Stakeholder Opinions: Primary Brain Cancer

Incidence of primary brain cancer across the seven major markets in 2007 is estimated to be 47,000. Over half of these cases will be glioblastoma multiforme, for which survival prospects are dismal. The median survival for this group of patients is 1.2 years and only 27% of patients are alive after two years. The level of unmet need is therefore high in this disease.


Report Highlights


The standard set by drugs that have been approved for primary brain cancer is low; therefore drugs only need to demonstrate relatively modest improvements in survival to be adopted by physicians. A substantial opportunity also exists for a second-line chemotherapy to enter the primary brain cancer market. Several molecular markers have been associated with glioma. It is possible that these markers could significantly affect treatment patterns, resulting in a stratified glioma market. Targeted therapies could be reserved solely for patients whose molecular profile indicates that they will benefit from such drugs. The potential of Phase III pipeline drugs is limited by factors such as low efficacy and complicated delivery methods. Of the drugs in the Phase II pipeline for glioma, targeted therapies show most potential. In particular, angiogenesis inhibitors have considerable commercial potential because they may reduce the co-morbidity edema.
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ABOUT DATAMONITOR HEALTHCARE 2
About the Oncology pharmaceutical analysis team 2
Andrew Paramore - Oncology Lead Analyst & Head of Product Development 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of the analysis 3
Datamonitor insight into the primary brain cancer market 4
Schering-Plough's Temodar (temozolomide) looks set to maintain its commercial success 4
Considerable levels of unmet need and other financial incentives should make the glioma market attractive to drug developers 5
The identification of molecular markers may change glioma treatment patterns in the future, by identifying those patients most likely to benefit from specific therapies 5
There are very few promising late-phase pipeline drugs for glioma; those that show the most promise are the angiogenesis inhibitors 6
Related reports 7
Upcoming reports 7
CHAPTER 2 PRIMARY BRAIN CANCER: BACKGROUND 9
Introduction to primary brain cancer 9
Primary brain cancer: a heterogeneous group of tumors 9
Classification of primary brain tumors 10
WHO primary brain tumor classification system widely used, but could be improved 10
Low-grade astrocytoma (WHO grade II) 11
High-grade astrocytoma (WHO grade III/IV) 11
Oligodendrogliomas 12
Prognosis: high-grade glioma patients face dismal survival prospects 12
Etiology: prior cranial irradiation is the only established risk factor 13
Epidemiology 14
Primary CNS tumors account for 1.35% of all cancers and 2.2% of all cancer-related deaths 14
Astrocytic and oligodendroglial tumors account for 77% of cases of primary brain cancer; glioblastoma is the most prevalent subtype 15
Glioblastoma is most prevalent in patients aged over 60 years 16
Incidence rates of primary brain cancer may be increasing; aging population likely to contribute to increased incidence of glioblastoma 17
CHAPTER 3 CURRENT GLIOMA TREATMENT PRACTICES 19
Overview of glioma treatment practices 19
Surgery and radiotherapy in glioma treatment 20
Surgery has four major purposes in glioma treatment 20
Radiotherapy 20
Chemotherapy in glioma treatment 20
Temodar/Temodal (temozolomide), Schering-Plough 21
Gliadel (carmustine polymer wafer), MGI Pharma 22
Temodar compares favorably to Gliadel for treatment of newly-diagnosed glioblastoma multiforme 24
Nitrosourea and PCV 24
Supportive therapy for glioma patients 24
Corticosteroids 24
Anticonvulsants 25
Treatment of newly diagnosed high-grade glioma 26
Treatment guidelines recommend daily use of Temodar for glioblastoma patients 26
Temodar is firmly established as the standard of care for newly-diagnosed high-grade glioma patients 27
Controversy surrounds use of Gliadel 28
Treatment of newly diagnosed low-grade glioma 29
Guidelines make no firm recommendations on the use of radiotherapy and chemotherapy for low-grade glioma patients 29
Low-grade glioma treatment strategies vary from physician to physician; chemotherapy is reserved for patients with progressive symptoms 30
Treatment of recurrent glioma 32
Guidelines recommend use of chemotherapy for treatment of recurrent high-grade and low-grade glioma 32
Temodar replaced by other chemotherapy for recurrent glioma patients 32
CHAPTER 4 UNMET NEEDS AND OPPORTUNITIES IN THE GLIOMA MARKET 34
Unmet needs in glioma 34
Unmet need 1: more effective first-line chemotherapy needed 34
Temodar only provides a modest survival benefit 34
Well designed Phase II trials needed to ensure potential glioma drugs not overlooked 35
Next step forward in first-line therapy may involve multidrug combinations 35
Unmet need 2: Blood-brain barrier likely to be an obstacle to drug delivery, particularly for monoclonal antibodies 36
Unmet need 3: alternative chemotherapies needed with efficacy equivalent to Temodar for second- and third-line 37
Unmet need 4: alternative to corticosteroids for edema treatment needed 37
Unmet need 5: need for neuroprotective therapy for a subset of high-grade glioma patients showing prolonged survival 38
Molecular markers for glioma - an emerging trend 39
Patients with active MGMT promoter gene show a limited survival benefit with Temodar; questions remain over feasibility and reliability of testing 39
Ip/19q loss of heterozygosity (LOH) used as diagnostic tool and to help make treatment decisions 41
EGFR and PTEN expression may help decide which glioma patients receive EGFR inhibitors 42
