Pharmacogenomics for Clinical Use and in Drug Development

Table of Contents

1. Overview

• 1.1 Statement of Report
• 1.2 Objectives of this Report
• 1.3 Scope of the Study
• 1.4 Methodology
• 1.5 Executive Summary

2. Introduction

• 2.1 Pharmacogenomic Testing Overview
  • 2.1.1 Clinical Applications
  • 2.1.2 Technologies for Pharmacogenomic Diagnostic Tools
  • 2.1.3 Drug and Diagnostic Combinations
  • 2.1.4 Economic Impact of Healthcare Costs
• 2.2 Genetic Variation among Individuals
  • 2.2.1 Population Genomics
  • 2.2.2 SNPs and Haplotypes
  • 2.2.3 HapMap
    • 2.2.3.1 The International HapMap Project
    • 2.2.3.2 HapMap Participants and Funding Sources
• 2.3 Drug Metabolism
  • 2.3.1 Adverse Drug Reactions (ADRs)
  • 2.3.2 Drug-Test Combinations
• 2.4 Impact of Pharmacogenomics
  • 2.4.1 How Will Gene Variation Be Used in Predicting Drug Response?
  • 2.4.2 How Will Drug Development and Testing Benefit from Pharmacogenomics?
  • 2.4.3 Advantages of Pharmacogenomics
  • 2.4.4 The Diagnostics-Therapeutics Fusion
  • 2.4.5 Potential Challenges
  • 2.4.6 Poor Metabolizer Phenotype Testing
  • 2.4.7 Drug Repositioning
• 2.5 Pharmacogenomic Tests
  • 2.5.1 CYP2D6
  • 2.5.2 CYP2C19 and CYP2C9
  • 2.5.3 CYP3A4 and CYP3A5 Genotyping
  • 2.5.4 CYP1A2 and CYP2B6
  • 2.5.5 NAT2, DPD, and UGT1A1
• 2.6 HercepTest
• 2.7 Drivers of Pharmacogenomic Testing
• 2.8 Pharmacogenomics and Drug Discovery
  • 2.8.1 Business Implications of Pharmacogenomics in Drug Discovery
  • 2.8.2 Impact of Pharmacogenomics on Drug Sales
  • 2.8.3 Pressure to Optimize Drug Discovery Drives Use of Pharmacogenomics

3. Pharmacogenomic Testing Market: Size, Growth and Share

• 3.1 Global Pharmacogenomic Testing Markets by Technology Segments
  • 3.1.1 Market Structure
  • 3.1.2 Market Drivers in the Pharmacogenomic Diagnostics Testing Sector
  • 3.1.3 Market Restraints in Pharmacogenomic Diagnostic Testing Segment
  • 3.1.4 Principal Market Segments for Genomics Testing
    • 3.1.4.1 Diagnostic Testing
    • 3.1.4.2 Pharmacogenomic Testing
    • 3.1.4.3 SNP Identification
  • 3.1.5 Key Players in the Pharmacogenomic Diagnostics Testing Segment
  • 3.1.6 Pharmacogenomic Testing Sector Analysis
• 3.2 U.S. Pharmacogenomic Testing Market
  • 3.2.1 Market Overview
  • 3.2.2 Diagnostic Testing Categories
• 3.3 European Pharmacogenomic Diagnostic Testing Market
• 3.4 Japanese Diagnostic Testing Market

