Innovations In Epigenetics: Advances In Technologies, Diagnostics & Therapeutics-Aarkstore Enterprise

Three main mechanisms - DNA methylation, histone				Figure 1.4: Epigenetic applications by the pharma
modifications and changes in non-coding RNA - have				industry 27
been elucidated in epigenetics. Each in its own way				Figure 2.5: Epigenetics in the drug discovery &
may provide the industry with a greater				development process 34
understanding into the underlying mechanism of				Figure 2.6: Schematic of key technologies used in
diseases, act as a potential source for biomarkers of				epigenetics 36
disease and provide new targets for therapeutic				Figure 2.7: Schematic of ChIP technology 37
intervention.				Figure 2.8: Epigenomics AG methylation specific PCR
Besides everyday DNA analytical tools, epigenetic				(MSP) methods 42
researchers have needed to adopt more complex				Figure 3.9: DNA methylation targets for epigenetic
technologies such as chromatin immunoprecipitation				cancer therapies 51
(ChIP) and DNA methylation methodologies as well as				Figure 3.10: Mechanism of action of HAT and HDAC
develop analytical tools to decipher the vast amount				61
of epigenetic information. Advances in these				Figure 3.11: Epi proColon high throughput colorectal
technologies should enable epigenetic research to				epigenetic test 70
reduce cost and increase sample throughput making it				Figure 3.12: Competitive pricing of Epi proColon 71
more commercially attractive in the industry to				Figure 3.13: EnVivo's HDAC project screening cascade
discover biomarkers and validate novel epigenetic				74
targets for diagnostic and pharmacological				Figure 3.14: Agouti mice and epigenetic manipulation
development.				79
Epigenetic medicine has arrived. The market is worth				Figure 3.15: Epizyme's rational design of small molecule
over $560 million derived from the sale of three				HMT inhibitors 85
anticancer products which target two epigenetic				Figure 4.16: Epigenetic therapies: product class and
pathways - DNA methyltransferase (DNMT) and				developmental phase 91
histone deacteylase (HDAC) – and around thirty				Figure 4.17: Epigenetic therapies: therapy target and
epigenetic drugs are under development from more				developmental phase 92
than a dozen biotechnology companies. These drugs				Figure 4.18: CUDU-101 structure & design:
focus mainly on the treatment of cancer,				combining multiple pharmacophores 97
neurodegenerative and infectious diseases although				List of Tables
research is underway to explore the role for				Table 2.1: DNA methylation PCR methods 40
epigenetics in cardiovascular, metabolic, ocular and				Table 2.2: Techniques to analyze DNA methylation 41
other diseases. Whilst this market is still in its infancy				Table 3.3: Examples of DNMT inhibitors: potential
KOLs believe it is on the cusp of a revolution, one				anticancer agents targeting epigenetic pathways 54
which could change how patients are diagnosed and				Table 3.4: Examples of DNMT inhibitor research tools
treated in the future.				55
Key features of this report				Table 3.5: HDAC inhibitors: potential anticancer agents
• Identify leading companies at the forefront of				targeting epigenetic pathways 57
epigenetic research who will drive the market to				Table 3.6: Examples of HDAC inhibitor research tools
develop a new generation of epigenetic therapies and				59
diagnostics.				Table 3.7: Histone modification and their effect on
• Provide case studies of these leading companies				gene expression 60
developing epigenetic therapies to treat cancer,				Table 3.8: Safety profiles of PCI-24781 rivals 64
neurodegenerative and infectious diseases.				Table 3.9: DNA methylation sites associated with
• Analyze the key trends and issues confronting				cancers 67
the development of epigenetic therapies.				Table 3.10: Validated and hypothetic miRNA targets
• Review the alliances, mergers, acquisitions and				for diabetes & obesity 81
business strategies adopted by biotechs and big				Table 4.11: Epigenetic therapeutic revenues ($m),
