AMRI BioDistrict Presentation
Content
[email protected] 1
ANY OF YOU YOU
YOU
VC
VC Biotech
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The Evolution of the Drug Discovery Landscape in 2011
Academia • Focused on early discovery/model development • Generation peer reviewed preclinicalof 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-ofconcept 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
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NIH Grants
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Non-Profits
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VC Funding
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Strategic Alliances
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Regional marketing licenses
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M&A
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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 manufacturi development manufacturing ng services to advance our clients goals.
AMRI advantages include: •
Comprehensive in vitro biology vitro biology and chemistry capability from lead generation to advanced development to manufacturing
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Substantial capacity located at multiple facilities throughout the world
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Integrated services providing a seamless product to the client
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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
High Quality & Value
Validated In Vivo Partners Vivo Partners
Seamless Management 6
Distinctive Global Integrated Drug Discovery
Target Discovery
Hit Generation
Lead Generation
Lead Discovery
Lead Optimization
Pre-clinical Development
Lead Optimization
Libraries Assay Development & Design
•
Medicinal Chemistry
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Parallel Chemistry
•
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Reagent Production High Throughput Screening
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Biocatalysis CADD
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Fragment Based Screening
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In Vitro ADME/Tox
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Natural Products Technologies
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Potency Selectivity
• • •
Experience + Technology = Efficiency 7
Collaboration Track Record
• 72
pre-clinical and clinical candidates
• 90
175 Drug Discovery Programs
Issued US Patents
(dozens additional filings) • 300
Peer reviewed publications
•
400 Verbal Presentations and Posters
Public collaborations with Pfizer, Merck, BMS, Eli Lilly, Genentech and CHDI 8
Therapeutic Area Industry-Leading Track Record 25 Metabolic Disease Programs
• 10
31 CNS Programs
• 19
16 Antibacterial Programs
30 Oncology Programs
pre-clinical and clinical candidates
pre-clinical and clinical candidates
• 6
pre-clinical and clinical candidates
• 12
pre-clinical and clinical candidates 9
Biology Therapeutic and Target Class Distinction
Target Discovery
Hit Generation
Lead Generation
Lead Optimization
GPCR s Kinases/Phosphatases Nuclear Hormone Receptors Phosphodiesterases Phosphodiesterase s Methyltransferases
Metabolic Disease CNS Antibacterials Oncology
Distinct Biology Strengths
Natural Products Fragments Diverse Screening Sets In Vivo Relationships 10
Strong R&D Pipeline
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Announced Integrated Programs BMS Partnership has yielded 3 compounds in development, 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
Initiation of sPhase I Study of Novel Drug for Obesity Treatment AMRI from AMRI internal discovery program
AMRI Publication of Results for On-going Phase I Clinical C linical Study of AMRI s Anti Cancer Compound Compound
Proven success through flexible business models
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Therapeutically Focused Discovery Infrastructure Therapeutic Area Leaders (TAL)
in Vitro Biology Vitro Biology Lead
Chemistry Lead
Established in Vivo Providers
ADMET Lead
Efficacy
PK/Tox
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Established in Vivo Partners Vivo Partners Several specialized in vivo providers vivo providers •
Broad in depth therapeutic expertise
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Limited monetary investment
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No ramp up time
• •
AMRI integration of relationship Flexibility 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
Cost
Quality
Hybrid Model
35-40% Global PhD Density
High level global expertise delivering quality and value
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Skilled International Project LeadershipContinuous Global Integration • Cultural Nuance Training • Enhanced global productivity
• IT integration • Global Access to central AMRI information services
• Local Time zone communication communication
We relieve you of the burden of project management 16
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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 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 Computationall Chemistry Computationa [email protected]
Fully Integrated Drug Discovery Speaking the Discovery Language
Computational Chemistry
Medicinal Chemistry
In Vitro Biology
In Vitro ADMET
Design & Synthesis Activity SAR
Optimization
Property SPR
Redesign
Or integrated into the Customer s Drug Discovery Team
AMRI Discovery Chemistry Strengthening the Early Drug Discovery Path
Target Discovery
Hit Generation
Lead Generation
Lead Optimization
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
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Establish proprietary chemotypes with best potential to advance to lead opt stage
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Parallel / traditional synthesis
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Evidence of in vivo activity – Proof of concept study
Lead Optimization •
Thorough SAR and SPR optimization
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Optimize in vivo PK/PD, minimize off-target activity activity,, minimize Tox Tox liabilities progress compounds that meet preclinical candidate selection criteria
Creation & Protection of Customer s Intellectual Property
AMRI Medicinal Chemistry Experience Design objective: create novel, patentable compounds
Comprehensive search of chemistry & patent databases
Assist customer with establishing Patent Strategy when necessary
Provide support for technical filing Patent 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
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Modern synthetic technologies
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Parallel synthesis and purification
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Focused Library Synthesis
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Full analytical support staff and facilities
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State-of-the-art library and search tools
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CADD and database support
Computer-Aided Drug Discovery •
Software and Hardware
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Virtual Screening •
2D
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Pharmacophore Searching
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Structure-Based VS
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Library Design and Enumeration
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Homology Modeling
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Medicinal Chemistry Integration
Chemistry and Biology Data Integration
D
E
A
C
B
Most descriptors automatically automatically calculated calculated
Why AMRI Medicinal Chemistry " " " " " "
Global organization with highest quality standards & support Constant involvement of senior leadership in project management State of the art synthesis and analytical facilities Strong track record of success Regular communication with project scientists Competitive pricing
AMRI Discovery Capabilities In Vitro Biology Vitro Biology & ADMET [email protected]
Introduction to AMRI IVB
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Well-equipped, established team
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Key scientists derived from large Pharma, Biotech & local academic institutions (Pharmacia, J&J, AZ, Icos, Arris, Sugen, Ceptyr)
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Continued investment in growth (expect 50% expansion in 2011)
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Average Discovery Biology experience of > 8 years
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Locations in US and Singapore to provide local integration with Chemistry teams
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Focus of providing custom, high quality in vitro biology.
