Using Glembatumumab Vedotin (CDX-011) and Immunotherapy

Transcription

1 Using Glembatumumab Vedotin (CDX-011) and Immunotherapy Jeffrey Raizer, M.D., Executive Medical Director-Clinical Science World ADC San Diego September 21, 2017

2 Forward Looking Statement This communication contains "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of All statements other than statements of historical fact are statements that could be forward-looking statements. You can identify these forward-looking statements through our use of words such as may, will, can, anticipate, assume, should, indicate, would, believe, contemplate, expect, seek, estimate, continue, plan, point to, project, predict, could, intend, target, potential and other similar words and expressions of the future. These forward-looking statements are subject to risks and uncertainties that may cause actual future experience and results to differ materially from those discussed in these forward-looking statements. Important factors that might cause such a difference include, but are not limited to, the timing, cost and uncertainty of obtaining regulatory approvals for product candidates; our ability to develop and commercialize products before competitors that are superior to the alternatives developed by such competitors; the validity of our patents and our ability to avoid intellectual property litigation, which can be costly and divert management time and attention; the risks relating to the integration of the businesses of Kolltan and Celldex; and the other factors listed under Risk Factors in our filings with the SEC, including Forms 10- K, 10-Q and 8-K. Celldex does not undertake any obligation to release publicly any revisions to such forward-looking statement to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. 2

3 Agenda Introduction to Celldex Brief Background and Clinical Experience with Glembatumumab Vedotin, an ADC Targeting gpnmb Rationale and Preclinical Data for Combining Glembatumumab Vedotin with Immunotherapy Current and Future Directions of Glembatumumab Vedotin with Immunotherapy 3

4 Pipeline of Celldex Sponsored Studies Drug Candidate and Indication Target Preclinical Phase 1 Phase 2 Phase 3 Glembatumumab vedotin Triple negative breast cancer gpnmb METRIC (registrational study) target enrollment complete Glembatumumab vedotin Metastatic melanoma Varlilumab Head and neck, ovarian, colorectal and renal cell carcinomas, and GBM CDX-0158 Gastrointestinal stromal tumors (GIST) and other KIT-positive tumors CDX-3379 Multiple solid tumors gpnmb CD27 KIT ErbB3 (3 arms: monotherapy complete; + varli & + checkpoint inhibitor ongoing) + nivolumab (BMS collaboration) monotherapy ongoing; combo planned in combo regimens CDX-014 Renal cell carcinoma TIM-1 monotherapy ongoing; combo planned 4

5 Pipeline of Third-Party Sponsored Studies Drug Candidate and Indication Target Preclinical Phase 1 Phase 2 Phase 3 Glembatumumab vedotin Uveal melanoma Sponsor: NCI (CRADA) Glembatumumab vedotin Squamous cell lung cancer Sponsor: PrECOG, LLC CDX-1401 / CDX-301 Multiple solid tumors Sponsor: CITN gpnmb gpnmb NY-ESO-1 Flt3L 5

6 Glycoprotein NMB (gpnmb): Overview

7 Glycoprotein NMB (gpnmb) gpnmb is a complex molecule involved in number of functional activities, not all of which are understood Implicated in cell differentiation and function Internalizable, type 1 transmembrane glycoprotein aberrantly expressed at high levels on epithelial tumor cells and supporting stromal cells in a wide range of cancers A soluble form is released from the membrane by metalloproteinase Related to melanocyte protein Pmel-17 (gp100) Expressed by osteocytes, macrophage/dc, melanocytes Extracellular domain (N-terminal domain) Intracellular domain (C-terminal domain) RGD motif Integrin binding KRG Domain (Kringle-like) Heparin binding Transmembrane domain Dileucine motif lysosome sorting ITAM motif 7 Rose, et al. Clin Cancer Res. 2010; 16(7):

