New England Drug Metabolism Discussion Group
2019
Summer Symposium
June 12th
Merck Research Laboratories
33 Avenue Louis Pasteur, Boston, MA
NEDMDG 2019 Summer Symposium Table of Contents 2019 Summer Symposium Agenda ...... 2 Posters ...... 3 Slido ...... 3 Our Sponsors & Exhibitors ...... 4 Sponsors ...... 5 Exhibitors ...... 7 Speakers (Morning Session I) ...... 19 Dan Wolak: In Vitro and In Vivo ADME of Biotherapeutic Proteins in Discovery and Development/Parallels to SM ADME ...... 19 Enrique Escandon: Integrated Fluorescent-Based Approach to Assess the In Vivo Fate of Experimental Biologics ...... 19 Jennifer Fretland: The Use of Modeling and Simulation in Early Discovery for Multispecific Antibody Design ...... 19 Speakers (Morning Session II) ...... 20 Meghan Flaherty: Fulfilling the Promise of Cell Therapies: Preclinical to Clinical Transition ...... 20 Chelsea Xue: Advancing Product Analytics for Cell Therapies ...... 20 Speakers (Afternoon Session I) ...... 21 Brooke Rock: Transforming Traditional SM ADME Assays to Support the Translation of siRNA Pharmacology from the Benchtop to the Clinic ...... 21 Jing-Tao Wu: The Use of ADME Sciences to Advance RNA Interference Therapeutics 21 Xiao Shelley Hu: PK/PD Modeling to Assist Early Stage Development of Antisense Oligonucleotides ...... 21 Speakers (Afternoon Session II) ...... 22 Kate Zhang: Preclinical Assessment of Efficacy, PK/PD and Tolerability of EDIT- 101 Following Subretinal Injection in Animal Models ...... 22 Poster Abstracts ...... 23 Attendees ...... 25
1 NEDMDG 2019 Summer Symposium 2019 Summer Symposium Agenda
Way beyond the rule of 5 – the future of DMPK in a multimodality world
8:00 am Continental Breakfast, Registration & Poster Set-Up 8:30 am Site Introduction – James Baker, Merck & Co., Inc. Morning Session I: Protein Biotherapeutics 8:40 am Symposium & Session I Introductions – Dean Hickman, Amgen Inc. 9:00 am Dan Wolak, Amgen Inc. “In Vitro and In Vivo ADME of Biotherapeutic Proteins in Discovery and Development/Parallels to SM ADME” 9:35 am Enrique Escandon, Merck & Co., Inc. “Integrated Fluorescent-Based Approach to Assess the In Vivo Fate of Experimental Biologics” 10:10 am Jennifer Fretland, Sanofi S.A. “The Use of Modeling and Simulation in Early Discovery for Multispecific Antibody Design” 10:45 am Break – Poster Session, Exhibits & Networking Morning Session II: Cellular Therapy 11:00 am Session Introduction – Hanlan Liu, KSQ Therapeutics, Inc. 11:05 am Meghan Flaherty, Takeda Pharmaceutical Co. Ltd. “Fulfilling the Promise of Cell Therapies: Preclinical to Clinical Transition” 11:40 am Chelsea Xue, Takeda Pharmaceutical Co. Ltd. “Advancing Product Analytics for Cell Therapies” Sponsor Presentations 12:15 pm Nexcelom Bioscience LLC: Leo Chan “Cell Counting Method Selection and Cell-Based Assays for Drug and Cell Therapy Development” 12:30 pm Lunch, Exhibits & Poster Session 1:30 pm Celerion Inc.: Rafiq Islam “Solutions for Success: Bioanalysis in the Changing Landscape of Multi-Modality World” Afternoon Session I: siRNA / ASO 1:45 pm Session Introduction – James Baker, Merck & Co., Inc. 1:50 pm Brooke Rock, Amgen Inc. “Transforming Traditional SM ADME Assays to Support the Translation of siRNA Pharmacology from the Benchtop to the Clinic” 2:25 pm Jing-Tao Wu, Alnylam Pharmaceuticals Inc. “The Use of ADME Sciences to Advance RNA Interference Therapeutics” 3:00 pm Xiao Shelley Hu, Wave Life Sciences Ltd. “PK/PD Modeling to Assist Early Stage Development of Antisense Oligonucleotides” 3:35 pm Break – Poster Session, Exhibits & Networking Afternoon Session II: Gene Therapy / CRISPR 3:50 pm Session Introduction – Wen Chyi Shyu, Takeda Pharmaceutical Co. Ltd. 3:55 pm Kate Zhang, Editas Medicine, Inc. “Preclinical Assessment of Efficacy, PK/PD and Tolerability of EDIT-101 Following Subretinal Injection in Animal Models” 4:30 pm Panel Discussion & Wrap-Up - Wen Chyi Shyu, Dean Hickman & Speakers Go to www.slido.com (event code 9484) or use SLI.DO App to pose questions to a speaker. Vote on which questions to be posed to the panel. 5:00 pm Poster Session, Exhibits, Networking & Cocktail Reception 6:00 pm Depart – Thank you!
