Pharmacogenomics for Clinical Use and in Drug Development

1. Overview 8
1.1 Statement of Report 8
1.2 Objectives of this Report 8
1.3 Scope of the Study 9
1.4 Methodology 10
1.5 Executive Summary 11
2. Introduction 17
2.1 Pharmacogenomic Testing Overview 17
2.1.1 Clinical Applications 18
2.1.2 Technologies for Pharmacogenomic Diagnostic Tools 19
2.1.3 Drug and Diagnostic Combinations 22
2.1.4 Economic Impact of Healthcare Costs 23
2.2 Genetic Variation among Individuals 33
2.2.1 Population Genomics 33
2.2.2 SNPs and Haplotypes 33
2.2.3 HapMap 35
2.2.3.1 The International HapMap Project 35
2.2.3.2 HapMap Participants and Funding Sources 36
2.3 Drug Metabolism 37
2.3.1 Adverse Drug Reactions (ADRs) 37
2.3.2 Drug-Test Combinations 39
2.4 Impact of Pharmacogenomics 39
2.4.1 How Will Gene Variation Be Used in Predicting Drug Response? 40
2.4.2 How Will Drug Development and Testing Benefit from Pharmacogenomics? 40
2.4.3 Advantages of Pharmacogenomics 40
2.4.4 The Diagnostics-Therapeutics Fusion 41
2.4.5 Potential Challenges 42
2.4.6 Poor Metabolizer Phenotype Testing 44
2.4.7 Drug Repositioning 45
2.5 Pharmacogenomic Tests 46
2.5.1 CYP2D6 46
2.5.2 CYP2C19 and CYP2C9 49
2.5.3 CYP3A4 and CYP3A5 Genotyping 52
2.5.4 CYP1A2 and CYP2B6 54
2.5.5 NAT2, DPD, and UGT1A1 55
2.6 HercepTest 56
2.7 Drivers of Pharmacogenomic Testing 56
2.8 Pharmacogenomics and Drug Discovery 57
2.8.1 Business Implications of Pharmacogenomics in Drug Discovery 58
2.8.2 Impact of Pharmacogenomics on Drug Sales 59
2.8.3 Pressure to Optimize Drug Discovery Drives Use of Pharmacogenomics 60
3. Pharmacogenomic Testing Market: Size, Growth and Share 61
3.1 Global Pharmacogenomic Testing Markets by Technology Segments 61
3.1.1 Market Structure 61
3.1.2 Market Drivers in the Pharmacogenomic Diagnostics Testing Sector 62
3.1.3 Market Restraints in Pharmacogenomic Diagnostic Testing Segment 62
3.1.4 Principal Market Segments for Genomics Testing 62
3.1.4.1 Diagnostic Testing 62
3.1.4.2 Pharmacogenomic Testing 64
3.1.4.3 SNP Identification 65
3.1.5 Key Players in the Pharmacogenomic Diagnostics Testing Segment 67
3.1.6 Pharmacogenomic Testing Sector Analysis 67
3.2 U.S. Pharmacogenomic Testing Market 68
3.2.1 Market Overview 69
3.2.2 Diagnostic Testing Categories 71
3.3 European Pharmacogenomic Diagnostic Testing Market 71
3.4 Japanese Diagnostic Testing Market 71
4. Pharmacogenomic Disease Markers 74
4.1 SNPs 74
4.1.1 SNP Identification Market 74
4.1.2 Overview of SNP Identification 75
4.1.3 Strategies for SNP Identification 76
4.1.4 Candidate Gene Selection 77
4.1.5 Whole-Genome Linkage Disequilibrium Mapping 77
4.1.6 SNP Databases 78
4.1.7 Computational Tools for SNP Identification 80
4.1.8 SNPbrowser, Applied Biosystems 80
4.1.9 Progeny Suite, Progeny Software, LLC 81
4.1.10 Sentrix Array Matrix, Illumina 81
4.1.11 Third Wave Technologies (a Hologic Company) 81
4.2 Predictive Pharmacogenomics 81
4.2.1 Cancer Testing 81
4.2.2 Breast Cancer 83
4.2.3 Melanoma 86
4.2.4 Colon Cancer 87
4.2.5 Predictive Cancer Testing Market Size 89
4.2.6 Prostate Cancer 89
4.2.7 Lung Cancer 89
4.2.8 Acute Myelocytic Leukemia (AML) 89
4.2.9 Cystic Fibrosis 90
4.2.10 Genetic Test for Cardiac Ion Channel Mutations (Cardiac Channelopathies) 91
