IN VITRO TOXICITY TESTING: TECHNOLOGIES AND GLOBAL MARKETS

Transcription

1 IN VITRO TOXICITY TESTING: TECHNOLOGIES AND GLOBAL MARKETS PHM017E January 2014 Robert Hunter Project Analyst ISBN: BCC Research 49 Walnut Park, Building 2 Wellesley, MA USA (toll-free within the USA), or (+1) information@bccresearch.com

2 TABLE OF CONTENTS CHAPTER 1 INTRODUCTION 3 STUDY GOALS AND OBJECTIVES 3 REASONS FOR DOING THE STUDY 3 SCOPE OF REPORT 3 INTENDED AUDIENCE 4 METHODOLOGY AND INFORMATION SOURCES 4 ANALYST'S CREDENTIALS 4 RELATED REPORTS 5 BCC RESEARCH ONLINE SERVICES 5 DISCLAIMER 5 CHAPTER 2 SUMMARY 7 SUMMARY TABLE TOTAL GLOBAL MARKET FOR PREDICTIVE, THROUGH 2017 ($ MILLIONS) SUMMARY FIGURE TOTAL GLOBAL MARKET FOR PREDICTIVE, ($ MILLIONS) 7 7 CHAPTER 3 OVERVIEW 11 BASICS OF 11 TYPES AND APPLICATIONS 11 REGULATORY RISK ASSESSMENT 12 PRODUCT TOXICITY TESTS 12 DEGREES OF TOXICITY 13 ABOUT DOSES 14 DOSE 14 DOSE RESPONSE 14 THRESHOLD DOSE 14 ABOUT TOXIC SUBSTANCES 14 TOXICANT 14 TOXIN 15 ACUTE AND CHRONIC TOXICITY 15 TOXICOKINETICS 15 ABSORPTION 15 Oral 15 Inhalation 16 Dermal and Parenteral Routes 16 DISTRIBUTION 16 METABOLISM 16 EXCRETION 17 TRADITIONAL (IN VIVO) 17 ISSUES WITH IN VIVO APPROACHES 17 Reduction, Refinement and Replacement - the '3Rs' Driver 17 Other Drivers 18 Background: Sheer Volume of Testing Required 18 Conflicting Data 18 Megadosing 19

3 Time and Cost 19 Mixtures of Chemicals 19 Example of Endocrine-Disrupting Chemicals: Bisphenol A 19 NEED FOR MORE EXPOSURE SCIENCE 20 EVOLUTION OF IN VITRO METHODS 21 TOXCAST 21 TOX REACH 22 EU RESEARCH FRAMEWORKS 22 CURRENT ADOPTION OF IN VITRO METHODS 23 INDUSTRY STRUCTURE 23 EXAMPLE OF COMMERCIAL ADOPTION: CARDIOVASCULAR TESTING 25 CHAPTER 4 SPECIFIC TOXICITY TESTS AND FOUNDATIONAL SOLUTIONS (SMALLER SCALE) TESTING FOR ADVERSE EFFECTS ON THE SKIN 27 SKIN IRRITATION 27 SKIN CORROSION 28 PHOTOTOXICITY 29 SKIN SENSITIZATION 29 TESTING FOR EYE IRRITATION 30 OVERVIEW OF ACUTE SYSTEMIC TOXICITY 31 TESTING FOR ACUTE TOXICITY 31 TABLE 1 APPROXIMATE RAT ORAL LD50 FOR VARIOUS CHEMICAL SUBSTANCES (MG/KG) USE OF CYTOTOXICITY ASSAYS FOR ACUTE TOXICITY TESTING 33 EXAMPLE OF COMMERCIALLY AVAILABLE CYTOTOXICITY ASSAY KIT 34 CHRONIC/REPEATED DOSE TOXICITY 34 GOALS OF CHRONIC/REPEATED DOSE TOXICITY STUDIES 35 Effects of Accumulation and Frequency of Exposure 35 Dosage Levels 36 Duration 36 Reversibility 36 Analysis 37 Development of Repeated Dose Toxicity Testing In Vitro 37 CARCINOGENICITY AND GENOTOXICITY 37 INTRODUCTION 37 IN VITRO METHODS: BACKGROUND AND RECENT DEVELOPMENTS 37 REGULATORY VERSUS DRUG DEVELOPMENT APPLICATIONS 38 THE AMES TEST 38 IN VITRO MICRONUCLEUS TEST (MNT) 39 EFFORTS TO REDUCE FALSE POSITIVES 39 EXAMPLE OF RECENT INNOVATIONS 39 FUTURE CHALLENGE: NONGENOTOXIC CARCINOGENS 40 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY 41 BACKGROUND 41 FOLLOWING THE REPRODUCTIVE CYCLE 41 Embryotoxicity

