Pharmacogenomics:
Finding the Competitive Edge in Genetic Variation

Executive Summary

Chapter 1

Introduction

Chapter 2

Translating Pharmacogenomics Information into Therapeutic Knowledge and Market Value

Dr. William Wardell, Chief Scientific Officer at Covance Inc.

2.1 Focusing on the Output of Pharmacogenomics

2.2 Establishing a Pharmacogenomic Claim

2.3 Challenges Ahead in Delivering the Pharmacogenomics Promise

 

Finding an Economic Model

 

Breaking Through Resistance to New Technology

 

Competing with Other Process Improvements

 

Reliance On Diagnostic Tests

 

Competing With Trial Therapy

 

Including Genetic Variability in Business Mindsets and Models

2.4 Requirements for Advancing Pharmacogenomics

2.5 Early Confirmation of the Pharmacogenomic Hypothesis

2.6 After Confirmation

2.7 Impact of Pharmacogenomics on the Stages of Drug Development

2.8 Where Will Pharmacogenomics Be Most Valuable?

2.9 Other Open Questions

Chapter 3

The Right Medicine to the Right Patient: Pharmacogenetics and Pharmacogenomics in the Discovery of Medicines

Allen D. Roses, Senior Vice President, Genetics Research, at GlaxoSmithKline

3.1 Justification of the Pharmacogenomic Approach

3.2 The GlaxoSmithKline Approach

3.3 SNP Mapping

3.4 SNP Mapping in Alzheimer’s Disease

3.5 SNP Mapping in Psoriasis

3.6 SNP Mapping in Migraine

3.7 SNP Mapping in Diabetes

3.8 Gene-to-Function-to-Target Strategies

3.9 Using SNP Mapping to Identify Patient Groups Susceptible to Adverse Effects

 

Case Study - Adverse-Effect Susceptibility with Abacavir Abbreviated SNP Linkage Disequilibrium Profiles

3.10 Development of Comprehensive Medicine-Response Profiles

3.11 Conclusion

3.12 References

Chapter 4

Application of Structural Pharmacogenomics to Clinical Testing and Pharmaceutical Research

Dr. Kal Ramnaryan, Chief Scientific Officer, Structural Bioinformatics

4.1 A Platform for Structural Pharmacogenomics

4.2 A Self-Organizing Pharmacogenomic Market

4.3 Reining in Unpredictability with Phamacogenomics

4.4 A Description of the Structural Pharmacogenomics Approach

4.5 A Database for Structural Pharmacogenomics

4.6 The Database Interface

4.7 Answers for Drug Design and Development Strategy

4.8 Case Study in Structural Pharmacogenomics

4.9 Conclusion

Chapter 5

Pharmacogenomic Drug Response Profiling as a Tool for Compound Triage in Drug Discovery

Dr. Bonnie Gould Rothberg, Goup Leader Pharmacogenomics at Curagen Corporation

5.1 The Need for Early Safety and Efficacy Profiling of Drug Candidates

5.2 The GeneCalling Method

5.3 Expression Pharmacogenomics

5.4 Candidate Genes for SSRI Cardiotoxicity in the Treatment of Obesity

5.5 Candidate Genes for Trogliterzone Hepatotoxicity in the Treatment of Diabetes

5.6 Candidate Genes in NSAIDs Toxicity and Steroid Hormone Hepatotoxicity

5.7 Connecting Expression Profiling to Pharmacogenomics

5.8 Conclusion

Chapter 6

Application of Functional Genomics to Patient Populations – The Pharmacology of SNPs