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Posters
# Presenter Affiliation Title 1 Yvonne Yannoni Merck & Co., Circumventing Challenges with Providing Inc. Actionable PK/PD/Efficacy Relationships with mAb Construct Origin and Design 2 Matthew D. SCIEX Extending the Lower Limits of Quantification of a Stone Therapeutic Oligonucleotide Through Microflow LC- MS/MS 3 Meiyao Wang Merck & Co., NanoString Evaluation for microRNA Quantification Inc. 4 Howard Kartstein Owlstone Breath Biopsy Using EVOC Probes for Determining Medical Ltd Metabolizer Phenotype 5 Amin Hossain Northeastern The Development of New In Vivo Cross-Linkers and University Their Applications as Pharmacological Chaperones, Polymer Building Blocks, and General Biological Cross-Linkers 6 Daniel Warren SCIEX Characterization of Synthetic Oligonucleotides Using LC-MS and LC MS/MS
Slido
At this event, we want to make sure we address your most burning questions. Therefore, we’ll be using a simple audience interaction platform called Slido.
Slido allows you to submit your questions as well as upvote the questions of other participants. Questions with the highest number of votes will stand a better chance to get answered by speakers.
To join:
1. Please take out your smartphone (sorry wifi is not available so you’ll need a data plan) 2. Open your web browser 3. Go to www.slido.com 4. Enter the event code, which is 9484
3 NEDMDG 2019 Summer Symposium Our Sponsors & Exhibitors
Thank you to our sponsors and exhibitors who helped make this event possible.
Sponsors:
Nexcelom Bioscience LLC Celerion Inc.
Exhibitors:
Absorption Systems LLC MicroConstants, Inc.
Agilent Technologies MilliporeSigma
Biomere Biomedical Research Models, Inc. Mispro Biotech Services
IVAL – In Vitro ADMET Laboratories, LLC Novabiosis
LabLogic Systems, Inc. Primera Analytical Solutions Corp.
MedChem Partners WuXi AppTec Laboratory Testing Division, Inc.
4 NEDMDG 2019 Summer Symposium Sponsors
Headquartered in Lawrence, MA, Nexcelom Bioscience LLC is a manufacturer of innovative Cellometer®, Cellaca™ MX, and Celigo® image cytometry products for cell analysis. Nexcelom’s solutions automate time-consuming procedures, enabling scientists to focus less on the process and more on the research results.
Contact Nexcelom Bioscience at +1 978-327-5340 or visit www.nexcelom.com.
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Celerion is a leader in early clinical research services and clinical bioanalysis industry. Our unique combination of medical expertise, clinical operations experience and scientific excellence, enables you to make timely decisions with expert advice and high-quality data.
Today, Celerion is one of the world's leading CROs providing comprehensive clinical development services from Phase 1-2b, working with pharmaceutical companies and patients around the globe. We are more than 1,000 full-time scientific and medical personnel with the skills to design, execute, and interpret complex clinical studies, while upholding the highest standard of ethics. Our facilities offer over 600 beds and are among the most extensive in the industry, and our clinical research professionals have extensive experience and expertise to help you transition through Proof of Concept and beyond across North America, Europe, and Asia. Using these resources, we help get your product into the world faster, so you can start making a difference in people’s lives.
Our laboratories focus on science, compliance and speed to deliver high-quality data. Our state-of-the-art automated facilities in Lincoln, Nebraska, USA and Zürich, Switzerland are among the most respected laboratories in the industry. We apply our 40+ years of experience to exceed your bioanalytical expectations from method development and validation through rapid sample analysis supporting discovery through late stage clinical studies. Our 100+ scientists, armed with the latest bioanalytical technologies, are committed to solving your challenges with scientific excellence. We perform, on average, over 100 method validations per year in small and large molecules as well as immunogenicity. Through continuous improvement in quality and compliance processes and systems, and investment in the latest automation technologies, Celerion has the global capacity to analyze more than 600,000 samples per year, providing industry-leading turnaround time.
6 NEDMDG 2019 Summer Symposium Exhibitors
Absorption Systems is a full service nonclinical contract research organization (CRO) developing innovative services and solutions for the pharmaceutical, biotech, medical device and regenerative medicine industry. Our services include research and testing for small molecules, large molecules, biologics, medical device and cell and gene therapy products. The company's mission is to continually develop innovative research tools that can be used to accurately predict human outcomes or to explain unanticipated outcomes when they occur. The company's facilities are strategically located in Philadelphia, San Diego, Boston and Panama, servicing hundreds of customers throughout the world. Our facilities are USDA registered, NIH assured, AAALAC accredited, GLP & cGMP compliant, ISO certified, DEA licensed, OLAW assured and FDA inspected. Our focus is to maintain accuracy, timelines, and reliability at every stage of development. For more information on the company's comprehensive contract services and applied research programs, please visit absorption.com.
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Agilent is a global leader in life sciences, diagnostics, and applied chemical markets
Agilent teams are passionate about providing our customers with trusted answers to complex challenges. Whether Agilent is helping its customers keep food supplies safe; reducing air, water or soil pollution; or fighting cancer with new, more personalized diagnostics and therapeutics, we know that together with our customers, we are making a tangible difference in the lives of people around the world.
Agilent’s mission is “to improve the human condition.” With more than 50 years of insight and innovation, Agilent instruments, software, services, solutions, and people provide trusted answers to customers’ most challenging questions.
