STUDY GOALS AND OBJECTIVES

This BCC Research report, Ubiquitin Proteasome: Global Markets for Research Tools, Diagnostics and Drug Discovery, provides an overview of the current overall state of ubiquitin proteasome market, focusing specifically on research tools, assay development, drug candidates and potential diagnostic applications. It describes existing drug pipelines and scientific platforms on the market, and provides a detailed analysis of the competitive environments, including new potential trends and markets for novel therapies and product development. This study includes information about significant players, trends and obstacles and other information affecting this market and its different sectors.

REASONS FOR DOING THIS STUDY

Ubiquitin proteasome system (UPS) represents one of the most studied and challenging areas in basic and applicable science. Indeed, the scientists who discovered this cellular phenomenon were awarded the Nobel Prize in Chemistry in 2004. Since 2004, ubiquitin ligases and proteasome function have become one of the major targets for pharmaceutical and drug development companies.

However, despite the accumulation of basic knowledge about the mechanism of action of ubiquitination process and proteasome function, progress in drug screening and therapeutic development has been delayed. However, the proven success of the proteasome inhibitor Velcade (bortezomib) in addition to a recent breakthrough in the identification of new drug candidates in the UPS research field bring new excitement and hope for further successful drug development. Indeed, new second-generation proteasome inhibitor Kyprolis was recently approved by the FDA.

Moreover, the real commercial potential of this research area has not yet been fully acknowledged. Therefore, this study will provide knowledge of the current state of drug discovery in this field and new technologies in assay development and, more importantly, will describe potential novel commercial venues in diagnostics and drug development.

Overall, this report highlights the main segments in the ubiquitin proteasome market: reagents and technological platforms required for the research, drug discovery pipelines and potential applications of UPS in different areas of industry. It discusses its major players, current and future trends, and influences. Drivers and challenges in each segment of this industry are described in detail, including forecasts for the next five years.

SCOPE AND FORMAT

This report is essentially a business tool that can help market players evaluate properly new commercial opportunities in the ubiquitin proteasome space especially in the drug discovery, diagnostics and research tools submarkets. The geographic scope of this study is global. This market is generally complex and consists of a number of different segments, each of which is affected differently by scientific and technological developments. This report identifies the main positive and negative factors affecting each segment and forecasts market growth, future trends and product development in every major segment of this market.

METHODOLOGY AND INFORMATION SOURCES

Both primary and secondary research methodologies were used in preparing this study. Initially, a comprehensive and exhaustive search of the literature on drug discovery and already marketed products was conducted. These secondary sources included drug discovery and science-related journals, textbooks, press releases, marketing literature, other product/promotional literature, annual reports, security analyst reports and other publications. A patent search and analysis were also conducted.

In a second phase, a series of semi-structured interviews was conducted with company representatives, bench scientists, marketing representatives and other personnel at biotechnology and pharmaceutical companies. Other sources included academics, technology and consulting companies. Subsequent analysis of the documents and interviews notes was iterative.

INTENDED AUDIENCE

This report is intended for business development professionals, entrepreneurs, and other investors who need to fully understand and properly evaluate each segment in the market for ubiquitin proteasome drug discovery, diagnostics and research tools applications. It provides insight into the market position of major companies and shows new opportunities otherwise overlooked or less known to the business community.

ANALYST CREDENTIALS

Dr. Marianna Tcherpakov has more than eight years of experience as a bench scientist specializing in biochemistry, cell biology and industrial assay development. She has contributed to a number of scientific publications and holds several patents. She has expertise as an assay development scientist and is familiar with different research field trends and likely future developments.

REPORT HIGHLIGHTS

This report provides:
• An overview of the state of research tools, diagnostics, and drug discovery in the global ubiquitin proteasome (UPS) research field.
• Analyses of global market trends, with data from 2012, estimates for 2013, and projections of compound annual growth rates (CAGRs) through 2018.
• Discussion of existing products in the market.
• Identification of two major research trends in UPS: proteasome inhibitors versus ubiquitination reaction components as drug targets.
• This study notes the trends that are going to affect further drug development in this area.

Table Of Contents

TABLE OF CONTENTS

CHAPTER 1 INTRODUCTION 2

STUDY GOALS AND OBJECTIVES 2
REASONS FOR DOING THIS STUDY 2
SCOPE AND FORMAT 2
METHODOLOGY AND INFORMATION SOURCES 3
INTENDED AUDIENCE 3
ANALYST CREDENTIALS 3
RELATED REPORTS 3
BCC ON-LINE SERVICES 4
DISCLAIMER 4

CHAPTER 2 SUMMARY 6

SUMMARY TABLE GLOBAL MARKET FOR UBIQUITIN PROTEASOME RESEARCH AND
DEVELOPMENT, THROUGH 2018 ($ MILLIONS) 7
SUMMARY FIGURE GLOBAL MARKET FOR UBIQUITIN PROTEASOME RESEARCH AND
DEVELOPMENT, 2010-2018 ($ MILLIONS) 7

