結腸直腸癌治療藥物的現狀及未來展望

Executive Summary

Introduction

Colorectal cancer (CRC) is the second most common cause of cancer death in much of the developed world. Cancer-related mortality is slowly decreasing as a result of better detection and significant advances in the treatment of advanced colorectal cancer over the past 5 years. This is most prominent due to the introduction of three novel cytotoxic agents -  Xeloda, Camptosar, and Eloxatin - and the recent approval of the two antibodies - Avastin and Erbitux.

Interestingly, an army of novel agents and targets are currently in Phase II clinical trials, and their contributions and impact on future therapy in colorectal cancer remains to be seen.

Scope of this report

• Thorough examination of status and impact of 70 novel drugs in development
• Discussion of the challenges in current drug development, including future clinical trials to be made, collaborations and inclusion of novel endpoints.
• Case studies on major CRC drugs on market
• Competitive landscape assessment, including more than 120 companies in the field and high lightening the top twenty competitors

Research and analysis highlights

Colorectal cancer has become an excellent tumor model for evaluating new therapeutic strategies. Development of a detailed understanding of how this cancer develops, spreads, and grows allows a tailored approach to all stages of treatment: prevention, adjuvant treatment, and therapy of advanced disease. As a result, specific molecular processes have been targeted for therapeutic intervention, including growth factor receptors, proliferation signaling, cell cycling, apoptosis, angiogenesis, and the immune system.

The anti-VEGF antibody Avastin has in recent clinical trials been shown to be safely and effectively used in combination with each of the active anticancer agents used in CRC. However, the chdevelopment of active combination regimens has not yet achieved any significant improvements in the actual cure rate.

Intense efforts are attempting to identify critical molecular biomarkers that can be used to predict for either clinical response to chemotherapy and/or targeted therapies and/or the drug-specific side effects. This has led the industry into a multitude of collaborations, for them to have the chance to successfully deliver on these issues.

Key reasons to read this report

• Explore the strengths and weaknesses associated with compounds in clinical development. Scientific rationale for 70 novel therapeutics in CRC, and the results of clinical trials to date.
• Novel targets and agents are discussed organized into: Growth factor receptors, Signaling transducers; Apoptopic agents, Anti-vascular agents and Immuno-modulators.
• Gain insight into the current challenges and commercial opportunities associated with CRC

Current and Future Therapies for Colorectal Cancer
- A Therapeutic & Competitive Insight

