Enabling Unbounded Possibilities
WuXi RSD Leadership: WuXi RSD Business Development: Steve Yang [email protected] US: Declan Ryan [email protected] EU: Dave Madge [email protected] Israel: Dana Yarden [email protected] Japan: Yan Zhu [email protected], Korea: Suk Young Cho [email protected] China: Marcher Xu [email protected] Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Comprehensive R&D enabling capability The WuXi AppTec Research Service Division (RSD) aims at and metabolic diseases), Crelux and newly acquired HD providing superior support to our partners and promoting Biosciences (HDB). This new integration will provide closer RSD integrated platforms enable anyone or any company to discover and develop new drugs and products benefit to efficiency and collaboration between WuXi’s business points of contacts for our partners and discovery teams, patients. RSD services deliver extraordinary performance and an unwavering focus on customer satisfaction. units. RSD combines WuXi’s capability and technology streamline the exceptional services offered across our platform in chemistry, biology, oncology, and immunology platform, and enhance efficiency and productivity to drug R&D Biological Science Chemistry to provide open access and integrated service for drug discovery. We will focus on boosting our scientific discovery and research. The services include in the new capabilities and leading technology development to . Target validation, CRISPR . Reference compounds RSD are the International Discovery Service Unit (IDSU), maintain WuXi’s industry leading position in technology . Protein production . Arrays, Libraries, DELs . HTS, FBDD the Chemistry Service Unit (CSU), the Oncology- and research service. We aim to provide outstanding Target-to-hit . Unique scaffolds, building blocks Immunology Unit, the Core Analytical Services Unit (CAS), service to our existing partners and to our broader . X-ray crystallography . DNA-Encoded Libraries . Biophysical analytics the Biology Unit (which includes HTS, in vitro screening, discovery community! . Customized screening decks infectious diseases, neurosciences, fibrosis, cardiovascular . CADD
Steve Yang, Ph.D. . In vitro efficacy & MoA . SAR generation Chief Business Officer . In vivo efficacy . Molecule design EVP & Head of RSD Hit-to-lead . PK/PD analysis . Building blocks
International Discovery Service Unit Chemistry Service Unit (CSU) Core Analytical Services Unit (IDSU) . Speed and quality syntheses (CAS) . In vitro SAR support . Optimization of hits and . Med. Chem. design solutions . Shorten synthesis cycle time . Analytical testing and release . Selectivity panel Lead leads . Project management . High throughput purification . Cell panel Optimization . Data interpretation . Deliver preclinical candidates . SFC large scale chiral . In vivo target engagement separation . Candidate selection . In vivo pharmacology . Impurity isolation and identification . Natural products
. hERG, other safety profiling . Scale up of candidates for IDSU CSU CAS services preclinical studies . Ligand binding Pre-clinical . Synthetic optimization of . Receptor profiling candidates . Additional in vitro and in vivo . Metabolic and impurity characterization identification synthesis Oncology Biology Immunology Crelux HDB
. PDX . Tumor TILs Clinical I - III . Biomarkers Biology Unit Oncology-Immunology Unit Crelux HD Biosciences (HDB) . CAP-certified FACS, pathology, . HTS and novel libraries . CRISPR, targeted oncology . High quality protein . Biology-focused molecular testing . In vitro screening (PDX), immuno-oncology, production preclinical drug platform translational oncology . Fragment screening discovery . General pharmacology Immunology Center and biophysical hit . Drug target validation . Infectious disease . Autoimmune and finding . HTS, H-T-L and LO platform inflammatory diseases . X-ray crystallography program support . Specialty models . Efficacy PK/PD, Commercial including NASH disease models Enabling Unbounded Possibilities Enabling Unbounded Possibilities
A steady flow of innovations and portfolio expansions Leadership and excellence in contract research
