AVEO Pharmaceuticals: Technologies and Vision

Technologies and Vision

Massachusetts Biotechnology Council

Drug Discovery Committee

February 19, 2009

MBC, Cambridge

Ronan C. O’Hagan

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

Platform & biological insight State-of-the-art antibody drug discovery/engineering

AVEO

Value Creation

• Platform = high value, for short time period

• Long term value = drug discovery & development

Relative Valuation

Time

Value Creation Models in Biotech

Platform Company

AVEO’s Innovative Platform: Better Models of Human Cancer

Mice seeded with Inducible oncogenic tissue Introduce human oncogene in select tissue

• Defined genetic context

• Oncogene activated post-natally

• Natural in vivo setting

• Heterogeneity across population

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 MAPK6 Edg2 MAP3K8 Kirrel1 Erbb3 vav3 PLK3 0 50 100 150 200 250 300 350 400 2 3 4 5 6 7 8 9 10 11-15 16-20 >20 Tumor Recurrence Integration Sites Esr1 Erbb3 Met Erbb2 EGFR

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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

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

•

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 Antibody 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

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

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

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 Antibody Drug Discovery Capabilities

•

Antibody diversity generation

•

Protein biochemistry

•

Antibody characterization

•

Development candidate generation

•

Functional assays

•

In vivo pharmacology

•

Preclinical development

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 reactivity; human cross-reactivity)

• 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

• 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

Cell culture creates

a very artificial environment

Adhesion to plastic substrate

Potent bovine serum growth 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] Tumor cells Tumor endothelium Myeloid cells lymphocytes Stromal cells

In vivo

context is complex

multicomponent environment

21% [O₂]

AVEO Target Identification and Validation:

The Importance of Context

MW U87MG tumors 1 2 3 U87MG cells In culture 50kDa 30kDa 120kDa 220kDa 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 vitroand 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

Antibody Targets: The Importance of Context

Inhibition of U87 growth by HGF mAb 3 days treatment--BrdU -2 -1 0 1 2 0 5000 10000

Log mAb Conc. (ng/ml)

RLU 0 200 400 600 800 1000 1200 5 10 15 20 25 dosing starts no FBS aHGF Ab 5% FBS aHGF Ab no FBS IgG 5% FBS IgG

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

Tumor volume (mm

3 )

Days

Antibody Targets: The Importance of Context

Days

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

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

0 400 800 1200 1600 2000 T u mo r V o lu me ( m m 3 ) hIgG 10 mpk AV299 10 mpk 0 200 400 600 800 1000 1200 1400 1600 0 5 10 15 Days Tum or V o lu m e ( m m 3 ) mIgG 10 mpk 2B8 10 mpk mIgG 10 mpk mu-299 10 mpk 0 500 1000 1500 2000 0 5 10 15 20 25 Days Tum or V o lum e ( m m 3 ) mIgG 10 mpk 2B8 10 mpk mIgG 10 mpk mu-299 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

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

MET/HGF driven Non-MET/HGF driven

Identifying a signature correlating with HGF responsiveness

provides candidate biomarkers for clinic

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

to responsive patient populations

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

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

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

1. 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

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

$39 $74 $51 $44 $42 0 10 20 30 40 50 60 70 80 Small 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

Similar productivity

to AV-299

Process Development costs likely required to generate

high titer cell lines

$39

$74

$51

$44

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

AVEO’s Competitive, Clinical and Commercial Advantage

Development

Capabilities

Antibody

Discovery

Commercialization

Proprietary Integrated Biology Platform

Synergy between Drug Development Capabilities and Cancer

Biology Platform Informs Clinical Strategy for Products & Pipeline

•

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

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