Therapeutic Cancer Vaccines: A Future of Possibilities Haunted By A History of Failures

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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 …

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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  • 1. Therapeutic Cancer Vaccines A Future of Possibilities Haunted by a History of Failures Preparedby2911Advisers
  • 2. Therapeutic CancerVaccines-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 followingColey’s introduction of immunotherapy, many attempts have been made to develop and bring cancer vaccines to market  Success, however, has been elusive Prepared by 2911 Advisers 1American Cancer Society 2
  • 3. Therapeutic CancerVaccines  Therapeutic cancer vaccines, orTCVs, 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 oneTCV  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 onTCVs Prepared by 2911 Advisers 1 PhRMA 2013 Medicines in Development: Biologics 2Trials for 3 vaccines have been stopped and a product acquisition has lowered the reported number
  • 4. Therapeutic Cancer Vaccines Possibilities and Promises in Development Preparedby2911Advisers
  • 5. TCVs in Development  One hundredTCVs are included in this review  These include most of the vaccines in the PhRMA report, and those identified through searches on, the InternationalTrials 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 231TCVs in clinical development1; a more recent report2 shows 196TCVs being developed Prepared by 2911 Advisers 1 HumVaccin. 2011 Nov;7(11):1124-9 2 Kaloroma
  • 6. A Snapshot  Among the 100TCVs, 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
  • 7. Targeted Indications andTypes ofTCVs 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/alloge nic) 12 mAB 9 Recombinant 8 Prepared by 2911 Advisers Other targeted cancers are renal, SCLC, sarcoma, endometrial, ovarian, colorectal,GI, pancreatic, bladder, head & neck, colon, urogenital, and mesothelioma Other types of vaccines include DNA, virus vector, virus replicon virus, antibody, bacterial and polyclonal antibody
  • 8. 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 Prepared by 2911 Advisers 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 recruiting Phase 1, 2 or 3 ready and completed.Trials with an unknown status are not included.
  • 9. Companies DevelopingTCVs 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) CelldexTherapeutics (2) Gradalis (1) Antigen Express (2) CGTherapeutics (1) Grupo Insud (1) ArgosTherapeutics (1) Colby Pharmaceuticals (2) GSK (3) AvaxTechnologies (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)
  • 10. Companies DevelopingTCVs 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) MabVaxTherapeutics (6) PiqueTherapeutics (1) Vaximm GmbH (1) Mediolanum Farmaceutici (1) Polynoma (1) Memgen (1) Prima BioMed (1)
  • 11. Therapeutic Cancer Vaccines A History of Development Failures, but Paradigms are Changing Preparedby2911Advisers
  • 12. TCVs-Long on Promises…………. Cancer vaccines targeted by many as the ‘holy grail’ for tumors Promising CancerVaccineCould ShrinkTumors By 80 Percent Brain CancerVaccine Promising Prostate CancerVaccine Looks Promising in EarlyTrial Personalized Immunotherapy Shows Promise in Mantle Cell Lymphoma PANVAC for breast, ovarian cancer shows early promise Surgical Oncologist Presents Promising Data for Novel Pancreatic CancerVaccine CouldThis BeThe 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 Prepared by 2911 Advisers Consider these headlines
  • 13. ………..But Short on Approvals  The preceding headlines come from press releases issued by companies either developingTCVs while some represent to failed TCVs  And whileTCVs 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 ofTime Magazine featuring noted immunologist Robert Good  Although new types ofTCVs are in clinical trials including, antigen, dendritic cell, vector-based, DNA and tumor cell and show positive results, Provenge remains the only FDA-approvedTCV and none are approved in the EU Prepared by 2911 Advisers
  • 14. 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 Prepared by 2911 Advisers 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 ongoing late-phase trial in Asia and is weighing the options of starting a further study. A decision, partly dependent on the outcome of talks with regulators, is expected this year.
