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Taking Immunotherapy to the Next level
- 1. NASDAQ: INO Taking Immunotherapy to the Next Level I T ’ S A L L A B O U T T H E T - C E L L S J. Joseph Kim, Ph.D President & CEO
- 2. Forward Looking Statement 2 Our commentary and responses to your questions may contain forward-looking statements, including comments concerning clinical trials and product development programs, evaluation of potential opportunities, the level of corporate expenditures, the assessment of Inovio’s technology by potential corporate partners, capital market conditions, timing of events, cash consumption and other subjects. Information concerning factors that could cause actual results to differ materially from those set forth in our Annual Report on Form 10-K for the year ended December 31, 2015, our Form 10-Q for the quarter ended March 31, 2016, and other regulatory filings from time to time.
- 3. Inovio Highlights 3 VGX-3100 Phase II clinical proof of concept in pre-cancer First to show CD8+ T cells generated in vivo can clear disease Published in The Lancet Two pharma partnership deals (~$1 billion in milestone payments) Over $130M in non-dilutive grants/contracts in last six years $146.8M in cash and short-term investments, Mar. 31 Highly experienced management team, board of directors, and scientific advisory board DNA-based immunotherapy and cancer vaccine technology Cancers | Infectious Diseases
- 4. What We Do
- 5. Immune Activating Technology • Genetic sequence encoded for specific immune mechanism • Activates target immune functions directly in the body • Highly optimized DNA plasmids • Novel sequences patentable Core Technology Leverages Synthetic Biology 5 Up-regulate desirable immune mechanisms Optimize manufacturing, safety, with in vivo mechanism To fulfill unmet needs in: CANCER | INFECTION
- 6. Multiple Immune Mechanisms, Products, Diseases. How? In-vivo generation of immune components capable of fighting disease 6 Generate • SynCon® antigens • Monoclonal antibodies Activating • CD8+ killer T cells • Polyclonal antibodies • Checkpoint inhibition • Tumor blocking pathways • Cytotoxicity Products • Multi-antigen • Monotherapies • Combinations • Prevention • Treatment Disease Targets • Cancer • Infectious diseases Driving synthetic biology to achieve vital immune activation outcomes Encoded DNA Plasmids
- 7. What Have We Accomplished? A N T I G E N G E N E R AT I O N / T C E L L A C T I VAT I O N
- 8. What does an Effective T Cell Activating Immunotherapy Need to Accomplish? 8 Target cell T Cell Cytotoxic T lymphocyte Must be CD8+ killer T cells Induce significant T cells in vivo Antigen-specific Activated with killing function Go to diseased tissue Seek and destroy diseased cells
- 9. The Proof: VGX-3100 Phase II in HPV Cervical Dysplasia 9 Placebo-Controlled, Randomized, Double Blind • Targets: HPV 16/18 E6/E7 oncogenes • 167 subjects • 18-55 year old females • High-grade cervical dysplasia (CIN2/3) • HPV 16 and/or 18 positive • 3:1 randomization Primary Endpoint • Regression of CIN2/3 to CIN1 or normal (6 months post third dose: week 36) Secondary Endpoint • Regression of CIN2/3 to CIN1 or normal and clearance of HPV
- 10. Best-in-Class Functional T Cell Responses Activated In Vivo… 10 Phase II study of VGX-3100 HPV antigen generating immunotherapy in high grade cervical dysplasia *Statistically significant; bars are 95% Cl VGX-3100800 600 400 200 0 0 5 10 15 20 25 30 35 40 Placebo Study Week VGX-3100SpecificTCells (SFU/106PBMCsAboveBaseline) Treatment at wks 0, 4, & 12 * * * * • 167 subjects • Paper published in The Lancet September 2015
- 11. Phase II Achieves Endpoints: Clinically Significant Efficacy 11 • Efficacy correlates to immune responses • PP and mITT p-values equal • 167 subjects • Paper published in The Lancet September 2015 Regression high grade to low grade cervical dysplasia or normal Dysplasia regression to low or normal AND HPV clearance Lesion regression to normal VGX-3100 49.5% 40.2% 40.2% Control 30.6% 14.3% 16.7% Difference 18.9% 25.9% 23.5% P-Value p=0.017 strata-adjusted p=0.001 strata-adjusted p=0.006 strata-adjusted Groups Primary Endpoint Secondary Endpoint Primary – Post Hoc