4.2.11 Cardiac Transplants 92
4.2.12 Thiopurine S-methyltransferase (TPMT) Genetic Test 92
4.2.13 CARING Study 92
4.2.14 Vilazodone 93
4.2.15 STRENGTH Trials (Statin Response Examined by Genetic HAP Markers) 94
4.2.16 HIV and AIDS 94
4.2.17 Herceptin and Tykerb 103
4.2.18 Asthma 104
4.2.19 Hepatitis C Viral Load 106
4.3 Examining the Impact of Pharmacogenomics in Specific Disease Application 107
4.3.1 The Impact of Pharmacogenomics in Bipolar and Other Psychiatric Disorders 107
4.3.2 Pharmacogenomics in Warfarin Treatment 109
4.3.3 Pharmacogenomics and Breast Cancer Treatment 110
4.3.4 Pharmacogenomics of Depression 110
4.3.4.1 Tricyclic Antidepressants 110
4.3.4.2 Serotonin Re-uptake Inhibitors 111
4.3.4.3 Mirtazapine and Venlafaxine 111
4.3.4.4 Nefazodone, Moclobemide, Reboxetine and Trazodone 111
4.3.5 Pharmacogenomics of Cardiovascular Disease 112
4.3.5.1 Beta-blockers 112
4.3.5.2 Angiotensin II Type 1 Receptor Antagonists and AT1 Receptor Antagonists (Sartans) 112
4.3.6 Pharmacogenomics of Thromboembolic Disorders 113
4.3.6.1 Warfarin 113
4.3.6.2 Acenocoumarol 113
4.3.6.3 Phenprocoumon 113
4.4 Gene Chips to Detect Cytochrome Variations 113
4.4.1 AmpliChip CYP450-Roche Diagnostics 114
4.4.2 GeneChip System-Affymetrix 114
4.4.3 NanoChip Molecular Biology Workstation-Nanogen, Inc. 115
5. Pharmacogenomic Testing: Development Issues 116
5.1 Adoption of Pharmacogenomic Testing 116
5.1.1 Pharmacogenomics Gatekeepers 116
5.1.1.1 Industry 116
5.1.1.1.1 Use of Pharmacogenomics in Drug Development 117
5.1.1.1.2 Co-development of Pharmacogenomics Diagnostics and Drugs 117
5.1.1.2 FDA as a Gatekeeper of Pharmacogenomics 118
5.2 Factors Influencing the Integration of Pharmacogenomics into Clinical Trials 118
5.3 Moderators of Growth 118
5.3.1 Classification of Extensive vs. Poor Metabolizer 118
5.3.2 Genetic Testing 119
5.3.3 Cost-Benefit of Pharmacogenomic Testing 120
5.3.4 Workforce Issues 121
5.3.5 Reimbursement 121
5.3.6 New CPT Test Codes and Payment Amounts 126
5.3.7 CMS and Other Third-party Payers 127
5.3.7.1 Reimbursement Challenges to Pharmacogenomic Testing 127
5.3.7.2 CMS Regulatory Responsibilities 131
5.3.7.3 Costs Associated with Pharmacogenomic Testing 132
5.4 Clinical Guidelines and Pharmacogenomic Testing 133
5.5 Good Laboratory Practice (GLP) 133
5.6 Quality Assurance Issues 133
5.6.1 Criteria Required to Establish a Genomic Test for Clinical Use 134
5.6.2 Microarrays in Clinical Diagnostic Use 134
5.7 Pre-therapeutic Pharmacogenomic Testing 135
5.8 Regulatory Requirements 135
5.9 Screening 136
5.10 Cost of Phenotyping vs. Genotyping 137
5.11 Pharmacogenomic Tests: New Product Development 138
5.12 Underutilization of Pharmacogenomic Tests 138
6. Business Trends in the Industry 140
6.1 Pharmacogenomic Initiatives within Pharmaceutical Companies 140
6.2 Pharmacogenomic Testing Growth Factors 146
6.3 Acquisition, License Agreements, Internal Development and Partnerships 146
6.4 Product Testing Depth in Pharmacogenomic Testing 149
6.5 Government Regulation 150
6.5.1 U.S. Regulations 151
6.5.2 U.K. Regulations 151
6.5.3 E.U. Regulations 153
6.5.4 Japanese Regulations 154
6.6 Increased Market Penetration in Pharmacogenomic Testing 155
6.7 Legal Issues 155
