AVEO Pharmaceuticals:Technologies and Vision

Massachusetts Biotechnology Council Drug Discovery Committee

February 19, 2009

MBC, Cambridge

Ronan C. O’Hagan

Group Leader, Target Biology

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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

AVEO’s Unique Niche

AVEO Pipeline

Platform & biological

insight

State-of-the-artantibody drug

discovery/engineeringAVEO

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Value Creation

• Platform = high value, for short time period

• Long term value = drug discovery & development

• Combination of Drug Discovery+ Biological Insight (Platform)

Rela

tive V

alu

ati

on

Time

= Enhanced Value

Value Creation Models in Biotech

Platform Company

Drug Discovery Company

AVEO Pipeline

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AVEO’s Innovative Platform: Better Models of Human Cancer

BreastHer2

LungEGFRL858R

Colon-Catenin

LungKRas

LungEGFRL858R,

T790M

Inject stem cells into 3 day mouse embryos

InducibleOncogenic

MouseStem Cell

Mouse Stem Cell

Mice seeded withInducible oncogenic

tissue

Introduce human

oncogene in select tissue

• Defined genetic context• Oncogene activated post-natally• Natural in vivo setting• Heterogeneity across population

Models Used for Target Identification, Validation & Human Response Prediction

AVEO Pipeline

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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)

2 3 4 5 6 7 8 9 10 11-15 16-20 >20

Met

MAPK6Edg2

MAP3K8

Kirrel1Erbb3vav3

PLK3

0

50

100

150

200

250

300

350

400

2 4 5 6 7 8 9 10 11-15 16-20 >203

Tumor Recurrence

Inte

gra

tio

n S

ites

Esr1

Erbb3Met

Erbb2

EGFR*

**

*

*

**

*Novel Cancer Targets identified in geneticScreens that are capable of complementingHER2 in vivo

AVEO Pipeline

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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

AVEO’s MaSS Screen: Identifies functionally relevant cancer targets

Additional Filters for Relevance in Human Cancers: e.g. Cancer Mutations Highlights well credentialed targets

Identifying Functionally Relevant Cancer Targets

AVEO Pipeline

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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

AVEO Pipeline

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• 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

AVEO Pipeline

AVEO Antibody Pipeline Powered by Unique Technology

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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

AVEO Pipeline

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Robust Antibody Pipeline Beyond AV-299

Effective discovery engine delivering novel, high quality oncology antibody drug candidates

Target Discovery & Validation

Antibody Generation/ Screening

Lead Antibody

Development Candidate

Preclinical Development Phase 1

HGF

RON

FGFR3

FGFR2

FGFR1

FGFR4

Notch1

Notch2

Notch3

ErbB3

EGFR790

AV-299

AVEO Pipeline

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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

AVEO Pipeline

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Building an Antibody Drug Discovery Engine

o 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

o 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

AVEO Pipeline

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AVEO Antibody Drug Discovery Capabilities

• Antibody diversity generation

• Protein biochemistry

• Antibody characterization

• Development candidate generation

• Functional assays

• In vivo pharmacology

• Preclinical development

AVEO Pipeline

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A repertoire of know-how and advanced tools to access targets efficiently

AVEO Drug Discovery Capabilities: Better Antibodies

• Antibody diversity generation

• Protein biochemistry

• Antibody characterization

• Dev. candidate generation

• Functional assays

• In vivo pharmacology

• Preclinical development

• Murine monoclonal antibodies (Maine Biotechnology Services)• Phage display (Dyax)

• 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)

AVEO Pipeline

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• 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

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• 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

Antibody Targets: Biological Insight Applied to Drug Discovery

AVEO Pipeline

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Cell culture createsa very artificial environment

Adhesion to plasticsubstrate

Potent bovine serumgrowth factors

• 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

Varied [O2]

Tumorcells

Tumorendothelium

Myeloid cells

lymphocytes

Stromal cells

In vivo context is complex multicomponent environment

21% [O2]

AVEO Target Identification and Validation: The Importance of Context

AVEO Pipeline

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MW

U87MG tumors

1 2 3

U87MG cellsIn culture

50kDa

30kDa

120kDa220kDa

60kDa

80kDa

100kDa

1 2 3

• 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

Pathway signaling varies dramatically between in vitro and in vivo environments

Higher levels of pTyr signaling are seen in a cell culture environment

AVEO Pipeline

Antibody Targets: The Importance of Context

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Inhibition of U87 growth by HGF mAb3 days treatment--BrdU

-2 -1 0 1 20

5000

10000no FBS aHGF Ab5% FBS aHGF Abno FBS IgG5% FBS IgG

Log mAb Conc. (ng/ml)

RL

U

0

200

400

600

800

1000

1200

1400

5 10 15 20 25 30

dosing starts

Inhibition of U87 growth by HGF mAb3 days treatment--BrdU

-2 -1 0 1 20

5000

10000no FBS aHGF Ab5% FBS aHGF Abno FBS IgG5% FBS IgG

Log mAb Conc. (ng/ml)