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Biomere is a preclinical CRO based in Worcester, MA that offers an extensive portfolio of pre-clinical research services including early discovery and proof-of- concept, pharmacology and discovery toxicology. With expertise in a variety of therapeutic areas including ophthalmology, autoimmune disorders, inflammation, metabolic diseases and virology, we strive to be a leading CRO that is customer service focused and provides resources and assets unlike that available in the industry.
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IVAL-the premiere provider of in vitro drug metabolism and toxicology products and contract research services.
As a pioneer of cryopreserved hepatocytes, cryopreserved enterocytes and cryopreserved intestinal mucosa, IVAL provides a comprehensive suite of in vitro ADMET products and contract research services: Products include cryopreserved primary hepatocytes; 999ELite™ cryopreserved highest quality hepatocytes; CHIM™: cryopreserved human and animal intestinal mucosa; OnDemand™ pre-plated hepatocytes, cryopreserved enterocytes and MetMax™ enterocytes and hepatocytes. Services include: solubility, permeability, metabolic stability, metabolite profiling, P450 inhibition and induction, transporter inhibition, and in vitro toxicity.
Our Pioneer products consist of:
Cryopreserved hepatocytes: o Human and animal; both suspension and plateable grades. These primary cells can be applied in drug uptake, metabolism, drug-drug interactions, and hepatotoxicity studies.
999Elite™ Cryopreserved hepatocytes: o Greater than 90% viability; greater than 90% confluency; over 9 days in culture
CHIM™: Cryopreserved Intestinal Mucosa and Enterocytes(patent pending): o We are the first to successfully isolate and cryopreserve human and animal intestinal mucosa epithelium and enterocytes to retain drug metabolism activities. IVAL’s enterocytes can be utilized to evaluate intestinal metabolism of orally-administered drugs as well as drug-drug and food-drug interactions in the intestines.
MetMax™ hepatocytes and enterocytes (US Patent 5,474,940): o Permeabilized, co-factor supplemented hepatocytes and enterocytes. MetMax™ cells can be used directly after thawing; do not require centrifugation and microscopic quantification of cell viability and cell number, thereby allowing convenient application for routine hepatic metabolism and hepatic drug-drug interaction studies.
Tissue culture support products: o UCRM: recovery; UPCM: plating, HIM: induction-long term culture and HQM: incubation-maintenance medium and tissue culture plate products
In Vitro ADME contract research services:
ROS/ATP Human Hepatocyte assay to identify sDILI drugs: This proprietary assay was co-developed with FDA National Center for Toxicological Research. The assay could identify (with >85% specificity and sensitivity) drugs that are known to be associated with severe liver toxicity, leading to deaths or a need for liver transplantation.
Plated Hepatocyte Relay Assay for slowly metabolized chemicals: This patented assay allows in vitro study of drugs with low hepatic clearance that cannot be readily evaluated with routine in vitro approaches. In this assay, compounds are incubated for 24 hrs with plated hepatocytes, with the incubated media transferred to newly plated hepatocyte cultures daily. Time-dependent parent disappearance is analyzed against model chemicals for up to 120 hrs (5 days), with the calculated hepatic intrinsic clearance similar to that observed in vivo.
Integrated Discrete Multiple Organ Co-culture (IdMOC™): This patented experimental system co-cultures cells from multiple organs. The cells are physically separated (discrete) but interconnected (integrated) by an overlying. IdMOC™ models the human/animal in vivo and allows the evaluation of organ-specific toxicity in the presence of multiple organ metabolism.
We strive to be the best in our field: best products, best service, best science, and best customer support.
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LabLogic Systems, Inc. is a leading provider of instruments and software for measurement and analysis of radioisotopes used in pharmaceutical, academic, nuclear medicine and research laboratories. Our systems include radiochromatography detectors and software for HPLC and TLC, liquid scintillation and gamma counters, radiation monitors, and microplate readers.
In addition to instruments LabLogic produce a range of specialist applications software including Laboratory Information Management Systems for ADME studies and PET production.
LabLogic products are backed by an extensive support network providing a comprehensive installation, validation, maintenance and technical support service. The company is ISO 9001 accredited and meets all recognised GLP standards.
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MedChem Partners is a specialty research and discovery organization founded in 2006 to provide value added services to drug discovery programs. We provide consultation, program and project planning, medicinal chemistry and custom synthesis services for pharma, biotech, and academic programs. Our expertise includes small molecule drug discovery and development with additional specialization in drug-polymer, drug-antibody, and drug-peptide conjugates, nanochemistry, and lipid chemistry.
MedChem Partners has a strong program focused on early development issues including: preparation of stable label compounds for use as internal standards, preparation of reference compounds, impurities, and metabolites to support scale up, CMC, and in vivo studies. In addition, we have a suite of profiling assays to address issues of purity, stability, formulation stability, solubility, and measurement of Log P and Log D. We are able to generate certificates of analysis to facilitate GLP studies and lot release, usually within 48h.
Our broad base of knowledge and experience, as well as our results focused approach, allows MedChem Partners to provide both material and intellectual contributions to our collaborators’ programs. We provide our clients with the experience, resources, and connections needed to successfully plan, implement and run their programs from discovery through development. MedChem Partners also participates in novel therapeutics programs and technologies on a risk- sharing/equity basis.
