Market Report Source

Overview

Introduction
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.

Scope of this report

• Incidence, diagnosis and treatment of primary brain cancer, including treatment regimens by stage and ongoing controversies
• Unmet needs, emerging trends and commercial incentives in primary brain cancer
• Examination of pipeline activity and potential future opportunities for drug developers
• Stakeholder opinions and interview transcripts based on qualitative interviews with six opinion leaders from the US and Europe

Research and analysis 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.

Key reasons to read this report

• Identify the limitations of current therapy available to primary brain cancer patients and the potential of future therapy
• Understand current epidemiological trends in primary brain cancer and ongoing treatment controversies
• Assess the opportunities for innovative targeted therapies in primary brain cancer, particularly in recurrent disease

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