Non-Hodgkin's Lymphoma - Is there room to emulate Rituxan's success?
Scope
Report Highlights
Reasons to Purchase
Table of Contents
- ABOUT DATAMONITOR HEALTHCARE - page 2
- About the Oncology pharmaceutical analysis team - page 2
- Andrew Paramore - Oncology Lead Analyst & Head of Product Development - page 2
- About the Oncology pharmaceutical analysis team - page 2
- CHAPTER 1 EXECUTIVE SUMMARY - page 3
- Scope of analysis - page 3
- Datamonitor insight into the non-Hodgkin's lymphoma market - page 3
- Related reports - page 5
- Upcoming reports - page 5
- CHAPTER 2 NON-HODGKIN'S LYMPHOMA: DISEASE BACKGROUND - page 7
- Chapter summary - page 7
- Disease overview and classification - page 7
- Disease overview - page 7
- Disease classification - page 8
- NHL is classified under the WHO classification system - page 8
- Immunophenotype differs between NHL subtypes - page 9
- Several genetic abnormalities linked to NHL - page 10
- NHL can follow an aggressive or indolent disease course - page 11
- Diagnosis, staging and prognosis in NHL - page 13
- Diagnosis of NHL - page 13
- Ann Arbor staging system - page 14
- Ann Arbor classification used for staging NHL but of limited prognostic use - page 14
- Determining prognosis for NHL - page 15
- International Prognostic Factor Index for aggressive NHL - page 15
- International Prognostic Factor Index for FL - page 16
- Molecular profiling in NHL - page 17
- Epidemiology - page 19
- Incidence of NHL in the seven major markets - page 19
- NHL is the most commonly occurring hematological malignancy in the seven major markets - page 19
- NHL incidence will total 122,000 in the seven major markets in 2007 - page 20
- Incidence of NHL by subtype in the seven major markets - page 22
- Distribution of NHL subtypes varies considerably across the seven major markets - page 22
- DLBCL and FL account for over 50% of new NHL diagnoses - page 23
- Age distribution of NHL incidence rate - page 26
- Mortality - page 27
- NHL mortality will reach 47,000 in the seven major markets in 2007 - page 27
- Incidence of NHL in the seven major markets - page 19
- Etiology - page 29
- Immunodeficiency and immunosuppression as risk factors for NHL - page 30
- Acquired immunodeficiency syndrome (AIDS) - page 30
- Congenital immunodeficiency - page 30
- Immunosuppressive drugs - page 30
- Autoimmune disorders - page 30
- Infections as risk factors for NHL - page 31
- Human T-cell lymphotrophic virus (HTLV-1) - page 31
- Epstein-Barr virus (EBV) - page 31
- Helicobacter pylori - page 31
- Hepatitis C - page 31
- Occupational, environmental and lifestyle risk factors - page 31
- Pesticides - page 31
- Hair dyes - page 32
- Lifestyle factors - page 32
- Immunodeficiency and immunosuppression as risk factors for NHL - page 30
- CHAPTER 3 CURRENT TREATMENT OPTIONS FOR NON-HODGKIN'S LYMPHOMA - page 33
- Chapter summary - page 33
- Overview of NHL treatment options - page 33
- Chemotherapy - page 34
- Targeted therapies - page 35
- Rituxan has made a large impact on NHL treatment outcomes - page 36
- Radioimmunotherapies combine a monoclonal antibody and radioactive component - page 36
- Drug developers aiming for widened indications for approved targeted therapies - page 36
- Other drug classes - page 38
- Combination regimens - page 38
- Radiotherapy - page 39
- Myeloablative therapy and stem cell transplantation - page 40
- Treatment outcome measurements for NHL - page 40
- Treatment of DLBCL - page 42
- DLBCL overview - page 42
- Induction therapy in DLBCL - page 42
- R-CHOP established as standard of care for induction therapy in DLBCL - page 42
- Treatment of refractory and relapsed DLBCL - page 45
- Debate remains over second-line chemotherapy combinations and whether to add Rituxan in relapsed patients - page 45
