The Future of Metabolomics: Building competitive advantage in drug discovery, clinical development and diagnostics

Table of Contents
The Future of Metabolomics
Executive Summary 10
Introduction 10
Platform technologies in metabolomics 11
Regulatory and standardization issues 12
Metabolomics in drug discovery & preclinical development 13
Metabolomics in clinical drug development 14
The role of metabolomics for marketed drugs 15
Metabolomics in diagnostics and health screening 16
Market size, alliances, acquisitions and future directions 17

Chapter 1 Introduction 20
Summary 20
What is metabolomics? 21
The metabolome 23
Metabolomics’ relationship with other ‘omics technologies 24
Uses of metabolomics in drug discovery and development 26
Advantages of metabolomics 27
Challenges to the field of metabolomics 28
Conclusions 29

Chapter 2 Platform technologies in metabolomics 32
Summary 32
Introduction 33
Technologies for metabolomics 33
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Mass Spectrometry (MS) 33
Nuclear Magnetic Resonance spectroscopy (NMR) 36
MS versus NMR 37
Other spectroscopic and chromatographic techniques 39
Fourier-transform infrared spectroscopy (FTIR) 39
Electrochemical array 39
Emerging technologies 40
Technology developments 40
Metabolomics in individual cells 41
Experimental design and analysis 41
Data transformation, peak deconvolution and quantification 42
Metabolite identification 42
Data mining and analysis: Chemometrics 44
Databases for metabolic pathway analysis 48
Conclusions 50

Chapter 3 Regulatory and standardization issues 52
Summary 52
Introduction 53
Regulatory issues 53
US Food and Drug Administration 53
European Medicines Agency (EMEA) and the Japanese Ministry of Health
and Welfare (MHLW) 54
Standardization in metabolomics 55
Incentives for pharma 56
Conclusions 56

Chapter 4 Metabolomics in drug discovery & preclinical development 58
Summary 58
Introduction 59
Target identification and validation 60
Lead prioritization 61
Pharmacology, efficacy and mechanism of action studies 63
Case study: Lipomics Technologies Inc 63
Case study: SIDMAP 64
Preclinical studies for non-target effects 65
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Case study: Icoria - liver toxicity biomarkers 66
Case study: Pfizer - biomarkers of vasculitis 67
Case study: GlaxoSmithKline - peroxisome proliferation 68
Case study: The Consortium for Metabonomics Technology (COMET) 69
Strengths and limitations of metabolomics for preclinical research 71
Metabolomics in systems biology 74
Case study: the Liver Toxicity Biomarker Study (LTBS) 74
Conclusions 76

Chapter 5 Metabolomics in clinical drug development 78
Summary 78
Introduction 79
Patient stratification and pharmacogenomics 80
Clinical pharmacometabolomics 83
Case study: Bayer’s biomarkers for response to sorafenib treatment 84
Metabolomics for biomarker discovery 86
Case study: Phenomenome Discoveries colorectal cancer biomarker 86
Case Study: biomarkers of asthma from the University of Alberta, Canada 88
The challenge of human variation 89
Conclusions 91

Chapter 6 The role of metabolomics for marketed drugs 94
Summary 94
Introduction 95
Product differentiation 95
Case study: Metabolon Inc and Bristol-Myers-Squibb study protease
inhibitors 95
Product lifecycle management 97
Seeking new indications 97
Case study: drug repositioning by GeneLogic 98
Researching efficacy and safety problems 98
Case study: SIDMAP predicts Gleevec resistance 99
Drug and transplant monitoring 100
Case study: toxicodynamic monitoring of immunosuppressants with NMR 100
Case study: transplant monitoring with metabolomics 101
Conclusions 104
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Chapter 7 Metabolomics in diagnostics and health screening 106
Summary 106
Introduction 107
Diagnostic applications of metabolomics 108
Case study: A NMR-based diagnostic test for atherosclerosis 108
Case study: A diagnostic test for coronary heart disease 109
Case study: A metabolic signature for motor neuron disease 111
Case study: novel biomarkers for pre-eclampsia 112
Case study: the Magnetic Resonance Diagnostics Centre 113
Metabolomics for population screening 115
Case study: newborn screening by Pediatrix Screening 116
Case study: the MolPAGE Consortium 118
Conclusions 119

Chapter 8 Market size, alliances, acquisitions and future directions 122
Summary 122
Introduction 123
Saving costs in preclinical drug development 124
Saving costs in clinical studies 125
Cost effective diagnostics 126
Key metabolomics companies and academic groups 127
Patent position 132
Current use of metabolomics in the pharma industry 135
The metabolomics market 138
Conclusions 139