Synthesis of stable label reference compounds Preparation of metabolites, impurities, and reference compounds Storage and logistics CofA preparation and purity assessment Stability and solubility testing Formulation
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MicroConstants is a GLP-compliant Contract Research Organization focused on performing regulated bioanalysis, drug metabolism and pharmacokinetic analysis in support of discovery, preclinical and clinical drug development studies. We specialize in method development, validation and sample analysis for small molecules, macromolecules, biomarkers and metabolites using LC/MS/MS, HPLC/UV, immunoassay, multiplex and qPCR techniques. We also assemble and distribute protocol-specific specimen collection kits to streamline and simplify the PK collection process for single and multi-site clinical trials.
MicroConstants, Inc. was founded in 1998 in San Diego, California by Gilbert Lam, Ph.D., a veteran in pharmaceutical development and a scientist trained in the field of pharmacokinetics. Our San Diego facility has since grown to become one of the largest bioanalytical LC/MS/MS laboratories on the West Coast of the United States, housing over 20 LC/MS/MS systems and occupying 34,000 square feet of office and laboratory space.
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MilliporeSigma is the U.S. life science business of Merck KGaA, Darmstadt, Germany. With 19,000 employees and 72 manufacturing sites worldwide, MilliporeSigma’s portfolio spans more than 300,000 products enabling scientific discovery. MilliporeSigma has customers in life science companies, university and government institutions, hospitals and industry. More than 1 million scientists and technologists use its products. The company is committed to solving the toughest problems in life science by collaborating with the global scientific community.
For ADME/Tox & DMPK scientists, performing Tier1/Tier2 safety testing assays, we provide more predictive in vitro model systems for intestine, liver, and kidney with primary, wild type and engineered cell lines, addressing transporters and nuclear receptors related to cyp induction, listed in the FDA and EMA preclinical guidance documents.
For more information, visit www.emdmillipore.com and www.sigma-aldrich.com.
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Animal Care & Compliance SO YOU CAN FOCUS ON SCIENCE
Now offering Mispro Insource, our on-site vivarium management & services solution
VIVARIUM SPACE & SERVICES FOR IN VIVO SCIENCE
Learn more at www.misprobiotech.com
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Primary Human Cells - Tissues - Organs
Novabiosis is the premier provider of isolated primary cells and whole non- transplantable organs and tissues for research. Utilizing our partnerships with 54 organ procurement organizations (OPOs) across the United States, Novabiosis has access to most whole human non-transplantable organs and tissues. With such access to these research organs and tissues, Novabiosis is able to isolate and cryopreserve most primary cell types from human: Lungs, Kidneys, Liver and Intestines. These cells are fully characterized to meet the highest of quality standards.
Hepatic Cell Types:
Hepatocytes (Plateable and Suspension) Stellate Cells Kupffer Cells Sinusoidal Endothelial Cells
Intrahepatic Biliary Epithelial Cells (Cholangiocytes) Cell Culture Media
Our customer support team is standing by to answer any questions you might have! Contact us at [email protected] or call at 1-833-354-1945
Novabiosis 7020 Kit Creek Road
Suite 200 Morrisville, NC 27560 1-833-354-1945 [email protected]
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Primera Analytical Solutions Corp.
ONE STOP SOLUTION FOR YOUR CONTRACT ANALYTICAL NEEDS
Primera Analytical Solutions is a contract analytical laboratory offering a broad number of services such as Method Development and Validation, Impurity Studies to include Genotoxic Impurities (LCMSMS, GCMS, ICPMS), Extractables & Leachables, Stability and Photostability Studies, Dissolution Studies, Abuse- Deterrent Studies, Product Release Testing, Method Transfers, Inhalation Products, and Raw Material Testing. We are in great standing with the FDA with regard to GMP and GLP.
In addition, our bioanalytical services for both small and large molecule drugs cover Assay/Method Development and Validation, PK/PD sample analysis, Metabolite Characterization, Bioavailability and Bioequivalence Studies, Impurities by ELISA, Anti-Drug Antibody Assays (ADA), Peptide Mapping and so much more. At Primera, quality and client satisfaction are our primary objectives. Our expert team strives to provide our customers with timely reports as well as quality of services unsurpassed in the industry.
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Speakers (Morning Session I)
Protein Biotherapeutics
Dan Wolak: In Vitro and In Vivo ADME of Biotherapeutic Proteins in Discovery and Development/Parallels to SM ADME
Dan Wolak is a Scientist in the Pharmacokinetics and Drug Metabolism department at Amgen Inc. Dan received his PhD degree from the University of Wisconsin-Madison, School of Pharmacy in Pharmaceutical Sciences. His research has focused on biophysical and biochemical characterization of large molecules and PKPD modeling.
Biotherapeutics represent nearly one third of drug approvals over the last five years and while there are several similarities between large molecule and small molecule ADME, it is important to understand the differences as well. The goal of this presentation is to outline the relevant ADME features of biotherapeutics; outline the key similarities, differences, and learnings from small molecule ADME; and illustrate some common in vitro and in vivo experiments used in biotherapeutic development.
Enrique Escandon: Integrated Fluorescent-Based Approach to Assess the In Vivo Fate of Experimental Biologics
Enrique Escandon is a Senior Principal Scientist in the ADME PPDM organization at Merck. Enrique received his PhD degree from Cornell University Graduate School of Medical Sciences in New York City. His entire postgraduate career has been in the biotechnology industry, specifically in pharmacology and disposition of experimental protein therapeutics.