4. Pharmacogenomic Disease Markers

• 4.1 SNPs
  • 4.1.1 SNP Identification Market
  • 4.1.2 Overview of SNP Identification
  • 4.1.3 Strategies for SNP Identification
  • 4.1.4 Candidate Gene Selection
  • 4.1.5 Whole-Genome Linkage Disequilibrium Mapping
  • 4.1.6 SNP Databases
  • 4.1.7 Computational Tools for SNP Identification
  • 4.1.8 SNPbrowser, Applied Biosystems
  • 4.1.9 Progeny Suite, Progeny Software, LLC
  • 4.1.10 Sentrix Array Matrix, Illumina
  • 4.1.11 Third Wave Technologies (a Hologic Company)
• 4.2 Predictive Pharmacogenomics
  • 4.2.1 Cancer Testing
  • 4.2.2 Breast Cancer
  • 4.2.3 Melanoma
  • 4.2.4 Colon Cancer
  • 4.2.5 Predictive Cancer Testing Market Size
  • 4.2.6 Prostate Cancer
  • 4.2.7 Lung Cancer
  • 4.2.8 Acute Myelocytic Leukemia (AML)
  • 4.2.9 Cystic Fibrosis
  • 4.2.10 Genetic Test for Cardiac Ion Channel Mutations (Cardiac Channelopathies)
  • 4.2.11 Cardiac Transplants
  • 4.2.12 Thiopurine S-methyltransferase (TPMT) Genetic Test
  • 4.2.13 CARING Study
  • 4.2.14 Vilazodone
  • 4.2.15 STRENGTH Trials (Statin Response Examined by Genetic HAP Markers)
  • 4.2.16 HIV and AIDS
  • 4.2.17 Herceptin and Tykerb
  • 4.2.18 Asthma
  • 4.2.19 Hepatitis C Viral Load
• 4.3 Examining the Impact of Pharmacogenomics in Specific Disease Application
  • 4.3.1 The Impact of Pharmacogenomics in Bipolar and Other Psychiatric Disorders
  • 4.3.2 Pharmacogenomics in Warfarin Treatment
  • 4.3.3 Pharmacogenomics and Breast Cancer Treatment
  • 4.3.4 Pharmacogenomics of Depression
    • 4.3.4.1 Tricyclic Antidepressants
    • 4.3.4.2 Serotonin Re-uptake Inhibitors
    • 4.3.4.3 Mirtazapine and Venlafaxine
    • 4.3.4.4 Nefazodone, Moclobemide, Reboxetine and Trazodone
  • 4.3.5 Pharmacogenomics of Cardiovascular Disease
    • 4.3.5.1 Beta-blockers
    • 4.3.5.2 Angiotensin II Type 1 Receptor Antagonists and AT1 Receptor Antagonists (Sartans)
  • 4.3.6 Pharmacogenomics of Thromboembolic Disorders
    • 4.3.6.1 Warfarin
    • 4.3.6.2 Acenocoumarol
    • 4.3.6.3 Phenprocoumon
• 4.4 Gene Chips to Detect Cytochrome Variations
  • 4.4.1 AmpliChip CYP450-Roche Diagnostics
  • 4.4.2 GeneChip System-Affymetrix
  • 4.4.3 NanoChip Molecular Biology Workstation-Nanogen, Inc.

5. Pharmacogenomic Testing: Development Issues

• 5.1 Adoption of Pharmacogenomic Testing
  • 5.1.1 Pharmacogenomics Gatekeepers
    • 5.1.1.1 Industry
      • 5.1.1.1.1 Use of Pharmacogenomics in Drug Development
      • 5.1.1.1.2 Co-development of Pharmacogenomics Diagnostics and Drugs
    • 5.1.1.2 FDA as a Gatekeeper of Pharmacogenomics
• 5.2 Factors Influencing the Integration of Pharmacogenomics into Clinical Trials
• 5.3 Moderators of Growth
  • 5.3.1 Classification of Extensive vs. Poor Metabolizer
  • 5.3.2 Genetic Testing
  • 5.3.3 Cost-Benefit of Pharmacogenomic Testing
  • 5.3.4 Workforce Issues
  • 5.3.5 Reimbursement
  • 5.3.6 New CPT Test Codes and Payment Amounts
  • 5.3.7 CMS and Other Third-party Payers
    • 5.3.7.1 Reimbursement Challenges to Pharmacogenomic Testing
    • 5.3.7.2 CMS Regulatory Responsibilities
    • 5.3.7.3 Costs Associated with Pharmacogenomic Testing
• 5.4 Clinical Guidelines and Pharmacogenomic Testing
• 5.5 Good Laboratory Practice (GLP)
• 5.6 Quality Assurance Issues
  • 5.6.1 Criteria Required to Establish a Genomic Test for Clinical Use
  • 5.6.2 Microarrays in Clinical Diagnostic Use
• 5.7 Pre-therapeutic Pharmacogenomic Testing
• 5.8 Regulatory Requirements
• 5.9 Screening
• 5.10 Cost of Phenotyping vs. Genotyping
• 5.11 Pharmacogenomic Tests: New Product Development
• 5.12 Underutilization of Pharmacogenomic Tests

