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Melanoma - Lucrative commercial opportunities persist

Melanoma comprises just 5% of all skin cancers but it is the most deadly. In 2006, more than 100,000 cases of the disease are expected to be diagnosed in the seven major pharmaceutical markets. High unmet needs still persist for this tumor type and despite three decades of extensive R&D, five-year survival of advanced patients remains below 20%.

Scope

Review of current treatment controversies and physician opinion of existing and future treatment strategies

Examination of unmet needs in melanoma treatment and market opportunities for drug developers

Insight and commercial potential of late-stage melanoma pipeline therapeutics

Stakeholder opinions based on qualitative interviews with five opinion leaders from the US and Europe

Report Highlights
Although the late-stage melanoma pipeline is diverse, five of the nine agents have had a turbulent development history. As a result of these developmental problems, stakeholders hold a generally pessimistic view of a significant proportion of the late-stage pipeline candidates.

As Bayer/Onyx's Nexavar (sorafenib) failed to meet its Phase III primary endpoint of improving progression-free survival in relapsed advanced melanoma patients, Nexavar's future is now dependent on a second Phase III trial. As this trial involves chemotherapy-naive patients, Nexavar may have an increased chance of demonstrating improved survival.

Phase III clinical data is needed to distinguish between Pfizer's ticilimumab and Medarex/Bristol-Myers Squibb's ipilimumab. Given the presence of two Big Pharma players, the melanoma arena could become increasingly competitive, with each company vying for first-to-market status and product supremacy.

Reasons to Purchase

Understand current epidemiological trends in melanoma and ongoing treatment controversies

Identify the limitations of current treatment and the potential of future pharmacotherapy

Enhance your commercial positioning through an increased understanding of melanoma market dynamics