A drug’s pharmacological outcome is determined by drug levels and kinetics of exposure to tissues leading to target engagement. Therefore, understanding its fate in vivo is a critical component in successful drug development programs. Here we describe a fully integrated quantitative fluorescent-based approach to conduct pharmacokinetics, metabolism and disposition studies at pharmacologically relevant doses including determination of concentration, catabolism, protein interactions, target binding and high- resolution immunohistochemical analysis.
Jennifer Fretland: The Use of Modeling and Simulation in Early Discovery for Multispecific Antibody Design
Jennifer Fretland is the Head of DMPK in the US for Sanofi. She received her PhD in Biochemistry and Molecular Biology followed by post-doctoral training in Pharmacology. Her career has mostly focused on DMPK project support for synthetic molecules and biotherapeutics in both the discovery and development stages.
The complexity of biotherapeutics has increased with an increase in modality diversity including multispecific targeting. The addition of multispecific targeting increases the need for understanding how to best cover multiple targets with a fixed stoichiometry. Model-based approaches can be used from inception of target antigen pairing through the discovery space to aid in identification of critical antigen and drug-related properties that would increase the likelihood of target coverage.
19 NEDMDG 2019 Summer Symposium Speakers (Morning Session II)
Cellular Therapy
Meghan Flaherty: Fulfilling the Promise of Cell Therapies: Preclinical to Clinical Transition
Meghan Flaherty is a Senior Director in the Cell Therapy Engine at Takeda. Meghan has also worked at Genzyme, AVEO Oncology and most recently in Novartis with a focus on developing novel modalities in the preclinical space. Meghan received her PhD from Duke University in Inorganic Chemistry and Toxicology.
Cell therapies (CT) are transformative medicines being empowered by emerging science in biology, immunology, and integrated “deep” analytics. Like traditional medicines, the preclinical to clinical transition for cell therapies establishes MoA and demonstrates a favorable risk/benefit profile for a target patient population. However, CTs have limited preclinical models, can rapidly validate a clinical MoA, and correlate/‘reverse translate’ from clinic to research. This presentation will discuss the pathway of a CT from discovery to the clinic.
Chelsea Xue: Advancing Product Analytics for Cell Therapies
Chelsea Xue is currently Head of Analytical Development for Cell Therapies in Takeda. She is building the analytical capabilities and developing an integrated analytical package to enable product quality control, drive product understanding and next-generation design. In her previous role at Novartis, Chelsea contributed significantly on product analytics and CQA discovery for CTL019 which was later approved for ALL as Kymriah. She later led a group focused on clinical biomarker development. Chelsea received her Ph.D. from Texas A&M Health Science Center and completed postdoc training at Yale University.
CAR T product has complicated composition and MOAs. As a result, analytical development for CAR T therapy has gone beyond traditional CMC focus and assumed responsibilities for product understanding and next generation product design. In this talk, we will review means to advance product analytics for cell therapies, including both in vitro and in vivo methods.
20 NEDMDG 2019 Summer Symposium Speakers (Afternoon Session I) siRNA / ASO
Brooke Rock: Transforming Traditional SM ADME Assays to Support the Translation of siRNA Pharmacology from the Benchtop to the Clinic
Brooke Rock is a Principal Scientist in the Pharmacokinetics and Drug Metabolism department at Amgen Inc. Brooke received her PhD degree from University of Washington, School of Pharmacy in medicinal chemistry. Her research has focused on in vitro-in vivo drug metabolism, enzymology, in silico kinetic modeling, clinical DDI predictions and pharmacokinetics.
Small interfering RNA (siRNA) is an emerging therapeutic with the first FDA approval occurring in late 2018. The physicochemical properties of siRNA push this new modality outside of the small molecule classification; however, there exist opportunities to apply learnings from small molecules to underwrite the PK-PD relationships, inform structural integrity, and understand biodistribution. The presentation will discuss the above three topics along with the strategy to effectively characterize siRNA from early discovery into the clinical setting.
Jing-Tao Wu: The Use of ADME Sciences to Advance RNA Interference Therapeutics
Jing-Tao Wu is the Vice President of Early Development at Alnylam Pharmaceuticals, where he oversees DMPK and investigative toxicology activities to support platform and pipeline. Prior to Alnylam, he was the DMPK site head of Takeda Boston. Jing-Tao got his Ph.D. in chemistry from the University of Michigan.
RNA interference (RNAi) evolved from a research concept to an FDA/EMA approved therapeutic during the last two decades. Numerous challenges were encountered and overcome from targeted delivery to accurate clinical dose selection. ADME sciences played an important role in advancing RNAi therapeutics through precisely characterizing the disposition properties of small interfering RNAs (siRNAs) and effectively translating the ADME and PK/PD properties from animals to humans. Strategic ADME considerations along with case examples will be presented.
Xiao Shelley Hu: PK/PD Modeling to Assist Early Stage Development of Antisense Oligonucleotides
Xiao Shelley Hu is a Director at Wave Life Sciences. Prior to Wave, she worked at Akebia and Biogen. Shelley received her Ph.D. and M.S. from the Ohio State University, M.S. from Chinese Academy of Sciences, and B.S. from Peking University, Heath Science Center.