pharma to capitalize on the latest epigenetic				2009-2020 93
developments.				Table 4.12: Preliminary clinical data for Pharmacyclics
Scope of this report				PCI-24781 106
• Identify the companies leading the field in				Table 4.13: Recent alliances, acquisitions and mergers
epigenetic research across a range of therapeutic				in the epigenetic arena 117
areas				Table 5.14: NIH Epigenetic Roadmap – funded
• Review their business strategies and the				epigenetic projects 129
development of their epigenetic programs
• Learn more about the latest developments in				Table of Contents
epigenetic research and how non-coding RNAs may				Innovations in Epigenetics
open up another Pandora's box for epigenetic				Executive summary 10
research.				Introduction 10
• Identify innovative pharmaceutical companies				Application in R&D & technological advances
and discover the strategies they are adopting to tap				10
into the epigenetic potential both as biomarkers of				Exploring new therapeutic targets 11
disease and targets for therapeutic intervention				Epigenetic market, leading companies &
				pharmaceutical strategies 12
Key Market Issues				The future of epigenetics 13
• Declining industry productivity: It is a well				Chapter 1 Introduction 16
documented fact that productivity in the pharma				What is epigenetics? 17
industry has declined during the past 15 years. The				Epigenetics and phenotypes 19
identification of new biomarkers of disease could aide				Epigenetics a new biological paradigm 19
the R&D process and support the preclinical and				Epigenetics, genetics, genomics &
clinical development of small molecule therapeutics.				pharmacogenomics 20
• Innovative new drug classes: The identification				Molecular mechanisms associated with epigenetics 22
of underlying mechanisms of diseases could identify				DNA methylation 22
new targetfor small molecule therapeutic intervention				Histone modifications 23
that may be used alone or in combination with				Nucleosome remodelling 23
traditional therapies toextend their usage.				Non-coding RNA 24
				X chromosome inactivation 24
Key findings from this report				Gene imprinting 24
• New epigenetic therapies have entered the				RNA interference 24
market. The first medicines were approved in 2006				Epigenetic basis of disease 25
for the treatment of cancer and a host of new small				Epigenetic syndromes 25
molecule therapies are now under development which				Angelmann syndrome 25
are more selective and target different classes of				Beckwith-Wiedemann syndrome 26
chromatin modifying enzymes enabling a more				Prader-Willi syndrome 26
targeted approach to treatment.				Why is epigenetics of interest to the pharmaceutical
• The ability of innovative companies to generate				industry? 27
intellectual property is a key driver for the sector as				Biomarker discovery & diagnostics 28
the market become more competitive in this new				Novel small molecule epigenetic therapeutics 28
area of science. The unraveling of the human				Novel antisense therapeutics 28
epigenome will be the first step in identifying new				Stem cells & regenerative medicines 29
epigenetic markers which may have potential as				Conclusions 29
biomarkers an area of considerable interest for the				Chapter 2 Application in R&D &
pharmaceutical industry at the present time.				technological advances 32
Key questions answered				The application of epigenetics in drug R&D 33
• Which companies are the market leaders in the				DNA methylation biomarkers 34
epigenetics industry, identified through therapeutic				Histone modification biomarkers 35
areas (cancer, infectious diseases, neurodegenerative				Technological advances in epigenetics 35
diseases, metabolic, cardiovascular, ophthalmic, other				Chromatin immunoprecipitation 36
diseases) and recent alliances with the pharmaceutical				DNA methylation technologies 38
companies?				Non-coding RNA technologies 43
• What are the key products of these companies				Bioinformatic modeling 43
