Report: Pipeline Insight: Therapeutic Cancer Vaccines - A turbulent path from bench to bedside TOC

CHAPTER 1 EXECUTIVE SUMMARY
- Scope of analysis
- Key metrics
CHAPTER 2 PIPELINE DYNAMICS
- Pipeline overview
  - Therapeutic cancer vaccines in late-phase development
  - Therapeutic cancer vaccines in Phase II development
  - Therapeutic cancer vaccines in Phase I development
- Pipeline by developmental phase and class
  - There are over 100 different therapeutic cancer vaccines in the clinical developmental pipeline
    - Antigen-specific vaccines account for over two-thirds of the current cancer vaccine pipeline
    - Segmentation of vaccines by developmental phase reflects high attrition rate in oncology drug development
- Pipeline by technology platform
  - Lack of precedent is reflected by diversity of technology platforms
- Pipeline by vaccine specificity
  - As expeceted, generalized vaccines dominate over personalized therapies
    - Generalized cancer vaccines represent nearly three quarters of the pipeline
- Pipeline by indication
  - Cancer vaccines are being investigated in 18 different tumor types
    - Melanoma is the leading indication for vaccine development while RCC, another immunologically driven malignancy, is gaining ground
    - As expected, the ' big four' tumor types feature heavily in the current cancer vaccine pipeline
    - Vaccines directed against solid tumors outnumber those targeting the hematological malignancies
    - The 14 Phase III and preregistered vaccines target eight different tumor types
- Pipeline by company
  - Developmental pipeline dominated by small pharma/biotech players
  - Only 14 companies/institutes have more than one candidate in the cancer vaccine developmental pipeline
    - Memorial Sloan-Kettering Cancer Center
    - Therion Biologics
    - A leading developer has yet to emerge
CHAPTER 3 DISEASE OVERVIEW
- A diverse range of disease subtypes
- Genetic basis of cancer evolution
  - Tumorigenesis is the result of co-operative 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
  - Therapeutic and generic competition reduces periods of market exclusivity
  - Segmentation of market will require changes in clinical trial methodology
CHAPTER 4 MARKET DEFINITION AND PIPELINE CLASSIFICATION
- Active, specific immunotherapy
- Overcoming immune tolerance is key to success
- Types of targets for vaccine therapy
- Classification of pipeline products
  - Antigen-specific vaccines
    - Tumor-associated antigen - carbohydrate
    - Peptide-based vaccine
    - Recombinant virus vaccine
    - Anti-idiotype vaccine
    - DNA vaccine
  - Polyvalent vaccines
    - Whole-cell vaccines
    - Tumor lysate vaccines
    - Shed antigens
    - Heat-shock proteins
  - Dendritic cell vaccines
  - Prophylactic vaccines
- Relative merits of therapeutic cancer vaccines
CHAPTER 5 NEW MARKET, NEW ISSUES
- Integrating therapeutic cancer vaccines into current treatment paradigms
  - Cancer vaccines are likely to broaden existing treatment options not replace them
  - Immunosuppressive therapy can compromise the efficacy of a cancer vaccine
  - Cancer vaccines are likely to be most effective in the setting of minimal residual disease
  - Multiple vaccinations can induce development of strong neutralizing antibodies
  - Adjuvants can improve the immunogenicity of a cancer vaccine
- Clinical trial design and surrogate endpoints for cancer vaccines
  - Clinical trial endpoints must adapt in line with changing needs
    - Multiple clinical trial endpoints are required to fully establish a vaccine' s therapeutic potential
    - Standard response criteria may have become somewhat redundant
    - Lack of adequate controls in the design of randomized clinical trials
  - Should immune monitoring be integral to assessing the efficacy of vaccine strategies?
