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.)
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