Cancer Vaccines: Elicit a Positive Response?

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1 Cancer Vaccines: Will The Latest Batch of Vaccines Elicit a Positive Response? Defined Health Insight Briefing June 21, 2010, Basking Ridge, NJ, USA September 8, 2010, Webinar November, 2010, Swissotel, Basel, Switzerland

2 Therapeutic Insight 2010 Oncology - Page 2

3 Therapeutic Insight 2010 Oncology - Page 3

4 Cancer Vaccines: Will The Latest Batch of Vaccines Elicit a Positive Response (from the Agency, Oncologists, Patients & Payers)? Jeffrey M. Bockman, PhD Vice President, Defined Health

The information in this report has been obtained from what are

5 The information in this report has been obtained from what are believed to be reliable sources and has been verified whenever possible. Nevertheless, we cannot guarantee the information contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change. Oncology - Page 5

6 Key Themes Introduction The Immune System in Cancer Quick Historical Overview Key Lessons Learned Over Past Decade Clinical Stage Pipeline Case Studies Prostate Cancer Melanoma Non-Hodgkin s Lymphoma Non-Small Cell Lung Cancer Next Generation Approaches Patients, Payers & Pricing Closing Thoughts Oncology - Page 6

7 Introduction The Immune System in Cancer: Good Cop/Bad Cop

8 Role of Immune System in Cancer No directly expressed role of the immune system in the original i Hanahan and Weinberg schematic. And as we now know, the immune system has a role, for good (immune surveillance) and/or bad (immune co-opting), opting), and is involved in many of the key hallmarks of cancer, such as tissue invasion and metastases and angiogenesis. Cell, Vol. 100, 57 70, January 7, 2000, Oncology - Page 8

9 Cancer Immunology A Tug of War Oncology - Page 9 Nat Rev Cancer Jan;6(1):24-37

10 Cancer Immunology A Tug of War Oncology - Page 10 Nat Rev Cancer Jan;6(1):24-37

tumors by eliminating or suppressing viral infections, the timely elimination of pathogens and prompt resolution of inflammation can prevent the

of their expression of tumor-specific antigens or molecules induced by cellular stress.

before they can cause harm. This concept was first discussed over a century ago.

11 After Intrinsic Controls Fail (e.g., Tumor Suppressors), a Last Line of Defense The immune system has three primary roles in the prevention of tumors: protect the host from virus- induced tumors by eliminating or suppressing viral infections, the timely elimination of pathogens and prompt resolution of inflammation can prevent the establishment of an inflammatory environment conducive to tumorigenesis, the immune system can specifically identify and eliminate tumor cells on the basis of their expression of tumor-specific antigens or molecules induced by cellular stress. The third process is referred to as tumor immune surveillance, whereby the immune system identifies cancerous and/or precancerous cells and eliminates them before they can cause harm. This concept was first discussed over a century ago. Oncology - Page 11 Despite tumor immune surveillance, tumors do develop in the presence of a functioning immune system, and therefore the updated concept of tumor immunoediting is a more complete explanation for the role of the immune system in tumor development. The tumor immunoediting concept is divided into elimination, equilibrium, and escape, as shown schematically above. J Clin Invest. Vol117(5), pp (May 1, 2007)

12 Why Cancer Vaccines Need to Be Different Although vaccines have been quite successful for preventing infectious disease, therapeutic immunization in the setting of established, chronic disease, including both chronic infections and cancer, has been much less successful. This difference is related to multiple factors. First, the immune response to acute and chronic disease is quite different. Humoral immunity (the antibody response) is essential for controlling and eradicating acute infections, whereas cellular immunity (the T-cell response) is responsible for eradicating established cancers and chronically infected host cells. Second, the immune system recognizes acute infections as foreign in an environment with limited immunoregulatory pathways to limit the response. In contrast, it recognizes chronically infected or transformed cells in the context of established immunoregulatory pathways that maintain a complex relationship between the affected cell and the host. Third, the burden of transformed host cells frequently overwhelms the immune response, thereby limiting the clinical impact of immunization (especially for significant tumor burden as in metastatic disease. A final challenge for the development of both prophylactic and therapeutic cancer vaccines is that, in contrast to infectious disease, the key antigens that serve as targets for the immune response to the cancer remain largely unknown. Oncology - Page 12

13 Cancer Immunotherapy Tipping the Balance Oncology - Page 13 N Engl J Med (2008) 358:

New Discoveries All the Time First Tregs, now Bregs?

keeping autoimmunity in check, B regs also help

14 New Discoveries All the Time First Tregs, now Bregs?! In individuals with cancer it might be desirable to suppress B regs. Preliminary evidence suggests that as well as keeping autoimmunity in check, B regs also help dampen the immune system's natural ability to recognize and destroy tumors. Oncology - Page 14