    - Both cellular and humoral responses appear to be attractive methods for monitoring immune responses
    - To date, little correlation exists between immune response and clinical outcome
- Strategic challenges facing the commercialization of cancer vaccines
  - Regulatory issues cloud the road to commercialization
    - FDA request for further clinical data led to cessation of Corixa US development of Melacine
  - Formulation and manufacturing of cancer vaccines can become a major cause for concern
    - M-Vax' s route to market hindered due to manufacturing and formulation considerations
  - Skepticism over cost-effectiveness hampers commercialization
    - Restrictive pricing and reimbursement policies may obstruct the potential uptake of an approved cancer vaccine
  - 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 18 different tumor types
- Significant hurdles challenge the path to commercialization
CHAPTER 6 ANTIGEN-SPECIFIC CANCER VACCINES ANALYSIS & FORECASTS
- Pipeline overview
  - Late-phase pipeline of antigen-specific cancer vaccines
  - Phase II pipeline of antigen-specific cancer vaccines
  - Phase I pipeline of antigen-specific cancer vaccines
- MGI Pharma Biologics' Amolimogene (Biotope-CD; ZYC101a)
  - Drug profile
  - Clinical trial data
    - Amolimogene edges closer to the market with a Phase III trial for cervical dysplasia
    - Amolimogene may be effective for anal dysplasia
    - Amolimogene may become the first DNA-based vaccine to reach the market
    - MGI Pharma will provide Amolimogene with valuable oncology experience
- Pharmexa' s GV1001
  - Drug profile
  - Clinical trial data
    - Phase III trials for GV1001 in metastatic pancreatic cancer have been initiated and will recruit around 1,500 patients
    - Previous studies results warrent further development of GV1001 in a number of indications
    - GV1001 Phase II study in hepatocellular carcinoma has been initiated
    - Promising Phase I/II in NSCLC should encourage further development within the ' Big Four' tumor types
    - GV1001 with Temodar is a feasible combination for melanoma
    - GV1001 set to become the first telomerase-targeted vaccine to reach the market
    - GV1001 may struggle to achieve optimal market penetration without a more experienced oncology player
- Bristol-Myers Squibb' s MDX-1379
  - Drug profile
  - Clinical trial data
    - MDX-1379 and ipilimumab Fast Tracked for malignant melanoma
    - If encouraging, results from an ongoing Phase III clinical trial will support a BLA
    - Phase II results demonstrate complete of partial responses for the MDX-1379 and ipilimumab combination in melanoma
    - Optimizing the risk-benefit ratio is paramount in progressing commercial development of MDX-1379
    - Partnership with Bristol-Myers Squibb will put Medarex at a significant advantage
- Oxford BioMedica' s TroVax (MVA-h5T4)
  - Drug profile
  - Clinical trial data
    - Oxford BioMedica initiates Phase III (TRIST) trial for TroVax in combination with standard treatment for RCC
    - Humoral immune responses induced in the majority of CRC patients following vaccination with TroVax
    - With trials now beginning in breast and prostate cancer, TroVax may potentially gain approval within three of the ' Big Four' tumor types
    - TroVax on course to achieve first-to-market advantage
    - Approval for RCC likely to be a quicker route to market while horizontal expansion into three of the ' Big Four' tumor types will give TroVax a much wider patient base
    - TroVax must be competitively priced to ensure extensive uptake
    - Oxford BioMedica actively seeking a partner for commercializing TroVax
- Progenics' GMK (GM2-KLH)
  - Drug profile
  - Clinical trial data
    - No further developments to the Phase III melanoma trial that was initiated in 2001
    - GMK proven inferior to standard treatment for stage III melanoma with high risk recurrence
    - Further development was based on earlier findings that GMK induces an antibody response in melanoma
    - Lack of commercialization experience and marketing partner will affect GMK' s potential
    - Negative Phase III data may have irrevocably damaged GMK' s potential
    - A superior strategy may be to shift investment to more lucrative opportunities
- Receptor BioLogix' s Insegia (G17DT)
  - Drug profile
  - Clinical trial data
    - 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, Insegia' s commercial potential will be promising
