DCVax Novel Personalized Immune Therapies For Solid Tumor Cancers SMi 4 th Annual Cancer Vaccines Conference September 16, 2015
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DCVax : A Fully Personalized Immune Therapy Personalized Product: autologous (personalized) dendritic cells Allows repeat doses, ongoing treatment Personalized Targets: tumor antigens from patient s own tumor Avoids Russian Roulette Broad Scope of Targets: full set of tumor antigens Not just 1 or a few pre-selected, standardized antigens Maximize obstacles to tumor escape Excellent safety profile Some flu-like symptoms; no additional drugs, no hospital stays 3
Cancer Is A Personalized Disease Extensive variation among cancers Extensive variation among patients, even with same cancer Significant variations within a single patient as disease progresses Extensive heterogeneity even within a single tumor 4
Cancer Is A Personalized Disease LB Alexandrov et al. Nature 000, 1-7 (2013) doi:10.1038/nature12477 5
Two Key Issues With Existing Cancer Treatments Current treatments are largely standardized, not personalized. This raises 2 key issues Russian Roulette The patient s tumor may or may not express the targets. (e.g., EGFRvIII mutation in GBM only expressed on ~30% of GBMs) Tumor escape Tumors can and do stop expressing 1 or a few targets. But tumor cells cannot stop expressing all targets. 6
Personalized Treatments Vary Across A Spectrum Standardized Product Standardized Targets Personalized Profiling Personalized Product Standardized Targets Personalized Product Personalized Targets Peptide vaccines DNA vaccines Checkpoint inhibitors CAR-Ts DC vaccines with pre-selected peptide antigens DCVax 7
Dendritic Cells Mobilize Overall Immune System DENDRITIC CELLS the master immune cells Signals activate & biomarkers educate Dendritic Cells INNATE IMMUNE SYSTEM First-responders (within hours/days) Response is automatic Response is non-specific (not tailored to each particular threat) Natural Killer Cells, Neutrophils, Granulocytes, Macrophages ADAPTIVE IMMUNE SYSTEM Follow-on defense (within week or weeks) Response is triggered by exposure to particular threat (activation + education ) Response is specific & creates memory (tailored to each particular threat) HUMORAL IMMUNITY B Cells Antibodies CELLULAR IMMUNITY Helper T Cells Killer T Cells Tumor Cell Death 8
Large Multiplier: Each Dendritic Cell Activates Hundreds of Anti-Cancer T Cells Dendritic Cell activated anti-cancer T cells travel to tumor site tumor target proteins anti-cancer T cell activated resting anti-cancer T cell attaches to DC activated anti-cancer T cells divide rapidly 9
DCVax Potentially Applicable to All Types of Solid Tumors (Both Operable & Inoperable) Market Product Composition Lead Program All Operable Solid Tumors DCVax -L Dendritic cells + biomarkers from tumor tissue sample surgically removed Brain cancer 348-patient Phase III trial underway Small ovarian cancer Phase I/II trial completed All Inoperable Solid Tumors DCVax - Direct Dendritic cells injected directly into tumor(s) + biomarkers picked up onsite in tumor All solid tumor cancers 60-patient Phase I/II trial underway Other Hormone independent prostate cancer DCVax - Prostate* Dendritic cells + recombinant prostate cancer biomarker (PSMA) Prostate cancer 600-patient Phase III trial previously cleared by FDA * The Company will seek to out-license this program 10
DCVax Is Expanding the Reach of Immunotherapy Front line treatment for newly diagnosed disease DCVax-L for newly diagnosed GBM, with SOC (Phase III) Front line treatment for lower grade cancers DCVax-L for all grades of gliomas, with SOC (Hosp. Exemp., Germany) Treatment for patients with very heavy tumor burdens DCVax-L for late stage, metastatic ovarian cancer DCVax-L for rapid progressor GBM DCVax-Direct for 4-5+ inoperable metastatic tumors DCVax-Direct for very large tumors (10 cm. lung; 15x19x17 cm. sarcoma) Long tail of Overall Survival 11
