OMP 59R5 N l Th i A ib d iOMP‐59R5: a Novel Therapeutic Antibody in Clinical Development for Patients with Cancer

Jakob Dupont MD MAJakob Dupont, MD, MAChief Medical Officer and Senior Vice President

OncoMed Pharmaceuticals Inc.

Adjunct Clinical Assistant ProfessorMedical Oncology

Stanford University Medical Centerf y

Disclosure

• I am employed by OncoMed PharmaceuticalsI am employed by OncoMed Pharmaceuticals.

Cancer Stem Cells: Driving Tumor Growth and Metastasis

Isolation of Cancer Stem Cells from Patient-Derived Colon Tumor

Signaling Pathways in Cancer

OncoMed Area of Focus

Self-Renewal/Differentiation GrowthSelf-Renewal/Differentiation

Traditional “Growth Factor” Pathways

CSC Pathways ModulateSelf-Renewal and Differentiation

RTKs

EGFVEGF

AngiogenesisNotch WntNotch1-4DLL4

FZD1-10Wnt Ligands

Her2

New PathwaysOncoMed Validated(e g RSPO-LGR)

y

EGFIGF

ALKMet

JaggedWnt Ligands(e.g. RSPO LGR)

No effect on CSC FrequencyReduce CSC Frequency

Cancer Stem Cells (CSCs) and the Notch Pathway

Cancer Stem Cells (CSCs)• CSCs first demonstrated in leukemia1

Therapeutic objective:

Inhibit CSC self‐renewal and/or force differentiation

• Clarke et al. were the first to identifytumor initiating cells in solid tumors2

• CSCs now demonstrated in numerous

Self-renewal

and/or force differentiation• CSCs now demonstrated in numerousmalignancies and associated withchemoresistance and metastasis

The Notch PathwayThe Notch Pathway•The Notch pathway mediates CSCself-renewal and proliferation

• Activation of Notch2 and/or Notch3 hasbeen implicated in several tumor types: lung, pancreatic, ovarian, and breastcancerscancers

1 Bonnet and Dick, 1997. Nature Med 3, 730-7372 Al-Hajj et al. 2003. PNAS 100, 3983-3988

Signal Transduction by the Notch Pathway 

Notch Pathway:LigandsDLL1, 3, 4, JAG1, 2, , , ,

ReceptorsNotch 1, 2, 3, 4Notch 1, 2, 3, 4

Targets for OMP-59R5

OMP‐59R5: Anti‐Notch 2/3

OMP-59R5 TargetsOMP 59R5 Targets Notch2 and Notch3 and Blocks Ligand Dependent Si liSignaling

OMP-59R5 is a fully humanOMP-59R5 is a fully human antibody - originally identified by binding Notch2 and subsequently found to also bind Notch3

Preclinical Data: OMP‐59R5 (Anti‐Notch2/3)Patient‐Derived Pancreatic Adenocarcinoma

Anti‐Notch2/3 Delays Tumor Recurrence After Gemcitabine Treatment in PN8 Tumors

Anti‐Notch 2/3 Decreases TumorigenicityOf CD44+; PROCR+ Cells in NOD/SCID mice

1500

Gem+Abs Abs alone

) 59R5: 20 mg/kg, weekly

Tumorigenicity(101 Days Post Cell Injection)

2000

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750

1000

1250

Control Ab +GemcitabineAnti-Notch2/3 + Gem

olum

e (m

m3 59 5 0 g/ g, ee y

Gemcitabine: 20 mg/kg, weekly

1000

1500

olum

e, m

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500

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or v

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Tum

or V

o33 38 43 48 53 58 63 68 73 78 83 88 93 98 103

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Days

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Gem + OMP-59R5 OMP-59R5

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Anti- Gem ComGem + control Ab control Ab

Ph1a Study of OMP‐59R5 in Solid Tumor PatientsStudy 59R5‐001y

University of Michigan Cancer Center, Ann Arbor, MI

David C Smith, Rashmi Chugh, Villette Thorpe

The START Center for Cancer Care, San Antonio, TXAnthony Tolcher, Amita Patnaik, Kyri Papadopoulos, Glenda ChambersAnthony Tolcher, Amita Patnaik, Kyri Papadopoulos, Glenda Chambers

OncoMed Pharmaceuticals Inc., Redwood City, CA Lu Xu, Ann M Kapoun, Jakob Dupont

Study 59R5‐001: Objectives and DesignObjectives:• Primary: Safety• Secondary: Pharmacokinetics, immunogenicity, efficacy• Exploratory: BiomarkersDesign:Design:• Repeating dose safety study in subjects with advanced solid tumors 

with DLT window first 28 days on study.• 3+3 design with 6 additional subjects at MTD

• Weekly (QW):  0.5, 1, 2.5, and 5 mg/kg  • Every Other Week (Q2W):   5, 7.5, 10mg/kg y (Q ) , , g/ g• Every Three Weeks (Q3W): 7.5mg/kg