CHAPTER 3 SCIENTIFIC BACKGROUND AND SIGNIFICANCE OF UBIQUITIN

PROTEASOME RESEARCH 9
OVERVIEW 9
UBIQUITIN PROTEASOME SYSTEM: ITS MAJOR COMPONENTS AND
ENZYMATIC PROCESS 9
FIGURE 1 SCHEMATIC REPRESENTATION OF ENZYMATIC STEPS IN UBIQUITINATION
REACTION 10
FIGURE 2 HIERARCHICAL STRUCTURE OF UBIQUITINE PROTEASOME SYSTEM 10
TABLE 1 ENZYMATIC COMPONENTS OF UBIQTUINATION/ DEUBIQUITINATION
REACTION 11
Chain Topology and its Significance in Cellular Function 11
PROTEASOME MACHINERY 12
20S Core Particle 12
19S Core Particle 13
Protein Degradation Process 13
Proteasome as a Target for Drug Discovery 14
UBIQUITIN DOMAIN PROTEINS AND UBIQUITIN-LIKE MODIFIERS 15
TABLE 2 UBIQUITIN LIKE MODIFIERS (UBLS), THEIR FUNCTION AND ASSOCIATED
SUBSTRATES 15

CHAPTER 4 UBIQUITIN PROTEASOME SYSTEM AND DRUG DISCOVERY 18

PROTEASOME MACHINERY IN DRUG DISCOVERY 18
OVERVIEW 18
Velcade: the First Ubiquitin Proteasome System Product 18
Chemical Structure of Velcade and Its Mechanism of Action 18
FIGURE 3 CHEMICAL STRUCTURE OF BORTEZOMIB 19
Pharmacodynamics, Administration and Side Effects 19
Velcade Sales Market 21
TABLE 3 U.S. STATISTICS FOR HEMATOLOGICAL MALIGNANCIES, 2011 21
Multiple Myeloma Symptoms and Treatment 21
TABLE 4 MARKET SIZE FOR MULTIPLE MYELOMA DRUG MARKET, THROUGH 2018 ($
BILLIONS) 22
NHL and Mantle Cell Lymphoma 23
Treatments for Mantle Cell Lymphoma and Other NHL 23
Current Major Market Participants in MM Treatment and Sales
Forecast 24
Millennium Pharmaceuticals (a Subsidiary of Takeda) 24
TABLE 5 EXAMPLE OF COST OF SIDE EFFECT FOR CHEMOTHERAPY TREATMENT IN
2006 IN U.S. PER PATIENT ($ THOUSANDS) 25
TABLE 6 U.S. AND WORLDWIDE NET SALES FOR VELCADE, THROUGH 2018 ($
MILLIONS) 26
FIGURE 4 U.S. AND WORLDWIDE NET SALES FOR VELCADE, 2009-2018 ($
MILLIONS) 26
Celgene 27
Revlimid 27
Thalomid 28
TABLE 7 NET SALES FOR REVLIMID AND THALOMID, THROUGH 2018 ($ MILLIONS) 28
FIGURE 5 NET SALES FOR REVLIMID AND THALOMID, 2009-2018 ($ MILLIONS) 29
Pomalyst 29
Onyx Pharmaceuticals 30
Kyprolis 30
TABLE 8 NET SALES FOR KYPROLIS, THROUGH 2018 ($ MILLIONS) 31
FIGURE 6 NET SALES FOR KYPROLIS, 2011-2018 ($ MILLIONS) 31
Market Shares of Millennium/Takeda, Celgene and Other Companies'
Drugs 32
TABLE 9 MARKET SHARE BETWEEN CELGENE AND MILLENIUM
PHARMACEUTICALS/TAKEDA AND OTHER DRUG COMPANIES IN 2009, 2012
AGAINST POSSIBLE MARKET SHARE IN 2016 AND AFTER
33
New Indications for Velcade and Second-Generation Proteasome
Inhibitors from Millenium/Takeda 34
TABLE 10 CURRENT R andD ACTIVITY IN UBIQUITIN/PROTEASOME RESEARCH IN
MILLENIUM PHARMACEUTICALS 35
COMPANIES WORKING ON SECOND-GENERATION PROTEASOME
INHIBITORS 36
Current Market Participants 36
TABLE 11 COMPANIES WITH CURRENT RandD IN PROTEASOME INHIBITION AS A
DRUG TARGET 37
Millennium Pharmaceuticals (a Subsidiary of Takeda) 37
Onyx Pharmaceuticals 37
Onx- 0912/Oprozomib 37
Onx-0914 38
TABLE 12 GENERAL MARKET WORTH FOR AUTOIMMUNE DISORDERS: LUPUS,
RHEUMATOID ARTHRITIS AND IBD IN 2010 ($ BILLIONS) 38
Cephalon (Teva) 38
CEP-18770/Delanzomib 38
Nereus Pharmaceuticals 39
NPI-0052/Marizomib 39
19S Inhibitors as Therapeutic Targets 39
ADDITIONAL MARKETS AND POTENTIAL THERAPEUTIC APPLICATIONS FOR
PROTEASOME ACTIVATORS/INHIBITORS 40
Proteasome Inhibitors in Treatment of Organ Transplant Patients 40
Autoimmune Diseases and Proteasome Inhibition 40
Anti - Inflammatory Activity of Proteasome Inhibitors 41
TABLE 13 ACTIVITY OF PROTEASOME INHIBITORS IN ANIMAL MODELS FOR
AUTOIMMUNE AND INFLAMMATORY DISEASES 41
Treatment of Reperfusion Injury after Stroke 42
Stimulation of Bone and Hair Growth by Proteasome Inhibitors 42
TABLE 14 MARKET SIZE FOR HAIR LOSS TREATMENT IN THE U.S. ($ BILLIONS) 43
Proteasome Activity Modulators as Skin Care and Cosmetic
Treatment 43
TABLE 15 GLOBAL MARKET SIZE FOR ANTI-AGING PRODUCTS ($ BILLIONS) 44
Proteasome Inhibitors as Anti-infectives 44
TABLE 16 STATISTICS FOR TUBERCULOSIS INFECTION WORLDWIDE AND IN THE
U.S., 2009 (MILLIONS) 45
TABLE 17 POTENTIAL MARKET WORTH FOR TUBERCULOSIS DRUG TREATMENT,
2009-2017 ($ MILLIONS) 46
Proteasome Inhibition as Dry Eye Treatment 46
TABLE 18 MARKET SIZE FOR DRY EYE TREATMENT, 2009 AND 2013 ($ BILLIONS) 46