With PD markers (mRNA and protein) usually available, PK/PD modeling has been applied to assist the development of antisense nucleotides. This presentation focuses on PK/PD modeling during preclinical stage to showcase how PK/PD modeling can be applied to support toxicity study design as well as early stage clinical development.
21 NEDMDG 2019 Summer Symposium Speakers (Afternoon Session II)
Gene Therapy / CRISPR
Kate Zhang: Preclinical Assessment of Efficacy, PK/PD and Tolerability of EDIT-101 Following Subretinal Injection in Animal Models
Kate Zhang is VP, Biological Development at Editas Medicine. Kate received her Ph.D. in Analytical Chemistry/Biochemistry at Queen’s University, Ontario, Canada. Prior to joining Editas, Kate was Senior Director in Global Translational Science at Sanofi and Global Biopharmaceutical Development at Genzyme/Sanofi.
CRISPR-based genome editing machine presents great potential as therapeutic modality to treat many serious and life-threating genetic diseases. EDIT-101, an AAV5 vector packaged with DNA encoding SaCas9 with two guide RNAs, is a therapeutic candidate designed to treat Leber Congenital Amaurosis Type 10 patients that carry the most prevalent causative CEP290 mutation. The presentation will discuss the bioassays used to demonstrate the PK/PD correlation, preclinical efficacy and tolerability in animal models.
22 NEDMDG 2019 Summer Symposium Poster Abstracts
# Presenter Affiliation Title Abstract / Introduction 1 Yvonne Merck & Co., Circumventing mAb targeting of immunosuppressive molecules Yannoni Inc. Challenges with has become foundational in providing clinical Providing POC for targeting the immunosuppressive tumor Actionable microenvironment in multiple cancers. While PK/PD/Efficacy decades of research have resulted in approved Relationships with and marketed mAbs for a variety of indications mAb Construct including immunotherapy, many challenges must Origin and Design be overcome in order to provide sufficient proof of mechanism to advance these compounds through discovery to preclinical development including construct design, choice of animal model, PK, PD, and efficacy. We present a case study highlighting challenges addressed in advancing a promising targeted immunotherapy directed at patients non- responsive to currently marketed options such as anti PD-1 inhibitors. 2 Matthew SCIEX Extending the Antisense oligonucleotides play an important role D. Stone Lower Limits of in modern drug development strategies. Today, Quantification of a the ion-pairing reversed phase (IP-RP) LC/MS is Therapeutic often the preferred solution for both qualitative Oligonucleotide and quantitative oligonucleotide analysis Through Microflow although several fundamental challenges remain LC-MS/MS with this approach. The concentration of ion pairing reagents required to adequately retain and separate the polar oligonucleotides on a reversed phase column contributes to charge competition resulting in electrospray ion suppression and mass spectrometer contamination accelerating front end cleaning and maintenance intervals. Here we present a solution to characterize the improvement of quantification and the reduction of instrument contamination for a phosphorothioate antisense oligonucleotide assay scaled down to µLC/MS. 3 Meiyao Merck & Co., NanoString Currently PK analysis for therapeutic microRNA Wang Inc. Evaluation for (<25 nt) drug is performed using high specificity microRNA LC-MS/MS methods. However, one big limitation Quantification of LC-MS/MS is poor sensitivity. In an effort to develop a high sensitivity bioanalytical method for therapeutic microRNA analysis we’ve explored the use of NanoString nCounter technology. Critical parameters were tested to evaluate the suitability of NanoString technique for microRNA assay, including LOD, LOQ and linear dynamic range, and compared with LC-MS/MS method. Representative microRNA MRK-A (24nt) was used as a representative target analyte in the study.
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# Presenter Affiliation Title Abstract / Introduction 4 Howard Owlstone Breath Biopsy Owlstone Medical is exploring development of a Kartstein Medical Ltd Using EVOC Breath Biopsy test using EVOC Probes that are Probes for metabolized by the same CYP450 enzymes that Determining process medications. By administering Metabolizer one/multiple EVOC Probes, and measuring breath Phenotype VOC levels, we will investigate utility of this approach to build patient-specific ADME profiles relevant to specific enzymatic pathways. Using Breath Biopsy to measure an individual’s metabolizer phenotype in vivo has the potential to improve drug development and treatment by enhancing predictive assessment of drug metabolism.
5 Amin Northeastern The Development Many diseases, including familial Amyotrophic Hossain University of New In Vivo Lateral Sclerosis (fALS), are associated with loss of Cross-Linkers and quaternary structure and protein destabilization Their Applications (SOD1,fALS). This work debuts new chemical tools, as disulfides, and cyclic-thiosulfinates that can Pharmacological selectively form crosslinks. We show, via FTICR-MS, Chaperones, that in vitro crosslinking efficiency is high and fast Polymer Building (t1/24 min). We have now applied them in different Blocks, and areas including targeting new disease-associated General Biological proteins, development of novel polymers, and as Cross-Linkers general crosslinkers for structural-elucidation of protein complexes.
6 Daniel SCIEX Characterization Oligonucleotide therapeutics represent a rapidly Warren of Synthetic growing class of biotherapeutics spanning a wide Oligonucleotides range of applications. Interest in the use of Using LC-MS and oligonucleotides has continued to expand from LC MS/MS their use as therapeutics to use in gene therapies. We will present high resolution LC-MS analysis for rapid assessment and confirmation of full-length sequences and failure sequences. In addition, we will present our initial work using research software for the interpretation and annotation of MS/MS spectra.
