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Introduction
 
Given an enhanced understanding of the biological basis for oncogenesis and the benefit of immunotherapy approaches such as Genentech/Roche's Rituxan, it is no surprise that targeted treatments and immunotherapy dominate the pipeline. Integrating these novel technologies into existing treatment paradigms and demonstrating the 'value' of these high cost treatments will provide major challenges.
 

 
Scope
 
Overview of hematological malignancy market including patient segmentation, unmet needs and how novel therapies will alter existing treatment patterns
 
Profiles of key agents in late stage development including cytotoxics, immunotherapies and targeted treatments
 
Analysis of trial data, marketing factors and sales forecasts for key technologies in late-stage clinical development
 
Clinical, regulatory and pharmacoeconomic challenges and strategies for commercialization
 
Highlights
 
Targeted therapies dominate the pipeline, constituting 47% of drugs in clinical development. The signal transduction inhibitors (STIs) dominate the MTT class. Focusing on STIs offers developers the potential to target drivers of oncogenesis that may exhibit commonality across a spectrum of hematological malignancies.
 

 
Of the drugs in late-stage clinical development, Datamonitor is of the opinion that Chiron's Proleukin and MGI Pharma/ Supergen's Dacogen hold the greatest commercial potential with estimated peak sales by 2014 of $200m and $500m respectively
 

 
While there is much hype surrounding the use of the MTTs for the pharmacotherapy of hematological malignancies, the cytostatic nature of some of these agents mean that it is likely that significant tumor regressions will more frequently be seen in context of combinatorial therapy employing traditional cytotoxic drugs.
 

 
Reasons to Purchase
 
Understand unmet needs in the hematological malignancy market based on opinion leader comments regarding both currently marketed and pipeline products
 
Gain a greater understanding how future economic and regulatory constraints may affect approval for hematological malignancy drugs
 
Assess the global sales forecasts of late-stage pipeline drugs for hematological malignancies and examine their clinical and commercial potential

TABLE OF CONTENTS
 
ABOUT DATAMONITOR HEALTHCARE 2
 
About the Oncology pharmaceutical analysis team 2
 
CHAPTER 1 XECUTIVE SUMMARY 3
 
Datamonitor insight into the hematological malignancy market 3
 
R&D pipeline dynamics 3
 
Cytotoxic drugs – first-line indication for MGI Pharma/Supergen’s Dacogen confers leading player designation 4
 
Immunotherapy – Chiron’s low-dose Proleukin provides rebranding opportunity 5
 
Molecular-targeted treatment – J&J’s Zarnestra forges the way 6
 
Millennium’s paradigm-changing Velcade to have significant impact beyond myeloma 7
 
Regulatory challenges – reduced rates of accelerated approval may affect hematological malignancy drug development 8
 
Pharmacoeconomic constraints 9
 
MTT era will necessitate an evolution in clinical trial design 9
 
CHAPTER 2 HEMATOLOGICAL MALIGNANCIES: PIPELINE OVERVIEW 21
 
Hematological malignancies are an intense focus of R&D activity with a total of 86 compounds in clinical development 21
 
Non-Hodgkin’s lymphoma remains the tumor type with the greatest developmental activity 26
 
Molecular-targeted therapy (MTT) dominates the hematological malignancy pipeline 28
 
Signal transduction inhibitors dominate the molecular-targeted treatment class 29
 
Glivec: the exception rather than the rule – targeting a single molecular aberration is unlikely to be a model for success 30
 
Resistance to signal transduction inhibitors an emerging problem 31
 
Immunotherapy accounts for 29% of the pipeline and most R&D activity is focused on nonspecific immunoadjuvants 31
 
Cytotoxics still focus of development 32
 
PHASE III DEVELOPMENT IS LED BY COMPANIES WITH AN ESTABLISHED ONCOLOGY FRANCHISE 33
 
High remission rates in certain hematological malignancies confer high barriers 34
 
Key metrics 35
 
Datamonitor pipeline assessment summary 41
 
CHAPTER 3 PATIENT POTENTIAL: A DYNAMIC AND LUCRATIVE MARKET 48
 
A diverse range of disease subtypes 48
 
Genetic basis of cancer evolution 48
 
Tumorigenesis is the result of cooperative accumulated mutations 50
 
Existing pharmacotherapy approaches provide limited treatment benefit 50
 
Cytotoxic drugs lack specificity 51
 
Optimizing current treatment strategies is paramount 51
 
The emergence of targeted treatment heralds a revolution in cancer pharmacotherapy 51
 
Dynamic cancer market offers significant commercial opportunity 52
 
Ongoing sales growth drives the market 52
 
Intensive R&D produces a rich developmental pipeline 53
 
Growing patient population and significant unmet needs propel innovation in the cancer market 54
 
