Epigenomics

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CHAPTER ONE: EXECUTIVE SUMMARY ...................................................................... 1

The Basic Science of Epigenomics- Basic Life Science R&D ........................................... 1
Epigenomics And Diagnostics ............................................................................................ 3
Outlook For Epigenomics R&D ......................................................................................... 5
CHAPTER TWO: THE BASIC SCIENCE OF EPIGENOMICS ........................................... 7
A New Look at Health and Disease. ................................................................................... 7
Lamarck............................................................................................................................. 7
Weissmann ........................................................................................................................ 8
The History of Epigenomics to the Present ....................................................................... 8
What This Report Covers ................................................................................................. 10
What is Epigenomics? ....................................................................................................... 11
The concept. .................................................................................................................... 11
A New Level of Challenge ................................................................................................. 13
Implications for the Healthcare industry ........................................................................ 15
The Big Picture: An interview with Dr. Michael Skinner ............................................. 16
The Molecular Biology of Epigenetic Control Mechanisms .......................................... 19
DNA methylation ............................................................................................................ 19
Histone acetylation and other modifications ................................................................ 22
Complex; not well understood ........................................................................................ 22
Histone Acetylation ......................................................................................................... 25
Histone phosphorylation ................................................................................................. 25
Methylation ..................................................................................................................... 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
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Challenges in the identification of epigenetic involvement in non-cancerous diseases...... 37

Summary, Conclusions ..................................................................................................... 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 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 ataxia ............................................................................................................ 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
Therapeutic Companies.................................................................................................... 79
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Acetylon Pharmaceuticals ............................................................................................... 80

Acylin Therapeutics ........................................................................................................ 81
CellCentric ...................................................................................................................... 82
Celdex ............................................................................................................................. 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 Motif .................................................................................................................... 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 Strategy ..... 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 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
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Market Drivers and Restraints .......................................................................................... 130

Market Forecasts and Competitive Analysis ................................................................ 130
Competitive Structure ................................................................................................... 131
Regional Market Considerations .................................................................................. 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

CHAPTER ONE: EXECUTIVE SUMMARY

Table 1-1
The most common epigenetic 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 molecule 5-hydroxymethylcytosine ........................................................................ 21

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Figure 2-5
DNA molecule wrapped twice around a Hisotne Octamer to 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
CHAPTER 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......................................................... 49
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&D from Major Pharma Companies ............................ 80
Figure 5-1
Constellations research classes of epigenetic regulators; chromatin writes,
erasers, and readers ......................................................................................................... 86
Figure 5-2
JUN/EPIZYME An Example of one of Epizymes inhibitors interacting with an
epigenetic enzyme ........................................................................................................... 89
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Figure 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
Technologies ..................................................................................................................... 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 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
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Table 6.10
Some Current Epigenomics Research Goals ..................................................................... 122

Table 6.11
Cancer Diagnostics Market ............................................................................................... 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

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The Basic Science of Epigenomics

8

result in an enduring beneficial alteration of the animals body and a quality that
could be passed to the offspring. This theory fell into disrepute in the late 19th century
as the modern concept of the genetic structure of the individual was gradually
elaborated.
Weissmann
Weissmann benefitted from the discoveries in cellular microscopy that
revealed the existence of nucleus and chromosomes, establishing that information
storage was sequestered in a discrete cellular compartment. But Weissmann had
experimental data to back up his theoretical model. He cut off the tails of mice,
allowed them to recover and breed, observing that the progeny of tailless mice
invariably had tails. He performed this experiment over and over again, always with
the same result. No matter how obvious and simple-minded it may appear from the
perspective of hindsight, it constituted a powerful argument against the inheritance of
acquired characteristics.

THE HISTORY OF EPIGENOMICS TO THE PRESENT

With the rediscovery of Mendelian inheritance in the early 20th century, the
observation that there exist defined packets of information, or genes, mounted on the
chromosomes in the cell nucleus, made any sort of feedback mechanism from the
environment increasingly untenable. With the exception of the bizarre theories of the
crackpot plant breeder Lysenko in the Soviet Union during the 1940s and 50s, it
became universally accepted by the world of bioscience that the flow of information
was one way. This thesis held that DNA was transcribed to RNA which was thence
translated into protein. The proteins represented the phenotype, and there appeared no
mechanism by which the flow of information could proceed in the reverse direction.
During this period an overwhelming body of evidence developed that genes
could only be modified through random mutations which were fixed within the
species by natural selection of the most successful genotypes. This concept became a
mantra which for years was not questioned even thought there were always
unexplained cases of modifications in gene expression that did not appear to be
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Market Drivers
52

that targeting post-translational modifications of histones H3 and H4 should be

considered as a possible therapy for Alzheimers disease.
Other investigators emphasize the possibility of pharmacologically targeting the
histone deacetylases for their potential benefit in the treatment of Alzheimers
disease.
Spinal muscular atrophy (SMA)
This common neuromuscular disorder results from the absence of the survival
motor neuron gene 1 (SMN1). The severity of the condition is correlated with the
number of SMN2 gene copies. The SMN2 gene is subject to gene silencing by DNA
methylation. SMN2 contains four CpG islands which present highly conserved
methylation patterns and little inter-individual variations in SMN1-deleted SMA
patients.
Analysis of SMN2 methylation in patients suffering from severe versus mild
Spinal muscular atrophy reveal a correlation of CpG methylation at the positions
290 and 296 with the disease severity and the activity of the first transcriptional
start site of SMN2 at position 296. These data support the hypothesis that SMN2
alleles are functionally not equivalent due to differences in DNA methylation.
It has additionally been demonstrated that the methyl-CpG-binding protein 2, a
transcriptional repressor, binds to the critical SMN2 promoter region in a methylationdependent manner. However, inhibition of SMN2 gene silencing conferred by DNA
methylation might represent a promising strategy for pharmacologic SMA therapy.
The histone deacetylase inhibitors including vorinostat and romidepsin are able to
bypass SMN2 gene silencing by DNA methylation, while others such as valproic acid
and phenylbutyrate do not, due to HDAC isoenzyme specificities. The bulk of
available evidence suggests that DNA methylation is functionally important to the
progression of the disease.
Parkinsons Disease
This brain disorder leads to tremors and increasing difficulty with walking,
movement, and coordination. It is characterized by late (post 50) onset. It is equally
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Companies Active in Epigenomics

92

trials have started global enrollment in relapsed MM (PANORAMA-1) and post

transplant HL maintenance (PATH).
Figure 5.3
Structure of LBH589 (panobinostat)
.

LBH589 (panobinostat) is an orally available HDAC inhibitor that crosses the bloodbrain barrier and is currently
in phase III clinical trials for several types of cancer. It restores cholesterol homeostasis in cultured NPC1 mutant
fibroblasts to almost normal levels within 72 h when used at 40 nM. Source: www.wikipedia.com

Figure 5.4
Action of Panbinostat

Source: Novartis
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