Expression profiling

CHAPTER 6 COMPANY PROFILES
6.1 Introduction
6.2 Genomics companies
6.2.1 AxyS Pharmaceuticals
6.2.2 diaDexus
6.2.3 Eurona
6.2.4 Genaissance Pharmaceuticals
6.2.5 Genome Therapeutics
6.2.6 Genset
6.2.7 Human Genome Sciences
6.2.8 Hyseq
6.2.9 Incyte
6.2.10 Lion Bioscience AG
6.2.11 Millennium
6.2.12 MitoKor
6.2.13 Myriad Genetics
6.2.14 OncorMed
6.2.15 Onyx
6.2.16 Oxagen
6.2.17 Professional Genetics Laboratory
6.2.18 Spectra Biomedical
6.2.19 Variagenics
6.3 Technology companies
6.3.1 Affymetrix
6.3.2 Amersham Pharmacia Biotech
6.3.3 Aurora
6.3.4 Darwin Molecular
6.3.5 GeneTrace
6.3.6 Genzyme
6.3.7 Hewlett-Packard
6.3.8 Molecular Dynamics
6.3.9 Nanogen
6.3.10 Oxford Genetic Technologies
6.3.12 Perkin-Elmer/Applied Biosystems
6.3.13 Sequenom
6.3.14 Synteni
6.3.15 Visible Genetics Inc
6.4 Pharmaceutical companies
6.4.1 Abbott Laboratories
6.4.2 American Home Products
6.4.3 Astra
6.4.4 Bayer
6.4.5 Bristol-Myers Squibb
6.4.6 Glaxo Wellcome
6.4.7 Johnson & Johnson
6.4.8 Lilly
6.4.9 Merck
6.4.10 Novartis
6.4.11 Pfizer
6.4.12 Pharmacia & Upjohn
6.4.13 Roche
6.4.14 Schering-Plough
6.4.15 SmithKline Beecham
6.4.16 Warner-Lambert
6.4.17 Zeneca

REFERENCES

LIST OF TABLES
Table 2.1 Allele frequencies for certain polymorphic CYP450 enzymes in Caucasians
Table 2.2 The effect of pharmacogenomics on pharmacological mechanisms - selected examples
Table 3.1 CETP and response to pravastatin

LIST OF FIGURES
Figure 1.1 Genetic factors determining drug response and toxicity
Figure 2.1 Classical definition of diabetes mellitus
Figure 2.2 Taxonomy of diabetes, based on genetic factors
Figure 4.1 Disease association using linkage disequilibrium
Figure 4.2 Explanations for linkage disequilibrium
Figure 5.1 Engines of change for pharmacogenomics

Executive Summary
Genetic factors have long been recognised to contribute to the variation in drug response and toxicity in patient populations. Classical pharmacogenetics defined many of the important phenotypes, particularly relating to drug metabolism, but the availability of molecular techniques has dramatically expanded this field now often referred to as 'pharmacogenomics'. Opportunities exist to utilise molecular information relating to drug metabolism enzymes in order to determine patterns of response and toxicity in patient populations before they are treated. Similarly, genetic information that will be used to define diseases mechanistically will aid in the more precise use of therapeutic interventions, producing higher response rates and lower risks of adverse events. Expression profiling may also prove to be an important adjunct in defining surrogate markers and toxicity before therapeutic agents are developed. Together, these important genetic insights will eventually change the face of clinical medicine and will have profound implications for the way drugs are developed and applied in the clinic. Although the field is still in its infancy, its promise is already clearly evident.

Chapter 1 describes the historical basis for pharmacogenomics. It begins with a discussion of the enzymes responsible for drug metabolism and the evolution of our understanding of variation in drug response from family and ethnic studies through the definition of the molecular basis for polymorphism in enzymes responsible for biotransformation. In addition, it identifies two other important areas of application of genetics in clinical pharmacology. The redefinition of disease around mechanisms and genetic susceptibility will inevitably create new opportunities for more precise targeting of therapeutic agents and the extensive array of drug target polymorphisms in receptors and signalling pathways may well also define individuals who respond differentially to particular therapies. All of these three aspects of genetics are likely to have an important impact on the way drugs are developed and applied. In addition, this chapter identifies the increasing molecular information which is available and which has converted the field of pharmacogenetics into that of pharmacogenomics. It also highlights the potential role of other genomic technologies, such as differential screening, as potential adjuncts to the development of new drugs.

