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
3
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
m3
0
250
500
tum
or v
o
0
500
Tum
or V
o33 38 43 48 53 58 63 68 73 78 83 88 93 98 103
0
Days
ontrol m
Abti-N
otch2/3
emcit
abine
ombination
0
Gem + OMP-59R5 OMP-59R5
Con
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