2 Executive Summary

3 Cancer Highlights

4 Methodology

5 Table of Contents

5.1 List of Boxes

5.2 List of Figures

5.3 List of Tables

6 Epidemiology

6.1 Disease Definition

6.2 Prognosis for Colorectal Cancer by Stage

7 Drugs on Market

7.1 A 50% Increase in Sales!

7.2 Topoisomerase inhibitor in First-line and Second-line Treatment

7.3 Fast Way to Approval

7.4 A Significant Reduction in the Risk of Death

7.5 Mice and Men

7.6 The Very Base

8 Key Drug Strategies in CRC

8.1 Apoptosis

8.1.1 An Answer to Drug Resistance

8.1.2 Novel Therapies at the Gate

8.2 Tumor Vascularization & Antivascular Agents

8.2.1 Anti-angiogenesis: Therapeutic Strategies

8.2.2 Single Agent Therapy: Poorly Active in Advanced Tumors

8.2.3 Synergistic Effects with Cytotoxic Therapies.

8.2.4 Vascular Targeting Agents

8.3 Vaccines

8.3.1 Tumor antigens

8.3.2 The Cell Vaccines Strategy

8.3.3 Potent antigen presenting cells

8.3.4 Emerging strategies

9 Competitive Landscape in CRC Drug Development

9.1 We are in the Lead

9.1.1 Amgen

9.1.2 Novartis and Schering

9.1.3 OSI, Genentech, Hoffmann La Roche & Pfizer

9.1.4 Sanofi-Aventis

10 Current CRC Drug Development

10.1 Chemotherapy and Cytotoxic Drugs - A strategy reborn

10.1.1 Progress Analysis: CoFactor

10.1.2 Progress Analysis: Trabectedin (ET-743)

10.1.3 Progress Analysis: Pemetrexed

10.1.4 Progress Analysis: TS-1

10.1.5 Progress Analysis: Edotecarin

10.1.6 Progress Analysis: Aroplatin

10.1.7 Progress Analysis: Ixabepilone

10.2 EGF-R Inhibition and Other Signal Transduction Inhibitors

10.2.1 Progress Analysis: Panitumumab

10.2.2 Progress Analysis: Erlotinib (Tarceva)

10.2.3 Progress Analysis: Gefitinib (Iressa)

10.2.4 Progress Analysis: Pelitinib

10.2.5 Progress Analysis: Sorafenib

10.3 Signal Transduction Inhibitors in CRC

10.3.1 Progress Analysis: BIO-117

10.3.2 Progress Analysis: PD 0325901

10.4 Antiangiogenetic- A team of players

10.4.1 Progress Analysis: Vatalanib

10.4.2 Progress Analysis: Thalidomide

10.4.3 Progress Analysis: AMG 706

10.4.4 Progress Analysis: Combretastatin A4 prodrug

10.4.5 Progress Analysis: MBT 0206

10.4.6 Progress Analysis: MEDI 522

10.4.7 Progress Analysis: Tetrathiomolybdate

10.4.8 Progress Analysis: WX-UK1

10.5 COX-2 Inhibitors - What will become of us?

10.5.1 Progress Analysis: P 54

10.5.2 Progress Analysis: CV-247

10.6 Apoptosis: An approach with a future

10.6.1 Progress Analysis: HGS-ETR1

10.6.2 Progress Analysis: APLIDIN

10.6.3 Progress Analysis: VELCADE

10.6.4 Progress Analysis: TELCYTA

10.6.5 Progress Analysis EPO 906

10.6.6 Progress Analysis: BIO-145

10.6.7 Progress Analysis: Genasense

10.6.8 Progress Analysis: Rexin-G

10.6.9 Progress Analysis: Indisulam

10.6.10 Progress Analysis: Seliciclib

10.6.11 Progress Analysis: SYMADEX

10.7 Necrotic Cell Death Inducers

10.7.1 Progress Analysis: RAV12

10.7.2 Progress Analysis: Cantuzumab mertansine

10.7.3 Progress Analysis: HuC242-DM4

10.7.4 Progress Analysis: COTARA

10.8 Vaccines: A high Threshold to Success

10.8.1 Cell Vaccine

10.8.2 Vaccine: Direct Immunization with Protein and peptides

10.8.3 Anti-idiotype Monoclonal Antibodies

10.8.4 DNA and Virally Encoded Vaccines

10.8.5 Passive Immunotherapy and Conjugated Antibodies

10.9 Immuno-modulators

10.9.1 Progress Analysis: Dacogen

10.9.2 Progress Analysis: GCAN-101

10.9.3 Progress Analysis: ZYC300

10.9.4 Progress Analysis: Clofarabine

10.10 Oncolytic Virotherapy in CRC - A team of four

10.10.1 Progress Analysis: OncoVEX

10.10.2 Progress Analysis: Oncolytic HSV

11 Disclaimer

12 Appendix I: Treatment Guide Lines

12.1.1 Medical Therapy of Colorectal Cancer

13 Appendix II: Selected Company Profiles

14 Drug Index

15 Company Index

5.1 List of Boxes

Box 1:Example of Observed Efficacy in preclinical models

Box 2: Anti-angiogenesis: Therapeutic strategies

Box 3: Anti-angiogenesis: Problems that has to be solved.