UBIQUITINATION ENZYMES AS A TARGET FOR DRUG DISCOVERY 47
E1 LIGASE AS A TARGET FOR DRUG DISCOVERY 47
TABLE 19 CURRENT DRUG DISCOVERY FOR E1 INHIBITORS 47
Pyr-41, the First E1 Inhibitor 47
Nae-E1 Ligase for Neddylation as a Drug Target 48
MLN4924- NAE-1 Inhibitor by Millennium Pharmaceuticals
(Takeda) 48
Benzothiazole/Thiazole Pyridine 49
E2 LIGASE AS A TARGET FOR DRUG DISCOVERY 49
TABLE 20 E2S AS A DRUG DISCOVERY TARGET AND ITS MARKET POTENTIAL ($
BILLIONS) 51
Blood Disorders Market for E2s 51
Ube2T: Fanconi Anemia 51
Spectrin Sickle-Cell Disease (SCD) 51
TABLE 21 MARKET POTENTIALS FOR SCA TREATMENT 52
Oncology and the Immune Disorders Market for E2s 52
Role of UbcH10 in Cancer 52
Ubc13 Cancer/Immune Disorders 53
Neurodegenerative Disorders Market for E2s 54
E2-25K Alzheimer's and Huntington's Diseases 54
E2s as Target for Plant Biotechnology 54
E3 LIGASES AS A DRUG DISCOVERY TARGET 54
TABLE 22 COMPANIES THAT WORK ON E3 LIGASES AS A DRUG TARGET 55
Overview of Companies Working on E3 Ligases as Drug Targets 55
Aegera Therapeutics (Pharmascience) 55
AEG35156 55
AEG40826 (HGS1029) 56
AEGXXXX 57
Amgen 57
Aprea AB 58
Ascenta Therapeutics 58
Celgene 59
Elan Pharmaceuticals 59
Genentech (Hoffmann La Roche) 59
Hoffman La Roche 60
Johnson and Johnson (Ortho Biotech Oncology Research and
Development) 61
Novartis 61
Priaxon AG 62
Progenra 62
Proteologics 63
Rigel Pharmaceuticals 64
TetraLogic Pharmaceuticals 64
HDM2 as a Target for Drug Discovery 64
TABLE 23 DRUG DISCOVERY APPROACH FOR P53 STUDIES 65
TABLE 24 COMPANIES WITH RandD IN P53 GENE THERAPY 66
Head and Neck Cancer as a Market Target for p53 Therapy 66
Ovarian Cancer as a Market Target for p53 Therapy 67
TABLE 25 U.S. STATISTICS AND GLOBAL MARKET SIZE FOR HEAD AND NECK AND
OVARIAN CANCERS, 2009 ($ MILLIONS) 67
HDM2-p53 Strategy for Drug Discovery 67
TABLE 26 STRATEGIES FOR HDM2-P53 DRUG DISCOVERY 68
TABLE 27 LIST OF COMPANIES AND DRUG CANDIDATES IN HDM2/P53 DRUG
DISCOVERY 69
The IAP Family as a Target for Drug Discovery 70
TABLE 28 CURRENT COMPANIES WITH RandD PROGRAM IN IAP DRUG DISCOVERY 71
TABLE 29 POTENTIAL MARKETS SIZE FOR IAPS DRUG DISCOVERY ($ BILLIONS) 73
Additional E3 Ubiquitin Ligases as Targets for Drug Discovery 73
TABLE 30 LIST OF E3 UBIQUITIN LIGASES IN DRUG DISCOVERY 73
APC Ligase Complex 74
SCF Complex 74
TRAF6 75
MuRF1 75
IDOL 75
Parkin 76
HRD1 76
TABLE 31 STATISTICS FOR RA IN THE U.S. AND GLOBAL ESTIMATE FOR RA MARKET,
2009 AND 2030 ($ BILLIONS) 76
POSH1 77
SMURF1 77
TABLE 32 STATISTICS FOR OSTEOPOROSIS IN THE U.S. AND GLOBAL ESTIMATE
FOR OSTEOPOROSIS MARKET ($ BILLIONS) 77
Cereblon 78
Midline-1 78
RNF146 and Bmi/Ring1B 78
TABLE 33 POTENTIAL MARKETS FOR CURRENT PROJECTS IN E3 LIGASE DRUG
DISCOVERY ($ BILLIONS) 79
Additional E3 Ligases as Potential Drug Targets 79
TABLE 34 ADDITIONAL E3 LIGASES AS POTENTIAL DRUG DISCOVERY TARGETS 79
AO7 80
Trim25 80
BRCA1 80
pVHL 80
E6-AP 80
LUBAC 80
TABLE 35 BREAST CANCER STATISTICS IN WOMEN IN THE U.S., 2009 (NUMBER OF
NEW CASES) 81
TABLE 36 MARKET FOR BREAST CANCER THERAPEUTICS, THROUGH 2016 ($
BILLIONS) 82
Companies with a Wide General Platform for Drug Discovery in
Ubiquitin-proteasome Systems 82
DEUBIQUITINASES AS A TARGET FOR DRUG DISCOVERY 83
OVERVIEW 83
TABLE 37 DEUBIQUITINASES AND THEIR ROLE IN CLINICAL CONDITIONS 83
POTENTIAL MARKETS BY DISEASE TYPE 84
Cancer 84
Neurodegeneration 84
Hematological Disorders 85
Virus Infections 85
Bacterial Infections 85
TABLE 38 EXAMPLES OF POTENTIAL MARKETS FOR DUBS DRUG DISCOVERY ($
BILLIONS) 86
TABLE 39 EXAMPLES OF DUBS INHIBITORS AND THEIR TARGETS 87
COMPANIES THAT WORK ON DUBS AS A DRUG TARGET 88
TABLE 40 COMPANIES WORKING ON DUBS AS DRUG TARGET 89
CellCentric 89
Cleave Biosciences 89
Genentech 90
Hybrigenics 90
Mission Therapeutics 90
Novartis 91
TABLE 41 STATISTICS AND COST OF MEDICAL CARE IN LUNG AND COLON CANCER
IN THE U.S., 2009 ($ BILLIONS) 91
Progenra 92
Proteostasis Therapeutics 92
UBIQUITIN-LIKE MODIFIERS AS TARGETS FOR DRUG DISCOVERY 93
Sumoylation Modification as a Drug Target Strategy 93
TABLE 42 ENZYMATIC MACHINERY OF SUMOYLATION 94
ISG15 Modification as a Drug Target Strategy 94
NEDDYLATION MODIFICATION AS A DRUG TARGET STRATEGY 95

