Stakeholder Opinions: Non-Hodgkins Lymphoma - Is there room to emulate Rituxans success? - Market Research Reports

Contents:

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Our insight into the non-Hodgkins lymphoma market 3
Related reports 5
Upcoming reports 5

CHAPTER 2 NON-HODGKINS LYMPHOMA: DISEASE BACKGROUND 7
Chapter summary 7
Disease overview and classification 7
Disease overview 7
Disease classification 8
NHL is classified under the WHO classification system 8
Immunophenotype differs between NHL subtypes 9
Several genetic abnormalities linked to NHL 10
NHL can follow an aggressive or indolent disease course 11
Diagnosis, staging and prognosis in NHL 13
Diagnosis of NHL 13
Ann Arbor staging system 14
Ann Arbor classification used for staging NHL but of limited prognostic use 14
Determining prognosis for NHL 15
International Prognostic Factor Index for aggressive NHL 15
International Prognostic Factor Index for FL 16
Molecular profiling in NHL 17
Epidemiology 19
Incidence of NHL in the seven major markets 19
NHL is the most commonly occurring hematological malignancy in the seven major markets 19
NHL incidence will total 122,000 in the seven major markets in 2007 20
Incidence of NHL by subtype in the seven major markets 22
Distribution of NHL subtypes varies considerably across the seven major markets 22
DLBCL and FL account for over 50% of new NHL diagnoses 23
Age distribution of NHL incidence rate 26
Mortality 27
NHL mortality will reach 47,000 in the seven major markets in 2007 27
Etiology 29
Immunodeficiency and immunosuppression as risk factors for NHL 30
Acquired immunodeficiency syndrome (AIDS) 30
Congenital immunodeficiency 30
Immunosuppressive drugs 30
Autoimmune disorders 30
Infections as risk factors for NHL 31
Human T-cell lymphotrophic virus (HTLV-1) 31
Epstein-Barr virus (EBV) 31
Helicobacter pylori 31
Hepatitis C 31
Occupational, environmental and lifestyle risk factors 31
Pesticides 31
Hair dyes 32
Lifestyle factors 32

CHAPTER 3 CURRENT TREATMENT OPTIONS FOR NON-HODGKINS LYMPHOMA 33
Chapter summary 33
Overview of NHL treatment options 33
Chemotherapy 34
Targeted therapies 35
Rituxan has made a large impact on NHL treatment outcomes 36
Radioimmunotherapies combine a monoclonal antibody and radioactive component 36
Drug developers aiming for widened indications for approved targeted therapies 36
Other drug classes 38
Combination regimens 38
Radiotherapy 39
Myeloablative therapy and stem cell transplantation 40
Treatment outcome measurements for NHL 40
Treatment of DLBCL 42
DLBCL overview 42
Induction therapy in DLBCL 42
R-CHOP established as standard of care for induction therapy in DLBCL 42
Treatment of refractory and relapsed DLBCL 45
Debate remains over second-line chemotherapy combinations and whether to add Rituxan in relapsed patients 45
Consolidation myeloablative therapy and ASCT recommended where possible in relapsed DLBCL 47
Lack of viable treatment of options in refractory patients 48
Improving treatment outcomes in DLBCL 48
Increasing the R-CHOP dose frequency may improve treatment outcomes in elderly patients 49
Rituxan use unlikely to extend to first-line maintenance therapy in DLBCL 49
Treatment of FL 50
FL overview 50
First-line therapy in FL 50
Initial treatment may be delayed for several years in some cases 50
Localized, non-bulky FL treated with radiotherapy 51
No established standard of care for patients with advanced FL 52
Addition of Rituxan to first-line chemotherapy improves treatment outcomes in FL 52
Radioimmunotherapy rarely used in first-line treatment of FL 55
Consolidation therapy in FL 56
Myeloablative therapy and ASCT superseded by Rituxan maintenance as a consolidation therapy in FL 56
Radioimmunotherapy may experience limited uptake as a consolidation therapy in FL despite promising data 58