- 12. VGX-3100 Efficacy Visualized: Lesion/HPV Clearance and Tumor Infiltrating T Cells 12 Week0:CIN3pathology IHC Staining: Lesion/HPV Week36:Nosignificantpathology IHC Staining: CD8 + Regression: CIN3/HPV to Normal Persistent Presence of Killer CD8s Significant increase of infiltrating CD8+ T Cells
- 13. Proof of Principle: Technology and VGX-3100 Product - A “First Ever” Result 13 Effective immune activating treatment • Select and encode any antigen • Simple injections into arm • Generate antigen-specific CD8+ killer T cells • Measurable in blood and observed in diseased tissue (tissue infiltrating T cells) • Regress disease to normal • Clear virus causing the disease • Direct correlation between CD8+ T cells and efficacy Immune system’s disease fighting mechanisms are common across all diseases • Data supports utility of SynCon® products across cancers and infectious diseases Favorable safety profile shown in over 600 treated subjects (without serious adverse events)
- 14. Data Supports Advancing HPV Immunotherapy • Potential as first non-surgical treatment option for cervical dysplasia • First-line therapy preceding surgery Phase III • Scaling biologic and electroporation device production • End-of-phase-II FDA meeting 1H 2016 • Market, pricing and payor research • Planned start 2016 • Targeting other HPV-caused neoplasia indications 14
- 15. EU: 15,000 HPV 16/18-Caused Pre-Cancer Annual Incidence 15 US: 195,000 EU: 233,000 US: 13,400 EU: 2,514 Annual incidences: US EU31 HIGH GRADE CERVICAL DYSPLASIA (CIN2/3) HIGH GRADE VULVAR NEOPLASIA (VIN) HIGH GRADE ANAL NEOPLASIA (AIN) Sources: Bruni L, Barrionuevo-Rosas L, Albero G, Aldea M, Serrano B, Valencia S, Brotons M, Mena M, Cosano R, Muñoz J, Bosch FX, de Sanjosé S, Castellsagué X. ICO Information Centre on HPV and Cancer (HPV Information Centre). Human Papillomavirus and Related Diseases in United States of America. Summary Report 2015-03-20., Henk et al J Low Genit Tract Dis (2010), Insigna et al, Am J Obs Gyn (2004), Hartwig et al. Papillomavir. Res (2015), CDC, www.hpvcentre.net, WHO IARC US: 23,000
- 16. Strategic Implications for Immuno-Oncology A minority of tumors have T cell responses that can respond to immune checkpoint inhibition – and even against those tumors, checkpoint inhibitors are only realizing 20 - 40% response rates 16 Leveraging the encouraging results of checkpoint inhibitors and taking immuno-oncology to the next level requires better T cell generation “You can block all the PD-L1 in the world but it means nothing without infiltrating T cells” — Roy Herbst, Yale “In the majority of patients, T cells either need to be trafficked to the tumor, T cells need to be generated or both in order to see higher response rates with the checkpoints” — Michael Atkins, Georgetown
- 17. Immuno-Oncology Clinical and Commercialization Strategy 17 Monotherapies | Single agent, multi-antigen T cell activating immunotherapies targeting early stage or slowly progressing cancers 1 Combination Therapies With Partners | Combine Inovio antigen-generating immunotherapies with third party checkpoint inhibitors or other immuno-oncology products 2 Combination Therapies In-House | Combine Inovio antigen- generating immunotherapies with proprietary checkpoint inhibitors or other immuno-oncology products based on DNA-based monoclonal antibodies (dMAbs). Keep product development, IP, and downstream profit under one roof; strategic power/flexibility 3
- 18. Validating Immuno-Oncology Partnership 18 Products INO-3112 HPV-driven cancer + 2 new R&D products Upfront Payment $27.5 million Development Costs All development costs Milestone Payments $700 million Royalties Up to double digit tiered royalties on INO-3112 + royalties for additional cancer vaccine products AstraZeneca/MedImmune (August 2015) MedImmune intends to study INO-3112 in combination with selected immuno-oncology molecules within its pipeline
- 19. Where Are We Going?
