THERAPIES AND BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE

THERAPIES AND BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE PHM125A January 2013 Willem Westra Project Analyst ISBN: 0-89336-715-X BCC Research 49 Walnut Park, Building 2 Wellesley, MA 02481 866-285-7215, 781-489-7301 www.bccresearch.com Custom Reports: carol.laverty@bccresearch.com

TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 1 STUDY GOALS AND OBJECTIVES 1 REASONS FOR DOING THE STUDY 1 SCOPE OF REPORT 1 INTENDED AUDIENCE 2 METHODOLOGY AND INFORMATION SOURCES 2 ANALYST CREDENTIALS 2 RELATED REPORTS 3 BCC ON-LINE SERVICES 3 DISCLAIMER 3 CHAPTER 2 SUMMARY 5 SUMMARY TABLE GLOBAL INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, THROUGH 2017 ($ MILLIONS) SUMMARY FIGURE GLOBAL INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, BY REGION, 2010-2017 ($ MILLIONS) 5 5 CHAPTER 3 OVERVIEW 7 INFLAMMATORY BOWEL DISEASE 7 DEFINITION OF INFLAMMATORY BOWEL DISEASE 7 Crohn's Disease 7 Ulcerative Colitis 7 EPIDEMIOLOGY OF INFLAMMATORY BOWEL DISEASE 8 Incidence and Prevalence of Inflammatory Bowel Disease 9 TABLE 1 GLOBAL INCIDENCE RANGES FOR CROHN S DISEASE AND ULCERATIVE COLITIS (PER 100,000) TABLE 2 GLOBAL PREVALENCE OF CROHN S DISEASE AND ULCERATIVE COLITIS 10 TABLE 3 GLOBAL INCIDENCE FOR CROHN S DISEASE 11 TABLE 4 GLOBAL PREVALENCE FOR CROHN S DISEASE 12 TABLE 5 GLOBAL INCIDENCE FOR ULCERATIVE COLITIS 13 TABLE 6 GLOBAL PREVALENCE FOR ULCERATIVE COLITIS 14 CURRENT TREATMENTS FOR INFLAMMATORY BOWEL DISEASE 15 TABLE 7 THERAPEUTIC OPTIONS FOR INFLAMMATORY BOWEL DISEASE 15 Symptom Management 16 Inflammation Reduction 16 Surgery 16 Surgery for Ulcerative Colitis 16 Surgery for Crohn's Disease 17 Alternative Therapies 17 Fecal Bacteriotherapy 17 Pre- and Probiotic Supplementation 17 Helminth Therapy 17 BIOMARKER DEFINITION 18 Biomarkers Types 18 Diagnostic Biomarkers 18 TABLE 8 DIAGNOSTIC BIOMARKER EXAMPLES 19 9

Prognostic Biomarkers 19 Predictive Biomarkers 19 TABLE 9 PREDICTIVE BIOMARKER EXAMPLES 20 Target-Engagement Biomarkers 20 Biomarkers for Inflammatory Bowel Disease 20 TABLE 10 BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE 21 TABLE 11 PUBMED-INDEXED SCIENTIFIC PUBLICATIONS REGARDING INFLAMMATORY BOWEL DISEASE BIOMARKERS, 2002-2012 TABLE 12 OPEN CLINICAL TRIALS FOR CROHN S DISEASE THERAPEUTICS BY LOCATION, 2012 (NUMBER OF TRIALS) TABLE 13 OPEN CLINICAL TRIALS FOR ULCERATIVE COLITIS THERAPEUTICS BY LOCATION, 2012 (NUMBER OF TRIALS) 21 22 23 CHAPTER 4 INFLAMMATORY BOWEL DISEASE PHYSIOLOGY 25 OVERVIEW 25 ANATOMY OF THE INTESTINES 25 Small Intestine 25 Large Intestine 25 BIOLOGICAL FUNCTION OF THE INTESTINES 26 INFLAMMATORY BOWEL DISEASE TYPES 26 Crohn's Disease 26 Epidemiology 26 Risk Factors 27 Symptoms 27 Classification 27 Physiology 27 Causes 27 Ulcerative Colitis 27 Epidemiology 27 Risk Factors 28 Symptoms 28 Classification 28 Severity 28 Other Inflammatory Bowel Disease Types 28 INFLAMMATORY BOWEL DISEASE DIAGNOSIS 29 Signs and Symptoms 29 Clinical Aspects of Inflammatory Bowel Disease 29 TABLE 14 CLINICAL ASPECTS OF INFLAMMATORY BOWEL DISEASE SUBTYPES 30 Clinical Conditions Associated with inflammatory Bowel Disease 30 Pyoderma Gangrenosum 30 Primary Sclerosing Cholangitis 31 Malnutrition, Limited Nutrient Absorption and Stunting 31 CLINICAL CALCULATION OF CROHN'S DISEASE ACTIVITY INDEX SCORE 31 TABLE 15 FACTORS FOR CALCULATING THE CROHN S DISEASE ACTIVITY INDEX SCORE 32 CLINICAL CALCULATION OF HARVEY-BRADSHAW INDEX 33 TABLE 16 FACTORS FOR CALCULATING THE HARVEY BRADSHAW INDEX 33 CLINICAL CALCULATION OF THE CROHN'S DISEASE ENDOSCOPIC INDEX SEVERITY 34 CALCULATION OF THE MAYO SCORE 34

