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1、Epigenomics August 2012 Kalorama Information A division of MarketR 38 East 29th Street Sixth Floor New York, New York 10016 212.807 .2660 t 800.298.5603 t 212.807 .2676 f Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter de
2、veloped, in whole or in any part, is strictly prohibited. EPIGENOMICS: PRESENT AND FUTURE APPLICATIONS FOR DIAGNOSTICS AND THERAPY AUGUST 2012 A KALORAMA INFORMATION MARKET INTELLIGENCE REPORT Author: K. John Morrow, Jr., PhD Copyright 2012 Kalorama Information Reproduction without prior written per
3、mission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. TABLE OF CONTENTS CHAPTER ONE: EXECUTIVE SUMMARY 1 The Basic Science of Epigenomics- Basic Life Science R not well understood 22 Histone Acetylation . 25 Histone phosphorylation . 25 Methy
4、lation . 25 Sumoylation 26 Histone “chaperones” 27 MicroRNAs (miRNAs) . 28 Summary, Conclusions 29 CHAPTER THREE: EPIGENETIC AND DIAGNOSIS . 31 Epigenetic drivers of disease . 33 Epigenomics and DNA methylation . 33 Role of histones 34 Early cancer diagnosis 35 Methylation Markers 36 Table of Conten
5、ts ii Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. Challenges in the identification of epigenetic involvement in non-cancerous diseases 37 Summary, Conclusions
6、 . 37 CHAPTER FOUR: MARKET DRIVERS 39 Epigenomics and Therapeutics: Market by major diseases 39 Cancers . 41 Hypo/Hypermethylation . 41 Anti-cancer therapy 42 Covalent histone modifications 42 Aberrant miRNA expression 42 Autoimmune dysfunction . 42 Cardiovascular 43 Mental disorders . 44 A classic
7、vision of mental illness 44 Schizophrenia . 46 Bipolar disorder 46 Autism 47 Alzheimers Disease . 51 Spinal muscular atrophy (SMA) . 52 Parkinsons Disease 52 Imprinting disorders 53 Praeder-Willi syndrome 54 Angelman syndrome . 54 Beckwith-Wiedemann syndrome 55 Fragile X syndrome . 56 Friedreichs at
8、axia 56 Concluding on a Cautionary Note . 58 CHAPTER FIVE: COMPANIES ACTIVE IN EPIGENOMICS. 63 Diagnostic companies 63 Enzo Life Sciences . 64 Epigenomics AG 65 Epiontis . 68 Exact Sciences 70 Illumina . 71 Novus Biologicals . 72 Oncomethylome Sciences . 74 Valirx 76 Volition Singapore 76 Therapeuti
9、c Companies 79 Table of Contents iii Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. Acetylon Pharmaceuticals . 80 Acylin Therapeutics 81 CellCentric 82 Celdex .
10、82 Celgene 84 Celzome (UK/DE) . 85 Chroma Therapeutics 85 Constellation Pharma 86 Eisai Co. Ltd 87 Epitherapeutics 88 EpiZyme 88 Methyl Gene 90 Novartis: 91 Orion . 92 RaNA Therapeutics . 93 Syndax Pharmaceuticals Inc. . 94 ValiRX (UK) . 96 Epigenomics research products supply companies 97 Active Mo
11、tif 97 Diagenode . 97 Epigentek . 98 Life Technologies 99 Qiagen . 99 Sigma-Aldrich . 100 Zymo Research Products . 100 Summary, Conclusions 101 CHAPTER SIX: OUTLOOK FOR THE EPIGENOMICS MARKET 103 Opportunities and Challenges . 103 Stephen Baylin, M.D.: Epigenomics Will Generate Clues On Biomarker St
12、rategy . 104 Growth in World Economies . 107 Testing: Need for Rapid, Easy to Use Technologies . 108 Dim Prospects for Pharma: How to Upend them 109 Dr. Pedro Cuatrecasas on Corporate Policies and Innovation . 112 Market Potential for Epigenetic-Drugs 113 Dr. Ping Chi: Confident That Discovery Will
