Immunosuppressants, Organ Transplants, and Potential of Regenerative Medicine: Market Size, Competitive Landscape, and Pipeline Analysis Introduction This report examines treatment protocols evolved over the last ten years. It also appraises novel compounds in development, highlighting potential clinical advances along with analysis of the potential impact of regenerative medicine (stem cells) on the market, with drivers and resistors to market growth. Scope Ten-year forecasts of the number of organ donors, transplants and maintenance populations by organ and country. Review of the regenerative medicine market, including estimates of the market size, analysis of over 200 clinical trials & focus on potential applications. In-depth analysis of late-stage pipeline products, with discussion of potential clinical advances and how they address current unmet needs. Overview of organ donation trends, e.g., maximum theoretical supply, impact of initiatives to increase donors, and impact of changing donor demographics. Analysis of US treatment protocols at discharge by drug class and review of graft survival rates by organ, including causes of graft loss. Research and analysis highlights Cellular-based therapies, which have the potential to induce graft tolerance, represent a major disruptive technology which could potentially replace, or reduce, the use of primary immunosuppressants. Modern immunosuppressive protocols have resulted in improvement in short-term graft survival rates and the focus is now shifting towards improving long-term graft survival, although achieving this goal will be challenging A distant goal of regenerative medicine is to develop bioengineered organs and tissues, although the replacement of whole kidneys, hearts or livers is not yet clinically feasible and the development of spatially complex organs will require many advances in tissue engineering Key reasons to purchase this research Understand the driving forces in the transplantation market Evaluate current market dynamics & learn which novel products offer the greatest potential clinical advances over the next several years and why Assess your competitive position vis-à-vis other companies Understand which market areas offer the greatest potential growth prospects Develop strategies to optimize your transplantation portfolio and identify new areas for market entry
Table of Contents Shaun Falkingbridge 2 Disclaimer 2 Executive summary 10 Market environment 10 Solid organ transplants 11 Regenerative medicine 11 Pipeline analysis 12 Chapter 1 Market environment 14 Summary 14 Background 15 Immunosuppression 15 Types of rejection 15 Immunosuppressive therapy 16 Blood group compatibility 18 Tapering of immunosuppression 18 Market valuation 18 Prograf 19 Background 19 Impact of new formulation and generics 19 Conclusion 21 Neoral 22 Background 22 Impact of tacrolimus and generics 22 Conclusion 23 CellCept 23 Background 23 Impact of generics 24 Other brands 24 Evolution in therapeutic protocols 25 Calcineurin inhibitors 26 Shift from ciclosporin to tacrolimus 26 Safety and efficacy 27 Side effects 27 Conclusion 28 Adjunctive agents 28 mtor inhibitors 30 Enhancing long-term graft survival 30 Sirolimus 30 CNI avoidance 30 Combination use 30 Early/late CNI conversion 30 Everolimus 31 Side effects 32
Conclusion 32 Induction therapies 33 Trends in graft-survival rates 35 Incremental/steady improvements in survival 35 Factors affecting survival rates 37 Non-related patient death 37 Immunosuppressants increase cardiovascular risk factors 38 Cancer 39 Acute rejection 39 Interstitial fibrosis/tubular atrophy 39 CNI nephrotoxicity 41 Glomerular disease 41 Delayed graft function 41 Non-adherence 42 Conclusion 42 Future outlook 43 Chapter 2 Solid organ transplants 45 Summary 45 Introduction 46 Trends in organ donation 47 Regional trends 47 Cause of death 50 Donor legislation 51 Religious factors 52 Number of transplants 52 Organ gap 53 Indications for transplants 54 Kidney 54 Liver 56 Heart 57 Increasing donor supply 57 Maximum theoretical number of donors 57 Strategies to increase the number of donors 57 Spain: active detection 58 The UK: establishment of the Organ Donation Taskforce 58 The US: the Organ Donation Breakthrough Collaborative 60 Forecast number of transplants/functioning grafts 61 Future outlook 65 Chapter 3 Regenerative medicine 66 Summary 66 Introduction 67 Types of cellular therapies 67 Embryonic stem cells 68 Adult stem cells 70 Fully differentiated cells 71 Organ augmentation and replacement 71
