Innovations In Epigenetics: Advances in Technologies, Diagnostics & Therapeutics

The study of epigenetics - changes in gene expression that occur without a change in a cell’s DNA code – is becoming increasingly important as scientists explore how internal and external factors trigger cellular dysfunction and influence disease progression. Three main mechanisms - DNA methylation, histone modifications and changes in non-coding RNA - have been elucidated in epigenetics. Each in its own way may provide the industry with a greater understanding into the underlying mechanism of diseases, act as a potential source for biomarkers of disease and provide new targets for therapeutic intervention.

Besides everyday DNA analytical tools, epigenetic researchers have needed to adopt more complex technologies such as chromatin immunoprecipitation (ChIP) and DNA methylation methodologies as well as develop analytical tools to decipher the vast amount of epigenetic information. Advances in these technologies should enable epigenetic research to reduce cost and increase sample throughput making it more commercially attractive in the industry to discover biomarkers and validate novel epigenetic targets for diagnostic and pharmacological development.

Epigenetic medicine has arrived. The market is worth over $560 million derived from the sale of three anticancer products which target two epigenetic pathways - DNA methyltransferase (DNMT) and histone deacteylase (HDAC) – and around thirty epigenetic drugs are under development from more than a dozen biotechnology companies. These drugs focus mainly on the treatment of cancer, neurodegenerative and infectious diseases although research is underway to explore the role for epigenetics in cardiovascular, metabolic, ocular and other diseases. Whilst this market is still in its infancy KOLs believe it is on the cusp of a revolution, one which could change how patients are diagnosed and treated in the future.

Key features of this report

• Identify leading companies at the forefront of epigenetic research who will drive the market to develop a new generation of epigenetic therapies and diagnostics.

• Provide case studies of these leading companies developing epigenetic therapies to treat cancer, neurodegenerative and infectious diseases.

• Analyze the key trends and issues confronting the development of epigenetic therapies.

• Review the alliances, mergers, acquisitions and business strategies adopted by biotechs and big pharma to capitalize on the latest epigenetic developments.

Scope of this report

• Identify the companies leading the field in epigenetic research across a range of therapeutic areas

• Review their business strategies and the development of their epigenetic programs

• Learn more about the latest developments in epigenetic research and how non-coding RNAs may open up another Pandora's box for epigenetic research.

• Identify innovative pharmaceutical companies and discover the strategies they are adopting to tap into the epigenetic potential both as biomarkers of disease and targets for therapeutic intervention

Key Market Issues

• Declining industry productivity: It is a well documented fact that productivity in the pharma industry has declined during the past 15 years. The identification of new biomarkers of disease could aide the R&D process and support the preclinical and clinical development of small molecule therapeutics.

• Innovative new drug classes: The identification of underlying mechanisms of diseases could identify new target
for small molecule therapeutic intervention that may be used alone or in combination with traditional therapies to
extend their usage.

Key findings from this report

• New epigenetic therapies have entered the market. The first medicines were approved in 2006 for the treatment of cancer and a host of new small molecule therapies are now under development which are more selective and target different classes of chromatin modifying enzymes enabling a more targeted approach to treatment.

• The ability of innovative companies to generate intellectual property is a key driver for the sector as the market become more competitive in this new area of science. The unraveling of the human epigenome will be the first step in identifying new epigenetic markers which may have potential as biomarkers an area of considerable interest for the pharmaceutical industry at the present time.

Key questions answered

• Which companies are the market leaders in the epigenetics industry, identified through therapeutic areas (cancer, infectious diseases, neurodegenerative diseases, metabolic, cardiovascular, ophthalmic, other diseases) and recent alliances with the pharmaceutical companies?

• What are the key products of these companies and how do they exemplify the future direction of the epigenetic therapies?

• How is the pharmaceutical industry approaching the need for new targeted epigenetic therapies and what strategies are they taking?

Companies mentioned in the report

4AC Ag, AstraZeneca, Aton Pharma, Celgene Corporation, CellCentric, Celldex Corporation, CuraGen Corporation, Curis, Chroma Therapeutics, Constellation Pharmaceuticals, Eisai, Epigenomics AG EnVivo Pharmaceuticals, Epizyme, EpiTherapeutics Aps, Fujisawa, GlaxoSmithKline, Gloucester Pharmaceuticals, Isis Pharma, Johnson Johnson, Merck & Co, MethylGene, MGI Pharma, Mirna Therapeutics, miRgen Therapeutics, Novarits, Nycomed, Otsuka Pharmaceuticals, OncoMethylome,
Orion Genomics, , Pharmacyclics, Pfizer, Progen Pharmaceuticals, Promocell, Qiagen, Repligen Corporation, Regulus Therapeutics, Santaris Pharma, Servier, Shinogi, Stem Cell Technologies, Syrrx, SuperGen, Syndax Pharmaceuticals, Taiho Pharmaceuticals, Takeda and TopoTarget.

