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AVEO Pharmaceuticals: Technologies and Vision

AVEO Pharmaceuticals: Technologies and Vision

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AVEO Pharmaceuticals: Technologies and Vision

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  1. AVEO Pharmaceuticals:Technologies and Vision Massachusetts Biotechnology CouncilDrug Discovery Committee February 19, 2009 MBC, Cambridge Ronan C. O’Hagan Group Leader, Target Biology

  2. AVEO Pipeline Platform & biological insight State-of-the-art antibody drug discovery/engineering AVEO AVEO’s Unique Niche • AVEO’s niche is its unique cancer biology platform applied to the discovery and development of functional anti-cancer antibodies • Faster, more efficient route to clinical POC

  3. AVEO Pipeline Drug Discovery Company Value Creation Models in Biotech Value Creation Platform Company Relative Valuation Time • Platform = high value, for short time period • Long term value = drug discovery & development • Combination of Drug Discovery • + Biological Insight (Platform) = Enhanced Value

  4. AVEO Pipeline AVEO’s Innovative Platform: Better Models of Human Cancer Inject stem cells into 3 day mouse embryos Inducible Oncogenic Mouse Stem Cell Introduce human oncogene in select tissue Mice seeded with Inducible oncogenic tissue Mouse Stem Cell • Defined genetic context • Oncogene activated post-natally • Natural in vivo setting • Heterogeneity across population Breast Her2 Lung KRas Lung EGFRL858R Lung EGFRL858R, Colon b-Catenin T790M Models Used for Target Identification, Validation & Human Response Prediction

  5. AVEO Pipeline Erbb2 400 * * 350 Novel Cancer Targets identified in genetic Screens that are capable of complementing HER2 in vivo EGFR 300 MAPK6 Edg2 * 250 Integration Sites Esr1 200 Kirrel1 Erbb3 vav3 * * 150 Erbb3 * Met 100 * * 50 0 2 3 4 5 6 7 8 9 10 11-15 16-20 >20 2 3 4 5 6 7 8 9 10 11-15 16-20 >20 MAP3K8 PLK3 Met Tumor Recurrence HER2 Complementation Screen Identifies Expected as well as Novel Cancer Targets Filtering by Recurrence in (~ 200) Independent Tumors Adjacent to or within candidate gene (~ 30 kb)

  6. AVEO Pipeline Identifying Functionally Relevant Cancer Targets • AVEO’s MaSS Screen: Identifies functionally relevant cancer targets • Additional Filters for Relevance in Human Cancers: e.g. Cancer Mutations • Highlights well credentialed targets • Targets Identified from MaSS Screen include Credentialed + Novel • Novel = Long term investment; take time to progress • Credentialed: • Enable early creation of value • Proof of Concept for novel targets

  7. AVEO Pipeline AVEO Antibody Drug Discovery • AVEO Drug Discovery engine is focused on development of • therapeutic antibodies • More rapid & cost effective to build necessary infrastructure • Enhanced specificity for target • Less risk of off-target toxicity • Faster, more sure path through clinical development • Rapid growth of mAbs as therapeutics

  8. AVEO Pipeline AVEO Antibody Pipeline Powered by Unique Technology • Better Validated Targets: • In vivo context is uniquely suited to identify best antibody targets • Better Antibodies: • Tools and know-how for drug discovery • Better Models: • Proprietary target-driven tumors enable optimal drug discovery • Better Biomarkers: • AVEO technology facilitates identification of response biomarkers

  9. AVEO Pipeline AVEO Antibody Drug Discovery Goals • Build a sustainable antibody pipeline through the generation of one antibody development candidate/year • This requires • Incubation of a pipeline of antibody projects • Antibody drug discovery and development capabilities

  10. AVEO Pipeline Robust Antibody Pipeline Beyond AV-299 Effective discovery engine delivering novel, high quality oncology antibody drug candidates AV-299

  11. AVEO Pipeline Pipeline • Current focus on target families that are involved in the regulation of distinct but overlapping biological processes • Pathways/targets validated by AVEO platform • AVEO platform may provide unique insights into complex biology • Synergy • Different therapeutic opportunities • Goals: 1. Discovery of potent humanized/human antagonistic antibodies • Direct inhibition of target function - no antibody effector functions (ADCC, CDC) required for activity 2. Develop a translational research program to guide clinical development and discovery of biomarkers that potentially identify human patient populations most likely to respond to drug

  12. AVEO Pipeline AVEO’s niche is its unique cancer biology platform applied to the discovery and development of functional anti-cancer antibodies Faster, more efficient route to clinical POC Requirements: State of the art antibody discovery/engineering tools Generate/engineer antibodies with ideal activity/pharmacologic profile Engineer desired cross-reactivity profile (mouse, cyno) to maximize the use of AVEO cancer biology platform and facilitate pre-clinical development Ability to cost effectively produce multiple antibody candidates Either for AVEO or partners When to outsource, when to build in house? Constantly evolving application of AVEO cancer biology platforms to address key issues associated with different drug discovery programs Building an Antibody Drug Discovery Engine

