Contents:

CHAPTER 1 EXECUTIVE SUMMARY Scope of analysis 3 CHAPTER 2 DISEASE OVERVIEW Introduction 6 Disease overview 6 Insufficient treatment options for advanced stages of disease 6 The recurring nature of non-invasive tumors leads to a great economic burden 6 Anatomy of the bladder 7 Bladder cancer 8 Definition 8 Pathology/histology 8 Transitional cell carcinoma is the most common cancer type in developed countries 9 Squamous cell carcinoma accounts for 75% of bladder tumors in developing countries 9 Adenocarcinoma is common in patients with exstrophy 10 Uncommon bladder cancer types 10 Clinical classifications 11 Epidemiology 11 Aging population contributes to rising incidence rates 11 Rising mortality rates highlight the need for better treatment options 13 Risk factors 15 Older age 15 Active and passive smokers are more likely to develop bladder cancer 15 Chemical industry employees are at greater risk 16 Medical risk factors and prior cyclophosphamide-based chemotherapy increases chances of developing bladder cancer 16 Urinary tract infections are directly related to invasive SCC 16 Greater incidence in men than women 16 Ethnicity and geographical location affect prognosis and risk of developing disease 17 Genetic factors also affect the chances of developing bladder cancer 17 Symptoms 18 All cases of hematuria should be investigated for bladder cancer 18 Screening 18 Urinary markers have not been embraced for bladder cancer screening 18 Diagnosis 19 Cystoscopy is the most widely used test for bladder cancer 19 Staging 20 The TNM system is the more descriptive method of staging 20 The World Health Organization (WHO) offers a modified grading system 21 75% of tumors are non-invasive at the time of diagnosis 22 Prognosis and survival 23 High-grade tumors have the worst prognosis as progression is more likely to occur 23 Growth factor receptors may serve as prognostic markers and therapy targets 23 Prevention 24 Lifestyle changes are advised to prevent bladder cancer. 24 CHAPTER 3 CURRENT TREATMENT OPTIONS AND CONTROVERSIES Introduction 25 Treatment guidelines 25 National Comprehensive Cancer Network treatment guidelines 25 Transurethral resection followed by intravesical BCG is the standard treatment for non-invasive tumors and CIS in the US 25 Radical cystectomy is the preferred treatment for continually recurring tumors 27 European treatment guidelines 28 EU clinicians use BCG therapy less than clinicians in the US 28 Japanese treatment guidelines 29 Cystectomy is the main treatment used for bladder cancer in Japan 29 Treatment by stage 30 Non-invasive bladder cancer 30 Recurrence and progression must be prevented by surgery and adjuvant intravesical therapy if long-term survival is to be achieved 30 TURBT is an appropriate primary treatment because it eliminates visible tumors 31 Immunotherapy is preferred to chemotherapy as an adjuvant to TURBT 32 Few options are available for BCG-refractory patients 33 Combination chemotherapy is more effective than single-agent chemotherapy 34 Invasive bladder cancer 36 Cystectomy is the standard therapy for invasive tumors... 36 ...however, only 50% of patients will survive past 5 years unless adjuvant chemotherapy is administered 37 Metastatic bladder cancer 39 Bladder-removing surgery remains the best life-saving strategy as adequate treatment has yet to be identified 39 Neoadjuvant chemotherapy is recommended for metastatic tumors 39 Cisplatin-based combination chemotherapy forms the cornerstone of first-line therapy for metastatic bladder cancer 40 Patients with a poor performance history receive radiotherapy 42 Recurrent tumors 42 CHAPTER 4 UNMET NEEDS Introduction 43 Unmet needs 43 No treatment available to prevent recurrent tumors in non-invasive bladder cancer 43 Limited treatment options for patients who are unfit for current treatment options 44 BCG-refractory patients usually fail to respond to chemotherapy 44 Patients who are unfit for cystectomy receive substandard treatment due to a lack of options 45 Metastatic disease treatment is not effective 45 No standard treatment schedule is available for adjuvant therapy with immunotherapy or chemotherapy 46 Better routes of administration than intravesically may lead to longer exposure time and better drug absorption 46 More sensitive detection methods as well as prognostic markers are needed to combat the high cost of follow-up 47 New drugs required for non-urothelial cell tumor treatment 48 Summary of unmet needs 48 CHAPTER 5 PIPELINE ANALYSIS Pipeline overview 50 The bladder cancer