- Consolidation myeloablative therapy and ASCT recommended where possible in relapsed DLBCL - page 47
- Lack of viable treatment of options in refractory patients - page 48
- Improving treatment outcomes in DLBCL - page 48
- Increasing the R-CHOP dose frequency may improve treatment outcomes in elderly patients - page 49
- Rituxan use unlikely to extend to first-line maintenance therapy in DLBCL - page 49
- Treatment of FL - page 50
- FL overview - page 50
- First-line therapy in FL - page 50
- Initial treatment may be delayed for several years in some cases - page 50
- Localized, non-bulky FL treated with radiotherapy - page 51
- No established standard of care for patients with advanced FL - page 52
- Addition of Rituxan to first-line chemotherapy improves treatment outcomes in FL - page 52
- Radioimmunotherapy rarely used in first-line treatment of FL - page 55
- Consolidation therapy in FL - page 56
- Myeloablative therapy and ASCT superseded by Rituxan maintenance as a consolidation therapy in FL - page 56
- Radioimmunotherapy may experience limited uptake as a consolidation therapy in FL despite promising data - page 58
- Treatment of relapsed and refractory FL - page 59
- Single-agent Rituxan or Rituxan-based regimens commonly used as second-line regimens in FL. - page 59
- Limited use of radioimmunotherapy in relapsed or refractory FL despite promising evidence of efficacy - page 60
- Benefit of myeloablative therapy and ASCT in treatment of relapsed or refractory FL uncertain - page 63
- Rituxan maintenance in FL - page 63
- Rituxan maintenance after first-line therapy and after second-line therapy improves PFS and overall survival in FL compared to observation - page 63
- Unclear whether Rituxan maintenance adds clinical benefit after first-line Rituxan-containing regimen - page 64
- Should Rituxan maintenance be used after induction therapy and after first relapse? - page 65
- Optimal dosing schedule remains to be determined - page 66
- Treatment of MALT lymphomas - page 66
- Gastric MALT lymphoma - page 66
- Localized gastric MALT lymphoma treated according to H. pylori status - page 66
- Advanced gastric MALT lymphoma treated in a similar fashion to FL - page 67
- Non-gastric MALT lymphoma - page 67
- Gastric MALT lymphoma - page 66
- Treatment of MCL - page 67
- First-line therapy in MCL - page 68
- Rituxan increases efficacy of chemotherapy regimens used as induction therapy for MCL - page 68
- Myeloablative therapy and ASCT used as consolidation therapy after induction therapy - page 68
- Second-line therapy in MCL - page 69
- Velcade is the first FDA-approved treatment option for relapsed MCL - page 69
- First-line therapy in MCL - page 68
- Treatment of SLL - page 70
- SLL treated in a similar fashion to indolent lymphomas - page 71
- Treatment of T-Cell Lymphoma (PTCL/CTCL) - page 71
- Treatment options in PTCL of unspecified subtype - page 72
- Lack of efficacious regimens in PTCL - page 72
- Treatment of CTCL - page 73
- Treatment options in PTCL of unspecified subtype - page 72
- Unmet needs in NHL - page 73
- CHAPTER 4 PIPELINE ANALYSIS - page 75
- Chapter summary - page 75
- Pipeline overview - page 75
- Phase III NHL product pipeline - page 76
- Phase II NHL product pipeline - page 77
- Pixantrone (Cell Therapeutics) - page 80
- Drug overview - page 80
- Pixantrone intended to be a more efficacious, less cardiotoxic alternative to traditional anthracyclines - page 80
- Overview of ongoing clinical trials and clinical trial data - page 80
- Phase III trials of pixantrone are ongoing in aggressive and indolent NHL - page 80
- Phase II data reported in aggressive NHL - page 83
- Phase II trials of pixantrone in indolent NHL - page 86
- Datamonitor comments - page 87
- Problems associated with trying to replace genericized drugs must be overcome - page 87
- Physician awareness and patient recruitment may be challenging - page 88
