The 9th Technology Presentation March 16, 2012 Table of Contents 1. Opening Remarks Hisashi Ietsugu, President and CEO 2. Strategy and Progress of R&D Mitsuru Watanabe, Member of Managing Board and Executive Officer, Head of R&D (1) Outline of Technology Strategy Strategy for Realizing Personalized Medicine (Initiatives Involving Companion Diagnostics) (2) Launch Stage New Product Technologies 1) XN Series: Proposing Incomparable Laboratory Workflow 2) Silent Design ® 3) CS-5100: Flagship Model in the Hemostasis Field 4) Lab Assay: C2P 5) Progress of OSNA (3) Practical Stage Status of Progress on Development Themes 1) Cervical Cancer Screening 2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology) 3) Diabetes Bio-Simulation 4) Methylated DNA 3. Status of Progress at the Research Stage Kaoru Asano, Executive Officer, Executive Vice President (1) New Activity: Metabolome Analysis Technology 1) Early Detection of Diabetic Nephropathy (2) High-Performance Protein Recombination Technology 1) Sugar Chain Modification Technology (3) Approach toward e-Health 1) Genetic Diagnosis Support System Using Secret Sharing Scheme 1 2. Strategy and Progress of R&D Mitsuru Watanabe, Member of Managing Board and Executive Officer, Head of R&D 2. Strategy & Progress of R&D (1) Outline of Technology Strategy Strategy for Realizing Personalized Medicine (Initiatives Involving Companion Diagnostics) (2) Launch Stage New Product Technologies 1) XN Series: Proposing Incomparable Laboratory Workflow 2) Silent Design ® 3) CS-5100: Flagship Model in the Hemostasis Field 4) Lab Assay: C2P 5) Progress of OSNA (3) Practical Stage Status of Progress on Development Themes 1) Cervical Cancer Screening 2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology) 3) Diabetes Simulation 4) Methylated DNA 3 2. (1) Outline of Technology Strategy Technologies for Realizing Personalized Medicine/ Changes in the Environment 1) Drug reaction simulation, upgrading through structural analysis 抗原Antigen “Humanization” of disease model using iPS cells Amino アミノ酸 acid Patient skin cell iPS cell iPS cell Antibody抗体 induction Cell transplantation Culturing, induction therapy (nerve regeneration treatment) Understanding the reasons for Myocardial neurological diseases cells Pancreatic Evaluation of drug Nerve cells Liver efficaciousness and side cells effects cells Identification of new treatments and diagnostic targets Changes in drug manufacturing process How the EML4- Normal gene creation Normal gene element ALK lung cancer with cytoskeleton causing cell Drug efficacy differs, depending on the patient gene evolves protein proliferation Normal second Responder chromosome Patient 1 Portion cut off and rotated Sudden change halfway Drug A S e con d ch rom o som e Intermediate of cancer patient Patient 2 responder Cancer gene demonstrating abnormal proliferation Patient 3 No responder 5 Technologies for Realizing Personalized Medicine/ Changes in the Environment 2) ChangesChanges inin drugdrug developmentdevelopment process:process: OpportunitiesOpportunities forfor participationparticipation inin companioncompanion diagnosticsdiagnostics (Major) Diagnostic (Major) Drug Target disease Technology Agent Manufacturers Manufacturers (Application) Cancer PCR (patient selection) IHC, ISH Infectious disease Microarray (monitoring) Cancer (patient selection) PCR Cancer (patient selection) PCR Cancer (patient selection) IHC, ISH The Japanese pharma industry is moving toward companion diagnostics. IHC: Immunohistochemistry ISH: In situ hybridization 6 Outline of Technology Strategy Vision of R&D Activity Providing highly valuable diagnostics Overall医療全体 medical testing to optimize and standardize market medical treatment In vivo Medical治療薬 diagnosis生体計測 treatment Companionコンパニオン診断 diagnostics ICT ﾌﾟﾗｲﾏﾘｰｹｱPrimary care 個別化医療Personalized medicine Emerging新興国 markets IVD 7 Creating Diagnostic Value by Strengthening the Technology Platform Personalized Medicine Theranostics Companion diagnostics Cancer, hematology, central nervous system, Primary Care cardiovascular disease Emerging markets Advanced markets Infectious diseases Chronic disease IVD Cell Gene Protein Biochemical compound Thrombosis, hemostasis Immunochromatography Thrombosis, hemostasis Immunochromatography Chemiluminescence Chemiluminescence Non- or minimally Non- or minimally Bio-simulator Bio-simulator DNA chip DNA DNA chip DNA OSNA invasive OSNA FCM invasive FCM TechnologyTechnology PlatformPlatform 8 Companion Diagnostics ◇◇CompanionCompanion diagnosticsdiagnostics (CDx)…(CDx)… 99IsIs an an effective effective approachapproach for for realizing realizing personalized personalized medicine medicine 99InvolvesInvolves development development of of therapeutic therapeutic and and diagnostic diagnostic