Pipeline Insight: Cancer Vaccines and Cell Therapies - Technical Know How Needs Translation Into Clinical and Commercial Rewards

TABLE OF CONTENTS

ABOUT DATAMONITOR HEALTHCARE

• About the Oncology pharmaceutical analysis team
• Richard Faint - Director of Oncology

CHAPTER 1 EXECUTIVE SUMMARY

• Datamonitor insight into the cancer vaccines market

CHAPTER 2 PIPELINE OVERVIEW & FUTURE FOCUS

• Pipeline overview
• Antigen-specific vaccines are the major focus of development
• Antigen-specific vaccines constitute over half of the current cancer vaccine pipeline
• High specificity and lower complexity of manufacture increase popularity of antigen-specific vaccine approaches
• Cell-based vaccines allow for the inclusion of a wide range of antigens, but present significant manufacturing, sterility and cost issues
• Potential commercial rewards dictate tumor focus
• Big four tumor types remain popular indications, joined by immunologically driven malignancies, such as melanoma and renal cell carcinoma
• As expected, the big four tumor types feature heavily in the current cancer vaccine pipeline
• Spontaneous tumor remissions and documented responses to cytokines in melanoma and renal cell carcinoma support employment of an immunotherapeutic approach
• In adopting a novel approach to tumor immunotherapy the high unmet needs of pancreatic cancer may be overcome
• Hematological malignancies are perhaps the ideal target for cancer vaccines due to facilitated infiltration of T-cells
• Cervical cancer and head & neck cancer are ideal candidates for the development of prophylactic vaccines
• Cancer vaccines for remaining indications exploit commonly overexpressed tumor-associated antigens or the potential of dendritic cells
• As anticipated, the majority of the pipeline is made up of generalized rather than personalized cancer vaccines
• Generalized cancer vaccines represent three quarters of the pipeline
• Fragmentation of the cancer vaccine market means strategic partnerships with major oncology players will ease the path to commercialization
• At least 64 companies are involved in the clinical development of cancer vaccines, 80% of which are small biotechnology firms
• Companies with multiple cancer vaccine candidates have relatively immature portfolios, therefore opportunity for commercial success cannot be based on pipeline volume alone
• Several companies are supported by strong strategic partnerships
• CSL/UniQuest Ltd, Medarex, MedImmune and Therion Biologics - key players in the cancer vaccine market
• Key metrics
• Datamonitor pipeline assessment summary
• Future focus - cancer vaccines face many challenges on route to approval

CHAPTER 3 PIPELINE DYNAMICS

• A diverse range of disease subtypes
• Genetic basis of cancer evolution
• Tumorigenesis is the result of cooperative accumulated mutations
• Existing pharmacotherapy approaches provide limited treatment benefit
• Cytotoxic drugs lack specificity
• Hormonal or endocrine therapy provides incremental benefit in selected tumors
• Optimizing current treatment strategies is paramount
• The emergence of targeted treatment heralds a revolution in cancer pharmacotherapy
• Dynamic cancer market offers significant commercial opportunity
• Ongoing sales growth drives the market
• Intensive R&D produces a rich developmental pipeline
• Growing patient population and significant unmet needs propel innovation in the cancer market
• Cancer epidemiology - an expanding patient base
• Significant areas of unmet need persist
• Clinical and strategic threats to the commercialization of cancer drugs
• Progressively rising R&D costs threaten industry productivity
• High attrition rates can be mitigated by improved strategic decision-making
• Lengthening drug approval process a consequence of increased regulatory demands
• Pharmacoeconomic pressures drive payers to implement restrictive pricing and reimbursement policies
• Increased therapeutic and generic competition results in reduced periods of market exclusivity
• Segmentation of market will require changes in clinical trial methodology

CHAPTER 4 CANCER VACCINES & CELL THERAPIES OVERVIEW

• The goal: active, specific immunotherapy
• Skepticism surrounds the history and future commercial viability of this technology
• Overcoming immune tolerance is the key to success
• Classification of pipeline products
• Polyvalent vaccines
• Whole-cell vaccines
• Tumor lysate vaccines
• Shed antigens
• Heat-shock proteins
• Antigen-specific vaccines
• Tumor-associated antigen - carbohydrate
• Tumor-associated antigen - recombinant protein
• Peptide-based vaccine
• Recombinant virus vaccine
• Anti-idiotype vaccine
• DNA vaccine
• Dendritic cell vaccines
• Prophylactic vaccines
• Relative merits of different cancer vaccine approaches show no clear market leader