Chapter 2 provides details of the genetics of drug response as determined by drug metabolising enzymes. In particular, the extensive diversity of cytochrome P450 (CYP450) enzymes is described, as are variations in other enzymes such as alcohol and aldehyde dehydrogenases, N-acetyltransferases (NATs) and glucose-6-phosphate dehydrogenase (G6PD). Detailed examples of drug target polymorphism are highlighted in this chapter as are those outlining how genetics is re-shaping our taxonomy of human disease.

Chapter 3 provides a range of examples of potential applications of pharmacogenomics currently available. It highlights known variation in drug response which has been characterised at a genetic level in the area of cancer therapeutics, central nervous system (CNS) and cardiovascular drugs, and infectious disease. Examples and opportunities for the application of polymorphisms already recognised are discussed, highlighting a range of options potentially applicable to current therapy.

Chapter 4 outlines the practical issues which need to be addressed before pharmacogenomics can be properly applied, although the most immediate opportunity lies with candidate genes known already to be involved in drug biotransformation or differential response, this will provide only a small component of the overall understanding of individual differences in variation of response and toxicity. A more systematic approach to this is likely to arise as more disease susceptibility genes and drug target molecules are identified and polymorphisms defined. It is possible that large-scale association studies may provide some of this information, although these will present considerable difficulties in the near future. Similarly, the use of differential expression strategies to define surrogate markers and toxicity profiles may be an exciting opportunity in the future, but has yet to be proved as an effective application of genomic technology to clinical pharmacology.

Chapter 5 looks at future challenges and describes the forces that are responsible for a change in the approach taken to develop drugs and to apply therapeutic intervention differently in the clinic. The difficulties in achieving effective drug development in the face of substantial patient heterogeneity and the difficulty in achieving a better cost-benefit ratio in clinical practice are driving the implementation of an individualisation of therapy. Pharmacogenomics will largely underlie this development in the future. The ability to embrace a better understanding of drug responsiveness in individuals will determine the competitive positions, not only of pharmaceutical companies, but will also be a major factor in determining the success of healthcare providers.

This chapter also discusses some of the methods currently being used for the detection of single nucleotide polymorphisms (SNPs) and those being developed for the large-scale analysis of such multiple polymorphisms simultaneously. These technological hurdles remain an important requirement for the widespread application of pharmacogenomic technology to patient populations.

Chapter 6 provides a summary of company activities and important alliances in this area, outlining the interests of genomics, biotechnology and large pharmaceutical companies and the burgeoning technological developments in this field.

Pharmacogenomics: A new approach to targeting therapies

Industry Alert

Pharmacogenomics is a hot topic that affects every pharmaceutical company whether large or small. It refers to the study of individuals' responses to a drug, according to their genetic profiles. Pharmacogenomics is predicted to radically change the treatment market. This new approach will greatly increase the chances of successful clinical trials and improve patient outcomes.

This new report ensures that you are up-to-date with these important developments, including new technologies expanding the field. It also covers the background of pharmacogenomics and provides you with an overview of current and future trends.

Pharmacogenomics: A new approach to targeting therapies will enable you to: clearly understand exactly what pharmacogenomics is; implement pharmacogenomics effectively into your drug development programme; recognise which technologies are involved; determine the impact of pharmacogenomics on the pharmaceutical industry; evaluate the effects of pharmacogenomics on clinical trial design and identify which companies are involved in pharmacogenomics activities.

PUBLISHED: MAY 1998
REF: BS953E
PAGES: 60+
PRICE: £143/$300/¥35,000

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© PJB Publications Ltd. 2001 All rights reserved.