4 FEMALE REPRODUCTIVE TOXICITY 42 MALE REPRODUCTIVE TOXICITY 42 TYPES OF REPRODUCTIVE AND DEVELOPMENT TESTING 43 Zebrafish Model for Developmental Toxicity Screening 43 Combinations of Zebrafish and Stem Cells 44 BIOMEDICAL FRONTIERS 44 ENDOCRINE DISRUPTOR SCREENING 45 BACKGROUND 45 ENVIRONMENTAL IMPACTS ON IN VITRO METHODS 45 U.S. EPA ENDOCRINE DISRUPTOR SCREENING PROGRAM 46 TABLE 2 ASSAYS INCLUDED IN THE TIER 1 SCREENING BATTERY, IN VITRO AND IN VIVO HIGH PRODUCTION VOLUME (HPV) CHEMICALS 47 EDSP 21 Initiative 47 Future Challenge: Thyroid Disruption 47 EXAMPLE OF RECENT DEVELOPMENT: 'BG1' ASSAY 47 CHALLENGE FOR CHEMICAL COMPANIES: DEPTH AND BREADTH 48 Example of a Resource with Full Depth and Breadth 48 TOXICOKINETICS 49 IN VITRO DEVELOPMENTS 50 METABOLISM 50 In Vitro Metabolism Offerings 51 Metabolism Reaction Phenotyping for Genetic Polymorphisms 51 DEVELOPMENTS IN ABSORPTION BARRIER MODELS 52 Gastrointestinal 52 Lung 52 Blood-Brain Barrier 53 REVENUE ESTIMATE 54 SUMMARY 54 TABLE 3 FORECAST FOR FOUNDATIONAL PRODUCTS AND SERVICES USED IN PREDICTIVE, THROUGH 2017 ($ MILLIONS) REVENUE ESTIMATE DETAILS AND PARTIAL LISTS OF SUPPLIERS 54 Tissues, Cell Lines, Primary Cells, Stem Cells 54 TABLE 4 EXAMPLES OF TISSUE-BASED PRODUCTS USED IN PREDICTIVE TABLE 5 EXAMPLES OF ORGANIZATIONS OFFERING IMMORTALIZED CELL LINES USED IN PREDICTIVE TABLE 6 EXAMPLES OF COMPANIES OFFERING PRIMARY CELLS FOR PREDICTIVE TABLE 7 EXAMPLES OF COMPANIES PROVIDING STEM CELLS FOR PREDICTIVE REAGENTS AND LABWARE 57 TABLE 8 EXAMPLES OF COMPANIES OFFERING REAGENTS AND LABWARE FOR PREDICTIVE Services 57 TABLE 9 EXAMPLES OF COMPANIES OFFERING SERVICES TAILORED FOR PREDICTIVE Basic Equipment