TABLE 17 FACTORS FOR CALCULATING THE MAYO SCORE 34 INFLAMMATORY BOWEL DISEASE SEROLOGIES 35 TABLE 18 INFLAMMATORY BOWEL DISEASE SEROLOGIES TO INFORM CLINICAL DIAGNOSES CAUSES OF INFLAMMATORY BOWEL DISEASE 36 Genetics of Inflammatory Bowel Disease 36 TABLE 19 GENETIC LOCI IMPLICATED IN INFLAMMATORY BOWEL DISEASE 36 NOD2 37 NOD2 Mutations 37 Environmental Risk Factors for Inflammatory Bowel Disease 38 TABLE 20 ENVIRONMENTAL RISK FACTORS FOR INFLAMMATORY BOWEL DISEASE 38 Stress as a Risk Factor for Inflammatory Bowel Disease 39 35 CHAPTER 5 INFLAMMATORY BOWEL DISEASE PRODUCT SEGMENTS 41 TABLE 21 INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET SEGMENTATION 41 NON-BIOLOGIC DRUGS FOR INFLAMMATORY BOWEL DISEASE 41 TABLE 22 COMPETITOR ASSESSMENT OF THE MAJOR MARKETED INFLAMMATORY BOWEL DISEASE THERAPEUTICS, 2012 TABLE 23 GLOBAL REVENUE FOR INFLAMMATORY BOWEL DISEASE-SPECIFIC NON-BIOLOGIC DRUGS, THROUGH 2017 ($ MILLIONS) TABLE 24 GLOBAL MARKET SHARES FOR INFLAMMATORY BOWEL DISEASE-SPECIFIC NON-BIOLOGIC DRUGS, 2011 ($ MILLIONS/%) ASACOL 43 PENTASA 44 ENTOCORT 44 LIALDA 45 SALOFALK 45 BIOLOGIC DRUGS FOR INFLAMMATORY BOWEL DISEASE 46 TABLE 25 GLOBAL REVENUE FOR INFLAMMATORY BOWEL DISEASE BIOLOGIC DRUGS, THROUGH 2017 ($ MILLIONS) TABLE 26 GLOBAL MARKET SHARE FOR INFLAMMATORY BOWEL DISEASE-SPECIFIC BIOLOGIC DRUGS, 2011 ($ MILLIONS) REMICADE 46 HUMIRA 47 CIMZIA 48 TYSABRI 48 GLOBAL MARKETS FOR INFLAMMATORY BOWEL DISEASE THERAPEUTICS 49 TABLE 27 LEADING INTERNATIONAL MARKETS FOR INFLAMMATORY BOWEL DISEASE THERAPEUTICS, THROUGH 2017 ($ MILLIONS) GLOBAL MARKETS 49 U.S. 49 TABLE 28 U.S. MARKET FOR INFLAMMATORY BOWEL DISEASE DRUGS, THROUGH 2017 ($ MILLIONS) Japan 50 TABLE 29 JAPANESE INFLAMMATORY BOWEL DISEASE DRUG MARKET, THROUGH 2017 ($ MILLIONS) EU5 51 TABLE 30 EU5 INFLAMMATORY BOWEL DISEASE DRUG MARKET, THROUGH 2017 ($ MILLIONS) 41 42 43 46 46 49 50 50 51

