バイオマーカーの商業的機会：創薬、臨床開発および分子診断の変革

Abstract

High clinical development costs coupled with declining drug discovery success rates have meant that pharmaceutical companies must re-evaluate their drug development process in order to reduce attrition rates and remain competitive. Over the next decade biomarkers will change the way in which pharma companies determine the economic viability of their drug discovery process. The use of biomarkers to aid the discovery of promising products will create an enhanced understanding of the clinical development process and help to facilitate the shift towards ' personalized medicine' . ' Commercial Opportunities from Biomarkers: Transforming drug discovery, clinical development and molecular diagnostics' is the latest addition to the drug discovery series, examining recent developments and applications within the biomarkers field. Using up-to-date case studies to indicate best practice strategies, this report will ensure that you are able streamline your R&D process and identify potential cost savings throughout drug discovery and development. Regulatory changes are analyzed and recent alliances are examined, enabling you to understand the role and future of this fast-moving field.

Table of Contents

Executive Summary

• Biomarkers in drug discovery, development and clinical diagnostics
• Regulatory acceptance of biomarkers now and in the future
• Fishing for new drug targets with biomarkers
• Biomarkers aiding go/no go decisions
• Imaging biomarkers directing clinical dosing studies
• Clinical biomarkers improving trial design
• Biomarkers as surrogate endpoints
• Market size, collaborations and future directions

Chapter 1 Biomarkers in drug discovery,development and clinical diagnostics

• Summary
• Introduction
• The role of biomarkers in drug discovery, preclinical, clinical development and diagnostics
• Biomarkers in the drug discovery process
• Safety/toxicology biomarkers
• Efficacy or outcome biomarkers and surrogate endpoints
• Biomarkers: challenges and opportunities

Chapter 2 Regulatory acceptance of biomarkers now and in the future

• Summary
• Introduction
• The critical path initiative and FDA guidance
• Regulatory guidance from the other major markets
• Europe - the European Medicines Agency (EMEA)
• Japan - the Ministry of Health and Welfare (MHLW)
• Regulatory agencies working together
• Other biomarker initiatives
• Regulatory acceptance of a valid biomarker
• Regulatory acceptance of in vitro diagnostic biomarkers
• Costs and incentives for biomarker development and validation
• Conclusions

Chapter 3 Fishing for new drug targets with biomarkers

• Summary
• Introduction
• Target discovery via functional genomics
• What is functional genomics?
• Target discovery
• New technologies in functional genomics
  • DNA and protein microarrays
  • New technologies
• The genomics-derived drug pipeline
  • Case study - target discovery by CuraGen Corporation
• The future of genomics technologies for drug target identification
• Biomarker discovery via proteomics
• What is proteomics?
• Proteomics in biomarker development: the HUPO Project
• Case studies - Biomarker development using proteomic technologies
  • Caprion Pharmaceuticals Inc. case study
  • Millennium Pharmaceuticals case study
• Limitations of proteomics for biomarker discovery
• Integrating ‘omics in biomarker discovery: metabonomics
• What is metabonomics?
• Metabonomics-based biomarker discovery - case studies
  • Metabolon Inc case study
  • Phenomenone Discoveries case study
• Limitations of metabonomics
• Conclusions

Chapter 4 Biomarkers aiding go/no go decisions

• Summary
• Introduction
• Technologies for safety biomarker discovery
• Toxicogenomics
  • Genomic biomarkers for drug-induced nephrotoxicity, genotoxicity and neutropenia
  • Proteomic biomarkers of drug-induced hepatotoxicity and cardiotoxicity
  • Metabonomic biomarkers for vasculitis and hepatotoxicity
• Databases for predictive toxicogenomics
  • Privately held databases
  • Publicly held databases
• Challenges and opportunities
• Challenges
• Opportunities
• Collaboration in biomarker discovery
• Conclusions

