トキシコゲノミクスと医薬品の副作用予測：市場および事業展望

Toxicogenomics and Predictive Toxicology: Market and Business Outlook addresses the significant need and potential for predictive toxicology in drug development. The report evaluates a number of novel approaches to toxicology research that have become available over the past five years that are raising optimism for dramatic improvements in the field. A detailed and insightful business outlook on the strategic, regulatory, and marketplace issues driving growth of toxicogenomic and predictive toxicology applications completes the analysis.

The ability to predict the toxic effects of potential new drugs is crucial to prioritizing compound pipelines and eliminating costly failures in drug development. The inability to accurately predict toxicity early in drug development cost the pharmaceutical industry $8 billion in 2003, approximately one-third the cost of all drug failures. Primarily, this is because safety problems are often detected late in the drug development pathway, after hundreds of millions of dollars have already been invested in potential therapeutics. Even when drugs successfully obtain FDA approval and reach the market, they remain vulnerable to costly safety issues. A recent example is Mercks withdrawal of the blockbuster drug Vioxx from the market due to safety concerns which caused the companys stock to plunge 25% in one day. Indeed, predictive toxicology and toxicogenomics technologies are of growing interest to government regulators, who have issued several reports recently calling for more predictive toxicology and toxicogenomics approaches to be used in assessing drug safety.

Toxicogenomics and Predictive Toxicology: Market and Business Outlook examines new predictive toxicology approaches including in vivo, in vitro, and in silico technologies such as toxicogenomics, metabolomics, new animal models, and computational methods. Predictive toxicology differs from traditional toxicology testing primarily by having a greater emphasis on low-cost, high through-put assays, anticipating toxic responses rather than measuring them after they occur; and by having a greater emphasis on understanding the underlying mechanisms of action rather than just monitoring toxic response.

Predictive toxicology is still in its early stages,characterized by the use of gene expression profiles to gain a basic understanding of whether a compound has a "clean" or "messy" profile. It is still some way off from replacing traditional toxicology testing. However, the tremendous advantages of these approaches, as well as pressure from the FDA to improve toxicology testing in drug development, indicate that advancements in predictive toxicology will play an increasing and accelerating role in drug development. This report is crucial reading for companies that are exploring the potential benefits of these methods and that wish to realize a maximum return on their R&D spending.

Table of Contents

Chapter 1. Introduction

1.1 Overview

1.2 Impact of Toxicology Issues on Drug Development

• Adverse Drug Reactions

1.3 Toxicology Background

• Effects of Toxicants

Chapter 2. The Role of Toxicology in Drug Development

2.1. The Drug Development Process

2.2 Traditional Approaches versus Predictive Toxicology

• Toxicity Testing in the Drug Development Process
• Traditional Approaches
• Animal Models
• Genotoxicity Tests
• Limits of Traditional Approaches
• Predictive Toxicology

2.3 Potential Benefits of Predictive Toxicology

• Reduce Adverse Drug Reactions
• Reduce Cost of Drug Development
• Reduce Length of Time of Drug Development
• Improve Drugs
• Reduce Animal Testing
• Increase Sensitivity
• Improve Other Industries
• Reduce Potential Lawsuits
• Provide Biomarkers
• Reduce Regulatory Requirements
• Rescue Failed Drugs

Chapter 3. Toxicogenomics

3.1 Overview

3.2 Background

• Genes and Genomics
• The Genome Structure
• Gene Expression
• Advantages of Genomics Approaches

3.3 Measuring Gene Expression

• DNA Microarrays
• Companies Selling Microarray Products for Toxicology Testing
• RNA Splicing

3.4 Applications of Toxicogenomics

• In Vitro Applications
• Predictive Versus Mechanism-Based Investigations

3.5 Toxicogenomics Data

• National Center for Toxicogenomics
• Standardization and Comparison of Toxicogenomics Data
• Toxicogenomics Data Analysis
• Proprietary Toxicogenomics Databases
• Public Toxicogenomics Databases

3.6. Collaborations in Toxicogenomics Research

• The Toxicogenomics Research Consortium
• HESI Collaborative Research Program

3.7. Case Study: Using Microarrays to Detect Kidney Toxicity

Chapter 4. Technologies for Predictive Toxicology

4.1. Metabolomics/Metabonomics

• Profiling Metabolites
• Detecting Metabolites
• Growth of Metabolomics
• Advantages of Metabolomics
• Future of Metabolomics
• Selected Companies Active in Metabolomics

4.2. Toxicoproteomics

• Primary Technologies for Toxicoproteomics
• In-House Approaches
• Selected Companies Providing Toxicoproteomic
• Products and Services

4.3. Pharmacogenomics

• Drug Metabolism
• Selected Companies Active in Pharmacogenomics

4.4. In Silico Predictive Toxicology

• Applications and Limitations in Predictive Toxicology
• In Silico Methods
• Programs and Companies Active in Predictive
• In Silico Toxicology
• Limitations and Appropriate Uses of In Silico Methods

4.5. New Animal Models

• Types of Animal Toxicity Tests
• Limitations of Toxicology Testing
• Companies Offering Approaches to Improving Current
• Animal Models
• Zebrafish
• Caenorhabditis elegans

4.6. Novel In Vitro Assays: Animal on a Chip

• Applications
• Three-Dimensional Tissue Models
• Animal on a Chip--Companies and Approaches
• Stem Cells

Chapter 5. Business and Strategic Issues

5.1 Overview

5.2 Potential Applications of Predictive Toxicology Throughout Drug Development

5.3 Cost Factors Driving the Adoption of New Toxicology Approaches

• Cost of the Assay Itself
• Cost of Drug Failures
• Primary Areas of Growth in Predictive Toxicology and
• Toxicogenomics

5.4. Factors Limiting Growth of New Toxicology Approaches

• Unknown Mechanisms of Drug Toxicity
• Regulatory Pressures That Promote Extremely Conservative
• Approaches to Toxicology Testing
• Drug Toxicity Research Primarily Takes Place Within
• Pharmaceutical Companies

5.5. Key Players

• Government
• Pharmaceutical Industry
• Biotechnology Industry
• Academia
• Vendors
• Healthcare Providers and Patients

5.6. Regulatory Issues

• U.S Regulatory Agencies Concerned with Safety/Toxicology-Related Issues
• United States
• Global Regulations
• Europe

5.7. Unmet Needs and Opportunities in Technology Development

• Biomarkers
• Data Quality and Analysis
• Databases
• Demonstrated Accuracy
• Heart Rhythm Abnormalities

5.8. Toxicology Technology Evaluations Using SWOT Analysis

• Comparison of Rodent Versus Zebrafish Models
• Cross Comparison of Toxicogenomics Versus Proteomics
• Versus Metabolomics

5.9. Conclusion

Chapter 6. Expert Interviews

• Dave Craford, Affymetrix
• Jacques Retief, Affymetrix
• Jim Neal, Iconix Pharmaceuticals, Inc.
• Thomas J. Colatsky, Icoria
• Peter Lord, Johnson & Johnson Pharmaceutical Research and Development
• Weida Tong, FDAs National Center for Toxicological Research
• Michael L. Shuler, Cornell University
• William B. Mattes, Gene Logic Inc.
• Donna Mendrick, Gene Logic Inc.

Appendix

References

Glossary

Index