15 Cancer Vaccines, Polymorphously Diverse* *Apologies to Woody Allen in Annie Hall Oncology - Page 15 Defined Health

16 Cancer Vaccinology 101: Basic Approaches Antigen/adjuvant vaccines Specific protein fragments or peptides stimulate the immune system to fight tumor cells. One or more cancer cell antigens are combined with a substance that causes an immune response, known as an adjuvant. Whole cell cancer vaccines Autologous or allogeneic whole cell vaccine preparations containing cancer antigens used to stimulate an immune response. Dendritic cell (DC) vaccines Autologous dendritic d cells (DCs) are obtained through h a leukapheresis. DCs are stimulated t with autologous or allogeneic cancer antigens and re-injected into the patient. Once injected, DC vaccines activate the immune system's T cells. Activation by DCs is expected to cause T cells to multiply and attack tumor cells expressing that antigen. Viral vectors and DNA vaccines Nucleic acid sequence of the tumor an autologous or allogeneic antigen is used to produce cancer antigen proteins. The DNA containing the gene for a specific cancer antigen is manipulated in the laboratory so that it will be taken up and processed by immune cells called antigen-presenting cells (APCs). The APC cells then display part of the antigen together with another molecule on the cell surface. The hope is that when these antigen-expressing g APC cells are injected into a person, the immune system will respond by attacking tumor cells containing the same antigen. Vector-based and DNA vaccines are attractive because they are easier to manufacture than some other vaccines. Idiotype vaccines Since antibodies are molecules containing protein and carbohydrate, they can themselves act as antigens and induce an antibody response. Antibodies produced by certain cancer cells (i.e., B-cell lymphomas and myelomas), called idiotype antibodies, are unique to each patient and can be used to trigger an immune response in a manner similar to antigen vaccines. Oncology - Page 16

17 To Go Specific Or Not To Go Specific One key conceptual (though preferably data-driven) decision is whether to go with one or several known tumor-specific antigens or take a more holistic, black box approach. Tumor-specific antigens (TSAs) versus tumor-associated antigens (TAAs) Expert Opin. Emerging Drugs (2008) 13(2): Oncology - Page 17

18 Immunotherapy and Chemotherapy a Practical Partnership * Data suggest that chemo may actually synergize with immunotherapy, especially if given afterwards. * Nature Reviews Cancer 5, (May 2005) Oncology - Page 18

19 Quick Historical Overview

20 Cancer Vaccines A Long History HPV vaccine Oncology - Page 20

In Memoriam, William Coley January 24, 1893, the first patient to receive Coley Vaccine was John Ficken, a sixteen-yearold boy with a massive abdominal tumor.

On each injection, there was a dramatic rise in body temperature and chills. The tumor gradually diminished in size.

21 In Memoriam, William Coley January 24, 1893, the first patient to receive Coley Vaccine was John Ficken, a sixteen-yearold boy with a massive abdominal tumor. Every few days, Coley injected his fluid directly into the tumor mass and produced the symptoms of an infectious disease, but did not produce the disease itself. On each injection, there was a dramatic rise in body temperature and chills. The tumor gradually diminished in size. By May 1893, after four months of intensive treatment, the tumor was a fifth its original i size. By August, the remains of the growth were barely perceptible. The boy received no further anticancer treatment and remained in good health until he died of a heart attack 26 years later. Coley published his results and by the turn of the century 42 physicians i from Europe and North America had reported cases of cancer that had been successfully treated with Coley Fluid. Coley Fluid became a mainstream cancer treatment and was successfully used in the treatment of most types of cancer. Until his death in 1936, Coley was the head of the bone tumor department at Memorial Hospital in New York City where he treated thousands of bone cancer patients with his fluid. In the United States the pharmaceutical company Parke Davis manufactured Coley Fluid until Even the Russian playwright Anton Chekhov, who was also a physician, noted the relationship between infections and anticancer effects in his diary in Oncology - Page 21

22 A Very Problematic Past Oncology - Page 22

23 Selected Success, Failures & Events Dec 2004: Serono/CancerVax Collaboration, Codevelopment, License, Co-Promotion for Canvaxin for melanoma - $290M BioCentury May 29, 2006 Oncology - Page 23