Rest of the World 51 TABLE 31 REST OF THE WORLD INFLAMMATORY BOWEL DISEASE DRUG MARKET, THROUGH 2017 ($ MILLIONS) EMERGING THERAPIES FOR INFLAMMATORY BOWEL DISEASE 52 CROHN'S DISEASE 52 TABLE 32 THERAPEUTIC PIPELINE FOR CROHN S DISEASE THERAPIES 52 TABLE 33 CLINICAL TRIAL RESULTS FOR EMERGING THERAPIES FOR CROHN S DISEASE 53 TXCell 54 Centocor Ortho Biotech 54 Enzo 54 ChemoCentryx 55 Osiris Therapeutics 55 Schering 55 Protein Design Labs BioPharma 56 NPS Pharmaceuticals 56 ULCERATIVE COLITIS 56 TABLE 34 THERAPEUTIC PIPELINE FOR ULCERATIVE COLITIS THERAPIES 57 TABLE 35 CLINICAL TRIAL RESULTS FOR EMERGING ULCERATIVE COLITIS THERAPIES, 2007-2012 Millennium/Takeda 58 Lipid Therapeutics 58 Abbott 58 Santarus and Cosmo Pharmaceuticals 59 Hutchison Medipharma 59 SUMMARY OF PROMISING INFLAMMATORY BOWEL DISEASE DRUGS IN DEVELOPMENT Monoclonal Antibodies 60 HuZAF (fontolizumab): Biogen Idec 60 Stelara (Ustekinumab): Johnson and Johnson 61 Vedolizumab (MLN02): Takeda 61 Simponi (Golimumab): Johnson and Johnson 61 Small Molecules 61 Tetomilast: Otsuka 61 Firategrast: GlaxoSmithKline 62 Other Therapies 62 Alicaforsen: Isis Pharmaceuticals 62 Alequel: Enzo 62 Nicotine and Bupropion 63 Mycobacterium Avium Subspecies Paratuberculosis Vaccine 63 EMERGING TECHNOLOGIES FOR INFLAMMATORY BOWEL DISEASE 63 52 58 60 CHAPTER 6 INFLAMMATORY BOWEL DISEASE RESEARCH AND DEVELOPMENT 66 CLINICAL GUIDELINES FOR MANAGING INFLAMMATORY BOWEL DISEASE 66 RECOMMENDATIONS FOR INITIAL TREATMENT OF CROHN'S DISEASE 66 RECOMMENDATIONS FOR MAINTENANCE OF REMISSION IN CROHN'S DISEASE 66 RECOMMENDATIONS FOR INITIAL TREATMENT OF ULCERATIVE COLITIS 67 RECOMMENDATIONS FOR MAINTENANCE OF REMISSION IN ULCERATIVE COLITIS 67 CURRENT THERAPIES FOR INFLAMMATORY BOWEL DISEASE 68

