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From Pariah to Darling: Biopharma FinallyFrom Pariah to Darling: Biopharma Finally Courts Immunotherapies

Jeffrey M. Bockman, PhD

Vice President

Defined Health

Insight Series Executive BriefingInsight Series Executive Briefing

Dec 5, 2013

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contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Cancer Progress, and though current as of the date of this report, are subject to change. The opinions and information set forth herein are expressed solely for the benefit of the addressee and only for the purpose(s) for which the report was produced. Without the prior written consent of Cancer Progress, this report may not be relied on in whole or in part for any other purpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law.This report may contain information provided by third parties such as Thomson Reuters, WoltersKluwer, EvaluatePharma, Datamonitor, Informa Healthcare, IMS Health and others with a proprietary interest in the data provided herein. Please note that you are not permitted to redistribute any such third party information without consent from the originator company.y p y g p y

Cancer Progress © 2013


Disclaimer (Cont.) - Discriminating Self From Non-Self

© Defined Health, 2013© Defined Health, 20134

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Defined Health

5

Setting the Context: Why is Immunotherapy So Appealing?


For the Most Part, We Are Not Curing Cancer…Yet

With the Caveat That Such Comparisons Are Necessarily Based on Median OS!


Clinical Cancer Res Vol 16, pp. 5951-5955, 2010

7

Challenges of Conventional Targeted Therapy: Inherent Heterogeneity and DiversityInherent Heterogeneity and Diversity• Leading Oncologists are increasingly worried about the reductionist approach,

given the complexities of the many aberrations and the heterogeneity and plasticity of tumors.p y


N Engl J Med Vol 366(10):883-892, March 8, 2012

Immunotherapy is Viewed by Many Oncologists as a Broadly Acting Approach That Frees Therapies From T N FToo Narrow a Focus


Challenges of Conventional Targeted Therapy: Plasticity, Evolution & Acquisition of Resistance• Acquired resistance: activation of survival

signaling pathways and the inactivation of downstream death signaling pathways; epigenetic tumor microenvironment, EMT; and cancer stem cells, which are intrinsically highly resistant to many therapeutic approaches.


Nature Reviews Cancer 6, 924-935; Nature Reviews Cancer 13, 714–726 (September 2013)

Immunotherapy is Viewed by Many Oncologists as a Broadly Acting Approach That Frees Therapies From T N FToo Narrow a Focus

• Does immunotherapy allow us to move past driver mutations?

Association between immunologic diversity of transferred T cells and improved clinical outcomes from adoptive cell transfer (ACT) in patients with metastatic melanoma. Autologous unfractionated tumor-infiltrating lymphocytes (TILs) infused in conjunction with systemic interleukin 2 yielded objective responses in 34% to 50% of patients. Biomarker studies correlating clinical responses with in vitro TIL properties of tumor-specific cytolysis and cytokine secretion led to development of more complex culture methods to deliberately select tumor-reactive subcultures for therapy. Combined with more intense chemoradiotherapy preconditioning regimensmore intense chemoradiotherapy preconditioning regimens, objective clinical response rates of 49% to 72% were achieved with selected TILs. In contrast, lower response rates were observed in ACT studies using T-cell receptor (TCR) –transduced T cells (mixtures of CD4and CD8cells) or monoclonal CD4or CD8T-cell cultures specific for single melanoma antigen (MART-1/Melan-A, gp100, NY-ESO-1). Outgrowth of antigen-loss tumor / , gp , ) g gvariants in these patients, reflect-ing successful antigen targeting, also indicated capacity of rapidly adaptable tumor cells to evade narrowly focused therapies. Although these summarizedresults are gleaned from nonrandomized ACT studies, there seems to be association between immunologic diversity of infused cells and likelihood of clinical activity.


J Clin Oncol 29:4828-4836, Dec 2011

“The Times They Are aThe Times They Are a Changin’”-Bob Dylan


The Buzz at ASCO the Past Two Years Has Really Been ImmunotherapyImmunotherapy

S i i h


Source: FierceBiotech

And Wall Street is Apparently No Longer Skeptical

Source: Citibank


New Companies Are Starting Up Seemingly Daily


Quick Historical OverviewQuick Historical Overview


A Very Problematic Past


Selected Successes, Failures & Events

Dec 2004: Serono/CancerVaxCollaboration, Codevelopment, License, Co-Promotion for Canvaxin for melanoma - $290M


BioCentury May 29, 2006

18

Selected Successes, Failures & Events

2006April 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

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

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

pays out a double-digit royalty to Avant on an approved therapy. Pfizer also gains exclusive rights to EGFRvIII vaccines for other uses.

cancer, but the company is exploring its utility in a range of cancers including colorectal, lung, breast and prostate cancer.

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

rights while Cell Genesys retains co-promotion rights in the U.S. for GVAX immunotherapy. Cell Genesys will also maintain responsibility for the worldwide manufacture and supply of the product.

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

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.

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 0.01.

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.

2008Q4 2008: Dendreon – Interim analysis showed 20% improvement in survival vs. predetermined endpoint of 22% August 27, 2008: Cell Genesys halts GVAX trial. Cell Genesys stops trial of

p pp y yDesignated 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.


Defined Health; company press releases; FierceBiotech

g , y y pprostate cancer vaccine GVAX because of increased patient deaths. Oct 16– Development halted – IDMC said less than 30 chance of hitting primary survival endpoint.

