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Stakeholder Opinions: Melanoma - Lucrative commercial opportunities persistPublished by: Datamonitor Published: Dec. 21, 2006 - 155 Pages Table of ContentsTABLE OF CONTENTS About the Oncology pharmaceutical analysis team 2 CHAPTER 1 EXECUTIVE SUMMARY 3 Datamonitor insight into the melanoma market 3 CHAPTER 2 DISEASE OVERVIEW 17 Melanoma comprises just 5% of all skin cancers, but it is the most deadly 17 The skin has a role of functions, including protection against solar ultraviolet damage 17 Melanoma: a disease of melanocytes which have accumulated genetic defects 19 Four major subtypes of melanoma exist although they do not affect treatment decisions 19 Lentigo maligna melanoma (LMM) is associated with the elderly 20 Superficial spreading melanoma (SSM) is the commonest subtype of melanoma 20 Nodular melanoma (NM) is characterised by rapid growth 21 Acral-lentiginous melanoma (ALM) may be related to delayed diagnosis 21 The pathogenesis of melanoma is believed to involve defective cell cycle regulation 21 The incidence of melanoma continues to rise 22 A range of risk factors are associated with the development of melanoma 25 Excessive exposure to sunlight and severe sunburn is thought to be a major contributing factor for cutaneous melanoma 25 Although evidence finds that sun-beds emit harmful UV radiation, their use is increasing in the young 26 More research is required to determine a safe method to obtain the protective effects of vitamin D 26 The presence of nevi (moles) is associated with increased risk of developing melanoma 27 Individuals with fair hair, a pale complexion and freckling are at the greatest risk of developing melanoma 27 Melanocortin-1 receptor (MC1R) alleles may be linked with melanoma 27 Hereditary factors and family history accounts for 10% of all melanomas 28 Half of all melanomas are found in those aged over 50 years 28 Due to increased sun exposure, males are twice as likely to develop melanoma than women 29 Xeroderma pigmentosum is an inherited autosomal recessive disorder which renders individuals more susceptible to UV radiation 29 A melanoma risk model is available for US patients that could aid clinical trial recruitment 29 Symptoms of melanoma are typically linked with changes in the apperance of nevi 30 The use of sunscreen is inadequate 31 Screening is low among high-risk patients 33 As diagnosis of melanoma is usually made histologically, it is vital that the thickness of the tumor is accurately determined 33 Melanoma biomakers could improve screening, diagnosis and treatment of the disease 34 A number of staging systems exist for melanoma 35 The prognosis of stage IV melanoma is poor 38 Relapse among melanoma patients is common 39 CHAPTER 3 CURRENT TREATMENT CONTROVERSIES 41 Melanoma treatment paradigms are tailored to suit individual patient needs 41 NCCN guidelines recommened clinical trials as a systemic therapy 41 Surgery forms the cornerstone of therapy for stage I-III melanoma 42 Narrow versus wide excision margins: debate still continues as to which should be employed 42 Mohs’s micrographic surgery is suitable for facial in situ melanomas 43 Lymph node dissection is only appropriate for stage III melanoma patients 44 The use of surgery at stage IV disease is extremely limited and serves only pallitative purposes 45 Radiotherapy is generally ineffective for melanoma 46 Radiotherapy resistance may be linked with DOPAchrome tautomerase (DCT) enzyme expression 46 Chemotherapeutic agents have limited activity in metastatic melanoma 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 48 Schering Plough’s Temodar (temozolomide) is used off-label for melanoma that has metastasized to the brain 53 Isolated limb perfusion may be used to deliver chemotherapy to a specific extremity 58 Immunotherapy plays a significant role in the treatment of melanoma in the US market 59 Schering-Plough’s Intron-A (interferon alpha-2b) is currently the only FDA-approved treatment for adjuvant melanoma 59 Pegylated INF-alpha monotherapy appears not to improve upon standard INF-alpha’s efficacy or toxicity profile… 65 …however, pegylated INF-alpha in combination with Temodar shows promise 66 Chiron’s Proleukin (aldesleukin) was the last agent to gain FDA approval for metastatic melanoma in 1998 68 Combinational systemic therapy has been intensively