Treatment of relapsed and refractory FL 59
Single-agent Rituxan or Rituxan-based regimens commonly used as second-line regimens in FL. 59
Limited use of radioimmunotherapy in relapsed or refractory FL despite promising evidence of efficacy 60
Benefit of myeloablative therapy and ASCT in treatment of relapsed or refractory FL uncertain 63
Rituxan maintenance in FL 63
Rituxan maintenance after first-line therapy and after second-line therapy improves PFS and overall survival in FL compared to observation 63
Unclear whether Rituxan maintenance adds clinical benefit after first-line Rituxan-containing regimen 64
Should Rituxan maintenance be used after induction therapy and after first relapse? 65
Optimal dosing schedule remains to be determined 66
Treatment of MALT lymphomas 66
Gastric MALT lymphoma 66
Localized gastric MALT lymphoma treated according to H. pylori status 66
Advanced gastric MALT lymphoma treated in a similar fashion to FL 67
Non-gastric MALT lymphoma 67
Treatment of MCL 67
First-line therapy in MCL 68
Rituxan increases efficacy of chemotherapy regimens used as induction therapy for MCL 68
Myeloablative therapy and ASCT used as consolidation therapy after induction therapy 68
Second-line therapy in MCL 69
Velcade is the first FDA-approved treatment option for relapsed MCL 69
Treatment of SLL 70
SLL treated in a similar fashion to indolent lymphomas 71
Treatment of T-Cell Lymphoma (PTCL/CTCL) 71
Treatment options in PTCL of unspecified subtype 72
Lack of efficacious regimens in PTCL 72
Treatment of CTCL 73
Unmet needs in NHL 73

CHAPTER 4 PIPELINE ANALYSIS 75
Chapter summary 75
Pipeline overview 75
Phase III NHL product pipeline 76
Phase II NHL product pipeline 77
Pixantrone (Cell Therapeutics) 80
Drug overview 80
Pixantrone intended to be a more efficacious, less cardiotoxic alternative to traditional anthracyclines 80
Overview of ongoing clinical trials and clinical trial data 80
Phase III trials of pixantrone are ongoing in aggressive and indolent NHL 80
Phase II data reported in aggressive NHL 83
Phase II trials of pixantrone in indolent NHL 86
Our comments 87
Problems associated with trying to replace genericized drugs must be overcome 87
Physician awareness and patient recruitment may be challenging 88
Pixantrone set to benefit from co-licensing agreement with Novartis 89
Avastin (bevacizumab; Genentech/Roche) 89
Drug overview 89
VEGF is a promising target in NHL 89
Overview of ongoing clinical trials and clinical trial data 90
Phase III trial of Avastin with R-CHOP in first-line DLBCL underway 90
Limited clinical trial data available to date 90
Our comments 92
Difficult to predict clinical benefit of Avastin in DLBCL at this stage 92
Use of Avastin in DLBCL could significantly add to cost of treatment 92
Genentech and Roches marketing power will be essential in driving uptake of Avastin in NHL 93
Enzastaurin (LY317615; Eli Lilly) 93
Drug overview 93
Enzastaurin is an orally administered multi-targeted kinase inhibitor 93
Ongoing clinical trials and clinical trial data 94
Phase III trial of enzastaurin as a maintenance therapy in DLBCL 94
Phase II data reported for enzastaurin as a second-line DLBCL therapy 95
Enzastaurin holding promise as a maintenance therapy in MCL 95
Our comments 96
Eli Lilly has adopted a risky strategy for enzastaurin in DLBCL with potentially high financial reward 96
Termination of Phase III trial for enzastaurin in glioma may hamper its potential in other indications 97
Galiximab (Anti-CD80 MAb; Biogen Idec) 98
Drug overview 98
Galiximab is a primatized monoclonal antibody targeting CD80 98
Overview of ongoing clinical trials and clinical trial data 98
Randomized Phase III trial and single-arm Phase III retreatment trial initiated in relapsed or refractory FL patients 98