6. Business Trends in the Industry

• 6.1 Pharmacogenomic Initiatives within Pharmaceutical Companies
• 6.2 Pharmacogenomic Testing Growth Factors
• 6.3 Acquisition, License Agreements, Internal Development and Partnerships
• 6.4 Product Testing Depth in Pharmacogenomic Testing
• 6.5 Government Regulation
  • 6.5.1 U.S. Regulations
  • 6.5.2 U.K. Regulations
  • 6.5.3 E.U. Regulations
  • 6.5.4 Japanese Regulations
• 6.6 Increased Market Penetration in Pharmacogenomic Testing
• 6.7 Legal Issues
  • 6.7.1 Federal Policy History
  • 6.7.2 State Policy History
  • 6.7.3 Federal Anti-Discrimination Laws and How They Apply to Genetics
  • 6.7.3.1 The Genetic Information Nondiscrimination Act of 2008 (GINA)
  • 6.7.4 Prescription Drug User Fee Act (PDUFA)
  • 6.7.5 Liability Concerns for Pharmacogenomics Drug and Diagnostic Developers
• 6.8 Barriers to Growth
• 6.9 Drivers of Growth
• 6.10 Product Launches and Developments
• 6.11 Investment Parameters for Diagnostic Companies
• 6.12 Key Elements of the Pharmaceutical Value Chain
• 6.13 An Evaluation of Successful Pharmacogenomic Business Models
• 6.14 Ethical Considerations for Pharmacogenomic Applications
• 6.15 Drug Repositioning Services
• 6.16 Patent Protection of Pharmacogenomic Technology
• 6.17 FDA Product Submission and Review Process
• 6.18 FDA Pipeline for Pharmacogenomic Tests
• 6.19 Adaptive Clinical Trial Design

7. Important Technology Trends in Pharmacogenomics

• 7.1 Trends in Pharmacogenomic Testing
  • 7.1.1 Toxicogenomics
• 7.2 Drug Metabolism
• 7.3 Personalized Medicine: the Genomic and Proteomic Approach
• 7.4 Biomarkers
  • 7.4.1 Cancer
    • 7.4.1.1 Leukemia: Gleevec and Dasatinib (BMS-354825)
    • 7.4.1.2 Gefitinib (Iressa)
    • 7.4.1.3 Colorectal Cancer
• 7.5 Cardiovascular Drugs
  • 7.5.1 Arrhythmia
  • 7.5.2 Hypertension
  • 7.5.3 Hyperlipidemia
  • 7.5.4 Myocardial Infarction
  • 7.5.5 Heart Failure
• 7.6 Future Developments
  • 7.6.1 GSK' s Pharmacogenomic Program
  • 7.6.2 Roche' s Biomarker Strategy
  • 7.6.3 Hypertension Markets
  • 7.6.4 Expression Data to Integrate Pharmacology and Chemistry Data
  • 7.6.5 Metabolomics
  • 7.6.6 Theranostics

8. Overview and Conclusions

• 8.1 The Unrealized Promise of Pharmacogenomics
• 8.2 The New Drug Pipeline
• 8.3 Pharmacogenomics and Regulation
• 8.4 Pharmacogenomics and Reimbursement
• 8.5 Key Considerations for Realizing the Promise of Pharmacogenomics
• 8.6 Development of Easy to Use Point of Care Pharmacogenomic Tests
• 8.7 Development of Pharmacogenomic Tests during Drug Development
• 8.8 Pharmacogenomics' Impact on Commercial Strategies
• 8.9 Pharmacogenomics' Impact on the Blockbuster Model of Drug Development
• 8.10 Pharmacogenomics' Impact on Clinical Trials
• 8.11 Pharmacogenomic Business Models
• 8.12 Structure of Pharmacogenomic Deals and Alliances
• 8.13 Challenges to Pharmacogenomics

