Drug Metabolism & Pharmacokinetics. Bridging Chemistry, Biology, Pharmacology and Toxicology, from discovery to IND/NDA.

Transcription

1 Drug Metabolism & Pharmacokinetics Bridging Chemistry, Biology, Pharmacology and Toxicology, from discovery to IND/NDA.

2 WuXi AppTec WuXi Pharmatech was founded in 2000 in WuXi, Jiangsu province, China, and soon after moved to Shanghai, China. The company began as an contract research organization (CRO) for chemical synthesis but rapidly expanded over the next few years into a process R&D company for drug discovery. In 2006, WuXi had its IPO on the NYSE and in 2007 acquired AppTec Laboratories, a drug/biologic discovery and development company. Through heavy capital reinvestment and recruitment of experts from major Pharmas and CROs around the world, WuXi AppTec constructed the facilities and assembled the talent to become a tour de force in drug discovery and development outsourcing. In 2014, WuXi AppTec established their synthetic and druggability-safety assessment organization, namely Lab Testing Division (LTD). LTD itself was further partitioned by expertise into individual business units that specialize in every aspect of drug discovery and development with the intention of creating a full-service CRO that can provide an integrated drug discovery and development platform or comprehensive assistance to pharmaceutical developers. At the end of 2015, WuXi AppTec again went private so they could focus on investing in areas that would keep them ahead of the technological curve in order to best serve their clientele. The exponential growth of WuXi from its inception is shown in Figure 1. Employees Revenue (US$ in Millions) E Launch of V-Lab App Launch of LabNetwork Acquisition of NextCODE Mammalian Cell Culture Manufacturing Facility in WuXi WuXi AppTec goes private Launch of Boshi360 Acquisition of XBL St. Paul Materials Characterization Cell Therapy Facility in Philadelphia Changzhou cgmp Manufacturing High-Potency API Lab Biologics Expansion Wuhan Site MedImmune JV PRA JV Biologics Clinical Genomics Large-scale Manufacturing Suzhou Toxicology Acquisition of AppTec Integrated Platform Tianjin Site Toxicology Formulation Biology Bio-analytical Manufacturing Process R&D Chemistry Chemistry WuXi Founded Figure 1. Year-over-year growth of WuXi AppTec s personnel and revenue.

3 Lab Testing Division The mission of LTD is to provide the scientific and regulatory expertise to streamline and reduce the costs of the discovery and development of new drugs so any company, large or small, can bring their vision to the market. To accomplish this, LTD established a division of expertise and specialized support across different disciplines while keeping all of them seamlessly integrated under the umbrella of LTD. The division contains seven business units (BUs) including the Analytical Service Unit (ASU) which is primarily responsible for CMC, Bioanalytical Services (BAS) which is responsible for drug and tissue quantification/analysis, Biology (BIO) and Oncology (ONCO) which are responsible for HTS and optimization of new chemical entities in addition to efficacy studies, Toxicology (TOX), and Drug Metabolism and Pharmacokinetics (DMPK) which is responsible for ADME and in-life studies in drug discovery and development (Figure 2). LTD has recently launched a medical device division (MD) to handle regulatory studies and filings within China while AppTec provides similar services for US filings. Discovery Screening Lead Optimization Candidate Nomination Preclinical Clinical Market (ASU) Analytical Chemistry & Separation Analytical Development & Stability (BIO) Biology (ONCO) Oncology (IMMU) Immunology Center 2. IND/NDA Package (DMPK) Drug Metabolism & Pharmacokinetics (BAS) BioanalyticalServices 1. Discovery Package (TOX) Toxicology 3. Device Package (MD) Medical Device Testing Figure 2. Division of labor between BUs within LTD and their contribution on the development timeline.