investigated 71 The future role of biochemotherapy within melanoma is unclear 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 74 CHAPTER 4 UNMET NEEDS IN MELANOMA 83 Melanoma patients represent a hugely underserved patient population 83 Current melanoma therapeutics have a high risk to benefit ratio 83 Over the past three decades there have been few significant advances in pharmacotherapy for metastatic disease 84 Early diagnosis is the key to curative treatment 84 Gene profiling will help individualize treatment approaches 85 CHAPTER 5 PIPELINE ANALYSIS 86 Genta’s Genasense (oblimersen) remains in development despite termination of agreement with Sanofi-Aventis 93 Genasense is under review with the EMEA despite failure to gain FDA approval for melanoma in 2004 93 Two-year follow-up data used for Genasense’s MAA finds the trial missed its overall survival primary endpoint 94 Normal serum lactate dehydrogenase (LDH) levels may be associated with improved overall survival 94 The combination of Genasense and dacarbazine is associated with increased toxicity 96 Approval of Genasense in combination with dacarbazine viewed as unlikely 97 Phase I study initiated to investigate Genasense in combination with Schering-Plough’s Temodar (temozolomide) and Abraxis Oncology’s Abraxane 98 Termination of agreement with Sanofi-Aventis is a major setback for Genta 99 Bayer/Onyx’s Nexavar (sorafenib): an orally active multi-kinase inhibitor stimulates stakeholder interest 99 Initial results from a Phase III melanoma study are disappointing 100 Phase II study shows Nexavar monotherapy has poor activity 102 The addition of carboplatin and paclitaxel to Nexavar improves progression-free survival over Nexavar monotherapy 103 Preliminary results from a randomized Phase II study of a Temodar and Nexavar combination shows promise 105 Nexavar with dacarbazine is well tolerated and is currently in Phase II development 107 The future of Nexavar in advanced melanoma looks uncertain following failure of the Phase III PRISM trial 107 Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibodies show promise in the management of melanoma 107 Medarex/Bristol-Myers Squibb’s ipilimumab (MDX-010, BMS-734016) has been awarded Fast Track status in melanoma 108 Pfizer hopes to file ticilimumab (CP-675,206) with the FDA in 2007 for melanoma 113 Distinguishing between ipilimumab and ticilimumab proves challenging 116 Melanoma vaccines: augmenting anti-tumor immunity 118 AVAX Technologies’ M-Vax is an autologous vaccine that has been launched in Switzerland 119 Financial constraints trouble M-Vax’s initial approval in Australia 120 M-Vax re-enters Phase III development in October 2006 121 Multiple hurdles challenge M-Vax’s future success 122 Improved second-generation formulation facilitates use in early-stage disease 124 Oncophage’s Phase III results prompt further investigation 124 Personalized nature could work in Oncophage’s favor 126 Lack of cost-effectiveness, clinical benefit and marketing experience will pose significant strategic challenges for Antigenics 126 If encouraging, results from an ongoing Phase III clinical trial will support a BLA 127 Phase II results demonstrate complete or partial responses for the MDX-1379 and ipilimumab combination in melanoma 127 Partnership with Bristol-Myers Squibb will put Medarex at a significant advantage 129 Vical/AnGes’s Allovectin-7: a gene transfer product involving a DNA plasmid/lipid complex 130 Phase III melanoma development continues despite suffering a major setback 130 Phase II data shows Allovectin-7 leads to durable responses lasting over six months 131 A further Phase II Allovectin-7 study demonstrates median overall survival of over 21 months 132 The market impact of Allovectin-7 still looks doubtful 132 CHAPTER 6 APPENDIX 134 Contributing experts 134 Opinion leader interview transcripts 134 Bibliography 135 List of tables 148 List of figures 151 About Datamonitor 152 About Datamonitor Healthcare 152 Datamonitor Healthcare’s research and analysis methodologies 153 Datamonitor Healthcare’s therapy area capabilities 153 About the Oncology analysis team 154 Disclaimer 155 AbstractIntroductionMelanoma 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 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 Get Full Details About This Report >> |
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