Incentives to enter the glioma market 43
Very few drugs on the market and low bar set by existing therapies 43
Uptake of glioma drugs less likely to be limited by same funding constraints as drugs for other cancer types 44
Glioma drugs benefit from orphan drug designation and Fast Track status 44
Commercial outlook for Temodar 45
CHAPTER 5 PIPELINE DRUGS 47
Drugs in Phase III trials 47
Overview of glioma drugs in Phase III development 47
Cotara (131I-chTNT-1/B), Peregrine Pharmaceuticals 48
Cotara's novel mechanism of action may prevent development of drug resistance 48
Pivotal product registration trial underway 49
Phase II trial results indicate potential efficacy of Cotara 49
Datamonitor comment: method of drug delivery and low physician awareness could significantly reduce uptake of Cotara 50
CDX-110, Celldex Therapeutics 51
CDX-110 is a cancer vaccine targeting EGFRvIII; Phase II/III trial initiated in April 2007 51
Datamonitor comment: like other therapeutic cancer vaccines, limited evidence of efficacy shown by CDX-110 to date 51
Cerepro (EG-009), Ark Therapeutics 52
Cerepro is a gene therapy designed to be used in conjunction with ganciclovir 52
Cerepro denied early marketing authorization in Europe on basis of Phase II trial data 53
Datamonitor comment: future success of Cerepro hinges on Phase III trial completion 54
Gleevec/Glivec (imatinib), Novartis 54
Use of Gleevec may be extended to glioma treatment 54
Phase II/III clinical trial of Gleevec currently recruiting glioblastoma multiforme patients 55
Phase II trial data indicate potential clinical efficacy of Gleevec for treatment of glioma 55
Datamonitor comment: despite marketing strength of Novartis, low clinical efficacy may hinder Gleevec's uptake as a glioma treatment 57
TheraCIM (nimotuzumab), YM BioSciences/Center of Molecular Immunology/Biocon Biopharmaceuticals/Oncoscience 58
TheraCIM is a monoclonal antibody targetting the EGFR signal transduction pathway 58
Phase III trial of TheraCIM underway for treatment of pontine glioma in children 58
Phase II trial data indicate that TheraCIM has a favorable side-effect profile and particular efficacy in pediatric pontine glioma patients 59
Datamonitor comment: favorable safety profile could make TheraCIM attractive to physicians, but questions remain over efficacy of EGFR inhibitors in glioma treatment. 60
Drugs in Phase II trials 61
Overview of glioma drugs in Phase II development: pipeline dominated by targeted therapies 61
Genentech/Roche's Avastin (bevacizumab) and AstraZeneca's Recentin (cediranib): anti-angiogenesis drugs show early signs of promise as glioma therapies 63
Phase II trial results indicate that Avastin could potentially find its use extended to treatment of glioma 63
Recentin Phase II trial results for recurrent glioblastoma patients show promise 64
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 64
AP-12009, Antisense Pharma 66
AP-12009 is an antisense oligonucleotide inhibiting expression of the tumor growth factor TGF-?2 66
Phase II studies indicate promising efficacy of AP-12009 in treatment of recurrent or refractory high-grade glioma 66
Panzem NCD (2-methoxyestradiol), EntreMed Inc 68
Panzem NCD is a formulation of 2-methoxyestradiol with several mechanisms of action 68
Phase II data show that Panzem NCD is well-tolerated and potentially shows activity against recurrent glioblastoma multiforme 68
EMD-121974 (cilengitide), Merck 68
EMD-121974 shows only modest activity against recurrent glioma 68
APPENDIX A 70
Bibliography 70
About Datamonitor 78
About Datamonitor Healthcare 78
About the Oncology analysis team 79
Disclaimer 80
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Table 1: Summary of major types of glioma 10
Table 2: WHO classification of glioma subtypes 10
Table 3: Glioma patient median survival times by tumor subtype/grade 13
Table 4: Estimated incidences of primary brain cancer across the seven major markets, 2002 and 2007 14
Table 5: Incidence rates and mean age of incidence of astrocytic and oligodendroglial tumors1 15
Table 6: Estimated incidences of glioma by subtype across the seven major markets, 2007 16
Table 7: Age distribution of glioblastoma multiforme incidences 16
Table 8: Overview of major approvals for Temodar/Temodal in glioma treatment, 1999-2006 21
Table 9: Summary of study showing effect of MGMT methylation status on response to Temodar in glioblastoma patients, 2005 40
Table 10: Summary of study showing effect of 1p/19q LOH on response to Temodar in anaplastic oligodendroglioma and anaplastic oligoastrocytoma, 2006 41
Table 11: Drugs for glioma in Phase III development, May 2007 48
Table 12: Drugs for glioma in Phase II development, June 2007 61
Table 13: Summary of Phase II data for treatment of recurrent/refractory glioblastoma with AP-12009, 2007 67
Table 14: Summary of Phase II data for treatment of recurrent/refractory anaplastic astrocytoma with AP-12009, 2007 67

Figure 1: Estimated proportion of population over 60 years in the seven major markets: 2005, 2010 and 2015 18
Figure 2: Summary of Phase III trial of Temodar with radiotherapy compared to radiotherapy alone for newly diagnosed glioblastoma multiforme, 2005 22
Figure 3: Summary of Phase III trial comparing Gliadel to polymer placebo, 2003 23
Figure 4: Phase II trial results for glioma treatment with Cotara, 2001 50
Figure 5: Phase II data: recurrent glioblastoma multiforme treatment with Gleevec, 2004 56
Figure 6: Phase II data: recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma treatment with Gleevec, 2006 57
Figure 7: Pediatric glioma treatment with TheraCIM (Phase II data), 2006 59
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