mattthew.reabold@amriglobal.

com
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 ANY OF YOU

YOU

VC VC
Biotech

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The Evolution of the Drug Discovery
Landscape in 2011

Academia Pharma/Academia Collaborations

• Focused on early discovery/model
development
• Generation of peer reviewed
preclinical data
• Use of patents to maximize utility of
new developments
• Pharma looking for low risk, high
success opportunities
• Requires Pharma Standards proof-of-
concept for licensing
• Robust patent protection needed for
major therapeutic development

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The Evolution of the Drug Discovery
Landscape in 2011

Biotechs
§  SBIR Grants
§  NIH Grants
§  Non-Profits
§  VC Funding
§  Strategic Alliances
§  Regional marketing licenses
§  M&A
§  IPO

How do you de-risk Discovery?

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AMRI Global Integrated Drug Discovery,
Development & Manufacturing Services
As a global leader in drug discovery, AMRI provides valuable contract discovery,
development, and manufacturing services to advance our clients goals.

AMRI advantages include:

•  Comprehensive in vitro biology and chemistry capability from lead generation
to advanced development to manufacturing
•  Substantial capacity located at multiple facilities throughout the world
•  Integrated services providing a seamless product to the client
•  Cost effective outsourcing solutions with flexible business models

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Key AMRI Distinctions

Proven Track Record We Deliver Results

Preclinical Experience Successful IND Filing

Biology Therapeutic and

True Integration
Target Class Distinction

Strong Internal Pipeline Proven Program Management

Global Integration Flexible Program Models

Global Tax Advantage High Quality & Value

Validated In Vivo Partners Seamless Management 6

Distinctive Global
Integrated Drug Discovery

Target Hit Lead Lead Pre-clinical

Discovery Generation Generation Optimization Development

Lead Discovery Lead Optimization

•  Libraries
•  Assay Development & Design
•  Reagent Production
•  High Throughput Screening
•  Fragment Based Screening
•  Natural Products Technologies
•  Medicinal Chemistry
•  Parallel Chemistry
•  Biocatalysis
•  CADD
•  In Vitro ADME/Tox
•  Potency Selectivity

Experience + Technology = Efficiency

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Collaboration Track Record

•  72
pre-clinical and clinical
candidates

•  90
Issued US Patents
(dozens additional filings)
175 Drug Discovery
Programs •  300
Peer reviewed
publications

•  400
Verbal Presentations and
Posters

Public collaborations with

Pfizer, Merck, BMS, Eli Lilly, Genentech and CHDI
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Therapeutic Area
Industry-Leading Track Record

25 Metabolic Disease Programs •  10

pre-clinical and clinical
candidates

31 CNS Programs •  19
pre-clinical and clinical
candidates

16 Antibacterial Programs •  6
pre-clinical and clinical
candidates

30 Oncology Programs •  12
pre-clinical and clinical
candidates

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Biology Therapeutic and
Target Class Distinction

Target Hit Lead Lead

Discovery Generation Generation Optimization

GPCR s Metabolic Disease

Kinases/Phosphatases CNS
Nuclear Hormone Receptors Antibacterials
Phosphodiesterases Oncology
Methyltransferases
Distinct
Biology
Strengths

Natural Products
Fragments
Diverse Screening Sets
In Vivo Relationships
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Strong R&D Pipeline

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Announced Integrated Programs

BMS Partnership has yielded 3 compounds in development, 2 have

progressed into the clinic

CHDI Extended Drug Discovery Collaboration (CNS program, Kinase

focus)

Genentech Research and Licensing Agreement on antibacterial

agents from AMRI s own Natural Product based program

AMRI Initiation of Phase I Study of Novel Drug for Obesity Treatment

from AMRI s internal discovery program

AMRI Publication of Results for On-going Phase I Clinical Study of

AMRI s Anti Cancer Compound

Proven success through flexible business models 12

Therapeutically Focused Discovery
Infrastructure

Therapeutic
Area Leaders
(TAL)

Established
in Vitro Biology
Chemistry Lead ADMET Lead in Vivo
Lead
Providers

Efficacy PK/Tox

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Established in Vivo Partners

Several specialized in vivo providers

•  Broad in depth therapeutic expertise
•  Limited monetary investment
•  No ramp up time
•  AMRI integration of relationship
•  Flexibility
Partners chosen through extensive due diligence
•  Specialization/Expertise
(e.g. Intervivo – CNS, Renasci – Metabolic)