A number of historical milestones characterize RSD’s process. Throughout the past decade, we have introduced journey from regional individual testing services to new testing technologies, animal models, libraries and integrated platforms and massive capacity that enable us other chemistry and biology services through a steady to provide outstanding and cost-effective services to help flow of innovations, expansions and acquisitions. our global clients tackle challenges in their drug discovery
Scale-up facility Acquired HD for peptide synthesis Biosciences
Immunology Core Acquired Crelux
Supported delivery Novel technologies - of >60 preclinical drug CRISPR, PDX, & CDX candidates
Benefits of Partnering with WuXi AppTec RSD
■ Track record of leadership and excellence in contract research Launched ■ A broad and integrated portfolio of discovery services and seamless transition development services OncoWuXi database ■ >5,000 scientists across integrated chemistry and biology platform
■ Fast turnaround, comprehensive services, cost-effective solutions and quality results
■ Global footprint with operations in North America, Asia and Europe GLP-certified hERG testing ■ Established stringent policies and procedures for IP protection
AAALAC accredited SPF animal facility Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Synthesis with speed and quality CSU Services The Chemistry Service Unit (CSU) is led by an experienced . WuXi-designed templates/template libraries. scientific leadership team staffed with over 1,300 synthetic . Extensive access to reagents and components through and analytical/purification chemists. Services by CSU range WuXi LabNetwork. from custom synthesis of client-directed molecules and . Compound collection management including storage, libraries to WuXi designed templates. Our focus on registration, distribution, etc. Synthetic Catalog Analytical Peptide technology and continued innovation allows us to offer . Impurity isolation, identification and structure chemistry reagents services services specialized services in peptides, nucleosides, fluorine assignment/confirmation. chemistry and natural products, all led by experts of the . Natural product extracts or purified natural product . Building block . Templates . Chiral separations . Non-GMP respective fields. sourcing, purifications, QA/QC and structure elucidation. synthesis . Reagent service . Impurity analysis peptide synthesis . Library synthesis . Compound . Natural products . GMP facility in . Custom synthesis management 2017 . Scale up synthesis . Route scouting . Discovery-process chemistry (DPC)
Discovery process chemistry Discovery scale & rapid scale-up (DPC) . Support for early-stage . Combination of strong research programs discovery chemistry . Rapid scale-up for late- experience stage needs . Strong route scouting capability Snapshot of Accomplishments CSU Service >17 years of experience in route design and synthesis Capabilities >1,000 clients worldwide Catalog >3 million compounds delivered, >20,000 each year . >3,000 templates developed Library synthesis . >14,000 unique scaffolds and . Rapid production >25,000 reagents plus 8,000+ novel building blocks in building blocks in stock . Diverse chemistries stock . 104K screening compounds >95% on-time delivery rate and short cycle time 20-30% client synthetic routes re-designed by CSU Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Enables discovery stage of drug research
The International Discovery Service Unit (IDSU) is WuXi’s IDSU’s peer-recognized expertise and WuXi’s solution to address our industry’s drug discovery integrated platform from hit identification to preclinical challenges through expertise in medicinal chemistry and candidate selection and beyond. With some of the program management. We collaborate closely with our industry’s finest and most experienced medicinal international customers ranging from pharma and biotech chemists at WuXi, we aspire to become the partner-of- to academia to rapidly advance programs towards key choice in externalized solutions to enable advancement inflection points and milestones by leveraging of programs in ways that are both smarter and faster.