Potentially Complementary With Checkpoint Inhibitors Large number of checkpoints built into the immune system Response rates (%s) to single checkpoint inhibitors limited to date T cells must be activated, to express checkpoints DCVax activates T cells DCVax mobilizes diverse T cell populations against diverse tumor antigens (targets) Source: Allison, J. (2014). Targeting Immune Checkpoints in Cancer Therapy: New Insights and Opportunities, http://www.sitcancer.org/sitc meetings/sitc2014/primer 12
Potentially Complementary With T Cell & Targeted Therapies T cell therapies (CAR-Ts, TCR, etc.) Focus on a particular tumor antigen (CD-19, EGFR, etc.) Designed to boost T cell numbers, affinity, etc. for that antigen Durability not yet clear Addressing diverse antigens may be more important in solid tumors Targeted therapies Focus on a particular cellular pathway Alternate/redundant pathways, tumor escape are an issue DCVax offers broad spectrum anti-tumor action which can complement key rifle shots 13
Robust Pipeline of DCVax Programs DCVax -L: Brain cancer Phase III under way (348 pts) Brain cancer Info Arm outside trial (51 pts) Brain cancer Hospital Ex./Other Early Access Metastatic ovarian cancer Phase I completed Compassionate use diverse cancers DCVax - Direct: All solid tumor cancers Phase I/II underway Additional Phase II trial(s) -- pending Pre-clinical Ph I Ph II Ph III DCVax - Prostate Hormone indep. -- Phase I/II completed (36 pts) 14
DCVax Direct Program
DCVax-Direct: Underlying Biology Immature DCs will effectively take up antigens (biomarkers) in situ in tumors, but will not activate T cells. Also, immature DCs are highly susceptible to suppression by the tumor. Mature DCs will not effectively take up antigens in situ in tumors, but will present antigens to T cells and activate them. ****************************** Partially mature, activated DCs. at a certain stage. will effectively take up antigens (biomarkers) in situ in tumors, and will effectively present antigens to T cells and activate them. 16
DCVax-Direct: Activated DCs CD1a: DC-specific marker involved in antigen presentation (not on all DCs, and large patient-to-patient variability) CD209: DC-specific marker involved in binding pathogens (also found on macrophages) pstat-1: phosphorylated STAT-1 signal transduction pathway molecule required for IL-12 production MHC-I, II: MHC molecules involved in antigen presentation CD83: DC activation marker CD40, CD80, CD86: surface molecules involved in T cell activation
DCVax Direct: Potential Clinical Effects Possible Clinical Effects Causes Seen in Pre Clinical Studies? Local effects in tumors injected with DCVax-Direct Tumor necrosis (tumor cell death) Secretion of cytokines (e.g., TNFα, IL-6, IL-8) by activated DCs Systemic effects in tumors not injected Tumor shrinkage or elimination Immune system activation Immune memory Lack of recurrence even when re-challenged Immune system activation 18
DCVax-Direct Phase I Trial: Overview 40 patients enrolled; 39 evaluable Patients had multiple metastases; had failed other treatments 13 different cancers treated 3 dose levels tested: 2M, 6M and 15M cells Only 1 tumor injected; treatments widely spaced Feasibility of image-guided injections tested (multiple methods) Both imaging and biopsies used to monitor responses, correlate with clinical outcomes and evaluate treatment schedule Both local and systemic responses evaluated Safety and potential endpoints evaluated 19