Clinical application of cellular therapies 73 Introduction 73 Cardiovascular disease 75 Bone marrow mononuclear cells 75 Endothelial progenitor cells 75 Mesenchymal stem cells 76 Stem cells and heart transplantation 76 Outlook 76 Kidney disease 77 Kidney repair and regeneration 77 Mesenchymal stem cells and transplantation 77 Mesenchymal stem cells and chronic/acute kidney disease 79 Development of whole organs 80 Outlook 81 Liver disease 81 Stem cells and treatment of cirrhosis 81 Hepatocyte transplantation 82 Stem cells and transplantation 82 Regenerative medicine market 82 Market value 82 Autologous chondrocyte implantation 83 Skin-substitutes 84 Apligraf 84 Dermagraft 85 Regulation of cellular therapies 86 US 86 EU 87 Japan 87 China 88 Future outlook 89 Chapter 4 Pipeline analysis 90 Summary 90 Introduction 91 Bristol-Myers Squibb 91 Belatacept 91 Astellas 93 Alefacept 93 ASKP-1240 (4D11) 94 ASP-015K 94 Novartis 95 Sotrastaurin 95 Pfizer 96 Tasocitinib 96 Isotechnika 96 Voclosporin 96 Other companies 96
Novel immunosuppressive agents impact on the market 97 Business models in cell therapy 100 Key success factors 100 Manufacturing process 101 Acute versus elective indications 101 Risk of product substitution 102 Estimates revenues for Prochymal in transplantation 103 Future outlook 104 Appendix 105 Primary research methodology 105 IMS sales data 105 Transplant data 106 Glossary 107 Bibliography 109 Table of figures Figure 1: Market share of Advagraf, Prograf and Neoral, Spain, 2006-2009 22 Figure 2: Ciclosporin and tacrolimus use in US kidney transplants prior to discharge, 1998 2007 28 Figure 3: Adjunctive agents used in US kidney transplant patients prior to discharge, 1998 2007 29 Figure 4: Sirolimus use in US kidney transplant patients between discharge and one year following transplantation, 1997 2006 33 Figure 5: Induction therapy use in US kidney transplants recipients, 1998 2007 34 Figure 6: Graft survival at one, five and ten years, deceased donor kidney transplants, US 36 Figure 7: Graft survival at one, five and ten years, deceased donor liver transplants, US 37 Figure 8: Graft survival at one, five and ten years, heart transplants, US 38 Figure 9: Reasons for loss of kidney grafts 40 Figure 10: Age of deceased donor kidney recipients (non-ecd), 1998 2007 43 Figure 11: Number of donors by type in the 7MM, 2000 2009 48 Figure 12: Organ donation rates per million population by donor type, 2009 49 Figure 13: Living donation rates per million population, 2000 2009 50 Figure 14: Kidney waiting list and kidney transplants, US, 2000 2009 54 Figure 15: Indications for kidney transplant, US, 1990 2009 55 Figure 16: Indications for liver transplant, US, 1990 2009 56 Figure 17: Number of deceased donors by type, UK, 2000 2009 60 Figure 18: Number of transplants and organ donors, 2010 2020 63 Figure 19: Types of cellular therapies 68 Figure 20: Number of clinical trials by stem cell type, 2002 2009 74 Figure 21: Drivers and resistors to regenerative medicine 88 Figure 22: The challenges of developing immunosuppressants 94 Figure 23: Comparison of uptake of Prograf and CellCept US kidney transplants, 1993 2006 98 Figure 24: Drivers and resistors for primary immunosuppressants 99
Table of tables Table 1: Types of immunosuppressants 17 Table 2: Immunosuppressants sales ($m) in the 7MMs, by class and brand, 2009 20 Table 3: Current access of donor supply by country 58 Table 4: Number of transplants and organ donors, 2010 2020 62 Table 5: Prevalence of functioning grafts, by country and organ, 2010 2020 64 Table 6: Selected stem cell clinical trials 78 Table 7: Examples of approved cell-based therapies 85