24 Selected Success, Failures & Events Sept 2007: Sanofi-Aventis hopped on the cancer vaccine bandwagon when it inked a $690 million licensing deal for Oxford BioMedica's TroVax. Oxford BioMedica is slated to get $39 million up front and $25 million payments as targets are hit. The deal includes additional payments if TroVax goes on to win approval for multiple indications--trovax is currently in Phase III for renal cancer, but the company is exploring its utility in a range of cancers including colorectal, lung, breast and prostate cancer April 2008: Pfizer will pay Avant Immunotherapeutics $40 million upfront and a $10 million equity stake in exchange for the worldwide rights to CDX-110 cancer vaccine for glioblastoma. CDX-110 is in a mid-stage trial designed to demonstrate its efficacy against EGFRvIII. Pfizer takes over all development activities and pays out a double-digit royalty to Avant on an approved therapy. Pfizer also gains exclusive rights to EGFRvIII vaccines for other uses. April 2008: Japan's Takeda Pharmaceutical will pay Cell Genesys $50 million upfront and up to $270 million more for hitting clinical and regulatory milestones in a marketing pact for its lead, late-stage prostate cancer therapy. Takeda gains global marketing rights while Cell Genesys retains copromotion rights in the U.S. for GVAX immunotherapy. Cell Genesys will also maintain responsibility for the worldwide manufacture and supply of the product. July 2008: Oxford BioMedica says that a late-stage trial of its lead drug therapy TroVax--a vaccine being studied for renal cancer--failed to hit its main objective. An advisory group said too many deaths in the vaccine trial would make it impossible for the therapy to achieve its primary endpoint. And that news sent the company's stock into a tailspin, with shares losing as much as three quarters of its value. Q4 2008: Dendreon Interim analysis showed 20% improvement in survival vs. predetermined endpoint of 22% Oncology - Page Defined Health; company press releases; FierceBiotech May 2008: San Diego-based Favrille has halted development of Specifid, a treatment for follicular B-cell non- Hodgkin's lymphoma. In a Phase III trial the drug failed to show a statistically significant improvement in the treatment arm, failing both primary and secondary endpoints July 2008: Biovest's BiovaxID mixed results. The vaccine met the primary endpoint of significantly improving disease-free survival in the multicenter, randomized, controlled Phase III trial in indolent follicular non-hodgkin's lymphoma (NHL). Patients receiving the vaccine had a median progression-free survival of 33.8 months compared to 21.2 months in the control arm (p = 0.047). While a "p" value of less than 0.05 normally would be sufficient, the "p" value specified in the trial's statistical analysis plan was August 22, 2008: NovaRx Corp. launched a pivotal study of therapeutic vaccine Lucanix (belagenpumatucel-l) in non-small-cell lung cancer (NSCLC) patients under a special protocol assessment approved early this year. Designated as STOP for its expected endpoints - survival, tumor-free survival, overall survival and progression-free survival - the trial is expected to enroll up to 700 patients with advanced-stage disease who have been treated with at least one prior platinum-based chemotherapy regimen. Patients will be randomized to receive Lucanix or placebo, administered intradermally, once-monthly for 18 months and then once at 21 months and at 24 months. August 27, 2008: Cell Genesys esys halts atsgvax trial. Cell Genesys esys stops trial of prostate cancer vaccine GVAX because of increased patient deaths. Oct 16 Development halted IDMC said less than 30 chance of hitting primary survival endpoint.

25 Selected Success, Failures & Events June, 2009: BioSante Pharmaceuticals is merging with Cell Genesys in an all-stock transaction valued at about $38 million. The deal will end Cell Genesys search for alternatives for the company, which began after its cancer immunotherapy failed in late-stage development and Takeda pulled out as partner for the program (Dec 2008). November, 2009: A vaccine consisting of gp100 protein, an antigen found on melanoma cells but not on healthy cells that stimulates T-cells to attack melanoma cells was shown in a phase 3 trial comparing to standard therapy with interleukin-2 that the vaccine more than doubled the response rate, and increased both progression-free and overall survival. March, 2010: EMD Serono announced that they have temporarily suspended the clinical ca program for Stimuvax (BLP25 liposome vaccine) in all recruiting studies worldwide as a result of a suspected unexpected serious adverse reaction (SUSAR). March, 2010: Oxford BioMedica is restarting clinical development of its TroVax cancer immunotherapy 12 months after the failure of a Phase III trial in renal cancer led partner Sanofi-Aventis SA to drop the product Aug & Oct 2008: Cell Genesys terminates VITAL-2 and VITAl-1 in, respectively, symptomatic and asymptomatic metastatic, hormonerefractory prostate cancer. VITAl-2 showed more deaths in the GVAX arm; VITAL-1 futility analysis by IDMC indicated low likelihood of meeting primary endpoint of improved survival. April 2009: Dendreon reports improved three-year survival in patients with advanced prostate cancer. Patients in the 512-subject study who received Provenge from Dendreon lived an average 4.1 months longer than those who received a placebo with no major adverse side effects (25.8 months vs months ). March, 2010: Novartis has put up $10 million and promised up to 700 million more in milestones in exchange for an option on Transgene's promising, late-stage cancer immunotherapy. France's Transgene will hold on to control of the upcoming Phase IIb/III pivotal trial of TG4010 that is slated to get under way by the end of this year after enrolling about a thousand patients with non-small cell lung cancer. April 29, 2010: FDA Approves a Cellular Immunotherapy for Men with Advanced Prostate Cancer The U.S. Food and Drug Administration today approved Provenge (sipuleucel-t), a new therapy for certain men with advanced prostate cancer that uses their own immune system to fight the disease. Provenge is indicated for the treatment of asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment June 17, 2010: EMD Serono (Merck KGaA) is resuming their Stimuvax (BLP25 liposome vaccine) clinical program in patients with non-small cell lung cancer (NSCLC) which includes the Phase III studies, START and INSPIRE. Defined Health; company press releases; FierceBiotech 2010 June, 2010: BMS drug ipilimumab improved median survival to 10 months vs. 6.4 months (P <.001) in advanced melanoma patients and nearly doubled the rates of survival at 12 months (46% vs 25%) and 24 months (24% vs 14%). Oncology - Page 25