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Last Name First Name Company
Akhlaghi Fatemeh University of Rhode Island Anderson Nathan Waters Corporation Appel Mark LabLogic Systems, Inc. Arciprete Michael Alnylam Pharmaceuticals Inc. Argikar Upendra Novartis Intl. AG Arimoto Rieko Vertex Pharmaceuticals, Inc. Bacolod Maria Alkermes PLC Baker James Merck & Co., Inc. Beg Nadeem WuXi AppTec Lab Testing Division, Inc. Berellini Giuliano Alkermes PLC Bhave Leena Merck & Co., Inc. Bohnert Tonika Biogen Inc. Bolat Ali Absorption Systems LLC Bolleddula Prakash Agios Pharmaceuticals Inc. Boodhun Ashvin LabLogic Systems, Inc. Brahme Rutali Novartis Intl. AG Buffone Elizabeth Lonza Group Byer-Alcorace Alexander Boehringer Ingelheim Intl. GmbH C P Aparna Northeastern University Cao Karen Alnylam Pharmaceuticals Inc. Chan Leo Nexcelom Bioscience LLC Chen Dapeng Merck & Co., Inc. Chen Weiqing Primera Analytical Solutions Corp. Cho Carolyn Merck & Co., Inc. Chong Saeho Alnylam Pharmaceuticals Inc. Chopda Girish Dicerna Pharmaceuticals, Inc. Chourb Sinang Celgene Corp. Chow Tim Sanofi S.A. Chowdhury Swapan Takeda Pharmaceutical Co. Ltd. Ci Lei Moderna Inc. Cui Dan Morphic Therapeutics Daniels J. Scott BASi-Seventh Wave Laboratories Decker Radford ERD Pharma Consulting, LLC Deng Lin Novartis Intl. AG Dong Jijun Alkermes PLC Duggal Ruchia Merck & Co., Inc. Dumouchel Jennifer Novartis Intl. AG Dykes Keisha WuXi AppTec Lab Testing Division, Inc. Eangoor Paddy Merck & Co., Inc.
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Egolf Richard MicroConstants, Inc. Escandon Enrique Merck & Co., Inc. Fan Peter Merck & Co., Inc. Farah Nadia Merck & Co., Inc. Fayad Ghassan Merck & Co., Inc. Flaherty Meghan Takeda Pharmaceutical Co. Ltd. Foti Robert Amgen Inc. France Dennis AIT Bioscience Frederick Kosea Bristol-Myers Squibb Co. Fretland Adrian AstraZeneca PLC Fretland Jennifer Sanofi S.A. Gao Hong Vertex Pharmaceuticals, Inc. Ge Pei Triplet Therapeutics Inc. Geiben Lynn Ralf Absorption Systems LLC Gilkes Janine MilliporeSigma Glencross Bill Mispro Biotech Services Gopal Sree Takeda Pharmaceutical Co. Ltd. Gosset James Pfizer Ltd Grant Christian Biomere Biomedical Research Models, Inc. Gu Chungang (Chuck) Biogen Inc. Gu Yongli Alnylam Pharmaceuticals Inc. Gunduz Mithat Novartis Intl. AG Guo Ellen Takeda Pharmaceutical Co. Ltd. Gupta Anshul Amgen Inc. Hainzl Dominik Novartis Intl. AG Harris Margaret Glen Research Corp. Heller Dennis WuXi AppTec Lab Testing Division, Inc. Hickman Dean Amgen Inc. Hinckley Sandy QurAlis Corp. Hogan Chris Biomere Biomedical Research Models, Inc. Hosea Natalie Takeda Pharmaceutical Co. Ltd. Hossain Amin Northeastern University Hou Xiuyun Massachusetts Institute of Technology Hu Haiqing Celgene Corp. Hu Xiao Shelley Wave Life Sciences Ltd. Islam Rafiqul Celerion Inc. Jain Shashank Agilent Technologies Jarres Russell Thermo Fisher Scientific Jawa Vibha Merck & Co., Inc. Jiang Lijuan Enanta Pharmaceuticals, Inc. Johnson David MicroConstants, Inc. Johnson Lei Alnylam Pharmaceuticals Inc. Josephs Jonathan Sanofi S.A. Kalgutkar Amit Pfizer Ltd
26 NEDMDG 2019 Summer Symposium
Karmel Jamie Amgen Inc. Kartstein Howard Owlstone Medical Ltd Kehoe Terry SCIEX Kim Joohwan Alnylam Pharmaceuticals Inc. Koeplinger Kenneth Merck & Co., Inc. Kramlinger Valerie Amgen Inc. Krishnan Rajesh Celerion Inc. Kwei Gloria Novartis Intl. AG Lazarova Tsvetelina MedChem Partners Lee Frank Lee Wan-Hung Dicerna Pharmaceuticals, Inc. Li Albert In Vitro ADMET Laboratories, LLC Li Jing Alnylam Pharmaceuticals Inc. Liou Steven Alnylam Pharmaceuticals Inc. Liu Hanlan KSQ Therapeutics, Inc. Liu Hong Novartis Intl. AG Locuson Chuck Agios Pharmaceuticals Inc. Lopes Felipe Dicerna Pharmaceuticals, Inc. Lu Chuang Sanofi S.A. Maclauchlin Chris Alnylam Pharmaceuticals Inc. Mannchen Nichole MD Biosciences, Inc. Manuel Melinda Takeda Pharmaceutical Co. Ltd. Martin Iain Merck & Co., Inc. Martinez Chris Agilent Technologies Maw Hlaing (Holly) Boehringer Ingelheim Pharmaceuticals, Inc. Mayer Christina Certara, L.P. McDougall Robin Alnylam Pharmaceuticals Inc. McMenemy Scott Nexcelom Bioscience LLC Melton Roger BASi-Seventh Wave Laboratories Meymaris Allysen Charles River Laboratories, Inc. Minshawi Omar In Vitro ADMET Laboratories, LLC Mitchell Walter In Vitro ADMET Laboratories, LLC Moore Dawn QPS Moradian Anya MD Biosciences Mullin Lauren Waters Corporation Mullins James QPS Holdings, LLC Neale Jason Magenta Therapeutics Nix Darrell Certara, L.P. Nozawa Takashi Astellas Pharma Inc. Oakes Jeffrey Tufts University School of Medicine O'Hearn Patrick Relay Therapeutics, Inc. Osbrey Chelsea Biomere Biomedical Research Models, Inc. Otte Karin Merck & Co., Inc. Owens Emanuel Celerion Inc.