5 TABLE 10 EXAMPLES OF COMPANIES SUPPLYING BASIC EQUIPMENT FOR FOUNDATIONAL INDUSTRY SEGMENTATION 59 COSMETICS INDUSTRY 59 TABLE 11 FOUNDATIONAL REVENUES ATTRIBUTED TO COSMETICS INDUSTRY, THROUGH 2017 ($ MILLIONS) PHARMACEUTICAL INDUSTRY 61 TABLE 12 FOUNDATIONAL REVENUES ATTRIBUTED TO PHARMACEUTICAL INDUSTRY, THROUGH 2017 ($ MILLIONS) CHEMICAL INDUSTRY 62 TABLE 13 FOUNDATIONAL REVENUES ATTRIBUTED TO CHEMICAL INDUSTRY, THROUGH 2017 ($ MILLIONS) CHAPTER 5 TOOLS USED FOR TRANSCRIPTOMICS, PROTEOMICS AND METABOLOMICS OVERVIEW 64 OVERVIEW OF TRANSCRIPTOMICS 64 TOOLS USED IN TRANSCRIPTOMICS 65 MICROARRAYS 65 NEXT-GENERATION SEQUENCING 66 OVERVIEW OF PROTEOMICS 66 OVERVIEW OF METABOLOMICS 67 OVERVIEW OF METALLOMICS 68 TOOLS USED IN PROTEOMICS 68 TABLE 14 PARTIAL LIST OF MASS SPEC SYSTEMS FOCUSED ON PROTEOMICS APPLICATIONS TOOLS USED IN METABOLOMICS 70 DETECTION 70 SEPARATION 71 HYPHENATED APPROACHES 71 TABLE 15 COMMON ANALYTICAL PLATFORMS USED IN METABOLOMICS 72 TOOLS USED IN METALLOMICS 73 REVENUE ESTIMATE FOR TRANSCRIPTOMICS TOOLS 73 TABLE 16 GLOBAL MARKET FOR TRANSCRIPTOMICS TOOLS USED IN PREDICTIVE, THROUGH 2017 ($ MILLIONS) TOOLS USED IN PROTEOMICS AND METABOLOMICS 73 DETECTION - USED IN PROTEOMICS AND METABOLOMICS 74 TABLE 17 GLOBAL MASS SPECTROMETRY MARKET, THROUGH 2017 ($ BILLIONS) 74 SEPARATION - USED IN METABOLOMICS 74 REVENUE ESTIMATE FOR PROTEOMICS AND METABOLOMICS TOOLS 75 TABLE 18 GLOBAL MARKET FOR PROTEOMICS AND METABOLOMICS TOOLS USED IN PREDICTIVE, THROUGH 2017 ($ MILLIONS) DISCUSSION CHAPTER 6 CELLOMICS 78 BACKGROUND 78 EARLIER APPLICATIONS OF FLUORESCENCE 78 HIGH CONTENT SCREENING (HCS) 79

6 TABLE 19 EXAMPLES OF COMPANIES SUPPLYING HIGH CONTENT SCREENING (HCS) SOLUTIONS FOR PREDICTIVE LABEL-FREE PLATFORMS 81 TABLE 20 EXAMPLES OF LABEL-FREE TECHNOLOGY AND THE COMPANIES SUPPLYING THEM ELECTROPHYSIOLOGY 82 TABLE 21 EXAMPLES OF COMPANIES PROVIDING SERVICES FOCUSED ON CELLOMICS (LARGER SCALE STUDIES) FOR PREDICTIVE RECAP OF PREDICTIVE VS. MECHANISTIC 83 SAFETY TESTING OF CARDIOVASCULAR DRUG CANDIDATES 84 MICROELECTRODE ARRAYS (MEA) BASED ON IMPEDANCE 84 MICROARRAY TECHNOLOGY USED IN CELLOMICS 85 REVENUE ESTIMATE 86 TABLE 22 ESTIMATED REVENUES FOR CELLOMICS TOOLS USED IN PREDICTIVE BY TYPE OF EQUIPMENT, THROUGH 2017 ($ MILLIONS) CHAPTER 7 ASSAY KITS, CELL LINES, STEM CELLS, CONSUMABLES AND SERVICES FOR LARGER SCREENING APPLICATIONS OVERVIEW 89 REAGENTS FOR 'HOMEBREW' ASSAY DEVELOPMENT 89 ASSAY KITS FOR HIGH CONTENT SCREENING 89 CELL-BASED ASSAYS: OVERVIEW AND NEWER DEVELOPMENTS 89 COMPONENTS OF CELL-BASED ASSAY SYSTEMS 90 Microplates 91 IMPORTANCE OF 3D VERSUS 2D SYSTEMS 92 Microfluidics and 'Organs on a Chip' 93 3D Models for Skin 93 TYPES OF CELLS USED IN CELL-BASED ASSAYS 93 Immortalized Cell Lines and Primary Cells for Screening 94 Stem Cells at Scale for Screening 94 MODEL FOR ADOPTION: CARDIOVASCULAR SAFETY TESTING 95 APPLICATIONS IN LIVER TOXICITY STUDIES 97 USE OF STEM CELL-DERIVED HEPATOCYTES 98 CURRENT CHALLENGES: APPLICATIONS TO IMMUNE MEDIATED DILI 98 APPLICATIONS IN KIDNEY TOXICITY STUDIES 99 FUTURE CHALLENGE: STEM-CELL DERIVED KIDNEY CELLS 100 REVENUE FORECAST 100 TABLE 23 ESTIMATED REVENUES FOR ASSAY KITS, OTHER CONSUMABLES AND ASSOCIATED SERVICES USED IN PREDICTIVE BY TYPE, THROUGH 2017 ($ MILLIONS) CHAPTER 8 OVERVIEW OF IN SILICO TOOLS USED IN PREDICTIVE 102 BACKGROUND 102 GENE EXPRESSION CLASSIFIERS BASED ON STATISTICAL ANALYSIS 102 FUNCTIONAL CLASSIFIERS BASED ON PATHWAYS AND NETWORKS 103 USE OF PATHWAY MAPS 104 QSARS 106 MODEL-BASED DRUG DEVELOPMENT 106 EXAMPLES OF COMMERCIALLY AVAILABLE SOLUTIONS 107