and how do they exemplify the future direction of				Conclusions 44
the epigenetic therapies?				Chapter 3 Exploring new therapeutic targets 48
• How is the pharmaceutical industry approaching				Potential new therapeutic targets 49
the need for new targeted epigenetic therapies and				Epigenetics in cancer 50
what strategies are they taking?				DNA methyltransferase & DNMT inhibitors 52
				Case study: Vidaza (Celgene Corporation) &
				Dacogen (Eisai /J&J) 53
Table of Contents :				Case study: Zebularine a research tool 56
Table of Contents				Histone acetylase (HAT) and histone deacetylase
Innovations in Epigenetics				(HDAC) 59
Executive summary 10				Case study: Zolinza (Merck & Co.) 61
Introduction 10				Case study: MGCD0103 (MethylGene/Taiho
Application in R&D & technological advances				Pharmaceutical) 62
10				Case study: PCI-24781 (Pharmacyclics/Servier) 63
Exploring new therapeutic targets 11				Histone demethylases and histone methyltranserases
Epigenetic market, leading companies &				65
pharmaceutical strategies 12				Case study: PG11144 & PG11047 (Progen
The future of epigenetics 13				Pharmaceuticals) 66
Chapter 1 Introduction 16				Potential epigenetic based diagnostics 67
What is epigenetics? 17				Diagnostic DNA methylation cancer biomarkers 67
Epigenetics and phenotypes 19				Case study: Epi proColon (Epigenomics AG) 69
Epigenetics a new biological paradigm 19				The next generation of epigenetic cancer biomarkers
Epigenetics, genetics, genomics &				71
pharmacogenomics 20				Epigenetics in neurological disorders 72
Molecular mechanisms associated with epigenetics 22				Case study: EVP-0334 (EnVivo Pharmaceuticals) 73
DNA methylation 22				Epigenetics in infectious diseases 75
Histone modifications 23				Case study: MGCD290 (MethylGene) 75
Nucleosome remodelling 23				Case study: siRNA targeting HIV-1 (Kevin Morris,
Non-coding RNA 24				Scripps, La Jolla) 76
X chromosome inactivation 24				Epigenetics in metabolic disorders 78
Gene imprinting 24				Epigenetics in cardiovascular disease 81
RNA interference 24				Epigenetics in ocular disorders 83
Epigenetic basis of disease 25				Case study: Kinase inhibitors (Otsuka Pharmaceutical
Epigenetic syndromes 25				MethylGene) 84
Angelmann syndrome 25				Case study: Kinase inhibitors/S-adenosyl methionine
Beckwith-Wiedemann syndrome 26				(SAM) (Epizyme). 85
Prader-Willi syndrome 26				Conclusions 86
Why is epigenetics of interest to the pharmaceutical				Chapter 4 Epigenetic market, leading companies
industry? 27				& pharmaceutical strategies 90
Biomarker discovery & diagnostics 28				Epigenetic market 91
Novel small molecule epigenetic therapeutics 28				Epigenetic therapeutic revenues: Now and the future
Novel antisense therapeutics 28				92
Stem cells & regenerative medicines 29				Leading epigenetic companies 93
Conclusions 29				4SC AG, Planegg-Martinsried, Germany 94
Chapter 2 Application in R&D &				Celgene Corporation, Summit, New Jersey 95
technological advances 32				Curis Inc, Cambridge, MA 96
The application of epigenetics in drug R&D 33				Chroma Therapeutics Ltd, Oxon, UK 98
DNA methylation biomarkers 34				Constellation Pharmaceuticals, Cambridge, MA 99
Histone modification biomarkers 35				EnVivo Pharmaceuticals, Watertown, MA 100
Technological advances in epigenetics 35				EpiTherapeutics Aps, Copenhagen, Denmark 101
Chromatin immunoprecipitation 36				Epizyme, Cambridge, MA 101
DNA methylation technologies 38				Gloucester Pharmaceuticals, Cambridge, MA 103
Non-coding RNA technologies 43				MethylGene, Inc. Montreal, Québec 104
Bioinformatic modeling 43				Pharmacyclics, Sunnyvale, CA 106
Conclusions 44				Progen Pharmaceuticals, Brisbane, Australia 107
Chapter 3 Exploring new therapeutic targets 48				Repligen Corporation, Waltham, MA 108
Potential new therapeutic targets 49				SuperGen, Dublin, CA 109
Epigenetics in cancer 50				Syndax Pharmaceuticals, Waltham, MA 112
DNA methyltransferase & DNMT inhibitors 52				TopoTarget, Copenhagen, Denmark 113
Case study: Vidaza (Celgene Corporation) &				Summary of epigenetic-based companies 114
