癌ワクチンと細胞治療のパイプライン分析

Overview

Introduction

Unmet need across the cancer market is high, with most therapies conferring low levels of specificity and high toxicity. Development of cancer vaccines may be the holy grail, with the promise of high specificity, low toxicity and prolonged activity. Despite years of R&D and enhanced understanding of tumor immunology, a reproducible survival benefit has proved elusive, leaving the market wide open.

Scope

• Examination of cancer vaccine pipeline with in-depth clinical and commercial profiles of Phase III candidates, incorporating Datamonitor opinion
• Seven market sales forecasts, commercial potential and research/clinical/commercial assessment of Phase III agents to 2014
• Analysis of the cancer vaccine market, identifying developmental, manufacturing, logistical, regulatory and commercialization issues
• Insight and commentary from qualitative interviews with oncology opinion leaders in the US and Europe

Report Highlights

Given the relative immaturity and lack of precedence of the cancer vaccine market, an entirely new set of clinical and strategic issues has been brought to light. Significant hurdles need to be overcome, both on a local and international level before successful commercialization of a cancer vaccine can be realized.

Cancer vaccines will complement current treatment approaches, rather than serve as a replacement. If the full potential of cancer vaccines is realized, the need for multiple-lines of treatment may be eliminated, ultimately driving the cost of oncology care down.

The majority of the cancer vaccine pipeline constitutes off-the-shelf vaccines rather than personalized or cell-based formulations. Although the former are capable of mass manufacture, the latter have shown greater clinical benefit, but encompass a more complex and expensive formulation. It is unclear which class will reach the market first.

Reasons to Purchase

• Identify the key cancer vaccines and cell therapies in the current pipeline based on sales forecasts to 2014 and Datamonitor drug assessments
• Assess opportunities and risks for cancer vaccines and cell therapies within the oncology market
• Optimize development and commercialization of cancer vaccines by improving strategic planning

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