Pipeline Insight: Hematological malignancies - Targeted treatments & immunotherapy
Scope
Report Highlights
Reasons to Purchase
Table of Contents
- ABOUT DATAMONITOR HEALTHCARE - page 2
- About the Oncology pharmaceutical analysis team - page 2
- CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Datamonitor insight into the hematological malignancy market - page 3
- R&D pipeline dynamics - page 3
- Cytotoxic drugs - first-line indication for MGI Pharma/Supergen's Dacogen confers leading player designation - page 4
- Immunotherapy - Chiron's low-dose Proleukin provides rebranding opportunity - page 5
- Molecular-targeted treatment - J&J's Zarnestra forges the way - page 6
- Millennium's paradigm-changing Velcade to have significant impact beyond myeloma - page 7
- Regulatory challenges - reduced rates of accelerated approval may affect hematological malignancy drug development - page 8
- Pharmacoeconomic constraints will increasingly influence up take of new agents - page 9
- MTT era will necessitate an evolution in clinical trial design - page 9
- Datamonitor insight into the hematological malignancy market - page 3
- CHAPTER 2 HEMATOLOGICAL MALIGNANCIES: PIPELINE OVERVIEW - page 21
- Hematological malignancies are an intense focus of R&D activity with a total of 86 compounds in clinical development - page 21
- Non-Hodgkin's lymphoma remains the tumor type with the greatest developmental activity - page 26
- Molecular-targeted therapy (MTT) dominates the hematological malignancy pipeline - page 28
- Signal transduction inhibitors dominate the molecular-targeted treatment class - page 29
- Glivec: the exception rather than the rule - targeting a single molecular aberration is unlikely to be a model for success - page 30
- Resistance to signal transduction inhibitors an emerging problem - page 31
- Immunotherapy accounts for 29% of the pipeline and most R&D activity is focused on nonspecific immunoadjuvants - page 31
- Cytotoxics still focus of development - page 32
- PHASE III DEVELOPMENT IS LED BY COMPANIES WITH AN ESTABLISHED ONCOLOGY FRANCHISE - page 33
- High remission rates in certain hematological malignancies confer high barriers - page 34
- Key metrics - page 35
- Datamonitor pipeline assessment summary - page 41
- CHAPTER 3 PATIENT POTENTIAL: A DYNAMIC AND LUCRATIVE MARKET - page 48
- A diverse range of disease subtypes - page 48
- Genetic basis of cancer evolution - page 48
- Tumorigenesis is the result of cooperative accumulated mutations - page 50
- Existing pharmacotherapy approaches provide limited treatment benefit - page 50
- Cytotoxic drugs lack specificity - page 51
- Optimizing current treatment strategies is paramount - page 51
- The emergence of targeted treatment heralds a revolution in cancer pharmacotherapy - page 51
- Dynamic cancer market offers significant commercial opportunity - page 52
- Ongoing sales growth drives the market - page 52
- Intensive R&D produces a rich developmental pipeline - page 53
- Growing patient population and significant unmet needs propel innovation in the cancer market - page 54
- Cancer epidemiology - an expanding patient base - page 54
- Significant areas of unmet need persist - page 58
- Clinical and strategic threats to the commercialization of cancer drugs - page 63
- Progressively rising R&D costs threaten industry productivity - page 63
- High attrition rates can be mitigated by improved strategic decision-making - page 63
- Lengthening drug approval process a consequence of increased regulatory demands - page 63
- Pharmacoeconomic pressures drive payers to implement restrictive pricing and reimbursement policies - page 64
- Increased therapeutic and generic competition results in reduced periods of market exclusivity - page 65
- Segmentation of market will require changes in clinical trial methodology - page 65
- Progressively rising R&D costs threaten industry productivity - page 63
- CHAPTER 4 R&D APPROACH - page 67
- Classification of pipeline products - page 67
- Cytotoxics drugs - page 67
- Molecular-targeted therapies (MTTs) - page 68
- Few pipeline MTTs meet the criteria suggested by some investigators in defining this drug class - page 68
- Development of targeted therapies relies on identification of biologic drivers of oncogenesis - page 70
- Signal transduction inhibitors - page 71
- Angiogenesis inhibitors - page 71
- Apoptosis inducers - page 71
- Cell cycle inhibitors - page 72
- Immunotherapy-based treatments - page 73