Phase II results show galiximab and Rituxan can be safely combined and produce promising response rates in follicular NHL patients 100
Our comments 102
Biogen Idec in a strong position to successfully market galiximab alone 102
Lack of standard-of-care for second-line treatment of FL will aid galiximabs approval prospects 102
Biogen Idec will need to effectively demonstrate the value of a combination of galiximab and Rituxan to payers 103
Ofatumumab (HuMax-CD20; Genmab/GlaxoSmithKline) 103
Drug overview 103
Ofatumumab is a fully human CD20-directed monoclonal antibody intended to show superior efficacy to Rituxan 103
Overview of ongoing clinical trials and clinical trial data 104
Genmab has initiated a pivotal Phase III trial in FL 104
Phase I/II data reported in relapsed/refractory FL 105
Our comments 106
Ofatumumab may offer hope for Rituxan-insensitive patients 106
Approval of other monoclonal antibodies being developed for NHL may restrict ofatumumabs potential even further 107
GlaxoSmithKline will offer invaluable experience to Genmab and aid commercialization of ofatumumab 108
Torisel (temsirolimus; Wyeth) 109
Drug overview 109
Torisel inhibits a key pathway in tumor cell proliferation 109
Overview of ongoing clinical trials and clinical trial data 110
Wyeth has initiated a Phase III trial for Torisel in MCL 110
Promising Phase II data reported for Torisel in MCL 111
Torisel also making headway in other NHL subtypes 112
Our comments 114
Torisel will have to compete with Velcade in the MCL market 114
Prior commercialization of Mylotarg, Neumega and launch of Torisel for RCC will provide Wyeth with valuable insight into the oncology market 115
Zanolimumab (HuMax-CD4; Genmab) 116
Drug overview 116
Zanolimumab is a fully human monoclonal antibody targeting CD4 116
Overview of ongoing clinical trials and clinical trial data 116
Zanolimumab in Phase III trial for CTCL 116
Positive Phase II results in CTCL presented 118
Zanolimumab may also hold promise for non-cutaneous PTCL patients 119
Our comments 120
The T-cell lymphoma market offers zanolimumab a limited commercial potential 120
Depletion of CD4+ T-cells by zanolimumab may render the patient susceptible to infections 120
BiovaxID (Accentia Biopharmaceuticals) 121
Drug overview 121
BiovaxID is an autologous vaccine combining a tumor-specific idiotype protein and a protein carrier 121
Overview of ongoing clinical trials and clinical trial data 122
Phase III trial of BiovaxID initiated in February 2000 in FL patients in first complete remission 122
BiovaxID inches closer to approval in the US and European markets for FL 123
Possible association between a specific negative chromosomal translocation following vaccination and disease-free survival in FL 123
Phase II results of BiovaxID in MCL are promising 124
Our comments 124
BiovaxID competing with Specifid and MyVax for first-to-market status 124
BiovaxIDs price should reflect the anticipated competition and current treatment costs 125
Specifid (FavId; Id-KLH; Favrille) 125
Drug overview 125
Overview of ongoing clinical trials and clinical trial data 126
Phase III trial of Specifid in FL initiated in 2004 126
Phase II clinical trials have shown prolongation of time to progression in FL 128
Single-agent Specifid demonstrates an objective response in indolent B-cell NHL 130
Favrille also intend to develop Specifid for DLBCL 131
Our comments 132
Specifid competing with BiovaxID and MyVax to reach the market first 132
Favrilles lack of commercial experience will be a barrier to optimizing market penetration 132
MyVax (GTOP-99; Genitope) 133
Drug overview 133
Overview of ongoing clinical trials and clinical trial data 134
MyVax received Fast Track status for FL while Phase III clinical trial approaches completion 134
