Table of Contents

Delivery Mechanisms for Large Molecule Drugs
Executive summary 10
Introduction 10
Drivers for new platform developments 11
Resistors of change 12
Key emerging technologies 13
Systemic targeting technologies 14
Ease of use systems 15
Conclusions 16

Chapter 1 Introduction 18
Summary 18
Introduction 19
The emergence of large molecule therapeutics 21
Definitions 23
Technology platform definitions 23
Product coverage 25
Market coverage 25
Leading technologies coverage 27
The measures for market success 28

Chapter 2 Drivers of new platform developments 30
Summary 30
Introduction 31
The growth of the large molecule market 32
Therapy area growth drivers 33
Clinical development spend 35
Cost-effective manufacturing 36
Existing failure rates 36
Unmet clinical needs 38
Boosting patient compliance 39
Overcoming stability, bioavailability and toxic effects 40
Improving efficacy 40

Chapter 3 Risk, costs and technology maturity 42
Summary 42
Introduction 43
Risk of failure with new technologies 43
Unknown drug candidate pharmacokinetics 45
Solubility and instability with oral candidates 45
Bioavailability 46
Toxicity and unknown long-term effects 47
The shifting regulatory framework 47
Case study: Insulin delivery and investor confidence 48
The impact of cost and revenue on the decision to innovate 51
Immaturity concerns 52
Maturity of the delivery technologies 52

Chapter 4 Key emerging technologies 58
Summary 58
The forecast market impact 59
Nanotechnology to enhance solubility profiles 60
The evolving nanotechnology industry 61
The development pipeline 63
Leading clinical applications 64
Parenteral delivery systems 66
Dermal platform systems 67
Nanostructured materials; oral and depot system use 68
Novel oral drug delivery systems 68
Investigative nanoshells, nanofilms and active control 69
Advances in microelectronics 71
Existing electronic applications 71
The development pipeline for microelectronics 73
Microchip technologies 73
Inkjet technology for drug delivery 74

Chapter 5 Systemic targeting techniques 78
Summary 78
Introduction 79
Systemic passive targeting techniques 81
Stealth technologies: Immune system evasion 81
PEGylation technologies 83
PEGylation in clinical pipelines 84
Preclinical PEGylation investigation 86
The limitations of PEG 86
Next generation PEGylation 87
Systemic active targeting techniques 88
Antibody techniques 89
Antibody fragments 90
Binding specificity 91
Novel combination technologies to improve targeting 92
Cost-effective manufacture 93
The development pipeline 94
The emergence of IgG4 antibody therapies 94
Small modular Immunopharmaceuticals as antibody alternatives 95
Pipeline novel conjugate technologies 96
Antibody fragments in targeted carrier systems 96
Investigational protein carrier Prodrug complexes 97
Clotting factor conjugate targeting 97
Molecular trojan horse techniques 98

Chapter 6 Ease of use systems 102
Summary 102
Introduction 103
Pulmonary delivery technologies 104
Particle engineering technologies for pulmonary delivery 105
Vaporization techniques and delivery control 106
Applications of electronics 106
Needle-free transdermal delivery 107
Leading technology platforms 109
Needle-free pressure-based systems 110
Microinjection platforms for intra-epidermal delivery 110
EMEA filing for first microinjection system 111
technology platform 112
Electrotransport systems 113
Electroporation in transdermal delivery 113
TransPharma Medical ltd’s RF-Microchannel technology 114
Novel approaches to active intra-epidermal delivery 115
Laser drug delivery systems 115
Thermal energy platform 116

Chapter 7 Conclusions 118
Summary 118
Introduction 119
Pharma vs biotech large molecule R&D investment 119
Leading technologies 121
Growth in particle engineering technologies 121
The impact of new routes of administration 122
Large molecule drug delivery market growth and maturity 123
Current and future market impact 127
Therapy area impact 127
Timeline of impact 130
Summary of technology success and impact 133
Appendix 136
Index 136
Methodology 137
Methodology 137
MedTRACK platform identification 137
Glossary 138