- Miscellaneous agents - page 74
- Evolution in oncology clinical trial design - page 74
- Patient selection is increasingly significant in the era of targeted treatment - page 74
- Clinical trials must have sufficient follow-up to establish true clinical benefit - page 75
- Diversity of targeted treatments will require an evolution in clinical trial design - page 76
- Most oncology clinical trials designate multiple endpoints - page 77
- Survival - page 77
- Quality of life - page 78
- Tumor response rates - page 78
- Toxicity - page 78
- Time to tumor progression - page 78
- Modification of accelerated approval process may impact significantly on approval times for hematologic oncology drugs - page 79
- Classification of pipeline products - page 67
- CHAPTER 5 CYTOTOXICS - FIRST-LINE INDICATION FOR MGI PHARMA/SUPERGEN'S DACOGEN CONFERS LEADING PLAYER DESIGNATION - page 82
- Bendamustine (SDX-105), Salmedix - page 83
- Bendamustine demonstrates promising single-agent activity in refractory and relapsed indolent NHL - page 84
- Synergy of bendamustine and rituximab without excessive toxicity - page 84
- Bendamustine/mitoxantrone/rituximab (BMR) combination, active in refractory and relapsed indolent lymphoma - page 86
- Activity in broad spectrum of the hematological malignancies affords expanded commercial opportunity - page 86
- Bendamustine's established safety profile will facilitate regulatory approval - page 87
- Nelarabine, GlaxoSmithKline - page 88
- Nelarabine demonstrates activity in aggressive, treatment-resistant pediatric patients with T-ALL - page 88
- Nelarabine fails to exhibit the same efficacy in adults - page 90
- Nelarabine hindered by limited patient population - page 91
- Decitabine, MGI Pharma/Supergen - page 91
- Decitabine demonstrates significant improvements in time to AML or death compared to best supportive care in patients with MDS - page 91
- Decitabine as a potential treatment for Glivec-resistant/refractory CML - page 92
- Enhanced understanding of molecular biology generates renewed interest in DNA demethylators - page 93
- Pixantrone, Cell Therapeutics - page 95
- Pixantrone demonstrates promising single agent activity - page 95
- Successful results from a randomized Phase III trial of CPOP versus CHOP will drive uptake - page 95
- Pixantrone would benefit from co-licensing agreement with Roche - page 96
- Pixantrone, high commercial potential if problems associated with genericization can be overcome - page 97
- Cloretazine (VNP-40101M), Vion Pharmaceuticals - page 98
- Leukemia and MDS are the focus of ongoing development - page 98
- Development of fast-tracked Cloretazine recently progressed to Phase III trials - page 99
- Phase II trials displayed encouraging results among patients with limited treatment options - page 99
- Significant opportunity for Vion Pharmaceuticals - page 100
- Cytotoxic sales forecasts to 2014 - page 101
- Datamonitor drug assessment summary - page 103
- Bendamustine (SDX-105), Salmedix - page 83
- CHAPTER 6 IMMUNOTHERAPY - CHIRON'S LOW-DOSE PROLEUKIN PROVIDES REBRANDING OPPORTUNITY - page 106
- Ceplene (histamine dihydrochloride, subcutaneous), Maxim Pharmaceuticals - page 107
- Ceplene improves leukemia-free survival but not overall survival in adult AML patients in first remission - page 108
- FDA requests additional Phase III trial despite primary endpoints being met - page 109
- Maxim will need to form a strategic alliance to ensure Ceplene's commercialization - page 109
- Proleukin (aldesleukin), Chiron - page 110
- Phase II trials demonstrate that Proleukin augments rituximab activity in NHL - page 110
- Low-dose approach is the key to success - page 111
- Chiron's long-standing association with IL-2 will facilitate Proleukin uptake following approval of expanded indication - page 112
- Revlimid (lenalidomide), Celgene - page 113
- Revlimid achieves significant improvements in time to progression in previously treated multiple myeloma patients - page 113
- Phase II trial demonstrates 85% response rate in newly diagnosed multiple myeloma patients - page 114
- Celgene anticipate initiating a Phase III trial examining Revlimid in MDS - page 115
- Phase II trials demonstrate Revlimid therapy facilitates transfusion independence in MDS patients - page 115
- Revlimid is most active in early-stage MDS - page 116
- Celgene's developmental strategy promises significant commercial potential - page 116