Chapter 5 Imaging biomarkers directing clinical dosing studies

• Summary
• Introduction
• Imaging biomarkers
• X-ray and computed tomography
• Magnetic resonance imaging
• Novel MRI imaging agents
• Positron emission tomography
• Molecular imaging
• The role of imaging biomarkers in preclinical studies
• Bioluminescence
• Matrix metalloproteinase inhibition
• The role of imaging biomarkers in clinical studies
• Phase 1: the role of imaging biomarkers in pharmacokinetic and dosing studies
  • Receptor occupancy studies
  • PET and MRI dosing strategies for anticancer agents
• Phase 2 and 3: imaging biomarkers as study endpoints
  • Oncology
  • Multiple sclerosis
  • Rheumatoid arthritis
  • Alzheimer' s disease
• Go/no-go decision making
  • Case study - VirtualScopics
• Regulatory aspects of imaging technologies
• Development of molecular imaging agents
• Imaging biomarkers and surrogate endpoints
• Conclusions

Chapter 6 Clinical biomarkers improving

• trial design
• Summary
• Introduction
• Patient enrichment in clinical trials
• Patient enrichment - advantages
• Patient enrichment - potential problems
• Targeted cancer treatments - case studies
• Herceptin case study
• Gleevec case study
• Iressa case study
• Patient enrichment via pharmacogenomics in therapeutic areas other
• than cancer
• Vilazodone - case study
• Pharmacogenomic testing in the pharmaceutical industry - an update
• Conclusions

Chapter 7 Biomarkers as surrogate

• endpoints
• Summary
• Introduction
• What is a surrogate endpoint?
• Benefits and drawbacks of surrogate endpoints
• Benefits
• Drawbacks
• Surrogate endpoint validation
• Effective use of surrogates and examples
• Case study - FDG-PET as a surrogate endpoint in oncology studies
• CA-125 as a surrogate endpoint in trials of ovarian cancer
• Costs of surrogate endpoint development
• Regulatory perspective on surrogate endpoints
• Conclusions

Chapter 8 Market size, collaborations and

• future directions
• Summary
• Introduction
• The biomarker market
• Potential cost savings in drug discovery and development
• Market size
  • Genomics and proteomics
  • Metabonomics
  • Bioinformatics
  • Imaging
  • Molecular diagnostics
• Companies and their alliances in the biomarker field
• Outline of key companies
• Key alliances
  • Alliances with pharmaceutical companies
  • Biomarker-diagnostic company alliances
  • Alliances with academia
• Pharma strategies for biomarkers
• Current and future trends for the evaluation of disease biomarkers
• Conclusions

Chapter 9 Appendix

• Biomarker discovery collaborations
• Bibliography
• Glossary
• Index
• Footnotes

List of Figures

• Figure 1.1: Types of biomarker and examples
• Figure 1.2: Low success rate of developmental drugs
• Figure 1.3: The many roles of biomarkers in drug development
• Figure 2.4: Voluntary genomic data submissions: process and outcomes
• Figure 2.5: The EMEA and FDA working together
• Figure 2.6: Valid DNA based biomarkers of enzyme activity
• Figure 2.7: Exploratory DNA based biomarkers of enzyme or transporter activity
• Figure 2.8: Fit-for-purpose qualification of biomarkers
• Figure 2.9: Proposed biomarker validation in preclinical drug safety assessment
• Figure 3.10: Genomics, proteomics and metabonomics: what is measured?
• Figure 3.11: Technologies and methods used in biomarker discovery
• Figure 3.12: A timeline for the introduction of various genomics technologies
• Figure 3.13: The branches of proteomics for biomarker discovery
• Figure 3.14: Scientific initiatives in the Human Proteome Organisation
• Figure 3.15: CellCarta®: uses for proteomic analysis
• Figure 3.16: An NMR metabonomic profile of urine
• Figure 3.17: Metabonomic analysis of data from patients with ALS and controls
• Figure 3.18: Biomarker discovery through metabolomics
• Figure 4.19: Toxicogenomics and traditional toxicology working together to provide a framework for systems toxicology
• Figure 4.20: Principal component analysis of gene expression changes following treatment with cisplatin, gentamicin and puromycin
• Figure 4.21: Principal component analysis of urine from rats treated with a vasculitis causing compound
• Figure 4.22: Database enabled predictive toxicology
• Figure 4.23: Example of rank ordering candidate leads using the ToxExpress® Program
• Figure 5.24: Imaging techniques and their uses
• Figure 5.25: Targeted MRI imaging agents from Kereos Inc.
• Figure 5.26: A PET/CT image indicating the uptake of 18F-fluoro-2-deoxy-D-glucose in a primary cancer lesion and a lymph node (orange areas)
• Figure 5.27: Whole body microPET images through a rat showing 18F-FDG distribution
• Figure 5.28: The VivoVision technology from Xenogen Inc.
• Figure 5.29: NIRF data from rats treated with prinomastat
• Figure 5.30: PET images of the serotonin 5-HT1A¬ receptors in the brain of a healthy volunteer before and after administration of pindolol
• Figure 5.31: An MRI from a multiple sclerosis patient showing a T2 lesion
• Figure 5.32: VirtualScopics' method for tumor growth measurement
• Figure 6.33: Targeted study designs
• Figure 6.34: Imatinib mechanism of action in chronic myeloid leukaemia
• Figure 6.35: Mechanism of action of gefinitib
• Figure 6.36: Frequency of mutations by exon (EGFR tyrosine kinase domain)
• Figure 6.37: The association between patients' alleles for the serotonin transporter long/short polymorphism and response to SSRIs
• Figure 7.38: Examples of biomarkers that have failed to serve as surrogate endpoints in clinical trials
• Figure 7.39: Reasons for surrogate endpoint ' failure'
• Figure 7.40: Use of surrogate endpoints in antiretroviral approvals
• Figure 8.41: Potential cost savings from the use of genomic biomarkers in drug discovery and development
• Figure 8.42: Alliances between major pharmaceutical and biomarker discovery companies
• Figure 8.43: Therapeutic areas represented by the major alliances of biomarker and pharmaceutical companies
• Figure 8.44: Therapeutic areas represented by biomarker patents
• Figure 8.45: Cancers represented by biomarker patents
• Figure 8.46: Estimated time to the widespread use of biomarkers in different therapeutic areas