CHAPTER 5 THE UBIQUITIN PROTEASOME SYSTEM AS A DIAGNOSTIC TOOL 97

OVERVIEW 97
TABLE 43 GLOBAL BIOMARKERS MARKET, THROUGH 2015 ($ BILLIONS) 98
TABLE 44 WORLDWIDE MARKET FOR BIOMARKERS ACCORDING TO DIFFERENT
RESEARCH AREAS, 2013 ($ BILLIONS/%) 98
CANCER BIOMARKERS 98
CARDIOVASCULAR DISEASE BIOMARKERS 99
CNS DISORDERS BIOMARKERS 100
THE UBIQUITIN PROTEASOME SYSTEM AS A POTENTIAL DIAGNOSTIC TOOL 100
TABLE 45 ANALYSIS OF SCIENTIFIC PUBLICATION ON UBIQUITIN PROTEASOME
SYSTEM 101
UPS and Cancer Diagnostics 101
TABLE 46 MARKET FOR BREAST CANCER DIAGNOSTICS, THROUGH 2016 ($
BILLIONS) 103
UPS and Immune Disorder Diagnostics 103
TABLE 47 WORLDWIDE STATISTICS AND GLOBAL MARKET SIZE FOR MULTIPLE
SCLEROSIS AND RHEUMATOID ARTHRITIS 103
TABLE 48 MARKET FOR IMMUNE DISORDERS DIAGNOSTICS ($ BILLIONS) 105
UPS and Neurodegenerative Disorders Diagnostics 105
TABLE 49 MARKET SIZE FOR REPRESENTATIVE NEURODEGENARATION DISORDERS
AND STATISTICS OF INCIDENCE IN THE U.S. 106
TABLE 50 NET SALES OF REQUIP, 2010-2012 ($ MILLIONS) 107
TABLE 51 NET SALES OF NAMENDA IN THE LAST THREE YEARS, 2010-2012 ($
MILLIONS) 108
TABLE 52 STATISTICS FOR HUNTIGNTON CONDITION IN THE U.S. AND GLOBAL
MARKET SIZE FOR HUNTINGTON’S DISEASE 108
UPS as a Diagnostic Tool in Other Pathologies 109
Inflammatory Bowel Disease 109
TABLE 53 STATISTICS AND COST OF IBD IN THE U.S. 110
Biomarkers for Hepatocellular Carcinoma (HCC) in Cirrhosis
Patients 110
TABLE 54 STATISTICS AND COST OF HCC IN USA 110

