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Taking Immunotherapy to the Next Level IT’S ALL ABOUT THE T-CELLS J. Joseph Kim, Ph.D. President & CEO March 2017 NASDAQ: INO Forward Looking Statement 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 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, 2016 and other regulatory filings from time to time. 2 Leading the Development of DNA-based Immunotherapies to Commercialization Powerful platform, multiple products Efficacy in phase II study Our purpose Develop immunotherapies and vaccines to fight cancers and infectious diseases Phase III and immuno-oncology combo studies starting 1H17 3 Major partnership: MedImmune/AstraZeneca Executing “Inovio Vision 2020” 1 2 HPV-related pre-cancers Immuno-Oncology (VGX-3100) Filed for marketing approval 4 Filed for marketing approval or in pivotal study 3 Infectious diseases Filed for marketing approval or in pivotal study Immune Responses by Design Optimized platform: SynCon® + CELLECTRA® • SynCon® antigen genetic code enables precise targeting of cancer or pathogen • Designed to break tolerance and cover mutating strains • Highly optimized SynCon plasmid + novel CELLECTRA delivery generate optimal antigen production IN THE BODY • Activates robust functional CD8+ killer T cell and antibody responses • Phase II efficacy • Highly favorable safety profile in over 1300 subjects and 3800 immunizations 5 SynCon Immunotherapy CELLECTRA 5PSP Device VGX-3100, HPV-Related Diseases Inovio Vision 2020 Roadmap Cervical Dysplasia Phase II completed Start PIII 1H17 Filing for marketing approval by 2020 Other HPV Neoplasias Preparing INDs (VIN, AIN) 6 Start PII 2017 1 Fulfill Unmet Treatment Needs of HPV Related Diseases Annual Incidence US: 195,000 CIN2/3 EU: 233,000 High Grade Cervical Dysplasia (CIN 2/3) • Current CIN excisional and ablative procedures increase risk of pre-term births from 5.6% to 10.7%; Kyrgiou et al meta-analysis published June 2016 in British Medical Journal US: 23,000 VIN EU: 15,000 US: 13,400 AIN EU: 2,514 • Existing procedures cannot eliminate HPV outside treated area; recurrence risk postLEEP is 10-16% • VGX-3100: potential first-line therapy; first non-surgical treatment option Vulvar & Anal Neoplasias • No good existing treatments • Surgery is disfiguring 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 7 Demonstrated Efficacy in Phase II Trial of VGX-3100 Placebo-Controlled, Randomized, Double Blind • VGX-3100 SynCon® product for HPV-related pre-cancers • Targets HPV 16/18 subtypes, E6/E7 oncogenes Primary Endpoint • Regression of CIN2/3 to CIN1 or normal (week 36) • 167 subjects • 18-55 year old females • High-grade cervical dysplasia (CIN2/3) • HPV 16 and/or 18 positive • 3:1 randomization • Dosing: week 0, 4, 12 8 Secondary Endpoint • Regression of CIN2/3 to CIN1 or normal and clearance of HPV (week 36) VGX-3100 Specific T Cells1 Robust Functional Antigen-Specific T Cells Measured in Blood 800 VGX-3100 Placebo 600 400 * * * 200 0 0 5 10 15 20 Study Week Treatment at wks 0, 4, & 12 *Statistically significant; bars are 95% Cl • 167 subjects • Published in The Lancet September 2015 • 1 Spot forming units/106 PBMCs above baseline 9 * 25 30 35 40 CD8+ T Cells Infiltrate Diseased Tissue, Clear HPV Virus and Lesion Regression of CIN3 & HPV to normal Increase and persistent presence of infiltrating CD8+ killer T cells Week 36 Week 0 “Cold” “Hot” IHC Staining: Lesion/HPV 10 IHC Staining: CD8 + Phase II Achieves Primary and Secondary Endpoints Groups 11 Secondary Endpoint 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=0.017 p=0.001 p=0.006 P-value1 • • • • • Primary – Post Hoc Primary Endpoint Efficacy correlates to immune responses PP and mITT p-values equal 167 subjects Paper published in The Lancet September 2015 1Strata-adjusted HPV