Phase II clinical trials show greater number of immune responses among previously untreated patients 135
Follow-up Phase II data of MyVax in MCL and DLBCL warrants further investigation 135
Our comments 137
Despite competition from BiovaxID and Specifid, MyVax increases its commercial potential by targeting an earlier stage treatment 137
Comparison of anti-idiotype vaccines 137

APPENDIX 141
Bibliography 141
Abbreviations 158
List of tables 160
List of figures 161
Contributing experts 162

List of Tables
Table 1: Subtypes of NHL under the WHO classification and relative incidence, 1998 9
Table 2: Characteristic immunophenotype of major NHL subtypes 10
Table 3: Chromosomal translocations associated with NHL 11
Table 4: Grading of FL according to proportion of large cells in lymphoma 12
Table 5: International Prognostic Factor Index for aggressive NHL (IPI) 15
Table 6: Survival rates for different risk groups in aggressive NHL classified by IPI 16
Table 7: Age-adjusted IPI (aaIPI) for aggressive lymphomas and associated survival rates 16
Table 8: International Prognostic Factor Index for FL (FLIPI) 17
Table 9: Survival rates for different risk groups in FL classified by FLIPI 17
Table 10: Crude NHL incidence rates (per 100,000 persons), seven major markets, 2002 20
Table 11: Forecast incidence of NHL in the seven major markets, 2007-16 21
Table 12: Relative distribution of NHL subtypes in the US, EU and Japan 23
Table 13: Forecast incidence of the six most commonly diagnosed NHL subtypes in the seven major markets, 2007 24
Table 14: Median age at diagnosis for the six major subtypes of NHL in the seven major markets, 1998 27
Table 15: NHL mortality rates (per 100,000 persons) in the seven major markets, 2002 27
Table 16: Forecast mortality from NHL in the seven major markets, 2002 and 2007 28
Table 17: Overview of chemotherapy agents used in NHL, 2007 34
Table 18: Overview of targeted therapies used in NHL, 2007 35
Table 19: Selected ongoing Phase III trials for approved targeted therapies in NHL, 2007 37
Table 20: Overview of drugs other than chemotherapy and targeted therapies used in NHL, 2007 38
Table 21: Overview of combination regimens commonly used in NHL 39
Table 22: Definition of response criteria and endpoints used in NHL 41
Table 23: Summary of randomized trials showing PFS and overall survival benefit of Rituxan maintenance in FL 64
Table 24: Summary of randomized Phase III trial comparing R-CHOP to CHOP in previously untreated MCL 68
Table 25: Summary of results from single-arm study of Velcade in relapsed/refractory MCL - The PINNACLE trial 70
Table 26: Overview of pipelines drugs in Phase III trials for NHL, November 2007 76
Table 27: Overview of pipelines drugs in Phase II trials for NHL, November 2007 77
Table 28: Interim Phase II results of pixantrone as part of the R-CPOP regimen vs. R-CHOP regimen for first-line DLBCL 83
Table 29: Interim Phase II results of pixantrone as part of the CPOP regimen in relapsed aggressive NHL 84
Table 30: Phase II results of pixantrone as part of the BSHAP regimen in aggressive NHL patients experiencing their first relapse 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 86
Table 32: Summary of Phase II results for single-agent Avastin in relapsed aggressive NHL 91
Table 33: Phase II results of enzastaurin in relapsed DLBCL 95
Table 34: Phase II study of galiximab in combination with Rituxan in relapsed/refractory FL 101
Table 35: Retrospective comparison of galiximab plus Rituxan with Rituxan monotherapy in relapsed/refractory FL 101
Table 36: Interim Phase I/II results of ofatumumab in relapsed/refractory FL 106
Table 37: GlaxoSmithKlines marketed oncology portfolio, 2007 108
Table 38: Phase II results of low-dose Torisel in relapsed/refractory MCL patients 112
Table 39: Phase II study of Torisel in relapsed NHL patients 113
