AVEO Pharmaceuticals: Technologies and Vision Massachusetts Biotechnology Council Drug Discovery...
-
Upload
lillian-wiggins -
Category
Documents
-
view
221 -
download
4
Transcript of AVEO Pharmaceuticals: Technologies and Vision Massachusetts Biotechnology Council Drug Discovery...
AVEO Pharmaceuticals:Technologies and Vision
Massachusetts Biotechnology Council Drug Discovery Committee
February 19, 2009
MBC, Cambridge
Ronan C. O’Hagan
Group Leader, Target Biology
2
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
3
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
4
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
5
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
6
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
7
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
8
• 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
9
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
10
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
11
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
12
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
13
AVEO Antibody Drug Discovery Capabilities
• Antibody diversity generation
• Protein biochemistry
• Antibody characterization
• Development candidate generation
• Functional assays
• In vivo pharmacology
• Preclinical development
AVEO Pipeline
14
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
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
• 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
17
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
18
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
19
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
21
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
22
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
23
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
24
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
25
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
28
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
29
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
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
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
32