agents agents inin parallelparallel developmentdevelopment Co-Co- Co-Co- Co-Co- DevelopmentDevelopment RegistrationRegistration ApprovalApproval Benefits and drawbacks of CDx Personalized medicine Reduces development risk, shortens development time V Realizes patient coverage CDx Patient benefit: Early realization of personalized medicine 9 Strategy for CDx Main Focuses in Working toward CDx Biomarker Assay Design Diagnostic Kit Discovery Development •Joint research with •Prototype development •Automation ✓ outside medical institutes •Evaluation of sensitivity/ •Reagent optimization ✓ •Joint business with other specificity for quality- •Proof of clinical benefits companies guaranteed samples with medium- to large- •License-in developed through joint scale clinical study✓ •Use of established research •Approvals ✓ markers ✓Proactively use external ✓Apply Sysmex technology ✓Use Sysmex expertise R&D resources (HISCL, FCM) for (Global sales channels) personalized medicine ✓Introduce PCR technology 10 Strengthening the Technology Platform Sample Initiative: Measurement of HISCL Hepatic Fibrosis Markers 11 Sugar Chain Cell type identification Protecting protein quality Gateway to infection Protein quality control Application in drugs Transport of drug within body Maturity Glycoproteome Sugar chain functions Glycoprotein Majority of proteins Extracellular Glycosylation Glycosyltransferase Protein Proteome Gene expression Proteins 100,000 types Intracellular Various types of stimulation or changes in the Genome environment alter the structure of the sugar chain such Genes that it expresses the “mode of dress” of the protein. 22,000 Nuclear 12 Hepatic Fibrosis and Liver Disease Acute Chronic Cirrhosis of Liver Infection感染 急性肝炎hepatitis 慢性肝炎hepatitis the 肝硬変 liver cancer 肝 癌 Pathology発症 5–155～15年 years Approx.約20年 20 years Approx.約25～30年 25–30 years HCC 年7～8%7–8% Interferonインターフェロン virus Fibrosis線維化進展スピード progression per year Cirrhosis肝硬変（F4） (F4) eradicationウイルス駆除 +0.10／年+0.10/year 3–4%年3～4% ↓ F1～3 per year 慢性肝炎重度（F3）Severe chronic 線維化寛解スピードFibrosis reduction 1–2%年1～2% hepatitis (F3) –0.28/year－0.28／年 per year 慢性肝炎中度（F2）Moderate chronic hepatitis (F2) 0.5%年0.5% per year 慢性肝炎軽度（F1）Slight chronic hepatitis (F1) Existing method(C.O.I.) Shiratori Y, et al: Annals Int Med 32: 517-524, 2000 13 Lectin–Sugar Chain Reaction and Combination with the HISCL Method Antigen / Antibody Reaction Lectin–Sugar Chain Reaction (Conventional Technology) (New Technology) ALP ALP ALP Object of ALP detection: protein Antigen Antigen Antigen (antigen) Antigen Sugar chain Magnetic Lectin particle MagneticMP Antibody particle Maintains identification through sugar chain detection, and enables use of the highly sensitive HISCL method a short period of time. ALP: Alkaline phosphatase 14 Clinical Research Results (Interim Report) Strong correlation with diagnostic requests, such as measurement of malignant alteration HISCLHISCL Method法 Correlation相関 120 100 100.0 25 20 80.0 15 C.O.I.） 60.0 10 （ 発光カウント比（ ％ ） 5 40.0 HISCL法 y = 1.73 x + 0.47 0 12345678 R = 0.93 20.0 F1 F2 F3 F4 (C.O.I) Method HISCL Luminescence Count Comparison (%) Comparison Count Luminescence 0.0 0.0 20.0 40.0 60.0 80.0 100.0 Hepatic肝線維化ステージ fibrosis stage Referenceリファレンス法（C.O.I.） Method (C.O.I.) Source: 2011BioJapan Future developments: Seek approval during FY2012, and after approval has been granted, look into simultaneous development of therapeutic and diagnostic agents 15 Reporting Subjects and Technology Presentation Policies 1. Reporting Subjects ・Technical features of Sysmex technologies and products ・Technical themes on which Sysmex conducts R&D and their clinical benefits ・Outline of Sysmex technology strategy 2. Policy regarding reporting of technological themes Explain R&D themes at the three stages below: <Research stage> Start of research and preliminary evaluation ・Magnitude of value in practical use ・Explanation of future R&D plans <Practical stage> Elemental research, practical and product commercialization stage ・Technological impact on characteristics of products <Launch stage> Accomplishment of development and introduction to market ・Details of technological features and superiority 16 Definition of R&D Stage ResearchResearch stagestage PracticalPractical stagestage LaunchLaunch stagestage Start of research or preliminary evaluation Objective means Start of full-scale R&D Completion of product establishment of 10–50% activity towards 50–80% commercialization and measurement commercialization determination of launch principle and verification of clinical value. value. WNRチャンネル WDFチャンネル FSC FSC FSC B ASO SFSFSF L L L NR BC ・フローサイトメトリー MONO IG LYMP H ・電気抵抗式 NEUT Debris Debris EO SFLSFLSFL Abnormal lymph BA SO SFL WPCチャンネル SSC PLT-Fチャンネル FSFSFS C C C Blast RETチャンネル