Dr. David Wiener, Principal Scientist at ACADIA PharmacoGenomics

6.1 Determining the Functional Relevance of SNPs

6.2 The R-SAT Functional Assay Adapted to Pharmacogenomic Analysis

6.3 Creating a Library of All Known GPCRs

6.4 Functional Characterization of GPCR SNPs

6.5 Measuring Constitutive Activity of GPCR Variants

6.6 Using the Assay to Screen Anti-Psychotic Drugs

6.7 Functional Similarity Between Certain GPCR SNPs and Market Consequences

6.8 Screening of Individual Patients for GPCR Polymorphism and Drug Response

6.9 Screening Alzheimer’s Patients for Muscarinic Receptor Phenotypic Variation

6.10 Screening Alzheimer’s Patients for Muscarinic Receptor Phenotypic Variation

6.11 Conclusion

6.12 References

Chapter 7

Pharmacogenomics, Drug Targets, and Early Drug Evaluation

Dr. Roy Bullingham, Vice President of Global Clinical Pharmacology at Pharmacia

7.1 A Need to Adapt the Discovery and Develoment Process to New Technology

7.2 Why change is required

7.3 The role of pharmacogenomics in generating change

7.4 Specific Near Term Pharmacogenomic Strategies

7.5 Long Term Pharmacogenomic Strategies

7.6 Transforming R&D to Incorporate Pharmacogenomics

7.7 Taking Advantage of Current Strengths to Transform R&D

7.8 Phenotypes of Interest for Pharmacogenomics

 

Placebo Responders

 

Placebo Non-Responders

 

Disease Resistant

7.9 Conclusion

Chapter 8

Structured Representations of Pharmacogenomic Datarmacology at Pharmacia

Dr. Russ Altman of the Stanford Medical InformaticsGroup

8.1 Origins of a Bioinformatics Tool for Pharmacogenetics

8.2 Architecture of the RiboWeb System

8.3 The Importance of Ontologies and Standardized Vocabularies

8.4 Structured Experimental Templates

8.5 What Is Pharmacogenetics?

8.6 Management of Pharmacogenetics-Related Data

 

Overview of the NIH’s Pharmacogenetics Research/Database Program

 

The PharmGKB System

8.7 Conclusion

Chapter 9

Third Party Genetic Banking to Facilitate Genetic Research, Diagnosis and Medical Treatment

Andrea Califano, Chief Technology Officer of First Genetic Trust

9.1 Creating an Infrastructure for Pharmacogenomics

9.2 Barriers to Pharmacogenomic Studies

9.3 Infrastructure to Facilitate IRB Approval, Medical Data Banking and Analysis

9.4 Approaches to Facilitating Data Acquisition

9.5 The Biggest Challenge for Pharmaceutical Companies – Integration of Data and Communications

Chapter 10

The Structure of a Pharmacogenomics Study – Abbott/Genset

Dr. Tom Chu, Senior Scientist at Genset Corporation

10.1 Building an Industrial Genomics Capability

10.2 Advantages of Pharmacogenomics

10.3 Structure of a Pharmacogenomic Collaboration

10.4 The Prototype Pharmacogenomics Collaboration – The Abbott/Genset Zyflo Study

10.5 Conclusion

10.6 Definitions

Chapter 11

Integration of Pharmacogenomics into the Drug Research and Development Process

Dr. Jeff Fairman, Senior Scientist at Clingenix, Inc.

11.1 The Clingenix Business Model

11.2 Incorporation of Pharmacogenomics from Pre-clinical Research through Phase IV

11.3 Incorporation of Pharmacogenomics and Genotyping into Bridging Trials

11.4 What can Pharmacogenomics Do Now?11.5 Defining Genotypes for Effective Clinical Trials

11.5 Defining Genotypes for Effective Clinical Trials

11.6 Factors Influencing Pharmacogenomics Adoption by Pharmaceutical Companies

11.7 The Taiwan Insulin Resistance Study

11.8 References

Chapter 12

Integrating Clinical Data into Genomic Analysis

Dr. Michael Liebman, Global Head of Computational Genetics at Roche Bioscience

12.1 Semantics

12.2 What is Biomedical Informatics?

12.3 Tactical Considerations in Target Selection

12.4 Strategic Considerations in Target Selection

 

Recycling ADME/Tox Information into Discovery

 