CROHN'S DISEASE TREATMENT 68 ULCERATIVE COLITIS TREATMENT 68 TABLE 36 THERAPIES FOR INFLAMMATORY BOWEL DISEASE 68 Anti-Diarrheals 69 TABLE 37 ANTI-DIARRHEAL THERAPIES FOR INFLAMMATORY BOWEL DISEASE 69 Class Description and Mechanism of Action 69 Dosing 69 Efficacy 69 Antibiotics 69 TABLE 38 ANTIBIOTIC THERAPIES FOR INFLAMMATORY BOWEL DISEASE 69 Class Description and Mechanism of Action 70 Dosing 70 Efficacy 70 Aminosalicylates 70 TABLE 39 AMINOSALICYLATE THERAPIES FOR INFLAMMATORY BOWEL DISEASE 70 Class Description and Mechanism of Action 70 Dosing 71 Efficacy 71 Corticosteroids 71 TABLE 40 CORTICOSTEROID THERAPIES FOR INFLAMMATORY BOWEL DISEASE 72 Class Description and Mechanism of Action 72 Dosing 72 Efficacy 73 Immunosuppressants 73 TABLE 41 IMMUNOSUPPRESSANT THERAPIES FOR INFLAMMATORY BOWEL DISEASE 73 Class Description and Mechanism of Action 73 Dosing 74 Biologics 74 TABLE 42 BIOLOGIC THERAPIES FOR INFLAMMATORY BOWEL DISEASE 75 Class Description and Mechanism of Action 75 Dosing 76 Efficacy 76 Clinical Trials for Inflammatory Bowel Disease Therapies 77 TABLE 43 OPEN CLINICAL TRIALS FOR CROHN S DISEASE THERAPEUTICS BY LOCATION, 2012 (TRIALS) TABLE 44 OPEN CLINICAL TRIALS FOR ULCERATIVE COLITIS THERAPEUTICS BY LOCATION, 2012 (TRIALS) 77 78 CHAPTER 7 BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE 80 TABLE 45 PUBMED-INDEXED SCIENTIFIC PUBLICATIONS FOR INFLAMMATORY BOWEL DISEASE BIOMARKERS, 2002-2012 INFLAMMATORY BOWEL DISEASE BIOMARKERS 80 SERUM BIOMARKERS 81 C-Reactive Protein 81 C-Reactive Protein in the Diagnosis of Inflammatory Bowel Disease 82 C-Reactive Protein in the Evaluation of Inflammatory Bowel Disease 82 Antibodies and Auto-Antibodies 82 TABLE 46 SERUM INFLAMMATORY BOWEL DISEASE BIOMARKERS 83 80

FECAL BIOMARKERS 83 TABLE 47 FECAL INFLAMMATORY BOWEL DISEASE BIOMARKERS 84 EMERGING BIOMARKERS 84 TABLE 48 NOVEL INFLAMMATORY BOWEL DISEASE BIOMARKERS 85 Metabolomic Inflammatory Bowel Disease Biomarkers 85 Gene-Expression Inflammatory Bowel Disease Biomarkers 86 CHAPTER 8 PATENT LANDSCAPE 88 INFLAMMATORY BOWEL DISEASE DIAGNOSTICS AND THERAPEUTICS INDUSTRY 88 IMPORTANT CONCEPTS 88 Priority Dates 88 Patent Cooperation Treaty 88 International Classification Codes 89 METHODOLOGY 89 NOTABLE PATENTS IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTIC MARKET TABLE 49 MAJOR PATENT HOLDERS IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTICS SPACE Prometheus Laboratories 90 TABLE 50 PUBLISHED PATENTS FOR PROMETHUES LABORATORIES IN INFLAMMATORY BOWEL DISEASE, 2005 2012 Exagen Diagnostics 90 TABLE 51 PUBLISHED PATENTS FOR EXAGEN DIAGNOSTICS IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 52 MAJOR PATENT HOLDERS IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTICS SPACE TABLE 53 PUBLISHED PATENTS FOR PFIZER IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 54 PUBLISHED PATENTS FOR NOVARTIS IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 55 PUBLISHED PATENTS FOR NOVARTIS IN INFLAMMATORY BOWEL DISEASE, 2005 2012 89 89 90 90 91 91 92 93 CHAPTER 9 COMPANY PROFILES 95 COMPANIES IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTICS SPACE 95 TABLE 56 INFLAMMATORY BOWEL DISEASE DIAGNOSTIC COMPANIES 95 REVENUE PER EMPLOYEE 95 TABLE 57 INFLAMMATORY BOWEL DISEASE DIAGNOSTIC COMPANIES BY REVENUE PER EMPLOYEE, 2011 EXAGEN LABORATORIES INC. 96 GENETIC ANALYSIS SA 97 GLYCOMINDS LTD. 98 INDEX PHARMACEUTICALS AB 98 PROMETHEUS LABORATORIES INC. 99 QUEST DIAGNOSTICS 100 SYNEXA LIFE SCIENCES 101 COMPANIES IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTICS SPACE 101 TABLE 58 INFLAMMATORY BOWEL DISEASE THERAPEUTIC COMPANIES 101 96