13、Lead to “Tumor Achillies Heel” 116 Epigenomics Market in Diagnostics 117 Therapeutic Market Areas . 120 Personalized Medicine and Epigenomics 124 Industry Challenges and Strategic Recommendations 126 Competitive landscape 128 Epigenomics Market Considerations . 128 Table of Contents iv Copyright 201
14、2 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. Market Drivers and Restraints 130 Market Forecasts and Competitive Analysis 130 Competitive Structure . 131 Regional Market Con
15、siderations 132 Market Share Analysis: Product Segments . 132 Biotechnology Market Worldwide 133 North America 133 EU . 133 Japan . 133 Asia Pacific . 135 The Way Forward . 137 South America 138 Summary, Conclusions . 140 TABLE OF EXHIBITS CHAPTER ONE: EXECUTIVE SUMMARY Table 1-1 The most common epi
16、genetic alterations . 2 CHAPTER TWO: THE BASIC SCIENCE OF EPIGENOMICS Figure 2-1 Timeline of epigenetic discoveries ourtesy Constellation Pharma . 10 Table 2-1 The most common epigenetic alterations . 12 Figure 2-2 Agouti Mice 14 Figure 2-3 Classic DNA methylation reaction . 20 Figure 2-4 The molecu
17、le 5-hydroxymethylcytosine 21 Table of Contents v Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. Figure 2-5 DNA molecule wrapped twice around a Hisotne Octamer t
18、o make a Nucleosome 22 Table 2-2 Varieties of histone modification and their properties 23 Figure 2-6 Acetylation and deacetylation of lysene residues 24 Figure 2-7 Shilatifard A. 2008 26 CHAPTER THREE: EPIGENETIC AND DIAGNOSIS Table 3-1 Examples of Clinically Relevant Epigenetic Biomarkers . 32 CHA
19、PTER FOUR: MARKET DRIVERS Table 4-1 Currently FDA-approved Epigenetic-Based Drugs 40 Figure 4-1 Structures of (A) 5-aza 2-deoxycytidine (5 aza dC, decitabine) and (B) zebularine 41 Figure 4-2 U.S. FDA-approved Epigenetic-Acting Drugs 41 Table 4-3 Prevalance of autism as a function time, 200-2008 . 4
20、9 Table 4-4 Current autism therapies 50 Figure 4-3 Map of the 11p15 imprinted region . 55 CHAPTER FIVE: COMPANIES ACTIVE IN EPIGENOMICS Table 5-1 Some Important Epigenomics Diagnostics Companies 63 Table 5-2 The Epigenomics Land Grab: R chromatin writes, erasers, and readers . 86 Figure 5-2 JUN/EPIZ
21、YME An Example of one of Epizymes inhibitors interacting with an epigenetic enzyme . 89 Table of Contents vi Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. Figur
22、e 5-3 Structure of LBH589 (panobinostat) 92 Figure 5-4 Action of Panbinostat . 92 Figure 5-5 Structure of entinostat . 94 CHAPTER SIX: OUTLOOK FOR THE EPIGENOMICS MARKET Table 6.1 GNP Growth by Country, Region . 107 Table 6.2 Conflicting Worldwide Economic Drivers And Their Impact On Epigenomics Tec
23、hnologies . 109 Figure 6.1 Vast Expenditures, Poor Returns 110 Table 6.3 Guidelines For A New Stage Of Drug Development 111 Table 6.4 Epigenomics Therapeutics Market, 2011 and 2017 (millions) . 113 Table 6.5 Global Pharma Market, 2010 and 2015 (billions) . 113 Figure 6.2 Epigenomic Drug Market, 2011
24、 and 2017 114 Table 6.6 FDA-Approved Epigenetic Anti-Cancer Agents 115 Figure 6.3 Epigenomics Diagnostics Market, 2010 and 2015 118 Table 6.7 Next Gen Cancer Diagnostics Market, 2010-2015 . 119 Table 6.8 Epigenomics in Cancer Diagnostics, 2010-2015 119 Table 6.9 Total IVD Market 2007-2011 . 119 Tabl
25、e of Contents vii Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. Table 6.10 Some Current Epigenomics Research Goals . 122 Table 6.11 Cancer Diagnostics Market .