Cervical Dysplasia Phase III Goal: Commercialize first medical alternative focused on preserving women’s reproductive health; regress HPVcaused lesions and eradicate virus itself • Scaled biologic manufacturing to commercial facility • Completed CELLECTRA® commercial delivery device design, manufacturing process, production • Phase III trial design similar to phase II • < 400 total subjects • Phase III trial package submitted. FDA requested additional device-related information; placed program on clinical hold prior to initiation • Aim to initiate phase III in 1H 2017 12 Immuno-Oncology Inovio Vision 2020 Roadmap INO-3112 HPV Cancer Killer T cells shown in phase I INO-5150 Prostate Cancer P1 enrollment completed IO combination trial start 1H17 Preliminary data 1H17 One pivotal study or filing for marketing approval by 2020 INO-1400 hTERT 9-cancer trial assessing immune responses Start PI/II 1H17 INO-5401 New Cancer Target Multi-antigen immunotherapy + checkpoint inhibitor 13 2 Holy Grail of Immuno-Oncology: Turning “Cold” Tumors to “Hot” Tumors Need presence of robust, antigenspecific, functional CD8+ killer T cells to leverage the capabilities of checkpoint inhibitors: KOLs Checkpoint combinations Checkpoint monotherapies Few tumors responsive. Successes: only 15-20% response rates in most cancers 14 Modestly higher response rates Toxicity up DRAMATICALLY Checkpoint inhibitors combined with Inovio’s cancer vaccines Two studies starting in 2017: - INO-3112 with MedImmune - INO-5401 Turning “Cold” Tumors to “Hot” Tumors Control: FoxP3 Before treatment with INO-3112 After treatment with INO-3112 15 CD8 Infectious Diseases Inovio Vision 2020 Roadmap CHRONIC INFECTIONS INO-1800 HBV P1 enrolling P1 data 2H17 EMERGING INFECTIONS INO-4212 Ebola P1 expanded: 200 patients GLS-5300 MERS P1 fully enrolled GLS-5700 Zika Two phase I studies 16 Additional data 1H17 Immune response data 1H17 Additional data 2017 Discuss potential regulatory path 2017 One pivotal study or filing for marketing approval by 2020 3 GLS-5700 Zika Vaccine Protects from Death and Illness ZIKV-prME pVax1 pVax1 i ZIKV-prME (x1) ii % Survival 100 v X20 80 X20 60 iii X40 iv vi n=10 2x106 40 X20 20 0 X20 0 5 10 15 20 25 X20 30 Post Challenge (Days) • ZIKV infection caused severe brain pathology in mice • In contrast, vaccinated animals presented with normal histopathology in brain tissues • Data supporting that protective antibodies induced by synthetic ZIKA-prME vaccine could limit viral induced disease in the brain Emerging Disease Vaccine Development Opportunities Rapid response technology platform desired by health authorities to fight emerging infectious diseases Development Time Frames DNA • Inovio technology demonstrates rapid design, manufacturing, and clinical development of new vaccines, e.g. Zika • Financial drivers • Grants, such as DARPA $45M Ebola award, Gates $8.8M • Priority review voucher potential • Stockpiling contracts: scale manufacturing • Commercial opportunity for some diseases 18 Design Alternative Technologies DNA Manufacturing Alternative Technologies Management & Financials Management 20 J. Joseph Kim, PhD President & CEO Peter Kies CFO Niranjan Y. Sardesai, PhD; COO Mark L. Bagarazzi, MD CMO • Decades of biotechnology/ pharma management • Merck: hepatitis A and B vaccines manufacturing; HIV vaccine (Ad5) R&D • Ernst & Young • Experience with growth companies • Extensive biotech management and product development experience • Led diagnostics development for mesothelioma, bladder cancer, and ovarian cancer for Fujirebio Diagnostics • Clinical research experience incl. Merck • Led clinical/regulatory for shingles and rotavirus vaccines; DNA vaccine expert Board of Directors Avtar Dhillon, MD Chairman, BOD • Seasoned venture capitalist and biotech entrepreneur J. Joseph Kim, PhD • President & CEO, Inovio 21 Simon X. Benito • Former Senior Vice President, Merck Vaccine Division Adel Mahmoud, PhD • Professor, Princeton Univ. • Former President, Merck Vaccines • Responsible for Gardasil®, Zostavax®, Proquad® and Rotateq® Angel Cabrera, PhD • President, George Mason University David B. Weiner, PhD • Executive VP, The Wistar Institute; Director, Vaccine Center Morton Collins, PhD • General Partner, Battelle Ventures and Innovations Valley Partners Nancy Wysenski, MBA • Former COO of Endo Pharmaceuticals and Vertex Pharmaceuticals Scientific Advisory Board 22 David B. Weiner, PhD Chairman Anthony W. FordHutchinson, PhD Stanley A. Plotkin, MD • “Father of DNA vaccines” • Executive VP, The Wistar Institute; Director, Vaccine Center • Former SVP, Vaccines R&D, Merck • Oversaw development: Singulair®, Januvia®, Gardasil®,Zostavax®, Proquad® and Rotateq® • Developed rubella and rabies vaccines • Oversaw Sanofi flu vaccine • Emeritus Professor, Wistar Institute & University of Pennsylvania Financial Information Recent share price1 $6.68 Shares outstanding2 74.1 M Market cap1 $494.9 M Cash & short-term investments2 3 $104.8 M Debt2 0M 1March 3 10, 2017 2December 31, 2016 Due from ApolloBio Corp: up to $50M in signing fee, milestone and equity investment, the latter two contingent upon lifting of clinical hold 23 Upcoming Value Drivers and Milestones Report MERS phase I immune response and safety data (interim) VGX-3100 (CIN) phase III study initiation Publish Zika phase I immune response and safety data 24 INO-3112 Initiate checkpoint inhibitor combo study Report INO-5150 (prostate) immune response and safety data (interim) Publish Ebola clinical data in peer-reviewed manuscript Advance INO-5401 new cancer target program VGX-3100 (VIN) phase II study initiation Investment Thesis: Inovio Positioned with Multiple Transformational Steps as an Immunotherapy Leader Taking immunotherapy to the next level Powerful technology platform Best-in-class data INO: NASDAQ Entering phase III 25 Validation: partners, publishing, grants Appendix Inovio Refines and Validates DNA Immunotherapies Inovio has built leading knowledge capital and IP Right Immune Targets, Genetic Sequences & Delivery Method Breakthrough in vivo generation of immune responses in large animals. 2005-2009 27 Immune Responses Validated in Humans Integrated technology platform achieves robust immune responses in humans. 2010-2013 T Cell Related Efficacy in Humans Late Stage Development & Commercialization Killer T cells generated in the body correlated to efficacy. Launching P3 and combo cancer studies. Pursuing efficacy data in multiple studies. Strong immune responses across multiple diseases. 2014-2016 2017-2020+ Optimized DNA with Safe & Effective Delivery to Generate Significant T Cells with Killing Activity Synthetic Consensus DNA Protective universal antibodies and killer T-cells produced by immune system against a virus or cancer self-antigen 28 Enhanced Cellular Delivery: Key Enabler of DNA Immunotherapies • DNA plasmids must get through protective membrane into a cell to work • Best method to enhance cellular uptake is electroporation • SynCon® DNA plasmid and CELLECTRA® delivery device are phase III ready CELLECTRA® 5PSP Device 29 CELLECTRA® 5PSP Electroporation Delivery Device Drug Array 30 Natural Immune Activation in the Body Effective, efficient, safe in vivo T cell and antibody activation Deliver plasmids into human cells using electroporation ANTIGENIC PROTEINS T cells eliminate cells displaying disease-specific antigen(s) 31 Immune system recognizes “foreign” antigens; activates antigenspecific T cells and antibodies Cellular machinery uses genetic code to produce disease antigens Design + Delivery = Improved Immune Responses T Cell Responses By ELISpot Assay Optimization 5000 