7 INGENUITY PATHWAY ANALYSIS (IPA) 107 GENEDATA SCREENER AND EXPRESSIONIST 109 THOMSON REUTERS METADRUG 109 ENTELOS PHYSIOLAB MODELER 110 REVENUE ESTIMATE 110 TABLE 24 ESTIMATED REVENUES FOR IN SILICO PRODUCTS AND ASSOCIATED SERVICES USED IN PREDICTIVE, BY TYPE, THROUGH 2017 ($ MILLIONS) 110 CHAPTER 9 BIOMARKERS AND OTHER BREAKOUT BUSINESS MODELS 112 BIOMARKERS 112 OVERVIEW AND SCOPE 112 CHALLENGES AND POSSIBLE SOLUTIONS 113 DRUG RESCUE 114 PRECISION MEDICINE APPLICATIONS 114 REVENUE ESTIMATE 115 TABLE 25 ESTIMATED REVENUES FOR BIOMARKERS AND OTHER BREAKOUT BUSINESS MODELS BASED ON PREDICTIVE BY TYPE, THROUGH 2017 ($ MILLIONS) 115 CHAPTER 10 APPENDIX 117 PATENT ANALYSIS 117 TABLE 26 EXAMPLES OF SOME IMPORTANT PATENTS RELATIVE TO PREDICTIVE SAMPLE COMPANY PROFILES 121 ACCELRYS INC. 121 ACEA BIOSCIENCES INC. 122 AGILENT TECHNOLOGIES INC. 123 APTUIT INC. 125 BIOGNOSYS AG 126 BIORELIANCE 128 CEETOX INC. 129 CELLULAR DYNAMICS INTERNATIONAL INC. 130 CENTER FOR ALTERNATIVES TO ANIMAL TESTING (CAAT) 131 CHANTEST 132 CHARLES RIVER LABORATORIES 133 CYPROTEX PLC 134 ENTELOS 135 ENZO LIFE SCIENCES INC. 136 EUROPEAN UNION REFERENCE LABORATORY FOR ALTERNATIVES TO ANIMAL TESTING (EURL) GE HEALTHCARE LIFE SCIENCES UK 138 GENEDATA 140 GENTRONIX LIMITED 140 THE HAMNER INSTITUTES FOR HEALTH SCIENCES 141 HEALTH AND ENVIRONMENTAL SCIENCES INSTITUTE (HESI) 142 HUMANE SOCIETY INTERNATIONAL (HSI) 143 HUREL CORPORATION 144 IMSTAR S.A

8 INGENUITY SYSTEMS 146 INSPHERO AG 147 INSTITUTE FOR IN VITRO SCIENCES INC. (IIVS) 148 INTELLICYT CORPORATION 149 KIYATEC INC. 150 MEDICYTE GMBH 151 METABOLON INC. 152 MOLECULAR DEVICES, LLC 153 NTP INTERAGENCY CENTER FOR THE EVALUATION OF ALTERNATIVE TOXICOLOGICAL METHODS (NICEATM) OCIMUM BIOSOLUTIONS LCC 156 PERKINELMER INC. 157 STEMINA BIOMARKER DISCOVERY INC. 158 STRATATECH CORPORATION 159 SYNVIVO INC. 160 THERMO FISHER SCIENTIFIC 161 TNO 162 VALA SCIENCES INC. 163 VISTAGEN THERAPEUTICS INC. 164 ZEN-BIO INC. 165 XRPRO CORPORATION