- Radioimmunotherapy (RIT) - extending the spectrum of indications beyond indolent NHL - page 117
- Dual mechanism of action enhances activity the radioimmunoconjugates (RICs) - page 118
- RICs are associated with a logistically complex administration schedule - page 118
- Radioisotope differences favor Biogen Idec's Zevalin - page 119
- Horizontal product expansion key to optimizing commercial value - page 120
- Opinion leaders remain divided about RICs' potential utility in DLBCL - page 121
- RICs have demonstrated promising single-agent activity in MCL - page 122
- Bexxar versus Zevalin: who will be the major player? - page 122
- Immunotherapy sales forecasts to 2014 - page 123
- Datamonitor drug assessment summary - page 124
- Ceplene (histamine dihydrochloride, subcutaneous), Maxim Pharmaceuticals - page 107
- CHAPTER 7 MOLECULAR-TARGETED TREATMENT - J&J'S ZARNESTRA FORGES THE WAY - page 128
- Temsirolimus (CCI-779), Wyeth Research - page 131
- Temsirolimus demonstrates significant antitumor activity in relapsed mantle cell lymphoma (MCL) in Phase II trial - page 132
- Phase III trials of temsirolimus may need to evaluate lower doses. - page 133
- Phase II trial suggests temsirolimus may have activity in ALL. - page 133
- Novelty of target and competition from Millennium's Velcade will challenge commercial potential - page 135
- Wyeth has the experience to launch novel oncology products successfully - page 136
- Tipifarnib (R-115777; Zarnesta), Janssen Pharmaceutica BV and Johnson & Johnson - page 136
- Tipifarnib demonstrates activity in poor risk, previously untreated elderly AML - page 137
- Molecular markers predict tipifarnib response in AML - page 138
- Phase II trials suggest activity in MDS with limited toxicity - page 139
- Tipifarnib most advanced farnesyl transferase inhibitor (FTI) in clinical development. - page 140
- J&J's global marketing and distribution presence will facilitate tipifarnib uptake - page 141
- Focus on gene expression profiling may lead to fragmentation of market - page 141
- First-to-market designation doesn't guarantee commercial success - page 142
- Arsenic trioxide (Trisenox), CTI - page 143
- Arsenic trioxide demonstrates activity in drug-resistant multiple myeloma - page 143
- Arsenic trioxide demonstrates synergy with ascorbic acid and dexamethasone. - page 143
- CTI-sponsored Phase III development for myeloma unlikely - page 144
- Arsenic trioxide is active in both high- and low-risk MDS - page 145
- Competitive landscape means that arsenic trioxide is unlikely to make a significant impact in the MDS market - page 145
- Arsenic trioxide will benefit from patent extension - page 145
- Arsenic trioxide will most likely be used in combination with other therapies - page 146
- Innovative early-stage MTTs - page 147
- BMS-354825, Bristol-Myers Squibb - page 147
- BMS-354825 overcomes Glivec resistance in chronic phase CML patients - page 147
- BMS-354825 already faces potential competition from Novartis's AMN107 - page 148
- Sorafenib (BAY 43-9006), Onyx and Bayer - page 149
- Multi-targeted approach makes sorafenib an attractive proposition - page 149
- Phase I trials demonstrate limited anti-leukemic activity - page 149
- Combinatorial treatment approaches are likely to be the key to success - page 150
- Flt-3 inhibition offers a lucrative new target - page 150
- Cephalon's Lestaurtinib demonstrates activity in preliminary Phase II AML trials - page 150
- Lestaurtinib represents the first generation of a of a new class of agents - page 151
- Cephalon's limited commercial experience will require augmenting - page 152
- Avastin, Genentech/Roche - page 152
- Combining Avastin with R-CHOP does not significantly increase toxicity - page 152
- Avastin's first-to-market status provides Genentech/Roche with valuable head start - page 153
- Genentech/Roche's established oncology franchise will help drive sales in what will be a competitive antiangiogenic market - page 154
- Suberanilohydroxyamic acid (SAHA), Merck & Co. - page 154
- Histone deacetylation plays a pivotal role in transcriptional regulation - page 154
- Phase I study demonstrates differences in DLTs between IV and oral formulations - page 155
- Phase II trial demonstrates promising activity in cutaneous T-cell lymphoma (CTCL) - page 156
- Commercial opportunity offered by CTCL indication is weak - page 156
- BMS-354825, Bristol-Myers Squibb - page 147
- MTT sales forecasts to 2014 - page 157
- Datamonitor drug assessment summary - page 159