19

Cancer Vaccines: Selected Success, Failures & Deals

2008

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

Aug & Oct 2008: Cell Genesys terminates VITAL-2 and VITAl-1 in , respectively, symptomatic and asymptomatic metastatic, hormone-refractory 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.

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

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. 21.7 months ).

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).

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.

pcomparing 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 d d th li i l f Sti ® (BLP25 li

April 29, 2010: FDA Approves a Cellular Immunotherapy for Men with Advanced Prostate CancerThe 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

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

suspended the clinical program for Stimuvax® (BLP25 liposome vaccine) in all recruiting studies worldwide as a result of a suspected unexpected serious adverse reaction (SUSAR).

symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment

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%)

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.

drop the product.


2010Defined Health; company press releases; FierceBiotech

and nearly doubled the rates of survival at 12 months (46% vs 25%) and 24 months (24% vs 14%).

20

Cancer Vaccines: Selected Success, Failures & Deals

2011

Amgen to Acquire BioVex for Up To $1B, to Obtain Cancer-Killing Virus TherapyAmgen has agreed to pay $425 million in cash to license a promising cancer

March 25, 2011: FDA Approves IpilumimabThe FDA has approved Bristol-Myers Squibb's Yervoy (ipilimumab), Ipilimumab is

vaccine from Woburn, MA-based BioVex, with another $575 million in milestones. OncoVex has a dual mechanism. It's an oncolytic--using a cancer-destroying virus modified from a cold sore virus designed to replicate in solid tumors, triggering cancer cell death--that also spurs the immune system to go in and tackle the cancer as well. OncoVEXGM-CSF is currently being evaluated in a Phase 3 multi-national study in metastatic melanoma and a Phase 3 study in squamous cell carcinoma of the head and neck.

pp y q y ( p ), pa fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on cytotoxic T lymphocytes that is plays a critical role in regulating natural immune responses. Ipilimumab is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells. According to Bloomberg, the groundbreaking treatment will cost $30,000 per dose and up to $120,000 for four courses of treatment. The drug could hit peak sales of $1.7 billion per year by 2015 according to analysts.

2012

2013


Defined Health; company press releases; FierceBiotech

21

Advanced Stage Vaccines, Nature Reviews, 2005Nature Reviews, 2005


Nature Rev. Drug Discov. 4, 623–624; 2005

22

Advanced Stage Vaccines, Nature Reviews, 2009


Nature Reviews Drug Discovery 8, 685-686 (September 2009)

23

THE PHASE III CLUB*THE PHASE III CLUB

*With a few exceptions


Yes, My Old Schematic Again…


Defined Health

Vaccines & Related Immunotherapies Represent an Increasingly Meaningful Portion of the Clinical PipelineIncreasingly Meaningful Portion of the Clinical Pipeline

Top 20 MOAs of the ~100 Phase III Oncology Compounds in the US20% are Immunotherapies of Some Kind

Source: Adis R&D Insight


Phase III Immunotherapies – Many Flavors


Phase III Immunotherapies

MOA/Platform Drug Company Phase III Cancer Comments

Autologous DCs plus total autologous tumor RNA - Arcelis™ Technology

• Phase 2 clinical trial showing that treatment with AGS-003, the company´s lead product candidate in combination with sunitinib induced memory T celltumor RNA Arcelis Technology

Platform - Arcelis is a fully personalized immunotherapy technology that captures mutated and variant antigens that are specific to each patient´s disease. It is designed to overcome immunosuppression by producing a durable memory T cell response without adjuvants that may

AGS 003 Argos Renal cell

product candidate, in combination with sunitinib, induced memory T cell responses in metastatic renal cell cancer (mRCC) patients that correlated with statistical significance to overall survival (OS).

• Phase III - The randomized, multicenter, open-label ADAPT clinical trial is designed to examine the potential for AGS-003 plus standard targeted drug therapy to extend OS versus standard therapy alone in newly diagnosed mRCCpatients. Argos is using BTSVQ to analyze multi-color flow cytometry data in the ADAPT trial, which will enroll a total of 450 patients in approximately 130 global sitesresponse without adjuvants that may

be associated with toxicity. global sites.

• Fast Track

HyperAcute vaccine technology - The vaccine is comprised of modified

• The open-label, two-armed, multi-center study evaluated algenpantucel-L plus standard-of-care adjuvant therapy (gemcitabine and 5-FU-modulated radiation therapy) in 69 patients with resected pancreatic cancer. The study defined disease-free survival at one year as its primary endpoint, and overall survival, safety and immunological correlative analysis as the secondary endpoints. The data from the study showed that one year disease-free survival was 62 percent while overall survival was 86 percent Data presented on elevatedvaccine is comprised of modified

allogeneic pancreatic cancer cells that contain the mouse α(1,3)-galactosyltransferase gene which enzyme alpha-galactosidase adds alpha-gal sugars to proteins and lipids in the cell membranes of lower mammals. Humans do not express these sugar moieties and therefore

Algenpantucel-L (HyperAcutePancreas)

Newlink Genetics Pancreatic cancer

percent, while overall survival was 86 percent. Data presented on elevated levels of three separate biomarkers (antibodies to mesothelin, CEA and/or alpha-gal) correlated with a statistically significant improvement in overall survival. Specifically, the data showed median overall survival was 42 months in patients with elevated levels of anti-mesothelin antibodies versus 20 months in patients without elevated levels. Moreover, the subset of patients that showed increases in two or more of the aforementioned biomarkers had median overall survival greater than 42 months (median overall survival not reached for this subset of patients)these sugar moieties and therefore

develop a strong immunological response to cells expressing these modifications-

reached for this subset of patients).• Phase 3 trial (IMPRESS: "Immunotherapy for Pancreatic Resectable cancer

Survival Study") under a Special Protocol Assessment with the U.S. Food and Drug Administration. This trial involves up to 722 patients with surgically resected pancreatic cancer. Algenpantucel-L is also being tested in a second Phase 3 study (PILLAR: "Pancreatic Immunotherapy with algenpantucel-L for Locally Advanced non-Resectable"), involving patients with locally advanced pancreatic cancer.