CHAPTER 6 REAGENTS AND ASSAY DEVELOPMENT FOR UPS RESEARCH AND DRUG

DISCOVERY 113
OVERVIEW 113
CURRENT MARKET PARTICIPANTS 113
TABLE 55 COMPANIES INVOLVED IN MARKETING OF RESEARCH TOOLS FOR UPS,
NUMBER OF PRODUCTS AND REVENUE OF THE COMPANY, 2010 (UNITS/$ MILLIONS) 113
Boston Biochem 114
Enzo Life Sciences 114
LifeSensors 114
Life Technologies (Thermo Fisher Scientific) 114
Meso Scale Discovery 115
Millipore (EMD4Biosciences) 115
UbiQ 115
Ubiquigent 115
Additional Market Participants 116
TABLE 56 EXAMPLE OF COMMON UPS REAGENTS PRICES IN MAJOR SUPPLIERS OF
UPS REAGENT TOOL COMPANIES ($) 117
FIGURE 7 EXAMPLE OF COMMON UPS REAGENTS PRICES IN MAJOR SUPPLIERS OF
UPS REAGENT TOOL COMPANIES ($) 117
ASSAY DEVELOPMENT FOR UPS DRUG DISCOVERY 117
TABLE 57 PROVIDERS OF SCREENING ASSAY TOOLS 118
Current Market Participants in Assay Development for UPS Research 118
LanthaScreen Technology for Ubiquitination/Deconjugation
Assays 118
AlphaScreen Approach for Ubiquitination/Deconjugation Assays 119
Cisbio Bioassays 119
Meso Scale Discovery 120
LifeSensors 120
Promega 121
BioGenova 121
Ubiquigent 121
Ubiquitin as a Research Tool for Other Drug Discovery Opportunities 122
TABLE 58 COMPANIES SELLING UBIQUITIN AND UBIQUITIN-LIKE MODIFIERS AS
REAGENT TOOL FOR OTHER DRUG DISCOVERIES APPLICATIONS 123
Scil Proteins 123
Dualsystems Biotech 124
LifeSensors 124
Life Technologies (Thermo Fisher Scientific) 125

CHAPTER 7 MILESTONES IN UBIQUITIN-PROTEASOME MARKET DEVELOPMENT AND
SIGNIFICANCE OF PATENTS 127

MAIN MILESTONES IN UBIQUITIN-PROTEASOME MARKET DEVELOPMENT 127
TABLE 59 SCIENTIFIC AND TECHNOLOGICAL BREAKTHROUGHS IN UPS, 1977-2012 127
PROTEASOME DISCOVERY AS A SCIENTIFIC BREAKTHROUGH 128
NEW DEVELOPMENTS IN UPS DRUG DISCOVERY 128
NEW MARKET OPPORTUNITIES FOR UPS: PLANT BIOTECHNOLOGY AS A
POTENTIAL MARKET FOR UPS 129
TABLE 60 MARKET VALUE OF COTTON AND CORN IN THE U.S. ($ BILLIONS) 130
SIGNIFICANCE OF PATENTS IN UPS RESEARCH 130
TABLE 61 PATENT APPLICATIONS FILED BY PHARMACEUTICAL COMPANIES DURING
2012 131
TABLE 62 PATENT APPLICATIONS FILED BY PHARMACEUTICAL COMPANIES DURING
2006 132
TABLE 63 NUMBER OF PATENT APPLICATIONS IN UBIQUITIN/ PROTEASOME
RESEARCH FILED BY LEADING PHARMACEUTICAL COMPANIES, 1995-2013 133
FIGURE 8 NUMBER OF PATENT APPLICATIONS IN UBIQUITIN/PROTEASOME
RESEARCH FILED BY LEADING PHARMACEUTICAL COMPANIES, 1995-2013
(NUMBER)
134
TABLE 64 PERCENTAGES OF PATENT APPLICATIONS IN UPS RESEARCH FILED IN
THE U.S., EUROPE AND JAPAN (%) 134