Table of Contents

• About the Oncology pharmaceutical analysis team - page 2
• CHAPTER 1 EXECUTIVE SUMMARY - page 3
  • Datamonitor insight into the melanoma market - page 3
• CHAPTER 2 DISEASE OVERVIEW - page 17
  • Melanoma comprises just 5% of all skin cancers, but it is the most deadly - page 17
  • The skin has a role of functions, including protection against solar ultraviolet damage - page 17
  • Melanoma: a disease of melanocytes which have accumulated genetic defects - page 19
  • Four major subtypes of melanoma exist although they do not affect treatment decisions - page 19
    • Lentigo maligna melanoma (LMM) is associated with the elderly - page 20
    • Superficial spreading melanoma (SSM) is the commonest subtype of melanoma - page 20
    • Nodular melanoma (NM) is characterised by rapid growth - page 21
    • Acral-lentiginous melanoma (ALM) may be related to delayed diagnosis - page 21
  • The pathogenesis of melanoma is believed to involve defective cell cycle regulation - page 21
  • The incidence of melanoma continues to rise - page 22
  • A range of risk factors are associated with the development of melanoma - page 25
    • Excessive exposure to sunlight and severe sunburn is thought to be a major contributing factor for cutaneous melanoma - page 25
    • Although evidence finds that sun-beds emit harmful UV radiation, their use is increasing in the young - page 26
    • More research is required to determine a safe method to obtain the protective effects of vitamin D - page 26
    • The presence of nevi (moles) is associated with increased risk of developing melanoma - page 27
    • Individuals with fair hair, a pale complexion and freckling are at the greatest risk of developing melanoma - page 27
    • Melanocortin-1 receptor (MC1R) alleles may be linked with melanoma - page 27
    • Hereditary factors and family history accounts for 10% of all melanomas - page 28
    • Half of all melanomas are found in those aged over 50 years - page 28
    • Due to increased sun exposure, males are twice as likely to develop melanoma than women - page 29
    • Xeroderma pigmentosum is an inherited autosomal recessive disorder which renders individuals more susceptible to UV radiation - page 29
    • A melanoma risk model is available for US patients that could aid clinical trial recruitment - page 29
  • Symptoms of melanoma are typically linked with changes in the apperance of nevi - page 30
    • The use of sunscreen is inadequate - page 31
  • Screening is low among high-risk patients - page 33
  • As diagnosis of melanoma is usually made histologically, it is vital that the thickness of the tumor is accurately determined - page 33
  • Melanoma biomakers could improve screening, diagnosis and treatment of the disease - page 34
  • A number of staging systems exist for melanoma - page 35
  • The prognosis of stage IV melanoma is poor - page 38
  • Relapse among melanoma patients is common - page 39
• CHAPTER 3 CURRENT TREATMENT CONTROVERSIES - page 41
  • Melanoma treatment paradigms are tailored to suit individual patient needs - page 41
  • NCCN guidelines recommened clinical trials as a systemic therapy - page 41
  • Surgery forms the cornerstone of therapy for stage I-III melanoma - page 42
    • Narrow versus wide excision margins: debate still continues as to which should be employed - page 42
    • Mohs's micrographic surgery is suitable for facial in situ melanomas - page 43
    • Lymph node dissection is only appropriate for stage III melanoma patients - page 44
    • The use of surgery at stage IV disease is extremely limited and serves only pallitative purposes - page 45
  • Radiotherapy is generally ineffective for melanoma - page 46
    • Radiotherapy resistance may be linked with DOPAchrome tautomerase (DCT) enzyme expression - page 46
  • Chemotherapeutic agents have limited activity in metastatic melanoma - page 47
    • Dacarbazine (Bayer's DTIC-Dome, now genericized) was FDA approved over thirty years ago, but it is still the most active agent within metastatic melanoma - page 48
      • Single-agent dacarbazine demonstrates a response rate of around 20%, although this has now been questioned - page 49
      • Attempts to improve dacarbazine's efficacy have led to the investigation of combinatorial cytotoxic regimens - page 49
    • Schering Plough's Temodar (temozolomide) is used off-label for melanoma that has metastasized to the brain - page 53
      • Temodar versus dacarbazine: which is the superior agent for the treatment of metastatic melanoma? - page 55
      • Temodar has been shown to improve quality of life... - page 55
      • Temodar has a convienent dosing schedule - page 55
      • ...but is associated with opportunistic infections - page 56
      • Could Temodar challenge dacarbazine within melanoma? - page 57
    • Isolated limb perfusion may be used to deliver chemotherapy to a specific extremity - page 58
  • Immunotherapy plays a significant role in the treatment of melanoma - page 59
    • Schering-Plough's Intron-A (interferon alpha-2b) is currently the only FDA and EMEA-approved treatment for adjuvant melanoma - page 59
      • INF-alpha monotherapy overall response rate is just 15% - page 60
      • INF-alpha has a range of toxicities that can limit its patient population - page 60
      • High-dose versus low-dose INF-alpha: debate continues in a bid to improve toxicity and quality of life - page 61
      • There is a lack of evidence to warrant the use of low or intermediate doses of INF-alpha - page 63
      • Half of all melanoma patients are willing to tolerate high-dose INF-alpha - page 64
    • Pegylated INF-alpha monotherapy appears not to improve upon standard INF-alpha's efficacy or toxicity profile... - page 65
    • ...however, pegylated INF-alpha in combination with Temodar shows promise - page 66
    • Chiron's Proleukin (aldesleukin) was the last agent to gain FDA approval for metastatic melanoma in 1998 - page 68
      • High-dose IL-2 monotherapy is associated with low but durable response rates... - page 68
      • ...and considerable toxicities - page 69
      • The use of high-dose IL-2 within the US is limited - page 70
      • Low-dose IL-2 has yet to demonstrate benefit within melanoma - page 70