4 WuXi DMPK WuXi DMPK is one of the largest BUs under the LTD umbrella. The BU is responsible for performing in vitro and in vivo assays to study the absorption, distribution, metabolism and excretion (ADME) of drug candidates. As part of LTD s seamless integration, DMPK collaborates with biology, pharmacology, medicinal and synthetic chemistry during the lead finding and optimization stages to assess the druggability of NCEs. Subsequently during the preclinical candidate (PCC) nomination and development stage, DMPK collaborates with toxicology, scale-up chemistry and pharmaceutical development by conducting the necessary ADME studies needed for filing investigational new drug (IND) and new drug applications (NDA). The DMPK Unit was established in January 2006 and after almost ten years of growth has become one of the largest and most established CROs in the world. We currently employ over 400 staff members across four sites in the US and China (Table 1). We endeavor to provide an end-to-end technical platform for our partners that spans discovery through NDA filing. We have solidified a wide client base consisting of over half of the Top-20 big-pharmas and over 300 mid- and small-sized biopharmaceutical, virtual, non-profit and academic institutions around the world. Shanghai, China Suzhou, China Nanjing, China Plainsboro, NJ Key Capabilities Early and developmental in vitro ADME Early and developmental rodent PK Met ID and mass balance (hot or cold) IND package generation GLP and non-glp bioanalysis Radioactive compound Large animal PK ADME and PK (NHPs and dogs) (mass balance, GLP bioanalysis routes of Large animal PK/ excretion and PD models Met ID) Preclinical DMPK (rodent, dog, NHP) Early in vitro ADME and Rodent PK Preclinical PK Clinical PK GLP and non GLP bioanalysis QWBA Discovery ADME and rodent PK Developmental ADME and rodent PK Clinical and nonclinical Met ID Definitive ADME studies Clinical and radio AME studies Routes of excretion QWBA and QTD Certifications FDA, EMA*, OECD*, CFDA, AAALAC (GLP) Table 1. WuXi DMPK s global facilities have different areas of expertise. *regulatory inspections only for the BA group.

5 Facilities and Regulatory Record WuXi DMPK has four viviaria located in Shanghai, China, neighboring Suzhou, Nanjing, China, and Plainsboro, NJ USA. The Shanghai and Suzhou China facilities are for non-glp ADME and PK studies for rodents and large animals, respectively. Both specialize in complex surgical models to facilitate DMPK studies and offer discovery and developmental studies. Nanjing and Plainsboro also offer discovery studies but primarily run developmental and definitive studies. Nanjing offers large animal PK studies while Plainsboro focuses on rodents including QWBA/QTD as well as NDA-enabling studies. Both Nanjing and Plainsboro studies are capable of working with radionuclides for nonclinical and clinical radioprofiling and Met ID studies. The details of our facilities can be found below. 11,600 ft 2 AAALAC accredited vivarium Shanghai DMPK 11 dedicated study rooms, 3 surgery/recovery rooms Regulatory inspections: AAALAC, CFDA Can dose over 300 study arms per week 18,000 ft 2 AAALAC accredited vivarium (within our toxicology facility) Over 200 beagles and 200 cynomolgus monkeys are always on-site for studies Can dose over 40 study arms per week Regulatory inspections: AAALAC, CFDA Suzhou DMPK 44,500 ft 2 facility 250+ in vitro/in vivo DMPK/ADME studies initiated in 2014 New Jersey DMPK 15,000+ bioanalytical samples analyzed per month Regulatory inspections: AAALAC, FDA, EPA, USDA, DEA 45,000 ft 2 facility Proven track record for IND/NDA data submission with no rejections in over 20 years Regulatory inspections: AAALAC, FDA, CFDA Nanjing DMPK

6 DMPK Management Our China-based management consists of 8 returnees from the US from a variety of companies including CROs and small/large Pharma. In addition to the Directors we also have 2 US-based consultants who work with our study director group to improve their scientific acumen and QC reports. Our Clients Our clients are our partners, in fact we are actively co-developing over 30 NCEs with companies around the world. Our partners come from virtual, small/mid, specialty, large and biopharma as well from every region of the world: US, Canada, Australia, New Zealand, Russia, South Africa, Israel, China, Japan, Republic of Korea, Hong Kong, Taiwan, Singapore, India and throughout the European Union. We are a US-traded company and use English as our operating language, though we do provide an option for Chinese reports for many of our clients who are looking to enter the large Chinese market. While we are constantly looking to expand our list of global partners, we are more focused on improving the relationships we already have as word of mouth is the best way to increase our business. Thus we are always receptive to our clients comments and concerns and constantly striving to improve our operations. We aim to offer top-class support for drug discovery and development throughout the world at a favorably competitive price.