26 Selected Success, Failures & Events: Sinking or Floating All Boats June, 2009: BioSante Pharmaceuticals is merging with Cell Genesys in an all-stock transaction valued at about $38 million. The deal will end Cell Genesys search for alternatives for the company, which began after its cancer immunotherapy failed in late-stage development and Takeda pulled out as partner for the program (Dec 2008). November, 2009: A vaccine consisting of gp100 protein, an antigen found on melanoma cells but not on healthy cells that stimulates T-cells to attack melanoma cells was shown in a phase 3 trial comparing to standard therapy with interleukin-2 that the vaccine more than doubled the response rate, and increased both progression-free and overall survival. March, 2010: EMD Serono announced that they have temporarily suspended the clinical ca program for Stimuvax (BLP25 liposome vaccine) in all recruiting studies worldwide as a result of a suspected unexpected serious adverse reaction (SUSAR). March, 2010: Oxford BioMedica is restarting clinical development of its TroVax cancer immunotherapy 12 months after the failure of a Phase III trial in renal cancer led partner Sanofi-Aventis SA to drop the product Aug & Oct 2008: Cell Genesys terminates VITAL-2 and VITAl-1 in, respectively, symptomatic and asymptomatic metastatic, hormonerefractory prostate cancer. VITAl-2 showed more deaths in the GVAX arm; VITAL-1 futility analysis by IDMC indicated low likelihood of meeting primary endpoint of improved survival. According to the Mentor Capital Cancer Immunotherapy Index, which tracks companies in the space, including Dendreon, on average, cancer immunotherapy stocks were up by 10 percent following FDA approval of Transgene's promising, late-stage cancer immunotherapy. Provenge. France's Transgene will hold on to control of the upcoming April 2009: Dendreon reports improved three-year survival in patients with advanced prostate cancer. Patients in the 512-subject study who received Provenge from Dendreon lived an average 4.1 months longer than those who received a placebo with no major adverse side effects (25.8 months vs months ). March, 2010: Novartis has put up $10 million and promised up to 700 million more in milestones in exchange for an option on Phase IIb/III pivotal trial of TG4010 that is slated to get under way by the end of this year after enrolling about a thousand patients with non-small cell lung cancer. April 29, 2010: FDA Approves a Cellular Immunotherapy for Men with Advanced Prostate Cancer The U.S. Food and Drug Administration today approved Provenge (sipuleucel-t), a new therapy for certain men with advanced prostate cancer that uses their own immune system to fight the disease. Provenge is indicated for the treatment of asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment June 17, 2010: EMD Serono (Merck KGaA) is resuming their Stimuvax (BLP25 liposome vaccine) clinical program in patients with non-small cell lung cancer (NSCLC) which includes the Phase III studies, START and INSPIRE. Defined Health; company press releases; FierceBiotech 2010 June, 2010: BMS drug ipilimumab improved median survival to 10 months vs. 6.4 months (P <.001) in advanced melanoma patients and nearly doubled the rates of survival at 12 months (46% vs 25%) and 24 months (24% vs 14%). Oncology - Page 26

27 Key Lessons Learned Over the Past Decade

28 Rationale for Vaccine Development To Date How are we deciding on which tumors to pursue and will these affect success rates? Some or all of the below have been or should have been used: prior evidence of immune responsiveness (e.g., melanoma, renal), relatively slow growing tumor (e.g., prostate, NHL), low disease burden (e.g., minimal residual disease), disease or recurrent disease can be diagnosed early (e.g., prostate, melanoma), surrogate marker for disease prognosis and outcome (e.g., PSA), limited quality options (standard of care therapy) that achieve long-lasting therapeutic effects. But, lest we be too critical, it is important to remember that those cancer vaccines in Phase III (that have been failing until Provenge) began clinical trials upwards of 10 or more years previous and hence are operating under old knowledge and assumptions. Oncology - Page 28

29 The Data Suggest Early Intervention is Ideal And yet Oncology - Page 29

Lessons from the Trials & Tribulations Failures had many

patients (due to cancer itself or heavily pre-treated

Tumor heterogeneity, with unpredictable and even rapid

Poor prognosis/short survival cancers (providing

30 Lessons from the Trials & Tribulations Failures had many root causes, but included: Targeting immunosuppressed patients (due to cancer itself or heavily pre-treated patients). Tumor heterogeneity, with unpredictable and even rapid clinical course (e.g., melanoma). Poor prognosis/short survival cancers (providing inadequate time for immune response). Single antigens are suspect. Decision error and context changes: Trial design (improper comparators), manufacturing issues, changes in standard of care, etc. Oncology - Page 30 Expert Rev Anticancer Ther Jan;9(1):67-74

31 Lessons from the Trials & Tribulations Immunosuppression and altered immune function in microenvironment by tumor Altered vasculature limiting immune cell access Immune tolerance (self antigens) Ongoing mutation & heterogeneity Oncology - Page 31