• Fast Track Orphan (EU)



Fast Track, Orphan (EU)



• Phase II trial in patients with NSCLC expressing the MAGE A3 antigen showed that patients treated with GSK 1572932A had a 27% reduction in the relative risk of cancer recurrence following surgery, compared with those given a placebo. The double-blind study randomized 182 patients with completely

Recombinant MAGE A3 protein combined with GSK's proprietary astuprotimut-R GSK NSCLC

resected stage IB or II NSCLC to receive either GSK 1572932A or placebo as adjuvant therapy. A retrospective study of 159 tumor biopsies revealed two immune-related gene expression signatures that are potentially predictive of clinical response. Stage IB patients with tumors not presenting one of the identified prognostic gene profiles, had a <3% risk of relapsing after surgery. Another gene signature was also identified; selection of patients with this signature resulted in a 2-fold increase in the clinical efficacy of MAGE-A3

• Phase III DERMA trial was not met. The trial is evaluating the benefit of adjuvant system (GSK 1203486A, GSK 1572932A) or QS-21 Stimulon

astuprotimut R GSK NSCLC astuprotimut-R (GSK 2132231A) in preventing disease relapse in patients with MAGE-A3-positive melanoma who have had their tumors removed (NCT00796445). The first co-primary endpoint was to evaluate disease-free survival (DFS) in the overall population. Results showed that there was no improvement in DFS with astuprotimut-R, compared with placebo. However, the Independent Data Monitoring Committee unanimously recommended that the trial continue as planned to allow evaluation of the second co-primary endpoint, which is DFS in the gene signature-positive sub-population.

• Phase III MAGRIT trial of astuprotimut-R (GSK 1572932A) as an adjuvant therapy in patients with stage IB, II, or IIIA resectable NSCLC whose tumors express the MAGE-A3 antigen (NCT00480025). The trial intends to enrolapproximately 2270 patients worldwide.

Gene Mediated Cytotoxic

• Phase II trial involving 60 patients with prostate cancer, gene therapy was administered through intratumoral injection of 5 x 1011 particles of an adenoviral vector expressing herpes simplex virus thymidine kinase (AdV-tk), which was followed by oral administration of the prodrug valacyclovir for 14

Immunotherapy (GMCI) involves the local/intratumoral delivery of an adenoviral vector with the Herpes thymidine kinase gene (AdV-tk) in combination with radiation therapy, and an oral anti-herpetic prodrug(ganciclovir or valacyclovir)

ProstAtak Advantagene Prostate cancer

days. Intensity modulated radiation therapy (IMRT) was used for all patients. Over 60 patients have been treated with at least 20 patients being followed for 2 years after treatment. Patients were divided into 3 arms, with patients in Arm A (low risk), who began radiation therapy within 48-72 hours after receiving AdV-tk, showing a transient rise in prostate-specific antigen (PSA) at two weeks which was significantly greater than in the control group treated with radiation alone. At 27 months follow up, all 8 patients in Arm A had a PSA <= 1, compared with 2 of 4 control patients. In Arm A and B, over 80% of


Source: Adis R&D Insightpatients had negative biopsies by 5-7 months and 100% by 21 months

• Fast TrackSource: Adis R&D Insight



• Pivotal phase III trial, the primary endpoint of prolonging disease-free survival was achieved in patients who received at least one injection of dasiprotimut T compared with those in the control group. In this study, patients with indolent

Lymphoma-associated, idiotypeimmunoglobulin antigen conjugated to keyhole limpet haemocyanin (KLH) and adjuvanted with granulocyte-macrophage colony-stimulating factor (GM-CSF)

dasiprotimut T or BiovaxID Biovest fNHL

p g p y, pfollicular lymphoma who had a complete response to prednisone, doxorubicin, cyclophosphamide and etoposide (PACE) were randomized to receive the B-cell lymphoma vaccine or a time-matched series of keyhole limpet haemocyanin (KLH) injections (control arm). Final results in patients who maintained complete response to chemotherapy for >=6 months showed that the median duration of complete remission in the B-cell lymphoma vaccine treatment arm was 44.2 months, with a median duration of cancer-free survival of 30.6 months. This represented a clinically and statistically significant p y y gresult compared with the control arm (p=0.045). The vaccine prolonged cancer-free survival by 13.6 months, with a median follow-up of 56.6 months. At 36 months, 61% of patients receiving the vaccine were cancer-free, compared with 37% in the control .