List of Figures
Figure 1.1: The role of drug delivery in the product R&D pipeline 20
Figure 1.2: Biopharmaceutical company dependence on large molecule drugs* 22
Figure 1.3: Defining the pathway from proprietary technology to clinical use 24
Figure 2.4: The global pipeline for chemical and biologic drugs, October 2008 33
Figure 2.5: Number of pipeline biologic drug candidates and products, by therapy area, October 2008 34
Figure 2.6: Pharma R&D spend 2004-2009e 35
Figure 2.7: Biotech R&D spend ($bn), 2004-2009e 36
Figure 2.8: Pharmacokinetic effects; resistors of market growth and opportunity for new technologies 38
Figure 3.9: Key innovative technologies, clinical drug failures and discontinued products, November 2008 44
Figure 3.10: Development pipeline for insulin devices, human insulins and analogues, October 2008 49
Figure 3.11: Discontinued insulin devices, human insulins and analogues, platforms for delivery, per year 2001-2008 51
Figure 3.12: Key particle engineering technologies; industry size and maturity 54
Figure 3.13: Key route of administration technologies; industry size and maturity 55
Figure 4.14: Investment deals and clinical applications in nanotechnology drug delivery platforms, 2002-Q2 2008 62
Figure 4.15: Product pipeline; large molecule nanotechnology innovations 64
Figure 4.16: Maturity of electronic active delivery platforms in transmembrane and pulmonary delivery systems 72
Figure 5.17: The market advantage of targeted drugs 80
Figure 5.18: Passive targeting strategies for large molecule delivery 81
Figure 5.19: The benefits of PEGylation to improve pharmacological profiles 83
Figure 5.20: Active targeting strategies for large molecule delivery 88
Figure 5.21: The global MAb product pipeline by phase, Q4 2008 89
Figure 5.22: Antibody fragmentation platforms – Competitive advantage 90
Figure 5.23: Antibody fragments: separating targeting domains 92
Figure 6.24: Transdermal and transmembrane active platform technologies, November 2008 108
Figure 6.25: Investment in and maturity of active transdermal delivery 109
Figure 7.26: Big biotech v big pharma large molecule patent applications, 2003-2007, global 120
Figure 7.27: Particle engineering technologies in drug R&D pipelines, by phase, October 2008 122
Figure 7.28: Industry growth and investment, leading innovative drug delivery platforms 124
Figure 7.29: Growth in technology deals; 1998-2007 126
Figure 7.30: Impact of new technology platforms developments on therapy area pipelines 127
Figure 7.31: Therapy area focus of innovative technology product candidates, October 2008 128
Figure 7.32: New medical device technologies, anticipated market impact 129
Figure 7.33: Emerging particle engineering technologies, anticipated market impact 130
Figure 7.34: The impact of new delivery technologies; timeline for success 131
Figure 7.35: Measures of technology success 133

List of Tables
Table 1.1: Nektar’s leading innovative technology pipeline 25
Table 1.2: Needle free delivery; Key routes of administration 26
Table 1.3: Technology market coverage 27
Table 2.4: The global pipeline for chemical and biologic drugs, October 2008 37
Table 3.5: Key innovative technologies, clinical drug failures and discontinued products, November 2008 45
Table 3.6: Key route of administration technologies; industry size and maturity 56
Table 4.7: Nanotechnology drug delivery platforms, large molecule vs small molecule applications, November 2008 63
Table 4.8: Nanoparticles as drug delivery carriers 64
Table 4.9: Leading clinical parenteral drug delivery 66
Table 5.10: Clinical PEGylation stealth targeting technologies 84
Table 5.11: Antibody fragment products, clinical applications 93
Table 5.12: Armagen’s proprietary CNS product pipeline: Trojan horse conjugate delivery 99
Table 6.13: Small molecule success of membrane transport technologies, November 2008 106
Table 6.14: Clinical use electronic pulmonary delivery technologies 107
Table 6.15: Transdermal and transmembrane active platform technologies, November 2008 108
Table 6.16: Novel electroporation platforms; transdermal alternatives 113
Table 7.17: Innovative technology products in R&D pipelines, October 2008 123
Table 7.18: Industry maturity and investment, leading innovative drug delivery platforms 125
Table 7.19: Growth in technology deals, 1998-2007 126
Table 7.20: Therapy area focus of innovative technology product candidates, October 2008 129