26、124 Table 6.12 Some Major Companies And Their Activities 127 Figure 6.4 Publications on Epigenomics and Cardiovascular Disease . 129 Table 6.13 Takeda regional portfolio balance . 134 Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or
27、hereafter developed, in whole or in any part, is strictly prohibited. CHAPTER ONE Executive Summary THE BASIC SCIENCE OF EPIGENOMICS- BASIC LIFE SCIENCE R no FDA approval Activation of transposable element Genomic instability, transcriptional noise DNA hypomethylation De novo hypermethylation of CpG
28、 islands within gene promoters leading to silencing of tumor suppressors and cancer-associated genes Genomic and chromosomal instability, increased proliferation, growth advantage Hypermethylation suppressors could be used as chemotherapeutic drugs Loss of imprinting (LOI) Reactivation of silent all
29、eles, biallelic expression of imprinted genes Expansion of precursor cell population Monitoring stem cell capability Relaxation of X- chromosome inactivation Mechanisms is unknown but it appears to be age- related Altered gene dosage, growth advantage Monitoring age-related conditions Histone acetyl
30、ation Gain-of-function Activation of tumor promoting genes prodrug xylitol butyrate inhibits histone acetylation Histone deacetylation Silencing of tumor suppressor genes Genomic instability, increased proliferation Putative biomarkers Histone methylation Loss of heritable patterns of gene expressio
31、n (“cellular memory”) Genomic instability, growth advantage Putative biomarkers MicroRNAs (miRNAs) amplification in cancer Function as oncogenes Neoplastic transformation Treatment with Vit D) and/or epigenetic drugs (5-Aza, TSA) modulated the VDR mRNA expression in melanoma cell lines MicroRNAs (mi
32、RNAs) deletion in cancer Function as tumor suppressors. Neoplastic transformation Target for anticancer drugs 2012 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Cre
33、ative Commons Attribution license (). Table of Contents 3 Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. EPIGENOMICS AND DIAGNOSTICS The significance of epigenom
34、ics changes and their relationship to a variety of diseases is now well documented. As it is now possible to link epigenetic modifications to pathological states, this opens the possibility of developing effective epigenetic-based diagnostic tools. Epigenomics and Therapeutics: Markets by major dise
35、ases There is currently much discussion and uncertainty concerning the role of epigenetic variation in the origins and development of various cancers. But despite many unanswered questions, there are already FDA approved therapeutics on the market, and many are in clinical trials. In this section we
36、 will consider in some depth various cancers, and the epigenetic component of their origins, development and treatment. However, there are still basic and clinical science issues to be resolved, and it will be several years before we can anticipate the appearance of new pharmaceutical agents in the
37、marketplace. Cancer and neurological disorders are two extremely important areas of investigation in which epigenetic modification have been demonstrated to play critical roles. Other pathological states known or suspected to have an epigenetic basis include autoimmune dysfunction, cardiovascular di
38、sease, obesity and mental disorders. Whereas these disorders have excited much interest within the scientific community, there are many unanswered questions regarding the precise mechanisms by which epigenetic changes are reflected in a range of different pathological states. Companies active in Epi
39、genomics: Diagnostic companies 1. Enzo Life Sciences 2. Epigenomics 3. Epiontis 4. Exact Sciences 5. Illumina 6. Novus Executive Summary 4 Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter developed, in whole or in any part,
40、 is strictly prohibited. 7. Oncomethylome Sciences 8. Valirx (London) 9. Volition Singapore Therapeutic companies 1. Acetylon Pharmaceuticals 2. Acylin Therapeutics 3. CellCentric 4. Celgen 5. Cellzome (UK/DE) 6. Chroma Therapeutics 7. Constellation Pharmaceuticals 8. Eisai Co. Ltd. 9. Epitherapeuti
41、cs 10. Epizyme 11. Merck 12. MethylGene Inc. 13. Novartis 14. Orion 15. RaNA Therapeutics 16. Syndax 17. ValiRX (UK) Epigenomics research products supply companies 1. Active Motif 2. Diagenode 3. Epigentek Table of Contents 5 Copyright 2012 Kalorama Information Reproduction without prior written per
42、mission, in any media now in existence or hereafter developed, in whole or in any part, is strictly prohibited. 4. Life Technologies 5. Qiagen 6. Sigma-Aldrich 7. Zymo Research Products OUTLOOK FOR EPIGENOMICS R and (2) a huge market for potential epigenomics drugs and diagnostics. At present the ma
43、jor pharma companies are faced with a downward spiral of profitability. Epigenetic technologies represent an escape from this corrosive cycle of greater and greater expenditures and poorer and poorer yields. Kalorama believes that the gravity of the challenge and the risk from inaction are serious i
44、ssues that must be addressed by a concerted effort. Such action must represent a partnership between the commercial and academic research institutions, including universities, the federal government and private foundations. An effort of this proposed magnitude offers tremendous opportunities for com
45、panies at all levels; epigenetic diagnostic companies, therapeutic companies and companies that focus on tool-based technologies that supply the industry. Executive Summary 6 Copyright 2012 Kalorama Information Reproduction without prior written permission, in any media now in existence or hereafter
46、 developed, in whole or in any part, is strictly prohibited. CLINICAL OF MARKETS FOR EPIGENOMICS Prediction for growth within the epigenomics sector by analysts have been extremely optimistic Our own model is that an epigenomic drug market of 800 million dollars could grow to 8 billion in six years,
47、 and that the diagnostic market for epigenomics could grow from 18 million in 2010 to 610 million in four years based on new drugs and tests. The reasons behind these market assessments are detailed in chapter six. Kalorama ordinarily follows a more onservative assessment of such parameters, but the
48、 research presented here forces the conclusion that growth within this sector will be explosive in the coming 5-10 years. While exigencies within the market, a severe and prolonged downturn in the world economy, unforeseen and drastic setbacks in clinical trials all are negative risk factors, progre
49、ss to date in epigenetic technologies leads to Kaloramas string endorsement of these overall numbers. From the standpoint of disease categories, Kalorama believes that the major part of this growth in the next five years will occur in the oncology sector. This conclusion reflects the demand of cancerous conditions and the absence in so many instances of effective therapies. Furthermore, thorough going epigenetic-based disease models have yet to be developed for neurological, imm