Table 40: Phase II results of zanolimumab in mycosis fungoides (MF) CTCL 118
Table 41: Phase II results of zanolimumab in non-cutaneous PTCL patients 119
Table 42: Interim results of Specifid monotherapy Phase III trial in FL: response to Rituxan 128
Table 43: Four-year follow up data from Phase II trial for Specifid in FL 129
Table 44: Phase II interim results of MyVax in MCL and DLBCL NHL patients, (1 of 2) 136
Table 45: Phase II interim results of MyVax in MCL and DLBCL NHL patients, (2 of 2) 136
Table 46: Comparisons of the late-phase anti-idiotype vaccines, 2007 138
Table 47: Abbreviations used in Stakeholders Opinions: Non-Hodgkins Lymphoma 158

List of Figures
Figure 1: Characterization of disease course of major NHL subtypes 12
Figure 2: Symptoms shown at presentation by NHL patients 13
Figure 3: Ann Arbor staging system for NHL 14
Figure 4: Incidence of hematological malignancies in the seven major markets, 2002 19
Figure 5: Forecast incidence of NHL in the seven major markets, 2007-16 22
Figure 6: Forecast incidence of the six most commonly diagnosed NHL subtypes in the seven major markets, 2007 25
Figure 7: Distribution of NHL incidence rates by age group, US, 2000-04 26
Figure 8: Forecast mortality from NHL in the seven major markets, 2002 and 2007 29
Figure 9: Summary of results of randomized study comparing R-CHOP to CHOP in elderly DLBCL patients 43
Figure 10: Summary of results of randomized study comparing Rituxan plus chemotherapy to chemotherapy alone in young, low risk DLBCL patients 44
Figure 11: Results of randomized study comparing R-CHOP to CHOP in the first-line treatment of FL 53
Figure 12: Results of randomized study comparing R-CVP to CVP in the first-line treatment of FL 54
Figure 13: Results of a Phase II trial of Bexxar as a first-line therapy in FL 55
Figure 14: Results of a Phase III trial comparing myeloablative therapy and ASCT to IFN( maintenance for FL patients in first remission 56
Figure 15: Results of a Phase III trial comparing myeloablative therapy and ASCT to CHVP/IFN( for FL patients in first remission 57
Figure 16: Results of a Phase III trial comparing myeloablative therapy and ASCT to CHVP/IFN( for FL patients in first remission 57
Figure 17: Results from a randomized study of Zevalin consolidation therapy compared to observation after first-line therapy in FL 58
Figure 18: Results of a Phase III trial comparing Zevalin to Rituxan for relapsed or refractory FL patients 61
Figure 19: Summary of collated results from five clinical trials for Bexxar in relapsed/refractory/transformed FL 62
Figure 20: Summary of persistent unmet needs in NHL, 2007 74
Figure 21: Phase III trial design for pixantrone in relapsed aggressive NHL 81
Figure 22: Phase III trial design for pixantrone in relapsed or refractory indolent NHL 82
Figure 23: Phase III study design for Avastin in combination with R-CHOP in DLBCL 90
Figure 24: Phase III trial design for enzastaurin as a maintenance therapy in DLBCL (the PRELUDE study) 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) 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) 100
Figure 27: Phase III study design for ofatumumab in Rituxan-refractory FL 105
Figure 28: Phase III trial design for Torisel in relapsed or refractory MCL 110
Figure 29: Phase II trial of Torisel in combination with Rituxan in second-line MCL patients 111
Figure 30: Phase III study design for zanolimumab in CTCL 117
Figure 31: Preliminary results for the first stage of the Phase III study for zanolimumab in CTCL 118
Figure 32: Summary of Phase III trial of BiovaxID in FL 122
Figure 33: Phase III study design for Specifid in FL 127
Figure 34: Trial design of Phase II study of Specifid in progressive NHL 131
Figure 35: Genitopes personalized immunotherapy (MyVax) production system 134