- 20. Antigen-Generating/T Cell Activating SynCon® Products 20 Product Name Indication Preclinical Phase I Phase II VGX-3100 INO-5150 INO-1400 Phase III INO-3112 Breast/Lung/Pancreatic Cancers Therapeutic Prostate Cancer Therapeutic Cervical and Head & Neck Cancer Therapeutic Cervical Dysplasia Therapeutic INO-1800 Hepatitis B Therapeutic EbolaINO-4212 Preventive PENNVAX®-GP HIV Preventive/ Therapeutic INO-8000 Hepatitis C Therapeutic Preventive/ Therapeutic EXTERNALLY FUNDED Infectious Disease Programs INTERNALLY FUNDED Cancer Programs EXTERNALLY FUNDED Cancer Programs GLS-5300 MERS Preventive/ Therapeutic INO-5400 Cancer Target Therapeutic Zika Preventive/ Therapeutic GLS-5700
- 21. Multi-Antigen Products Position Inovio to be a Leader in Immuno-Oncology 21 Develop multi-antigen cancer immunotherapies based on scientific rationale, unmet need, and commercial attractiveness Create DNA plasmids for multiple antigens to target heterogeneous tumors 50+ well characterized antigens known to have high levels of over-expression in cancer cells Partnership with MedImmune to develop two new cancer products Inovio will initiate a new multi-antigen cancer program in 2016 Plan strategic checkpoint inhibitor combinations
- 23. Peter Kies CFO • Ernst & Young • Experience with growth companies Mark L. Bagarazzi, MD CMO • Clinical research experience incl. Merck • Led clinical/regulatory for shingles and rotavirus vaccines; DNA vaccine expert Management 23 J.Joseph Kim, PhD President & CEO • Decades of biotechnology/ pharma management • Merck: hepatitis A and B vaccines manufacturing; HIV vaccine (Ad5) R&D Niranjan Y. Sardesai, PhD; COO • Extensive biotech management and product development experience • Led diagnostics development for mesothelioma, bladder cancer, and ovarian cancer for Fujirebio Diagnostics
- 24. Board of Directors 24 Nancy Wysenski, MBA • Former COO of Endo Pharmaceuticals and Vertex Pharmaceuticals Simon X. Benito • Former Senior Vice President, Merck Vaccine Division Avtar Dhillon, MD Chairman, BOD • Former President & CEO, Inovio Biomedical Morton Collins, PhD • General Partner, Battelle Ventures and Innovations Valley Partners Angel Cabrera, PhD • President, George Mason University • Former President, Thunderbird School of Global Management J. Joseph Kim, PhD • President & CEO, Inovio Adel Mahmoud, PhD • Professor, Princeton University • Former President, Merck Vaccines • Responsible for Gardasil®, Zostavax®, Proquad® and Rotateq® David B. Weiner, PhD • “Executive VP, The Wistar Institute; Director, Vaccine Center
- 25. Scientific Advisory Board 25 Anthony W. Ford- Hutchinson, PhD • Former SVP, Vaccines R&D, Merck • Oversaw development: Singulair®, Januvia®, Gardasil®,Zostavax®, Proquad® and Rotateq® Stanley A. Plotkin, MD • Developed rubella and rabies vaccines • Oversaw Sanofi flu vaccine • Emeritus Professor, Wistar Institute & University of Pennsylvania David B. Weiner, PhD Chairman • “Father of DNA vaccines” • Executive VP, The Wistar Institute; Director, Vaccine Center Philip Greenberg, MD • Expert in T cell immunology • Head, Immunology Program, Fred Hutchinson Cancer Research Center
- 26. Financial Information 26 1May 20, 2016 2March 31, 2016 Cash & short-term investments2 $146.8 M 0 MDebt2 Shares outstanding2 72.3 M Recent share price1 $10.45 Market cap1 $755.5 M
- 27. Value Drivers and Milestones 34 2016 VGX-3100 End-of-phase II FDA meeting VGX-3100 phase III study initiation Report top-line Ebola vaccine phase I immunogenicity and safety data 27 INO-3112 Conduct checkpoint inhibitor combo study Report Zika large animal data