- Pixantrone set to benefit from co-licensing agreement with Novartis - page 89
- Drug overview - page 80
- Avastin (bevacizumab; Genentech/Roche) - page 89
- Drug overview - page 89
- VEGF is a promising target in NHL - page 89
- Overview of ongoing clinical trials and clinical trial data - page 90
- Phase III trial of Avastin with R-CHOP in first-line DLBCL underway - page 90
- Limited clinical trial data available to date - page 90
- Datamonitor comments - page 92
- Difficult to predict clinical benefit of Avastin in DLBCL at this stage - page 92
- Use of Avastin in DLBCL could significantly add to cost of treatment - page 92
- Genentech and Roche's marketing power will be essential in driving uptake of Avastin in NHL - page 93
- Drug overview - page 89
- Enzastaurin (LY317615; Eli Lilly) - page 93
- Drug overview - page 93
- Enzastaurin is an orally administered multi-targeted kinase inhibitor - page 93
- Ongoing clinical trials and clinical trial data - page 94
- Phase III trial of enzastaurin as a maintenance therapy in DLBCL - page 94
- Phase II data reported for enzastaurin as a second-line DLBCL therapy - page 95
- Enzastaurin holding promise as a maintenance therapy in MCL - page 95
- Datamonitor comments - page 96
- Eli Lilly has adopted a risky strategy for enzastaurin in DLBCL with potentially high financial reward - page 96
- Termination of Phase III trial for enzastaurin in glioma may hamper its potential in other indications - page 97
- Drug overview - page 93
- Galiximab (Anti-CD80 MAb; Biogen Idec) - page 98
- Drug overview - page 98
- Galiximab is a primatized monoclonal antibody targeting CD80 - page 98
- Overview of ongoing clinical trials and clinical trial data - page 98
- Randomized Phase III trial and single-arm Phase III retreatment trial initiated in relapsed or refractory FL patients - page 98
- Phase II results show galiximab and Rituxan can be safely combined and produce promising response rates in follicular NHL patients - page 100
- Datamonitor comments - page 102
- Biogen Idec in a strong position to successfully market galiximab alone - page 102
- Lack of standard-of-care for second-line treatment of FL will aid galiximab's approval prospects - page 102
- Biogen Idec will need to effectively demonstrate the value of a combination of galiximab and Rituxan to payers - page 103
- Drug overview - page 98
- Ofatumumab (HuMax-CD20; Genmab/GlaxoSmithKline) - page 103
- Drug overview - page 103
- Ofatumumab is a fully human CD20-directed monoclonal antibody intended to show superior efficacy to Rituxan - page 103
- Overview of ongoing clinical trials and clinical trial data - page 104
- Genmab has initiated a pivotal Phase III trial in FL - page 104
- Phase I/II data reported in relapsed/refractory FL - page 105
- Datamonitor comments - page 106
- Ofatumumab may offer hope for Rituxan-insensitive patients - page 106
- Approval of other monoclonal antibodies being developed for NHL may restrict ofatumumab's potential even further - page 107
- GlaxoSmithKline will offer invaluable experience to Genmab and aid commercialization of ofatumumab - page 108
- Drug overview - page 103
- Torisel (temsirolimus; Wyeth) - page 109
- Drug overview - page 109
- Torisel inhibits a key pathway in tumor cell proliferation - page 109
- Overview of ongoing clinical trials and clinical trial data - page 110
- Wyeth has initiated a Phase III trial for Torisel in MCL - page 110
- Promising Phase II data reported for Torisel in MCL - page 111
- Torisel also making headway in other NHL subtypes - page 112
- Datamonitor comments - page 114
- Torisel will have to compete with Velcade in the MCL market - page 114
- Prior commercialization of Mylotarg, Neumega and launch of Torisel for RCC will provide Wyeth with valuable insight into the oncology market - page 115