  13. AVEO Pipeline AVEO Antibody Drug Discovery Capabilities • Antibody diversity generation • Protein biochemistry • Antibody characterization • Development candidate generation • Functional assays • In vivo pharmacology • Preclinical development

  14. AVEO Pipeline AVEO Drug Discovery Capabilities: Better Antibodies A repertoire of know-how and advanced tools to access targets efficiently • Murine monoclonal antibodies (Maine Biotechnology Services) • Phage display (Dyax) • Antibody diversity generation • Protein biochemistry • Antibody characterization • Dev. candidate generation • Functional assays • In vivo pharmacology • Preclinical development • Immunization strategy (Antigen design, stimulatory adjuvant oligonucleotides, etc.) • Antigen expression and purification (Lonza) • Protein engineering (pegylation, deglycosylation, biotinylation, TRAP production) • Biacore T100 (Screening, kinetic analysis, epitope mapping) • Octet (High-througput kinetic screening, Ab concentration, neutralization, assay dvlp.) • KinExA (Cell surface affinity); Meso Scale (Electrochemiluminescence detection) • Superhumanization (Arana) • Design, synthesis, and expression of competitor antibodies • Cell surface binding/internalization • Neutralization of ligand binding • Cellular biochemistry (FDCP, BaF3) • Phenotypic assays (dBase of human cancer cell lines) • Multiplex detection pathway modulation • High-throughput soft agar assays • Mouse (+/- tumor), Rat, Cyno monkey • PK/PD/efficacy relationship • Murine tumor archive • Human primary tumors (under development) • Target driven DC tumors • Knock in/knock out mouse models • In house (PK, ADA, neutralization assays, multiplex serum markers, CTC biomarker development, ADCC, CDC) • Outsourced GLP work (Cyno toxicology, pharmacology, and cross-reactivity; human cross-reactivity)

  15. The completion of the human genome has provided the entire field with a comprehensive list of human protein encoded genes Bioinformatics analyses can identify antibody target candidates (cell surface and secreted proteins) based on amino acid structure, and relatedness to other known proteins of these classes Everybody has access to the most obvious targets – difficult to gain competitive advantage against these targets The current challenge, and AVEO’s advantage, is in developing and applying sophisticated in vivo biological systems that can help us identify which targets are the most functionally relevant for driving tumor growth and survival AVEO Pipeline Antibody Targets: The Challenge

  16. AVEO Pipeline Antibody Targets: Biological Insight Applied to Drug Discovery • Identification of functionally relevant cancer targets from in vivo genetic screen • Preservation of tumor-stromal interactions • Targets identified in micro-environment-dependent settings • Target validation with context-dependent emphasis • Validation using in vivo models • Evaluation of candidate therapeutics using context-specific approaches • Consideration of context at early stage • Rapid progression to testing using in vivo models of human cancers

  17. AVEO Pipeline Cell culture creates a very artificial environment 21% [O2] Potent bovine serum growth factors Adhesion to plastic substrate • Cell culture cannot capture the complex interactions that occur in an real tumor environment • Genetic screens in an in vivo context could provide more relevant antibody targets • Target validation & antibody discovery using in vivo models preserves interactions between tumor and microenvironment, including receptor/ligand interactions AVEO Target Identification and Validation: The Importance of Context Varied [O2] In vivo context is complex multicomponent environment Stromal cells Tumor cells lymphocytes Tumor endothelium Myeloid cells

  18. AVEO Pipeline Antibody Targets: The Importance of Context Pathway signaling varies dramatically between in vitro and in vivo environments U87MG tumors U87MG cells In culture MW 1 2 3 1 2 3 Higher levels of pTyr signaling are seen in a cell culture environment 220kDa 120kDa 100kDa 80kDa 60kDa 50kDa 30kDa • Phospho-tyrosine signaling reflects key RTK and TK signaling activity in a cell • Differing conditions result in different pathway signaling in vitro and in vivo

  19. AVEO Pipeline Antibody Targets: The Importance of Context Although HGF and Met are thought to be important in human cancer, HGF would not have been identified as an essential target in cell culture models Tumor regression induced By 2x wk 10mg/kg HGF mAb No inhibition of U87 growth by HGF mAb 3 days treatment--BrdU Relative growth in culture Tumor volume (mm3) Days

  20. AVEO Pipeline AVEO Antibody Pipeline: Better Models Proprietary AVEO inducible tumor models enable the rapid switching of oncogenes in primary tumors Days Unique AVEO breast c-met / HGF driven tumor is sensitive to AV-299 but not to Herceptin