CHAPTER 5 NEW MARKET, NEW ISSUES

• Lack of precedent confers unique strategic challenges
• Regulatory issues cloud the road to commercialization
• FDA request for further clinical data led to cessation of Corixas US development of Melacine
• Formulation and manufacturing concerns raised by regulatory bodies
• M-Vaxs route to market hampered due to manufacturing and formulation considerations
• Skepticism over cost-effectiveness hampers commercialization
• Expense of manufacture may hamper the widespread uptake of Intracels OncoVAX
• Prophylactic vaccines have demonstrable clinical benefit
• Prophylactic BCG vaccines are gold standard for bladder cancer
• Wide range of indications under development makes it difficult to compare efficacies of each class of cancer vaccine
• Datamonitor research has shown pipeline cancer vaccines to be in development for at least 17 tumor types
• Changing the paradigm in clinical trial design
• Clinical trial endpoints are starting to evolve to accommodate changing needs
• Multiple clinical trial endpoints are required to gain complete overview of a drugs therapeutic potential
• Composite endpoints and patient selection can significantly alter clinical trial outcomes in light of the evolving oncology market
• Investigators must establish and consistently employ standard response criteria specific to the assessment of cancer vaccines
• Standard response criteria may have become somewhat redundant
• Lack of adequate controls in the design of randomized clinical trials
• Immune monitoring should be integral to assessing the efficacy of vaccine strategies
• Increasing evidence shows that immune monitoring may constitute a viable clinical trial endpoint in cancer vaccine development
• Optimizing cancer vaccine delivery strategies
• Cancer vaccines are likely to be most efficacious in the setting of minimal residual disease
• Tumor response is more likely in the adjuvant setting, yet clinical trials continue to focus on metastatic patients
• Timing of vaccine delivery is crucial if part of multi-modality regimen
• Immunosuppressive therapy can compromise the efficacy of cancer vaccines
• Strategies to overcome the influence of neutralizing antibodies following vaccine administration
• Multiple vaccinations induce development of strong neutralizing antibodies that leave subsequent administration futile
• Significant hurdles challenge the path to commercialization

CHAPTER 6 POLYVALENT VACCINES DRUG ANALYSIS & FORECASTS

• In comparison to autologous vaccines, allogeneic approaches are likely to realize an expedited path to commercialization
• Pipeline overview
• Cell Genesyss GVAX counters the belief that there is no dose-related effect with cancer vaccines
• First-generation GVAX demonstrates survival benefit in Phase II clinical trials
• Re-engineered second-generation GVAX confers increased potency, as confirmed by second round of Phase II clinical trials
• Ongoing Phase III clinical trials need to confirm benefits of GVAXs increased potency
• Existing manufacturing infrastructure and potential clinical viability of GVAX make Cell Genesys a leading player in the race to commercialization
• Cell Genesys will require an expansion of its marketing and distribution resources to optimize GVAXs commercialization
• CancerVax/Seronos Canvaxin - despite FDA action hampering developmental partnership increases first-to-market potential
• Phase II clinical trials demonstrate promising survival benefits
• Results from Phase III trial anticipated by late 2005/early 2006, despite temporary FDA suspension of study
• Canvaxins formulation allows achievable economies of scale
• Melanoma patients have limited treatment options, so an effective vaccine is likely to enjoy significant uptake
• CancerVaxs partnership with Serono bolsters Canvaxins first-to-market potential
• Antigenicss Oncophage - early-stage trials have demonstrated limited clinical benefit
• Improved second-generation formulation facilitates use in early-stage disease
• Phase II trials have demonstrated limited clinical benefit in renal cell carcinoma
• Promising early evidence of immune activity shown in melanoma
• NHL as an appropriate tumor target expands commercial potential
• Personalized nature could work in Oncophages favor although the regulatory and logistical issues that cloud the commercialization of these vaccines prevail
• Lack of cost-effectiveness, clinical benefit and marketing experience will pose significant strategic challenges for Antigenics
• Forecasts
• Datamonitor drug assessment summary

