SPI Infoamtion

Table of Contents

Executive summary

Introduction
Application in R&D & technological advances
Exploring new therapeutic targets
Epigenetic market, leading companies & pharmaceutical strategies
The future of epigenetics

Chapter 1 Introduction

What is epigenetics?

Epigenetics and phenotypes
Epigenetics a new biological paradigm

Epigenetics, genetics, genomics & pharmacogenomics
Molecular mechanisms associated with epigenetics

DNA methylation
Histone modifications
Nucleosome remodelling
Non-coding RNA
X chromosome inactivation
Gene imprinting
RNA interference

Epigenetic basis of disease

Epigenetic syndromes

Angelmann syndrome
Beckwith-Wiedemann syndrome
Prader-Willi syndrome

Why is epigenetics of interest to the pharmaceutical industry?

Biomarker discovery & diagnostics
Novel small molecule epigenetic therapeutics
Novel antisense therapeutics
Stem cells & regenerative medicines

Conclusions

Chapter 2 Application in R&D & technological advances

The application of epigenetics in drug R&D

DNA methylation biomarkers
Histone modification biomarkers

Technological advances in epigenetics

Chromatin immunoprecipitation
DNA methylation technologies
Non-coding RNA technologies
Bioinformatic modeling

Conclusions

Chapter 3 Exploring new therapeutic targets

Potential new therapeutic targets
Epigenetics in cancer

DNA methyltransferase & DNMT inhibitors

Case study: Vidaza (Celgene Corporation) & Dacogen (Eisai /J&J)
Case study: Zebularine a research tool

Histone acetylase (HAT) and histone deacetylase (HDAC)

Case study: Zolinza (Merck & Co.)
Case study: MGCD0103 (MethylGene/Taiho Pharmaceutical)
Case study: PCI-24781 (Pharmacyclics/Servier)

Histone demethylases and histone methyltranserases

Case study: PG11144 & PG11047 (Progen Pharmaceuticals)

Potential epigenetic based diagnostics

Diagnostic DNA methylation cancer biomarkers

Case study: Epi proColon (Epigenomics AG)

The next generation of epigenetic cancer biomarkers

Epigenetics in neurological disorders

Case study: EVP-0334 (EnVivo Pharmaceuticals)

Epigenetics in infectious diseases

Case study: MGCD290 (MethylGene)
Case study: siRNA targeting HIV-1 (Kevin Morris, Scripps, La Jolla)

Epigenetics in metabolic disorders
Epigenetics in cardiovascular disease
Epigenetics in ocular disorders

Case study: Kinase inhibitors (Otsuka Pharmaceutical/MethylGene)
Case study: Kinase inhibitors/S-adenosyl methionine (SAM) (Epizyme).

Conclusions

Chapter 4 Epigenetic market, leading companies & pharmaceutical strategies

Epigenetic market

Epigenetic therapeutic revenues: Now and the future

Leading epigenetic companies

4SC AG, Planegg-Martinsried, Germany
Celgene Corporation, Summit, New Jersey
Curis Inc, Cambridge, MA
Chroma Therapeutics Ltd, Oxon, UK
Constellation Pharmaceuticals, Cambridge, MA
EnVivo Pharmaceuticals, Watertown, MA
EpiTherapeutics Aps, Copenhagen, Denmark
Epizyme, Cambridge, MA
Gloucester Pharmaceuticals, Cambridge, MA
MethylGene, Inc. Montreal, Qu?bec
Pharmacyclics, Sunnyvale, CA
Progen Pharmaceuticals, Brisbane, Australia
Repligen Corporation, Waltham, MA
SuperGen, Dublin, CA
Syndax Pharmaceuticals, Waltham, MA
TopoTarget, Copenhagen, Denmark

Summary of epigenetic-based companies
Recent alliances, mergers & acquisitions in epigenetics
Pharmaceutical strategies in epigenetics

GlaxoSmithKline, Middlesex, UK
Novartis, Basel, Switzerland
Merck & Co., Whitehouse, NJ
Eisai Corporation of North America, NJ
Takeda, Osaka, Japan

Overall conclusions

Chapter 5 The future of epigenetics

The future of epigenetics
Epigenetic consortia; unraveling the human epigenome

NIH's Roadmap Epigenomics Program initiative
European Epigenome Network of Excellence
Human Epigenome Consortium

KOLs in epigenetics

John Mattick, Institute for Molecular Bioscience, University of Queensland, Australia

Overview
Technology
Applications
Future

Kevin Morris, Scripps Institue, La Jolla, CA

Overview
Technology
Applications
Future

Monika Lachner, Max-Planck Institute of Immunobiology, Department of Epigenetics, Freiburg, Germany

Overview
Technology
Applications
Future

Johnathan Whetstine, Department of Medicine, Massachusetts General Hospital Cancer Center

Overview
Technology
Applications
Future

Peter Fraser, Head, Senior Fellow of the Medical Research Council, UK, The Babraham Institute, Cambridge

Overview
Technology
Applications
Future

Summary of KOLs commentary Challenges

Fundamental research
Technological demands
Financial constraints
Intellectual property

Opportunities

Biomarker discovery & diagnostics
Therapeutic intervention
Regenerative medicines

Conclusions

Chapter 6 Appendices

Glossary
Acknowledgements
Index
Index
Bibliography
Endnotes

List of Figures
Figure 1.1: Timeline of epigenetics study
Figure 1.2: Schematic of chromatin structure
Figure 1.3: Schematic of epigenetic mechanisms associated with health and disease
Figure 1.4: Epigenetic applications by the pharma industry
Figure 2.5: Epigenetics in the drug discovery & development process
Figure 2.6: Schematic of key technologies used in epigenetics
Figure 2.7: Schematic of ChIP technology
Figure 2.8: Epigenomics AG methylation specific PCR (MSP) methods
Figure 3.9: DNA methylation targets for epigenetic cancer therapies
Figure 3.10: Mechanism of action of HAT and HDAC
Figure 3.11: Epi proColon high throughput colorectal epigenetic test
Figure 3.12: Competitive pricing of Epi proColon
Figure 3.13: EnVivo's HDAC project screening cascade
Figure 3.14: Agouti mice and epigenetic manipulation
Figure 3.15: Epizyme's rational design of small molecule HMT inhibitors
Figure 4.16: Epigenetic therapies: product class and developmental phase
Figure 4.17: Epigenetic therapies: therapy target and developmental phase
Figure 4.18: CUDU-101 structure & design: combining multiple pharmacophores

List of Tables
Table 2.1: DNA methylation PCR methods
Table 2.2: Techniques to analyze DNA methylation
Table 3.3: Examples of DNMT inhibitors: potential anticancer agents targeting epigenetic pathways
Table 3.4: Examples of DNMT inhibitor research tools
Table 3.5: HDAC inhibitors: potential anticancer agents targeting epigenetic pathways
Table 3.6: Examples of HDAC inhibitor research tools
Table 3.7: Histone modification and their effect on gene expression
Table 3.8: Safety profiles of PCI-24781 rivals
Table 3.9: DNA methylation sites associated with cancers
Table 3.10: Validated and hypothetic miRNA targets for diabetes & obesity
Table 4.11: Epigenetic therapeutic revenues ($m), 2009-2020
Table 4.12: Preliminary clinical data for Pharmacyclics PCI-24781
Table 4.13: Recent alliances, acquisitions and mergers in the epigenetic arena
Table 5.14: NIH Epigenetic Roadmap - funded epigenetic projects