8 gpnmb is an Attractive Target for Drug Development High membrane expression in tumors and efficient internalization is optimal for antibody-drug-conjugate approaches Predominantly intracellular in normal cells (bone marrow, skin, GI and eye) Target Population Est. % Patients gpnmb+ Est. # Patients gpnmb+ All Breast Cancers (invasive) Metastatic Triple Negative Breast Cancer Metastatic Melanoma (Stage III/IV unresectable) ~20% ( 25% expression) ~40% ( 25% expression) 50,000 8,000 >80% 16,500 Squamous Cell Lung Cancer >85% 45,900 Osteosarcoma >60% 500 Head and Neck Cancer >40% 25,000 Pancreatic Cancer >55% 29,000 Glioblastoma >66% 7,900 *Estimated patient numbers are calculated based on American Cancer Society incidence projections for Rose, et al. Clin Cancer Res. 2010; 16(7):

9 gpnmb is Highly Expressed in TNBC and Promotes Tumor Growth and Metastasis High gpnmb mrna levels are associated with poor prognosis in human breast cancer High gpnmb associated with significantly shorter metastasis-free survival and overall survival 9 Rose, et al. Clin Cancer Res. 2010; 16(7): Rose et. al. Mol. Cancer Res 2007

10 Potential Mechanisms Through Which gpnmb Promotes Malignant Cellular Phenotypes Within Cancer Cells 10 Maric et al. Onco Targets Ther 2013,

11 Summary: gpnmb as a Cancer Therapy Target Over-expressed in a number of cancer types Melanoma 1, breast cancer 2, NSCLC 3, osteosarcoma 4, uveal melanoma 5 Over-expression correlated with poor prognosis in breast cancer High tumor expression of gpnmb specifically correlated to poor prognosis in triple-negative breast cancer (TNBC) 2,6 Implicated as a negative regulator of anti-tumor immune response 7-9 Membrane expression in tumors accessible to antibody therapy, efficiently internalized for antibody-drug conjugate approaches 1. Tse, et al. Clin Cancer Res. 2006; 12(4): Yardley, et al. J Clin Oncol. 2015; 33(14): Rose, et al. Clin Cancer Res. 2010; 16(7): Selim. Med Sci Monit. 2009; 15(2):MT19-MT Data on file. 8. Singh, et al. Crit Rev Eukaryot Gene Expr. 2010; 20: Zhao, et al. Neoplasma. 2012; 59: Zhao, et al. Neoplasma. 2012; 59: Williams, et al. Melanoma Res. 2010; 20(3):

12 Glembatumumab Vedotin: Overview

13 CR011 Recognizes gpnmb on the Surface of Cancer Cell Lines of Multiple Lineages SK-Mel-2 (melanoma) XF-498 (glioblastoma) MG63 (osteosarcoma) PE-conjugated anti-human Ig Human IgG2 isotype control CR011 (glembatumumab vedotin) 13 Tse, et al. Clin Cancer Res. 2006; 12(4):1373. Rose, et al. AACR 2008 Annual Meeting. Abstract# 3681

14 Glembatumumab Vedotin: An MMAE containing Antibody-Drug Conjugate (ADC) Antibody-drug conjugate designed to release monomethylauristatin (MMAE; cytotoxic drug) upon internalization into gpnmbexpressing tumor cells Celldex proprietary target and antibody Toxin and linker licensed from Seattle Genetics Same technology as brentuximab vedotin (Adcetris ) Proposed Mechanism of Action Adcetris is a registered trademark of Seattle Genetics 14

15 Effect of Glembatumumab Vedotin on Tumor Growth Breast Cancer Cell Lines and Xenografts 2 Human SK-MEL-2 Melanoma Xenografts 1 1. Pollack et al. Cancer Chemother Pharmacol. 2007; 60(3): Rose, et al. Clin Cancer Res. 2010; 16(7):