• Pivotal phase 3 trial. It has orphan drug designation in the US and Europe for the treatment of RCC in HLA-A*02 positive patients. The phase 3 trial is designed to evaluate overall survival with IMA901 in combination with sunitinib (Sutent®, Pfizer), the current standard first-line therapy, compared

10 tumor-associated peptides (TUMAPs) that are found in the majority of patients with renal cancer -XPRESIDENT[trademark] technology platform, which combines mass spectrometry, genomics, biochemistry and immunology to identify TUMAPs f i h t t i l

IMA901 immatics Renal cancer

( , ), py, pwith sunitinib alone in patients with metastatic and/ or locally advanced RCC. The trial has completed inclusion of 339 patients at sites in the US and Europe. Interim overall survival results are expected in 2014, with final data in 2015.

• IMA 901 plus leukine was associated with a disease control rate (primary endpoint) of between 12% and 31% in patients with renal cancer, in a phase II study. Patients receiving a single infusion of cyclophosphamide showed a trend towards increased overall survival and a significant decrease of FoxP3-positive regulatory T-cells (p = 0.014), particularly in Ki67+ T-cells (p = 0.006). MDSC from primary human tumor material g y (p ), p y (p )levels were significantly increased in patient samples as compared to matched healthy donors (p < 0.0001 to p = 0.0043). Two populations (CD14+ HLA-DR-and CD14- CD11b+ CD15+) were negatively correlated with survival (p = 0.033 and p = 0.005).

• Orphan Status (US/EU)





• Estimated overall survival rate of 81 percent at one year across all MK-3475 monotherapy doses evaluated. The objective response rate (patients who had

Humanized monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein

lambrolizumab Merck Malignant melanoma

o ot e apy doses e a uated e object e espo se ate (pat e ts o adeither a complete or partial response) across all doses improved with longer duration of follow-up; at the time of this analysis, the objective response rate was 41 percent (9 percent complete response rate), as evaluated by a blinded central review committee using RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

• In interim results from 135 patients with advanced (inoperable and metastatic) melanoma in a phase Ib trial (P07990), the overall response rate for treatment with lambrolizumab was 38% as measured by RECIST. The highest overall ( ) p y gresponse rate observed was 52%, which occurred in the 10 mg/kg, Q2W dosing regimen. A total of 10% of patients in this dose group demonstrated a complete response. The duration of confirmed responses, after 12 weeks, ranged >= 28 days to >= 8 months at the time of the analysis, with 80% of responding patients continuing on treatment. The median duration of response had not been reached at the time of analysis with a median follow-up time of 11 months.

Leukocyte interleukin is an • Long-term survival data from a phase II trial demonstrated that first-lineLeukocyte interleukin is an immunotherapeutic comprised of naturally occurring cytokines, including interleukins, interferons, chemokines and colony-stimulating factors

Multikine Cel-Sci SCCHN

Long term survival data from a phase II trial demonstrated that first line treatment with leukocyte interleukin prior to standard of care treatment (surgery + radiation, or surgery + chemotherapy) improved the median survival rate by 40% at 3.5 years post-surgery. The median survival rate was 67% for patients receiving leukocyte interleukin, versus 47% for patients only receiving standard of care alone.

• In a Phase II randomized, double-blind trial, patients with resected melanoma metastatic to regional nodes (American Joint Committee on Cancer stage III) received, by intradermal administration, melanoma vaccine 40Âµg (n = 24) or

Polyvalent, shed-antigen vaccine -pooled, partially purified soluble melanoma antigens from three proprietary melanoma cell lines

POL 103A Polynoma Malignant melanoma

received, by intradermal administration, melanoma vaccine 40Âµg (n 24) or placebo (human albumin) vaccine (n = 14) (both bound to alum as adjuvant) every 3 weeks (x 4), then monthly (x 3), then every 3 months (x 2) and then every 6 months for 5 years or until disease progression. The median observation period was 2.5 years. The median time to disease progression was significantly longer in melanoma vaccine recipients than in placebo recipients (1.6 vs 0.6 years; p = 0.03). Overall survival was also longer in recipients of melanoma vaccine than in placebo recipients (3.8 vs 2.7 years), but this difference was not statistically significant


Source: Adis R&D Insightdifference was not statistically significant



• Phase III: intravesicular MCC appeared to be effective in patients with BCG-refractory non-muscle invasive bladder cancer, according to interim results from a phase III study (NCT00406068). The overall 1-year disease-free survival

Mycobacterium Cell Wall-DNA Complex (MCC) Urocidin Bioniche Bladder cancer

p y ( ) yrate was 25% (35% in patients with only papillary tumors and 21% in those with carcinoma in situ with or without papillary tumors).

• MCC showed strong synergistic activity with gemcitabine. Unlike the BCG vaccine which primarily stimulates the immune system, MCC instillation was found to induce the release of urinary markers of apoptosis in addition to immune stimulation activity.

• NeuVax targets the approximately 50%-60% of these women who are HER2 low to intermediate (IHC 1+/2+ or FISH < 2.0) and achieve remission with

E75, an extracellular domain peptide f th HER 2/ t i GMCSF nelipepimut S, G l B t

( / )current standard of care, but have no available HER2-targeted adjuvant treatment options.

• Phase 3 PRESENT HER2 1+/2+ patients confirmed as optimal treatment population and immune T-cell response targeting HER2 expressing cancer cells correlates with reduction in recurrences.