32 Clinical Stage Pipeline

33 Cancer Vaccine Pipeline Activity Cancer Vaccines and Immunomodulatory Products by Phase Phase III 14% Launched 13% Phase I 21% Phase II 52% Cancer Vaccines Autologous 29% Non-autologous 71% Adis R&D Insight Oncology - Page 33

auto vaccines Autologous Cancer Vaccines

Pharma 24% Non-pharma 97% Non-pharma 76%

34 Biotech Dominates Overall But Pharma s interest is growing and increases the more one moves away from complexity: proteins/antibodies > non-auto vaccines >>> auto vaccines Autologous Cancer Vaccines Pharma 3% Non-autologous Cancer Vaccines Pharma 24% Non-pharma 97% Non-pharma 76% Immunomodulatory Agents Pharma 33% Non-pharma 67% Adis R&D Insight Oncology - Page 34

35 Top Indications * This chart displays top 20 records Oncology - Page 35 Adis R&D Insight

36 Advanced Stage Vaccines, Nature Reviews, 2009 Oncology - Page 36 Nature Reviews Drug Discovery 8, (September 2009)

37 Advanced Stage Vaccines, Nature Reviews, 2005 Nature Rev. Drug Discov. 4, ; 2005 Oncology - Page 37

38 Advanced Stage Vaccines, Nature Reviews, 2005 Nature Rev. Drug Discov. 4, ; 2005 Oncology - Page 38

39 Advanced Stage Vaccines, Nature Reviews, 2005 Nature Rev. Drug Discov. 4, ; 2005 Oncology - Page 39

40 Case Studies

41 Prostate Cancer The Winner

42 What a Difference a Year Makes BNET Oncology - Page 42

43 April 29, 2010: Good News At Last for Cancer Vaccines Dendreon Oncology - Page 43

Why CRPC/HRPC Made Sense for a Vaccine From a clinical perspective, several aspects of prostate

allowing time for an activated immune system to mount an effective e response.

In addition, the prostate is a nonessential organ, so aside from the already anticipated safety of

44 Why CRPC/HRPC Made Sense for a Vaccine From a clinical perspective, several aspects of prostate cancer make it an ideal target for immune-based therapies: Prostate cancer is an indolent disease, allowing time for an activated immune system to mount an effective e response. Low tumor burden and serum PSA levels allow for the detection of minimal disease. In addition, the prostate is a nonessential organ, so aside from the already anticipated safety of vaccines, targeting prostate-specific tumor-associated antigens was expected to have little negative clinical ca effect. ec Oncology - Page 44

45 In 2004, When DH First Profiled Provenge, the Future Was Very Uncertain Oncology - Page 45

Provenge: A Cancer Vaccine Blockbuster on Par with Conventional

loaded basis (including all infusion fees, tests, supportive care

46 Provenge: A Cancer Vaccine Blockbuster on Par with Conventional Vaccine Blockbusters Adoption: will pricing, manufacturing, other logistics hinder the ramp? Provenge - EvaluatePharma Consensus Analyst Forecast - WW Sales $93,000 cost per course of therapy. Some have tried to justify the price as similar to Taxotere onafully loaded basis (including all infusion fees, tests, supportive care drugs) but $93K is not the fully loaded cost for administering Provenge. Prevnar - EvaluatePharma Consensus Analyst Forecast - WW Sales On the other hand, in relation to Taxotere s benefit in overall survival, Provenge has a two-fold advantage 4.1 months for Provenge versus 2.4 months for Taxotere. Oncology - Page 46

47 Them s Fightin Words! Oncology - Page 47

48 CRPC/HRPC Gets Another Approval And It is an Intensely Competitive Space! Prostate t Cancer, Clinciali l Prostate Cancer, Advanced/HRPC Adis R&D Insight Oncology - Page 48

49 Melanoma The Runner-Up & Poster Child

Longstanding Efforts Melanoma has been one of

around 15% of patients) to immunotherapy

1992 Jan 15;148(2):638-43 Shared human melanoma

Recognition by tumorinfiltrating lymphocytes in

Kawakami Y, Zakut R, Topalian SL, Stötter H,

50 Longstanding Efforts Melanoma has been one of the few cancers responsive (albeit in only around 15% of patients) to immunotherapy (interferon). J Immunol Jan 15;148(2): Shared human melanoma antigens. Recognition by tumorinfiltrating lymphocytes in HLA-A2.1-transfected melanomas. Kawakami Y, Zakut R, Topalian SL, Stötter H, Rosenberg SA. Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD Defined Health Oncology - Page 50

Ipilimumab: Looking Good Ipilimumab is a fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4).

4 months for patients receiving the vaccine alone (P <.001).

to the efficacy over ipilimumab (and in fact appeared to attenuate the response).