16 Glembatumumab Vedotin: Clinical Experience

17 Glembatumumab Vedotin: Summary of Clinical Experience Three completed clinical studies (n=283, including control; patients treated with glembatumumab vedotin=255) Phase 1/2 unresectable stage III or stage IV melanoma (n=117) 1 MTD (RP2D) was established as 1.88 mg/kg q3w in melanoma study; more frequent dosing regimens (q2/3w and qw) were associated with increased toxicity Observed toxicity includes rash, neutropenia, fatigue, nausea, vomiting, alopecia, decreased appetite and peripheral neuropathy 1.88 mg/kg q3w (n=43) 1.5 mg/kg q2/3w (n=6) 1.0 mg/kg qw (n=15) Response Rate [n (%)] 5 of 40* (13%) 2 of 6 (33%) 3 of 12* (25%) Median PFS [months] * Excludes patients without postbaseline assessment of measurable lesions Phase 1/2 advanced, heavily pre-treated breast cancers (n=42) 2 Maximum dose 1.88 mg/kg q3w (Phase 2 dose) but no DLT seen Grade 3 treatment-related events included neutropenia, neuropathy, fatigue, and rash All Ph 2 Dose (n=33) TNBC (n=10) gpnmb+ (n=11) gpnmb+ TNBC (n=4) Response Rate [n (%)] 4 (12%) 2 (20%) 2 (18%) 1 (25%) Median PFS [weeks] Phase 2 EMERGE study in advanced, heavily pre-treated breast cancers (n=124) 3 1. Ott, et al. J Clin Oncol. 2014; (32)32: Bendell, et al. J Clin Oncol. 2014; 32(32): Yardley, et al. J Clin Oncol. 2015; 33(14):

18 EMERGE: Randomized Phase 2 Study in Patients with Advanced Breast Cancer Planned sample size = 120 Locally advanced or metastatic, gpnmb+ breast cancer Refractory/resistant to approved therapies (taxane, anthracycline, capecitabine; and if HER2+, trastuzumab and lapatinib) 2-7 prior lines of cytotoxic chemotherapy for advanced disease Progression within 6 months of last regimen glembatumumab vedotin (1.88 mg/kg, 90 minute IV infusion, once every three weeks) Randomize (2:1) Cross-over to glembatumumab vedotin permitted upon centrally confirmed PD and continued eligibility Investigator s Choice single-agent chemotherapy (IC) PD Endpoints: overall response rate [primary]; progression-free survival; duration of response; safety; PK/PD Study designed to examine whether anti-cancer activity of glembatumumab vedotin is dependent upon distribution/intensity of gpnmb expression Stratified for stromal intensity vs. epithelial cell expression Study initiated Sept 2010; enrollment completed Dec Yardley, et al. J Clin Oncol. 2015; 33(14):

19 EMERGE: Tumor Response (ITT) All Patients Triple Negative High gpnmb Expression Triple Negative and High gpnmb Expression Glemba (n=83) IC (n=41) Glemba (n=28) IC (n=11) Glemba (n=23) IC (n=11) Glemba (n=10) IC (n=6) Partial Response (PR) [n (%)] Confirmed PR [n (%)] Stable Disease or Better [n (%)] 10 (12%) 5 (12%) 5 (18%) 0 7 (30%) 1 (9%) 4 (40%) 0 5 (6%) 3 (7%) 2 (7%) 0 3 (13%) 1 (9%) 1 (10%) 0 41 (49%) 19 (46%) 17 (61%) 3 (27%) 15 (65%) 3 (27%) 9 (90%) 1 (17%) On target effect clearly demonstrated in targeted patient populations Responses per RECIST 1.1; analysis of all randomized patients (intent to treat) Thresholds of 10% and 25% gpnmb-positive tumor epithelial cells both show significant enrichment of responders 19 Yardley, et al. J Clin Oncol. 2015; 33(14):