27 NEDMDG 2019 Summer Symposium
Penner Natalia Biogen Inc. Petty Joseph Takeda Pharmaceutical Co. Ltd. Piekos Stephanie Boehringer Ingelheim Intl. GmbH Popovski Melissa Thermo Fisher Scientific Pusalkar Sandeepraj Takeda Pharmaceutical Co. Ltd. Qian Mark Takeda Pharmaceutical Co. Ltd. Ramsden Diane Alnylam Pharmaceuticals Inc. Rice William Nexcelom Bioscience LLC Riesinger Steven MedChem Partners Rioux Nathalie Certara, L.P. Robitaille Yolaine Mispro Biotech Services Rocca Carrie Alnylam Pharmaceuticals Inc. Rock Brooke Amgen Inc. Roesner Joseph Merck & Co., Inc. Rohde Ellen Intellia Therapeutics, Inc. Romagnoli Janel Tarveda Therapeutics, Inc. Rong Haojing Kymera Therapeutics LLC Sane Ramola Bristol-Myers Squibb Co. Sanfilippo Leah MilliporeSigma Schmitt Nicholas Northeastern University Shadid Mohammad Sarepta Therapeutics Inc. Shanmugasundaram Veer Celgene Corp. Sheldon Adrian Charles River Laboratories, Inc. Shi Pu Takeda Pharmaceutical Co. Ltd. Shipton Matthew Novabiosis Shyu Wen Chyi Takeda Pharmaceutical Co. Ltd. Siu Amy AbbVie Inc. Siu Ka Tat Dicerna Pharmaceuticals, Inc. Smith Dustin Merck & Co., Inc. Smith Sherri Relay Therapeutics, Inc. Stedman Justin Celgene Corp. Stone Matt SCIEX Sudsakorn Sirimas Sanofi S.A. Sugimoto Hiroshi Takeda Pharmaceutical Co. Ltd. Suri Ajit Takeda Pharmaceutical Co. Ltd. Syed Muzeeb Biogen Inc. Tannenbaum Steven Massachusetts Institute of Technology Tarabelsi Lucien Thermo Fisher Scientific Thomas Tristan MilliporeSigma Tweedie Donald Merck & Co., Inc. Vincent Stella Merck & Co., Inc. Wang Bonnie Bristol-Myers Squibb Co. Wang Meiyao Merck & Co., Inc. Wang Qingping Sanofi S.A.
28 NEDMDG 2019 Summer Symposium
Wang Yang Sanofi S.A. Wei Dong Takeda Pharmaceutical Co. Ltd. Wei Zixuan Tufts University School of Medicine Wexler Eric Cambridge Biomedical, Inc. Wolak Dan Amgen Inc. Wong Nancy Bioverativ Inc. Woodcock Stephen Homology Medicines, Inc. Wu Jing-Tao Alnylam Pharmaceuticals Inc. Xia Cindy Takeda Pharmaceutical Co. Ltd. Xiao Yingwen Merck & Co., Inc. Xie Keqiang Fulcrum Therapeutics Xu Bibo Primera Analytical Solutions Corp. Xu Lin Takeda Pharmaceutical Co. Ltd. Xu Weifeng Merck & Co., Inc. Xue Chelsea Takeda Pharmaceutical Co. Ltd. Yan Siyang Dicerna Pharmaceuticals, Inc. Yang Jun Johnny Wave Life Sciences Ltd. Yannoni Yvonne Merck & Co., Inc. Yin Wei Takeda Pharmaceutical Co. Ltd. Zhang Daping Merck & Co., Inc. Zhang George Corning Inc. Zhang Kate Editas Medicine, Inc. Zhang Xuemei Alnylam Pharmaceuticals Inc. Zhao Zhiyang Alliance Pharmaceuticals Ltd. Zhu Sean (Xiaochun) Takeda Pharmaceutical Co. Ltd. Zuo Rongjun Corning Inc.
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