THE BENEFITS OF OUTSOURCING DRUG DISCOVERY TO AN END-TO-END CRO

EVERY STEP OF THE WAY

TRENDS IN PRECLINICAL DRUG DISCOVERY: WHY OUTSOURCE?

~30% of the preclinical pipeline

is occupied by biologics*.

Interest in integrated offerings

to streamline discovery.

Requirement for specialized in vitro assays

and relevant in vivo models that translate to

human disease.

Earlier safety/toxicology studies to manage pipeline attrition

(fail early).

Rising number of biotech companies with

limited capacity and virtual biotech

companies.

RECENT TRENDS IN DRUG DISCOVERY

* Source: Citeline Pharma R&D Annual Review 2015

Outsourcing in Drug Discovery is expected to increase

* Source: LEK analysis, Charles River Laboratories

$7B

$10B

$13B

$12.1B

2015

2020 FORECASTED

GLOBAL DISCOVERY AND SPEND

OUTSOURCED

OUTSOURCED 35%APPROX.

OUTSOURCED

45%APPROX.

OUTSOURCED

6% CAGR

IN A CROWDED SPACE, WHY SHOULD YOU CONSIDER CHARLES RIVER FOR

PRECLINICAL DRUG DISCOVERY?

COMPELLING AND CONSISTENT SUCCESS RATES

- 65 preclinical candidates delivered- At least 5 preclinical candidates delivered per year for the last 10 years- More than 1,000 in vivo pharmacology studies per year

HIGH IMPACT INNOVATIVE TEAMS

- Flexible working options – modular projects or end-to-end solutions- Diversity of thought within multi-disciplinary teams with excellent

pharma and biotech pedigree- Focus on aggressive timelines to delivery

SECURE IP AND CONFIDENTIALITY ENVIRONMENT

- No internal drug discovery programs that compete with your projects- Firewalled teams ensure project confidentiality- Secure databases

RISK SHARING OPPORTUNITIES

Why Discovery from Charles River?

Consistently Delivering Quality Candidates65 candidates delivered | 29 clinical candidates | More than 3,000 studies performed per year | Contribution to 300 patents

*Nature Drug Discovery, 2010, 9, 203; DDT, 2003, 8(23), 1067; DDT, 2013, 19(3), 341* *There are a number of the candidates that we do not know their current status. A number of these may also have achieved clinical PoC or be moving towards that goal

25% candidates have progressed to clinical PoC or beyond

- better than the industry standard (12-24%)*- additional 11 being progressed towards clinical PoC**- delivering 5 candidates per year for past 10 years

DISEASE AREANO. OF

CANDIDATES Preclinical Phase I Phase IIa Phase IIb Phase III Registration

Inflammation 13CHEMOKINE, INTEGRIN, GPCR, CYTOKINE, KINASE, ENZYME

Respiratory 24GPCR, PROTEASE NHR, KINASE

CNS 6GPCR, NHR

Metabolic disease 4ENZYME, KINASE, PROTEASE

Oncology 13ENZYME, KINASE, PPI

Anti-bacterial 1UNKNOWN

Anti-viral 1PROTEASE

Cardiovascular 2ION CHANNEL

Gastrointestinal 1ION CHANNEL

END–TO-END SOLUTIONS OR MODULAR PROJECTS

Flexible working options fit project needs and budgets

PARTNER IN VIVO PHARMACOLOGY

SINGLE FUNCTION

STRUCTURAL BIOLOGY

NETWORK PROJECT WITH MULTIPLE INTERACTIONS MED CHEMISTRY

ADME/PK

IN VIVO PHARMACOLOGY

ELECTROPHYSIOLOGYPARTNERACADEMIC

GROUP

CONSULTANT

PARTNER

INTEGRATED PROJECT

MED CHEMISTRY

ADME/PK

STRUCTURAL BIOLOGY

IN VITRO ASSAYS

IN VIVO PHARMACOLOGY

HOW DOES CHARLES RIVER SUPPORT PRECLINICAL

DRUG DISCOVERY?

We use a translationally focused approachIN VITRO ASSAYS TO IN VIVO MODELS USING MULTIPLE SPECIES GENERATES RELEVANT DATA TO MAXIMIZE CLINICAL SUCCESS

Target Discovery & Validation Hit ID Lead-to-CandidateHit–to-Lead

cDNA, shRNA, CRISPR/Cas9, RNAi AND GENOME EDITING

COMPLEX CELL BASED ASSAYS IN HUMAN/PRIMARY CELLS

IN VIVO EFFICACY

EX VIVO ANALYSIS

USE OF PATIENT DERIVED TISSUE

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80%

90%

100%

shRNA_1 shRNA_2 shRNA_3 shRNA_4 shRNA_5 shRNA_6

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NA

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-9 -8 -7 -6 -50

50

100

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200

6-OHDAHealthy

Delivering ‘end-to-end’ integrated programs

With a breadth of expertise across multiple therapeutic areas

ONCOLOGY CNS IMMUNOLOGY CV/METABOLISM RESPIRATORY

TARGETDISCOVERY & VALIDATION

Adenovirus technology ● Human primary cell assays ● High-content platforms ● Mechanism of action studies ● CRISPR gene editing

HIT FINDING Compound screening libraries ● Virtual and Fragment Screening ● Knowledge-based design ● Phenotypic screening