Leveraging WuXi Integrated Discovery Capability
. >2,700 chemists . Discovery to candidate selection & scale-up . Radiolabel synthesis Synthetic Chemistry . Rodents to NHPs Snapshot of Accomplishments . Discovery to IND- enabling >113,000 compounds delivered in . Protein crystallography Structural 74 patent applications with WuXi ADME & . Metabolite ID . FBDD, SBDD Biology & 2017 inventors DMPK . Radiolabeled studies . Modeling & Computational Medicinal >190 clients globally and >80% 27 preclinical candidates (PCCs) Chemoinformatics Chemistry from biotech and non-profit delivered in 2017 organizations 1st FDA-approved drug from 34 publications in 2017 WuXi integrated platform
In Vitro Biology Safety Assessment . Multiple biology screening & In Vivo & Toxicology platforms Pharmacology . HTS, component collection . Electrophysiology . Non-GLP and GLP . Biophysical characterization . Toxicokinetics & bioanalytical . Oncology, immuno-oncology, Partnering with IDSU immunology core, infectious . Pathology diseases, neuroscience & CV/MED Collaborative. Having delivered 27 preclinical candidates in 2017 for our partners, we understand the unique challenges . Translational models and needs of each program. We work closely with partners to establish strategy, customize resources and guide project execution to deliver on goals. . Genomic Center (CLIA-certified) . Biomarkers China Platform WuXi’s IDSU Team Partner
Execution of HTS & chemistry Medicinal chemistry Disease biology Target Hit project execution target of interest Lead Submission in vitro & in vivo biology to to Preclinical Phase I Phase II Phase III program management in-house expertise optimization & launch DMPK & formulation hit lead safety assessment
Efficient. We provide our customers with access to WuXi’s best-in-class, fully integrated drug discovery and development platform to seamlessly progress programs from target through to preclinical candidate selection and beyond. Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Provide high quality integrated analytical services in a rapid & cost saving manner Dedicated to Provide Analytical, Purification and Structure Elucidation Services
Discovery Chemistry CHINA The Core Analytical Services Unit (CAS) is led by a . SFC and/or HPLC chiral separation (mg to multi kg) dedicated and knowledgeable team with extensive . Regulated Analytical Research Services (ARS) for Drug experience. Our focus on technology and continued Development innovation allows us to offer specialized services in chiral . High-throughput purification (500,000-700,000 compounds separation, high-throughput purification, physiochemical annually) property determination, and impurity isolation and Tianjin . Structure confirmation/elucidation (HRMS, 1D/2D NMR) Core Analytical Services Unit (CAS) identification to our clients, and to meet their needs for . Physicochemical property determination (pKa, LogP/LogD, accurate and high quality data analysis on tight budget. thermodynamic and kinetic solubility, concentration) Shanghai The CAS Unit is equipped with best-in-class automated Wuhan instruments to provide extensive GMP and non-GMP . Natural products extraction, purification, structure conditions in both small and large scales. identification and quality analysis . Isolation and structure elucidation for impurities of Process Chemistry regulatory starting materials, intermediates, APIs and drug products.
Integrated Analytical Services . Physiochemical properties: pKa, LogD/LogP, thermodynamic and . Drug substance services kinetic solubility, etc. . Drug product services . Structure confirmation/elucidation . Stability studies . Reference material Physiochemical . Capability to purify / standardization Property characterize 500,000 . Impurity isolation and Determination compounds structure elucidation . MS and UV triggered Prep Regulated HPLC fraction collection Snapshot of Chiral Separation Accomplishments High- Analytical . Standard LC-UV-ELSD-MS throughput Research CAS platform for QC of isolated Purification compound ■ 14 sets analytical SFC, two equipped with MS detector Services ■ 12 sets semi-preparative SFC (flow rate 70-80 ml/min) equipped with 2.5cm and 3cm columns Major Services Chiral ■ 11 sets prep-SFC instruments (flow rate 200-350 ml/min) equipped for Natural Separation with 5cm columns . High purity single compound Products Services . SFC/HPLC chiral separation as reference . Separation method ■ 130 sets semi-prep and prep-HPLC to purify samples from mg to . Most major natural product development multi-kg scales classes covered in CAS Library, . Milligram and multi-kg scale ~16% novel . (Non-exclusive separation ■ Centralized CO2 delivery system with two 2,000-liter tanks basis ) . ee Determination . Bioassay guided isolation . Pure enantiomer racemization . Quality analysis of crude or study enriched extracts . Isolation of impurities/by- . Large scale single compound products extraction and isolation. Enabling Unbounded Possibilities Enabling Unbounded Possibilities
