PARTNERING FOR SUCCESSResearch Models and ServicesSrna Vlaho, Business Innovation Manager

1

EVERY STEP OF THE WAY

EVERY STEP OF THE WAY

Species

RESEARCH MODELS

2 EVERY STEP OF THE WAY

A Leader In Animal Production Worldwide

Therapeutic Areas

Study Ready Animals

Knockout Repository

• Oncology• Cardiovascular• Inflammation• Neuroscience • Metabolic

Disease

• Surgery• Custom Diets• Aging Services• Pre-ID™ services• Pre-screening

services • Pre-dosing/pre-

injection services

• In collaboration with genOway

• Over 2000 models available

• Bred and housed by Charles River

• Mice• Rats• Gerbils• Guinea Pigs• Hamsters• Rabbits

MODEL CREATION REQUIRES STRONG SCIENTIFIC TEAMS

3 EVERY STEP OF THE WAY

For in vitro and in vivo work

In vitro In vivo

From microinjection to Germ Line Transmission

Prepare /validate genetic materials for injection

Breeding to F1 & F2 generation

Bioinformatic / Molecular Biology

plasmid, Bac, CRISPR ES clones

Injection

Global PartnersMirimus, Inc

Phenomin-ICSTsukuba University

Charles River

ONE-STOP SHOP FOR YOUR TRANSGENIC COLONY NEEDS

4 EVERY STEP OF THE WAY

World’s Largest Rodent Breeder

01. Breeding genetically engineered animals for more than two decades.

Expertise

02. Delivering animals to you when you need them, in the exact quantities you specify, for as long as you need

Customized Services

03. Scale up or down depending on project needs Flexibility

04. Each project has its own dedicated isolator spaceStrong Biosecurity

05. Internet Colony ManagementData Integrity

06.Embryology, quarantine, and comprehensive genetic testing

Additional Services

Insourcing Solutions

INDEX

DIAGNOSTIC TESTING LABORATORY (RADS)

5 EVERY STEP OF THE WAY

One-stop Shop

Protocols include pathology, serology, microbiology, parasitology, and PCR infectious agent testingBiosecurity Helping clients build a foundation of contamination prevention measures and follow up methods in the event of a breach in their biosecurity

PARTNERING FOR SUCCESS

EVERY STEP OF THE WAY

EVERY STEP OF THE WAY6

Discovery ServicesMarcus Wagstaff, Associate Director, Business Development

“END TO END” INTEGRATED DRUG DISCOVERY

DP DP Clinical CandidateTargets

Functional Genomics

Adenoviral PlatformCRISPR Human 1°

Cells

Molecular CellBiology Generation

Structural Biology

FBDD

Library Design

SyntheticChemistryCADD

ProcessChemistry

Chemo-genomics

Analytical& Purification

Pharmaceutics

Formulation

Dose to HumanPredictions

Discovery Pathology

ADME

Bioanalysis Safety Pharmacology

Non-GLP/GLP Toxicology

Anatomic & Clinical Pathology

B/D

Imaging/Microdialysis

Ch

Hit Finding:HTS, HCS

PharmacologyIn Vitro/In Vivo

Biomarker Development

IND EnablingStudies

MedicinalChemistry

Target Discovery& Validation

Discovery PathwayDP ChemistryCh Biology/Discovery TechnologiesB/D DMPK/Pharmacology/Safety/In Vivo Models

EVERY STEP OF THE WAY

In Vivo Animal Model PK/PD In Vivo Large Animal SafetyValidation Development Efficacy Efficacy Models Assessment

Inhaled Drug Discovery – Respiratory Disease Project

CRL contributed• In vitro assay development and biochemical and cellular screening.• Target engagement biomarker assays (in vitro and ex vivo).• Enzyme kinetics and selectivity screens.• Medicinal chemistry and structure-activity relationship analysis.

In vitro biology assays PD, PK and Safety Efficacy and PK/PD

Inflammatory and immune pathways can be targeted to address the underlying disease pathology and significantly improve clinical outcome.• Charles River Discovery scientific expertise and influence contributed directly to the advancement of inhaled drug discovery capability and understanding at partner.• Inhaled (topical) delivery of compound to lungs with limited systemic exposure to reduce on-target side effect liabilities• Lung retention and an intracellular site of action required optimum physicochemical properties. Limited systemic exposure required targeted ADME/PK properties unique to inhaled delivery.• Integrated project team with structural biology, chemistry, pharmaceutics, biology, DMPK, in vivo pharmacology and toxicology expertise progressed project from hits to IND clinical candidate.• 24 months to first-in-class candidate nomination and IND enabling inhaled (rodent and non-rodent) safety package provided within 9 months of GMP material delivery.

Primary biochemical screen (+/- pre-incubation). Selected molecules evaluated in cellular assay.

Ex vivo biomarker model established for monitoring compound activity in lung

CRL contributed• In vitro ADME screens including lung binding and stability.• Intranasal, intratracheal and inhaled dose preclinical studies.• PK and PD, and safety (GLP) data generation with interpretation.

Preclinical target engagement was a key in vivo screen in a pharmacodynamically driven screening cascade.

Compounds exhibiting good lung target engagement progressed into a PK screen.