CHAPTER 8 MARKET SUMMARY 137

TABLE 65 WORLDWIDE MARKET FOR VELCADE AND KYPROLIS, THROUGH 2018 ($
MILLIONS) 137
FIGURE 9 WORLDWIDE MARKET FOR VELCADE AND KYPROLIS, 2010-2018 ($
MILLIONS) 138
TABLE 66 DIFFERENT TARGETS OF UPS IN CURRENT DRUG DEVELOPMENT
COMPANIES 139
TABLE 67 REAGENTS AND ASSAY DEVELOPMENT COMPANIES FOR UPS DRUG
DISCOVERY 139

CHAPTER 9 SELECT COMPANIES AND PROFILES 142

CELGENE CORPORATION 142
ELAN PHARMACEUTICALS 143
GENENTECH (HOFFMANN-LA ROCHE AG) 144
F. HOFFMANN-LA ROCHE LTD. 145
JOHNSON and JOHNSON 146
MILLENNIUM PHARMACEUTICALS: THE TAKEDA ONCOLOGY COMPANY 147
ONYX PHARMACEUTICALS INC. 147
PROGENRA 148
PROTEOLOGICS LTD. 149
PROTEOLOGICS LTD. (U.S.) 149
UBIQUIGENT LTD. 149

CHAPTER 10 LIST OF COMPANIES MENTIONED IN REPORT 152

ACENTA THERAPEUTICS 152
AEGERA THERAPEUTICS INC. (PART OF PHARMASCIENCE INC.) 152
AMGEN INC. 152
ASTELLAS PHARMA U.S. INC. 152
BIOGENOVA CORP. 152
BOSTON BIOCHEM INC. (RandD SYSTEMS) 153
BRISTOL-MYERS SQUIBB 153
CELGENE CORPORATION 153
CELLCENTRIC LTD. 153
CELLXPLORE 153
CISBIO 154
CLEAVE BIOSCIENCES 154
DUALSYSTEMS BIOTECH AG 154
ELAN PHARMACEUTICAL 154
ENZO LIFE SCIENCES INC. 154
GENENTECH INC. (ROCHE GROUP) 155
GSK (GLAXOSMITHKLINE PLC) 155
HYBRIGENICS 155
JOHNSON AND JOHNSON 155
F. HOFFMANN-LA ROCHE AG 155
LIFE SENSORS INC. 156
LIFE TECHNOLOGIES CORP. (THERMO FISHER SCIENTIFIC) 156
MESO SCALE DISCOVERY 156
MERCK CORPORATE HEADQUARTERS 156
MILLENIUM PHARMACEUTICAL (THE TAKEDA ONCOLOGY COMPANY) 156
MISSION THERAPEUTICS LTD. 157
NEXUSPHARMA INC. 157
NOVARTIS INTERNATIONAL AG 157
ONYX PHARMACEUTICALS INC. 157
PRIAXON AG 157
PROGENRA INC. 158
PROTEOLOGICS LTD. 158
PROTEOSTASIS THERAPEUTICS 158
RIGEL PHARMACEUTICALS INC. 158
SCIL PROTEINS GMBH 158
SIGMA-ALDRICH 159
THERMO FISHER SCIENTIFIC INC. 159
TEVA PHARMACEUTICALS 159
TETRALOGICS PHARMACEUTICALS 159
UBIQ BIO BV 159
UBIQUIGENT LTD. 160



