The Future Of Metabolomics: Building Competitive Advantage In Drug Discovery, Clinical Development And Diagnostics

Published by: Business Insights

Published: Aug. 1, 2006 - 156 Pages

Table of Contents

Executive Summary

Introduction

Platform technologies in metabolomics

Regulatory and standardization issues

Metabolomics in drug discovery & preclinical development

Metabolomics in clinical drug development

The role of metabolomics for marketed drugs

Metabolomics in diagnostics and health screening

Market size, alliances, acquisitions and future directions

Chapter 1 Introduction

Summary

What is metabolomics?

The metabolome

Metabolomics’ relationship with other ‘omics technologies

Uses of metabolomics in drug discovery and development

Advantages of metabolomics

Challenges to the field of metabolomics

Conclusions

Chapter 2 Platform technologies in metabolomics

Summary

Introduction

Technologies for metabolomics

Mass Spectrometry (MS)

Nuclear Magnetic Resonance spectroscopy (NMR)

MS versus NMR

Other spectroscopic and chromatographic techniques

Fourier-transform infrared spectroscopy (FTIR)

Electrochemical array

Emerging technologies

Technology developments

Metabolomics in individual cells

Experimental design and analysis

Data transformation, peak deconvolution and quantification

Metabolite identification

Data mining and analysis: Chemometrics

Databases for metabolic pathway analysis

Conclusions

Chapter 3 Regulatory and standardization issues

Summary

Introduction

Regulatory issues

US Food and Drug Administration

European Medicines Agency (EMEA) and the Japanese Ministry of Health and Welfare (MHLW)

Standardization in metabolomics

Incentives for pharma

Conclusions

Chapter 4 Metabolomics in drug discovery & preclinical development

Summary

Introduction

Target identification and validation

Lead prioritization

Pharmacology, efficacy and mechanism of action studies

Case study: Lipomics Technologies Inc

Case study: SIDMAP

Preclinical studies for non-target effects

Case study: Icoria - liver toxicity biomarkers

Case study: Pfizer - biomarkers of vasculitis

Case study: GlaxoSmithKline - peroxisome proliferation

Case study: The Consortium for Metabonomics Technology (COMET)

Strengths and limitations of metabolomics for preclinical research

Metabolomics in systems biology

Case study: the Liver Toxicity Biomarker Study (LTBS)

Conclusions

Chapter 5 Metabolomics in clinical drug development

Summary

Introduction

Patient stratification and pharmacogenomics

Clinical pharmacometabolomics

Case study: Bayer’s biomarkers for response to sorafenib treatment

Metabolomics for biomarker discovery

Case study: Phenomenome Discoveries colorectal cancer biomarker

Case Study: biomarkers of asthma from the University of Alberta, Canada

The challenge of human variation

Conclusions

Chapter 6 The role of metabolomics for marketed drugs

Summary

Introduction

Product differentiation

Case study: Metabolon Inc and Bristol-Myers-Squibb study protease inhibitors

Product lifecycle management

Seeking new indications

Case study: drug repositioning by GeneLogic

Researching efficacy and safety problems

Case study: SIDMAP predicts Gleevec resistance

Drug and transplant monitoring

Case study: toxicodynamic monitoring of immunosuppressants with NMR

Case study: transplant monitoring with metabolomics

Conclusions

Chapter 7 Metabolomics in diagnostics and health screening

Summary

Introduction

Diagnostic applications of metabolomics

Case study: A NMR-based diagnostic test for atherosclerosis

Case study: A diagnostic test for coronary heart disease

Case study: A metabolic signature for motor neuron disease

Case study: novel biomarkers for pre-eclampsia

Case study: the Magnetic Resonance Diagnostics Centre

Metabolomics for population screening

Case study: newborn screening by Pediatrix Screening

Case study: the MolPAGE Consortium

Conclusions

Chapter 8 Market size, alliances, acquisitions and future directions

Summary

Introduction

Saving costs in preclinical drug development

Saving costs in clinical studies

Cost effective diagnostics

Key metabolomics companies and academic groups

Patent position

Current use of metabolomics in the pharma industry

The metabolomics market

Conclusions

Chapter 9 Appendix

Index

Bibliography

Endnotes

List of Figures

Figure 1.1: Established biochemical pathways

Figure 1.2: Number of publications in metabolomics, 1997-2005

Figure 1.3: The human metabolome

Figure 1.4: The ‘omics technologies

Figure 1.5: Preclinical and clinical uses of metabolomics

Figure 2.6: Mass spectrometry - a summary

Figure 2.7: NMR spectroscopy

Figure 2.8: 1H NMR spectrum of urine showing functional windows

Figure 2.9: Analysis of metabolomics data

Figure 2.10: Examples of PCA and PLS-DA plots for biomarker discovery

Figure 2.11: Algorithms for metabolomic data analysis

Figure 2.12: Metabolic pathway map: biosynthesis of isoleucine

Figure 3.13: The metabolomics standardization initiative

Figure 4.14: Metabolomics for target identification

Figure 4.15: Metabolon case study: prioritization of lead anti-infective compounds