• FDA granted NeuVax a Special Protocol Assessment (SPA) for its Phase 3 PRESENT (P revention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment) of the HER-2/neu protein + GMCSF,

intradermal

p p ,NeuVax Galena Breast cancer p )

based on the Phase 2 data.• Early breast cancer patients with low levels of human epidermal growth factor

receptor-2 (HER2) expression benefit more from nelipepimut S than those with high levels of expression, according to a subset analysis review of 163 patients. E75 peptide reactive T-cells were still present after 1 year in the low-expressors, but high-expressors had only prevaccination levels. At a median follow-up of 30 months, the disease recurrence rate in the low-expression treated patients was 8%, compared with 21% in the controls. Moreover, in the


p , p ,treated low-expressors with recurrence, the mortality rate was 0%, compared with 20% in the controls (p = 0.04)




• Objective response rate of 33% is better than Ipi’ s 10% – 15% for a similar metastatic melanoma patient population, and with somewhat less severe overall side-effectsoverall side effects

• Two Ph1 dose-ranging studies in advanced cancers (metastatic melanoma, NSCLC, RCC, HRPC, CRC) have demonstrated clean safety (MTD not reached, absence of immune-related AEs) and high/durable response rates (15/46 [33%] mets melanoma, 7/19 [37%] RCC)

• Reported Dec 2 - Researchers evaluated nivolumab response in 90 patients with unresectable stage III or IV melanoma. The analysis included 56 patients who experienced progression after treatment with ipilimumab. Of patients who were ipilimumab naive, two (6%) had complete response, six (18%) had

Fully human IgG4 monoclonal antibody targeting the programmed cell death-1 receptor

Nivolumab Bristol-Myers Squibb

Metastic melanoma, NSCLC, RCC, HRPC, CRC

p , ( ) p p , ( )partial response and seven (21%) had stable disease at 24 weeks. Nineteen patients (55%) experienced disease progression. The disease control rate was 45%. Fifty-three patients with ipilimumab-refractory melanoma were evaluable for response. Of them, 14 (26%) had partial response and 11 (21%) had stable disease. Twenty-eight (53%) patients experienced disease progression. The disease control rate was 47%. Median duration of response was not reached in ipilimumab-naive responders (range, 24 to 140+ weeks) or ipilimumab-refractory responders (range, 12+ to 60+ weeks). Results of p y p ( g , )additional biomarker analyses showed the overall response rate for patients with positive PD-L1 membranous staining (>5%) was higher than for those with negative staining (67% vs. 19%). Responders and patients with stable disease (P<.001) had significantly lower NY-ESO-1 and MART-1-specific CD8+ T cells at baseline than nonresponders (P<.003).

• Ph1 combination study with Ipi : The concurrent use of ipilimumab and nivolumab in a step-wise increase of either drug demonstrated response rates (40% to 53%) that have previously not been seen in the outpatient treatment


( ) p y pof metastatic melanoma with immune-targeting agents. Encouragingly, the toxicity of the combination did not appear to be additive from a clinical standpoint and there were no deaths related to therapy.

• Fast Track




The preferential replication of reovirusin transformed cells with activated Rasis due to the inhibition of double-stranded RNA activated protein kinase • Analysis of 105 patients with evaluable metastatic tumors revealed a better ratestranded RNA-activated protein kinase(PKR) activity. In untransformed (normal) cells, PKR is autophosphorylated and activated by viral products, which leads to phosphorylation of the eukaryotic initiation factor 2a-subunit (eif2a) andinhibition of viral protein synthesis. Phosphorylation of eif2a activates a Pelareorep Reolysin Oncolytics Biotech SCCHN

• Analysis of 105 patients with evaluable metastatic tumors revealed a better rate of stabilization or tumor shrinkage in recipients of pelareorep + carboplatin + paclitaxel than carboplatin + paclitaxel alone (86% vs 67% of patients; p=0.025).• An analysis pf the intent-to-treat basis of the 118 patients with loco-regional head and neck cancer, with or without metastases showed a median progression free survival (PFS) of 94 days (13.4 weeks) in the test arm (n=62), versus 50 days (7.1 weeks) in the control arm (n=56). The test arm maintained a PFS benefit over the control arm through five cycles of therapy. Eighty-eight loco-regional patients did not receive additional therapy following discontinuation of study treatmentPhosphorylation of eif2a activates a

signaling pathway termed the integrated stress response where upregulation of activating transcription factor 4 (ATF4) is a key mediator. Activation of Ras inhibits PKR and subsequent eif2a phosphorylation and therefore allows translation to continue resulting in an

Pelareorep , Reolysin Oncolytics Biotech SCCHN did not receive additional therapy following discontinuation of study treatment. An analysis of these patients showed a median overall survival (OS) of 150 days (21.4 weeks) in the test arm (n=50), versus 115 days (16.4 weeks) in the control arm (n=38), and as of the time of reporting, there have not been a sufficient number of events (i.e. patient deaths) to conduct a survival analysis of patients in the metastatic-only group (i.e. those patients with no loco-regional recurrence). • Oncolytics intends to treat this expanded first stage of the REO 018 clinical trial as a separate supportive study to a planned registration study that will be similar to and take the place of the original second stage of the REO 018 clinical trialtranslation to continue, resulting in an

accumulation of viral particles inside cancer cells

to, and take the place of, the original second stage of the REO 018 clinical trial

Imprime PGG is an aqueous solution consisting of soluble polymers of poly-(1-6)-beta-D-glucopyranosyl-(1-3)-beta-D-glucopyranose (PGG-glucan) which form triple helix fibrils with an

• Top-line results from a phase IIb trial showed the combination of Imprime PGG with cetuximab and carboplatin/paclitaxel showed statistically significant improvement in objective response rate (primary endpoint) compared to the control group, in patients with non-small cell lung cancer (NSCLC). Additionally, in a subset of patients displaying an undisclosed biomarker linked to thewhich form triple-helix fibrils with an

average molecular mass of 150 kDa. PGG-glucan is derived from cell wall components of a patented strain of the yeast Saccharomyces cerevisiaeand acts by priming neutrophils and other innate immune cells with beta-glucan, which enhances their immune response

PGG glucan, Imprime PGG Biothera CRC

in a subset of patients displaying an undisclosed biomarker linked to the disease, the objective response rate was further improved; overall survival was improved by nearly six months among biomarker-positive patients.