Dacogen (Eisai /J&J) 53				Recent alliances, mergers & acquisitions in
Case study: Zebularine a research tool 56				epigenetics 115
Histone acetylase (HAT) and histone deacetylase				Pharmaceutical strategies in epigenetics 118
(HDAC) 59				GlaxoSmithKline, Middlesex, UK 118
Case study: Zolinza (Merck & Co.) 61				Novartis, Basel, Switzerland 119
Case study: MGCD0103 (MethylGene/Taiho				Merck & Co., Whitehouse, NJ 121
Pharmaceutical) 62				Eisai Corporation of North America, NJ 122
Case study: PCI-24781 (Pharmacyclics/Servier) 63				Takeda, Osaka, Japan 123
Histone demethylases and histone methyltranserases				Overall conclusions 123
65				Chapter 5 The future of epigenetics 126
Case study: PG11144 & PG11047 (Progen				The future of epigenetics 127
Pharmaceuticals) 66				Epigenetic consortia; unraveling the human epigenome
Potential epigenetic based diagnostics 67				128
Diagnostic DNA methylation cancer biomarkers 67				NIH's Roadmap Epigenomics Program initiative 128
Case study: Epi proColon (Epigenomics AG) 69				European Epigenome Network of Excellence 130
The next generation of epigenetic cancer biomarkers				Human Epigenome Consortium 130
71				KOLs in epigenetics 131
Epigenetics in neurological disorders 72				John Mattick, Institute for Molecular Bioscience,
Case study: EVP-0334 (EnVivo Pharmaceuticals) 73				University of Queensland,
Epigenetics in infectious diseases 75				Australia 132
Case study: MGCD290 (MethylGene) 75				Overview 132
Case study: siRNA targeting HIV-1 (Kevin Morris,				Technology 133
Scripps, La Jolla) 76				Applications 133
Epigenetics in metabolic disorders 78				Future 134
Epigenetics in cardiovascular disease 81				Kevin Morris, Scripps Institue, La Jolla, CA 134
Epigenetics in ocular disorders 83				Overview 134
Case study: Kinase inhibitors (Otsuka Pharmaceutical				Technology 135
MethylGene) 84				Applications 135
Case study: Kinase inhibitors/S-adenosyl methionine				Future 136
(SAM) (Epizyme). 85				Monika Lachner, Max-Planck Institute of
Conclusions 86				Immunobiology, Department of
Chapter 4 Epigenetic market, leading companies				Epigenetics, Freiburg, Germany 136
& pharmaceutical strategies 90				Overview 136
Epigenetic market 91				Technology 136
Epigenetic therapeutic revenues: Now and the future				Applications 137
92				Future 137
Leading epigenetic companies 93				Johnathan Whetstine, Department of Medicine,
4SC AG, Planegg-Martinsried, Germany 94				Massachusetts General
Celgene Corporation, Summit, New Jersey 95				Hospital Cancer Center 137
Curis Inc, Cambridge, MA 96				Overview 138
Chroma Therapeutics Ltd, Oxon, UK 98				Technology 138
Constellation Pharmaceuticals, Cambridge, MA 99				Applications 138
EnVivo Pharmaceuticals, Watertown, MA 100				Future 139
EpiTherapeutics Aps, Copenhagen, Denmark 101				Peter Fraser, Head, Senior Fellow of the Medical
Epizyme, Cambridge, MA 101				Research Council, UK, The
Gloucester Pharmaceuticals, Cambridge, MA 103				Babraham Institute, Cambridge 139
MethylGene, Inc. Montreal, Québec 104				Overview 139
Pharmacyclics, Sunnyvale, CA 106				Technology 140
Progen Pharmaceuticals, Brisbane, Australia 107				Applications 140
Repligen Corporation, Waltham, MA 108				Future 141
SuperGen, Dublin, CA 109				Summary of KOLs commentary 141
Syndax Pharmaceuticals, Waltham, MA 112				Challenges 142
TopoTarget, Copenhagen, Denmark 113				Fundamental research 142
Summary of epigenetic-based companies 114				Technological demands 142
Recent alliances, mergers & acquisitions in				Financial constraints 143
epigenetics 115				Intellectual property 144
Pharmaceutical strategies in epigenetics 118				Opportunities 144
GlaxoSmithKline, Middlesex, UK 118				Biomarker discovery & diagnostics 144
Novartis, Basel, Switzerland 119				Therapeutic intervention 145
Merck & Co., Whitehouse, NJ 121				Regenerative medicines 145
Eisai Corporation of North America, NJ 122				Conclusions 146
Takeda, Osaka, Japan 123				Chapter 6 Appendices 150
Overall conclusions 123				Glossary 150