Report Highlights

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Table of Contents
Innovations in Epigenetics
Executive summary 10
Introduction 10
Application in R&D & technological advances 10
Exploring new therapeutic targets 11
Epigenetic market, leading companies & pharmaceutical strategies 12
The future of epigenetics 13
Chapter 1 Introduction 16
What is epigenetics? 17
Epigenetics and phenotypes 19
Epigenetics a new biological paradigm 19
Epigenetics, genetics, genomics & pharmacogenomics 20
Molecular mechanisms associated with epigenetics 22
DNA methylation 22
Histone modifications 23
Nucleosome remodelling 23
Non-coding RNA 24
X chromosome inactivation 24
Gene imprinting 24
RNA interference 24
Epigenetic basis of disease 25
Epigenetic syndromes 25
Angelmann syndrome 25
Beckwith-Wiedemann syndrome 26
Prader-Willi syndrome 26
Why is epigenetics of interest to the pharmaceutical industry? 27
Biomarker discovery & diagnostics 28
Novel small molecule epigenetic therapeutics 28
Novel antisense therapeutics 28
Stem cells & regenerative medicines 29
Conclusions 29
Chapter 2 Application in R&D & technological advances 32
The application of epigenetics in drug R&D 33
DNA methylation biomarkers 34
Histone modification biomarkers 35
Technological advances in epigenetics 35
Chromatin immunoprecipitation 36
DNA methylation technologies 38
Non-coding RNA technologies 43
Bioinformatic modeling 43
Conclusions 44
Chapter 3 Exploring new therapeutic targets 48
Potential new therapeutic targets 49
Epigenetics in cancer 50
DNA methyltransferase & DNMT inhibitors 52
Case study: Vidaza (Celgene Corporation) & Dacogen (Eisai /J&J) 53
Case study: Zebularine a research tool 56
Histone acetylase (HAT) and histone deacetylase (HDAC) 59
Case study: Zolinza (Merck & Co.) 61
Case study: MGCD0103 (MethylGene/Taiho Pharmaceutical) 62
Case study: PCI-24781 (Pharmacyclics/Servier) 63
Histone demethylases and histone methyltranserases 65
Case study: PG11144 & PG11047 (Progen Pharmaceuticals) 66
Potential epigenetic based diagnostics 67
Diagnostic DNA methylation cancer biomarkers 67
Case study: Epi proColon (Epigenomics AG) 69
The next generation of epigenetic cancer biomarkers 71
Epigenetics in neurological disorders 72
Case study: EVP-0334 (EnVivo Pharmaceuticals) 73
Epigenetics in infectious diseases 75
Case study: MGCD290 (MethylGene) 75
Case study: siRNA targeting HIV-1 (Kevin Morris, Scripps, La Jolla) 76
Epigenetics in metabolic disorders 78
Epigenetics in cardiovascular disease 81
Epigenetics in ocular disorders 83
Case study: Kinase inhibitors (Otsuka Pharmaceutical/MethylGene) 84
Case study: Kinase inhibitors/S-adenosyl methionine (SAM) (Epizyme). 85
Conclusions 86
Chapter 4 Epigenetic market, leading companies & pharmaceutical strategies 90
Epigenetic market 91
Epigenetic therapeutic revenues: Now and the future 92
Leading epigenetic companies 93
4SC AG, Planegg-Martinsried, Germany 94
Celgene Corporation, Summit, New Jersey 95
Curis Inc, Cambridge, MA 96
Chroma Therapeutics Ltd, Oxon, UK 98
Constellation Pharmaceuticals, Cambridge, MA 99
EnVivo Pharmaceuticals, Watertown, MA 100
EpiTherapeutics Aps, Copenhagen, Denmark 101
Epizyme, Cambridge, MA 101
Gloucester Pharmaceuticals, Cambridge, MA 103
MethylGene, Inc. Montreal, Québec 104
Pharmacyclics, Sunnyvale, CA 106
Progen Pharmaceuticals, Brisbane, Australia 107
Repligen Corporation, Waltham, MA 108
SuperGen, Dublin, CA 109
Syndax Pharmaceuticals, Waltham, MA 112
TopoTarget, Copenhagen, Denmark 113
Summary of epigenetic-based companies 114
Recent alliances, mergers & acquisitions in epigenetics 115
Pharmaceutical strategies in epigenetics 118
GlaxoSmithKline, Middlesex, UK 118
Novartis, Basel, Switzerland 119
Merck & Co., Whitehouse, NJ 121
Eisai Corporation of North America, NJ 122
Takeda, Osaka, Japan 123
Overall conclusions 123
Chapter 5 The future of epigenetics 126
The future of epigenetics 127
Epigenetic consortia; unraveling the human epigenome 128
NIH’s Roadmap Epigenomics Program initiative 128
European Epigenome Network of Excellence 130
Human Epigenome Consortium 130
KOLs in epigenetics 131
John Mattick, Institute for Molecular Bioscience, University of Queensland,
Australia 132
Overview 132
Technology 133
Applications 133
Future 134
Kevin Morris, Scripps Institue, La Jolla, CA 134
Overview 134
Technology 135
Applications 135
Future 136
Monika Lachner, Max-Planck Institute of Immunobiology, Department of
Epigenetics, Freiburg, Germany 136
Overview 136
Technology 136
Applications 137
Future 137
Johnathan Whetstine, Department of Medicine, Massachusetts General
Hospital Cancer Center 137
Overview 138
Technology 138
Applications 138
Future 139
Peter Fraser, Head, Senior Fellow of the Medical Research Council, UK, The
Babraham Institute, Cambridge 139
Overview 139
Technology 140
Applications 140
Future 141
Summary of KOLs commentary 141
Challenges 142
Fundamental research 142
Technological demands 142
Financial constraints 143
Intellectual property 144
Opportunities 144
Biomarker discovery & diagnostics 144
Therapeutic intervention 145
Regenerative medicines 145
Conclusions 146
Chapter 6 Appendices 150
Glossary 150
Acknowledgements 156
Index 157
Index 157
Bibliography 159
Endnotes 165