    • Combinational systemic therapy has been intensively investigated - page 71
    • The future role of biochemotherapy within melanoma is unclear - page 73
    • Use of systemic therapeutics across the five major European markets finds interferon dominates early-stage melanoma, while dacarbazine is favored for stage IV patients - page 74
• CHAPTER 4 UNMET NEEDS IN MELANOMA - page 79
  • Melanoma patients represent a hugely underserved patient population - page 79
    • Current melanoma therapeutics have a high risk to benefit ratio - page 79
    • Over the past three decades there have been few significant advances in pharmacotherapy for metastatic disease - page 80
    • Early diagnosis is the key to curative treatment - page 80
    • Gene profiling will help individualize treatment approaches - page 81
• CHAPTER 5 PIPELINE ANALYSIS - page 82
  • Genta's Genasense (oblimersen) remains in development despite termination of agreement with Sanofi-Aventis - page 89
    • Genasense is under review with the EMEA despite failure to gain FDA approval for melanoma in 2004 - page 89
    • Two-year follow-up data used for Genasense's MAA finds the trial missed its overall survival primary endpoint - page 90
    • Normal serum lactate dehydrogenase (LDH) levels may be associated with improved overall survival - page 90
      • Selection of trial patients with normal LDH levels could aid drug development - page 92
    • The combination of Genasense and dacarbazine is associated with increased toxicity - page 92
    • Approval of Genasense in combination with dacarbazine viewed as unlikely - page 93
    • Phase I study initiated to investigate Genasense in combination with Schering-Plough's Temodar (temozolomide) and Abraxis Oncology's Abraxane - page 94
    • Termination of agreement with Sanofi-Aventis is a major setback for Genta - page 95
  • Bayer/Onyx's Nexavar (sorafenib): an orally active multi-kinase inhibitor stimulates stakeholder interest - page 95
    • Initial results from a Phase III melanoma study are disappointing - page 96
    • Phase II study shows Nexavar monotherapy has poor activity - page 98
    • The addition of carboplatin and paclitaxel to Nexavar improves progression-free survival over Nexavar monotherapy - page 99
    • Preliminary results from a randomized Phase II study of a Temodar and Nexavar combination shows promise - page 101
    • Nexavar with dacarbazine is well tolerated and is currently in Phase II development - page 103
    • The future of Nexavar in advanced melanoma looks uncertain following failure of the Phase III PRISM trial - page 103
  • Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibodies show promise in the management of melanoma - page 103
    • Medarex/Bristol-Myers Squibb's ipilimumab (MDX-010, BMS-734016) has been awarded Fast Track status in melanoma - page 104
      • Ipilimumab's second Phase III melanoma study is currently underway - page 105
      • Ipilimumab in combination with dacarbazine shows promise but there are concerns over toxicity - page 106
      • Long-term follow up data shows the additon of dacarbazine to ipilimumab improves median progression-free survival - page 107
      • Phase II interim results shows ipilimumab and a MART vaccine may reduce relapse rates in the adjuvant setting - page 108
      • Strong partnership between Medarex and Bristol-Myers Squibb will facilitate commercialization - page 109
    • Pfizer hopes to file ticilimumab (CP-675,206) with the FDA in 2007 for melanoma - page 109
      • Long-term data from two Phase I ticilimumab melanoma trials presented at ASCO 2006 - page 110
      • A Phase I/II study shows that ticilimumab clinical activity correlates with supression of T-regulatory cells - page 111
      • Pfizer seeking to expand its oncology franchise - page 112
  • Distinguishing between ipilimumab and ticilimumab proves challenging - page 112
  • Melanoma vaccines: augmenting anti-tumor immunity - page 114
  • AVAX Technologies' M-Vax is an autologous vaccine that has been launched in Switzerland - page 115
    • Financial constraints trouble M-Vax's initial approval in Australia - page 116
      • M-Vax suffers a notable setback after FDA requires AVAX to address formulation issues - page 116
    • M-Vax re-enters Phase III development in October 2006 - page 117
      • Previous M-Vax Phase III results show the vaccine lead to a 44% five-year overall survival rate - page 118
    • Multiple hurdles challenge M-Vax's future success - page 118
    • Improved second-generation formulation facilitates use in early-stage disease - page 120
    • Oncophage's Phase III results prompt further investigation - page 120
      • Previous Phase II studies suggested antitumor activity in melanoma - page 121
    • Personalized nature could work in Oncophage's favor - page 122
    • Lack of cost-effectiveness, clinical benefit and marketing experience will pose significant strategic challenges for Antigenics - page 122
    • If encouraging, results from an ongoing Phase III clinical trial will support a BLA - page 123
      • Phase II results demonstrate complete or partial responses for the MDX-1379 and ipilimumab combination in melanoma - page 123
    • Partnership with Bristol-Myers Squibb will put Medarex at a significant advantage - page 125
  • Vical/AnGes's Allovectin-7: a gene transfer product involving a DNA plasmid/lipid complex - page 126
    • Phase III melanoma development continues despite suffering a major setback - page 126
    • Phase II data shows Allovectin-7 leads to durable responses lasting over six months - page 127
    • A further Phase II Allovectin-7 study demonstrates median overall survival of over 21 months - page 128
    • The market impact of Allovectin-7 still looks doubtful - page 128
• CHAPTER 6 APPENDIX - page 130
  • Contributing experts - page 130
  • Opinion leader interview transcripts - page 130
  • Bibliography - page 131
  • List of tables - page 144
  • List of figures - page 147
  • About Datamonitor - page 148
    • About Datamonitor Healthcare - page 148
    • Datamonitor Healthcare's research and analysis methodologies - page 149
  • Datamonitor Healthcare's therapy area capabilities - page 149
    • About the Oncology analysis team - page 150
    • Disclaimer - page 151