- 28. Value Drivers and Milestones 34 2016 Initiate clinical study for INO-5400 Report INO-5150 prostate immunogenicity data (interim) Report INO-1400 hTERT immunogenicity data (interim) Initiate phase I study for Zika vaccine 28 Report on MERS vaccine phase I immunogenicity and safety study Publish Ebola clinical data in peer-reviewed manuscript
- 29. Value Drivers and Milestones 34 Additional corporate development deals Additional external funding BEYOND 29
- 30. Investment Summary 30 Mono- & combo therapy strategy with DNA multi- antigen & mAb products Best-in-class efficacy data from in vivo immunotherapy Missing link to take T cell therapies to the next level Multi billion dollar potential across all cancers and infectious diseases Entering phase III 3rd party validation: MedImmune, Roche, DARPA, NIAID, Lancet Taking immunotherapy to the next level
- 31. Appendix
- 32. SynCon® Immune Control: Antigens and T Cells by Design 32 Identify pertinent disease-specific antigens for target disease Encode a DNA plasmid with genetic code for each targeted antigen T cells eliminate cells displaying disease-specific antigen(s) Immune system recognizes “foreign” antigens; activates antigen- specific T cells and antibodies Effective, efficient, safe in vivo T cell and antibody activation Cellular machinery uses genetic code to produce encoded disease antigens ANTIGENIC PROTEINS Deliver plasmids into human cells using electroporation
- 33. Perforin Granulysin GranzymeA GranzymeB • Lytic phenotype: patient PBMCs stimulated 120 hours in vitro with antigen. No co- stimulation; no cytokine added at any time. • Activation markers: CD38, CD69, CD137 • Lytic proteins: perforin, granzyme A, granzyme B, granulysin INO-3112 Drives Antigen Specific CD8+ T Cells with Lytic Phenotype in Patient with HPV16/18 Head & Neck Cancer 33
- 34. HPV 16/18 Specific CD8+ T Cell Activation and Expression of Lytic Proteins HPV 16/18 Specific Binding Antibody Titers 10 of 10 patients show cellular responses to INO-3112 10 of 10 patients show humoral responses to INO-3112 Inovio Pharmaceuticals: Proprietary Data; Sardesai et al. Presentation at World Vaccine Congress, Washington DC (2015) INO-3112 CD8+ Activation, Lytic Protein Synthesis, and Humoral Immune Responses to HPV 16/18 Head & Neck Cancer Patient 34
- 35. dMAB™ Products: Development Milestones and Catalysts 35 > 6 new publications expected in the next year Two dMAb scientific publications to date Technology development fueled by two DARPA grants totaling $57M Advance a portfolio of over 30 dMAb products (cancer, checkpoint inhibitors, infectious diseases, others) First clinical study planned for 2016
- 36. dMAbs™: Multiple Immune Mechanisms & Products Inovio’s DNA-based monoclonal antibody products target: 36 Cancers Infectious Diseases • Influenza A • Influenza B • Pseudomonas • MRSA/Staph • Ebola • MERS • Dengue • CHIKV • Other infectious diseases • Checkpoint Inhibitors (CI) • PD-1 • PD-L1 • 4 additional CIs • Herceptin • Anti-Tregs • Other anti-cancer pathways DARPA funded programs
- 37. Promising Preclinical dMAb Data DARPA awards $57M to advance dMAb application and develop products for Ebola, influenza and antibiotic resistant bacteria 37 0% 20% 40% 60% 80% 100% TumorClearance(%) Cancer dMAb Prostate cancer model in mice (Unpublished data) dMAb (7 of 10) Control (0 of 10) 70% 0% 0% 20% 40% 60% 80% 100% ProtectioninChallengewithDengue Virus(%) Dengue dMAb (Nature Scientific Reports 2015) dMAb (10 of 10) Control (0 of 10) 100% 0%
- 38. CELLECTRA® 5PSP Electroporation Delivery Device 38