    - Receptor BioLogix yet to initiate any further trials for Insegia
- Accentia Biopharmaceuticals' BIOVAXID
  - Drug profile
  - Clinical trial data
    - BIOVAXID inches closer to approval in the US and European markets for follicular NHL
    - Phase III trial initiated in February 2000 is ongoing and continues to show favorable survival benefits of BIOVAXID
    - Possible association between a specific negative chromasomal translocation following vaccination and disease free survival in follicular NHL
    - Phase II results of BIOVAXID in mantle cell lymphoma are promising
    - BIOVAXID competing with FavId and MyVax to first-to-market status
    - BIOVAXID' s price-tag should reflect the anticipated competition and current treatment costs
- Favrille' s FavId (Id-KLH)
  - Drug profile
  - Clinical trial data
    - FavId receives Fast Track status by the FDA for follicular NHL
    - Single-agent FavId demonstrates an objective response in indolent B-cell NHL
    - Favrille initiate FavId Phase III trial in DLBCL NHL
    - FavId competing with BIOVAXID and MyVax to reach the market first
    - Favrille' s lack of commercial experience will be a barrier to optimizing market penetration
- Genitope' s MyVax (GTOP-99)
  - Drug profile
  - Clinical trial data
    - MyVax received Fast Track status for follicular NHL while Phase III clinical trial approaches completion
    - Phase II clinical trials show greater number of immune responses among previously untreated patients
    - Genitope initiate Phase I/II trial for MyVax in chronic lymphocytic leukemia
    - Follow up Phase II data of MyVax in mantle cell and diffuse large B-cell lymphoma warrants further investigation
    - Despite competition from BIOVAXID and FavId, MyVax increases its commercial potential by targeting an earlier stage treatment
    - With trials ongoing in CLL, MyVax may ultimately emerge as the most adaptable anti-idiotype vaccine
- Comparison of anti-idiotype vaccines
- Forecasts
- Datamonitor drug assessment summary
CHAPTER 7 POLYVALENT CANCER VACCINES ANALYSIS & FORECASTS
- Pipeline overview
  - Late-phase pipeline of polyvalent cancer vaccines
  - Phase II pipeline of polyvalent cancer vaccines
  - Phase I pipeline of polyvalent cancer vaccines
- AVAX Technologies' M-Vax
  - Drug profile
  - Clinical trial data
    - Financial constraints trouble M-Vax' s initial approval
    - M-Vax suffers a notable setback after AVAX is forced to address formulation issues
    - M-Vax re-enters Phase III development
    - Multiple hurdles challenge M-Vax' s future success
- Cell Genesys' GVAX
  - Drug profile
  - Clinical trial data
    - Ongoing Phase III clinical trials need to confirm benefits of GVAX' s increased potency
    - High-dose GVAX demonstrates 13-month survival improvement over standard chemotherapy
    - Re-engineered second-generation GVAX confers increased potency in second round of Phase II clinical trials
    - Two-year survival data for GVAX in pancreatic cancer will encourage development for this indication
    - Phase II trial suggests GVAX is active in AML
    - Cell Genesys discontinues GVAX development for NSCLC and myeloma
    - GVAX' s approval for prostate cancer will be greatly anticipated
    - Cell Genesys will require an expansion of its marketing and distribution resources to optimize GVAX' s commercialization
- Intracel' s OncoVAX
  - Drug profile
  - Clinical trial data
    - FDA grants Intracel SPA for pivotal Phase III study for OncoVAX
    - Earlier studies demonstrate OncoVAX significantly improves survival in stage II colon cancer
    - Stage II colon cancer is a good place to start for OncoVAX but line extensions will be key to continued success
    - OncoVAX is the only vaccine in Phase III for CRC but a number of other candidates exist in the pipeline
- Antigenics' Oncophage (Vitespen; HSPPC-96)
  - Drug profile
  - Clinical trial data
    - Oncophage in development for a range of tumor types
    - Improved second-generation formulation facilitates use in early-stage disease
    - Promising Phase III results encourages further investigation in melanoma
    - Phase III study in RCC is halted after no increase in overall survival is achieved
    - Approval in other tumor types will increase Oncophage' s commercial potential
    - Personalized nature could work in Oncophage' s favor
    - Lack of cost effectiveness, clinical benefit and marketing experience will pose significant strategic challenges for Antigenics