CHAPTER 7 ANTIGEN-SPECIFIC VACCINES DRUG ANALYSIS & FORECASTS

• High rate of clinical failure associated with antigen-specific vaccines in late-stage development
• Pipeline overview
• Aphton/Sanofi-Aventiss Insegia (G17DT) fails to meet primary endpoint in Phase III pancreatic cancer study
• Combination of Insegia and Gemzar fails to meet primary endpoints in Phase III clinical trial for pancreatic cancer
• Insegia monotherapy shows benefit in pancreatic cancer patients unable to receive chemotherapy
• If Phase II benefits in gastric cancer are replicated in a Phase III study, commercial potential of Insegia will be enhanced
• Aphtons partnership with Sanofi-Aventis will help drive Insegias market uptake following regulatory approval
• Biomiras Theratope - failed Phase III study casts doubt over commercial viability
• Breast cancer Phase III clinical trial fails to meet primary endpoints
• Phase II study provides basis for continued development in colorectal cancer
• Biomira would benefit from collaboration with a developmental partner
• Progenics GMK - despite relevance of antigen, Phase III trials have failed to demonstrate clinical benefit
• Early-phase results demonstrate GMKs ability to induce an antibody response
• GMK proven inferior to standard treatment for stage III melanoma, although a separate ongoing Phase II study in the adjuvant setting may garner better results
• Lack of commercialization experience and marketing partner will affect GMKs potential
• A superior strategy may be to shift investment to more lucrative opportunities
• Medarex/Bristol-Myers Squibbs MDX-1379 - evidence of enhanced immune response is accompanied by potentially dose-limiting autoimmunity
• Autoimmunity induced in Phase II clinical trials proves that MDX-010 and MDX-1379 are heightening the level of immune response
• If encouraging, results from an ongoing Phase III clinical trial will support a BLA
• Optimizing the risk-benefit ratio is paramount in progressing commercial development
• Partnership with Bristol-Myers Squibb will put Medarex at a significant advantage
• Therion Biologics PANVAC-VF - validity of antigen targets could offer hope to pancreatic cancer patients
• Development of PANVAC-VF characterized by promising Phase I results but a notable absence of reported Phase II data
• Clinical potential of PANVAC-VF remains to be definitively established and would benefit from a collaborative relationship with an well-known oncology player
• Igeneons IGN-101 - low awareness of both the company and its lead product candidate present a major hurdle
• Ongoing Phase III trials target three of the big four tumor types
• Phase II clinical trials demonstrate vaccine immunogenicity bur show limited survival benefit
• Aphtons acquisition of Igeneon may help drive development of IGN-101
• Favrilles FavID - by targeting patient population with few recognized treatment options, regulatory bar is lowered
• Phase II clinical trials have shown prolongation of TTP
• Ongoing Phase III trial needs to confirm clinical benefit and safety profile
• Favrilles lack of commercial experience will be a barrier to optimizing market penetration
• Biovest/Accentias BIOVAXID - companies should strive to exploit potential first-to-market advantage
• Long-term Phase II study follow-up suggests favorable survival benefits
• Ongoing Phase III trial was initiated in January 2000, indicating proximity to completion
• Genitopes MyVax - second-to-market status may be saved by targeting slightly different patient population than BIOVAXID
• Phase II clinical trials show greater number of immune responses among previously untreated patients
• Phase III clinical trials approaching completion
• Despite being a year behind its main competitor, MyVax increases its commercial potential by targeting an earlier stage treatment
• Vicals Allovectin-7 - another vaccine that confounds the theory of an absence of dose-related effect
• Phase III studies investigating low-dose Allovectin-7 terminated due to lack of efficacy
• Phase III trial investigating high-dose Allovectin-7 recently granted clearance following completion of SPA with the FDA
• Vical intends to seek development partner, which will greatly aid Allovectin-7s prospects for commercialization
• Results from second Phase III are pivotal to Allovectins commercial viability
• Forecasts
• Datamonitor drug assessment summary

