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Therapeutic Cancer Vaccines

A Future of Possibilities Haunted by a History of Failures

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Therapeutic Cancer Vaccines-The Genesis

Over a century ago, Dr. William B. Coley, a bone surgeon, developed a method of immunotherapy Believing that bacterial toxins stimulated the immune system,

he injected a cancer patient with live bacteria; the patient made a complete recovery1,2

Dr. Coley went on to develop a safe and effective mixture of bacteria for treating cancer patients known as Coley’s mixed bacterial toxins

Through the decades following Coley’s introduction of immunotherapy, many attempts have been made to develop and bring cancer vaccines to market Success, however, has been elusive

1 American Cancer Society2 www.cancerresearch.org/about/history

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Therapeutic Cancer Vaccines

Therapeutic cancer vaccines, or TCVs, as with the whole of immunotherapy, hold a tremendous amount of promise Some of that promise has already been realized in several

approved immunotherapeutics, but only one TCV

The pipeline for biologics is robust PhRMA reports over 900 biologics in development in 15 different

therapeutic areas, targeting a wide range of indications1

Cancer vaccines comprise nearly 36% of all biologic vaccines in development in the report2 and 28% of all cancer biologics being developed

Preventative cancer vaccines are included in the report

These slides focus only on TCVs1 PhRMA 2013 Medicines in Development: Biologics2 Trials for 3 vaccines have been stopped and a product acquisition has lowered the reported number

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Therapeutic Cancer VaccinesPossibilities and Promises in Development

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TCVs in Development

One hundred TCVs are included in this review These include most of the vaccines in the PhRMA report,

and those identified through searches on clinicaltrials.gov, the International Trials Registry, and company pipelines

New and/or discontinued indications were identified during the searches of company pipelines

Trials conducted by the NCI and other agencies, research centers and universities are not included, unless the trial is being conducted on behalf of a company

A 2011 University of Michigan found that there were 231 TCVs in clinical development1; a more recent report2 shows 196 TCVs being developed

1 Hum Vaccin. 2011 Nov;7(11):1124-92 Kaloroma

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A Snapshot

Among the 100 TCVs, a total of 34 different cancer indications are targeted

Ten indications have received orphan designation, 6 received fast track designation, and 4 were designated both orphan and fast track

There are 12 specific types of vaccines, i.e. dendritic cell, among the 100 in development

Twenty-six of the vaccines are in Phase 3 clinical trials Four of these trials have been completed, of which two missed

their primary endpoints: Merck KGaA/Oncothyreon (NSCLC) and Kael-GemVax (pancreatic)

Seventy-three companies are represented

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Targeted Indications and Types of TCVs

Indication Number

Prostate 16

Breast 15

Glioblastoma 14

NSCLC 12

Melanoma 12

Solid tumors 10

Hematological 10

Type Number

Peptide 20

Genetically-modified

14

Dendritic 12

Cell (autologous/allogenic)

12

mAB 9

Recombinant 8

Other targeted cancers are renal,SCLC, sarcoma, endometrial, ovarian, colorectal, GI, pancreatic, bladder, head & neck, colon, urogenital, andmesothelioma

Other types of vaccines include DNA,virus vector, virus replicon virus, antibody,bacterial and polyclonal antibody

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TCVs by Clinical Stage

The vaccines in development are shown by their respective clinical stage in the table below. Note that none are in regulatory review

Stage Number

Phase 0 3

Phase I 28

Phase II 34

Phase III 26

Phase I/II 31

Phase II/III 3

Clinical stage includes recruiting, ongoing, ongoing and recruiting, ongoing but not recruitingPhase 1, 2 or 3 ready and completed. Trials with an unknown status are not included.

Companies Developing TCVs

Activartis Biotech (1) Bioven Europe (1) Endocyte (1)

Adamis Pharmaceuticals (1)

Biovest International (1) Etubics (1)

Aduro Biotech (5) B-MS/Medarex (1) Galena Biopharma (2)

Advaxis (1) BN ImmunoTherapeutics (3)

Gliknik (1)

Agenus (3) Cancer Advances (1) GlobeImmune (3)

AlphaVax (2) Celldex Therapeutics (2) Gradalis (1)

Antigen Express (2) CG Therapeutics (1) Grupo Insud (1)

Argos Therapeutics (1) Colby Pharmaceuticals (2)

GSK (3)

Avax Technologies (2) Dendreon (2) Heat Biologics (1)

Bayer (1) DCPrime (1) Hemispherex (1)

Bellicum Pharmaceuticals (1)

EMD Millipore (1) Immatics biotech (2)

BioCancell Ltd (1) EMD/Oncothyreon (1) Immunicum AB (1)

Companies Developing TCVs

Immunitor (1) Merck/Vical (1) PsiOxus (1)

ImmunoCellular (1) Mologen AG (1) Stemline Therapeutics (1)