20 P ro g re s s io n -fre e S u rv iv a l (% ) Progression Free Survival (%) P ro g re s s io n -fre e S u rv iv a l (% ) P ro g re s s io n -fre e S u rv iv a l (% ) P ro g re s s io n -fre e S u rv iv a l (% ) EMERGE: Progression Free Survival (ITT) A ll E n r o lle d P a tie n ts All Patients T N B C Triple Negative H ig h g p N M B E x p r e s s io n High gpnmb Expression T N B C a n d H ig h T u m o r g p N M B E x p re s s io n TN & High gpnmb M o n th s Months Months Months Months M o n th s Glembatumumab vedotin Investigator s choice (IC) M o n th s M o n th s All Patients Triple Negative High gpnmb Expression Triple Negative and High gpnmb Expression Glemba (n=83) IC (n=41) Glemba (n=28) IC (n=11) Glemba (n=23) IC (n=11) Glemba (n=10) IC (n=6) Median PFS (months) HR=1.19, p=0.42 HR=0.69, p=0.38 HR=0.63, p=0.18 HR=0.11, p= Yardley, et al. J Clin Oncol. 2015; 33(14):

21 O v e ra ll S u rv iv a l (% ) Overall Survival (%) O v e ra ll S u rv iv a l (% ) O v e ra ll S u rv iv a l (% ) O v e ra ll S u rv iv a l (% ) EMERGE: Overall Survival (ITT) A ll E n r o lle d P a tie n ts T N B C H ig h g p N M B E x p r e s s io n T N B C a n d H ig h T u m o r g p N M B E x p re s s io n All Patients Triple Negative High gpnmb Expression TN & High gpnmb Months Months Months Months M o n th s Glembatumumab vedotin Investigator s choice (IC) M o n th s M o n th s M o n th s All Patients Triple Negative High gpnmb Expression Triple Negative and High gpnmb Expression Glemba (n=83) IC (n=41) Glemba (n=28) IC (n=11) Glemba (n=23) IC (n=11) Glemba (n=10) IC (n=6) Median OS (months) HR=1.37, p=0.20 HR=0.65, p=0.30 HR=0.67, p=0.31 HR=0.14, p= Yardley, et al. J Clin Oncol. 2015; 33(14):

22 EMERGE: Development of Rash in Cycle 1 is Associated with Improved Progression-Free Survival and Overall Survival Progression Free Survival and Overall Survival (ITT) Following Treatment by Glembatumumab Vedotin (n=83) 22 Yardley, et al. J Clin Oncol. 2015; 33(14):

23 RANDOMIZE (2:1) METRIC: Phase 2b Registration Study Design in Triple Negative Breast Cancer (NCT ) Patients with metastatic TNBC overexpressing gpnmb ( 25% tumor cells by IHC) n=300 glembatumumab vedotin 1.88 mg/kg IV Day 1 of 21-day cycles capecitabine (Xeloda ) 1250 mg/m 2 BID Days 1-14 of 21-day cycles Treat until unacceptable toxicity or disease progression Tumor assessments (6 week intervals x 6 months; 9 week intervals thereafter) until documented progression Survival follow-up (12 week intervals) Primary endpoint: PFS (203 events by central review) Secondary endpoints: OS, ORR, DOR Exploratory endpoint: QOL Involved approximately 150 sites across U.S., Canada, Australia and Europe Enrollment closed August 2017 with a total of 327 patients randomized Xeloda is a registered trademark of Genentech 23

24 Summary of Glembatumumab Vedotin Single-Agent Data Cell surface expression is required for glembatumumab vedotin binding Internalization into the cell leads to cleavage of the cytotoxin MMAE The compound and its metabolites do not accumulate over time In early studies, ORR and PFS at the Phase 2 dose have been favorable for the heavily-pretreated populations studied (advanced melanoma and breast cancer) Patients with tumors expressing higher levels of gpnmb consistently appear to derive greater clinical benefit from glembatumumab vedotin as compared to the entire population of treated patients The EMERGE Study showed promising activity in triple-negative breast cancer (TNBC), where treatment options are limited Glembatumumab vedotin response rate of 18% in TNBC compared to 0% for IC Both TNBC and high gpnmb expression (41% of patients with TNBC) resulted in a response rate of 40% and doubling of PFS (p=0.0017) and OS (p=0.003) Trials of glembatumumab vedotin in other indications as a single-agent are in progress or completed accrual (uveal melanoma, squamous cell lung) 24 Yardley, et al. J Clin Oncol. 2015; 33(14): Data on File