Chapter 9 Appendix 142
Index 142
Bibliography 144
Endnotes 150
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List of Figures
Figure 1.1: Established biochemical pathways 21
Figure 1.2: Number of publications in metabolomics, 1997-2005 22
Figure 1.3: The human metabolome 24
Figure 1.4: The ‘omics technologies 25
Figure 1.5: Preclinical and clinical uses of metabolomics 26
Figure 2.6: Mass spectrometry – a summary 34
Figure 2.7: NMR spectroscopy 36
Figure 2.8: 1H NMR spectrum of urine showing functional windows 37
Figure 2.9: Analysis of metabolomics data 42
Figure 2.10: Examples of PCA and PLS-DA plots for biomarker discovery 45
Figure 2.11: Algorithms for metabolomic data analysis 46
Figure 2.12: Metabolic pathway map: biosynthesis of isoleucine 48
Figure 3.13: The metabolomics standardization initiative 55
Figure 4.14: Metabolomics for target identification 60
Figure 4.15: Metabolon case study: prioritization of lead anti-infective compounds 62
Figure 4.16: Metabolomics for toxicity screening in preclinical drug development 65
Figure 4.17: Principal component analysis of urine from rats treated with a vasculitis causing
compound 68
Figure 4.18: Operation of the COMET expert system for predicting main organ toxicity 70
Figure 4.19: Organization of the Liver Toxicity Biomarker Study 75
Figure 5.20: Drug development: cumulative cost per step including failures 79
Figure 5.21: Uses of metabolomics in clinical drug development 80
Figure 5.22: Pharmacogenomic approach to patient stratification in clinical trials 81
Figure 5.23: Patient stratification: value for business and public health from the use of
pharmacogenomics in Herceptin development 82
Figure 5.24: The pharmacometabonomic hypothesis tested in rats 83
Figure 5.25: Metabolomic biomarker discovery protocol for sorafenib 85
Figure 5.26: Biomarker discovery at Phenomenome Discoveries Inc: Colorectal Cancer example 87
Figure 5.27: NMR spectra of urine from asthmatic patients and healthy individuals 89
Figure 6.28: Metabolite expression in adipocytes by five protease inhibitors 96
Figure 6.29: Metabolic flux analysis using carbon-13 labelled glucose as a tracer 99
Figure 7.30: Relationship between LDL particles and LDL cholesterol, HDL cholesterol and
triglycerides 109
Figure 7.31: Classification of coronary artery disease with metabolomics 110
Figure 7.32: Metabolomic analysis of data from patients with ALS and controls 111
Figure 7.33: Diagnosis of community acquired pneumonia using metabolomics: the MRDC project
114
Figure 7.34: PCA and metabolite correlation maps for diagnosis of pulmonary diseases from the
Magnetic Resonance Diagnostics Centre 115
Figure 8.35: Better data improves productivity 123
Figure 8.36: The biology-centric drug discovery process 125
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List of Tables
Table 1.1: Advantages of metabolomics 27
Table 2.2: Comparison of NMR vs. MS for metabolomics applications 38
Table 2.3: Publicly available databases of metabolite spectra 43
Table 2.4: Commercial metabolite identification software 44
Table 2.5: Metabolomics data analysis software 47
Table 2.6: Publicly available databases of metabolic pathways 49
Table 4.7: Strengths and limitations of metabolomics in toxicology 72
Table 4.8: Metabolites often detected in metabolomic studies 73
Table 6.9: Number of metabolites up- and down-regulated by five protease inhibitors 97
Table 6.10: A summary of statistically significant metabolomic or metabolite measurements
relevant to organ transplantation or organ dysfunction 102
Table 7.11: Metabolic disorders identified by the Pediatrix StepOne™ test 117
Table 7.12: Partners in the MolPAGE consortium 118
Table 8.13: Leading suppliers and service companies in metabolomics 128
Table 8.14: Bioinformatics/Chemometrics companies interested in metabolomics 130
Table 8.15: Key academic centers for metabolomics research 131
Table 8.16: Number of patents issued by metabolomics-based biomarker discovery and service
companies 132
Table 8.17: Patents for metabolomic methods 133
Table 8.18: Patents applying metabolomic technologies to drug/diagnostic development 134
Table 8.19: Alliances between leading metabolomics companies and pharma, academia and
platform developers 136
Table 8.20: Alliances between leading metabolomics companies and pharma, academia and
platform developers 137
Table 8.21: Metabolomics market size and forecast: 2005-2012 ($bn) 138