Immunocore (1) NewLink Genetics (3) Sunovion (1)

ImmunoFrontier (1) Northwest Bio (1) Tapimmune (1)

Immunotope (1) NovaRx (2) Transgene/Novartis (1)

Immunovaccine (2) OncoPep (1) Tvax Biomedical (2)

ImmunovativeTherapies (1)

Oncothyreon (1) UbiVac (1)

Inovio Pharmaceuticals (1)

Onyvax (1) Vaccinogen (1)

Kael-GemVax (1) Optimer Biotech (1) Vaxil Bio (1)

MabVax Therapeutics (6) Pique Therapeutics (1) Vaximm GmbH (1)

Mediolanum Farmaceutici (1)

Polynoma (1)

Memgen (1) Prima BioMed (1)

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Therapeutic Cancer VaccinesA History of Development Failures, but Paradigms are Changing

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TCVs-Long on Promises………….

Cancer vaccines targeted by many as the ‘holy grail’ for tumors

Promising Cancer Vaccine Could Shrink Tumors By 80 Percent

Brain Cancer Vaccine Promising

Prostate Cancer Vaccine Looks Promising in Early Trial

Personalized Immunotherapy Shows Promise in Mantle Cell Lymphoma

PANVAC for breast, ovarian cancer shows early promise

Surgical Oncologist Presents Promising Data for Novel Pancreatic Cancer Vaccine

Could This Be The End Of Cancer? …scientists say vaccines could hold the key—not just to a cure but to wiping out cancer forever

Therapeutic polyvalent vaccine shows promise against melanoma

MUC1 peptide vaccines still show promise for lung cancer victims

Consider these headlines

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………..But Short on Approvals

The preceding headlines come from press releases issued by companies either developing TCVs while some represent to failed TCVs

And while TCVs and their promises continue to excite physicians, patients, investors, scientists and analysts a speaker at ASCO 2013 reminded his audience that the

promises of immunotherapy extend back at least 40 years, displaying the March 19, 1973 cover of Time Magazine featuring noted immunologist Robert Good

Although new types of TCVs are in clinical trials including, antigen, dendritic cell, vector-based, DNA and tumor cell and show positive results, Provenge remains the only FDA-approved TCV and none are approved in the EU

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Failure Is Not An Option

The path to approval is littered with failures; Phase 2 vaccines that have shown great promise fail in Phase 3; below are some examples Biopharmaceutical companies with failed cancer vaccines

Genzyme: Melan-A Genitope: MyVax

Imclone: Mitumomab IDM Pharma: UVIDEM and COLLIDEM

Titan Pharmaceuticals: CeaVac Therion: PANVAC-VF

TeloVac: GV1001 CancerVax: Canvaxin

Corixa: Melacine Oncothyreon/Merck KGaA: Stimuvax*

Oxford Biomedica: TroVax Cell Genesys: GVAX prostate*Despite missing its primary Phase 3 endpoint for NSCLC, the companies decided to proceed with an ongoinglate-phase trial in Asia and is weighing the options of starting a further study. A decision, partly dependent onthe outcome of talks with regulators, is expected this year.

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Some Failures Get a Second Chance

PROSTVAC failed to demonstrate a reduced TTP for prostate cancer Two years later, it was discovered that PROSTVAC had

demonstrated a statistically significant OS; Bavarian Nordic licensed the drug, which is now in Phase 3

Aduro Biotech resurrected two TCVs it acquired, one for metastatic pancreatic cancer, now in Phase 2, and the second for prostate cancer (preclinical)

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Why Do TCVs Fail?

A recently published paper suggested that some TCV failures can be blamed on a self-sabotaging adjuvant1; instead of destroying tumors, T-cells accumulate at the vaccination site, with the miss-targeting due to incomplete Freund's adjuvant

Trial design: selection of clinical trial endpoints, disease stage, patient population, and trial duration2

A retrospective analysis of 23 completed or terminated P3 studies showed that 74% (17/23) failed to demonstrate significant efficacy in the primary endpoint, suggesting tumor burden may not be the only prognostic factor3

Considering the above, the current oncology drug development paradigm doesn’t fit

1 Nature Medicine: Willem Overwijk, Assistant Professor, MD Anderson Cancer Center2 http://obroncology.com/documents/OBR_JAN10_CV.pdf3 www.landesbioscience.com/journals/vaccines/article/23917/

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It’s Not a One-Size-Fits-All Development Paradigm

Conventional Oncology Drug Development Paradigm, designed for cytotoxics

Phase N (variable) Purpose

1 20 to 80 healthyvolunteers, or patients (may or may not have target disease)

Determine safety, dose range, MTD, DLT Characterize pK If mixed population, find target

2 100 to 300 patient volunteers with targeted disease

Evaluate effectiveness, look for side effects. May provide estimate of effect size for Phase 3

Discuss continuation with regulatory authorities

3 500 to 1,000 patient volunteers

Verify effectiveness, monitor adverse reactions from long- term use

4 Large number of patients

Post-marketing surveillance

Modified from Cheney T. & Kaspar P. Overview of Clinical Research, 1996.