• PD assessments: Whole blood RNA, Plasma, Hair Follicles, Tumor• Response assessment: Day 56 then every 8 weeks with continued• Response assessment:  Day 56, then every 8 weeks with continued 

treatment until progression of disease or unacceptable toxicity

Key Eligibility Criteria and DLT Definitionand DLT Definition

Key Eligibility Criteria:• Advanced, refractory solid tumor patientsAdvanced, refractory solid tumor patients• No uncontrolled ≥ Grade 1 diarrhea• ECOG PS <2• > 18 years of age

DLT d fi i iDLT definition• Any Grade 3 or greater adverse event

Except for:Except for:• Grade 3 infusion reactions that resolve within 24hrs• Grade 3 diarrhea, nausea, and/or vomiting that responds to standard medical treatment within 48hrs

• Grade 3 electrolyte disturbances that correct within 24hrs

Patient Demographics

Number of Patients Enrolled 39Median Age (range) 59

(28‐90)Gender N (%) M: 20 (51%)

F: 19 (49%)F:  19 (49%)Tumor Types (N) • Colorectal Cancer (10)

• Breast Cancer (5)( )• Adenoid Cystic Cancer (3)• Pancreatic Cancer (3)• Chondrosarcoma (2)• Chondrosarcoma (2)• Liposarcoma (2)• Prostate Cancer (2)• Other (11)

Dose Limiting Tox (DLT) & Maximum Tolerated Dose (MTD)

Schedule* Dose (mg/kg) Enrolled(N) DLTs (N) DLT description

Weekly 0.5 3 ‐ ‐

1 3 ‐ ‐

2.5 6 ‐ ‐

5 9 2 1. Gr3 hypokalemia (Gr3 5  9 2 yp (diarrhea)

2. Gr3 diarrhea

Every 2 Week 5 6 ‐ ‐y

7.5 5 ‐ ‐

10 3 2 1. Gr3 diarrhea2 Gr3 diarrhea2. Gr3 diarrhea

Every 3 Weeks 7.5 6 ‐ ‐

TOTAL 41 4 All di h l t d DLTTOTAL 41 4 All diarrhea related DLTs

Related Adverse Events: All Grades (>5%)CTCAE Version 4.02

OMP‐59R5 dose level (mg/kg) (N=36)OMP 59R5 dose level (mg/kg)    (N=36)All Grades Related AEs (≥5%) 0.5QW

(N=3)1QW(N=3)

2.5QW(N=6)

5QW(N=9)

5QoW(N=6)

10QoW(N=3)

7.5Q3W(N=6)

ALL(%)

Diarrhea ‐ ‐ 4 8 2 3 4 21 (58%)

Fatigue ‐ ‐ 1 4 2 1 2 10 (28%)

Nausea 1 1 1 2 ‐ 1 2 8 (22%)

Decreased Appetite ‐ ‐ ‐ 3 1 1 ‐ 5 (14%)

Vomiting 1 1 1 1 4 (11%)Vomiting 1 ‐ 1 1 ‐ 1 ‐ 4 (11%)

Dehydration ‐ ‐ 1 2 ‐ ‐ ‐ 3 (8%)

Dizziness ‐ 1 1 ‐ 1 ‐ 3 (8%)

Increased ALT ‐ ‐ 1 ‐ ‐ 2 ‐ 3 (8%)Increased ALT 1 2 3 (8%)

Hypokalemia ‐ ‐ ‐ 3 ‐ ‐ ‐ 3 (8%)

Abdominal pain ‐ ‐ 1 1 ‐ 1 ‐ 3 (8%)

Anemia ‐ ‐ 1 2 ‐ ‐ ‐ 3 (8%)

Thrombocytopenia ‐ ‐ 2 1 ‐ ‐ ‐ 3 (8%)

Hypersensitivity ‐ 1 ‐ 1 ‐ ‐ ‐ 2 (6%)

Urticaria ‐ ‐ ‐ ‐ ‐ 1 1 2 (6%)

Increased AST ‐ ‐ ‐ ‐ ‐ 2 ‐ 2 (6%)

Constipation ‐ ‐ 1 1 ‐ ‐ ‐ 2 (6%)

Hypercalcemia ‐ ‐ 1 ‐ ‐ 1 ‐ 2 (6%)

Related Adverse Events: All Grades 3‐5CTCAE Version 4.02

OMP‐59R5 dose level (mg/kg)    (N=36)**All Grades Related AEs (≥5%) 0.5QW 1QW 2.5QW 5QW 5QoW 10QoW 7.5Q3W ALL

All Grade 3 AEs. No Grade 4 or 5 related AEs

(N=3) (N=3) (N=6) (N=9) (N=6) (N=3) (N=6) (%)

Diarrhea ‐ ‐ ‐ 2 ‐ 3 ‐ 5 (14%)

Anemia ‐ ‐ 1 1 ‐ ‐ ‐ 2 (3%)