List of Tables

• Table 3.1: Investments by pharmaceutical companies in genomics companies
• Table 3.2: Highlights of drug discovery and development based on genomics technologies
• Table 3.3: Companies predominantly using genomic and proteomic technologies for drug development
• Table 4.4: Types of toxicogenomic biomarker
• Table 4.5: Drugs extensively metabolized by CYP2C19 and CYP2D6
• Table 5.6: Glucose-based imaging biomarkers for a variety of diseases
• Table 5.7: Advantages of molecular imaging of whole animals for preclinical studies
• Table 6.8: Comparison of targeted and untargeted study designs
• Table 6.9: List of targeted cancer treatments
• Table 6.10: Phase 3 trial outcome for Herceptin with and without HER2 diagnosis
• Table 6.11: Examples of pharmacogenomic developments in therapeutic areas other than cancer
• Table 6.12: Approval success rates for different therapeutic drug classes
• Table 6.13: Currently marketed drugs that might benefit from pharmacogenomics
• Table 7.14: Examples of surrogate endpoints and related clinical outcomes
• Table 7.15: Sample size for Alzheimer' s disease clinical trials using volumetric MRI measures surrogate endpoint
• Table 7.16: Uses of CA-125 in routine clinical care
• Table 8.17: Biomarker market size and forecast ($bn), 2005-2012
• Table 8.18: Molecular diagnostics market size and forecast ($bn), 2005-2012
• Table 8.19: Genomics-based biomarker discovery companies
• Table 8.20: Proteomics-based biomarker discovery companies
• Table 8.21: Metabonomics-based biomarker discovery companies
• Table 8.22: Bioinformatics companies in biomarker discovery
• Table 8.23: Summary of major pharmaceutical company biomarker alliances
• Table 8.24: Key diagnostic-biomarker company alliances
• Table 8.25: Number of patents filed by various pharma and biomarker discovery companies
• Table 9.26: Biomarker discovery collaborations with major pharma
• Table 9.27: Biomarker discovery collaborations with major pharma (cont.)
• Table 9.28: Biomarker discovery collaborations with major pharma (cont.)
• Table 9.29: Biomarker discovery collaborations with smaller pharma or biotechnology companies
• Table 9.30: Biomarker discovery collaborations with smaller pharma or biotechnology companies (cont.)
• Table 9.31: Biomarker discovery alliances with academia
• Table 9.32: Biomarker discovery alliances with academia (cont.)