6.7.1 Federal Policy History 156
6.7.2 State Policy History 157
6.7.3 Federal Anti-Discrimination Laws and How They Apply to Genetics 157
6.7.3.1 The Genetic Information Nondiscrimination Act of 2008 (GINA) 158
6.7.4 Prescription Drug User Fee Act (PDUFA) 160
6.7.5 Liability Concerns for Pharmacogenomics Drug and Diagnostic Developers 160
6.8 Barriers to Growth 160
6.9 Drivers of Growth 161
6.10 Product Launches and Developments 162
6.11 Investment Parameters for Diagnostic Companies 162
6.12 Key Elements of the Pharmaceutical Value Chain 162
6.13 An Evaluation of Successful Pharmacogenomic Business Models 162
6.14 Ethical Considerations for Pharmacogenomic Applications 163
6.15 Drug Repositioning Services 163
6.16 Patent Protection of Pharmacogenomic Technology 165
6.17 FDA Product Submission and Review Process 167
6.18 FDA Pipeline for Pharmacogenomic Tests 167
6.19 Adaptive Clinical Trial Design 168
7. Important Technology Trends in Pharmacogenomics 170
7.1 Trends in Pharmacogenomic Testing 170
7.1.1 Toxicogenomics 170
7.2 Drug Metabolism 171
7.3 Personalized Medicine: the Genomic and Proteomic Approach 172
7.4 Biomarkers 173
7.4.1 Cancer 173
7.4.1.1 Leukemia: Gleevec and Dasatinib (BMS-354825) 174
7.4.1.2 Gefitinib (Iressa) 175
7.4.1.3 Colorectal Cancer 175
7.5 Cardiovascular Drugs 176
7.5.1 Arrhythmia 177
7.5.2 Hypertension 178
7.5.3 Hyperlipidemia 179
7.5.4 Myocardial Infarction 179
7.5.5 Heart Failure 179
7.6 Future Developments 181
7.6.1 GSK's Pharmacogenomic Program 181
7.6.2 Roche's Biomarker Strategy 181
7.6.3 Hypertension Markets 182
7.6.4 Expression Data to Integrate Pharmacology and Chemistry Data 182
7.6.5 Metabolomics 183
7.6.6 Theranostics 183
8. Overview and Conclusions 185
8.1 The Unrealized Promise of Pharmacogenomics 185
8.2 The New Drug Pipeline 186
8.3 Pharmacogenomics and Regulation 186
8.4 Pharmacogenomics and Reimbursement 186
8.5 Key Considerations for Realizing the Promise of Pharmacogenomics 187
8.6 Development of Easy to Use Point of Care Pharmacogenomic Tests 188
8.7 Development of Pharmacogenomic Tests during Drug Development 188
8.8 Pharmacogenomics' Impact on Commercial Strategies 189
8.9 Pharmacogenomics' Impact on the Blockbuster Model of Drug Development 189
8.10 Pharmacogenomics' Impact on Clinical Trials 189
8.11 Pharmacogenomic Business Models 190
8.12 Structure of Pharmacogenomic Deals and Alliances 190
8.13 Challenges to Pharmacogenomics 190
9. Company Profiles 191
9.1 Abbott Laboratories 191
9.2 Affymetrix 192
9.3 Agilent Technologies, Inc. 194
9.4 Ambry Genetics 194
9.5 ARCA Biopharma, Inc. 194
9.6 Asper Biotech 195
9.7 AstraZeneca 195
9.8 Bayer 195
9.9 BioTrove, Inc. 197
9.10 Bristol-Myers Squibb 197
9.11 Celera Group 198
9.12 Clinical Data 199
9.13 CombinatoRx, Inc. 200
9.14 Complement Genomics Ltd. 201
9.15 Covance Inc. 201
9.16 CuraGen Corporation 202
9.17 Cypress Bioscience, Inc. 203
9.18 Dako (formerly DakoCytomation) 203
9.19 deCODE Genetics 204
9.20 DNAPrint Genomics 205
9.21 DxS 206
9.22 EraGen Biosciences 206
9.23 EXACT Sciences 207
9.24 Expression Analysis 207
9.25 FivePrime Therapeutics 207
9.26 GE Healthcare 208
9.27 Gene Express, Inc. 208
9.28 GeneGO Inc. 209
9.29 Genelex Corporation 210
9.30 Genentech 210