LIST OF TABLES

SUMMARY TABLE GLOBAL MARKET FOR UBIQUITIN PROTEASOME RESEARCH AND
DEVELOPMENT, THROUGH 2018 ($ MILLIONS) 7
TABLE 1 ENZYMATIC COMPONENTS OF UBIQTUINATION/ DEUBIQUITINATION
REACTION 11
TABLE 2 UBIQUITIN LIKE MODIFIERS (UBLS), THEIR FUNCTION AND ASSOCIATED
SUBSTRATES 15
TABLE 3 U.S. STATISTICS FOR HEMATOLOGICAL MALIGNANCIES, 2011 21
TABLE 4 MARKET SIZE FOR MULTIPLE MYELOMA DRUG MARKET, THROUGH 2018 ($
BILLIONS) 22
TABLE 5 EXAMPLE OF COST OF SIDE EFFECT FOR CHEMOTHERAPY TREATMENT IN
2006 IN U.S. PER PATIENT ($ THOUSANDS) 25
TABLE 6 U.S. AND WORLDWIDE NET SALES FOR VELCADE, THROUGH 2018 ($
MILLIONS) 26
TABLE 7 NET SALES FOR REVLIMID AND THALOMID, THROUGH 2018 ($ MILLIONS) 28
TABLE 8 NET SALES FOR KYPROLIS, THROUGH 2018 ($ MILLIONS) 31
TABLE 9 MARKET SHARE BETWEEN CELGENE AND MILLENIUM
PHARMACEUTICALS/TAKEDA AND OTHER DRUG COMPANIES IN 2009, 2012 AGAINST
POSSIBLE MARKET SHARE IN 2016 AND AFTER
33
TABLE 10 CURRENT R andD ACTIVITY IN UBIQUITIN/PROTEASOME RESEARCH IN
MILLENIUM PHARMACEUTICALS 35
TABLE 11 COMPANIES WITH CURRENT RandD IN PROTEASOME INHIBITION AS A DRUG
TARGET 37
TABLE 12 GENERAL MARKET WORTH FOR AUTOIMMUNE DISORDERS: LUPUS,
RHEUMATOID ARTHRITIS AND IBD IN 2010 ($ BILLIONS) 38
TABLE 13 ACTIVITY OF PROTEASOME INHIBITORS IN ANIMAL MODELS FOR
AUTOIMMUNE AND INFLAMMATORY DISEASES 41
TABLE 14 MARKET SIZE FOR HAIR LOSS TREATMENT IN THE U.S. ($ BILLIONS) 43
TABLE 15 GLOBAL MARKET SIZE FOR ANTI-AGING PRODUCTS ($ BILLIONS) 44
TABLE 16 STATISTICS FOR TUBERCULOSIS INFECTION WORLDWIDE AND IN THE
U.S., 2009 (MILLIONS) 45
TABLE 17 POTENTIAL MARKET WORTH FOR TUBERCULOSIS DRUG TREATMENT,
2009-2017 ($ MILLIONS) 46
TABLE 18 MARKET SIZE FOR DRY EYE TREATMENT, 2009 AND 2013 ($ BILLIONS) 46
TABLE 19 CURRENT DRUG DISCOVERY FOR E1 INHIBITORS 47
TABLE 20 E2S AS A DRUG DISCOVERY TARGET AND ITS MARKET POTENTIAL ($
BILLIONS) 51
TABLE 21 MARKET POTENTIALS FOR SCA TREATMENT 52
TABLE 22 COMPANIES THAT WORK ON E3 LIGASES AS A DRUG TARGET 55
TABLE 23 DRUG DISCOVERY APPROACH FOR P53 STUDIES 65
TABLE 24 COMPANIES WITH RandD IN P53 GENE THERAPY 66
TABLE 25 U.S. STATISTICS AND GLOBAL MARKET SIZE FOR HEAD AND NECK AND
OVARIAN CANCERS, 2009 ($ MILLIONS) 67
TABLE 26 STRATEGIES FOR HDM2-P53 DRUG DISCOVERY 68
TABLE 27 LIST OF COMPANIES AND DRUG CANDIDATES IN HDM2/P53 DRUG
DISCOVERY 69
TABLE 28 CURRENT COMPANIES WITH RandD PROGRAM IN IAP DRUG DISCOVERY 71
TABLE 29 POTENTIAL MARKETS SIZE FOR IAPS DRUG DISCOVERY ($ BILLIONS) 73
TABLE 30 LIST OF E3 UBIQUITIN LIGASES IN DRUG DISCOVERY 73
TABLE 31 STATISTICS FOR RA IN THE U.S. AND GLOBAL ESTIMATE FOR RA MARKET,
2009 AND 2030 ($ BILLIONS) 76
TABLE 32 STATISTICS FOR OSTEOPOROSIS IN THE U.S. AND GLOBAL ESTIMATE FOR
OSTEOPOROSIS MARKET ($ BILLIONS) 77
TABLE 33 POTENTIAL MARKETS FOR CURRENT PROJECTS IN E3 LIGASE DRUG
DISCOVERY ($ BILLIONS) 79
TABLE 34 ADDITIONAL E3 LIGASES AS POTENTIAL DRUG DISCOVERY TARGETS 79
TABLE 35 BREAST CANCER STATISTICS IN WOMEN IN THE U.S., 2009 (NUMBER OF
NEW CASES) 81
TABLE 36 MARKET FOR BREAST CANCER THERAPEUTICS, THROUGH 2016 ($
BILLIONS) 82
TABLE 37 DEUBIQUITINASES AND THEIR ROLE IN CLINICAL CONDITIONS 83
TABLE 38 EXAMPLES OF POTENTIAL MARKETS FOR DUBS DRUG DISCOVERY ($
BILLIONS) 86
TABLE 39 EXAMPLES OF DUBS INHIBITORS AND THEIR TARGETS 87
TABLE 40 COMPANIES WORKING ON DUBS AS DRUG TARGET 89
TABLE 41 STATISTICS AND COST OF MEDICAL CARE IN LUNG AND COLON CANCER
IN THE U.S., 2009 ($ BILLIONS) 91
TABLE 42 ENZYMATIC MACHINERY OF SUMOYLATION 94
TABLE 43 GLOBAL BIOMARKERS MARKET, THROUGH 2015 ($ BILLIONS) 98
TABLE 44 WORLDWIDE MARKET FOR BIOMARKERS ACCORDING TO DIFFERENT
RESEARCH AREAS, 2013 ($ BILLIONS/%) 98
TABLE 45 ANALYSIS OF SCIENTIFIC PUBLICATION ON UBIQUITIN PROTEASOME
SYSTEM 101
TABLE 46 MARKET FOR BREAST CANCER DIAGNOSTICS, THROUGH 2016 ($ BILLIONS) 103
TABLE 47 WORLDWIDE STATISTICS AND GLOBAL MARKET SIZE FOR MULTIPLE
SCLEROSIS AND RHEUMATOID ARTHRITIS 103
TABLE 48 MARKET FOR IMMUNE DISORDERS DIAGNOSTICS ($ BILLIONS) 105
TABLE 49 MARKET SIZE FOR REPRESENTATIVE NEURODEGENARATION DISORDERS
AND STATISTICS OF INCIDENCE IN THE U.S. 106
TABLE 50 NET SALES OF REQUIP, 2010-2012 ($ MILLIONS) 107
TABLE 51 NET SALES OF NAMENDA IN THE LAST THREE YEARS, 2010-2012 ($
MILLIONS) 108
TABLE 52 STATISTICS FOR HUNTIGNTON CONDITION IN THE U.S. AND GLOBAL
MARKET SIZE FOR HUNTINGTON’S DISEASE 108
TABLE 53 STATISTICS AND COST OF IBD IN THE U.S. 110
TABLE 54 STATISTICS AND COST OF HCC IN USA 110
TABLE 55 COMPANIES INVOLVED IN MARKETING OF RESEARCH TOOLS FOR UPS,
NUMBER OF PRODUCTS AND REVENUE OF THE COMPANY, 2010 (UNITS/$ MILLIONS) 113
TABLE 56 EXAMPLE OF COMMON UPS REAGENTS PRICES IN MAJOR SUPPLIERS OF
UPS REAGENT TOOL COMPANIES ($) 117
TABLE 57 PROVIDERS OF SCREENING ASSAY TOOLS 118
TABLE 58 COMPANIES SELLING UBIQUITIN AND UBIQUITIN-LIKE MODIFIERS AS
REAGENT TOOL FOR OTHER DRUG DISCOVERIES APPLICATIONS 123
TABLE 59 SCIENTIFIC AND TECHNOLOGICAL BREAKTHROUGHS IN UPS, 1977-2012 127
TABLE 60 MARKET VALUE OF COTTON AND CORN IN THE U.S. ($ BILLIONS) 130
TABLE 61 PATENT APPLICATIONS FILED BY PHARMACEUTICAL COMPANIES DURING
2012 131
TABLE 62 PATENT APPLICATIONS FILED BY PHARMACEUTICAL COMPANIES DURING
2006 132
TABLE 63 NUMBER OF PATENT APPLICATIONS IN UBIQUITIN/ PROTEASOME
RESEARCH FILED BY LEADING PHARMACEUTICAL COMPANIES, 1995-2013 133
TABLE 64 PERCENTAGES OF PATENT APPLICATIONS IN UPS RESEARCH FILED IN THE
U.S., EUROPE AND JAPAN (%) 134
TABLE 65 WORLDWIDE MARKET FOR VELCADE AND KYPROLIS, THROUGH 2018 ($
MILLIONS) 137
TABLE 66 DIFFERENT TARGETS OF UPS IN CURRENT DRUG DEVELOPMENT
COMPANIES 139
TABLE 67 REAGENTS AND ASSAY DEVELOPMENT COMPANIES FOR UPS DRUG
DISCOVERY 139