DCVax-Direct Phase I Trial -- Highlights Half of patients still alive, at up to ~22 mos. after first injection Treatment effects observed in diverse cancers Survival correlates with dose levels Survival correlates with number of injections Survival correlates with absence of progression Stable disease (SD) at Wk 8 (4 th injection visit) strongly correlates with survival 21 of 35 patients achieved SD at Wk 8 (progression data n/a on 4 pts) Encouraging immunological responses observed post treatment Induction of immune checkpoint expression Both local effects (in injected tumor) and systemic effects (in non-injected tumors) observed 20
DCVax-Direct Phase I Trial Update: Ongoing OS As of Sept 2015 Pancr mcrc Sarcoma mcrc Pancr NET Melan Other Lung Melan Breast mcrc Lung Lung NET Ovarian Bladder NET Pancreas Sarcoma Sarcoma Sarcoma Sarcoma Sarcoma Sarcoma mcrc Melan Melan Sarcoma Pancr Desmo Melan mcrc Pancr NET Melan Lung mcrc Pancreas mcrc Pancr Breast Alive Dead 0.0 5.0 10.0 15.0 20.0 25.0 Months
Dose Level Correlates With Survival As of Feb 2015 16 14 12 10 Alive Dead 8 6 4 2 0 7 10 4 15 1 2 2 million 6 million 15 million 22
Number of Injections Correlates With Survival As of Feb 2015 12 10 Alive Dead 8 6 4 2 0 2 injections 3 injections 4 injections 5 injections 6 injections 23
Tumor Control (Stable Disease At Week 8) Correlates With Survival As of Feb 2015 p=0.002 20 18 16 14 alive dead 12 10 8 6 4 2 19 2 5 9 0 SD week 8 PD week 8 24
Stable Disease at Week 8 Correlates With Survival As of Sept 2015 1.0 0.8 p=0.031 Proportion Alive 0.6 0.4 0.2 0.0 0 6 12 18 24 Months
TNFα Correlates With SD vs. PD At Week 8 As of Feb 2015 p<0.01 In a multivariate analysis, TNFα production is significantly associated with survival (p=0.018) 26
IL-8 Production Correlates with Survival As of Feb 2015 1.0 0.8 IL-8 >1,000 Proportion alive 0.6 0.4 0.2 IL-8 <1,000 0.0 0 5 10 15 20 25 Months
Immunological Responses: Tumor Infiltrating T Cells TILs, including both CD4 + helper T cells and CD8 + killer T cells increased from baseline in 15 of 27 assessed patients Example: clear cell sarcoma CD3 CD4 CD8 Day 0 Day 7 TILs sharing sequences with peripheral T cells also increased, indicating a systemic response 28
Immunological Responses: Intra-tumoral Responses Day 0 CD3 + T cells Interferon gamma TNF α Week 8 Expression of T cell cytokines demonstrate anti-tumor activity of infiltrating T cells following DCVax-Direct administration 29
Induction of Immune Checkpoint Expression Expression of immune checkpoint molecules in tumor tissue modulates antitumor immune responses Checkpoint inhibitors (CIs) can unblock an existing anti-tumor immune response, but may be ineffective in absence of such pre-existing response 14 of 22 evaluable patients (64%) in DCVax-Direct Phase I trial, showed either de novo or significantly increased expression of the PDL-1 checkpoint molecule after DCVax-Direct treatment; potential candidates for CI treatment Example: De novo PDL-1 staining on sarcoma tissue, 8 weeks after initiation of DCVax-Direct treatment 30
PD-L1 On Macrophages In Tumor Correlates With Survival As of Sept 2015 1.0 Emerging or significantly increased PD-L1 expression 0.8 Proportion Alive 0.6 0.4 0.2 No emerging or significantly increased PDL-1 expression 0.0 0 6 12 18 24 Months
Phase II Trial Plans Injection of multiple tumors, as well as multiple injections into larger tumors, at each visit More frequent injection schedule Indications with promising activity, as well as diverse indications Soft tissue sarcoma Include Quality of Life measurements Trials both in US and outside US 32
DCVax L Program
