Timothy HoeySr. Vice President, Cancer BiologyOncoMed PharmaceuticalsApril 7, 2013
Development of FZD8-Fc (OMP-54F28), a Wnt signaling antagonist that inhibits tumor growth and reduces tumor initiating cell frequency
2
Disclosure Information
Timothy Hoey
2013 AACR Annual Meeting
I have the following financial relationships to disclose:
Stockholder in and employee of OncoMed Pharmaceuticals.
I will not discuss off label use and/or investigational use in my presentation.
3
Therapeutic Promise of Targeting Cancer Stem Cells
CSCs have been implicated in tumor progression, recurrence, and metastasis
4
Establishment of Patient Derived Xenograftsfor Studying Tumor Cell Heterogeneity
Established > 160 tumors to date
• Breast, Colon, Pancreas, Lung, etc.
• Extensive genomic characterization
• CSC identification
p1 p2
5
OncoMed Human Tumor Bank Status
Tumor Type Total Specimens Established (up to p1) In Progress
Breast 105 24 16Colon 61 44 0Liver 14 2 9
Lung (NSCLC) 79 21 13Lung (SCLC) 9 6 3
Pancreas 40 20 2Melanoma 16 13 0
Ovarian 55 11 1Brain 7 2 0
Bladder 6 3 0AML 26 12 14
Leukemia 16 4 12Uterine 6 2 2Total 440 164 72
6
Correlation of Patient Survival and Engraftment Derived Xenografts
• Correlation of engraftment in xenograft experiments and clinical outcome
• Other groups have also shown a correlation between treatment response in patient derived xenografts and clinical response
• Demonstrates the clinical relevance of these types of xenograft models
Kaplan–Meier survival curves as a function of engraftment of pancreatic tumors
N=27
N=42
Garrido-Laguna I et al. Clin Cancer Res 2011;17:5793-5800
7
Models for Studying Cancer Stem Cells A Diverse Bank of Minimally Passaged Human Tumors
Copy Number & SNP Analysis
HistologyKRAS mutations in OMP Tumor BankTumor Nucleotide Changes Coding Change? Hetero/HomozygousC4 GGT->GAT G12D HetC6 GGC->GAC G13D HetC9 GGT->GTT G12V HomC12 GGC->GAC G13D HomC13 GGT->AGT G12S HomC18 GGT->GTT G12V HetC22 CAA->CAT Q61H HetC29 CAG->AAG Q22K HomC30 GGT->GAT G12D HetC39 GGC->TGT G12C HetPN8 GGT->GAT G12D HetPN13 GGT->GAT G12D Hom
Tumor Nucleotide Changes Coding Change? Hetero/HomozygousC4 GGT->GAT G12D HetC6 GGC->GAC G13D HetC9 GGT->GTT G12V HomC12 GGC->GAC G13D HomC13 GGT->AGT G12S HomC18 GGT->GTT G12V HetC22 CAA->CAT Q61H HetC29 CAG->AAG Q22K HomC30 GGT->GAT G12D HetC39 GGC->TGT G12C HetPN8 GGT->GAT G12D HetPN13 GGT->GAT G12D Hom
Microarray and deep sequencing
Oncogene Mutations
FACSERBB2 Amplification in B51Frequency Distribution
Amplifications & Deletions
Well characterized patient-derived tumors from breast, colon, lung, pancreas, etc.
0 10 20 30 40 50 60 70 80 900
500
1000
1500
2000
2500CSC (7/8)Other (0/10)
Day post-injection
Tum
or V
olum
e (m
m3)
Tumorigenicity
8
Stem Cell Pathways Implicated in Cancer
• Key “developmental” pathways have been strongly implicated in cancer– Notch Pathway– Adhesion– BMP/TGFβ Pathway– Wnt Pathway– FGF Pathway– Hedgehog Pathway– Others
Therapeutic objective: Inhibit capability for self-renewal and/or enhance differentiation
Self-renewal
Differentiation
10
Wnt Signaling in Cancer
• 1982:
• 1997:
APC mutants are defective in their ability to inhibit β-catenin.
β-catenin mutants are constitutively active.