- Temsirolimus (CCI-779), Wyeth Research - page 131
- CHAPTER 8 ALTERNATE INNOVATIVE PROJECTS - MILLENIUM'S PARADIGM-CHANGING VELCADE TO HAVE SIGNIFICANT IMPACT BEYOND MYELOMA - page 162
- Velcade (bortezomib), Millennium Pharmaceuticals - page 162
- Potential clinical utility of Velcade in indolent NHL - page 163
- Velcade demonstrates particularly promising activity in MCL - page 165
- Millennium will need to define how this novel technology should be integrated into conventional NHL treatment paradigms - page 166
- Parentin, Ligand Pharmaceuticals - page 166
- Development of Ligand Pharmaceuticals' Parentin capsules (alitretinoin) for the treatment of hematological malignancies appears to have stalled - page 166
- Promising early-stage results in APL but despite initiation of a Phase III trial no results have been forthcoming - page 167
- Suboptimal treatment tolerability limits development for MDS - page 167
- Velcade (bortezomib), Millennium Pharmaceuticals - page 162
- APPENDIX A - page 169
- Report methodology - page 169
- Datamonitor forecast methodology - page 169
- Datamonitor drug assessment summary - page 169
- List of tables - page 172
- List of figures - page 174
- Report methodology - page 169
- APPENDIX B - page 177
- Opinion leader interview transcripts - page 177
- Contributing experts - page 177
- Opinion leader 1 - page 178
- Opinion leader 2 - page 183
- Opinion leader 3 - page 191
- Opinion leader 4 - page 199
- APPENDIX C - page 207
- Bibliography - page 207
- APPENDIX D - page 215
- About Datamonitor - page 215
- About Datamonitor Healthcare - page 215
- Datamonitor Healthcare's therapy area capabilities - page 216
- About the Oncology analysis team - page 217
- Disclaimer - page 219
- About Datamonitor - page 215
- List of Tables
- Table 1: Abbreviations used in PI: Hematological Malignancies - page 20
- Table 2: Drugs in development for the treatment of hematological malignancies, 2005 - page 21
- Table 3: Developmental pipeline of drugs targeting hematological malignancies by phase and class, 2005 - page 28
- Table 4: Forecast incidence of hematological malignancies in the seven major pharmaceutical markets, 2004-14 - page 36
- Table 5: Late-phase pipeline malignant hematology sales forecasts ($m), 2005-14 - page 37
- Table 6: Datamonitor drug assessment summary - page 41
- Table 7: Common mutations involved in tumor development - page 49
- Table 8: Forecast incidence of hematological malignancies in the seven major pharmaceutical markets, 2004-14 - page 54
- Table 9: FDA approval information for drugs used to treat hematologic malignancies - page 80
- Table 10: Pipeline cytotoxic drugs for hematological malignancies, 2005 - page 82
- Table 11: Single-agent bendamustine demonstrates acceptable hematological toxicity and moderate non-hematological toxicity - page 84
- Table 12: Nelarabine is active in aggressive, refractory childhood T-ALL - page 89
- Table 13: Nelarabine in adult CTCL and PTCL demonstrated low efficacy - page 90
- Table 14: Nelarabine trial in adult CTCL and PTCL was halted due to unacceptable toxicity - page 90
- Table 15: Comparison between Vidaza and Dacogen - page 94
- Table 16: Replacing doxorubicin with pixantrone in CHOP regime has tolerable toxicity profile - page 96
- Table 17: Ongoing clinical trials exploring Cloretazine in hematological malignancies - page 98
- Table 18: Cytotoxic drugs sales forecast assumptions - page 101
- Table 19: Cytotoxic drugs sales forecasts, 2005-14 - page 101
- Table 20: Research, clinical and commercial attractiveness summary for pipeline cytotoxic drugs - page 103
- Table 21: Immunotherapy drugs in development for hematological malignancies - page 106
- Table 22: Proleukin augments rituximab activity in rituximab-resistant NHL, Phase II trial results - page 111
- Table 23: Phase II trial results of Revlimid in patients with refractory multiple myeloma - page 114
- Table 24: Ongoing clinical trials exploring Revlimid in hematological malignancy - page 115
- Table 25: Comparison of radioisotopes in Bexxar and Zevalin - page 119
- Table 26: Ongoing studies evaluating RICs - page 120
- Table 27: Immunotherapy sales forecasts assumptions - page 123
- Table 28: Immunotherapy drugs sales forecasts, 2005-14 - page 124
- Table 29: Research, clinical and commercial attractiveness summary for pipeline immunotherapy drugs - page 125
- Table 30: MTTS drugs in development for hematological malignancies - page 128