TABLE 59 INFLAMMATORY BOWEL DISEASE DIAGNOSTIC COMPANIES BY REVENUE PER EMPLOYEE, 2011 ABBOTT LABORATORIES 103 ASTRAZENECA PLC 103 BIOGEN IDEC 104 FERRING PHARMACEUTICALS 105 HUTCHISON MEDIPHARM 105 IRONWOOD PHARMACEUTICALS 106 JANSSEN BIOTECH INC 106 KYORIN PHARMACEUTICAL 107 MILLENNIUM PHARMACEUTICALS 107 MYLAN INC. 108 NEOVACS AG 109 NOVARTIS AG 110 OSIRIS THERAPEUTICS 110 PFIZER 111 SHIRE PHARMACEUTICALS 112 UNION CHIMIQUE BELGE, S.A. 112 WARNER CHILCOTT 113 MERGERS AND ACQUISITIONS: DIAGNOSTICS 113 TABLE 60 SIGNIFICANT MERGERS AND ACQUISITIONS IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTIC MARKET, 2008 2012 TABLE 61 SIGNIFICANT VENTURE-CAPITAL DEALS IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTIC MARKET, 2004 2012 ($ MILLIONS) TABLE 62 SIGNIFICANT STRATEGIC ALLIANCES IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTIC MARKET, 2008 2012 MERGERS AND ACQUISITIONS: THERAPEUTICS 115 TABLE 63 SIGNIFICANT MERGERS AND ACQUISITIONS IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, 2008 2012 TABLE 64 SIGNIFICANT VENTURE-CAPITAL DEALS IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, 2008 2012 ($ MILLIONS) TABLE 65 SIGNIFICANT STRATEGIC ALLIANCES IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, 2008-2012 102 113 114 115 115 116 116 CHAPTER 10 MARKET FACTORS 118 STRENGTH, WEAKNESS, OPPORTUNITY AND THREAT ANALYSIS 118 TABLE 66 STRENGTH, WEAKNESS, OPPORTUNITY AND THREAT ANALYSIS FOR THE GLOBAL INFLAMMATORY BOWEL DISEASE MARKET MARKET FACTORS 118 Market Drivers 119 Increasing Disease Incidence 119 Chronic Nature of the Disease 119 Increased Diagnostic Sensitivity 119 Novel Therapeutics 119 Market Restrictors 120 Cure for Inflammatory Bowel Disease 120 Murky Disease Etiology 120 Limitations of Novel Therapies 120 118

CHAPTER 11 APPENDIX DEFINITIONS 122 ANTIBODY 122 AUTOIMMUNE DISEASE 122 BIOLOGIC THERAPY 122 BOWEL 122 COMPANION DIAGNOSTIC 122 CLINICAL LABORATORY IMPROVEMENT AMENDMENT 123 CROHN'S DISEASE 123 CURRENT PROCEDURAL TERMINOLOGY 123 DIAGNOSTIC SENSITIVITY 123 DIAGNOSTIC SPECIFICITY 123 ILEUM 123 INCIDENCE 123 INFLAMMATORY BOWEL DISEASE 124 MICROBIOTA AND MICROBIOME 124 NUCLEOTIDE 124 PREVALENCE 124 SEROLOGY 124 SINGLE-NUCLEOTIDE POLYMORPHISM 124 TUMOR NECROSIS FACTOR ALPHA 124 ULCERATIVE COLITIS 125