DCVax-L for Operable Tumors: Newly Diagnosed GBM PHASE I/II TRIALS 20 newly diagnosed GBM; 14 recurrent GBM; 5 lower grade gliomas Standard of care (surgery & 6 weeks radiation & chemo) + DCVax-L Primary endpoint: safety; Secondary endpoint: progression free survival Standard of Care* Matched Concurrent DCVax-L Controls** Progression 6.9 mos 8.1 mos 2 years (Tumor Recurrence) Overall Survival 14.6 mos 17 mos 3 years Long Tail of Survival 2 3% alive at 5 years To date: 33% alive >4 yrs 27% alive >6 yrs 2 pts alive >12 yrs * N Engl J Med 352: 987-96, 2005 **matched for age, gender, Karnofsky score, extent of surgical resection, and same std of care treatment, at same hospital, in same time period 34
International Phase III Trial With DCVax-L for GBM Newly diagnosed GBM; trial under way in both US & Europe 348 patient, randomized (2:1), double blind, placebo controlled Phase III trial: the gold standard in clinical trial design o o Primary endpoint: PFS (progression free survival) Secondary endpoints include OS (overall survival) o 3 DCVax-L treatments upfront (Day 0, 10, 20), then 3 boosters (months 2, 4, 8) then 4 treatments twice/year for maintenance phase (months 12, 18, 24, 30) Multiple protections built into trial design 4-month extension of PFS required to meet primary endpoint (less than 1/3 as long as extension of PFS seen in Phase I/II trials) Trial designed to reach p value = 0.02 if 4-month difference in PFS shown Trial also powered for secondary endpoint of Overall Survival Multiple sub-group analyses were prospectively included 35
Information Arm open label, for patients with apparent PD post chemo-radiation 51 patients had evidence (25% increase or new lesion) of apparent disease progression in imaging at Baseline Visit following 6 weeks chemo radiation Patients re imaged at Month 2 after Baseline Visit to confirm actual disease progression (another 25% increase or new lesion) (patients categorized by independent medical imaging company) 20 patients had further progression (another 25% increase or new lesion) at Month 2: Rapid Progressors 25 patients had stable disease, or modest (<25%) progression or some (<25%) regression at Month 2 Indeterminate 1 patient had all original 25% increase gone at Month 2: Confirmed Pseudoprogressor 5 patients Unclassified due to lack of images 36
20 Rapid-Progressor Patients: OS in Sept. vs Jan. 2015 Patient alive in Jan. 2015 remains alive; OS now > 3-1/2 years Overall, median OS 15.3 months (with Std of Care, 8.3 10.8 months) Alive Dead 0 12 24 36 48 Recurrent GBM median OS 8.3 10.8 months in literature Months
25 Indeterminate Patients: OS in Sept. vs Jan. 2015 Only 1 patient died during Jan. to Sept, 2015 40% of patients (10 of 25) now have OS approx. 3 years 20% of patients now have OS 3-1/2 years Median OS is 21.5 months (vs. 14.6 months with Std of Care) Alive Sept 2015 ** Alive Jan. 2015 ** ** (extension periods vary based on timing of data collection) Dead Sept 2015 Dead Jan 2015 0.0 12.0 24.0 36.0 48.0 60.0 Months Median OS of regular GBM patients with Std of Care: ~14.6 mos
DCVax -L: Cost-Effective, Rapid Batch Manufacturing DAY 1: Tumor tissue & blood at manufacturing facility. DAY 2: Precursors of dendritic cells isolated. DAY 2-7: Precursors differentiated into dendritic cells. DAY 7: DAY 8: Dendritic cells educated by exposure to biomarkers from tumor tissue. Educated dendritic cells harvested & frozen. Manufacturing finished. (Release tests follow) Single manufacturing run yields 3 5 years of doses of DCVax L product. Only 2 grams of tumor tissue needed for full batch. With <2 grams of tumor tissue, a partial batch can be produced. 39
Manufacturing Established At Logistics Hubs In US & Europe Memphis, TN: worldwide hub for both FedEx & UPS 80,000 sq ft facility; capacity for up to 5,000 DCVax patients/year Leipzig, Germany: Europe-wide hub for DHL, Lufthansa Cargo, others 40