the benefits of outsourcing drug discovery to an … mortem examination shows reduced formation of...
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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
0%
10%
20%
30%
40%
50%
60%
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80%
90%
100%
shRNA_1 shRNA_2 shRNA_3 shRNA_4 shRNA_5 shRNA_6
mR
NA
kno
ck-d
own
gene X
Log [M]
Norm
alis
ed m
etric
-9 -8 -7 -6 -50
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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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