Weighing the Components of Biological Activity

12.5 The Advantages of Understanding Disease Complexity

12.6 Models Employed to Understand Disease Complexity

12.7 Modeling and Database Building – From Early Disease Stages to Transplant Rejection

12.8 Modeling Menopause

12.9 Conclusion

Chapter 13

Application of CYP450 Genotyping as Prelude to Clinical Studies

Dr. Thomas Rushmore of the Department of Drug Metabolism at Merck and Company

13.1 Introduction

13.2 Clinical Use of Variant CYP450 Genes

13.3 Analysis of Kinetic Outliers

13.4 The P450 Gene Family

 

Phenotypes

 

Genotypes

13.5 Example CYP450 Gene: CYP2C9

13.6 Example P450 Gene: CYP2C19

13.7 Genotyping and Ethnicity

13.8 Conclusions

Chapter 14

Applications of Pharmacogenomics in Clinical Trials Phases I-IV

Ronald Norton, Director of Technical Services at PPGx Inc.

14.1 The Costs of Ignoring Pharmacogenomics

14.2 Pharmacogenomics in Practice Today

14.3 The Role of Prospective Genotyping in Phase I Trials

14.4 The Role of Pharmacogenomics in Phases II-IV

14.5 Role of Genome Banking in Phases II-IV

14.6 Incorporating Pharmacogenomics Into a Trial

14.7 Conclusion

14.8 References

Chapter 15

How the Genomics Revolution Affects FDA Regulation

Dr. Joseph Hackett, Associate Director for Clinical Laboratory Devices at the U.S. Food and Drug Administration

15.1 Balancing Interests While Adapting to New Technology

15.2 The Same Old FDA – Business as Usual

 

510 (k)

 

Pre-Market Approval

15.3 Adapting to New Developments in the Industry

 

A New 510(k) Paradigm

 

Third Party Review

 

Revised Pre-Market Review

 

Other Reform Activities

15.4 Main Objectives and Challenges in Reform

15.5 Common Pitfalls in Regulatory Approval

15.6 Expected Growth Areas

15.7 A Plea for Industry Collaboration for the Development of New Regulatory Policy

Chapter 16

Panel Discussion on the Clinical Applications of Pharmacogenomics

What are the factors that will determine how fast and to what degree pharmacogenomics will be integrated into development plans across the industry. Where will it take hold first? How will physicians react? How will it affect the way the FDA regulates the administration and marketing of drugs?

Chapter 17

Commercial Implications of Pharmacogenomics: Sales and Marketing

Craig Fitzgerald, Vice President of Commercial Genetics, Glaxo Wellcome

17.1 The Glaxo Wellcome Genetics Directorate

17.2 Educating the Industry and Consumers

17.3 Pharmacogenetics Impact

 

Differentiation

 

Diagnostics

 

Disintermediation

17.4 Anticipating New Pharmaceutical Market Economics

17.5 From Mass Market to Mass Customization

17.6 Conclusion

Chapter 18

Maximizing the Economic Impact of Pharmacogenomics

Dr. Trevor Nicholls, Chief Executive Officer of Oxagen Ltd.

18.1 Examining Areas of Greatest Impact and Economic Models

18.2 Distinguishing Current Opportunities from Future (or Misplaced) Promise

18.3 Oxagen Strategy

18.4 The Need for Better Drug Targeting

18.5 What the Industry Hopes to Gain from Pharmacogenomics

18.6 Pharmacogenomics, Drug Metabolism and Drug Responsiveness

18.7 Which Are the Most Relevant Targets For Pharmacogenomics?

18.8 SNP Discovery

18.9 Epidemiological Studies as Prelude to Disease Stratification

18.10 Increasing the Power of Clinical Trials – Osteoporosis Case Study

18.11 Increasing Market Potential by Identifying Preventative Applications

18.12 Prospecting for Genes

18.13 Opportunities – Now and Later

18.14 Financial Models

18.15 Conclusion

18.16 References

Chapter 19

Panel Discussion on the Commercial Implications of Pharmacogenomics

Issues discussed ranging from informed consent in gene banking, critical choices that affect the size and cost of genotyping efforts, prioritization of candidate genes, co-marketing of diagnostic tests, physician education, a shifting intellectual property landscape and the prospects for premium pricing.

Chapter 20

Table of Collaborative Activity in Pharmacogenomics and Genotyping 1999-2001