Clinical and strategic threats to the commercialization of cancer drugs 63
 
Progressively rising R&D costs threaten industry productivity 63
 
Pharmacoeconomic pressures drive payers to implement restrictive pricing and reimbursement policies 64
 
Increased therapeutic and generic competition results in reduced periods of market exclusivity 65
 
Segmentation of market will require changes in clinical trial methodology 65
 
CHAPTER 4 R&D APPROACH 67
 
Classification of pipeline products 67
 
Cytotoxics drugs 67
 
Molecular-targeted therapies (MTTs) 68
 
Immunotherapy-based treatments 73
 
Miscellaneous agents 74
 
Evolution in oncology clinical trial design 74
 
Patient selection is increasingly significant in the era of targeted treatment 74
 
Clinical trials must have sufficient follow-up to establish true clinical benefit 75
 
Diversity of targeted treatments will require an evolution in clinical trial design 76
 
Most oncology clinical trials designate multiple endpoints 77
 
Modification of accelerated approval process may impact significantly on approval times for hematologic oncology drugs 79
 
CHAPTER 5 CYTOTOXICS – FIRST-LINE INDICATION FOR MGI PHARMA/SUPERGEN’S DACOGEN CONFERS LEADING PLAYER DESIGNATION 82
 
Bendamustine (SDX-105), Salmedix 83
 
Bendamustine demonstrates promising single-agent activity in refractory and relapsed indolent NHL 84
 
Synergy of bendamustine and rituximab without excessive toxicity 84
 
Bendamustine/mitoxantrone/rituximab (BMR) combination, active in refractory and relapsed indolent lymphoma 86
 
Activity in broad spectrum of the hematological malignancies affords expanded commercial opportunity 86
 
Bendamustine’s established safety profile will facilitate regulatory approval 87
 
Nelarabine, GlaxoSmithKline 88
 
Nelarabine demonstrates activity in aggressive, treatment-resistant pediatric patients with T-ALL 88
 
Nelarabine fails to exhibit the same efficacy in adults 90
 
Nelarabine hindered by limited patient population 91
 
Decitabine, MGI Pharma/Supergen 91
 
Decitabine demonstrates significant improvements in time to AML or death compared to best supportive care in patients with MDS 91
 
Decitabine as a potential treatment for Glivec-resistant/refractory CML 92
 
Enhanced understanding of molecular biology generates renewed interest in DNA demethylators 93
 
Pixantrone, Cell Therapeutics 95
 
Pixantrone demonstrates promising single agent activity 95
 
Successful results from a randomized Phase III trial of CPOP versus CHOP will drive uptake 95
 
Pixantrone would benefit from co-licensing agreement with Roche 96
 
Pixantrone, high commercial potential if problems associated with genericization can be overcome 97
 
Cloretazine (VNP-40101M), Vion Pharmaceuticals 98
 
Leukemia and MDS are the focus of ongoing development 98
 
Development of fast-tracked Cloretazine recently progressed to Phase III trials 99
 
Phase II trials displayed encouraging results among patients with limited treatment options 99
 
Significant opportunity for Vion Pharmaceuticals 100
 
Cytotoxic sales forecasts to 2014 101
 
Datamonitor drug assessment summary 103
 
CHAPTER 6 IMMUNOTHERAPY – CHIRON’S LOW-DOSE PROLEUKIN PROVIDES REBRANDING OPPORTUNITY 106
 
Ceplene (histamine dihydrochloride, subcutaneous), Maxim Pharmaceuticals 107
 
Ceplene improves leukemia-free survival but not overall survival in adult AML patients in first remission 108
 
FDA requests additional Phase III trial despite primary endpoints being met 109
 
Maxim will need to form a strategic alliance to ensure Ceplene’s commercialization 109
 
Proleukin (aldesleukin), Chiron 110
 
Phase II trials demonstrate that Proleukin augments rituximab activity in NHL 110
 
Low-dose approach is the key to success 111
 
Chiron’s long-standing association with IL-2 will facilitate Proleukin uptake following approval of expanded indication 112
 
Revlimid (lenalidomide), Celgene 113
 
Revlimid achieves significant improvements in time to progression in previously treated multiple myeloma patients 113
 
Phase II trial demonstrates 85% response rate in newly diagnosed multiple myeloma patients 114
 
Celgene anticipate initiating a Phase III trial examining Revlimid in MDS 115
 
Phase II trials demonstrate Revlimid therapy facilitates transfusion independence in MDS patients 115
 
