Stakeholder Opinions: Primary Brain Cancer

Table of Contents

• ABOUT DATAMONITOR HEALTHCARE
  • About the Oncology pharmaceutical analysis team
    • Andrew Paramore - Oncology Lead Analyst & Head of Product Development
• CHAPTER 1 EXECUTIVE SUMMARY
  • Scope of the analysis
  • Datamonitor insight into the primary brain cancer market
    • Schering-Plough' s Temodar (temozolomide) looks set to maintain its commercial success
    • Considerable levels of unmet need and other financial incentives should make the glioma market attractive to drug developers
    • The identification of molecular markers may change glioma treatment patterns in the future, by identifying those patients most likely to benefit from specific therapies
    • There are very few promising late-phase pipeline drugs for glioma; those that show the most promise are the angiogenesis inhibitors
  • Related reports
  • Upcoming reports
• CHAPTER 2 PRIMARY BRAIN CANCER: BACKGROUND
  • Introduction to primary brain cancer
    • Primary brain cancer: a heterogeneous group of tumors
    • Classification of primary brain tumors
      • WHO primary brain tumor classification system widely used, but could be improved
      • Low-grade astrocytoma (WHO grade II)
      • High-grade astrocytoma (WHO grade III/IV)
      • Oligodendrogliomas
    • Prognosis: high-grade glioma patients face dismal survival prospects
    • Etiology: prior cranial irradiation is the only established risk factor
  • Epidemiology
    • Primary CNS tumors account for 1.35% of all cancers and 2.2% of all cancer-related deaths
    • Astrocytic and oligodendroglial tumors account for 77% of cases of primary brain cancer; glioblastoma is the most prevalent subtype
    • Glioblastoma is most prevalent in patients aged over 60 years
    • Incidence rates of primary brain cancer may be increasing; aging population likely to contribute to increased incidence of glioblastoma
• CHAPTER 3 CURRENT GLIOMA TREATMENT PRACTICES
  • Overview of glioma treatment practices
  • Surgery and radiotherapy in glioma treatment
    • Surgery has four major purposes in glioma treatment
    • Radiotherapy
  • Chemotherapy in glioma treatment
    • Temodar/Temodal (temozolomide), Schering-Plough
    • Gliadel (carmustine polymer wafer), MGI Pharma
    • Temodar compares favorably to Gliadel for treatment of newly-diagnosed glioblastoma multiforme
    • Nitrosourea and PCV
  • Supportive therapy for glioma patients
    • Corticosteroids
    • Anticonvulsants
  • Treatment of newly diagnosed high-grade glioma
    • Treatment guidelines recommend daily use of Temodar for glioblastoma patients
    • Temodar is firmly established as the standard of care for newly-diagnosed high-grade glioma patients
    • Controversy surrounds use of Gliadel
  • Treatment of newly diagnosed low-grade glioma
    • Guidelines make no firm recommendations on the use of radiotherapy and chemotherapy for low-grade glioma patients
    • Low-grade glioma treatment strategies vary from physician to physician; chemotherapy is reserved for patients with progressive symptoms
  • Treatment of recurrent glioma
    • Guidelines recommend use of chemotherapy for treatment of recurrent high-grade and low-grade glioma
    • Temodar replaced by other chemotherapy for recurrent glioma patients
• CHAPTER 4 UNMET NEEDS AND OPPORTUNITIES IN THE GLIOMA MARKET
  • Unmet needs in glioma
    • Unmet need 1: more effective first-line chemotherapy needed
      • Temodar only provides a modest survival benefit
      • Well designed Phase II trials needed to ensure potential glioma drugs not overlooked
      • Next step forward in first-line therapy may involve multidrug combinations
    • Unmet need 2: Blood-brain barrier likely to be an obstacle to drug delivery, particularly for monoclonal antibodies
    • Unmet need 3: alternative chemotherapies needed with efficacy equivalent to Temodar for second- and third-line
    • Unmet need 4: alternative to corticosteroids for edema treatment needed
    • Unmet need 5: need for neuroprotective therapy for a subset of high-grade glioma patients showing prolonged survival
  • Molecular markers for glioma - an emerging trend
    • Patients with active MGMT promoter gene show a limited survival benefit with Temodar; questions remain over feasibility and reliability of testing
    • Ip/19q loss of heterozygosity (LOH) used as diagnostic tool and to help make treatment decisions
    • EGFR and PTEN expression may help decide which glioma patients receive EGFR inhibitors
  • Incentives to enter the glioma market
    • Very few drugs on the market and low bar set by existing therapies
    • Uptake of glioma drugs less likely to be limited by same funding constraints as drugs for other cancer types
    • Glioma drugs benefit from orphan drug designation and Fast Track status
  • Commercial outlook for Temodar
• CHAPTER 5 PIPELINE DRUGS
  • Drugs in Phase III trials
    • Overview of glioma drugs in Phase III development
    • Cotara (131I-chTNT-1/B), Peregrine Pharmaceuticals
      • Cotara' s novel mechanism of action may prevent development of drug resistance
      • Pivotal product registration trial underway
      • Phase II trial results indicate potential efficacy of Cotara