  21. AVEO Pipeline AV-299 Example: MET/HGF and HGF Complemented Murine Breast Tumors Showed Variable Response to AV-299/2B8 Treatment 6534- 2B8 6535- 2B8 TGI: 86%, p=0.0079 6612-AV299 TGI: 99.7%, p=0.0007

  22. AVEO Pipeline Hiarachical clustering by ~800 differentially expressed genes between MET/HGF driven and non-Met driven DC tumors Identifying a signature correlating with HGF responsiveness provides candidate biomarkers for clinic MET/HGF driven Non-MET/HGF driven

  23. AVEO Pipeline AVEO: Innovative cancer therapies targeted to responsive patient populations Rapidly Maturing Pipeline Functional in vivo screens for target discovery Powerful antibody discovery engine yields rich pipeline Lead antibody – AV-299 anti-HGF – in Phase 1 Programs focused on exciting targets (e.g. FGFR, Notch, ErbB3) Human Response Platform (HRP™) Unique human-relevant cancer models facilitate identification of mechanisms of drug response and resistance Informs clinical strategy for AV-951, pipeline, partners’ products

  24. AVEO Pipeline Development of drug discovery capabilities enables maximal exploitation of biological insights from platform technologies Require drug development capabilities beyond preclinical proof-of-concept and clinical hypotheses to realize this value

  25. AVEO Pipeline Preclinical Development • GLP work outsourced: • Cyno toxicology, Cyno and human tissue cross-reactivity, Cyno pharmacology, assays • In house: • PK, ADA, neutralization assays • Multiplex serum markers • CTC biomarker development • ADCC, CDC

  26. AVEO Pipeline The Cost of Manufacturing: Major Hurdle for Antibody Clinical Development The cost associated with production provides a high barrier to take antibody programs to clinical POC Changing manufacturing paradigms Improved cell engineering technologies – fast generation of stable, high producing cell lines Chromosomal insulator regions to increase expression and stability of expression Selexis (Insulator Genetic Elements) Catalent GPEx (Gene Product Expression) - retrovirus (MoMuLV) based expression system Millipore UCOE (Ubiquitos Chromatine Opening Elements) Improved process development High-throughput selection of highly productive cell line/media combinations Invitrogen: automated colony picker robot Xcellerex: high throughput cell sorting for high producers Development of alternative cell lines (PER.C6)– higher yield due to high density XDA perfusion technology (ability of the cell line to produce over a long period of time) Percivia/Crucell Disposable manufacturing (Xcellerex FlexFactory) – disposable bioreactors, self-contained purification units Flexibility, easy to switch production Parallel production of different antibodies Cheaper to set up than traditional manufacturing No one company has all of these pieces together Confidential Information – Property of AVEO Pharmaceuticals, Inc.

  27. AVEO Pipeline New technologies that allow higher productivity have the potentialto bring clinical costs to a level similar to small molecules Antibody Research & Development Costs (Preclinical through Phase 2) Millions of Dollars Similar productivity to AV-299 $74 Drug Product (Finish / Fill) Variable Costs Process Development costs likely required to generate high titer cell lines $51 Drug Substance (Manufacturing) $44 $42 Almost $40M in costs between preclinical and Phase II are fixed $39 Formulation Dvlp Preclinical Tox Analytical Dvlp Stability Testing Cell Line Dvlp Fixed Costs Process Dvlp Translational Res. FTE Costs OOP Costs Note : * See Appendix for assumptions Increasing Antibody Titer Confidential Information – Property of AVEO Pharmaceuticals, Inc.

  28. AVEO Pipeline AV-299: Anti-HGF Monoclonal Antibody

  29. AVEO Pipeline AVEO’s Competitive, Clinical and Commercial Advantage Proprietary Integrated Biology Platform • Discovery and validation of functionally relevant targets • Rapidly maturing pipeline of novel functional antibodies • Identification of responsive patient populations increases probability of clinical success • Informs rational choice of drug combinations • Opportunity for differentiation in large markets • Supports optimal pricing and reimbursement Synergy between Drug Development Capabilities and Cancer Biology Platform Informs Clinical Strategy for Products & Pipeline Antibody Discovery Development Capabilities Commercialization

  30. Products Lead programs target 3 of the most important pathways in cancer (VEGFR, EGFR, HGF) Lead product in Phase 2 Platform Discovery and validation of functionally relevant targets Identification of responsive patient populations increases probability of success Informs rational choice of drug combinations Supports optimal pricing and reimbursement Pipeline Powerful antibody discovery engine yields rich pipeline Lead antibody program in Phase 1 AVEO Summary AVEO – Compelling Value Proposition

  31. AVEO’s Enduring Value - People Skill sets in a platform company often differ from those required for drug discovery Retraining & re-assigning personnel is central to AVEO philosophy and a key to the successful transition from platform focus to fully-integrated bio-pharmaceutical company