51 Ipilimumab: Looking Good Ipilimumab is a fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4). Patients receiving ipilimumab (Bristol- Myers Squibb) plus a peptide vaccine had a median survival of 10 months, compared with 6.4 months for patients receiving the vaccine alone (P <.001). Ipilimumab also showed, compared with the peptide vaccine, a near doubling of the rates of survival at 12 months (46% vs. 25%) and 24 months (24% vs. 14%). But while the data is another coup for monoclonals, it is not good news for the single antigen vaccine approach as gp100 did not add to the efficacy over ipilimumab (and in fact appeared to attenuate the response). Gp100 is strongly expressed in more than 90% of melanoma tumors, regardless of stage. In a randomized, phase 3 study involving patients with metastatic melanoma, a significant improvement in PFS and RR, and a non- significant improvement in overall survival, were seen with gp100-plus-high-dose interleukin-2, as compared with interleukin-2 alone. Oncology - Page 51

52 Ipilimumab Was Highlighted by DH in 2008 Oncology - Page 52

A Tweak on the Vaccines: Oncolytic Viruses OncoVEX-GM-CSF functions in a dual manner, with the engineered virus: 1) replicating selectively in tumors, leading to direct cell killing; and 2) inducing

Both local and distant modes of action have been validated in the clinic, where multiple patients with metastatic disease progressing at enrollment have become free of disease.

The median overall survival was greater than sixteen months for all patients. In those achieving PR, CR or surgical complete response (scr) (15) the one-year survival rate was 93%.

53 A Tweak on the Vaccines: Oncolytic Viruses OncoVEX-GM-CSF functions in a dual manner, with the engineered virus: 1) replicating selectively in tumors, leading to direct cell killing; and 2) inducing a powerful immune response via cell lysis and stimulation with GM- CSF. Both local and distant modes of action have been validated in the clinic, where multiple patients with metastatic disease progressing at enrollment have become free of disease. In a Phase II trial, 20% of patients t achieved a CR without t additional surgery and 26% had no evidence of disease with three patients getting surgery. The median overall survival was greater than sixteen months for all patients. In those achieving PR, CR or surgical complete response (scr) (15) the one-year survival rate was 93%. OncoVex is generally well tolerated. In the Phase II 85% of patients had AEs related to treatment, all of which were grade 1-2. The AEs seen in 33 patients were associated with a mild influenza-like like syndrome (fever [52%], chills [48%], fatigue/malaise [32%], nausea [30%], vomiting [20%], and headache [20%]). Grade 3 AEs were infrequent with 6 patients experiencing pain (may be disease related) and 4 each of fatigue and dyspnea. Expert Opin. Biol. Ther. (2010) 10(7): ; Journal of Clinical Oncology, Vol 27, 2009: pp ; ASCO, 2009 Oncology - Page 53

54 Competition in the Space? Or Combinations? Inhibitors of mutant BRAF (V600E) are another very promising MOA for melanoma (and selected other tumors). Cancer Research 70(13); OnlineFirst 1 7, June 15, 2010 Oncology - Page 54

but patient base is small (unless one can push survival

Get all the Stage III/IV patients from a given year at a

Defined Health Assumption Table Recent Melanoma Forecast

55 How Big Is the Opportunity? Unmet need is high, pricing set by other monoclonals, but patient base is small (unless one can push survival and duration of therapy). Get all the Stage III/IV patients from a given year at a six figure repriceand you have eaus drug of around $500M. Defined Health Assumption Table Recent Melanoma Forecast EvaluatePharma Consensus Analyst Forecasts for Ipilimumab Analyst Forecast for Synta s Elesclomol Oncology - Page 55

56 Non-Hodgkin s Lymphoma The Ideal?

The Unmet Need Is Moderate, But the Disease Is Well Suited In

multiple myeloma (MM) were the clearest targets for an Id-based

In MM, the antigen abundantly circulates in the bloodstream and

presents the antigen on the surface of its cells and the Ig has

Despite the logistics of obtaining the antigen, the generally

57 The Unmet Need Is Moderate, But the Disease Is Well Suited In Its Clinical Course From the start, follicular NHL (FL) and multiple myeloma (MM) were the clearest targets for an Id-based vaccine strategy. In MM, the antigen abundantly circulates in the bloodstream and therefore is very easily obtainable, whereas FL consistently presents the antigen on the surface of its cells and the Ig has to be isolated from the tumor cells themselves. Despite the logistics of obtaining the antigen, the generally better prognosis of these patients have made FL very suitable for clinical research into anti- Id vaccines. Oncology - Page 57 Defined Health

58 .And an Anti-Id Is a Fascinating Approach, With a Promising Pedigree Anti-Id vaccines: Individualizing and targeting therapy long before the idea was broadly in vogue. Oncology - Page 58

Trial Outcomes Have Been Modest at Best Several studies have

vaccination and two clinical trials have shown the clinical

One study has demonstrated clinical benefit associated with

However, three randomized clinical trials have recently failed

59 Trial Outcomes Have Been Modest at Best Several studies have confirmed the biological efficacy of soluble protein idiotypic vaccination and two clinical trials have shown the clinical efficacy of this procedure. One study has demonstrated clinical benefit associated with idiotypic vaccination. However, three randomized clinical trials have recently failed to achieve their main end points for reasons that might be unrelated to the vaccine. vaccine Nature Reviews Cancer 9, , 681 Sept 2009 Oncology - Page 59