      • Datamonitor comment: method of drug delivery and low physician awareness could significantly reduce uptake of Cotara
    • CDX-110, Celldex Therapeutics
      • CDX-110 is a cancer vaccine targeting EGFRvIII; Phase II/III trial initiated in April 2007
      • Datamonitor comment: like other therapeutic cancer vaccines, limited evidence of efficacy shown by CDX-110 to date
    • Cerepro (EG-009), Ark Therapeutics
      • Cerepro is a gene therapy designed to be used in conjunction with ganciclovir
      • Cerepro denied early marketing authorization in Europe on basis of Phase II trial data
      • Datamonitor comment: future success of Cerepro hinges on Phase III trial completion
    • Gleevec/Glivec (imatinib), Novartis
      • Use of Gleevec may be extended to glioma treatment
      • Phase II/III clinical trial of Gleevec currently recruiting glioblastoma multiforme patients
      • Phase II trial data indicate potential clinical efficacy of Gleevec for treatment of glioma
      • Datamonitor comment: despite marketing strength of Novartis, low clinical efficacy may hinder Gleevec' s uptake as a glioma treatment
    • TheraCIM (nimotuzumab), YM BioSciences/Center of Molecular Immunology/Biocon Biopharmaceuticals/Oncoscience
      • TheraCIM is a monoclonal antibody targetting the EGFR signal transduction pathway
      • Phase III trial of TheraCIM underway for treatment of pontine glioma in children
      • Phase II trial data indicate that TheraCIM has a favorable side-effect profile and particular efficacy in pediatric pontine glioma patients
      • Datamonitor comment: favorable safety profile could make TheraCIM attractive to physicians, but questions remain over efficacy of EGFR inhibitors in glioma treatment.
  • Drugs in Phase II trials
    • Overview of glioma drugs in Phase II development: pipeline dominated by targeted therapies
    • Genentech/Roche' s Avastin (bevacizumab) and AstraZeneca' s Recentin (cediranib): anti-angiogenesis drugs show early signs of promise as glioma therapies
      • Phase II trial results indicate that Avastin could potentially find its use extended to treatment of glioma
      • Recentin Phase II trial results for recurrent glioblastoma patients show promise
      • Datamonitor comment: difficult to say yet whether anti-angiogenesis drugs genuinely reduce size of tumor but reduction of edema could be a significant selling point
    • AP-12009, Antisense Pharma
      • AP-12009 is an antisense oligonucleotide inhibiting expression of the tumor growth factor TGF-β2
      • Phase II studies indicate promising efficacy of AP-12009 in treatment of recurrent or refractory high-grade glioma
    • Panzem NCD (2-methoxyestradiol), EntreMed Inc
      • Panzem NCD is a formulation of 2-methoxyestradiol with several mechanisms of action
      • Phase II data show that Panzem NCD is well-tolerated and potentially shows activity against recurrent glioblastoma multiforme
    • EMD-121974 (cilengitide), Merck
      • EMD-121974 shows only modest activity against recurrent glioma
• APPENDIX A
  • Bibliography
  • List of tables
  • List of figures
  • About Datamonitor
    • About Datamonitor Healthcare
    • About the Oncology analysis team
  • Disclaimer
  • List of Tables
    • Table 1: Summary of major types of glioma
    • Table 2: WHO classification of glioma subtypes
    • Table 3: Glioma patient median survival times by tumor subtype/grade
    • Table 4: Estimated incidences of primary brain cancer across the seven major markets, 2002 and 2007
    • Table 5: Incidence rates and mean age of incidence of astrocytic and oligodendroglial tumors1
    • Table 6: Estimated incidences of glioma by subtype across the seven major markets, 2007
    • Table 7: Age distribution of glioblastoma multiforme incidences
    • Table 8: Overview of major approvals for Temodar/Temodal in glioma treatment, 1999-2006
    • Table 9: Summary of study showing effect of MGMT methylation status on response to Temodar in glioblastoma patients, 2005
    • Table 10: Summary of study showing effect of 1p/19q LOH on response to Temodar in anaplastic oligodendroglioma and anaplastic oligoastrocytoma, 2006
    • Table 11: Drugs for glioma in Phase III development, May 2007
    • Table 12: Drugs for glioma in Phase II development, June 2007
    • Table 13: Summary of Phase II data for treatment of recurrent/refractory glioblastoma with AP-12009, 2007
    • Table 14: Summary of Phase II data for treatment of recurrent/refractory anaplastic astrocytoma with AP-12009, 2007
  • List of Figures
    • Figure 1: Estimated proportion of population over 60 years in the seven major markets: 2005, 2010 and 2015
    • Figure 2: Summary of Phase III trial of Temodar with radiotherapy compared to radiotherapy alone for newly diagnosed glioblastoma multiforme, 2005
    • Figure 3: Summary of Phase III trial comparing Gliadel to polymer placebo, 2003
    • Figure 4: Phase II trial results for glioma treatment with Cotara, 2001
    • Figure 5: Phase II data: recurrent glioblastoma multiforme treatment with Gleevec, 2004
    • Figure 6: Phase II data: recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma treatment with Gleevec, 2006
    • Figure 7: Pediatric glioma treatment with TheraCIM (Phase II data), 2006