DCVax Novel Personalized Immune Therapies For Solid Tumor Cancers. SMi 4 th Annual Cancer Vaccines Conference September 16, 2015

Transcription

1 DCVax Novel Personalized Immune Therapies For Solid Tumor Cancers SMi 4 th Annual Cancer Vaccines Conference September 16, 2015

2 Disclaimer Certain statements made in this presentation are forward-looking statements of NW Bio as defined by the Securities and Exchange Commission ( SEC ). All statements, other than statements of historical fact, included in this presentation that address activities, events or developments that NW Bio believes or anticipates will or may occur in the future are forward-looking statements. These statements are based on certain assumptions made based on experience, expected future developments and other factors NW Bio believes are appropriate in the circumstances. Such statements are subject to a number of assumptions, risks and uncertainties, many of which are beyond the control of NW Bio. Investors and others are cautioned that any such statements are not guarantees of future performance. These forward-looking statements could cause actual results and developments to differ materially from those expressed or implied in such statements, including our ability to raise funds for general corporate purposes and operations, including our clinical trials, the commercial feasibility and success of our technology, our ability to recruit qualified management and technical personnel, our ability to scale up the manufacturing of our product candidates for commercialization, the success of our clinical trials and our ability to obtain and maintain required regulatory approvals for our products. Furthermore, NW Bio does not intend (and is not obligated) to update publicly any forward-looking statements. The contents of this presentation should be considered in conjunction with the risk factors contained in NW Bio s recent filings with the SEC, including its most recent Form 10K. This communication is neither an offer to sell nor a solicitation of an offer to buy any securities mentioned herein. This publication is confidential for the information of the addressee only and may not be reproduced in whole or in part; copies circulated, or disclosed to another party, without the prior written consent of Northwest Biotherapeutics (NW Bio) are strictly prohibited. 2

3 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

4 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

5 Cancer Is A Personalized Disease LB Alexandrov et al. Nature 000, 1-7 (2013) doi: /nature

6 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

7 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

8 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

9 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

10 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

11 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

12 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, meetings/sitc2014/primer 12

13 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

14 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

15 DCVax Direct Program

16 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

17 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

18 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

19 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

20 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

21 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 Months

22 Dose Level Correlates With Survival As of Feb Alive Dead million 6 million 15 million 22

23 Number of Injections Correlates With Survival As of Feb Alive Dead injections 3 injections 4 injections 5 injections 6 injections 23

24 Tumor Control (Stable Disease At Week 8) Correlates With Survival As of Feb 2015 p= alive dead SD week 8 PD week 8 24

25 Stable Disease at Week 8 Correlates With Survival As of Sept p=0.031 Proportion Alive Months

26 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

27 IL-8 Production Correlates with Survival As of Feb IL-8 >1,000 Proportion alive IL-8 <1, Months

28 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

29 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

30 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

31 PD-L1 On Macrophages In Tumor Correlates With Survival As of Sept Emerging or significantly increased PD-L1 expression 0.8 Proportion Alive No emerging or significantly increased PDL-1 expression Months

32 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

33 DCVax L Program

34 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: , 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

35 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

36 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

37 20 Rapid-Progressor Patients: OS in Sept. vs Jan Patient alive in Jan remains alive; OS now > 3-1/2 years Overall, median OS 15.3 months (with Std of Care, months) Alive Dead Recurrent GBM median OS months in literature Months

38 25 Indeterminate Patients: OS in Sept. vs Jan Only 1 patient died during Jan. to Sept, % 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 months with Std of Care) Alive Sept 2015 ** Alive Jan ** ** (extension periods vary based on timing of data collection) Dead Sept 2015 Dead Jan Months Median OS of regular GBM patients with Std of Care: ~14.6 mos

39 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

40 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