• Imprime PGG plus cetuximab appeared to be effective in patients with stage IV KRAS-mutated colorectal cancer in a phase II trial (NCT00912327). Objective response (a decrease of >=30% in tumor burden; primary endpoint) was seen in one patient. Other outcomes were: median survival 28 weeks; 1-year survival 28%; and disease control rate 39%. These outcomes were better compared with historical data for Erbitux alone



response. compared with historical data for Erbitux alone

Phase III ImmunotherapiesPhase IIIMOA/Platform Drug Company Phase III Cancer Comments

Polyclonal antibody stimulator (PAS):Diphtheria Toxoid (DT) linked to a synthetic peptide similar to a portion of the gastrin 17 hormone (GT) to induce anti-gastrin 17 antibodies,

hi h t d t li thG17DT Cancer Advances Pancreatic and

gastric cancers

• . In a phase I/II trial in patients with advanced end-stage colorectal cancer conducted in the UK, 40 evaluable patients immunized with PAS had a median survival of 338 days vs 184 days for the placebo group. The increased survival in the immunized group was statistically significant both by univariate and multivariate analysis. On average, 70% of patients were antibody responders

ft PAS t t t d f th 59 9% f ti t d t t d d tiwhich cross-react and neutralize the gastrin 17 hormone, thus preventing the hormone acting as a growth factor for gastrointestinal malignancies

g after PAS treatment and, of these, 59.9% of patients demonstrated a reduction in free gastrin. Antibody responders with a higher level antibody response had a significant increase in overall survival time (p=0.01) and time to disease progression (p<0.01)

Vaccinia-PSA (V) primes/generates an initial immune response (rilimogene

• Currently in Phase III (under a SPA) - PROSPECT is expected to enroll 1,200 asymptomatic or minimally symptomatic mCRPC patients across up to 200 clinical trial centers and up to 15 countries. In combination with GM-CSF.

• phase II trial had a significantly longer median overall survival time of 8.5 th d ith ti t i th l b ( 0 006) Th h dp ( g

galvacirepvec), and fowlpox-PSA (F) boosts the response (rilimogeneglafolivec). The vaccine also incorporates TRICOM(TRIad of CO-stimulatory Molecules), with ICAM-1, B7.1 and LFA-3.

Rilimogenegalvacirepvec-rilimogeneglafolivec, ProstVac

BN ImmunoTherapeutics (Bavarian Nordic)

Prostate

months compared with patients in the placebo group (p=0.006). The hazard ratio estimate for overall survival from the trial is 0.56 (95% CI 0.37-0.85). A total of 122 patients in the study were randomized 2:1 to receive rilimogenegalvacirepvec-rilimogene glafolivec plus GM-CSF or an empty vector plus placebo, respectively. Further data analysis revealed patients benefited from rilimogene galvacirepvec-rilimogene glafolivec treatment regardless of their condition and previously predicted survival time. The HLA-A2 positive subset of patients exhibited the largest therapeutic effect. F t t k• Fast track

Peptide (EGFRvIII) from a tumor specific splice variant of the epidermal growth factor receptor (EGFR). EGFRvIII is the result of exon 1 joining

• Patients with EGFRvIII-positive glioblastoma typically have a worse prognosis than the overall glioblastoma population, including poor long term survival. The ReACT Phase II results demonstrated promising signs of clinical activity in advanced patients wit recurrent GBM, including patients both naïve and refractory to bevacizumab (Avastin®). A trend toward both an overall survival (OS) and progression-free survival (PFS) benefit have been observed on the rindopepimut arm to date (12 vs. 7.9 mo for OS). The study suggests that early d l t f hi h ti EGFR III tit b di ti f i dj g

to exon 8 in the EGFR gene and is one of the best clinically characterized examples of an alternative splice variant that is only found in tumor cells.

Rindopepimut , CDX 110 Celldex GBM

development of high anti-EGFRvIII titer may be predictive of improved outcomes in this patient population.

• Across three Phase 2 studies of rindopepimut, survival data remains consistent and suggests a substantial and continuing survival benefit in comparison to independent control datasets (see chart below) at the median and at all other time points evaluated. The pooled overall long-term survival results continue to be consistent with the ACT III Phase 2 study (18% for 4-years and 14% for 5-years vs 0% for matched historical controls). The Phase 3 registration study, ACT IV i d l d ft th ACT III t d



ACT IV, is modeled after the ACT III study.• Fast Track



Herpes simplex type 1 virus backbone carrying the gene encoding human granulocyte macrophage-colony

• Treatment with talimogene laherparepvec significantly improved the durable response rate (DRR), compared with GM-CSF (16% vs 2%; 95% CI, 12-21% vsgranulocyte macrophage colony

stimulating factor (GM-CSF). The herpes simplex viral genome has been modified and contains mutations in the herpes gene, ICP34.5 and ICP47 deletion, which makes it non-pathogenic to normal cells and capable of selectively targeting and replicating in tumor cells, stimulating

talimogenelaherparepvec Amgen (BioVex) Malignant

melanoma

response rate (DRR), compared with GM CSF (16% vs 2%; 95% CI, 12 21% vs95% CI, 0-5%, p<0.0001) in patients with advanced, unresectable melanoma, meeting the primary endpoint in a phase III trial (OPTiM).