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The Conventional Paradigm Doesn’t Fit: TCVs Are Not Cytotoxics

General principles of oncology drug development

Why these principles don’t adapt to cancer vaccines

Increasing dose increases efficacy MTDs aren’t optimal doses; cancer vaccines usually have low toxicity; no proof for a linear dose-potency relationship

PK is relevant for finding optimal dose Cancer vaccines aren’t metabolized; not evident that a MTD will be coincident with the optimal dose to reach the vaccine effect

Objective responses (OR) predict clinical benefit

OR is not a good predictor of survival

Endpoints based on selected tumor size

Tumors may progress prior to immune response and regression

Mixed tumor trials for target selection Many cancer vaccines are designed to address only one tumor type

Objective progression is considered a failure; drugs aren’t active if tumor is growing

Cancer vaccines could be actives beyond disease progression; translating immune response into antitumor response takes time

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Changing the Paradigm

Over the course of a year, the Cancer Vaccine Clinical Trial Working Group, comprised of more than 50 individuals from academia, the pharmaceutical and biotech industries, and regulatory bodies developed and proposed changes to the existing paradigm1

The Cancer Immunotherapy Consortium of the Cancer Research Institute, from 2004 to 2009, evaluated an immunotherapy-focused development paradigm, creating principles for redefining trial endpoints2

Other scientists, researchers, regulatory officials and academicians reviewed the current paradigm and proposed changes3

1 The Cancer Vaccine Clinical Trial Working Group, J Immunother Jan 20062 JNCI J Natl Cancer Inst, Vol 102, Issue 18 Pp. 1388-13973 Cancer vaccines: Will we ever learn? Expert Review of Anticancer Therapy, January 2009, Vol. 9, no. 1, Pages 67-74

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Recommendations for a New Paradigm: The Cancer Vaccine Clinical Trial Working Group

Phase of development Purpose Endpoints

Proof-of-Principle-N>20-Defined patient population with no end stage-No mandate to investigate exact mechanism of action disease

-Safety database initiated-Establish immunogenicity, biologic activity, clinical activity-Use established and reproducible immune assays-Cohort design determines dose and schedule of vaccination

-Impact of the vaccine on immune response or on investigated disease -Sequential samples for assays-No mandate to demonstrate clinical activity with conventional endpoints

Phase 2 comparative randomized,powered for statistically significant difference between two arms in a well-defined population,a well-defined primary outcome measure (may be a surrogate)

-Expansion of safety database-Establishment of efficacy-Flexibility of development, e.g. allow for sample size re-calculation, allow for modification of Phase 3 eligibility criteria

-Validated surrogates or biomarkers as efficacy endpoints-Validation needs proof-of-correlation between outcome and biological marker in single-arm or randomized studies (prognostic factor), or-needs randomized trial showing that intervention-induced surrogate correlates with outcome (immune response)

Phase 3 conventional trial-Data from Phase 3 component not to be pooled with Phase 2 data

www.sitcancer.org/meetings/am05/workshop_presentations/workstream_2.pdf, not all recommendations included

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Recommendations for a New Paradigm: The Cancer Immunotherapy Consortium

Source: JNCI J Natl Cancer Inst, Vol 102, Issue 18 Pp. 1388-1397

Endpoint Cellular immune response

Antitumor response Survival

Challenges -Complex assays exist -Results are highly variable and not reproducible across trials -Assay procedures are not harmonized

-Conventional and novel response patterns are observed -Translating immune response into antitumor response takes time -No systematic criteria to capture new response patterns exist

-Time it takes to translate immune and antitumor response into a survival effect -Conventional statistical models don’t account for non-proportional hazards and delayed separation of curves

Recommendations -Harmonized assay use through SOPs that accompany individual assay protocols

-Identify relevant response patterns-Use systematic criteria (irRC*) to reproducibly capture new patterns

-Employ statistical models that account for the delayed effect-Carefully consider use of early interim and futility analyses

The core aspects of all recommendations are included in Guidance for Industry: Clinical Considerations for Therapeutic Cancer VaccinesUS Dept. of Health and Human Services, FDA, CBER, October 2011* immune-related response criteria

Regulatory Comments and Considerations

May or may not determine MTD (and that’s OK)

Vaccine-specific toxicities as endpoint for early stage trials-clinical activity is secondary objective