- Table 31: Phase II trial results of temsirolimus in refractory mantle cell lymphoma - page 133
- Table 32: Ongoing Phase II and Phase I trials for temsirolimus - page 135
- Table 33: Phase I/II/III trials of tipifarnib in hematological malignancies - page 138
- Table 34: Toxicities associated with tipifarnib in high-risk MDS patients - page 140
- Table 35: Phase II drug regime of multiple myeloma patients receiving arsenic trioxide, ascorbic acid and dexamethasone - page 144
- Table 36: Phase I/II/III/IV trials of arsenic trioxide in hematological malignancies - page 146
- Table 37: Phase II trials of Avastin in AML and NHL - page 153
- Table 38: MTT sales forecasts assumptions - page 157
- Table 39: MTT sales forecasts, 2004-15 - page 158
- Table 40: Research, clinical and commercial attractiveness summary for pipeline MTT drugs - page 159
- Table 41: Alternative innovative drugs in clinical development for the treatment of hematological malignancies - page 162
- Table 42: Phase II study of Velcade in NHL: Owen et al., 2003 - page 163
- Table 43: Phase II study of Velcade in NHL: Goy et al., 2003 - page 164
- Table 44: Ongoing and planned trials of Velcade in hematological malignancies - page 165
- Table 45: Datamonitor drug assessment parameters - page 170
- List of Figures
- Figure 1: Number of compounds in clinical development for hematological malignancies, 2005 - page 26
- Figure 2: Number of compounds in clinical development by drug class, 2005 - page 27
- Figure 3: Molecular-targeted treatment dominates the hematological malignancy pipeline - page 29
- Figure 4: Signal transduction inhibitors dominate the MTT class - page 30
- Figure 5: Non-specific immunoadjuvants dominate immunotherapy class - page 32
- Figure 6: Topoisomerase inhibitors dominate the cytotoxic pipeline - page 33
- Figure 7: Phase III development is dominated by companies with an existing oncology franchise - page 34
- Figure 8: Phase II development reflects a more heterogeneous mix of company profiles - page 35
- Figure 9: Cytotoxics for hematological malignancies sales forecasts, 2005-14 - page 38
- Figure 10: Molecular-targeted agents for hematological malignancies sales forecasts, 2005-14 - page 39
- Figure 11: Immunotherapy agents for hematological malignancies sales forecasts, 2005-14 - page 40
- Figure 12: Datamonitor drug assessment summary for pipeline cytotoxics in development for malignant hematology - page 42
- Figure 13: Drug assessment summary for the late-phase immunotherapy drugs - page 43
- Figure 14: Datamonitor's drug assessment summary for the late-phase pipeline MTT drugs - page 44
- Figure 15: Future focus the challenges - page 47
- Figure 16: Forecasted global oncology sales, 2002-09 - page 52
- Figure 17: Oncology pipeline, 2003 - page 53
- Figure 18: Forecast incidence of hematological malignancies across the seven major markets, 2004-14 - page 55
- Figure 19: Increasing combined incidence of leukemia, lymphoma and myeloma with increasing age, 2004 - page 56
- Figure 20: Incidence increases, while the rate of cure and death reduces disease prevalence - page 57
- Figure 21: Disparity in relative point prevalence compared to incidence for leukemia and lymphoma, 2004 - page 58
- Figure 22: Unmet needs in cancer, 2005 - page 62
- Figure 23: Kaplan-Meier estimates of disease-free survival with bendamustine and rituximab in indolent and mantle cell lymphoma - page 85
- Figure 24: Bendamustine versus chlorambucil in treatment-naïve B-CLL patients, Phase III trial design - page 87
- Figure 25: Over half of treatment-resistant pediatric patients with T-ALL exhibited a response to nelarabine - page 89
- Figure 26: Phase III trial of decitabine in MDS patients demonstrates significant - page 93
- Figure 27: Cytotoxic drugs sales forecasts, 2005-14 - page 102
- Figure 28: Drug assessment summary for the late-phase pipeline cytotoxic drugs. - page 104
- Figure 29: Phase III PEaRL trial design - page 110
- Figure 30: Immunotherapy drugs sales forecasts, 2005-14 - page 124
- Figure 31: Drug assessment summary for the late-phase immunotherapy drugs - page 126
- Figure 32: MTT sales forecasts, 2004-15 - page 158
- Figure 33: Datamonitor's drug assessment summary for the late-phase pipeline MTT drugs - page 160
- Figure 34: Example of Datamonitor drug assessment scorecard - page 171
- Figure 35: Example of Datamonitor drug assessment graph - page 172
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