Optimization of PK profile to increase effective free drug lung concentration and limit systemic exposure.

CRL contributed• Polymorph screens and salt selection• Solid state characterization.• Micronization of crystalline form & particle size control.• De-risking of physical form for inhaled drug delivery.• Design of compounds targeting potency, selectivity, specific lung retention properties and low systemic exposure

Chemistry and Pharmaceutics

CRL contributed• PD and translational efficacy study design (dose and regimen) and PK/PD analysis.• Human dose prediction and safety margin evaluation.• Data for IND, patent filings and publication.

Compounds with optimized lung retention and pharmaceutical properties for dry powder inhaled dosing demonstrated preclinical efficacy.

Human dose prediction for compounds with potent lung based target engagement and preclinical efficacy with limited peripheral exposure.

Polymorph screening, compound crystallization and characterization for dry powder inhaled (DPI) administration in vivo.

Particle size control for optimal lung deposition.

Early characterization of crystalline form minimized late-stage risk.

Development and delivery of a screening cascade from knowledge-based compound design, to efficacy based on increasing the free drug concentration in the lung with limited systemic exposure.

CRL inhaled drug design strategy balanced dissolution and solubility, permeability, and modulation of basicity to optimize lung retention and receptor kinetics, incorporating.

Approaches to understanding inhaled PK/PD.

A patentable, lung delivered small molecule inhibitor of a kinase implicated in lung disease pathology with a potential systemic side effect liability.

Nomination of a first-in-class candidate and back-up within 24 months from hit ID.Completed IND enabling GLP safety package on lead which entered clinical development.Patents and high profile publication.CRL scientific expertise and influence contributed directly to the advancement of inhaled drug discovery capability and understanding at partner.The PK/PD model and data interpretation were critical to the design of compounds with appropriate lung PK, efficacy and miminal systemic exposure. Novel PD study designs, including Css studies, enhanced PK/PD knowledge and understanding of the drivers of target engagement and efficacy.

Long term business and science partnership with a large biotech. Standard FTE model working at defined global market FTE rates for each discipline. Project team driven on timely delivery of highest quality candidates via an interactive & highly collaborative working relationship.

Establishing validated screening and selectivity assays.

Target engagement biomarker upregulation assay development.

Design of lung retained compounds with efficacy at an intracellular target.

Optimization of compound form for inhaled delivery.

Understanding lung PK/PD.

Illustration of efficacy and no side effects with limited systemic exposure

Inhaled drug discovery medicinal chemistry knowledge.

CADD and structural biology to influence compound design.

Pharmaceutics expertise to optimize solid state properties.

Development of in vivo PD screening model to demonstrate lung target engagement.

IND-enabling preclinical safety package for inhaled drug development.

24 months to candidate nomination. IND enabling inhaled (rodent & non-rodent) safety studies within 9 months of GMP material delivery.

Business Basis

Partner goals

Challenges Inputs Technologies

Timeline

Milestones and Achievements

Inhaled Drug Discovery – Respiratory Disease Project

CHARLES RIVER: A STABLE, SCALABLE PARTNER

10 EVERY STEP OF THE WAY

PARTNERING FOR SUCCESSSafety AssessmentKristin Power, Business Development Director

DP DP Clinical CandidateTargets

Functional Genomics

Adenoviral PlatformCRISPR Human 1°

Cells

Molecular CellBiology Generation

Structural Biology

FBDD

Library Design

SyntheticChemistryCADD

ProcessChemistry

Chemo-genomics

Analytical& Purification

Pharmaceutics

Formulation

Dose to HumanPredictions

Discovery Pathology

ADME

Bioanalysis Safety Pharmacology

Non-GLP/GLP Toxicology

Anatomic & Clinical Pathology

B/D

Imaging/Microdialysis

Ch

Hit Finding:HTS, HCS

PharmacologyIn Vitro/In Vivo

Biomarker Development

IND EnablingStudies

MedicinalChemistry

Target Discovery& Validation

Discovery PathwayDP ChemistryCh Biology/Discovery TechnologiesB/D DMPK/Pharmacology/Safety/In Vivo Models

EVERY STEP OF THE WAY

In Vivo Animal Model PK/PD In Vivo Large Animal SafetyValidation Development Efficacy Efficacy Models Assessment

SAFETY ASSESSMENTWe conduct approximately 250 IND programs per year

+ + =

Facilities around the globe, including US, Canada, Mainland Europe and the UK

SCIENTIFIC DEPTH

Over 1,000 scientists across general and specialty toxicology,

laboratory sciences, and pathology

DEDICATION TOCUSTOMER SUPPORT

Responsiveness and communication at the

center of our clientinteractions

Successful execution and sound study data

GLOBAL RESOURCES

CONFIDENCE

EVERY STEP OF THE WAY13

BASIC RESEARCH

DISCOVERY CLINICAL SUPPORT

SAFETY ASSESSMENT

MANUFACTURING

EVERY STEP OF THE WAY

A leading, full-service drugdiscovery and early-stagedevelopment company

Founded in 1947 by Dr. Henry Foster

Our scientists worked on~85% of the drugs approvedby the FDA in 2017

EVERY STEP OF THE WAY14