End-to-end service and solution to enable cancer drug discovery
Part of the Oncology and Immunology Unit, WuXi immune profiling platform including TILs analysis, IHC Oncology team works efficiently with partners to enable and TCR repertoire to advance immune-oncology OncoWuXi Database cancer drug discovery through our leading oncology and discovery. Our CRISPR screening and surrogate immuno-oncology service capabilities. We provide a wide antibodies can offer target validation service. The >1,500 tumor models panel of in vivo tumor model systems including human oncology topnotch team has extensive experience in cancer cell line-derived xenograft (CDX) models, murine IND-enabling studies for both FDA and CFDA filing as Full annotation syngeneic tumor models/humanized models, and patient- either standalone or integrated drug discovery o >3,000 growth curves derived xenograft (PDX) models with in-depth genomic programs, plus clinical biomarker service to support characterization. We have established a comprehensive clinical trials. o >2,800 histology images o >250 SOC studies WuXi Oncology Capabilities Solutions o >800 WES, CNV, Microarray & RNAseq
>340 scientists, 70% with Services MS/PhD
AAALAC credited SPF animal facility
>6,000 IVC-cages capacity in SPF barrier
Oncology Platforms Oncology Platforms from Drug Discovery to Translational Science
. CRISPR library in vitro & in vivo . Xenograft Models CRISPR/Cas9 Oncology TI/TS LO/TS IND/TS Clinical/Beyond screening o >180 cell- linederived xenograft o 18,000 genes (CDX) models o Customized library o 27 orthotropic models . KO/KI of target genes o >1,000 patient-derived Enable . In vitro cancer biology xenograft (PDX) models o SOC and genomic profiling o Pathology services Medicinal Chemistry Toxicology cGMP Biology . Biomarker discovery o 18-color FACS-based analysis & sorting . 54 syngeneic models o Pathology lab Biologics WuXi NextCODE CDx Analytics Discovery & o Validated with checkpoint o Multiplexed IHC Immuno- Clinical inhibitors . Clinical Biomarker Services Oncology Biomarkers o Immune profiling capability DMPK Clinical Trial CMC Commercial o IHC, FISH, DISH, FACS o CAP accreditation and GCP o Humanized models compliance Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Efficacy and MoA study to facilitate immunotherapy drug discovery
Immunology Center Services Part of the Oncology and Immunology Unit, WuXi efficacy and in depth mechanism of action (MoA) studies Immunology Center is built to provide a comprehensive by utilizing our cancer immunology platform, autoimmune open platform for immunological service of preclinical and & inflammatory animal models, and biomarker detection clinical studies, and to facilitate immunotherapy drug services. Our pathology lab and flow cytometry lab are discovery in cancer, autoimmune and inflammatory equipped with best-in-class automated instruments and diseases. Led by a group of US and European trained set up to follow GCP compliance and CAP regulation. immunologists, the team primarily serves clients’ needs for In Vitro/Ex Vivo Flow Cytometry In Vivo Models Histology Core Immunology Core
. Adoptive T cell . Immune cell . IHC, FISH, DDISH . Surface & intracellular therapy functions . Pre-clinical & markers . Autoimmune & . Cytokines/ clinical studies . Pre-clinical & inflammatory chemokines . GCP/CAP diseases clinical studies . Adoptive T cell compliance . GCP/CAP . Cancer therapy . Biomarker services immunotherapy compliance . Biomarker services
Immunology Center Capability
Autoimmune diseases, Cancer inflammatory immunology animal models platform
Integrated Snapshot of Accomplishments Cell-based Lab with GCP biomarkers (flow- Immunology compliance & CAP ■ >100 validated biomarkers cytometry lab) Platform accreditation ■ Laboratories with GCP compliance and CAP accreditation ■ Top flow cytometry service lab among CROs ■ Combination immunotherapy evaluation Soluble biomarkers Tissue-based (ELISA, Luminex, biomarkers CBA, MSD) (pathology lab)
Enabling Unbounded Possibilities Enabling Unbounded Possibilities Biology
An open access biology platform for global drug innovation
Snapshot of Accomplishments The Biology Unit offers plate-based screening services cardiovascular diseases, metabolic disorders including HTS, SAR screening support, compound fibrotic diseases. The 310+ membered team is >250 global collaborators including 14 partners from top 20 selectivity and early safety profiling, and cancer cell panel composed of 11% PhD, 54% MSc, and led by 14 profiling. In addition, we offer disease models and seasoned scientific leaders with an average of 15 pharmaceutical companies therapeutic expertise in CNS and pain, infectious diseases, years of R&D experience in US, Canada, and UK. >40 drug candidates delivered in 2008-2014 through integrated platforms 1st GLP-certified hERG testing; CAP-certified FACS, pathology and molecular testing Lab (clinical virology) Global Biology Footprint with Global Centers of Excellence