- Drug overview - page 109
- Zanolimumab (HuMax-CD4; Genmab) - page 116
- Drug overview - page 116
- Zanolimumab is a fully human monoclonal antibody targeting CD4 - page 116
- Overview of ongoing clinical trials and clinical trial data - page 116
- Zanolimumab in Phase III trial for CTCL - page 116
- Positive Phase II results in CTCL presented - page 118
- Zanolimumab may also hold promise for non-cutaneous PTCL patients - page 119
- Datamonitor comments - page 120
- The T-cell lymphoma market offers zanolimumab a limited commercial potential - page 120
- Depletion of CD4+ T-cells by zanolimumab may render the patient susceptible to infections - page 120
- Drug overview - page 116
- BiovaxID (Accentia Biopharmaceuticals) - page 121
- Drug overview - page 121
- BiovaxID is an autologous vaccine combining a tumor-specific idiotype protein and a protein carrier - page 121
- Overview of ongoing clinical trials and clinical trial data - page 122
- Phase III trial of BiovaxID initiated in February 2000 in FL patients in first complete remission - page 122
- BiovaxID inches closer to approval in the US and European markets for FL - page 123
- Possible association between a specific negative chromosomal translocation following vaccination and disease-free survival in FL - page 123
- Phase II results of BiovaxID in MCL are promising - page 124
- Datamonitor comments - page 124
- BiovaxID competing with Specifid and MyVax for first-to-market status - page 124
- BiovaxID's price should reflect the anticipated competition and current treatment costs - page 125
- Drug overview - page 121
- Specifid (FavId; Id-KLH; Favrille) - page 125
- Drug overview - page 125
- Overview of ongoing clinical trials and clinical trial data - page 126
- Phase III trial of Specifid in FL initiated in 2004 - page 126
- Phase II clinical trials have shown prolongation of time to progression in FL - page 128
- Single-agent Specifid demonstrates an objective response in indolent B-cell NHL - page 130
- Favrille also intend to develop Specifid for DLBCL - page 131
- Datamonitor comments - page 132
- Specifid competing with BiovaxID and MyVax to reach the market first - page 132
- Favrille's lack of commercial experience will be a barrier to optimizing market penetration - page 132
- MyVax (GTOP-99; Genitope) - page 133
- Drug overview - page 133
- Overview of ongoing clinical trials and clinical trial data - page 134
- MyVax received Fast Track status for FL while Phase III clinical trial approaches completion - page 134
- Phase II clinical trials show greater number of immune responses among previously untreated patients - page 135
- Follow-up Phase II data of MyVax in MCL and DLBCL warrants further investigation - page 135
- Datamonitor comments - page 137
- Despite competition from BiovaxID and Specifid, MyVax increases its commercial potential by targeting an earlier stage treatment - page 137
- Comparison of anti-idiotype vaccines - page 137
- APPENDIX - page 141
- Bibliography - page 141
- Abbreviations - page 158
- List of tables - page 160
- List of figures - page 161
- Contributing experts - page 162
- About Datamonitor - page 163
- About Datamonitor Healthcare - page 163
- About the Oncology analysis team - page 164
- Disclaimer - page 165
- List of Tables
- Table 1: Subtypes of NHL under the WHO classification and relative incidence, 1998 - page 9
- Table 2: Characteristic immunophenotype of major NHL subtypes - page 10
- Table 3: Chromosomal translocations associated with NHL - page 11
- Table 4: Grading of FL according to proportion of large cells in lymphoma - page 12
- Table 5: International Prognostic Factor Index for aggressive NHL (IPI) - page 15
- Table 6: Survival rates for different risk groups in aggressive NHL classified by IPI - page 16