- Forecasts
CHAPTER 8 DENDRITIC CELL CANCER VACCINES ANALYSIS & FORECASTS
- Pipeline overview
- Dendreon' s Provenge (Sipuleucel-T; APC-8015)
  - Drug profile
  - Clinical trial data
    - 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 results suggest synergy between Provenge and Genentech/Roche' s Avastin
    - Provenge may ultimately need to be compared with Taxotere if it is to expand its use in the HRPC market
    - Provenge may need to tackle the impact of its probable high cost, complex manufacture and potential competition in the HRPC market
    - Provenge' s commercial potential could be enhanced with the backing of an established oncology player
- Forecasts
APPENDIX A
- List of tables
- List of figures
- Methodology
  - Datamonitor forecast methodology
  - Datamonitor drug assessment summary
- Abbreviations
- Contributing experts
- Key opinion leader interview transcripts
- Bibliography
APPENDIX B
- About the Oncology analysis team
- Disclaimer
- List of Tables
  - Table 1: Late-phase pipeline therapeutic cancer vaccines sales forecasts for the seven major markets ($m), 2006-2015
  - Table 2: Datamonitor drug assessment summary for late-phase pipeline cancer vaccine therapies, 2006
  - Table 3: Therapeutic cancer vaccines in late-phase development, 2006
  - Table 4: Therapeutic cancer vaccines in Phase II development, 2006
  - Table 5: Therapeutic cancer vaccines in Phase I development, 2006
  - Table 6: Pipeline therapeutic cancer vaccines by developmental phase & class, 2006
  - Table 7: Proportion of personalized versus generalized cancer vaccines by phase, 2006
  - Table 8: Pipeline therapeutic cancer vaccines by indication, 2006
  - Table 9: Companies/Institutes with two or more vaccines in the pipeline, 2006
  - Table 10: Memorial Sloan-Kettering Cancer Center' s cancer vaccine therapies portfolio, 2006
  - Table 11: Therion Biologics' cancer vaccine therapies portfolio, 2006
  - Table 12: Common mutations involved in tumor development
  - Table 13: Forecast incidence of cancer across the seven major markets, 2005-2013
  - Table 14: Three main categories of cancer vaccines exist
  - Table 15: Advantages of peptide-based vaccines, 2006
  - Table 16: Advantages and disadvantages of cancer vaccines
  - Table 17: Relative efficacy merits of cancer vaccines
  - Table 18: Relative formulation merits of cancer vaccines
  - Table 19: Types of immune adjuvants
  - Table 20: Late-phase pipeline antigen-specific cancer vaccines, 2006
  - Table 21: Phase II pipeline antigen-specific cancer vaccines, 2006
  - Table 22: Phase I pipeline antigen-specific cancer vaccines, 2006
  - Table 23: Ongoing clinical trial involving Amolimogene, 2006
  - Table 24: Ongoing clinical trial involving GV1001, 2006
  - Table 25: Ongoing clinical trial involving MDX-1379, 2006
  - Table 26: Phase II initial data for MDX-1379 in melanoma
  - Table 27: Ongoing clinical trials involving TroVax, 2006
  - Table 28: Interim Phase II results of TroVax in CRC
  - Table 29: Ongoing clinical trials involving BIOVAXID, 2006
  - Table 30: Ongoing clinical trials involving FavId, 2006
  - Table 31: Interim results of FavId monotherapy Phase III trial in fNHL: Response to Rituxan, December 2006
  - Table 32: Ongoing clinical trial involving MyVax, 2006
  - Table 33: Phase II interim results of MyVax in MCL and DLBCL NHL patients, 1 of 2
  - Table 34: Phase II interim results of MyVax in MCL and DLBCL NHL patients, 2 of 2
  - Table 35: Comparisons of the late-phase anti-idiotype vaccines
  - Table 36: Forecasting assumptions for late-phase antigen-specific cancer vaccines, 2006 (1 of 3)
  - Table 37: Forecasting assumptions for late-phase antigen-specific cancer vaccines, 2006 (2 of 3)
  - Table 38: Forecasting assumptions for late-phase antigen-specific cancer vaccines, 2006 (3 of 3)
  - Table 39: Antigen-specific cancer vaccines sales forecasts, 2006-2015 ($m)
  - Table 40: Research/clinical and commercial attractiveness of the pipeline antigen-specific cancer vaccines, 2006 (1 of 2)
  - Table 41: Research/clinical and commercial attractiveness of the pipeline antigen-specific cancer vaccines, 2006 (2 of 2)
  - Table 42: Late-phase pipeline polyvalent cancer vaccines, 2006
  - Table 43: Phase II pipeline antigen-specific cancer vaccines, 2006
  - Table 44: Phase I pipeline antigen-specific cancer vaccines, 2006
  - Table 45: Ongoing clinical trials involving M-Vax, 2006
  - Table 46: Ongoing clinical trials involving GVAX, 2006
