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VC Biotech
YOU
ANY OF YOU
VC
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The Evolution of the Drug Discovery Landscape in 2011
Academia • Focused on early discovery/model
development • Generation of peer reviewed
preclinical data • Use of patents to maximize utility of
new developments
Pharma/Academia Collaborations • 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 Target Class Distinction True Integration
Strong Internal Pipeline Proven Program Management
Global Integration Flexible Program Models
Global Tax Advantage
Seamless Management Validated In Vivo Partners
High Quality & Value
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Hit Generation
Lead Generation
Lead Optimization
Target Discovery
Pre-clinical Development
Distinctive Global Integrated Drug Discovery
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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175 Drug Discovery Programs
• 72 pre-clinical and clinical candidates
• 90 Issued US Patents (dozens additional filings)
• 300 Peer reviewed publications
• 400 Verbal Presentations and Posters
Collaboration Track Record
Public collaborations with Pfizer, Merck, BMS, Eli Lilly, Genentech and CHDI
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25 Metabolic Disease Programs
• 19 pre-clinical and clinical candidates
Therapeutic Area Industry-Leading Track Record
31 CNS Programs
30 Oncology Programs
16 Antibacterial Programs
• 10 pre-clinical and clinical candidates
• 6 pre-clinical and clinical candidates
• 12 pre-clinical and clinical candidates
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Hit Generation
Lead Generation
Lead Optimization
Target Discovery
Biology Therapeutic and Target Class Distinction
Metabolic Disease CNS
Antibacterials Oncology
Natural Products Fragments
Diverse Screening Sets In Vivo Relationships
GPCR’s Kinases/Phosphatases
Nuclear Hormone Receptors Phosphodiesterases Methyltransferases
Distinct Biology
Strengths
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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
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Therapeutically Focused Discovery Infrastructure
Therapeutic Area Leaders
(TAL)
in Vitro Biology Lead Chemistry Lead ADMET Lead
Established in Vivo
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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Quality Cost
East Meets West
Hybrid Model
35-40% Global PhD Density
High level global expertise delivering quality and value
US, Europe, Asia
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Skilled International Project Leadership- Continuous Global Integration
We relieve you of the burden of project management
• IT integration • Global Access to central AMRI information services
• Cultural Nuance Training
• Enhanced global productivity • Local Time zone communication
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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
Fully Integrated Drug Discovery
Optimization Property SPR
Activity SAR
Design & Synthesis
Redesign
Computational Chemistry
In Vitro Biology Medicinal Chemistry In Vitro ADMET
Speaking the “Discovery Language”
Or integrated into the Customer’s Drug Discovery Team
Hit Generation
Lead Generation
Lead Optimization
Target Discovery
Pre-clinical 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
AMRI Discovery Chemistry Strengthening the Early Drug Discovery Path
Creation & Protection of Customer’s Intellectual Property
Design objective: create novel, patentable
compounds
AMRI Medicinal Chemistry Experience
Comprehensive search of chemistry & patent
databases
Provide technical support for filing Patent
Applications
Assist customer with establishing Patent Strategy
when necessary
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
C
B
D
E
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
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
Reagent production
Assay development HTS
Gene reporter. Cytotox. / Prolif.
Enzyme inhibition. Receptor & ion
channel functional assays.
Ligand displacement. ELISA
96, 384 & 1536- well plates.
Fluorescence (all modes). Luminescence
(red & blue). Absorbance (UV/Vis).
Radioactive (SPA; filter). Biochemical & cell-based.
FLIPR
Candidates SAR
Mammalian cell lines
Pure proteins. Receptor
preparations.
Potency. Selectivity.
MOA ADMET
Bioanalysis
Small molecule, synthetic libraries
Natural product libraries
Chemistry &
biocatalysis
AMRI
Biology
AMRI
Chemistry
Software & Hardware Assets
ActivityBase 7.3: • Oracle database and associated clients • Excel & XLFit for data analysis • Automated data processing
ORCA-based HTS system: • Fully automated screening
Stand alone workstations: • Beckman FX96 & FX384 (4), Hummingbird (3) &
Janus (1) liquid handling robots • Analyst GT (3), Synergy 4 (1) & Envision (1)
multi-mode plate readers • CLIPR CCD-based luminescence reader • FLIPR Tetra Plus Calcium flux & membrane
potential reader • 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
DXP-R Rxn Linearity 10 minObservedPredicted
Fluo
resce
nce
Minutes0 3 6 9 12
25000
35000
45000
55000
65000
75000
85000
95000
R2
0.9976
• 6 – 100 µL reaction volumes
• 80 - 1,280 test samples per plate
• 16 - 256 wells of controls & standards
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
Full spectrum of target classes Multiple assay formats & detection strategies
Target / Assay Class Assay Formats / Detection Strategies Receptor tyrosine kinase ELISA / 33P / IMAP-FP / IMAP-FRET
Kinase (other) ELISA / 33P / IMAP-FP / IMAP-FRET / Kinase Glo / Alphascreen / SPA
Nuclear hormone receptor FP / radioligand displacement / gene reporter
GPCRs FLIPR / Radioligand displacement / cAMP / 35S-GTPS / gene reporter / HTRF / SPA
Oxidoreductase Fluorescence / absorbance
Ion channel FLIPR / conductance
Protease / peptidase Absorbance / fluorescence / FRET
Methyl Transferase Radioisotope incorporation
Histone Deacetylase Fluorescence / SPA
Nucleic acid binding protein (other) Radioligand displacement / FP / FRET / ELISA
Transporter Radioligand displacement / radiosubstrate uptake / Cytostar T
Cell Pathway Gene reporter / HTRF / activity / fluorescence translocation (LTS) / fluorescence
Cell proliferation & cytotoxicity 3H-Thymidine uptake / Alamar Blue / MTT / MTS / CellTiter-Glo® / ApoGlow®
Antimicrobial Turbidity / Alamar Blue / gene reporter / phenotype / fluorescence translocation
Phenotype (low throughput) Colony forming units / filamentation / septum formation
ADMET/ PK Services Selected AMRI in vitro ADMET Assays
Absorption/ Bioavailability
Metabolism Toxicity Bioanalytical Services
Ø Physicochemical property determinations
Ø Metabolic Stability (microsomes, S9, hepatocytes, plasma)
Ø Cytotoxicity with numerous cell lines; multiple endpoints
Ø Bioanalytical Method Development
Ø Cell-based permeability models
Ø CYP Inhibition/ Induction
Ø Time-dependent CYP inhibition mechanisms
Ø Metabolite profiling and exposure in vivo
Ø PAMPA (passive diffusion)
Ø Metabolizing Enzyme Identification
Ø Reactive metabolites Ø Discovery PK Studies
Ø Protein binding (Plasma, target proteins, species)
Ø Metabolite profiling Ø Modeling-based Toxicology Predictions
Ø PK and TK modeling
Ø Gastric Stability Ø Animal Model Comparison/ Prediction
Ø Mutagenicity (Mini- and Full Ames tests)
Ø Target Organs
Ø Stability to Intestinal flora
Ø Metabolite Structural Characterization
Ø Micronucleus Ø Tissue Concentrations
Ø Metabolite synthesis Ø Metabolite toxicity/ hepatotoxicity
Ø Drug Mass Balance
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Key AMRI Distinctions
Proven Track Record We Deliver Results
Preclinical Experience Successful IND Filing
Biology Therapeutic and Target Class Distinction True Integration
Strong Internal Pipeline Proven Program Management
Global Integration Flexible Program Models
Global Tax Advantage
Seamless Management Validated In Vivo Partners
High Quality & Value