LIST OF TABLES TABLE HEADING SUMMARY TABLE GLOBAL INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, THROUGH 2017 ($ MILLIONS) TABLE 1 GLOBAL INCIDENCE RANGES FOR CROHN S DISEASE AND ULCERATIVE COLITIS (PER 100,000) TABLE 2 GLOBAL PREVALENCE OF CROHN S DISEASE AND ULCERATIVE COLITIS 10 TABLE 3 GLOBAL INCIDENCE FOR CROHN S DISEASE 11 TABLE 4 GLOBAL PREVALENCE FOR CROHN S DISEASE 12 TABLE 5 GLOBAL INCIDENCE FOR ULCERATIVE COLITIS 13 TABLE 6 GLOBAL PREVALENCE FOR ULCERATIVE COLITIS 14 TABLE 7 THERAPEUTIC OPTIONS FOR INFLAMMATORY BOWEL DISEASE 15 TABLE 8 DIAGNOSTIC BIOMARKER EXAMPLES 19 TABLE 9 PREDICTIVE BIOMARKER EXAMPLES 20 TABLE 10 BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE 21 TABLE 11 PUBMED-INDEXED SCIENTIFIC PUBLICATIONS REGARDING INFLAMMATORY BOWEL DISEASE BIOMARKERS, 2002-2012 TABLE 12 OPEN CLINICAL TRIALS FOR CROHN S DISEASE THERAPEUTICS BY LOCATION, 2012 (NUMBER OF TRIALS) TABLE 13 OPEN CLINICAL TRIALS FOR ULCERATIVE COLITIS THERAPEUTICS BY LOCATION, 2012 (NUMBER OF TRIALS) TABLE 14 CLINICAL ASPECTS OF INFLAMMATORY BOWEL DISEASE SUBTYPES 30 TABLE 15 FACTORS FOR CALCULATING THE CROHN S DISEASE ACTIVITY INDEX SCORE 32 TABLE 16 FACTORS FOR CALCULATING THE HARVEY BRADSHAW INDEX 33 TABLE 17 FACTORS FOR CALCULATING THE MAYO SCORE 34 TABLE 18 INFLAMMATORY BOWEL DISEASE SEROLOGIES TO INFORM CLINICAL DIAGNOSES 35 TABLE 19 GENETIC LOCI IMPLICATED IN INFLAMMATORY BOWEL DISEASE 36 TABLE 20 ENVIRONMENTAL RISK FACTORS FOR INFLAMMATORY BOWEL DISEASE 38 TABLE 21 INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET SEGMENTATION 41 TABLE 22 COMPETITOR ASSESSMENT OF THE MAJOR MARKETED INFLAMMATORY BOWEL DISEASE THERAPEUTICS, 2012 TABLE 23 GLOBAL REVENUE FOR INFLAMMATORY BOWEL DISEASE-SPECIFIC NON-BIOLOGIC DRUGS, THROUGH 2017 ($ MILLIONS) TABLE 24 GLOBAL MARKET SHARES FOR INFLAMMATORY BOWEL DISEASE-SPECIFIC NON-BIOLOGIC DRUGS, 2011 ($ MILLIONS/%) TABLE 25 GLOBAL REVENUE FOR INFLAMMATORY BOWEL DISEASE BIOLOGIC DRUGS, THROUGH 2017 ($ MILLIONS) TABLE 26 GLOBAL MARKET SHARE FOR INFLAMMATORY BOWEL DISEASE-SPECIFIC BIOLOGIC DRUGS, 2011 ($ MILLIONS) TABLE 27 LEADING INTERNATIONAL MARKETS FOR INFLAMMATORY BOWEL DISEASE THERAPEUTICS, THROUGH 2017 ($ MILLIONS) TABLE 28 U.S. MARKET FOR INFLAMMATORY BOWEL DISEASE DRUGS, THROUGH 2017 ($ MILLIONS) TABLE 29 JAPANESE INFLAMMATORY BOWEL DISEASE DRUG MARKET, THROUGH 2017 ($ MILLIONS) TABLE 30 EU5 INFLAMMATORY BOWEL DISEASE DRUG MARKET, THROUGH 2017 ($ MILLIONS) TABLE 31 REST OF THE WORLD INFLAMMATORY BOWEL DISEASE DRUG MARKET, THROUGH 2017 ($ MILLIONS) TABLE 32 THERAPEUTIC PIPELINE FOR CROHN S DISEASE THERAPIES 52 TABLE 33 CLINICAL TRIAL RESULTS FOR EMERGING THERAPIES FOR CROHN S DISEASE 53 5 9 21 22 23 41 42 43 46 46 49 50 50 51 52