  - Table 47: Ongoing clinical trial involving OncoVAX, 2006
  - Table 48: Ongoing clinical trial involving Oncophage, 2006
  - Table 49: Final Phase III results for Oncophage in stage IV melanoma
  - Table 50: Staging system for stage IV melanoma
  - Table 51: Forecasting assumptions for late-phase polyvalent cancer vaccines, 2006
  - Table 52: Polyvalent cancer vaccines sales forecasts ($m), 2006-2015
  - Table 53: Research/clinical and commercial attractiveness of the pipeline polyvalent cancer vaccines, 2006
  - Table 54: Pipeline dendritic cell cancer vaccines in clinical trials, 2006
  - Table 55: Ongoing clinical trials involving Provenge, 2006
  - Table 56: Three-year final survival analysis for Phase III D9901 Provenge study
  - Table 57: Three-year final survival analysis for Phase III D9902A Provenge study
  - Table 58: Integrated data from D9901/D9902A trials for patients treated with Provenge followed by Taxotere, 1 of 2
  - Table 59: Integrated data from D9901/D9902A trials for patients treated with Provenge followed by Taxotere, 2 of 2
  - Table 60: Forecasting assumptions for Provenge, 2006
  - Table 61: Provenge sales forecasts, 2006-2015 ($m)
  - Table 62: Research/clinical and commercial attractiveness of Provenge, 2006
  - Table 63: Datamonitor drug assessment parameters
  - Table 64: Abbreviations used in Pipeline Insight: Therapeutic Cancer Vaccines (1 of 2)
  - Table 65: Abbreviations used in Pipeline Insight: Therapeutic Cancer Vaccines (2 of 2)
- List of Figures
  - Figure 1: Antigen-specific cancer vaccines sales forecasts ($m), 2006-2015
  - Figure 2: Polyvalent cancer vaccines sales forecasts, 2006-2015 ($m)
  - Figure 3: Provenge sales forecasts, 2006-2015 ($m)
  - Figure 4: Datamonitor drug assessment summary for late-phase pipeline cancer vaccine therapies, 2006
  - Figure 5: Pipeline therapeutic cancer vaccines by developmental phase & class, 2006
  - Figure 6: Pipeline therapeutic cancer vaccines by class, 2006
  - Figure 7: Pipeline therapeutic cancer vaccines by phase, 2006
  - Figure 8: Antigen-specific cancer vaccines by developmental phase, 2006
  - Figure 9: Polyvalent cancer vaccines by developmental phase, 2006
  - Figure 10: Dendritic cell cancer vaccines by developmental phase, 2006
  - Figure 11: Pipeline therapeutic cancer vaccines by technology platform, 2006
  - Figure 12: Proportion of personalized versus generalized cancer vaccines, 2006
  - Figure 13: Proportion of personalized versus generalized cancer vaccines by phase, 2006
  - Figure 14: Pipeline therapeutic cancer vaccines by indication, 2006
  - Figure 15: Proportion of solid tumors versus hematological malignancies, 2006
  - Figure 16: Late-phase pipeline therapeutic cancer vaccines by indication, 2006
  - Figure 17: Pipeline therapeutic cancer vaccines by company, 2006
  - Figure 18: Global oncology sales ($m), 2002-09
  - Figure 19: Oncology pipeline including supportive care, 2006
  - Figure 20: Forecast incidence of cancer across the seven major markets, 2005-2013
  - Figure 21: Combined incidence for breast, lung, prostate and colorectal cancer rises with age in seven major markets, 2003
  - Figure 22: Incidence increases, while the rate of cure and death reduces disease prevalence
  - Figure 23: Point prevalence for colorectal and lung cancer differs markedly despite similar rates of incidence
  - Figure 24: Unmet needs in cancer, 2006
  - Figure 25: To achieve success, cancer vaccines need to overcome immune tolerance
  - Figure 26: Disadvantages associated with cancer vaccines are currently more significant than advantages
  - Figure 27: TeloVac Phase III trial outline, 2006
  - Figure 28: GMK' s mode of action
  - Figure 29: Trial design of Phase II study of FavId in progressive NHL
  - Figure 30: Gernitope' s personalized immunotherapy (MyVax) production system
  - Figure 31: Antigen-specific cancer vaccines sales forecasts ($m), 2006-2015
  - Figure 32: Research/clinical and commercial attractiveness of pipeline antigen-specific cancer vaccines, 2006
  - Figure 33: Polyvalent cancer vaccines sales forecasts, 2006-2015 ($m)
  - Figure 34: Research/clinical and commercial attractiveness of the pipeline polyvalent cancer vaccines, 2006
  - Figure 35: Provenge sales forecasts, 2006-2015 ($m)
  - Figure 36: Research/clinical and commercial attractiveness of Provenge, 2006

Pipeline Insight: Therapeutic Cancer Vaccines - A turbulent path from bench to bedside

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