3000 2000 1000 EP 1 x 10-6 spleenocytes 4000 0 Display of GFP gene expression after electroporation delivery into rabbit muscle 32 +EP Immunized 3x with 15ug pNP responses @2 wk post Imm Clinical Confirmation of Inovio Electroporation Benefit HIV Antigen Response P= 0.0003 90 P < 0.0001 80 % Responders 70 60 50 + EP 40 30 • CD4 and CD8 intracellular cytokine staining (IFN-γ, IL-2) response associated with IL-12 and EP administration (2 clinical studies) with HIV gag, pol, env antigens/plasmids • Dosing at 0, 4, 12 weeks • Performed by independent HVTN Core Lab at University of Washington in NIH-sponsored trials - EP Responses to three doses of vaccine delivered with EP are greater than responses to four doses of vaccine delivered IM 20 † 10 0 - IL-12 + IL-12 CD4+ Responders (%) 33 - IL-12 + IL-12 CD8+ Responders (%) Spyros A. Kalams, et al., The Journal of Infectious Diseases 2013;208:818–29 HVTN 080 (N = 48 total). Responses shown against global peptides post-third dose, based on evaluable responders. ‡ HVTN 070 (N = 120 total). Responses shown against global peptides post-third dose, based on evaluable responders. First Partnership to Initiate Immuno-Oncology Strategy AstraZeneca/MedImmune (deal signed August 2015) Products INO-3112 HPV-driven cancer immunotherapy + 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 MedImmune intends to study INO-3112 in combination with selected immuno-oncology molecules within its pipeline 34 Granulysin Granzyme A Granzyme B INO-3112 Drives Antigen Specific CD8+ T Cells with Lytic Phenotype in Patient with HPV16/18 Head & Neck Cancer Perforin • Lytic phenotype: patient PBMCs stimulated 120 hours in vitro with antigen. No costimulation; no cytokine added at any time. • Activation markers: CD38, CD69, CD137 • Lytic proteins: perforin, granzyme A, granzyme B, granulysin 35 Induction of CD8+ Activation, Lytic Protein Synthesis, and Humoral Immune Responses to HPV 16 and 18 in INO-3112 Treated HNSCC Patient % C D 8 /C D 3 8 & C D 6 9 & C D 1 3 7 IN O - 3 1 1 2 HPV 16/18 Specific CD8+ T Cell Activation 1 .0 0 .8 0 .6 0 .4 0 .2 0 .0 B e fo re A fte r IN O - 3 1 1 2 IN O - 3 1 1 2 HPV 16/18 Specific CD8+ T Cell Activation and Expression of Lytic Proteins 8 of 9 patients show CD8+ responses to INO-3112 Representative patient 36 Before INO-3112 After INO-3112 Before INO-3112 After INO-3112 dMAb™ Products: Multiple Immune Mechanisms & Products Inovio’s DNA-based monoclonal antibody products target: Cancers • Checkpoint Inhibitors (CI) • PD-1 • PD-L1 • 4 additional CIs • Herceptin • Anti-Tregs • Other anti-cancer pathways 37 Infectious Diseases • • • • • • • • • Influenza A Influenza B Pseudomonas MRSA/Staph Ebola MERS Dengue CHIKV Other infectious diseases DARPA funded programs Promising Preclinical dMAb Data Dengue dMAb (Nature Scientific Reports 2015) Tumor Clearance (%) 100% 80% 60% 70% 40% 20% 0% 0% dMAb (7 of 10) Control (0 of 10) Protection in Challenge with Dengue Virus (%) Cancer dMAb Prostate cancer model in mice (Unpublished data) 100% 100% 80% 60% 40% 20% 0% 0% dMAb (10 of 10) Control (0 of 10) DARPA awards $57M to advance dMAb application and develop products for Ebola, influenza and antibiotic resistant bacteria 38 Antigen-Generating/T Cell Activating SynCon® Products Product Name Indication Preclinical VGX-3100 Cervical Dysplasia Therapeutic INO-3112 HPV-Related Cancers Therapeutic INO-1400 hTERT (antigen) Therapeutic INO-5150 Prostate Cancer Therapeutic INO-5401 Cancer Target Therapeutic INO-1800 Hepatitis B Therapeutic INO-8000 Hepatitis C PENNVAX®-GP HIV Therapeutic Preventive Preventive/ Therapeutic INO-4212 Ebola Preventive GLS-5300 MERS Preventive GLS-5700 Zika Preventive EXTERNALLY FUNDED Cancer Programs 39 INTERNALLY FUNDED Cancer Programs Phase I Phase II EXTERNALLY FUNDED Infectious Disease Programs Phase III