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East Meets West

US, Europe, Asia

Quality Cost

Hybrid
Model

35-40% Global PhD Density

High level global expertise delivering quality and value 15

Skilled International Project Leadership-
Continuous Global Integration
•  Cultural •  IT integration
Nuance •  Global Access to
Training central AMRI
•  Enhanced global information services
productivity
•  Local Time zone
communication

We relieve you of the burden of project management

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Global Tax Advantage

Up to a 30% Tax Credit for R&D

•  Crédit d Impôt Recherche (C.I.R.) Certification - French
Ministry of Research

•  Singapore Productivity & Innovation Credit

http://iras.gov.sg/irashome/PIcredit.aspx

•  Potential for R&D grant supports from Singapore Government

(RISC)

Programs executed by French or Singaporean companies may

benefit from government support
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AMRI Discovery Capabilities

Global Medicinal and

Computational Chemistry
Matthew.reabold@amriglobal.com
Fully Integrated Drug Discovery

Speaking the Discovery Language

Computational Chemistry

In Vitro Biology Medicinal Chemistry In Vitro ADMET

Design & Synthesis

Activity Property
Optimization
SAR SPR

Redesign

Or integrated into the Customer s Drug Discovery Team

AMRI Discovery Chemistry
Strengthening the Early Drug Discovery Path

Target Hit Lead Lead Pre-clinical

Discovery Generation Generation Optimization Development

Hit Generation
•  Screening based approach: structure-based drug design/virtual library screening, AMRI
compound libraries, open access libraries, custom library synthesis
•  Fast follower/scaffold-hopping approach
Lead Generation
•  Hit-to-Lead optimization - iterative parallel optimization of SAR & SPR
•  Establish proprietary chemotypes with best potential to advance to lead opt stage
•  Parallel / traditional synthesis
•  Evidence of in vivo activity – Proof of concept study
Lead Optimization
•  Thorough SAR and SPR optimization
•  Optimize in vivo PK/PD, minimize off-target activity, minimize Tox liabilities progress
compounds that meet preclinical candidate selection criteria
Creation & Protection of
Customer s Intellectual Property

AMRI Medicinal Chemistry Experience

Design objective: create Assist customer with

novel, patentable establishing Patent Strategy
compounds when necessary

Comprehensive search of Provide technical support

chemistry & patent for filing Patent
databases Applications

Confidentiality of Customer IP is integral part of AMRI Corporate Culture

Global Medicinal Chemistry

Highly experienced global staff of 450

(40% Ph.D.)

Facilities Overview
•  >450 fume hoods
•  Modern synthetic technologies
•  Parallel synthesis and purification
•  Focused Library Synthesis
•  Full analytical support staff and facilities
•  State-of-the-art library and search tools
•  CADD and database support
Computer-Aided Drug Discovery

•  Software and Hardware

•  Virtual Screening
•  2D
•  Pharmacophore Searching
•  Structure-Based VS

•  Library Design and Enumeration

•  Homology Modeling

•  Medicinal Chemistry Integration

Chemistry and Biology Data Integration

A B

C Most descriptors automatically calculated

Why AMRI Medicinal Chemistry

ü  Global organization with highest quality standards & support

ü  Constant involvement of senior leadership in project management
ü  State of the art synthesis and analytical facilities
ü  Strong track record of success
ü  Regular communication with project scientists
ü  Competitive pricing
AMRI Discovery Capabilities

In Vitro Biology & ADMET

Matthew.reabold@amriglobal.com
Introduction to AMRI IVB

•  Well-equipped, established team

•  Key scientists derived from large Pharma, Biotech & local academic
institutions (Pharmacia, J&J, AZ, Icos, Arris, Sugen, Ceptyr)

•  Continued investment in growth (expect 50% expansion in 2011)

•  Average Discovery Biology experience of > 8 years

•  Locations in US and Singapore to provide local integration with Chemistry

teams

•  Focus of providing custom, high quality

in vitro biology.
 AMRI: in vitro Biology Services

AMRI Small molecule, synthetic libraries Chemistry &

Natural product libraries biocatalysis
Chemistry

Reagent Assay
HTS SAR Candidates
production development

Mammalian cell Gene reporter. 96, 384 & 1536- Potency.

lines Cytotox. / Prolif. well plates. Selectivity.
Pure proteins. Enzyme inhibition. Fluorescence (all modes). MOA
Receptor Receptor & ion Luminescence ADMET
preparations. channel AMRI
(red & blue). Bioanalysis
functional assays. Absorbance (UV/Vis). Biology
Ligand displacement. Radioactive (SPA; filter).
ELISA Biochemical & cell-based.
FLIPR
Software & Hardware Assets
ActivityBase 7.3:
•  Oracle database and associated clients
•  Excel & XLFit for data analysis
DXP-R Rxn Linearity 10 min
•  Automated data processing Observed
Predicted