• A prespecified interim analysis of overall survival showed no significant difference between the talimogene laherparepvec and sargramostim arms (23.3 vs 19.0 months; HR 0.79, 95%CI 0.6, 1.02; p > 0.05). However, survival benefits were observed with talimogene laherparepvec therapy in the subgroups of patients with stage M1a disease and in those with previously untreated disease.p g , g

apoptosis and necrosis.

25-mer peptide fragment of the MUC-1 antigen encapsulated in a liposomal delivery system. Tecemotide is designed to induce a specific immune response to MUC-1, a mucin

d b h 90% f

Tecemotide, LPBLP25, Stimuvax

Biomira, Merck KGaA NCSLC

• Maintenance therapy with tecemotide did not improve overall survival, compared with placebo, in the phase III START trial, in patients with stage III non-small cell lung cancer. START included 1514 patients with stage III, unresectable NSCLC who had achieved a clinical response or stable disease with chemotherapy.

• According to an exploratory analysis of a predefined subgroup of patients in the START trial who received tecemotide after concurrent chemotherapy, aexpressed by more than 90% of

common solid tumors

the START trial who received tecemotide after concurrent chemotherapy, a median overall survival of 30.8 months was seen in patients receiving tecemotide, compared with 20.6 months in patients receiving placebo.

• Fast Track

Intradermal injection of patient-derived (autologous) DCs pulsed with recombinant PMSA for prostate cancer DCVx-prostate,

( )Northwest Prostate, GBM

• 85% of patients treated with the brain cancer vaccine lived longer than 14.6 months (achieved with standard of care). Moreover, 22% of patients treated with the vaccine survived for >=6 years, compared with only <5% of patients treated with standard of care (surgery plus radiation and chemotherapy) still alive at 5 years. Median survival time for patients treated with the vaccine wasrecombinant PMSA for prostate cancer

or an extract of the patient’s own tumor for GBM (double autologous)

DCVax-L (GBM) Biotherapeutics Prostate, GBM alive at 5 years. Median survival time for patients treated with the vaccine was 36.4 months and median progression time was 26.4 months. Recurrence-free rates for 1, 2, 3, 4, and 5 years with the vaccine were 74%, 45%, 33%, 28%, and 22%, respectively.




3

S Adi & I i h



OBSERVATIONSOBSERVATIONS


Immunotherapy Continues to Be a Rich Source of Diversity of Approach & Platform: e.g., Checkpoint I hibi Off h Sh lf M l l A ib diInhibitors – Off-the-Shelf Monoclonal Antibodies

Nature 480, 480–489 (22 December 2011); clinicaltrials.gov


Nature 480, 480 489 (22 December 2011); clinicaltrials.gov

39

Immunotherapy Continues to Be a Rich Source of Diversity of Approach & Platform: e.g., Checkpoint Inhibitors Off the Shelf Monoclonal AntibodiesInhibitors – Off-the-Shelf Monoclonal Antibodies


Company web sites; Science 331, 1612 (2011);

40

Immunotherapy Continues to Be a Rich Source of Diversity of Approach & Platform: e.g., Checkpoint I hibi Off h Sh lf M l l A ib diInhibitors – Off-the-Shelf Monoclonal Antibodies• Blockade of an immune-checkpoint will only induce tumor regressions when there is a pre-existing antitumor immune

response to be ‘unleashed’O th th h d i di t d ti ti f tit i b i ff ti if t d b• On the other hand, vaccine-mediated activation of an antitumor immune response may be ineffective if tumors respond by response may be ineffective if tumors respond by upregulating immune-checkpoint ligands.


Nat.Rev.Cancer 2012 Mar 22;12(4):252-64

41

Immunotherapy Continues to Be a Rich Source of Diversity of Approach and Platform: e.g., CARTs –G i ll E i d A l P i T C llGenetically Engineered Autologous Patient T-Cells

Nature Reviews


Cancer 13, 525–541 (2013)

Immunotherapy Continues to Be a Rich Source of Diversity of Approach and Platform: e.g., CARTs –G i ll E i d A l P i T llGenetically Engineered Autologous Patient T-cells

• Brentjens, Sadelain and others: “Here, we summarize the outcomes of five adults with relapsed B-ALL, four of whichoutcomes of five adults with relapsed B ALL, four of which demonstrated persistent disease after salvage chemotherapy at the time of CAR T cell infusion. Overall, we report that in all patients, ranging from overt morphologic disease to MRD, treatment with autologous T cells uniformly resulted in MRD− CRs independent of tumor burden at the time of T cell therapy.” Sci Transl Med 20 March 2013


N Engl J Med 2013;368:1509-18

Sci Transl Med 20 March 2013

Immunotherapy Goes for the Tough Cancers, Not Just the “Immuno-responsive” Ones – And Succeedsthe Immuno responsive Ones And Succeeds

• “For these patients, the single-agent response rate to second-line chemotherapy with d l f l i 8% d h d i f i f h d ’docetaxel, for example, is 8%, and the duration of response is a few months, so we don’t have a lot of good options for advanced-stage lung cancer,” Rizvi said. “The initial data with nivolumab and other compounds is that patients who have been heavily pretreated have a response rate of over 20%, with 24% alive 2 years later.”