- Table 7: Age-adjusted IPI (aaIPI) for aggressive lymphomas and associated survival rates - page 16
- Table 8: International Prognostic Factor Index for FL (FLIPI) - page 17
- Table 9: Survival rates for different risk groups in FL classified by FLIPI - page 17
- Table 10: Crude NHL incidence rates (per 100,000 persons), seven major markets, 2002 - page 20
- Table 11: Forecast incidence of NHL in the seven major markets, 2007-16 - page 21
- Table 12: Relative distribution of NHL subtypes in the US, EU and Japan - page 23
- Table 13: Forecast incidence of the six most commonly diagnosed NHL subtypes in the seven major markets, 2007 - page 24
- Table 14: Median age at diagnosis for the six major subtypes of NHL in the seven major markets, 1998 - page 27
- Table 15: NHL mortality rates (per 100,000 persons) in the seven major markets, 2002 - page 27
- Table 16: Forecast mortality from NHL in the seven major markets, 2002 and 2007 - page 28
- Table 17: Overview of chemotherapy agents used in NHL, 2007 - page 34
- Table 18: Overview of targeted therapies used in NHL, 2007 - page 35
- Table 19: Selected ongoing Phase III trials for approved targeted therapies in NHL, 2007 - page 37
- Table 20: Overview of drugs other than chemotherapy and targeted therapies used in NHL, 2007 - page 38
- Table 21: Overview of combination regimens commonly used in NHL - page 39
- Table 22: Definition of response criteria and endpoints used in NHL - page 41
- Table 23: Summary of randomized trials showing PFS and overall survival benefit of Rituxan maintenance in FL - page 64
- Table 24: Summary of randomized Phase III trial comparing R-CHOP to CHOP in previously untreated MCL - page 68
- Table 25: Summary of results from single-arm study of Velcade in relapsed/refractory MCL - The PINNACLE trial - page 70
- Table 26: Overview of pipelines drugs in Phase III trials for NHL, November 2007 - page 76
- Table 27: Overview of pipelines drugs in Phase II trials for NHL, November 2007 - page 77
- Table 28: Interim Phase II results of pixantrone as part of the R-CPOP regimen vs. R-CHOP regimen for first-line DLBCL - page 83
- Table 29: Interim Phase II results of pixantrone as part of the CPOP regimen in relapsed aggressive NHL - page 84
- Table 30: Phase II results of pixantrone as part of the BSHAP regimen in aggressive NHL patients experiencing their first relapse - page 85
- Table 31: Phase I/II trial results of pixantrone as part of the FPD-R regimen, to replace mitoxantrone in FND-R in indolent NHL - page 86
- Table 32: Summary of Phase II results for single-agent Avastin in relapsed aggressive NHL - page 91
- Table 33: Phase II results of enzastaurin in relapsed DLBCL - page 95
- Table 34: Phase II study of galiximab in combination with Rituxan in relapsed/refractory FL - page 101
- Table 35: Retrospective comparison of galiximab plus Rituxan with Rituxan monotherapy in relapsed/refractory FL - page 101
- Table 36: Interim Phase I/II results of ofatumumab in relapsed/refractory FL - page 106
- Table 37: GlaxoSmithKline's marketed oncology portfolio, 2007 - page 108
- Table 38: Phase II results of low-dose Torisel in relapsed/refractory MCL patients - page 112
- Table 39: Phase II study of Torisel in relapsed NHL patients - page 113
- Table 40: Phase II results of zanolimumab in mycosis fungoides (MF) CTCL - page 118
- Table 41: Phase II results of zanolimumab in non-cutaneous PTCL patients - page 119
- Table 42: Interim results of Specifid monotherapy Phase III trial in FL: response to Rituxan - page 128
- Table 43: Four-year follow up data from Phase II trial for Specifid in FL - page 129
- Table 44: Phase II interim results of MyVax in MCL and DLBCL NHL patients, (1 of 2) - page 136
- Table 45: Phase II interim results of MyVax in MCL and DLBCL NHL patients, (2 of 2) - page 136
- Table 46: Comparisons of the late-phase anti-idiotype vaccines, 2007 - page 138
