The Future of Targeted Therapeutics Key technologies, new therapy area applications and leading players

Executive Summary 10
Emergence of targeted therapeutics 10
Analysis of stakeholder incentives 11
Types of targeted therapeutics 12
Role of targeted therapeutics in selected therapy areas 13

Chapter 1 Emergence of targeted therapeutics 16
Summary 16
Introduction 17
Decline of the blockbuster model 18
The “nichebuster” model 22
The emergence of targeted therapeutics 23
Convergence of biotechnology and pharmaceutical companies 25
Licensing incentives 26
Risk management 29
Role of biomarkers and diagnostics 32
Academic research and technology transfer 34

Chapter 2 Analysis of stakeholder
incentives 36
Summary 36
Introduction 37
Institutional payors 37
Regulators 39
Patients and patient advocacy groups 41
Physicians 43
Pharmaceutical companies 44

Chapter 3 Types of targeted therapeutics 48
Summary 48
Introduction 49
Innovative small molecules 49
Mechanism of action 50
Examples 52
Gleevec 52
Lapatinib (Tykerd/Tyverb) 52
SNS-032 53
PLX4032 53
Market synopsis 53
Protein/Peptide drugs 54
Mechanism of action 55
Examples 57
AGRO100 57
PRX321 58
Market synopsis 58
Monoclonal antibodies and antibody-like structures 60
Mechanism of action 60
Examples 62
Rituximab (Rituxan) 62
Alemtuzumab (Campath) 62
Erbitux/cetuximab 63
Avastin/bevacizumab 64
Herceptin/trastuzumab 64
Ibritumomab tiuxetan (Zevalin) 65
Tositumomab (Bexxar) 65
Market synopsis 65
Nucleic acid therapies 67
Mechanism of action 68
Examples 68
Genasense (oblimersen sodium) 68
Nexagon 69
4-Thio FAC 69
Market synopsis 69
RNA interference 70
Mechanism of action 70
Examples 72
CALAA-01 72
siRNA AV-34 72
Bioral SiRNA 72
Market synopsis 72
Stem cell therapies 73
Market synopsis 74
Future therapeutic applications 74
Regulatory concerns 76
Gene therapy 76
Drug delivery and nanotechnology in targeted therapeutics 77
Mechanism of action 78
Examples 79
BioVant 79
ATI-1123 (docetaxel) 80
Rexin-G 80
Abraxane 80
131I-TM-601 81
Market synopsis 81
Conclusion 83

Chapter 4 Role of targeted therapeutics in selected therapy areas 86
Summary 86
The cancer market 87
Targeting cancer cells for destruction 88
Blocking growth signalling pathways 88
Epidemiology 88
Current treatments 90
Unmet needs and innovation 96
Medical Needs 96
High toxicity and side effect profiles 96
Variable efficacy rates 96
The multifactorial nature of disease 96
Targeting brain tumors 97
Economic Needs 97
Reimbursement policies 97
Targeted therapeutics in cancer 99
Antineoplastics 100
Innovative small molecule therapies 101
Monoclonal antibody therapies 102
Proteins and Peptides 103
Application of genetic technology 103
RNAi in cancer 104
Applications of nanotechnology 106
Novel drug delivery approaches 107
The Cardiovascular Market 108
Epidemiology 108
Current market scenario 109
Unmet needs and innovation 111
Pill burden and patient compliance 111
Inefficient mechanism of action 111
Drug delivery technology limitations 111
Targeted therapeutics in cardiovascular diseases 113
Protein and nucleic acid therapies 113
Targeted small molecule drugs 113
Monoclonal antibody therapies 114
Stem cells 114
Nanotechnology 115
The CNS Market 117
Epidemiology 118
Current treatments 120
Unmet needs and innovation 121
Crossing the blood-brain barrier 122
Improving specificity and affinity 122
Accuracy in determining drug bioavailability 123
Improved side effect profiles 123
Appropriate clinical trial design – defining target patient subsets 124
Diagnosis-specific unmet needs 124
Depression 124
Schizophrenia 124
Sleep disorders 125
Alzheimer’s disease and other dementias 125
Epilepsy 125
Parkinson’s disease and movement disorders 126
Pain therapeutics 126
Targeted therapeutics in CNS 127
Innovative small molecules 128
Nucleic acid therapies 129
Monoclonal antibodies 130
Stem cell and gene therapy 131
Novel therapeutic mechanisms of action 134
Synthetic toxins 134
Targeted viral delivery systems 134
Innovative diagnostic devices 135
The Infectious Diseases Market 136
Epidemiology 136
Viral Infections 137
Hepatitis 137
Influenza 138
Herpes simplex virus 139
Bacterial infections 139
Fungal infections 140
Current market scenario 140
Unmet Needs and Innovations 141
Efficacy 141
Emerging resistance to existing treatments and lack of innovation 142
Immunoglobin (vaccination) drug delivery mechanisms 143
Targeted therapeutics in infectious diseases 143
Innovative small molecules 143
Applications of genetic technology 145
Therapeutic proteins and peptides 146
RNAi in infectious diseases 146
Antibodies 148
Novel targeted drug delivery mechanisms 150