  • 15. Some Failures Get a Second Chance  PROSTVAC failed to demonstrate a reducedTTP for prostate cancer  Two years later, it was discovered that PROSTVAC had demonstrated a statistically significantOS; Bavarian Nordic licensed the drug, which is now in Phase 3  Aduro Biotech resurrected twoTCVs it acquired, one for metastatic pancreatic cancer, now in Phase 2, and the second for prostate cancer (preclinical) Prepared by 2911 Advisers
  • 16. Why DoTCVs Fail?  A recently published paper suggested that someTCV 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 Prepared by 2911 Advisers 1 Nature Medicine:Willem Overwijk,Assistant Professor, MD AndersonCancer Center 2 3
  • 17. 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 healthy volunteers, 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 Prepared by 2911 AdvisersModified from CheneyT. & Kaspar P. Overview of Clinical Research, 1996.
  • 18. The Conventional Paradigm Doesn’t Fit: TCVs Are Not Cytotoxics Prepared by 2911 Advisers 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
  • 19. Changing the Paradigm  Over the course of a year, the CancerVaccineClinicalTrialWorking 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 Prepared by 2911 Advisers 1The CancerVaccine ClinicalTrialWorking Group, J Immunother Jan 2006 2 JNCI J Natl Cancer Inst,Vol 102, Issue 18 Pp. 1388-1397 3 Cancer vaccines:Will we ever learn? Expert Review of AnticancerTherapy, January 2009,Vol. 9, no. 1, Pages 67-74
  • 20. Recommendations for a New Paradigm:The CancerVaccineClinicalTrialWorking Group Prepared by 2911 Advisers 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, not all recommendations included
  • 21. Recommendations for a New Paradigm: The Cancer Immunotherapy Consortium Prepared by 2911 Advisers 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:ClinicalConsiderations forTherapeuticCancerVaccines US Dept. of Health and Human Services, FDA,CBER, October 2011 * immune-related response criteria
  • 22. 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 overTTP OS remains the gold standard and may be the bestTCV endpoint as PFS has yet to be successful DFS in adjuvant setting US Regulatory Considerations forTherapeutic Cancer Vaccines Peter Bross, MD,Team Leader,Clinical Oncology, FDA CBER;2012 AACR Annual Meeting
  • 23. CBER: Going Beyond Comments and Considerations  CBER included the core aspects of a number of the recommendations made by theCancerVaccine ClinicalTrialWorking 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 Prepared by 2911 Advisers 1 Guidance for Industry:Clinical Considerations forTherapeuticCancerVaccines,Oct 2011 2 Nat Med 2013 Apr;19(4):452-7,Coagulation factor X shields adenovirus type 5 from attack by natural antibodies and complement. Xu Z,Qiu Q,Tian J, Smith JS, Conenello GM, MoritaT, Byrnes AP 3 CBER Strategic Plan for Regulatory Science and Research FY 2012-2016; Draft 4 Guidance for Industry:ClinicalTrial Endpoints for the Approval of Cancer Drugs and Biologics; May 2007
  • 24. The Business ofTherapeutic CancerVaccines Deals,Terms and Partnering
  • 25. Selected Deals andTerms-FailedTCVs 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 SanofiAventis/IDM Pharma 07/01 UVIDEM, melanoma Phase 2 WW license; up to $545M MerckSerono/Canva x 12/04 Canvaxin, melanoma License; $25M upfront, $12M in equity, up to $253M in milestones Takeda/CellGenesys 03/08 GVAX prostate, Phase 3 AcquiredWW rights; $50M upfront, up to $270M in milestones, tiered double-digit royalties on net sales in US, flat double-digit RoW
  • 26. Selected Deals andTerms-TCVs in Development Licensee/Licensor Date Assets Terms Aduro Biotech/BioSante Pharma 04/11 GVAX pancreas, prostate vaccines Phase 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 licenseVical technology forTCVs; $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
  • 27. Selected Deals andTerms-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 (nowOncothyreon) 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 toWW rights; $10M upfront, additional $950M if option exercised
  • 28. PartneringTCVs 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
  • 29. 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 Prepared by 2911 Advisers