Box 4: Mechanisms which tumor cells use to evade an immune reaction

Box 5: Quick Facts - ANX-510

Box 6: Quick Facts - Trabectedin

Box 7: Quick Facts - Pemetrexed

Box 8: Quick Facts - TS-1

Box 9: Quick Facts - Edotecarin

Box 10: Quick Facts - Aroplatin

Box 11: Quick Facts - Ixabepilone

Box 12: Quick Facts - Panitumumab

Box 13: Quick Facts - Erlotinib

Box 14: Scientific Data on Erlotinib

Box 15: Quick Facts - Gefitinib

Box 16: Scientific Data on Gefitinib

Box 17: Quick Facts - Pelitinib

Box 18: Quick Facts - Sorafenib

Box 19: Quick Facts - BIO-117

Box 20: Quick Facts - PD 0325901

Box 21: Quick Facts - Vatalanib

Box 22: Quick Facts - Thalomide

Box 23: Quick Facts - AMG 706

Box 24: Quick Facts - Combretastatin

Box 25: Quick Facts - MBT 0206

Box 26: Quick Facts - MEDI 522

Box 27: Quick Facts - Tetrathiomolybdate

Box 28: Quick Facts - WX-UK1

Box 29: Quick Facts - P 54

Box 30: Quick Facts - CV-247

Box 31: Targets for Apoptosis Directed Therapy

Box 32: Selection of Patents Relating to Apoptosis

Box 33: Quick Facts - HGS-ETR1

Box 34: Quick Facts - APLIDIN

Box 35: Quick Facts - VELCADE

Box 36: Millenniums License Agreement with Ortho Biotech

Box 37: Quick Facts - TELCYTA

Box 38: Quick Facts - EPO 906

Box 39: Quick Facts - BIO-145

Box 40: Quick Facts - Genasense

Box 41: Quick Facts - Rexin-G

Box 42: Quick Facts - Indisulam

Box 43: Quick Facts - Seliciclib

Box 44: Quick Facts - SYMANDEX

Box 45: Quick Facts - RAV12

Box 46: Quick Facts - Cantuzumab mertansine

Box 47: Quick Facts - HuC242-DM4

Box 48: Quick Facts - Cotara

Box 49: Quick Facts - OncoVAX

Box 50: Quick Facts - Canvaxin

Box 51: Quick Facts - Collidem

Box 52: Quick Facts - Dendricell

Box 53: Quick Facts - Neuvenge

Box 54: Quick Facts - Onyvax-CR

Box 55: Quick Facts - Ras-VAX

Box 56: Quick Facts - Avicine

Box 57: Quick Facts - Oncophage

Box 58: Quick Facts - EP 2101

Box 59: Quick Facts - MSI Vaccine

Box 60: Quick Facts - MUC-vaccine

Box 61: Quick Facts - OncoVAX

Box 62: Quick Facts - CeaVac

Box 63: Quick Facts - Onyvax-105

Box 64: Quick Facts - TroVax

Box 65: Quick Facts - ALVA-CEA-B7.1

Box 66: Quick Facts - CEA-TRICOM

Box 67: Quick Facts - IR 705

Box 68 Quick Facts - Amplivax

Box 69: Quick Facts - IGN 101

Box 70: Quick Facts - CEA-Cide

Box 71: Quick Facts - LMB 9

Box 72: Quick Facts - KSB 303

Box 73: Quick Facts - ING-1

Box 74: Quick Facts -Dacogen

Box 75: Quick Facts - GCAN-101

Box 76: Quick Facts - ZYC300

Box 77: Quick Facts - Clofarabine

Box 78: Quick Facts - OncoVEX

Box 79: Quick Facts - NV 1020

5.2 List of Figures

Figure 1: Summarized Description of Colon Cancer Development and Clinical Outcome

5.3 List of Tables

Table 1: 5-year Survival Rate in CRC

Table 2: Risk Factors for Colon Cancer Development

Table 3: Summary of Colorectal Cancer Regimens

Table 4: Summary of Chemotherapy Drugs

Table 5: Capecitabine - Major Developmental Milestones

Table 6: Ironotecan - Major Developmental Milestones

Table 7: Bevacizumab - Major Developmental Milestones

Table 8: Sales Predictions on Bevacizumab

Table 9: Oxaliplatin - Major Developmental Milestones

Table 10: Cetuximab - Major Developmental Milestones

Table 11: Sales Predictions on Cetuximab

Table 12: Common Gene/Protein Defects in Apoptotic Pathways

Table 13: A Selection of Apoptosis Targets in Development

Table 14: Selection of VTA agents under clinical development as cancer therapeutics

Table 15: Colorectal Cancer Vaccines in Development

Table 16: The Representation of Investigators in the CRC Drug Pipeline

Table 17: Drugs with Four or more Investigators

Table 18: Phase III Competitors

Table 19: Industrial Investigators with the Highest Number of CRC Drugs in Phase I to Phase III

development

Table 20: Phase I-phase III Chemotherapy and Cytotoxic Drugs in Development

Table 21: Phase I-Phase III EGF-R Inhibitors as CRC Therapeutics

Table 22: Phase I-Phase III Signal Transduction Inhibitors in CRC

Table 23: Phase I-Phase III Antiangiogenic Drugs in Development

Table 24: Current COX-2 Inhibitors in Development

Table 25: Apoptotic Cell Death Inducers in Development

Table 26: Necrotic Cell Death Inducers in Development

Table 27 Cell therapy based platform in pipeline as potential treatment of colorectal cancer

Table 28: Protein/peptide vaccine as potential treatment of colorectal cancer

Table 29: Anti-idiotype monoclonal antibodies

Table 30: Nucleic acid and virally encoded vaccines

Table 31: Monoclonal Antibodies

Table 32: Immuno-modulators in CRC