Positioning in the Face of Entrenched Rituxan

entrenchment of Rituxan: In patients not

aband chemotherapy, rituximab maintenance was

50% in patients with newly diagnosed follicular

60 Positioning in the Face of Entrenched Rituxan Where can a vaccine be positioned, given the entrenchment of Rituxan: In patients not receiving maintenance In combination In partial responders and non-responders? After front-line etherapy eapywith rituximab aband chemotherapy, rituximab maintenance was found to reduce the risk of disease recurrence by 50% in patients with newly diagnosed follicular lymphoma Roche press releases, Clinical Care Options, Defined Health, ASCO 2010 Oncology - Page 60

61 Where Does the Vaccine Penetrate? Where can a vaccine be positioned, given the entrenchment of Rituxan: In patients not receiving maintenance In combination In partial responders and non-responders? Oncology - Page 61

62 Non-Small Cell Lung Cancer The Big Bet

63 A Tough Cancer to Target by Immunotherapy NSCLC is classically considered a poorly immunogenic tumor. Downregulation of MHC molecules. l Secretion of NKG2D, TGFB, IL-10 and other soluble factors that can induce anergy/tolerance and increase T-reg activity that can limit expansion (promising and proliferation) of effector cells like CTLs. Oncology - Page 63 Expert Opin Emerg Drugs 2006 Sep;11(3):445-59

64 Taking On the Challenge of an Early Stage Disease Trial A Big Pharma Play GSK s MAGRIT (MAGE-A3 as Adjuvant Non- Small Cell Lung Cancer Immunotherapy): World-wide Phase III trial A large scale worldwide Phase III study investigating efficacy and safety of MAGE-A3 antigen (plus a multi-component adjuvant) in MAGE-A3-positive A3 NSCLC patients. Positive phase II data: 25% reduction in the relative cancer recurrence following surgery at 44 months. However, no significant effect on OS or PFS Well-tolerated with excellent compliance Preventing cancer relapse, when given after tumor resection in patients with MAGE-A3-positive stages IB, II and IIIA NSCLC. 2,300 patients, randomized, double-blind, placebo-controlled trial. Treatment will be administered as 13 intramuscular a injections over 27 months. Patients will be followed up every six months for five years, and then annually until 10 years from the start of treatment. One third of NSCLC tumors are MAGE-A3 positive. Surgical resection is the cornerstone of treatment for patients with early NSCLC, but relapse is high with 50-60% resected still dying of this disease. Oncology - Page 64 Expert Opin. Biol. Ther. (2010) 10(7):

Highlighting the Unexpected Stimuvax(R) is a synthetic MUC1 peptide vaccine. Stimuvax(R) incorporates a 25-amino acid sequence of the MUC1 cancer mucin, encapsulated in a liposomal delivery system.

first-line standard chemotherapy with or without radiation therapy.

65 Highlighting the Unexpected Stimuvax(R) is a synthetic MUC1 peptide vaccine. Stimuvax(R) incorporates a 25-amino acid sequence of the MUC1 cancer mucin, encapsulated in a liposomal delivery system. Phase IIb data, April 2006: The controlled, open-label Phase IIb trial enrolled 171 men and women with NSCLC whose disease was stable or who had responded to treatment following completion of their first-line standard chemotherapy with or without radiation therapy. Patients were randomized to either Stimuvax(R) plus best supportive care or to best supportive care alone The analysis confirms a median survival in Stage IIIB patients on vaccine being 30.6 months, while Stage IIIB patients on the control had a median survival of 13.3 months. Program was suspended in March of this year(2010) due to occurrence of encephalitis in the myeloma trial. Company press releases, FierceBiotech Oncology - Page 65

NSCLC Vaccine Space Heats Up TG4010 is based on a recombinant vaccinia virus expressing the MUC1 antigen and the human cytokine, Interleukin-2 (IL2).

non-small cell lung cancer (NSCLC), at 21 months of median follow up confirms a statistically-significant 6-month increase in median survival (17.1 months in the experimental arm versus 11.

66 NSCLC Vaccine Space Heats Up TG4010 is based on a recombinant vaccinia virus expressing the MUC1 antigen and the human cytokine, Interleukin-2 (IL2). Novartis offers $955M deal to snare Transgene drug option February, 2009: The data, from the ongoing controlled Phase IIb clinical as an adjunct to first line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC), at 21 months of median follow up confirms a statistically-significant 6-month increase in median survival (17.1 months in the experimental arm versus 11.3 months in the control arm) in patients with normal levels of activated Natural Killer cells at baseline. 75% of the patients in the trial. A subpopulation identified by Transgene s biomarker program based on flow cytometry. Company press releases, FierceBiotech Oncology - Page 66

