New England Drug Metabolism Discussion Group

2019

Summer Symposium

June 12th

Merck Research Laboratories

33 Avenue Louis Pasteur, Boston, MA

NEDMDG 2019 Summer Symposium

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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

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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”

12:15 pm

Sponsor Presentations

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

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

# Presenter Affiliation Title

1 Yvonne Yannoni Merck & Co.,

Inc.

Circumventing Challenges with Providing

Actionable PK/PD/Efficacy Relationships with mAb

Construct Origin and Design

2 Matthew D.

Stone

SCIEX Extending the Lower Limits of Quantification of a

Therapeutic Oligonucleotide Through Microflow LC-

MS/MS

3 Meiyao Wang Merck & Co.,

Inc.

NanoString Evaluation for microRNA Quantification

4 Howard Kartstein Owlstone

Medical Ltd

Breath Biopsy Using EVOC Probes for Determining

Metabolizer Phenotype

5 Amin Hossain Northeastern

University

The Development of New In Vivo Cross-Linkers and

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

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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.

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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.

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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 custserv@novabiosis.com or call at 1-833-354-1945

Novabiosis 7020 Kit Creek Road Suite 200 Morrisville, NC 27560 1-833-354-1945 custserv@novabiosis.com

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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.

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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.

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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.

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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.

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Poster Abstracts

# Presenter Affiliation Title Abstract / Introduction

1 Yvonne

Yannoni

Merck & Co.,

Inc.

Circumventing

Challenges with

Providing

Actionable

PK/PD/Efficacy

Relationships with

mAb Construct

Origin and Design

mAb targeting of immunosuppressive molecules

has become foundational in providing clinical

POC for targeting the immunosuppressive tumor

microenvironment in multiple cancers. While

decades of research have resulted in approved

and marketed mAbs for a variety of indications

including immunotherapy, many challenges must

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

D. Stone

SCIEX Extending the

Lower Limits of

Quantification of a

Therapeutic

Oligonucleotide

Through Microflow

LC-MS/MS

Antisense oligonucleotides play an important role

in modern drug development strategies. Today,

the ion-pairing reversed phase (IP-RP) LC/MS is

often the preferred solution for both qualitative

and quantitative oligonucleotide analysis

although several fundamental challenges remain

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

Wang

Merck & Co.,

Inc.

NanoString

Evaluation for

microRNA

Quantification

Currently PK analysis for therapeutic microRNA

(<25 nt) drug is performed using high specificity

LC-MS/MS methods. However, one big limitation

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

Kartstein

Owlstone

Medical Ltd

Breath Biopsy

Using EVOC

Probes for

Determining

Metabolizer

Phenotype

Owlstone Medical is exploring development of a

Breath Biopsy test using EVOC Probes that are

metabolized by the same CYP450 enzymes that

process medications. By administering

one/multiple EVOC Probes, and measuring breath

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

Hossain

Northeastern

University

The Development

of New In Vivo

Cross-Linkers and

Their Applications

as

Pharmacological

Chaperones,

Polymer Building

Blocks, and

General Biological

Cross-Linkers

Many diseases, including familial Amyotrophic

Lateral Sclerosis (fALS), are associated with loss of

quaternary structure and protein destabilization

(SOD1,fALS). This work debuts new chemical tools,

disulfides, and cyclic-thiosulfinates that can

selectively form crosslinks. We show, via FTICR-MS,

that in vitro crosslinking efficiency is high and fast

(t1/24 min). We have now applied them in different

areas including targeting new disease-associated

proteins, development of novel polymers, and as

general crosslinkers for structural-elucidation of

protein complexes.

6 Daniel

Warren

SCIEX Characterization

of Synthetic

Oligonucleotides

Using LC-MS and

LC MS/MS

Oligonucleotide therapeutics represent a rapidly

growing class of biotherapeutics spanning a wide

range of applications. Interest in the use of

oligonucleotides has continued to expand from

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.

NEDMDG 2019 Summer Symposium

25

Attendees

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.

NEDMDG 2019 Summer Symposium

26

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

NEDMDG 2019 Summer Symposium

27

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.

NEDMDG 2019 Summer Symposium

28

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.

NEDMDG 2019 Summer Symposium

29

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.