9 LIST OF TABLES TABLE HEADING SUMMARY TABLE TOTAL GLOBAL MARKET FOR PREDICTIVE, THROUGH 2017 ($ MILLIONS) TABLE 1 APPROXIMATE RAT ORAL LD50 FOR VARIOUS CHEMICAL SUBSTANCES (MG/KG) TABLE 2 ASSAYS INCLUDED IN THE TIER 1 SCREENING BATTERY, IN VITRO AND IN VIVO TABLE 3 FORECAST FOR FOUNDATIONAL PRODUCTS AND SERVICES USED IN PREDICTIVE, THROUGH 2017 ($ MILLIONS) TABLE 4 EXAMPLES OF TISSUE-BASED PRODUCTS USED IN PREDICTIVE 54 TABLE 5 EXAMPLES OF ORGANIZATIONS OFFERING IMMORTALIZED CELL LINES USED IN PREDICTIVE TABLE 6 EXAMPLES OF COMPANIES OFFERING PRIMARY CELLS FOR PREDICTIVE TABLE 7 EXAMPLES OF COMPANIES PROVIDING STEM CELLS FOR PREDICTIVE TABLE 8 EXAMPLES OF COMPANIES OFFERING REAGENTS AND LABWARE FOR PREDICTIVE TABLE 9 EXAMPLES OF COMPANIES OFFERING SERVICES TAILORED FOR PREDICTIVE TABLE 10 EXAMPLES OF COMPANIES SUPPLYING BASIC EQUIPMENT FOR FOUNDATIONAL TABLE 11 FOUNDATIONAL REVENUES ATTRIBUTED TO COSMETICS INDUSTRY, THROUGH 2017 ($ MILLIONS) TABLE 12 FOUNDATIONAL REVENUES ATTRIBUTED TO PHARMACEUTICAL INDUSTRY, THROUGH 2017 ($ MILLIONS) TABLE 13 FOUNDATIONAL REVENUES ATTRIBUTED TO CHEMICAL INDUSTRY, THROUGH 2017 ($ MILLIONS) TABLE 14 PARTIAL LIST OF MASS SPEC SYSTEMS FOCUSED ON PROTEOMICS APPLICATIONS TABLE 15 COMMON ANALYTICAL PLATFORMS USED IN METABOLOMICS 71 TABLE 16 GLOBAL MARKET FOR TRANSCRIPTOMICS TOOLS USED IN PREDICTIVE, THROUGH 2017 ($ MILLIONS) TABLE 17 GLOBAL MASS SPECTROMETRY MARKET, THROUGH 2017 ($ BILLIONS) 73 TABLE 18 GLOBAL MARKET FOR PROTEOMICS AND METABOLOMICS TOOLS USED IN PREDICTIVE, THROUGH 2017 ($ MILLIONS) TABLE 19 EXAMPLES OF COMPANIES SUPPLYING HIGH CONTENT SCREENING (HCS) SOLUTIONS FOR PREDICTIVE TABLE 20 EXAMPLES OF LABEL-FREE TECHNOLOGY AND THE COMPANIES SUPPLYING THEM TABLE 21 EXAMPLES OF COMPANIES PROVIDING SERVICES FOCUSED ON CELLOMICS (LARGER SCALE STUDIES) FOR PREDICTIVE TABLE 22 ESTIMATED REVENUES FOR CELLOMICS TOOLS USED IN PREDICTIVE BY TYPE OF EQUIPMENT, THROUGH 2017 ($ MILLIONS) TABLE 23 ESTIMATED REVENUES FOR ASSAY KITS, OTHER CONSUMABLES AND ASSOCIATED SERVICES USED IN PREDICTIVE BY TYPE, THROUGH 2017 ($ MILLIONS) TABLE 24 ESTIMATED REVENUES FOR IN SILICO PRODUCTS AND ASSOCIATED SERVICES USED IN PREDICTIVE, BY TYPE, THROUGH 2017 ($ MILLIONS) TABLE 25 ESTIMATED REVENUES FOR BIOMARKERS AND OTHER BREAKOUT BUSINESS MODELS BASED ON PREDICTIVE BY TYPE, THROUGH 2017 ($ MILLIONS)

10 TABLE HEADING TABLE 26 EXAMPLES OF SOME IMPORTANT PATENTS RELATIVE TO PREDICTIVE 116

11 LIST OF FIGURES FIGURE TITLE SUMMARY FIGURE TOTAL GLOBAL MARKET FOR PREDICTIVE, ($ MILLIONS) 6