9.31 Genizon Biosciences Inc. 212
9.32 Genomic Health 212
9.33 Gentris 213
9.34 Genzyme 213
9.35 GlaxoSmithKline 215
9.36 g-Nostics Ltd. 217
9.37 Hologic 217
9.38 Human Genome Sciences 218
9.39 Illumina 220
9.40 Incyte, Inc. 221
9.41 InterGenetics Inc. 222
9.42 Interleukin Genetics 222
9.43 Iris BioTechnologies Inc. 223
9.44 Johnson & Johnson 223
9.45 Lab21 224
9.46 Life Technologies Corporation 225
9.47 Luminex Corp. 225
9.48 MediBIC Group 227
9.49 Melior Discovery Inc. 227
9.50 Merck & Co. 227
9.51 Merck Serano 228
9.52 Millennium Pharmaceuticals 229
9.53 Monogram Biosciences, Inc. 229
9.54 Myriad Genetics, Inc. 230
9.55 Nanogen 231
9.56 Nanosphere 232
9.57 Nitromed 232
9.58 Ocimum Biosolutions 233
9.59 Orchid Cellmark 233
9.60 Ore Pharmaceuticals 234
9.61 PharmaSeq 234
9.62 Prediction Sciences 234
9.63 Predictive Biosciences 234
9.64 Prometheus Laboratories 235
9.65 Progeny Software, LLC 235
9.66 Roche Diagnostics 236
9.67 Response Genetics, Inc. 237
9.68 Sequenom 238
9.69 SimuGen Ltd. 239
9.70 Sosei Group Corporation 239
9.71 Transgenomic, Inc. 239
9.72 TrimGen Corp. 239
9.73 Tripos International 239
9.74 Vertex Pharmaceuticals 240
9.75 VIA Pharmaceuticals, Inc. 240
9.76 Warnex 241
9.77 Wyeth 241
9.78 XDx, Inc. 242
INDEX OF FIGURES
Figure 2.1: Roche AmpliChip 20
Figure 2.2: FDA Approval Rates for NME Drug Applications vs. R&D Expenditures, 1998-2008 24
Figure 2.3: Steps Involved in Bringing a Drug to Market 26
Figure 2.4: CYP2C9 50
Figure 6.1: Total Spending on Healthcare in the U.S., 1960-2008 141
Figure 6.2: The Healthcare Dollar, 2008 142
INDEX OF TABLES
Table 1.1: The Success of Pharmacogenomics: Drugs that Utilize Companion Tests, 2008 16
Table 2.1: The Difference between Pharmacogenomics and Pharmacogenetics 18
Table 2.2: Clinical Applications of Diagnostic Pharmacogenomic Testing 20
Table 2.3: Comparison of New Molecular Entity Outcomes for FDA and EMEA (Jan 2006 - October 2008) 24
Table 2.4: Timeline for Development of Companion Diagnostics 27
Table 2.5: Valid Genomic Biomarkers in the Context of FDA-Approved Drug Labels 28
Table 2.6: Potential Benefits of Biomarkers as Companion Diagnostics in Drug Development 33
Table 2.7: Groups Participating in the International HapMap Project 36
Table 2.8: High-Profile Drug Withdrawals from the Marketplace 39
Table 2.9: Response Rates of Patients to a Major Drug for Selected Therapeutic Areas 41
Table 2.10 Factors That Determine a Successful Pharmacogenomic Test 43
Table 2.11: Pharmacogenomics' Influence on Drug Sales 43
Table 2.12: Pharmacogenomics' Effect on Maximizing R&D Productivity 44
Table 2.13: Prevalence of Metabolically-Active Enzymes 44
Table 2.14: Pharmacogenomics in Phase II and Phase III Trials 44
Table 2.15: Drug Testing 45
Table 2.16: Factors Affecting Variability in Individual Response to Drug Therapy 45
Table 2.17: CYP2D6 Characteristics 47
Table 2.18: CYP2D6 Metabolism of Drug Types 48
Table 2.19: CYP2C19 49
Table 2.20: CYP2C19 Metabolism of Drug Types 49
Table 2.21: CYP2C9 Characteristics 50
Table 2.22: CYP2C9 Metabolism of Drug Types 51
Table 2.23: CYP3A4/5/7 Metabolism of Drug Types 53
Table 2.24: CYP1A2 Metabolism of Drug Types 54
Table 2.25: CYP2B6 Metabolism of Drug Types 55
Table 2.26: Drivers of Pharmacogenomic Testing 56
