Report: Stakeholder Opinions: Non-Hodgkin's Lymphoma - Is there room to emulate Rituxan's success? TOC

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

Stakeholder Opinions: Non-Hodgkin's Lymphoma - Is there room to emulate Rituxan's success?

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