pipeline 50 Phase III pipeline 50 Phase II pipeline 51 Targeted therapy strives for a place in the bladder cancer market 52 Phase III drug profiles 52 EOquin (apaziquone; Spectrum Pharmaceuticals) 52 Drug overview 52 Key historical events 53 Clinical development in bladder cancer 53 Datamonitor comments 58 Iressa (gefitinib; AstraZeneca) 58 Drug overview 58 Key historical events 59 Clinical development in bladder cancer 60 Datamonitor comments 62 Urocidin (MCC; Bioniche Life Science) 64 Drug overview 64 Key historical events 64 Clinical development in bladder cancer 64 Datamonitor comments 68 Valstar (valrubicin; Indevus) 69 Drug overview 69 Key historical events 69 Clinical development in bladder cancer 70 Datamonitor comments 70 Larotaxel (XRP9881; Sanofi-Aventis) 71 Drug overview 71 Key historical events 71 Clinical development in bladder cancer 72 Datamonitor comments 73 CHAPTER 6 KEY OPINION LEADER INTERVIEW TRANSCRIPTS Contributing experts 75 Key opinion leader interview transcripts 75 APPENDIX 76 Bibliography 76 List of Tables Table 1: Clinical subtypes of bladder cancer 11 Table 2: Crude incidence rates for bladder cancer (per 100,000 persons) in the seven major markets, 2002 12 Table 3: Forecast incidence of bladder cancer in the seven major markets, 2002-2017 12 Table 4: Crude mortality rates for bladder cancer in the seven major markets, 2002 14 Table 5: Risk factors associated with bladder cancer 15 Table 6: Diagnostic tests for bladder cancer 19 Table 7: TNM and Jewett staging systems for primary bladder tumors 20 Table 8: Lymph node classifications in the TNM staging system 21 Table 9: Distant metastasis classification in the TNM staging system 21 Table 10: World Health Organization grading system for non-invasive bladder tumors 22 Table 11: Rate of progression and survival of non-invasive tumors in bladder cancer 23 Table 12: National Comprehensive Cancer Network (NCCN) guidelines for primary bladder cancer treatment in the US, 2008 26 Table 13: National Comprehensive Cancer Network (NCCN) guidelines for recurrent bladder cancer treatment in the US, 2008 28 Table 14: European treatment guidelines for bladder cancer, 2008 28 Table 15: Japanese treatment guidelines for bladder cancer 29 Table 16: Late-phase bladder cancer pipeline, 2008 50 Table 17: Phase II bladder cancer pipeline, 2008 51 Table 18: EOquin: key historical events, 2007-08 53 Table 19: Ongoing clinical trials involving EOquin, 2008 54 Table 20: Iressa: key historical events, 2002-08 59 Table 21: Ongoing clinical trials involving Iressa, 2008 60 Table 22: Cost of TICE BCG and Iressa per week based on price of drugs alone 62 Table 23: Ongoing trials in the metastatic transitional cell carcinoma (TCC) setting 63 Table 24: Urocidin: key historical events, 2006-08 64 Table 25: Ongoing clinical trials involving Urocidin, 2008 65 Table 26: Valstar: key historical events, 1998-2007 69 Table 27: Larotaxel: key historical events, 2004-08 71 Table 28: Ongoing clinical trials involving larotaxel, 2008 72 List of Figures Figure 1: Anatomy of the bladder 7 Figure 2: Bladder tumor histology and their abundance in the US, 2008 8 Figure 3: Forecast incidence of bladder cancer in the seven major markets, 2002-2017 13 Figure 4: Incidence and mortality of bladder cancer in the seven major markets, 2008 and 2017 14 Figure 5: Stage of bladder cancer at diagnosis 22 Figure 6: Phase III trial demonstrating that GC is less toxic than MVAC in metastatic bladder cancer patients 27 Figure 7: Phase III trial of neoadjuvant MVAC combination therapy in invasive transitional cell carcinoma (TCC) 38 Figure 8: Phase III trial comparing CG and MVAC combination chemotherapy in metastatic bladder cancer 41 Figure 9: Summary of unmet needs in bladder cancer, 2008 49 Figure 10: Phase III study design of EOquin in low-grade papillary tumors 55 Figure 11: Phase II marker tumor trial of EOquin in non-invasive bladder cancer 56 Figure 12: Phase I trial to demonstrate safety of EOquin following surgery 57 Figure 13: Phase III trial of Iressa in patients with high-risk non-invasive transitional cell carcinoma (TCC) 61 Figure 14: Phase III trial of Urocidin monotherapy in BCG-refractory non-invasive transitional cell carcinoma (TCC) 65 Figure 15: Phase II study investigating Urocidin in high-risk non-invasive bladder cancer 66 Figure 16: Phase I/II study of Urocidin monotherapy in patients with carcinoma in situ (CIS) tumors 67 Figure 17: Phase III study design for larotaxel in combination with cisplatin in metastatic transitional cell carcinoma (TCC) 73