LIST OF FIGURES

SUMMARY FIGURE GLOBAL MARKET FOR UBIQUITIN PROTEASOME RESEARCH AND
DEVELOPMENT, 2010-2018 ($ MILLIONS) 7
FIGURE 1 SCHEMATIC REPRESENTATION OF ENZYMATIC STEPS IN UBIQUITINATION
REACTION 10
FIGURE 2 HIERARCHICAL STRUCTURE OF UBIQUITINE PROTEASOME SYSTEM 10
FIGURE 3 CHEMICAL STRUCTURE OF BORTEZOMIB 19
FIGURE 4 U.S. AND WORLDWIDE NET SALES FOR VELCADE, 2009-2018 ($ MILLIONS) 26
FIGURE 5 NET SALES FOR REVLIMID AND THALOMID, 2009-2018 ($ MILLIONS) 29
FIGURE 6 NET SALES FOR KYPROLIS, 2011-2018 ($ MILLIONS) 31
FIGURE 7 EXAMPLE OF COMMON UPS REAGENTS PRICES IN MAJOR SUPPLIERS OF
UPS REAGENT TOOL COMPANIES ($) 117
FIGURE 8 NUMBER OF PATENT APPLICATIONS IN UBIQUITIN/PROTEASOME
RESEARCH FILED BY LEADING PHARMACEUTICAL COMPANIES, 1995-2013 (NUMBER) 134
FIGURE 9 WORLDWIDE MARKET FOR VELCADE AND KYPROLIS, 2010-2018 ($
MILLIONS) 138

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