MEDICINAL CHEMISTRY Informatics and molecular modeling ● Chemical synthesis and scale-up ● Analysis and purification

IN VITRO/IN VIVO

PHARMACOLOGY

2D and 3D cultures> 400 PDX ModelsSyngeneic ModelsHumanized ModelsXenograft Models

NeurologyPsychiatryNeuropathic painNeuromuscular deficiencyNeurodegenerative disease

PsoriasisT-cell activationPeritonitisColitisOsteoarthritisCytokine releaseVaccine assessment

DiabetesDiabetic complicationsAtherosclerosisNASH

AsthmaCOPDPulmonary inflammationMucocilliary clearanceFibrosis

BIOMARKERDEVELOPMENT Biomarker identification ● Ex vivo development and validation ● Dose-to-man predictions ● Translation into clinic

IND ENABLING STUDIES

In vitro Toxicology ● DMPK (non-GLP and GLP) ● Exploratory Toxicology ● Genetic Toxicology ● Safety PharmacologySubchronic/Chronic Toxicology ● Development and Reproductive Toxicology

In vitro discovery platforms across all therapeutic areas

TARGET DISCOVERY & VALIDATION HIT FINDING MEDICINAL CHEMISTRY IN VITRO PHARMACOLOGY

CADD, SCALE UP PROCESS

CRYSTALLOGRAPHY, BIOPHYSICS

HIGH THROUGHPUT SCREENING &

COMPOUND LIBRARIES

GENE FAMILY EXPERTISE

COMPLEX BIOLOGY: PRIMARY/PATIENT DERIVED

CELL LINES FOR ASSAY DEVELOPMENT

IN VITRO SAFETY

PHARMACEUTICS,FORMULATIONS

ADME/PK

Best In Class Animal Models Across Multiple Therapeutic Areas to Support In Vivo Pharmacology and Safety/Toxicology Studies

- Diabetes plus diabetic complications

- Atherosclerosis- NASH- Translational animal models

CV & Metabolic- >550 PDX models- Syngeneic models- Humanized models- Xenograft models

Oncology

- Asthma – acute and severe- COPD- Pulmonary inflammation- Mucocilliary clearance- Fibrosis

Respiratory

- Psoriasis- T-cell activation- Peritonitis- Colitis

- Arthritis, OA joint pain

- Cytokine release- Vaccine assessment

Inflammation & immunology

- Neurology: acute and chronic

- Psychiatry - Neuropathic pain- Neuromuscular deficiency

CNS/pain- Dermatology- Others

Other

- Macular degeneration- Glaucoma- Diabetic retinopathy- Uvelitis- Primary ocular irritation- In vitro eye irritation- Neovascularization

Ocular- Huntington’s disease- ALS- Rett’s syndrome- Cystic fibrosis- Autism- Spinocerebellar ataxia

Rare & orphan

In vivo discovery models

v

Global presence: Centers of excellence across North America and Europe

CNS

Complex cell biology

Integrated drug discovery

Oncology

Metabolic disease

Inflammation Oncology

Ion channel

Breadth of scientific expertise and pedigree in the Charles River discovery team

• 650 scientists

• Diverse pharmaceutical and biotech company pedigree

• Largest group on certified veterinary pathologists in the world

• Over 300 patents awarded

• Library of peer-reviewed publications

• No internal programs, no competition

Charles River Chemistry won the 2015 RSC SCI Retrosynthesis competition

Balanced scientific expertise within the team

38%

30%

27%5% In vivo biologists

Chemists

In vitro biologists

ADME scientists

SAMPLE CASE STUDIES

Development of a PI3 Kinase Inhibitor

COMPOUND IS CURRENTLY IN PHASE III CLINICAL TRIALS

- Glioblastoma multiforme (GBM) is the most common and aggressive primary CNS tumour in adults

- Rapid growth and invasion- Median survival after diagnosis is

~14 months

- The PI3K pathway is implicated in more than 80% of GBM cases

- PI3Kα is highly mutated in cancers

- A novel, high quality, PI3K-sparing compound was identified as an HTS hit

- Synthesis of a pan-selective brain penetrant compound was developed for the treatment of glioblastoma

HTS hit – efflux substrate so poor blood brain barrier penetration

Development of compound that requires low dose for efficacious response

In silico drug design, synthetic chemistry, potency, PK and ADME optimization at Charles River Discovery

Published in J Med Chem. 2013 Jun 13;56(11):4597-610

Case Study: Oncology

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Case Study: CNSDevelopment of 11β-HSD1 Inhibitors

- Reduction of cortisol levels in the brain has been linked to reduced cognitive impairment in patients in the early stages of Alzheimer's disease

- 11β-HSD1 previously targeted for the treatment of metabolic disease

- CNS penetration by known inhibitors is very low

- Starting points identified by virtual screening/ knowledge based design

- Lead optimisation led to discovery of compound

- orally bioavailable with excellent CNS penetration

- improved memory demonstrated in rodent models of age-related cognitive impairment

- disease modifying effects in pre-clinical models

Compound disposition in murine brain 10mg/kg p.o.MALDI FTIR-MS of brain slices at 1, 4 and 6 hrs

PARTNER COMPOUND IN PHASE II TARGETING ALZHEIMER'S DISEASE

15 mo Tg2576 mice: 10mg/kg 28 daysPassive avoidance test shows indication of improved memory (left) Post mortem examination shows reduced formation of Aβ plaques (right)

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