Explore continuation of vaccine after initial progression if

Subject continues to meet eligibility criteria

No clinical deterioration

No curative salvage therapy exists

Consider randomized Phase 2 trials

PFS, TTP, DFS can’t be interpreted in single arm trials

Single arm trials may lead to overly optimistic interpretation of effect size

Phase 3 endpoints

PFS is preferred over TTP

OS remains the gold standard and may be the best TCV endpoint as PFS has yet to be successful

DFS in adjuvant settingUS Regulatory Considerations for Therapeutic Cancer VaccinesPeter Bross, MD, Team Leader, Clinical Oncology, FDA CBER;2012 AACR Annual Meeting

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CBER: Going Beyond Comments and Considerations

CBER included the core aspects of a number of the recommendations made by the Cancer Vaccine Clinical Trial Working Group and the Cancer Immunotherapy Consortium in a 2011 guidance document1

Support of virology, molecular and tumor biology, and safety and efficacy immunology studies of gene transfer and tumor vaccines has begun2,3

Improved tools for clinical trial and design are being developed

The division is evaluating and implementing novel methods to improve reliability, sensitivity, and specificity of assays for product development and lot release

CBER acknowledges that endpoints based on tumor assessments4 may not be appropriate endpoints for a late phase clinical trial for a cancer vaccine

1 Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines, Oct 20112 Nat Med 2013 Apr;19(4):452-7, Coagulation factor X shields adenovirus type 5 from attack bynatural antibodies and complement. Xu Z, Qiu Q, Tian J, Smith JS, Conenello GM, Morita T, Byrnes AP3 CBER Strategic Plan for Regulatory Science and Research FY 2012-2016; Draft4 Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics; May 2007

The Business of Therapeutic Cancer VaccinesDeals, Terms and Partnering

Selected Deals and Terms-Failed TCVs

Licensee/Licensor

Date Assets Terms

Sanofi Aventis/Oxford Biomedica

03/07

TroVax, renal cancer; Phase 2

WW license; $38.6M upfront, $25.3M development milestone; total deal value $690M

Sanofi Aventis/IDM Pharma

07/01

UVIDEM, melanomaPhase 2

WW license; up to $545M

MerckSerono/Canvax

12/04

Canvaxin, melanoma

License; $25M upfront, $12M in equity, up to $253M in milestones

Takeda/Cell Genesys

03/08

GVAX prostate, Phase 3

Acquired WW rights; $50M upfront, up to $270M in milestones, tiered double-digit royalties on net sales in US, flat double-digit RoW

Selected Deals and Terms-TCVs in Development

Licensee/Licensor

Date Assets Terms

Aduro Biotech/BioSante Pharma

04/11

GVAX pancreas, prostate vaccinesPhase 2 & Phase 3

License; milestones, royalties when commercialized

02/13

All GVAX vaccines;Phase 1, Phase 2 and Phase 3

Acquisition; $1M upfront, additional milestones & royalties when commercialized

Merck/Vical 06/05

Non-viral gene delivery technology

Exercised 3 options to license Vical technology for TCVs; $3M upfront, milestones, royalties

Accentia/Biovest 04/03

Biovax ID; Phase 3

$20M equity (81% stake)

Pfizer/Celldex(Pfizer returned rights in 2010)

04/08

Peptide vaccine, glioma; Phase 2

WW license; $40M upfront, $10M equity, over $390M in milestones, royalties, fund development

Selected Deals and Terms-TCVs in Development

Licensee/Licensor

Date Assets/Phase Terms

Private investor/Argos Therapeutics

11/08

Dendritic cell vaccine; Phase 1/2

$35.2M Series C financing

Merck KGaA/Biomira (now Oncothyreon)

05/01

Stimuvax & Theratope vaccines

WW license; $33.5M in upfront and equity, share development costs, 50/50 sales split in US, Canada, royalties elsewhere

01.06

Stimuvax; Phase 3

Acquisition of full US rights; royalties and regulatory milestones

12/08

Manufacturing;Phase 3

License/acquisition; $13M to license mfg. rights and acquire mfg. assets for Stimuvax

Novartis/Transgene

03/10

Genetically-modified vaccine; Phase 2

Option to WW rights; $10M upfront, additional $950M if option exercised

Partnering TCVs in Development

There are 5 partnerships identified among the 73 companies in this review B-MS/Medarex (B-MS has acquired Medarex) Merck KgaA/Oncothyreon Merck/Vical Transgene/Novartis GlobeImmune/Celgene (Celgene has an exclusive option

to license all of GlobeImmune’s oncology programs)

A review of the partnering strategies of the remaining companies reveals at least 44 are or will be seeking a commercialization partner

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About 2911 Advisers

2911 Advisers is a Life Sciences consulting firm in Nashua, NH and is owned by Michael Sheckler, MBA. With a focus on oncology and pain management, he assists clients with business/strategy development, product & technological assessment, opportunity identification, market valuation, market/competitive analysis and negotiating licenses.

He can be reached at 603 809-9936 or at michael.sheckler@gmail.com.