7 Jianling Wang, PhD Head of Global DMPK (Shanghai) Over 20 years experience in ADMET/DMPK with a project focus on oncology and infectious disease Former Head of Discovery ADME in Novartis - Cambridge PhD in biophysical chemistry from the University of New Mexico and postdoc at Bell Laboratories A book published in 2014, 55+ publications in peer-reviewed journals Genfu Chen, PhD Head of In Vitro ADME (Shanghai) Over 15 years experience in DMPK Former Head of Drug Metabolism at Abbott Worcester and Senior Study Director at IVT/Celsis PhD in toxicology from the University of Arkansas and postdoc at the FDA Mingdan Wu, PhD Head of Metabolite ID (Shanghai) Over 18 years experience in DMPK for preclinical development and IND filing Formerly Principal Investigator at Sanofi, Purdue Pharma and Celgene Bin Zhu, PhD, MD Head of PK/PD (Shanghai) Over 18 years experience in screening and candidate selection using in vivo models & PK; 8 years experience in clinical practice and human physiology research Formerly a Team Leader with Takeda, GSK, Sanofi and Eisai R&D Centers in USA, UK and Singapore PhD in Neuroscience from University of Cambridge UK and MD from Xiangya Medical School of Central South University Liang Shen, PhD Head of Study Directors (Shanghai) Over 9 years of research and industrial experience in pharmacokinetics, toxicokinetics, clinical pharmacology and IND filing PhD in pharmacokinetics and postdoc in toxicology and clinical pharmacology from the University of Georgia Yi Tao, PhD Head of Non-GLP Bioanalysis (Shanghai) Over 10 years experience in drug discovery bioanalysis and metabolite identification Formerly Research Investigator at Bristol-Myers Squibb and Senior Principal Investigator at Chempartner PhD in medicinal chemistry from the University of Illinois at Chicago Sharon Tong, PhD Head of Discovery DMPK US (New Jersey) Over 20 years experience in bioanalysis/dmpk Formerly a Senior Investigator and Director at Merck & Co. PhD in analytical science at University of Wisconsin-Madison, postdoc at Cornell University Peter L. Wang, PhD Head of Drug Metabolism and Biotransformation (New Jersey) Over 14 years experience in ADME/DMPK and agrochemical studies Formerly a Senior Metabolism Scientist at FMC Corporation PhD in organic chemistry jointly from Shanghai Institute of Materia Medica (Chinese Academy of Sciences) and the Institute of Natural Medicine, Japan Alfred W. Lordi, MS Head of Preclinical Services/QWBA (New Jersey) Over 20 years experience in ADME/DMPK and expert in QWBA, mass balance and human dosimetry studies Served at various toxicology/drug safety and ADME/QWBA scientific posts at Schering-Plough, Exxon Biomedical and Biodynamics Inc. MS in biology from Seton Hall University Tao Jing, MBA Head of Large Animal PK (Suzhou) Over 10 years experience in PK, toxicology and pharmacology with a focus on CNS, ophthalmic and metabolic diseases Formerly a scientist at Xenoport; co-founder of SRC and JatBio MBA from Vlerick Business School; postgraduate in pharmacology and experimental neuroscience from University of Nebraska Medical Center Dennis Heller, PhD DMPK/ADME BD and Technical Advisor (New Jersey) Over 18 years experience in radiolabeled ADME, expert in dosimetry Formerly at Pharmaceutical Profiles, MDS Pharma and Assistant Professor at the University of Cincinnati Dept. of Radiation Oncology PhD in Medical Physics/Radiation Biology from Carleton University Ying Huang, MD Head of Rodent PK (Shanghai) Over 8 years experience in PK, TK, preclinical formulation Previously worked as a project manager and study director; DMPK representative for the design, planning and implementation of IND packages for the CFDA and FDA MD from Tongji Medical College, Huazhong University of Science and Technology

8 Why Choose WuXi DMPK? Scientific credentials We employee 15 senior and mid-level leaders with over 150 cumulative years of US experience. We have forged partnerships with over 30 global partners for the discovery of NCEs generating 12 PCCs, 32 IND and 2 NDA studies. We have validated the most critical ADME assays against literature data. Our study directors and lab heads have previously been asked to join our partners study design teams allowing us to become an active solution provider rather than a passive data generator. We provide professional custom-support from quote inquiry to data/solution delivery. We have state of the art technologies in the lab including lab automation and latest models for LC-MS. Highly efficient operations We maintain a large animal cohort on location to eliminate the project lead-in time for rodents, dogs and NHPs. Our streamlined process has allowed us to provide data within 5 days for over 90% of our PK and ADME studies. Green Channel status allows expedited clearance of imported samples through Customs. A DMPK-IT group strives to keep us at the forefront of technology through electronic data capture and real-time study monitoring as well as maximizing IP protection. WuXi s end-to-end development capabilities allow your project to transfer easily between departments to maximize efficiency while minimizing costs.

9 DMPK Table of Contents Physicochemical Property Analysis In Vitro Permeability Assays In Vitro Metabolic Stability Assays Metabolite ID In Vitro Drug-Drug Interaction Assays In Vitro Transporter Assays In Vitro Protein Binding and Partitioning Assays In Vivo Studies Prodrug Studies PK/PD Studies Formulation Development Biologics Development IND-enabling Studies Post-IND Studies Non-GLP Bioanalysis Laboratory Automation List of Abbreviations