11
Deliver Axin or dn-TCF
via Lentivirus
Infect isolatedcancer stem cells
ex vivo
Inject transduced CSCs in mouse
Sort transduced cells by FACS
Breast Colon
Wnt Blockade Blocks Growth of Patient DerivedXenograft Tumors
Results: in CSCs from patient-derived tumors, the Wnt pathway is required for tumor growth providing additional evidence that the Wnt signaling is an important therapeutic therapeutic target
12
Wnt Pathway
• Strongly implicated in many major cancers
• Clearly attractive pathway for targeting cancer stem cells
• No drugs approved yet targeting pathway
• Multiple ligands and receptors
• Identifying appropriate pre-clinical models
• Developing effective drug discovery strategy
The Opportunity 2009 OutlookThe Challenge
13
FZD8-Fc (OMP-54F28) is a Wnt Signaling Antagonist with Potent In Vivo Activity
FZD8extracellular(Wnt binding)
domain
ImmunoglobulinFc domain
Wnt activatedβ-catenin reporter gene assay
0.0001 0.01 1 1000
2000
4000
6000
8000
10000
FZD8-Fc Ref StdMouse JAG1-Fc Neg cont54F28 UFX-002-026No Wnt3A+JAG1-Fc
µg/mL
Luci
fera
se a
ctiv
ity (
RLU
)
23 28 33 380
200
400
600
800
1000
1200
1400
Control AbFZD8-Fc
MMTV-Wnt1 Tumor Model
Days
tum
or v
olum
e (m
m3 )
mass41500 41750 42000 42250 42500 42750 43000 43250
%
0
100JB20101103_07 420 (8.227) M1 [Ev198952,It53] (Sp,0.496,1532:3402,1.00,L10,R10); Sm (SG, 20x10.00)
1.12e441930.1
41910.0
41949.7
41986.4
ASA… >98% homogeneousN-terminus
Domain Structure
Mass Spec Characterization
14
FZD8-Fc Reduces Tumor Recurrence After Gemcitabine Treatment
• Fzd8-Fc (OMP-54F28)
– MOA distinct from vantictumab (anti-FZD, OMP-18R5)
– IND filed 2012
– Currently in Phase 1 clinical testing
– Partnered with Bayer Healthcare
Pancreatic Tumor
PN13 = PDAC,. Poorly differentiatedKRAS wtGemcitabine:100 mg/kg, weeklyFZD8-Fc : 10 mg/kg, weekly
0 10 20 30 40 50 60 70 80 900
500
1000
1500
2000
2500
Gemcitabine
Gem->Control mAb
FZD8-Fc
Gem->FZD8Fc
Days Post Cell Injection
Tum
or V
olum
e, m
m3
15
Activity of FZD8-Fc in Patient Derived Pancreatic Cancer Xenograft, OMP-PN4
0 5 10 15 20 25 30 35 400
200
400
600
800
1000
1200
1400
Control Ab
FZD8-Fcgem+FZD8-Fc
gemcitabine
Days Post Treatment
tum
or v
olum
e (m
m3 )
Tumor Growth
PN4 = PDAC, KRAS wtFZD8-Fc: 15 mg/kg, weeklyGemcitabine: 20 mg/kg, weekly
12.7% 1.9%
13.9% 1.7%
CD44+ Frequency
16
FZD8-Fc Regulated Wnt Target Genes in PN4 Tumors and Promotes Tumor Cell Differentiation
CDH1MUC2
MUC5ACMUC16
MUC20AXIN2
MYC0
2
4
6
8
Control mAbFZD8-FcGemcitabineCombination
Rel
ativ
e Q
uant
ity v
s.C
ontr
ol m
Ab
FZD8FcControl
Gemcitabine Gem + FZD8Fc
Gene Expression Alcian Blue Staining
17
Tumor Growth Day 82
Control 3
0
Control 9
0
Control 2
70
FZD8Fc 3
0
Fzd8F
c 90
Fzd8F
c 270
Gem 30
Gem 90
Gem 27
0
Combo 30
Combo 90
Combo 270
0
100
200
300
400
500
1:280 1:695 1:476 _CSC Frequency
tum
or v
olum
e (m
m3 )
FZD8-Fc Treatment Reduces Tumor Initiating CellFrequency in PN4 Tumors
PN4 tumors were treated with Control Ab, FZD8-Fc, Gemcitabine or the combination
Harvested tumors from treatment groups, 4 weeks post treatment initiation
Purified human tumor cells from the xenograft
Serially passaged 30, 90, or 270 cellsfrom each treatment group toNOD/SCID mice, grow 82days without further treatment
Calculate CSC Frequency
18
35 40 45 50 55 60 65 70 75 80 850
250
500
750
1000
1250
Control Ab
FZD8-Fcgemcitabine
gem+FZD8-Fc
Days
tum
or v
olum
e (m
m3 )
Inhibition of Tumor Growth and Reduction of CSC Frequency by FZD8-Fc in Combination with Gemcitabine (OMP-PN21)
Serial transplant,post treatment
Control m
Ab
FZD8-Fc
Gemcit
abine
FZD8-Fc+
Gem0.000
0.002
0.004
0.006
0.008
1:222
1:976
1:175
1:5472
CSC Frequency
CSC
Fre
quen
cy
