Market Report Source

Overview

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

Table of Contents

Commercial Opportunities from Biomarkers

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

iv

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

v

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

vi

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

vii

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

viii

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

ix

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 as a

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