Source: OncLive: Rizvi, Chemotherapy Foundation, 2013, New York; Topalian, ASCO 2013, Chicago


Immunotherapy Goes Stratified

• PD-L1 expression by the tumor is actively b i d di i k f

• Phase III programs with biomarkersbeing pursued as a predictive marker for tumor activity of PD-1– and PDL1–directed antibodies. In a retrospective analysis of a small subset of patients who were treated i th h I i l b t d (th j itin the phase I nivolumab study (the majority with melanoma, renal cell carcinoma, and NSCLC), none of the patients with tumors lacking PD-L1 expression had a tumor

Thi b ti h l d t thresponse. This observation has led to the selection of patients based on tumor PD-L1 expression in some of the ongoing anti-PD-1 and anti-PD-L1 clinical development

It i i t t t h i th t S Adi R&D I i htprograms. It is important to emphasize that the data from the nivolumab study are preliminary.Clin Cancer Res 2013;19:5300-5309



Immunotherapy Goes Stratified


Journal for ImmunoTherapy of Cancer 2013, 1:7

Delayed Effects & PFS-OS Disconnect• One of the key benefits, and key challenges to clinical development, with immunotherapy is

that short-term treatment with some of these immunotherapy approaches – whether antigen-based vaccine or immunomodulatory antibody – can provide disease control for extended periods after treatment stops, and in fact the delayed effect has likely confounded extended periods after treatment stops, and in fact the delayed effect has likely confounded many past studies.

– And on the other hand, apparent progression and increase in tumor volume due to immune infiltration.

Source: Cancer Research Institute (CRI) and CancerSource: Cancer Research Institute (CRI) and Cancer Immunotherapy Consortium (CIC): Immuno-Oncology: Creating the Framework for a New Era of Cancer Therapy,Axel Hoos, MD, PhDCo-Chair, CIC Executive CommitteeMedical Lead, Ipilimumab Program, Bristol-Myers


Squibb

47

Immunotherapy Clinical Paths: Developers Are Finally Pursuing Settings Other Than Last Line• Adjuvant, maintenance, and early intervention in minimal tumor burden/minimal residual

disease states….


Despite Some Significant - and Unexpected –Monotherapy Data, Most Experts Think Combinations, Especially Combinations of Immune Agents, Will be Key

Immunostimulant(e.g., adjuvant, Toll agonist)

T-cells B-cells

APCsNK

cells

TumorImmunosuppression

Inhibitors (e.g., Antigen-based vaccine

APCs cells

( gcheckpoint antagonists)

Reducing tumor burden and promoting t mor cell death

g

promoting tumor cell death (including hitting cancer stem cells): debulking, radiotherapy, cytotoxic

chemotherapy, targeted agents

Source: Defined Health


So Having Multiple Platforms/Modalities in One’s Toolkit Could Be Critical for Owning Immuno-Oncology

♦ As reported at ASCO in June 2013, concurrent treatment with BMS’s anti-PD1 mAbnivolumab plus ipilimumab led to objective

i 0% f i i h i lresponses in 40% of patients with previously treated stage III or IV melanoma

l ( ) b


Source: Clin Cancer Res; 19(19) October 1, 2013; ASCO 2013

Planting Early Seeds: Roche 2012-2013 Deal-making Activity in Immuno-OncologyActivity in Immuno Oncology

R h

Immatics - Research and development collaboration , $17M/$1B

Tumor-associated peptide (TUMAP)-based cancer vaccines for gastric, prostate and non-small cell lung cancer, including IMA942 (pre-Phase I)

Immunocore - Research collaboration/licensing, $20M/$300

Platform of bi-specific biological drugs, Called ImmTACs, which exploit the power of T Cell Receptors (TCRs) to recognize intracellular changes that occur during cancer or viral infection.

Roche

Inovio – Licensing of INO-5150, preclinical dual-antigen synthetic DNA PSA & PSMA

vaccine, $5M/$211MSynCon® DNA vaccine for prostate cancer was designed with PSA and PSMA synthetic consensus immunogens based on human and macaque

l i i i id hsequences, resulting in amino acid sequences that differ slightly from the native human protein.

Source: EvaluatePharma


FINAL THOUGHTSFINAL THOUGHTS


Changing the Curve

• Combinations of therapeutic di i l dagents – traditional, targeted,

and immunotherapies – may change the nature of responses and outcomes to anticancer t t ttreatment.

Ott P A et al. Clin Cancer Res 2013;19:5300-5309


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BioEurope Spring25h Annual Cancer Progress Conference BioEurope Spring March 10 – 12, 2014

Turin, Italywww.therapeuticinsight.com

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New York Citywww.cancerprogressbyDH.com

Defined Health will also be participating in the following industry events:

ASH Annual Meeting | December 7 10 2013 | New Orleans LA | http://dfndhlth com/ASH 2013ASH Annual Meeting | December 7 - 10, 2013 | New Orleans, LA | http://dfndhlth.com/ASH-2013Biotech Showcase™ 2014 | January 13 -14, 2014 | San Francisco, CA | http://dfndhlth.com/BTS-2014

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