Figure 4.16: Metabolomics for toxicity screening in preclinical drug development

Figure 4.17: Principal component analysis of urine from rats treated with a vasculitis causing compound

Figure 4.18: Operation of the COMET expert system for predicting main organ toxicity

Figure 4.19: Organization of the Liver Toxicity Biomarker Study

Figure 5.20: Drug development: cumulative cost per step including failures

Figure 5.21: Uses of metabolomics in clinical drug development

Figure 5.22: Pharmacogenomic approach to patient stratification in clinical trials

Figure 5.23: Patient stratification: value for business and public health from the use of pharmacogenomics in Herceptin development

Figure 5.24: The pharmacometabonomic hypothesis tested in rats

Figure 5.25: Metabolomic biomarker discovery protocol for sorafenib

Figure 5.26: Biomarker discovery at Phenomenome Discoveries Inc: Colorectal Cancer example

Figure 5.27: NMR spectra of urine from asthmatic patients and healthy individuals

Figure 6.28: Metabolite expression in adipocytes by five protease inhibitors

Figure 6.29: Metabolic flux analysis using carbon-13 labelled glucose as a tracer

Figure 7.30: Relationship between LDL particles and LDL cholesterol, HDL cholesterol and triglycerides

Figure 7.31: Classification of coronary artery disease with metabolomics

Figure 7.32: Metabolomic analysis of data from patients with ALS and controls

Figure 7.33: Diagnosis of community acquired pneumonia using metabolomics: the

project 114 Figure 7.34: PCA and metabolite correlation maps for diagnosis of pulmonary diseases from the Magnetic Resonance Diagnostics Centre

Figure 8.35: Better data improves productivity

Figure 8.36: The biology-centric drug discovery process

List of Tables

Table 1.1: Advantages of metabolomics

Table 2.2: Comparison of NMR vs. MS for metabolomics applications

Table 2.3: Publicly available databases of metabolite spectra

Table 2.4: Commercial metabolite identification software

Table 2.5: Metabolomics data analysis software

Table 2.6: Publicly available databases of metabolic pathways

Table 4.7: Strengths and limitations of metabolomics in toxicology

Table 4.8: Metabolites often detected in metabolomic studies

Table 6.9: Number of metabolites up- and down-regulated by five protease inhibitors

Table 6.10: A summary of statistically significant metabolomic or metabolite measurements relevant to organ transplantation or organ dysfunction

Table 7.11: Metabolic disorders identified by the Pediatrix StepOne™ test

Table 7.12: Partners in the MolPAGE consortium

Table 8.13: Leading suppliers and service companies in metabolomics

Table 8.14: Bioinformatics/Chemometrics companies interested in metabolomics

Table 8.15: Key academic centers for metabolomics research

Table 8.16: Number of patents issued by metabolomics-based biomarker discovery and service companies

Table 8.17: Patents for metabolomic methods

Table 8.18: Patents applying metabolomic technologies to drug/diagnostic development

Table 8.19: Alliances between leading metabolomics companies and pharma, academia and platform developers

Table 8.20: Alliances between leading metabolomics companies and pharma, academia and platform developers

Table 8.21: Metabolomics market size and forecast: 2005-2012 ($bn)

Abstract

• An update on how regulatory authorities in the US and
Europe are preparing for the use of metabolomics and biomarker data in drug submissions.
• In-depth case studies on how leading metabolomics innovators and pharmaceutical companies are applying metabolomics at all stages of the drug and diagnostic development process.
• Analysis of the platform technology, service and bioinformatics companies at the forefront of the metabolomics market.
• A detailed breakdown of the potential of metabolomics to reduce costs, time and clinical development.

• Future growth of the metabolomics market will be driven by three areas: biomarker discovery services, the application of bioinformatics/chemometrics and the development of technology platforms, leading to a market size of over US $2 billion by 2012.
• Metabolomics can be applied in lifecycle management by identifying new indications for a marketed product, or by developing a test that will optimize dosing and help patients to receive a dose that is both efficacious and safe.
• Metabolomics can be used to uncover new drug targets, prioritize lead compounds, and assess toxicity non-invasively, enabling the development of novel, smarter and safer drugs.
• Within the next 10 years it is anticipated that metabolomics will become a standard tool in the pharma industry as validated metabolomic-based biomarkers begin to emerge and cost-effective screens are established.

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