Table 2.27: Markets for Pharmacogenomic Testing 57
Table 3.1: Worldwide Pharmacogenomic Market Size by Technology Segments, 2004-2012 61
Table 3.2: Total Pharmacogenomic Testing Market Size, 2001-2012 61
Table 3.3: Diagnostic Pharmacogenomic Testing Market Size, 2001-2012 63
Table 3.4: Benefits of Pharmacogenomic Diagnostics in Patient Care 64
Table 3.5: Genotyping Pharmacogenomic Testing Market Size, 2001-2012 64
Table 3.6: Benefits of Pharmacogenomics in Clinical Trials and Drug Development 64
Table 3.7: Five Key Action Points for Pharmaceutical Companies 65
Table 3.8: Global SNP Identification Tools Market Size, 2004-2012 65
Table 3.9: Pharmacogenomic Testing Market Structure 66
Table 3.10: P450 Isozymes and Pharmaceuticals 66
Table 3.11: List of Companies that Market Pharmacogenomic Tests 69
Table 3.12: Key Collaborations in the Pharmacogenomics Industry 70
Table 3.13: Prominent Drugs Withdrawn from the Market 70
Table 3.14: Key Elements in the Drug Development Process 70
Table 3.15: Major Suppliers of PCR-based Assays and PCR-based Technologies 70
Table 4.1: Methods for Performing NAT 74
Table 4.2: SNP Databases 80
Table 4.3: Myriad Genetics Predictive Medicine Sales, 2001-2008 89
Table 4.4: DNA-based Predictive Medicine Product Sales for Cancer, 2006-2010 89
Table 4.5: Developmental Atherosclerosis Drugs 94
Table 4.6: Summary of Assays for HIV Viral Load Testing 95
Table 4.7: U.S. Market Share of HIV Testing Kits 95
Table 4.8: Global HIV Statistics, 2007 96
Table 4.9: List of Approved HIV/AIDS Rapid Test Kits, 2009 97
Table 4.10: Monogram Bioscience, Inc. Products for HIV Testing 102
Table 4.11: CCR-5 Receptor Agonists in Development, 2009 103
Table 4.12: Asthma Therapeutic Drug Pipeline 105
Table 4.13: Psychiatric Case Studies, Organized Pharmacokinetically 108
Table 4.14: Antidepressant Drugs Decreased Clearance with DME CYP2D6 111
Table 4.15: Antidepressant Drugs with No Effect Clearance with DME CYP2D6 112
Table 5.1: Examples of Gene-Drug Pharmacogenomic Relationships 120
Table 5.2: Estimated Cost and Time for Typing of the BRCA1 Gene by Direct Sequencing vs. SNP Array 123
Table 5.3: Average Cost of Resistance Testing, 2007 138
Table 6.1: U.S. Prescription Drug Expenditures, 2003-2015 140
Table 6.2: U.S. Pharmaceutical Market, 1996-2009 142
Table 6.3: Top Ten Global Pharmaceutical Companies by Global Sales, 2007 143
Table 6.4: Pharmaceutical Companies Ranked by Total R&D Expenditures, 2007 143
Table 6.5: Leading Therapy Classes for R&D, 2008 143
Table 6.6: Leading Therapy Classes by Global Pharmaceutical Sales (Audited Market), 2007 144
Table 6.7: Number of NME Approvals and Mean Approval Times, 1984-2008 144
Table 6.8: Global Market for Tools and Consumables Used in Drug Discovery and Development, 1999-2010 145
Table 6.9: Leading Therapeutic Classes by U.S. Sales, 2006 and 2007 145
Table 6.10: Top Ten Therapeutic Classes by U.S. Dispensed Prescriptions, 2006 and 2007 145
Table 6.11: Top Ten Brand Drugs by U.S. Retail, 2007 146
Table 7.1: Select Companies Developing Cancer Diagnostics Available as Analyte Specific Reagents (ASRS) 174
Table 7.2: Emerging Fields in Biological Science with the Potential to Impact Personalized Medicine 184