95000

ORCA-based HTS system:

2
85000 R
75000 0.9976

Fluorescence
•  Fully automated screening 65000
55000
45000

Stand alone workstations: 35000

25000
0 3 6 9 12
•  Beckman FX96 &
FX384 (4), Hummingbird (3) & M inutes

Janus (1) liquid handling robots

•  Analyst GT (3), Synergy 4 (1) & Envision (1)
multi-mode plate readers • 6 – 100 µL reaction volumes
•  CLIPR CCD-based luminescence reader • 80 - 1,280 test samples per plate
•  FLIPR Tetra Plus Calcium flux & membrane
• 16 - 256 wells of controls &
potential reader
standards
•  Topcount NXT and Microbeta TriLux (2) liquid
scintillation counters
•  Flexstation II384 Calcium flux readers (2)
•  ELX405 plate washer (with stacker)
•  BioRaptor 4/8 nL volume bulk dispenser
•  Multidrop384 (4), Multidrop Combi (4) and
Wellmate (4) bulk dispensers
•  Shimadzu LC-MS
Screening Libraries

•  Over 170,000 Screening-Ready Diverse Synthetics

•  Over 250,000 Synthetics as open access
•  Over 320,000 Natural Products
•  Fragment Library – 4,000 compounds
Examples of Target Classes Screened &
Technologies Employed
Target / Assay Class
Receptor tyrosine kinase
Kinase (other)
Nuclear hormone receptor
GPCRs
Oxidoreductase
Ion channel
Protease / peptidase
Methyl Transferase
Histone Deacetylase
Nucleic acid binding protein (other)
Transporter
Cell Pathway
Cell proliferation & cytotoxicity
Antimicrobial
Phenotype (low throughput)
Full spectrum of target classes
Multiple assay formats & detection strategies
Assay Formats / Detection Strategies
ELISA / 33P / IMAP-FP / IMAP-FRET
ELISA / 33P / IMAP-FP / IMAP-FRET / Kinase Glo / Alphascreen / SPA
FP / radioligand displacement / gene reporter
FLIPR / Radioligand displacement / cAMP / 35S-GTPS / gene reporter / HTRF /
SPA
Fluorescence / absorbance
FLIPR / conductance
Absorbance / fluorescence / FRET
Radioisotope incorporation
Fluorescence / SPA
Radioligand displacement / FP / FRET / ELISA
Radioligand displacement / radiosubstrate uptake / Cytostar T
Gene reporter / HTRF / activity / fluorescence translocation (LTS) / fluorescence
3H-Thymidine uptake / Alamar Blue / MTT / MTS / CellTiter-Glo® / ApoGlow®
Turbidity / Alamar Blue / gene reporter / phenotype / fluorescence translocation
Colony forming units / filamentation / septum formation
ADMET/ PK Services
Selected AMRI in vitro ADMET Assays

Absorption/ Metabolism Toxicity Bioanalytical

Bioavailability Services
Ø Physicochemical Ø Metabolic Stability Ø Cytotoxicity with Ø Bioanalytical Method
property (microsomes, S9, numerous cell lines; Development
determinations hepatocytes, plasma) multiple endpoints
Ø Cell-based Ø CYP Inhibition/ Ø Time-dependent CYP Ø Metabolite profiling
permeability models Induction inhibition mechanisms and exposure in vivo
Ø PAMPA (passive Ø Metabolizing Enzyme Ø Reactive metabolites Ø Discovery PK Studies
diffusion) Identification
Ø Protein binding Ø Metabolite profiling Ø Modeling-based Ø PK and TK modeling
(Plasma, target Toxicology Predictions
proteins, species)
Ø Gastric Stability Ø Animal Model Ø Mutagenicity (Mini- Ø Target Organs
Comparison/ Prediction and Full Ames tests)
Ø Stability to Intestinal Ø Metabolite Structural Ø Micronucleus Ø Tissue Concentrations
flora Characterization
Ø Metabolite synthesis Ø Metabolite toxicity/ Ø Drug Mass Balance
hepatotoxicity
Key AMRI Distinctions

Proven Track Record We Deliver Results

Preclinical Experience Successful IND Filing

Biology Therapeutic and

True Integration
Target Class Distinction

Strong Internal Pipeline Proven Program Management

Global Integration Flexible Program Models

Global Tax Advantage High Quality & Value

Validated In Vivo Partners Seamless Management 33

Distinctive Global Integrated
Drug Discovery

Questions???

mattthew.reabold@amriglobal.com