OMP-305B83: A Novel, Potent DLL4 & VEGF Targeting Bispecific Antibody for the Treatment Of Solid Tumors

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1 OMP-305B83: A Novel, Potent DLL4 & VEGF Targeting Bispecific Antibody for the Treatment Of Solid Tumors Jakob Dupont MD MA CMO, SVP: OncoMed Pharmaceuticals Adjunct Clinical Faculty: Stanford University Boston, MA USA 29 Sept 2016

2 Disclosure I am an employee of OncoMed OncoMed 2

3 About OncoMed Targeting Cancer Stem Cells and IO Targets Established in April 2004 Located in San Francisco Bay Area in Redwood City, California Approximately 120 people 7 Biologics in the clinic 2 IO INDs upcoming in 6 months OncoMed 3

4 PRECLINICAL CLINICAL OncoMed s Pipeline 7 Drugs in Clinic, 2 Immuno-Oncology INDs Therapeutic Pathway Preclinical IND Phase 1a Phase 1b Phase 2 Demcizumab Anti-DLL4; OMP-21M18 Tarextumab Anti-Notch2/3; OMP-59R5 Vantictumab Anti-Fzd7, OMP-18R5 Ipafricept Fzd8-Fc; OMP-54F28 Anti-RSPO3 OMP-131R10 Brontictuzumab Anti-Notch1; OMP-52M51 OMP-305B83 Notch Notch WNT WNT R-Spondin Notch Notch GITRL-Fc I/O#2 I/O #3 Undisclosed Small Molecules WNT inhibitors I/O I/O I/O WNT OncoMed 4

5 Why Target Cancer Stem Cells? CSCs drive tumor growth, recurrence, and metastasis CSCs are not reduced by standard chemotherapy, radiation, and targeted therapies Novel anti-csc therapy has vast potential for more durable clinical outcomes Anti-CSC therapy promotes differentiation Anti-CSC therapy can inhibit proliferation OncoMed Wnt-inhibitor vantictumab in pancreatic cancer model 5

6 Targeting Critical Cancer Pathways Notch Pathway Wnt Pathway RSPO/LGR Pathway Immuno-oncology Targets Demcizumab Vantictumab Anti-RSPO3 GITR Tarextumab Ipafricept Other RSPOs IO#2 (undisclosed) Brontictuzumab bispecific Small Molecules Other LGRs IO#3 (undisclosed) OncoMed 6

7 Signal Transduction by the Notch Pathway Ligands - DLL1, 3, 4 - JAG1, 2 Receptors - Notch1, 2, 3, 4 The Notch pathway mediates intercellular signaling in stem cell self-renewal, proliferation, and differentiation DLL4 is a key angiogenic factor that causes functional vascular lumen development OncoMed 7

8 Anti-DLL4: Three Mechanisms of Action Monocytic Myeloid-Derived Suppressor Cells (Mo-MDSC): a key population of immunosuppressive cells that inhibit anti-tumor immune responses OncoMed 8

9 Demcizumab in First-Line NSCLC Differentiated MOA in NSCLC Regimen Phase 1b Safety Demcizumab 5 mg/kg Q3W (truncated) with Carbo + PEM x4 PEM Current regimen well tolerated Most common AEs = fatigue, nausea, manageable hypertension Truncated dosing mitigates cardiopulmonary toxicities 50% Objective Response Rate (n=40) 1 CR (3%); 19 PR (48%); 15 SD (38%) Published rates*: 27% PR Survival Phase 1b Efficacy Continuous cohort: 10 of 23 (~40%) alive > 2 years Truncated cohort: 8 of 23 (35%) alive between months Status Phase 2 DENALI trial Data in late 2017/2018 N=201 randomized into 3 arms 1 course demcizumab + chemo 2 courses demcizumab +chemo placebo + chemo Primary endpoint PFS OncoMed 9 Source: McKeage, et al - ASCO 2016 * Alimta (pemetrexed) package insert

10 Demcizumab in First-line Pancreatic Cancer Data and Potential for Opt-in in 2017 Regimen Phase 1b Safety Phase 1b Efficacy Demcizumab 3.5 mg/kg Q2W (truncated) with gemcitabine + Abraxane Current regimen well tolerated Most common AEs = fatigue, nausea, vomiting Truncated dosing successful mitigates cardiopulmonary toxicities 50% Objective Response Rate (n=28) 14 PR (50%); 11 SD (39%) Published rates*: 23% PR, 27% SD Survival mpfs = 7.1 months mos = 12.7 months Published rates* mpfs = 5.5 months mos = 8.5 months Status Phase 2 YOSEMITE trial data in 1H 2017 N=201 randomized into 3 arms 1 course demcizumab + chemo 2 courses demcizumab +chemo placebo + chemo Primary endpoint: PFS OncoMed Source: Hidalgo, et al Gastrointestinal Cancers Symposium *MPACT Phase 3 study; Von Hoff, et al, NEJM