CHAPTER 8 DENDRITIC CELL VACCINES ANALYSIS & FORECASTS

• Dendreons Provenge forges the way in the technologically appealing dendritic cell approach
• Pipeline overview
• Dendreons Provenge (APC-8015) - promises to be first to market within this class of vaccines
• First Phase III trial failed to meet primary endpoints, although increase in overall survival was demonstrated
• Second Phase III clinical trial targets patient cohort most likely to derive clinical benefit
• Phase II clinical trial results suggest synergy between Provenge and Genentech/Roches Avastin
• Provenges probable high cost and complex manufacture may be offset by being the first immunotherapeutic to demonstrate a survival benefit in HRPC
• Provenges commercial potential could be enhanced with the backing of an established oncology player
• Forecasts
• Datamonitor drug assessment summary

APPENDIX A

• List of tables
• List of figures
• Methodology
• Datamonitor forecast methodology
• Datamonitor drug assessment summary
• Contributing experts
• Opinion leader interview transcripts
• Doctor Vincenzo Cerundolo, Professor of Immunology, Head Cancer Research UK Tumor Immunology Program, Associate Director of MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
• Doctor John Grange, Professor, Centre for Infectious Diseases and International Health, Department of Medicine, Royal Free and University College Medical School, London, UK
• Doctor Elke Jaeger, Medical Oncologist, Department of Oncology, Krankenhaus Nordwest, Frankfurt, Germany
• Doctor Howard Kaufman, Vice Chairman of Surgical Oncology & Associate Professor of Clinical Surgery, Department of Surgery, Columbia University, New York, US
• Doctor Philip Livingston, Medical Oncologist, Memorial Sloan-Kettering Cancer Center, New York, US
• Doctor Daniel Speiser, Associate Member, Division of Clinical Onco-immunology, Ludwig Institute for Cancer Research, Lausanne, Switzerland
• Bibliography