Fatigue 1 1 (3%)Fatigue ‐ ‐ ‐ ‐ 1 ‐ ‐ 1 (3%)

Increased ALT ‐ ‐ 1 ‐ ‐ ‐ ‐ 1 (3%)

Hypokalemia ‐ ‐ ‐ 1 ‐ ‐ ‐ 1 (3%)

Si ifi C l i B Di h G d d D f OMP 59R5Significant Correlation Between Diarrhea Grade and Dose of OMP‐59R5 

3

4

G d 0

1

2

Grade 0

Grade 1

Grade 2

Grade 3# of

pts

Correlation between diarrhea grade & dose for weekly dosing: p-value = 0.01022** Cochran-Armitage trend test

0

0.5QW 1QW 2.5QW 5QW 5Q2W 10Q2W 7.5Q3W

Pharmacokinetics and Immunogenicity

• Fast nonlinear clearance suggests target‐mediated drug disposition

A T1/2 47 24 h• Apparent T1/2= 47 ±24 hours @ 7.5 mg/kg

• Q3W dosing of OMP‐59R5Q3W dosing of OMP 59R5 provides a period of drug wash‐out

• Anti‐drug antibody formation (18 %, 5/28) did not affect PK

Symbol: group mean and SD; Line: model fit

Study 59R5-001: Days on Study*

Triple Negative Breast Cancer (Jag1 Amp): 7.5mg/kg Q3wk

Liposarcoma: 10mg/kg Q2wk

9)

Adenoid cystic ca: 5mg/kg Q2wk

Rectal ca: 5mg/kg QwkKaposi’s Sarcoma: 5mg/kg Qwkbj

ects

(N=3

9

Kaposi s Sarcoma: 5mg/kg Qwk

Adenoid cystic ca: 2.5mg/kg Qwk

Sub

0 20 40 60 80 100 120 140 160 180

ongoingDays on StudyDLT Window Tumor

AssessmentTumor

Assessment

* Four patients currently on study

Pharmacodynamic DataGene Expression in Bloodp

Blood RNA: HES1 Gene ExpressionBaseline to d28, d56, d112

Blood RNA: HES1 Gene ExpressionBaseline to d28 by Dose

Weekly OMP-59R5 dosingPD samples taken prior to

t d inext dosing

HES1 HES1

Pharmacodynamic DataSerial Tumor Biopsiesp

OMP-59R5 Up-Regulated mir150, Target of the NOTCH Pathway in Tumor Biopsies

OMP-59R5 Down-regulated Notch3 PD Biomarker in Tumor Biopsies

miR150: ↑ expression ↓ T cell Notch3

Pt14KS

Pt27PC

Pt28CRC

Pt29CRC

Pt14KS5 QW

Pt27PC10QoW

Pt28CRC5QoW

Pt29CRC5QoW

KS5 QW

PC10QoW

CRC5QoW

CRC5QoW

ConclusionsOMP 59R5 (A i N h2/3) i ll l d i i i h• OMP‐59R5 (Anti‐Notch2/3) is well tolerated in patients with advanced solid tumor

D li iti t i it di h• Dose‐limiting toxicity: diarrhea 

• Maximum tolerated doses (MTDs) were: 2.5mg/kg QW, 7.5mg/kg Q3W Q2WMTD still being determinedQ3W. Q2W MTD still being determined

• Pharmacokinetics: Fast, nonlinear clearance 

• Pharmacodynamics: Modulation of Notch pathway at ≥1mg/kg, sustained ≥1 week in surrogate tissues and tumor biopsies.

• Prolonged stable disease in some patients at doses ≥2.5mg/kg 

• Ph1b/2 studies in solid tumors including pancreatic cancer

Antibody Therapy In Ph1b/2 Study in FL Pancreatic CancerAntibody Therapy In

First-Line

y

Pancreatic Cancer

IGemcitabine*

+Anti-Notch2/3Investigating

anti-Notch

First-line Metastatic Pancreatic Ca

(Tissue Required)1:1

Anti Notch2/3 Ph1b: Safety Run-In

Efficacy and safety

Gemcitabine*+

Placebo

Study is ongoing

ALPINEOMP-59R5 in Pancreatic Cancer

ALPINEOMP-59R5 in Pancreatic Cancer * Gemcitabine: 1000mg/m2 weekly for 3 weeks, 1 week rest

Study is ongoing

AcknowledgementsAcknowledgements

Patients their families and care giversPatients, their families, and care givers

University of Michigan STARTDavid Smith, MDRashmi Chugh, MDTerri O’Neill RN

Anthony Tolcher, MDKyri Papadopoulos, MDAmita Patnaik MDTerri O Neill, RN

Kim Feldhaus, RNVillete ThorpeElaine Granch

Amita Patnaik, MDGlenda Chambers

OncoMedElaine Granch OncoMedDawn HillAnn Kapoun, PhDL X PhDLu Xu, PhD