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These slides provide an overview of 100 therapeutic cancer vaccines in development, a look at some of the failures, what's been and is being done to address the clinical development of these vaccines and a snapshot of some deals, terms and the number of companies seeking commercializations partners.
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Therapeutic Cancer Vaccines
A Future of Possibilities Haunted by a History of Failures
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
………..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
Prepared by 2911 Advisers
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.
Prepared by 2911 Advisers
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)
Prepared by 2911 Advisers
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/
Prepared by 2911 Advisers
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.
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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
Prepared by 2911 Advisers
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 [email protected].