PN21 = PDAC, KRAS mutFZD8-Fc: 15 mg/kg, weeklyGemcitabine: 20 mg/kg, weekly
19
Anti-Metastatic Activity of FZD8-Fc- Orthotopic Model (OMP-PN8)
0
1.0×107
2.0×107
3.0×107
4.0×107
Control AbFZD8-Fc
Lung Mets
0
5.0×108
1.0×109
1.5×109
2.0×109
2.5×109
Primary Tumor
tum
or v
ol (p
hoto
ns/s
ec)
0
4.0×107
8.0×107
1.2×108Liver Mets
• Luciferase labeled OMP-PN8 tumors implanted orthotopically in the pancreas
• Tumors were allowed to grow for 30 days and randomized based on primary tumor size
(determined by in vivo imaging for bioluminescence)
• Tumor bearing mice were treated with FZD8-Fc, dosed at 20 mg/kg weekly for 4 weeks
• Metastatic growth in distal organs was determined by in vivo imaging
20
0 5 10 15 20
200
400
600
800 Control mAbGemcitabine (100 mg/kg)
PN8 (GemS)
Days Post Treatment
Tum
or V
olum
e, m
m3
generation of Gem resistantversion of PN8 by continuouspassage in the presence of increasing drug concentration
0 10 20 300
500
1000
1500 Control mAbGemcitabine (100 mg/kg)
PN8 (GemR)
Days Post Treatment
Tum
or V
olum
e, m
m3
Development of Gemcitabine Resistant Pancreatic Tumor Model
21
Activity of FZD8-Fc in Gemcitabine-Resistant Pancreas Tumor
0 10 20 30 400
300
600
900
1200
1500
1800
Control Ab
FZD8-Fc54F28+5FU+Irino
5FU+Irinotecan
Days Post Treatment
Tum
or V
olum
e, m
m3
Control A
b
FZD8-Fc
5FU + Iri
no
FZD8-Fc +
5FU+Ir
ino0
20
40
60
CD
201+
ESA
+(%
Liv
e H
uman
)
Antibodies, FZD8-Fc = 45 mg/kg, Q3W5-FU = 25 mg/kg, weeklyIrinotecan = 7.5 mg/kg, weekly
Tumor Growth Flow Cytometry
22
FZD8-Fc is Active in Combination withGem + Abraxane (Protein bound Paclitaxel)
OMP-PN8
0 20 40 600
250
500
750
1000
1250Control mAbGem/AbrxFZD8-Fc + Gem/Abrx
Days Post Treatment
Tum
or V
olum
e, m
m3
Gemcitabine: 10 mg/kg; Abraxane 30 mg/kgFZD8-Fc: 25 mg/kg, q2wk
OMP-PN8
0 20 40 600
50100150200250300350400
Gem/AbrxFZD8-Fc + Gem/Abrx
Days Post Treatment
Tum
or V
olum
e, m
m3
23
FZD8-Fc Pre-clinical data summary
• OMP-54F28 (FZD8-Fc) is a potent antagonist of Wnt Signaling
• FZD8-Fc is active as a single agent and in combination with chemotherapeutic agents in patient derived pancreatic xenografts
• FZD8-Fc is active in a broad spectrum of pancreatic cancer models– Promotes differentiation– Reduces CSC frequency– Inhibits metastatic growth
24
Summary
• Stem cell pathways such Wnt are required for CSC function in a broad spectrum of tumors
• OncoMed has developed the first Wntpathway antagonist biologics – Anti-FZD (OMP-18R5, vantictumab) – FZD8-Fc (OMP-54F28)– Currently in Phase I clinical testing and
partnered with Bayer Healthcare
• Inhibition of Wnt signaling with FZD8-Fc reduces tumorigenicity and promotes the differentiation of cancer cells in several major tumor types
Self-renewal
Differentiation
25
• Safety study in pts with advanced solid tumors
• Repeat dose study, 3-6 pts/cohort
• Dose levels: 0.5, 1, 2.5, 5 and 10 mg/kg once every 3 weeks
• DLT Window: assessed on days 0-28
• Expansion: 6 additional patients at MTD
• Potential future tumor-specific expansion cohort(s) - various indications including pancreatic
• Response assessed on day 56, then every 8 weeks
• Pts may remain on treatment until PD
• Dose escalation currently ongoing
Investigators
Michael GordonPinnacle, Scottsdale, AZ
Antonio JimenoU of Colorado, Aurora, CO
David SmithU of Michigan, Ann Arbor, MI
FZD8-Fc Clinical DevelopmentSingle-agent Phase 1 trial for OMP-54F28
26
Acknowledgements Chris MurrielAngie ParkKellie PickellAaron SatoSanjeev SatyalMichelle StroudRay TamWan-Ching YenPete Yeung
Austin GurneyJohn Lewicki
Fumiko AxelrodLucia BevigliaChris BondJennifer CainCecile ChartierLucas DonigianMarcus FischerAurélie ChaudhariMay JiAnn KapounAndrew LamSatyajit Mitra
OncoMedRedwood City, CA