9. Company Profiles

• 9.1 Abbott Laboratories
• 9.2 Affymetrix
• 9.3 Agilent Technologies, Inc.
• 9.4 Ambry Genetics
• 9.5 ARCA Biopharma, Inc.
• 9.6 Asper Biotech
• 9.7 AstraZeneca
• 9.8 Bayer
• 9.9 BioTrove, Inc.
• 9.10 Bristol-Myers Squibb
• 9.11 Celera Group
• 9.12 Clinical Data
• 9.13 CombinatoRx, Inc.
• 9.14 Complement Genomics Ltd.
• 9.15 Covance Inc.
• 9.16 CuraGen Corporation
• 9.17 Cypress Bioscience, Inc.
• 9.18 Dako (formerly DakoCytomation)
• 9.19 deCODE Genetics
• 9.20 DNAPrint Genomics
• 9.21 DxS
• 9.22 EraGen Biosciences
• 9.23 EXACT Sciences
• 9.24 Expression Analysis
• 9.25 FivePrime Therapeutics
• 9.26 GE Healthcare
• 9.27 Gene Express, Inc.
• 9.28 GeneGO Inc.
• 9.29 Genelex Corporation
• 9.30 Genentech
• 9.31 Genizon Biosciences Inc.
• 9.32 Genomic Health
• 9.33 Gentris
• 9.34 Genzyme
• 9.35 GlaxoSmithKline
• 9.36 g-Nostics Ltd.
• 9.37 Hologic
• 9.38 Human Genome Sciences
• 9.39 Illumina
• 9.40 Incyte, Inc.
• 9.41 InterGenetics Inc.
• 9.42 Interleukin Genetics
• 9.43 Iris BioTechnologies Inc.
• 9.44 Johnson & Johnson
• 9.45 Lab21
• 9.46 Life Technologies Corporation
• 9.47 Luminex Corp.
• 9.48 MediBIC Group
• 9.49 Melior Discovery Inc.
• 9.50 Merck & Co.
• 9.51 Merck Serano
• 9.52 Millennium Pharmaceuticals
• 9.53 Monogram Biosciences, Inc.
• 9.54 Myriad Genetics, Inc.
• 9.55 Nanogen
• 9.56 Nanosphere
• 9.57 Nitromed
• 9.58 Ocimum Biosolutions
• 9.59 Orchid Cellmark
• 9.60 Ore Pharmaceuticals
• 9.61 PharmaSeq
• 9.62 Prediction Sciences
• 9.63 Predictive Biosciences
• 9.64 Prometheus Laboratories
• 9.65 Progeny Software, LLC
• 9.66 Roche Diagnostics
• 9.67 Response Genetics, Inc.
• 9.68 Sequenom
• 9.69 SimuGen Ltd.
• 9.70 Sosei Group Corporation
• 9.71 Transgenomic, Inc.
• 9.72 TrimGen Corp.
• 9.73 Tripos International
• 9.74 Vertex Pharmaceuticals
• 9.75 VIA Pharmaceuticals, Inc.
• 9.76 Warnex
• 9.77 Wyeth
• 9.78 XDx, Inc.

INDEX OF FIGURES

• Figure 2.1: Roche AmpliChip
• Figure 2.2: FDA Approval Rates for NME Drug Applications vs. R&D Expenditures, 1998-2008
• Figure 2.3: Steps Involved in Bringing a Drug to Market
• Figure 2.4: CYP2C9
• Figure 6.1: Total Spending on Healthcare in the U.S., 1960-2008
• Figure 6.2: The Healthcare Dollar, 2008