RL

U

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 inducedBy 2x wk 10mg/kg HGF mAb

No inhibition of U87 growth by HGF mAb3 days treatment--BrdU

Tu

mo

r v

olu

me

(mm

3)

Days

AVEO Pipeline

Antibody Targets: The Importance of Context

Rel

ati

ve

gro

wth

in

cu

ltu

re

20

AVEO Pipeline

Days

Proprietary AVEO inducible tumor models enable the rapid switching of oncogenes in primary tumors

Unique AVEO breast c-met / HGF driven tumor issensitive to AV-299 but not to Herceptin

AVEO Antibody Pipeline: Better Models

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0

400

800

1200

1600

2000

5 10 15 20 25 30 35

Days

Tu

mo

r V

olu

me

(mm

3)

hIgG 10 mpk

AV299 10 mpk

0

200

400

600

800

1000

1200

1400

1600

0 5 10 15

Days

Tu

mo

r V

olu

me

(mm

3)

mIgG 10 mpk

2B8 10 mpk

0

500

1000

1500

2000

0 5 10 15 20 25

Days

Tum

or V

olum

e (m

m3)

mIgG 10 mpk

2B8 10 mpk

AV-299 Example: MET/HGF and HGF Complemented Murine Breast Tumors Showed Variable Response to AV-299/2B8 Treatment

6534- 2B8 6535- 2B8

6612-AV299

TGI: 86%, p=0.0079

TGI: 99.7%, p=0.0007

AVEO Pipeline

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Hiarachical clustering by ~800 differentially expressed genes between MET/HGF driven and non-Met

driven DC tumors

MET/HGF driven

Non-MET/HGF driven

Identifying a signature correlating with HGF responsiveness provides candidate biomarkers for clinic

AVEO Pipeline

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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

AVEO: Innovative cancer therapies targetedto responsive patient populations

AVEO Pipeline

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Development of drug discovery capabilities enables maximalexploitation of biological insights from platform technologies

Require drug development capabilities beyond preclinicalproof-of-concept and clinical hypotheses to realize this value

AVEO Pipeline

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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

AVEO Pipeline

26Confidential Information – Property of AVEO Pharmaceuticals, Inc.

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 paradigms1. 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)

2. 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

3. 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

o No one company has all of these pieces together

AVEO Pipeline

27Confidential Information – Property of AVEO Pharmaceuticals, Inc.

New technologies that allow higher productivity have the potentialto bring clinical costs to a level similar to small molecules

$39

$74

$51

$44$42

0

10

20

30

40

50

60

70

80

SmallMolecule

0.4 g/L 1.5 g/L 5 g/L 20 g/L

Antibody Research & Development Costs (Preclinical through Phase 2)Millions of Dollars

OOP Costs

FTE Costs

Preclinical Tox

Cell Line Dvlp

Stability Testing

Translational Res.

Process Dvlp

Analytical Dvlp

Drug Substance (Manufacturing)

Drug Product (Finish / Fill)

Formulation Dvlp

Variable Costs

Fixed Costs

Almost $40M in costs between preclinical and

Phase II are fixed

Increasing Antibody Titer

Similar productivity to AV-299

Process Development costs likely required to

generate high titer cell lines

Note : * See Appendix for assumptions

AVEO Pipeline

$39

$74

$51

$44$42

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AV-299: Anti-HGF Monoclonal Antibody

Novel target • Hepatocyte Growth Factor (HGF); no approved drugs

Broad potential

• Multiple Solid Tumors

• 30-40% of breast cancers

• 30-40% of pancreatic cancers

• 40-70% of lung cancers

• 75-90% of gliomas

Differentiated • Potential first- and best-in-class HGF inhibitor

Partnership • Discovered at AVEO

• Development and commercialization partnership with Schering-Plough worth up to $477M plus royalties

• AVEO responsible for research and clinical development through Phase 2 at SP’s expense

• AVEO retains co-promotion rights in US for certain oncology indications

IP • Applications filed

Status • Entered FIH in September 2008

AVEO Pipeline

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AVEO’s Competitive, Clinical and Commercial Advantage

DevelopmentCapabilities

AntibodyDiscovery

Commercialization

• Identification of responsive patient populations increases probability of clinical success

• Informs rational choice of drug combinations

• Discovery and validation of functionally relevant targets

• Rapidly maturing pipeline of novel functional antibodies

• Opportunity for differentiation in large markets

• Supports optimal pricing and reimbursement

Proprietary Integrated Biology Platform

Synergy between Drug Development Capabilities and Cancer Biology Platform Informs Clinical Strategy for Products & Pipeline

AVEO Pipeline

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• 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

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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 thesuccessful transition from platform focus to fully-integrated bio-pharmaceutical company

AVEO’s Enduring Value - People

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