25 Glembatumumab Vedotin and IO Combinations

26 Combining Antibody-drug Conjugates and Immunemediated Cancer Therapy: What to Expect? Distinct mechanisms of action of cytotoxic payloads leading to anti-tumor responses 1. Direct induction of tumor cell death by the cytotoxic payload employed 2. Cytotoxic compounds that induce ICD, cause the release of danger signals by the tumor cell 3. Direct activation and maturation of dendritic cells by the cytotoxic payloads released in the TME Leads to: Increased cross priming of CD8+ T-cells in the lymph nodes by activated dendritic cells CD8+ T-cell infiltration into the tumor core followed by cytolytic killing of tumor cells 26 Gerber et al. Biochem Pharmacol Feb 15;102:1-6.

27 Microtubule-depolymerizing Agents Used in ADCs Induce Antitumor Immunity by Stimulation of Dendritic Cells Dolastatins trigger phenotypic and functional activation of tumor resident DCs When combined with tumor antigen specific vaccination or checkpoint inhibitorblocking antibodies, dolastatins show synergistic antitumor activity and promote tumor destruction ADCs coupled to MMAE lead to augmentation of tumor-specific immunity Muller et al. Cancer Immunol Res Aug;2(8):741-55

28 Trastuzumab Emtansine (T-DM1) Renders HER2 + Breast Cancer Highly Susceptible to CTLA-4/PD-1 Blockade The therapies were non-redundant but complementary: The ADC reinstates immunosurveillance by driving a distinct DC maturation program and, subsequently, T cell infiltration CTLA-4/PD-1 blocking therapy potentially reinvigorates exhausted T cells 28 Muller et al. Sci Transl Med Nov 25;7(315):315ra188.

29 Biological Functions of gpnmb in Cancer Progression and Potential gpnmb-targeting Strategies Rose, et al., Targeting GPNMB with glembatumumab vedotin: Current developments and future opportunities for the treatment of cancer, Pharmacology & Therapeutics (2017) 29

30 Varlilumab Induced Immune Responses Are Maintained or Increased in Combination Treatment with ADC Data support that varlilumab may enhance the development and survival of T cell responses to newly released antigens from tumors that are at least partially sensitive to glembatumumab vedotin and may increase and/or prolong the clinical benefit derived from glembatumumab vedotin treatment 30 Celldex data on file

31 Phase 2 Study of Glembatumumab Vedotin as Monotherapy or in Combination with Immunotherapies in Patients with Advanced Melanoma (NCT ) Open-label Phase 2 study of glembatumumab vedotin in patients with unresectable Stage III or IV melanoma who have previously received CPIs Three cohorts Cohort 1- Glembatumumab Vedotin monotherapy (N=60) Cohort 2- Glembatumumab Vedotin and Varlilumab (N=30) Cohort 3- Glembatumumab Vedotin and a PD-1 inhibitor (N=30) Primary endpoint To evaluate the anti-cancer activity of glembatumumab vedotin as monotherapy and in combination with varlilumab, or in combination with a PD-1 targeted checkpoint inhibitor (CPI), in advanced melanoma as measured by the objective response rate (ORR) per RECIST

32 CDX Phase 2 Study Design 32

33 Demographics and Disease Characteristics 34

34 Clinical Efficacy 35

35 Early Development of Rash Associated with Improved Outcome Presented By Patrick Ott at 2017 ASCO Annual Meeting 36

36 Current and Future plans Analysis of data for cohort 2 Continued accrual in cohort 3 Possible other IO combinations? 37

37 Conclusion Combining antibody-drug conjugates and immune-mediated cancer therapy: What to expect? ADC IO Direct cell killing and bystander effect ICD and release of neo-antigens Maturation of DC Improve T-Cell function Increase Teff/Treg ratio 37 Gerber, et al. Biochemical Pharmacology. 2015; 102, 1-6.

38 QUESTIONS?