Chapter 5 Appendix 151
Research methodology 151
ATC Codes 151
Cancer Therapies 151
Antineoplastic and immunomodulating agents 151
L1: Cytostatics 151
L2: Cytostatic hormone therapy 151
L3: Immunostimulating agents 152
Cardiovascular Therapies 152
B1: Anti-thrombotic agents 152
C1: Cardiac Therapy 152
C2 Antihypertensives 152
C3 Diuretics 152
C7 Beta Blockers 152
C8 Calcium antagonists 152
C9 Agents acting on the renin-angiotensin system 152
C10 Hypolipidaemics/Anti-Atheroma Preparations 152

Index 153

List of Figures
Figure 1.1: Forecast growth for the top 20 biopharmaceutical companies, 2006-12 21
Figure 1.2: Evolution of the biopharmaceutical corporation 28
Figure 1.3: Reliance on licensed products vs. forecast revenue growth, top 20 pharmaceutical firms, 2006-12 29
Figure 1.4: FDA new drug approvals and Phase 3 failures, 2006-2007 31
Figure 2.5: Typical health economic value proposition for innovative or personalized therapies 39
Figure 3.6: Mechanism of action of targeted small-molecule inhibitors 51
Figure 3.7: Schematic presentation of targeted delivery of therapeutic proteins and peptides to antigen-positive tumor cells or tumor vasculature 57
Figure 3.8: Mechanism of action of monoclonal antibodies 61
Figure 3.9: Mechanism of post-transcriptional gene silencing by siRNA 71
Figure 4.10: Global cancer innovatives market, 2003-2006 94
Figure 4.11: Targeted oncology pipeline by indication, 2006 100

List of Tables
Table 1.1: Global revenues from blockbuster drugs, top 10 pharma companies, 2006 ($m) 20
Table 1.2: Complementary strengths of pharma and biotech companies 25
Table 4.3: Estimated annual incidence of cancer diagnoses (‘000s), global, 2002 census 89
Table 4.4: Breakdown of the global antineoplastic market by drug class, 92
Table 4.5: Leading therapies in the global antineoplastics market, 2005–07 93
Table 4.6: Antineoplastic sales forecast, 2006-12 101
Table 4.7: Chemotherapeutic siRNA targets in drug development pipelines 105
Table 4.8: Key pipeline oncology drugs and technologies utilizing nanotechnology, 2008 106
Table 4.9: Estimated prevalence of CVD across the seven major markets, 2006 109
Table 4.10: Breakdown of the global CVD market by drug class, 2003-07 110
Table 4.11: Estimated prevalence of CNS disorders across the seven major markets, 2006 118
Table 4.12: Global sales of CNS products by disease indication, 2005-2007, $m 120
Table 4.13: Top 10 CNS brands, sales revenues, global, 2007, $m 121
Table 4.14: Medicinal chemical properties of a successful CNS drug 123
Table 4.15: Estimated prevalence of infective diseases across seven major markets, 2005 137
Table 4.16: The anti-infectives market, global sales revenues, 2003-2007, $m 141