- Table 47: Abbreviations used in Stakeholders Opinions: Non-Hodgkin's Lymphoma - page 158
- List of Figures
- Figure 1: Characterization of disease course of major NHL subtypes - page 12
- Figure 2: Symptoms shown at presentation by NHL patients - page 13
- Figure 3: Ann Arbor staging system for NHL - page 14
- Figure 4: Incidence of hematological malignancies in the seven major markets, 2002 - page 19
- Figure 5: Forecast incidence of NHL in the seven major markets, 2007-16 - page 22
- Figure 6: Forecast incidence of the six most commonly diagnosed NHL subtypes in the seven major markets, 2007 - page 25
- Figure 7: Distribution of NHL incidence rates by age group, US, 2000-04 - page 26
- Figure 8: Forecast mortality from NHL in the seven major markets, 2002 and 2007 - page 29
- Figure 9: Summary of results of randomized study comparing R-CHOP to CHOP in elderly DLBCL patients - page 43
- Figure 10: Summary of results of randomized study comparing Rituxan plus chemotherapy to chemotherapy alone in young, low risk DLBCL patients - page 44
- Figure 11: Results of randomized study comparing R-CHOP to CHOP in the first-line treatment of FL - page 53
- Figure 12: Results of randomized study comparing R-CVP to CVP in the first-line treatment of FL - page 54
- Figure 13: Results of a Phase II trial of Bexxar as a first-line therapy in FL - page 55
- Figure 14: Results of a Phase III trial comparing myeloablative therapy and ASCT to IFN( maintenance for FL patients in first remission - page 56
- Figure 15: Results of a Phase III trial comparing myeloablative therapy and ASCT to CHVP/IFN( for FL patients in first remission - page 57
- Figure 16: Results of a Phase III trial comparing myeloablative therapy and ASCT to CHVP/IFN( for FL patients in first remission - page 57
- Figure 17: Results from a randomized study of Zevalin consolidation therapy compared to observation after first-line therapy in FL - page 58
- Figure 18: Results of a Phase III trial comparing Zevalin to Rituxan for relapsed or refractory FL patients - page 61
- Figure 19: Summary of collated results from five clinical trials for Bexxar in relapsed/refractory/transformed FL - page 62
- Figure 20: Summary of persistent unmet needs in NHL, 2007 - page 74
- Figure 21: Phase III trial design for pixantrone in relapsed aggressive NHL - page 81
- Figure 22: Phase III trial design for pixantrone in relapsed or refractory indolent NHL - page 82
- Figure 23: Phase III study design for Avastin in combination with R-CHOP in DLBCL - page 90
- Figure 24: Phase III trial design for enzastaurin as a maintenance therapy in DLBCL (the PRELUDE study) - page 94
- Figure 25: Outline of randomized Phase III trial for galiximab in combination with Rituxan in relapsed or refractory FL (study ID: 114-NH-301) - page 99
- Figure 26: Outline of single-arm Phase III trial for retreatment with galiximab in combination with Rituxan in relapsed or refractory FL (study ID: 114-NH-302) - page 100
- Figure 27: Phase III study design for ofatumumab in Rituxan-refractory FL - page 105
- Figure 28: Phase III trial design for Torisel in relapsed or refractory MCL - page 110
- Figure 29: Phase II trial of Torisel in combination with Rituxan in second-line MCL patients - page 111
- Figure 30: Phase III study design for zanolimumab in CTCL - page 117
- Figure 31: Preliminary results for the first stage of the Phase III study for zanolimumab in CTCL - page 118
- Figure 32: Summary of Phase III trial of BiovaxID in FL - page 122
- Figure 33: Phase III study design for Specifid in FL - page 127
- Figure 34: Trial design of Phase II study of Specifid in progressive NHL - page 131
- Figure 35: Genitope's personalized immunotherapy (MyVax) production system - page 134
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