• List of Tables
• Table 1: Crude incidence rates of skin melanoma by gender (per 100,000) in the seven major markets, 2002 - page 24
• Table 2: Melanoma incidence forecast in the seven major markets, 2002-16 - page 24
• Table 3: AJCC TNM staging of melanoma - page 36
• Table 4: AJCC TNM staging of melanoma - page 36
• Table 5: Clark's and Breslow's classification for melanoma - page 37
• Table 6: M1a-M1c staging system for stage IV melanoma - page 38
• Table 7: Five-year survival rates by pathologic stage for melanoma - page 39
• Table 8: Current guidelines for excision margins based on primary tumor thickness - page 43
• Table 9: Response rates and dosage regimens for currently used single-agent cytotoxic melanoma drugs - page 48
• Table 10: Dosing levels for common melanoma chemotherapy regimens - page 50
• Table 11: Summary of Agarwala et al. (2004) results of Temodar in treating melanoma brain metastasis - page 53
• Table 12: Summary of Schadendorf et al. (2006) results of Temodar in treating melanoma brain metastasis - page 54
• Table 13: Various interferon alpha-2b dosing regimens for the treatment of melanoma - page 61
• Table 14: Summary of results of Eastern Cooperative Oncology Group 1684, 1690 and 1694 trials - page 62
• Table 15: Summary of efficacy results of pegylated INF-alpha - page 66
• Table 16: Summary of Proleukin's metastatic melanoma efficacy results - page 69
• Table 17: Dosing levels for common melanoma biochemotherapy regimens - page 71
• Table 18: Summary of Legha et al. (1996) biochemotherapy results - page 72
• Table 19: Percentage of melanoma patients who receive systemic therapeutics across the five EU markets, by disease stage - page 74
• Table 20: Percentage of melanoma patients who receive multiple lines of systemic therapy, by disease stage (I-IV) across the five EU markets - page 75
• Table 21: Leading systemic regimens prescribed for stage I-III melanoma patients, across the five EU markets - page 76
• Table 22: Leading systemic regimens prescribed for stage IV melanoma patients, across the five EU markets - page 77
• Table 23: Late-phase pipeline compounds for melanoma, 2006 - page 82
• Table 24: Phase II pipeline compounds for melanoma, 2006 (1/5) - page 83
• Table 25: Phase II pipeline compounds for melanoma, 2006 (2/5) - page 84
• Table 26: Phase II pipeline compounds for melanoma, 2006 (3/5) - page 85
• Table 27: Phase II pipeline compounds for melanoma, 2006 (4/5) - page 86
• Table 28: Phase II pipeline compounds for melanoma, 2006 (5/5) - page 87
• Table 29: Phase I pipeline compounds for melanoma, 2006 - page 88
• Table 30: Kirkwood et al. (2005) intent-to-treat results of Genasense versus dacarbazine - page 90
• Table 31: Bedikian et al. (2006) multivariate analysis based on normal LDH level; results of Genasense versus dacarbazine - page 91
• Table 32: Ongoing Nexavar melanoma clinical trials, 2006 - page 98
• Table 33: Nexavar response data according to dose when in combination with carboplatin and paclitaxel - page 99
• Table 34: Efficacy results from Amaravadi et al. (2006) Phase II melanoma trial comparing two doses of Temodar in combination in Nexavar - page 102
• Table 35: Ongoing Ipilimumab clinical trials in melanoma , 2006 - page 105
• Table 36: Summary of Ipilimumab's Phase II efficacy results - page 107
• Table 37: Ongoing ticilimumab melanoma clinical trials, 2006 - page 110
• Table 38: Ticilimumab immune-related adverse effects and related response rate results - page 111
• Table 39: Ongoing clinical trials involving M-Vax, 2006 - page 116
• Table 40: Phase III Oncophage efficacy results in stage IV melanoma - page 121
• Table 41: Phase II initial data for MDX-1379 in melanoma - page 124


• List of Figures
• Figure 1: The structure of the skin - page 18
• Figure 2: Melanoma incidence forecast in the seven major markets, 2002-16 - page 25
• Figure 3: NCCN guidelines for the treatment of melanoma, 2006 - page 42
• Figure 4: Design of Amaravadi et al. (2006) Phase II melanoma trial comparing two doses of Temodar in combination in Nexavar - page 101

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