TABLE HEADING TABLE 34 THERAPEUTIC PIPELINE FOR ULCERATIVE COLITIS THERAPIES 57 TABLE 35 CLINICAL TRIAL RESULTS FOR EMERGING ULCERATIVE COLITIS THERAPIES, 2007-2012 TABLE 36 THERAPIES FOR INFLAMMATORY BOWEL DISEASE 68 TABLE 37 ANTI-DIARRHEAL THERAPIES FOR INFLAMMATORY BOWEL DISEASE 69 TABLE 38 ANTIBIOTIC THERAPIES FOR INFLAMMATORY BOWEL DISEASE 69 TABLE 39 AMINOSALICYLATE THERAPIES FOR INFLAMMATORY BOWEL DISEASE 70 TABLE 40 CORTICOSTEROID THERAPIES FOR INFLAMMATORY BOWEL DISEASE 72 TABLE 41 IMMUNOSUPPRESSANT THERAPIES FOR INFLAMMATORY BOWEL DISEASE 73 TABLE 42 BIOLOGIC THERAPIES FOR INFLAMMATORY BOWEL DISEASE 75 TABLE 43 OPEN CLINICAL TRIALS FOR CROHN S DISEASE THERAPEUTICS BY LOCATION, 2012 (TRIALS) TABLE 44 OPEN CLINICAL TRIALS FOR ULCERATIVE COLITIS THERAPEUTICS BY LOCATION, 2012 (TRIALS) TABLE 45 PUBMED-INDEXED SCIENTIFIC PUBLICATIONS FOR INFLAMMATORY BOWEL DISEASE BIOMARKERS, 2002-2012 TABLE 46 SERUM INFLAMMATORY BOWEL DISEASE BIOMARKERS 83 TABLE 47 FECAL INFLAMMATORY BOWEL DISEASE BIOMARKERS 84 TABLE 48 NOVEL INFLAMMATORY BOWEL DISEASE BIOMARKERS 85 TABLE 49 MAJOR PATENT HOLDERS IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTICS SPACE TABLE 50 PUBLISHED PATENTS FOR PROMETHUES LABORATORIES IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 51 PUBLISHED PATENTS FOR EXAGEN DIAGNOSTICS IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 52 MAJOR PATENT HOLDERS IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTICS SPACE TABLE 53 PUBLISHED PATENTS FOR PFIZER IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 54 PUBLISHED PATENTS FOR NOVARTIS IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 55 PUBLISHED PATENTS FOR NOVARTIS IN INFLAMMATORY BOWEL DISEASE, 2005 2012 TABLE 56 INFLAMMATORY BOWEL DISEASE DIAGNOSTIC COMPANIES 95 TABLE 57 INFLAMMATORY BOWEL DISEASE DIAGNOSTIC COMPANIES BY REVENUE PER EMPLOYEE, 2011 TABLE 58 INFLAMMATORY BOWEL DISEASE THERAPEUTIC COMPANIES 101 TABLE 59 INFLAMMATORY BOWEL DISEASE DIAGNOSTIC COMPANIES BY REVENUE PER EMPLOYEE, 2011 TABLE 60 SIGNIFICANT MERGERS AND ACQUISITIONS IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTIC MARKET, 2008 2012 TABLE 61 SIGNIFICANT VENTURE-CAPITAL DEALS IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTIC MARKET, 2004 2012 ($ MILLIONS) TABLE 62 SIGNIFICANT STRATEGIC ALLIANCES IN THE INFLAMMATORY BOWEL DISEASE DIAGNOSTIC MARKET, 2008 2012 TABLE 63 SIGNIFICANT MERGERS AND ACQUISITIONS IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, 2008 2012 TABLE 64 SIGNIFICANT VENTURE-CAPITAL DEALS IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, 2008 2012 ($ MILLIONS) TABLE 65 SIGNIFICANT STRATEGIC ALLIANCES IN THE INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, 2008-2012 58 77 78 80 89 90 90 91 91 92 93 96 102 113 114 115 115 116 116

TABLE HEADING TABLE 66 STRENGTH, WEAKNESS, OPPORTUNITY AND THREAT ANALYSIS FOR THE GLOBAL INFLAMMATORY BOWEL DISEASE MARKET 118

LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE GLOBAL INFLAMMATORY BOWEL DISEASE THERAPEUTIC MARKET, BY REGION, 2010-2017 ($ MILLIONS) 5