. MoA . Stand alone services . HTS & novel screening libraries . Integrated programs . HTS & novel screening libraries . Assay development . Broad therapeutic area coverage . Established in 2015 . In vitro & in vivo pharmacology . Broad industry experiences . Structural biology . >43,000 sq ft of Biology Labs, AAALAC- Snapshot of Capabilities accredited SPF animal facility . >250 global partners ~340 experienced scientists in in vivo and in vitro biology . >40 drug candidates delivered in 2008-2014 13 Senior managers trained in US & Canada, 10 with >15 years through integrated team effort R&D experience . 1st GLP-certified hERG testing; CAP-certified molecular testing Lab (clinical virology) HTS services in US, Europe and China to support global clients 43,000 sq ft biology labs and AAALAC-accredited animal facility
One Stop Shop at WuXi – Integrated Discovery Roadmap
Partner Hit Validation R&D Idea In Vitro Assay Lead HTS & Hit & Hit to Lead New Target Development Optimization Confirmation Series Optimization /Biology 384 & 1536 to PCC /Mechanism Expansion . Global leader in crystallography & biophysical compound validation . Rapid, high quality protein production . Biophysical assays & screening The Only Comprehensive CRO Offers HTS Services in US, EU, & China . Structural biology for difficult targets China: Assay Development, Transfer . FBDD US: Assay Design & Screening EU: Protein & Screening . >10 orthogonal biophysical assays for screening & characterization . Close to 200 targets ready for complex structure solution with client ligands . XPRESS, XPEDITE, XPERT services . 100s of structures, greater than 15 target classes, small molecules, antibody structures . >80 global partners (pharma, biotech, academic institutes) Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Global leader in structural biology and biophysical solutions
Crelux, founded in 2005 at the Innovation & Startup including protein production, biophysical assays, Snapshot of Accomplishments Center for Biotechnology (IZB) in Martinsried, Germany, is fragment screening, and X-ray crystallography. The a global leader in structure-based drug discovery. Crelux acquisition represents a further step in the growing >200 New structures every year, across 30 or more protein has been providing the drug discovery industry with highly European presence of WuXi AppTec and reaffirms targets individualized and efficient solutions to inform and WuXi's strong commitment to better serving and Comprehensive coverage of target classes and therapeutic accelerate their programs for more than a decade. Crelux interacting with European customers. It provides a modalities provides a number of customized services to support hit- solid foundation for WuXi to expand its integrated Multiple drug discovery programs leading to launched products finding, conformational analysis and lead optimization, drug discovery services within Europe. supported with Crelux structural biology data >80% Returning clients
Hit Finding Validation Optimization High Quality Proteins · FBDD · Biophysical Assays and Screening · X-ray Crystallography Snapshot of Capabilities
High quality protein production >10 Orthogonal biophysical assays and screening systems >170 Targets ready for XPRESS complex structure solution with client ligands Fragment-based screening with >3,000-member novel fragment library Cryo-EM Cell-based thermal shift assays (CETSA) for target engagement
STRUCTURE INFORMED DISCOVERY Delivering Individualized Structure-Based Drug Discovery Solutions
>170 established targets for fast-track complex structures X-ray crystallography of challenging targets
Your discovery. Our solutions. At Europe’s #1 bio hub >10 biophysical validation technologies Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Key Elements and Gap Analysis Exercise: When a Collaboration Starts Your world-class partner for accelerated drug discovery • Resources & Procurement • Logistics Requirements • Infrastructure and teams HD Biosciences was founded in 2002 and is Biosciences is an important step in strengthening • Team and specific expertise headquartered in Shanghai, China with operating facilities WuXi’s biology and preclinical service capability from • SOP driven process in Beijing, China and San Diego, USA. As a leading biology target validation to lead discovery and optimization, and preclinical service provider, our plate-based improving and expanding WuXi’s open-access • Infrastructure gap enabling