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

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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.

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Therapeutic Promise of Targeting Cancer Stem Cells

CSCs have been implicated in tumor progression, recurrence, and metastasis

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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

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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

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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

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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

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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

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Wnt Signal Transduction

Polakis P Cold Spring HarbPerspect Biol 2012;4:a008052

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Wnt Signaling in Cancer

• 1982:

• 1997:

APC mutants are defective in their ability to inhibit β-catenin.

β-catenin mutants are constitutively active.

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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

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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

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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

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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

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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

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FZD8-Fc Regulated Wnt Target Genes in PN4 Tumors and Promotes Tumor Cell Differentiation

CDH1MUC2

MUC5ACMUC16

MUC20AXIN2

MYC0

2

4

6

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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

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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

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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

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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

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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

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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

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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

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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

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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

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• 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

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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