Chapter 5 The future of epigenetics 126				Acknowledgements 156
The future of epigenetics 127				Index 157
Epigenetic consortia; unraveling the human epigenome				Index 157
128				Bibliography 159
NIH's Roadmap Epigenomics Program initiative 128				Endnotes 165
European Epigenome Network of Excellence 130				List of Figures
Human Epigenome Consortium 130				Figure 1.1: Timeline of epigenetics study 18
KOLs in epigenetics 131				Figure 1.2: Schematic of chromatin structure 22
John Mattick, Institute for Molecular Bioscience,				Figure 1.3: Schematic of epigenetic mechanisms
University of Queensland,				associated with health and disease 23
Australia 132				Figure 1.4: Epigenetic applications by the pharma
Overview 132				industry 27
Technology 133				Figure 2.5: Epigenetics in the drug discovery &
Applications 133				development process 34
Future 134				Figure 2.6: Schematic of key technologies used in
Kevin Morris, Scripps Institue, La Jolla, CA 134				epigenetics 36
Overview 134				Figure 2.7: Schematic of ChIP technology 37
Technology 135				Figure 2.8: Epigenomics AG methylation specific PCR
Applications 135				(MSP) methods 42
Future 136				Figure 3.9: DNA methylation targets for epigenetic
Monika Lachner, Max-Planck Institute of				cancer therapies 51
Immunobiology, Department of				Figure 3.10: Mechanism of action of HAT and HDAC
Epigenetics, Freiburg, Germany 136				61
Overview 136				Figure 3.11: Epi proColon high throughput colorectal
Technology 136				epigenetic test 70
Applications 137				Figure 3.12: Competitive pricing of Epi proColon 71
Future 137				Figure 3.13: EnVivo's HDAC project screening cascade
Johnathan Whetstine, Department of Medicine,				74
Massachusetts General				Figure 3.14: Agouti mice and epigenetic manipulation
Hospital Cancer Center 137				79
Overview 138				Figure 3.15: Epizyme's rational design of small molecule
Technology 138				HMT inhibitors 85
Applications 138				Figure 4.16: Epigenetic therapies: product class and
Future 139				developmental phase 91
Peter Fraser, Head, Senior Fellow of the Medical				Figure 4.17: Epigenetic therapies: therapy target and
Research Council, UK, The				developmental phase 92
Babraham Institute, Cambridge 139				Figure 4.18: CUDU-101 structure & design:
Overview 139				combining multiple pharmacophores 97
Technology 140				List of Tables
Applications 140				Table 2.1: DNA methylation PCR methods 40
Future 141				Table 2.2: Techniques to analyze DNA methylation 41
Summary of KOLs commentary 141				Table 3.3: Examples of DNMT inhibitors: potential
Challenges 142				anticancer agents targeting epigenetic pathways 54
Fundamental research 142				Table 3.4: Examples of DNMT inhibitor research tools
Technological demands 142				55
Financial constraints 143				Table 3.5: HDAC inhibitors: potential anticancer agents
Intellectual property 144				targeting epigenetic pathways 57
Opportunities 144				Table 3.6: Examples of HDAC inhibitor research tools
Biomarker discovery & diagnostics 144				59
Therapeutic intervention 145				Table 3.7: Histone modification and their effect on
Regenerative medicines 145				gene expression 60
Conclusions 146				Table 3.8: Safety profiles of PCI-24781 rivals 64
Chapter 6 Appendices 150				Table 3.9: DNA methylation sites associated with
Glossary 150				cancers 67
Acknowledgements 156				Table 3.10: Validated and hypothetic miRNA targets
Index 157				for diabetes & obesity 81
Index 157				Table 4.11: Epigenetic therapeutic revenues ($m),
Bibliography 159				2009-2020 93
Endnotes 165				Table 4.12: Preliminary clinical data for Pharmacyclics
List of Figures				PCI-24781 106
Figure 1.1: Timeline of epigenetics study 18				Table 4.13: Recent alliances, acquisitions and mergers
Figure 1.2: Schematic of chromatin structure 22				in the epigenetic arena 117
Figure 1.3: Schematic of epigenetic mechanisms				Table 5.
associated with health and disease 23

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Innovations In Epigenetics: Advances In Technologies, Diagnostics & Therapeutics-Aarkstore Enterprise