Revlimid is most active in early-stage MDS 116
 
Celgene’s developmental strategy promises significant commercial potential 116
 
Radioimmunotherapy (RIT) – extending the spectrum of indications beyond indolent NHL 117
 
Dual mechanism of action enhances activity the radioimmunoconjugates (RICs) 118
 
RICs are associated with a logistically complex administration schedule 118
 
Radioisotope differences favor Biogen Idec’s Zevalin 119
 
Horizontal product expansion key to optimizing commercial value 120
 
Opinion leaders remain divided about RICs’ potential utility in DLBCL 121
 
RICs have demonstrated promising single-agent activity in MCL 122
 
Bexxar versus Zevalin: who will be the major player? 122
 
Immunotherapy sales forecasts to 2014 123
 
Datamonitor drug assessment summary 124
 
CHAPTER 7 MOLECULAR-TARGETED TREATMENT – J&J’S ZARNESTRA FORGES THE WAY 128
 
Temsirolimus (CCI-779), Wyeth Research 131
 
Temsirolimus demonstrates significant antitumor activity in relapsed mantle cell lymphoma (MCL) in Phase II trial 132
 
Phase III trials of temsirolimus may need to evaluate lower doses. 133
 
Phase II trial suggests temsirolimus may have activity in ALL. 133
 
Novelty of target and competition from Millennium’s Velcade will challenge commercial potential 135
 
Wyeth has the experience to launch novel oncology products successfully 136
 
Tipifarnib (R-115777; Zarnesta), Janssen Pharmaceutica BV and Johnson & Johnson 136
 
Tipifarnib demonstrates activity in poor risk, previously untreated elderly AML 137
 
Molecular markers predict tipifarnib response in AML 138
 
Phase II trials suggest activity in MDS with limited toxicity 139
 
Tipifarnib most advanced farnesyl transferase inhibitor (FTI) in clinical development. 140
 
J&J’s global marketing and distribution presence will facilitate tipifarnib uptake 141
 
Focus on gene expression profiling may lead to fragmentation of market 141
 
First-to-market designation doesn’t guarantee commercial success 142
 
Arsenic trioxide (Trisenox), CTI 143
 
Arsenic trioxide demonstrates activity in drug-resistant multiple myeloma 143
 
Arsenic trioxide demonstrates synergy with ascorbic acid and dexamethasone. 143
 
CTI-sponsored Phase III development for myeloma unlikely 144
 
Arsenic trioxide is active in both high- and low-risk MDS 145
 
Competitive landscape means that arsenic trioxide is unlikely to make a significant impact in the MDS market 145
 
Arsenic trioxide will benefit from patent extension 145
 
Arsenic trioxide will most likely be used in combination with other therapies 146
 
Innovative early-stage MTTs 147
 
BMS-354825, Bristol-Myers Squibb 147
 
Sorafenib (BAY 43-9006), Onyx and Bayer 149
 
Flt-3 inhibition offers a lucrative new target 150
 
Avastin, Genentech/Roche 152
 
Suberanilohydroxyamic acid (SAHA), Merck & Co. 154
 
MTT sales forecasts to 2014 157
 
Datamonitor drug assessment summary 159
 
CHAPTER 8 ALTERNATE INNOVATIVE PROJECTS – MILLENIUM’S PARADIGM-CHANGING VELCADE TO HAVE SIGNIFICANT IMPACT BEYOND MYELOMA 162
 
Velcade (bortezomib), Millennium Pharmaceuticals 162
 
Potential clinical utility of Velcade in indolent NHL 163
 
Velcade demonstrates particularly promising activity in MCL 165
 
Millennium will need to define how this novel technology should be integrated into conventional NHL treatment paradigms 166
 
Parentin, Ligand Pharmaceuticals 166
 
Development of Ligand Pharmaceuticals’ Parentin capsules (alitretinoin) for the treatment of hematological malignancies appears to have stalled 166
 
Promising early-stage results in APL but despite initiation of a Phase III trial no results have been forthcoming 167
 
Suboptimal treatment tolerability limits development for MDS 167
 
APPENDIX A 169
 
Report methodology 169
 
Datamonitor forecast methodology 169
 
Datamonitor drug assessment summary 169
 
List of tables 172
 
List of figures 174
 
APPENDIX B 177
 
Opinion leader interview transcripts 177
 
Contributing experts 177
 
Opinion leader 1 178
 
Opinion leader 2 183
 
Opinion leader 3 191
 
Opinion leader 4 199
 
APPENDIX C 207
 
Bibliography 207
 
APPENDIX D 215
 
About Datamonitor 215
 
About Datamonitor Healthcare 215
 
Datamonitor Healthcare’s therapy area capabilities 216
 
About the Oncology analysis team 217
 
Disclaimer 219