service platform. The combination of WuXi pharmacology, screening capability and AGMTM based Gaps & AppTec and HD Biosciences will also provide additional • Team & expertise gap target validation are industry leading platforms with great common resources and space to take our biology focused challenges • Technology gap reputation. HD Biosciences also provides hit identification, capabilities to the next level and to speed up the • Process gap lead discovery, in vivo pharmacology and other related growth of our business into a leading global player services. During the past 14 years, HD Biosciences has within our sector. We will provide better services to our • Leadership identification & capability assessments, key to the solution developed into a global company with wide recognition. current clients and expand services to WuXi’s global Shared practice • Resources availability, conventional & alternatives, time line for procurement The business combination of WuXi AppTec and HD customers. for solution • Expertise & infrastructure, internal and external; solutions for in house buildup, backup plan development • Process and PM, faster implementation with open communication & execution • Mindset for continual improvement • Talent team with track record Competitive • Experience in running multiple programs & multiple clients Snapshot of Capabilities advantages at HD Biosciences • Established structure with partners and clients in logistics/PM, IT/data support, etc. Plate-based pharmacology with comprehensive assay technologies • All established SOPs, EHS that compatible with industry standard and matching screening capability (SAR, HTS, profiling) Advanced Gene Manipulation (AGMTM) platform featured by CRISPR, AAV, shRNA for both in vitro and in vivo target validation Assay & Biology Tumor cell panel profiling on 1000+ cell lines supported by proprietary database with genetic information State-of-the-art facility with high end instrumentation providing high throughput solution including RapidFire/ADDA, iQue, Biacore 8k, for bioanalytical and biomarker analysis Drug Target Efficacy PK/PD Disease Comprehensive animal models covering Oncology, Immuno- Validation Model Oncology, Metabolic/liver diseases, and Inflammatory diseases, etc. Platforms & Services to Accelerate Drug Discovery Process
Snapshot of Accomplishments Hit to Lead & ADME/Safety Lead Discovery
Partners with all top 10 world largest pharma and biotech Great reputation on scientific expertise & value delivery 20 million data points delivered annually from screening center 1,000+ assays developed for hit identification and lead discovery 50+ HTS campaigns launched in the past 3 years HD Biosciences Core Competences for Client’s Drug Development R&D 50+ SAR/Hit Triage running in parallel throughout the years
Target ID & Hit ID & Lead ID & Safety & Preclinical & Discovery H2L Optimization Profiling IND Enabling Unbounded Possibilities Enabling Unbounded Possibilities
Structural biology case study: in collaboration with a major pharma partner HCV: discovery of Elbasvir (NS5A inhibitor) Zepatier® : Breakthrough Therapy co-invented through Merck-WuXi partnership Objective Scope of Partnership An integrated Med. Chem. program to identify a potent and selective inhibitor for epigenetic target. Fully integrated program (Med. Chem., biological testing, DMPK) with WuXi designers. Biology Achievements Results Repeated expression & purification of protein and optimized the purification protocol. Obtained >120 co-crystal structures with >80% successful rate. Key intellectual contributions by WuXi medicinal chemists leading to more than 10 patents Analyzed co-crystal structures, crystal packing and biological data. Med. Chem. designed by WuXi chemists Deployed the structures to design novel targets and improve binding potency (200x), selectivity Biology contributed to nomination of 4 preclinical candidates (PCCs) including elbasvir (NCE) (50x), and aqueous solubility. Co-authors in publication. Scientific and Medical Significance 1st Breakthrough Therapy to be designed in “China for the world” Milestones For the patients, significant treatment for hard-to-treat HCV genotypes Demonstrated in vivo efficacy and studies. identified candidates that meet PCC profiles. Completed in vivo toxicology experiments. Value to Merck Full realization of an externalized discovery strategy leading to an approved drug
May 2009 Oct 2010 Dec 2010 Nov 2008 In vitro screens FIH for 2nd PCC delivered In vivo PK at WuXi at WuXi MK-4882 MK-8742 (elbasvir)
May 2008 Jan 2010 program initiation 1st PCC delivered MK-4882
Jan 2016 Oct 2013 Nov 2011 US and Canada Breakthrough therapy FIH for approved Zepatier® designation MK-8742 (elbasvir + grazoprevir) Structural Medicinal biology, chemistry biology
DMPK, Computational Tox, process
1.1 Å resolution