INDEX OF TABLES

• Table 1.1: The Success of Pharmacogenomics: Drugs that Utilize Companion Tests, 2008
• Table 2.1: The Difference between Pharmacogenomics and Pharmacogenetics
• Table 2.2: Clinical Applications of Diagnostic Pharmacogenomic Testing
• Table 2.3: Comparison of New Molecular Entity Outcomes for FDA and EMEA (Jan 2006 - October 2008)
• Table 2.4: Timeline for Development of Companion Diagnostics
• Table 2.5: Valid Genomic Biomarkers in the Context of FDA-Approved Drug Labels
• Table 2.6: Potential Benefits of Biomarkers as Companion Diagnostics in Drug Development
• Table 2.7: Groups Participating in the International HapMap Project
• Table 2.8: High-Profile Drug Withdrawals from the Marketplace
• Table 2.9: Response Rates of Patients to a Major Drug for Selected Therapeutic Areas
• Table 2.10 Factors That Determine a Successful Pharmacogenomic Test
• Table 2.11: Pharmacogenomics' Influence on Drug Sales
• Table 2.12: Pharmacogenomics' Effect on Maximizing R&D Productivity
• Table 2.13: Prevalence of Metabolically-Active Enzymes
• Table 2.14: Pharmacogenomics in Phase II and Phase III Trials
• Table 2.15: Drug Testing
• Table 2.16: Factors Affecting Variability in Individual Response to Drug Therapy
• Table 2.17: CYP2D6 Characteristics
• Table 2.18: CYP2D6 Metabolism of Drug Types
• Table 2.19: CYP2C19
• Table 2.20: CYP2C19 Metabolism of Drug Types
• Table 2.21: CYP2C9 Characteristics
• Table 2.22: CYP2C9 Metabolism of Drug Types
• Table 2.23: CYP3A4/5/7 Metabolism of Drug Types
• Table 2.24: CYP1A2 Metabolism of Drug Types
• Table 2.25: CYP2B6 Metabolism of Drug Types
• Table 2.26: Drivers of Pharmacogenomic Testing
• Table 2.27: Markets for Pharmacogenomic Testing
• Table 3.1: Worldwide Pharmacogenomic Market Size by Technology Segments, 2004-2012
• Table 3.2: Total Pharmacogenomic Testing Market Size, 2001-2012
• Table 3.3: Diagnostic Pharmacogenomic Testing Market Size, 2001-2012
• Table 3.4: Benefits of Pharmacogenomic Diagnostics in Patient Care
• Table 3.5: Genotyping Pharmacogenomic Testing Market Size, 2001-2012
• Table 3.6: Benefits of Pharmacogenomics in Clinical Trials and Drug Development
• Table 3.7: Five Key Action Points for Pharmaceutical Companies
• Table 3.8: Global SNP Identification Tools Market Size, 2004-2012
• Table 3.9: Pharmacogenomic Testing Market Structure
• Table 3.10: P450 Isozymes and Pharmaceuticals
• Table 3.11: List of Companies that Market Pharmacogenomic Tests
• Table 3.12: Key Collaborations in the Pharmacogenomics Industry
• Table 3.13: Prominent Drugs Withdrawn from the Market
• Table 3.14: Key Elements in the Drug Development Process
• Table 3.15: Major Suppliers of PCR-based Assays and PCR-based Technologies
• Table 4.1: Methods for Performing NAT
• Table 4.2: SNP Databases
• Table 4.3: Myriad Genetics Predictive Medicine Sales, 2001-2008
• Table 4.4: DNA-based Predictive Medicine Product Sales for Cancer, 2006-2010
• Table 4.5: Developmental Atherosclerosis Drugs
• Table 4.6: Summary of Assays for HIV Viral Load Testing
• Table 4.7: U.S. Market Share of HIV Testing Kits
• Table 4.8: Global HIV Statistics, 2007
• Table 4.9: List of Approved HIV/AIDS Rapid Test Kits, 2009
• Table 4.10: Monogram Bioscience, Inc. Products for HIV Testing
• Table 4.11: CCR-5 Receptor Agonists in Development, 2009
• Table 4.12: Asthma Therapeutic Drug Pipeline
• Table 4.13: Psychiatric Case Studies, Organized Pharmacokinetically
• Table 4.14: Antidepressant Drugs Decreased Clearance with DME CYP2D6
• Table 4.15: Antidepressant Drugs with No Effect Clearance with DME CYP2D6
• Table 5.1: Examples of Gene-Drug Pharmacogenomic Relationships
• Table 5.2: Estimated Cost and Time for Typing of the BRCA1 Gene by Direct Sequencing vs. SNP Array
• Table 5.3: Average Cost of Resistance Testing, 2007
• Table 6.1: U.S. Prescription Drug Expenditures, 2003-2015
• Table 6.2: U.S. Pharmaceutical Market, 1996-2009
• Table 6.3: Top Ten Global Pharmaceutical Companies by Global Sales, 2007
• Table 6.4: Pharmaceutical Companies Ranked by Total R&D Expenditures, 2007
• Table 6.5: Leading Therapy Classes for R&D, 2008
• Table 6.6: Leading Therapy Classes by Global Pharmaceutical Sales (Audited Market), 2007
• Table 6.7: Number of NME Approvals and Mean Approval Times, 1984-2008
• Table 6.8: Global Market for Tools and Consumables Used in Drug Discovery and Development, 1999-2010
• Table 6.9: Leading Therapeutic Classes by U.S. Sales, 2006 and 2007
• Table 6.10: Top Ten Therapeutic Classes by U.S. Dispensed Prescriptions, 2006 and 2007
• Table 6.11: Top Ten Brand Drugs by U.S. Retail, 2007
• Table 7.1: Select Companies Developing Cancer Diagnostics Available as Analyte Specific Reagents (ASRS)
• Table 7.2: Emerging Fields in Biological Science with the Potential to Impact Personalized Medicine