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Table 2.1: DNA methylation PCR methods 40
Table 2.2: Techniques to analyze DNA methylation 41
Table 3.3: Examples of DNMT inhibitors: potential anticancer agents targeting epigenetic pathways 54
Table 3.4: Examples of DNMT inhibitor research tools 55
Table 3.5: HDAC inhibitors: potential anticancer agents targeting epigenetic pathways 57
Table 3.6: Examples of HDAC inhibitor research tools 59
Table 3.7: Histone modification and their effect on gene expression 60
Table 3.8: Safety profiles of PCI-24781 rivals 64
Table 3.9: DNA methylation sites associated with cancers 67
Table 3.10: Validated and hypothetic miRNA targets for diabetes & obesity 81
Table 4.11: Epigenetic therapeutic revenues ($m), 2009-2020 93
Table 4.12: Preliminary clinical data for Pharmacyclics PCI-24781 106
Table 4.13: Recent alliances, acquisitions and mergers in the epigenetic arena 117
Table 5.14: NIH Epigenetic Roadmap – funded epigenetic projects 129
Figure 1.1: Timeline of epigenetics study 18
Figure 1.2: Schematic of chromatin structure 22
Figure 1.3: Schematic of epigenetic mechanisms associated with health and disease 23
Figure 1.4: Epigenetic applications by the pharma industry 27
Figure 2.5: Epigenetics in the drug discovery & development process 34
Figure 2.6: Schematic of key technologies used in epigenetics 36
Figure 2.7: Schematic of ChIP technology 37
Figure 2.8: Epigenomics AG methylation specific PCR (MSP) methods 42
Figure 3.9: DNA methylation targets for epigenetic cancer therapies 51
Figure 3.10: Mechanism of action of HAT and HDAC 61
Figure 3.11: Epi proColon high throughput colorectal epigenetic test 70
Figure 3.12: Competitive pricing of Epi proColon 71
Figure 3.13: EnVivo’s HDAC project screening cascade 74
Figure 3.14: Agouti mice and epigenetic manipulation 79
Figure 3.15: Epizyme’s rational design of small molecule HMT inhibitors 85
Figure 4.16: Epigenetic therapies: product class and developmental phase 91
Figure 4.17: Epigenetic therapies: therapy target and developmental phase 92
Figure 4.18: CUDU-101 structure & design: combining multiple pharmacophores 97
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