67 Selected Other Approaches

68 Multi-Component Protein Product: Non-Autologous, Cell-Derived IRX-2 is the Product of Optimally Stimulated T cells: Active cytokines are IL-1, IL-2, IL-6, IL-8, GM-CSF, TNF- & IFN- IRX-2 Stimulates t Rituxan-Mediated t d ADCC Company non-confidential documents Oncology - Page 68

composed of a mixture of irradiated, allogeneic,

modified to add α(1,3)-galactosyl (αgal) residues

patient's immune system into thinking a tumor is

species while also retraining the immune system

69 Exploiting Xenotransplantion HyperAcute immunotherapies are off-the-shelf products composed of a mixture of irradiated, allogeneic, whole cancer cells that have been genetically modified to add α(1,3)-galactosyl (αgal) residues to cell-surface lipids and proteins. The cellular components of HyperAcute immunotherapy are designed to essentially trick a patient's immune system into thinking a tumor is similar to an organ transplanted from a different species while also retraining the immune system to attack the patient's cancer cells. Oncology - Page 69 Company non-confidential documents

70 Evolving and Combining Strategies Oncology - Page 70.Expert Rev Vaccines 2009 May;8(5):567-76

Epigenetic Modulators & Cancer Vaccines Decitabine may enhance the effect of CG antigen-tumor vaccines by increasing tumor cell expression of CG antigens and MHC molecules for antigen presentation.

71 Epigenetic Modulators & Cancer Vaccines Decitabine may enhance the effect of CG antigen-tumor vaccines by increasing tumor cell expression of CG antigens and MHC molecules for antigen presentation. In addition, Decitabine increases expression of tumor suppressor genes and results in reduced cell proliferation and increased apoptosis and differentiation. Expert Opin. Biol. Ther. (2010) 10(7): Oncology - Page 71

72 Patients, Payers & Pricing

73 FDA Office of Cellular, Tissue, and Gene Therapy (OCTGT): Cellular therapies Cancer vaccines Immunotherapy Gene therapies Tissue and tissue based products Xenotransplantation t ti products Devices used for cells/tissues Similarities between Tumor Vaccines and Drugs Need to be internally controlled (randomized) Similar objectives: improved survival, disease- free survival, or time to progression Evaluated in context of available therapy and standard of care Regulatory consistency (CBER/CDER) Statistical considerations primary analysis of Intent to Treat (ITT) population Differences between Cancer Vaccines and Drugs Minimal residual disease patients may be more likely to benefit from vaccine Blinding may be more feasible Anti-tumor activity may occur without to tumor shrinkage Treatment effects may be delayed Oncology - Page 73 Based on FDA and Cancer Vaccine Development, Celia Witten, Ph.D., M.D., Office Director, Office of Cellular, Tissue and GeneTherapy CBER/FDA, ASCO 2008

74 Patient Advocacy Oncology - Page 74

75 Pricing Example: Pricing of Provenge is not glaringly out of whack Oncology - Page 75 Journal of Clinical Oncology, Vol 27, No 13 (May 1), 2009: pp ; Journal of Clinical Oncology, Vol 25, No 2 (January 10), 2007: pp

76 & Payers Going forward, reimbursement is another challenge. About three-quarters of the target population are Medicare-eligible. Dendreon missed the January deadline to approve for a product-specific J-code, but anticipates a temporary code, and until CMS assigns a permanent code, coverage and payment will be up to local Medicare contractors. Provenge's side effect profile is of course much more favorable than chemotherapy a value proposition frequently cited for cancer vaccines and this could influence payers looking at overall costs of administering and managing patients. Journal of Clinical Oncology, Vol 27, No 13 (May 1), 2009: pp ; Journal of Clinical Oncology, Vol 25, No 2 (January 10), 2007: pp Oncology - Page 76

77 Closing Thoughts

78 Who Will Step Up Now? Who will fund discovery? Do VC have the stomach for novel platforms? Who will fund the clinical i l trials, especially as science and clinical i l data move vaccines to earlier, adjuvant use? Will Pharma drive this back towards their comfort zone of large, long outcomes trials? Will all cancer vaccines be blockbusters? Bear in mind that some of these vaccines, especially tumor-specific and tumorassociated antigen-based ones, can have applicability across multiple tumors and hence are neither patient-specific not tumor-specific and, if they work, could have broad blockbuster potential like Avastin or Erbitux. Many improvements remain to be pursued in the types of antigen(s) and their context: auto versus allo, single versus multiple, their presentation to APCs, costimulatory and anti-suppressive combinations. Plus the low-hanging improvements of increased dosing frequency and timing relative to standard treatment modalities, dosage and duration, priming versus boosting, early disease intervention and adjuvant usage versus metastatic, etc. Oncology - Page 78

79 Therapeutic Insight 2010 Oncology - Page 79

80 Therapeutic Insight 2010 Oncology - Page 80

GRNVAC DCVax-Brain AGS Glionix CYT004-MelQbG CDX-110 (PF ) GI TABLE 23 OCCURRENCE OF

GRNVAC DCVax-Brain AGS Glionix CYT004-MelQbG CDX-110 (PF ) GI TABLE 23 OCCURRENCE OF CHAPTER ONE: INTRODUCTION.1 STUDY GOALS AND OBJECTIVES... 1 REASONS FOR DOING THIS STUDY... 1 INTENDED AUDIENCE... 1 SCOPE OF REPORT... 2 METHODOLOGY... 2 INFORMATION SOURCES... 3 AUTHOR S CREDENTIALS...