AMRI: in vitro Biology Services
AMRI Chemistry
Small molecule, synthetic libraries
Chemistry &
Natural product libraries
biocatalysis
Reagent production
Assay development
HTS
SAR
Mammalian cell
Gene reporter.
96, 384 & 1536-
Potency.
lines Pure proteins. Receptor preparations.
Cytotox. / Prolif. well plates. Selectivity. Enzyme inhibition. Fluorescence (all modes). MOA Receptor & ion ADMET Luminescence channel Bioanalysis (red & blue). functional assays. Absorbance (UV/V (UV/Vis). is). Ligand displacement. Radioactive (SPA; filter). ELISA Biochemical & cell-based. FLIPR
Candidates
AMRI Biology
Software & Hardware Assets ActivityBase 7.3: • • •
Oracle database and associated clients Excel & XLFit for data analysis Automated data data processing
DXP-R Rxn Linearity L inearity 10 min Observed Predicted 95000
ORCA-based HTS system: •
2
R
85000
Fully automated screening
e c n e c s e r o u l
0.9976
75000 65000 55000
F
45000
Stand alone workstations: • • • • • • • •
FX96 &
35000
FX384 (4),
Beckman Hummingbird (3) & Janus (1) liquid handling robots Analyst GT (3), (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 384
• •
Multidrop Multidrop Combi (4) and Wellmate (4) (4), bulk dispensers Shimadzu LC-MS
25000 0
3
6 Minutes
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• 6 – 100 L reaction volumes •80 80 - 1,280 test samples per plate •16 - 256 wells of controls & standards
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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 Class
Assay Formats / Detection Strategies 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 Deacetyla Deacetylase se
Fluorescence Fluores cence / 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 CellTiter-Glo® ® / ApoGlow®
Antimicrobial
Turbidity / Alamar Blue / gene reporter / phenotype / fluorescence translocation translocation
Phenotype (low throughput)
Colony forming units / filamentation / septum formation
Full spectrum of target classes
Multiple assay formats & detection strategies
ADMET/ PK Services Selected AMRI in vitro ADMET vitro ADMET Assays Absorption/ Bioavailability
Metabolism
Toxicity
Bioanalytical Services
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Physicochemical property determinations
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Metabolic Stability (microsomes, S9, hepatocytes, plasma)
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Cytotoxicity with numerous cell lines; multiple endpoints
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Bioanalytical Method Bioanalytical Development
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Cell-based permeability models models
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CYP Inhibition/ Induction
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Time-dependent CYP inhibition mechanisms
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Metabolite profiling and exposure in vivo
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PAMPA (passive diffusion)
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Metabolizing Enzyme Identification
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Reactive metabolites
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Discovery PK Studies
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Protein binding (Plasma, target
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Metabolite profiling
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Modeling-based Toxicology Predictions
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PK and TK modeling
proteins, species) !
Gastric Stability
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Animal Model Comparison/ Prediction
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Mutagenicity (Miniand Full Ames tests)
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Target Organs
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Stability to Intestinal flora
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Metabolite Structural Characterization
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Micronucleus
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Tissue Concentrations
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Metabolite synthesis
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Metabolite toxicity/
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Drug Mass Balance
hepatotoxicity
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
High Quality & Value
Validated In Vivo Partners Vivo Partners
Seamless Management 33
Distinctive Global Integrated Drug Discovery Questions???