APPENDIX B

• About Datamonitor
• About Datamonitor Healthcare
• Datamonitor Healthcares therapy area capabilities
• About the Oncology analysis team
• Disclaimer
• List of Tables
• Table 1: Late-phase cancer vaccines in development, 2005 (1 of 2)
• Table 2: Late-phase cancer vaccines in development, 2005 (2 of 2)
• Table 3: Phase II cancer vaccines in development, 2005 (1 of 2)
• Table 4: Phase II cancer vaccines in development, 2005 (2 of 2)
• Table 5: Phase I cancer vaccines in development, 2005 (1 of 4)
• Table 6: Phase I cancer vaccines in development, 2005 (2 of 4)
• Table 7: Phase I cancer vaccines in development, 2005 (3 of 4)
• Table 8: Phase I cancer vaccines in development, 2005 (4 of 4)
• Table 9: Therapeutic pipeline cancer vaccines by developmental phase & class, 2005
• Table 10: Pipeline cancer vaccines by indication, 2005
• Table 11: Proportion of personalized versus generalized cancer vaccines, 2005
• Table 12: Companies/research institutions with three or more pipeline cancer vaccines
• Table 13: Companies with most influential cancer vaccine pipelines
• Table 14: Forecast incidence and mortality of the major indications for cancer vaccines in the seven major pharmaceutical markets, 2005
• Table 15: Late-phase pipeline cancer vaccine sales forecasts ($m), 2005-14
• Table 16: Datamonitor drug assessment summary
• Table 17: Common mutations involved in tumor development
• Table 18: Forecast incidence of cancer across the seven major markets, 2005-13
• Table 19: Three main categories of cancer vaccines exist
• Table 20: Advantages and disadvantages of cancer vaccines
• Table 21: Relative efficacy merits of cancer vaccines
• Table 22: Relative formulation merits of cancer vaccines
• Table 23: Currently marketed cancer vaccines, 2005
• Table 24: Pipeline polyvalent cancer vaccines in Phase II and III clinical trials, 2005
• Table 25: Pipeline polyvalent cancer vaccines in Phase I clinical trials, 2005
• Table 26: Polyvalent cancer vaccines sales forecasts assumptions
• Table 27: Polyvalent cancer vaccines sales forecasts ($m), 2005-14
• Table 28: Research, clinical and commercial attractiveness summary for pipeline polyvalent cancer vaccines
• Table 29: Pipeline antigen-based cancer vaccines in Phase III clinical trials, 2005
• Table 30: Pipeline antigen-based cancer vaccines in Phase II clinical trials, 2005
• Table 31: Pipeline antigen-based cancer vaccines in Phase I clinical trials, 2005 (1 of 2)
• Table 32: Pipeline antigen-based cancer vaccines in Phase I clinical trials, 2005 (2 of 2)
• Table 33: Antigen-specific cancer vaccines sales forecasts assumptions (1 of 3)
• Table 34: Antigen-specific cancer vaccines sales forecasts assumptions (2 of 3)
• Table 35: Antigen-specific cancer vaccines sales forecasts assumptions (3 of 3)
• Table 36: Antigen-specific cancer vaccines sales forecasts ($m), 2005-14
• Table 37: Research, clinical and commercial attractiveness summary for pipeline antigen-specific cancer vaccines (1 of 3)
• Table 38: Research, clinical and commercial attractiveness summary for pipeline antigen-specific cancer vaccines (2 of 3)
• Table 39: Research, clinical and commercial attractiveness summary for pipeline antigen-specific cancer vaccines (3 of 3)
• Table 40: Pipeline dendritic cell cancer vaccines in clinical trials, 2005
• Table 41: Dendritic cell cancer vaccines sales forecasts assumptions
• Table 42: Dendritic cell cancer vaccines sales forecasts ($m), 2005-14
• Table 43: Research, clinical and commercial attractiveness summary for pipeline dendritic cell cancer vaccines
• Table 44: Datamonitor drug assessment parameters
• List of Figures
• Figure 1: Antigen-specific vaccines dominate the pipeline
• Figure 2: Antigen-specific vaccines dominate all phases of development
• Figure 3: Big four tumor types, plus melanoma & RCC remain popular indications
• Figure 4: Generalized vaccines dominate the cancer vaccine pipeline
• Figure 5: Small biotechnology companies dominate cancer vaccines R&D pipeline
• Figure 6: Pipeline polyvalent cancer vaccines sales forecasts, 2005-14
• Figure 7: Pipeline antigen-specific cancer vaccines sales forecasts, 2005-14
• Figure 8: Pipeline dendritic cell cancer vaccines sales forecasts, 2005-14
• Figure 9: Datamonitor drug assessment summary for pipeline polyvalent cancer vaccines
• Figure 10: Datamonitor drug assessment summary for pipeline antigen-specific cancer vaccines
• Figure 11: Datamonitor drug assessment summary for pipeline dendritic cell cancer vaccines
• Figure 12: Significant challenges stand in the way of successful cancer vaccine commercialization
• Figure 13: Global oncology sales, 2002-09
• Figure 14: Oncology pipeline, 2003
• Figure 15: Forecast incidence of cancer across the seven major markets, 2005-13
• Figure 16: Increasing combined incidence for breast, lung, prostate and colorectal cancer with increasing age, 2003
• Figure 17: Incidence increases, while the rate of cure and death reduces disease prevalence
• Figure 18: Point prevalence for colorectal and lung cancer differs markedly despite similar rates of incidence
• Figure 19: Unmet needs in cancer
• Figure 20: To achieve success, cancer vaccines need to overcome immune tolerance
• Figure 21: Disadvantages associated with cancer vaccines are currently more significant than advantages
• Figure 22: Sales of Canvaxin and Oncophage restricted by size of target melanoma patient population
• Figure 23: Canvaxin appears most commercially attractive, while GVAX appears most research and clinically attractive
• Figure 24: Sales forecasts appear low due to the relatively cheap manufacturing costs of antigen-specific vaccines
• Figure 25: Lack of compelling clinical evidence makes differentiation of antigen-specific products difficult
• Figure 26: Provenge is the clear leader of the dendritic cell class of vaccines
• Figure 27: Provenge is the obvious market leader with this class of cancer vaccines
• Figure 28: Example of Datamonitor drug assessment scorecard
• Figure 29: Example of Datamonitor drug assessment graph