11 Demcizumab Phase 2 Trials YOSEMITE First-line Pancreatic Cancer DENALI First-line NSCLC Data in 1H 2017 Data in late 2017/2018 OncoMed 11

12 Structure of 305B83 Bispecific Antibody Dual inhibitor of both DLL4 and VEGF Proprietary bispecific antibody technology Two distinct heavy chains recognizing DLL4 and VEGF respectively Common light chain Humanized IgG2 Bispecific anti-dll4 + anti-vegf Anti-DLL4 Heavy chain CH3 domain engineered to promote heterodimerization Anti-VEGF Heavy chain OncoMed Yen et al AACR

13 Background and Rationale for Bispecific Targeting in Cancer retains the anti-csc impact of targeting DLL4-Notch signaling in tumor cells DLL4 and VEGF are central regulators of tumor angiogenesis and VEGF is a validated therapeutic target Inhibition of either DLL4 or VEGF achieves antiangiogenic activity, but through distinct mechanisms DLL4 blockade inhibits functional lumen development VEGF blockade inhibits endothelial proliferation Tumor Volume, mm CSC Tumorigenicity Assay Control Anti-DLL4 Avastin bispecific Combination blockade of DLL4 and VEGF may combine beneficial aspects of each approach for potent anti-angiogenic activity Preclinical experiments provide support enhanced antitumor activity of anti-dll4/vegf combination Hicklin DJ (2007) Nature Biotechnol 25: OncoMed Yen et al AACR

14 OMP-305B83: High Affinity for VEGF and DLL4 OncoMed Yen et al AACR

15 OMP-305B83: Pre-Clinical Single agent and Combination Efficacy Bi-specific Antibody Inhibits Colon Xenograft Tumor Growth. Kras mutant colon xenograft tumors OMP- C8 were treated with either control mab, 7.5 mg/kg irinotecan, 7.5 mg/kg bevacizumab or 15 mg/kg bi-specific mab once a week for 4 weeks. *:p<0.05 vs. control mab, **: p<0.05 vs. irinotecan by two-way ANOVA. OncoMed Yen et al AACR

16 Establishment of Minimally Passaged Patient Derived Xenografts Established ~280 tumors to date Focused on major tumor types - Breast, colon, lung, pancreas, etc. - Continually expanding Extensive genomic characterization - Gene expression (RNA-seq) - Oncogene mutational analysis - Gene amplifications and deletions Models retain tumor cell heterogeneity - Better predict therapeutic response - Enable CSC characterization and biomarker discovery p1 p2 OncoMed 16

17 OMP-305B83: Anti-Tumor & Anti-CSC Bi-specific Antibody Delay Tumor Recurrence and Reduces Colon Cancer Stem Cell Frequency. Left: OMP-C8 colon tumors were treated with either irinotecan, bevacizumab, demcizumab or bi-specific mab once a week for 5 weeks. Thereafter, irinotecan was terminated and followed with mab alone. Right: Control and treated OMP-C8 colon tumors were were harvested 4 weeks post treatment, isolated into single cell suspension and serially passaged into OncoMed Yen et al AACR

18 Anti-VEGF Effect is Dominant over anti-dll4 Effect on Angiogenic Hyperproliferation OncoMed Yen et al AACR

19 DEM BiSp OMP-305B83: Potentially Improved Safety Profile C OncoMed Yen et al Mol Targ Can Thera

20 Pre-clinical Data: Immune Competent Model Increased Efficacy of BiSpecific + anti-pd1 Colorectal Cancer OncoMed Srivastava et al SITC

21 Pre-clinical Data: Immune Competent Model Increased Efficacy of BiSpecific + anti-pd1 Renal Cell Carcinoma OncoMed Srivastava et al SITC

22 Pre-clinical Data: BiSpecific + Anti-PD1 Augments CD8 and CD4 T cell responses OncoMed Srivastava et al SITC

23 Clinical Development of OMP-305B83 Phase 1a: Refractory Solid Tumor Patients Dose escalation Dose expansion ClinicalTrials.gov Identifier: NCT Initiated: November 2014 Presentation: EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium; Munich, Germany; Nov-Dec 2016 Ph1b: combination trials (distinct Solid Tumors) Dose escalation Dose expansion Combination with standard-of-care Initiating EOY 2016 OncoMed 23

24 Thank you OncoMed 24