VGX-3100: Induction of Potent Immune Responses in Post-LEEP CIN 2/3 Following Immunotherapy with HPV 16 & 18 Syncon DNA Vaccines

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1 VGX-3100: Inductin f Ptent Immune Respnses in Pst-LEEP CIN 2/3 Fllwing Immuntherapy with HPV 16 & 18 Syncn DNA Vaccines Niranjan Y. Sardesai, Ph.D. Sr. Vice President, Research & Develpment Vaccines Renaissance Cnference IV Prvidence, RI Octber 21, 2010 Page 1 Signs f ur times O Hare Airprt, Mar 2010 San Dieg Airprt, Jan 2010 Page 2 1

2 Pints t Cnsider Nt enugh attentin t vaccines US GDP = $14.2 Trillin Ttal healthcare spending = 15.3% f GDP Of which US gvt. cvers 45.8% HHS budget = 879 Bn Glbal Pharmaceutical Market Size = $773 Bn (2008) Glbal vaccine sales = $20 Bn Develpment cst f an average drug = $ 1.32 Bn (2006) Vaccine innvatin is critical Lw hanging fruit have been plucked New technlgies are needed References: 2009 WHO Statistics n Glbal Healthcare Expenditure; PhRMA 2010 Prfile; Sci. Am. Pathways 2010 Page 3 Attractiveness f DNA Vaccines Safety - eliminate vectr induced respnses Able t bst repeatedly Generate T-cell and/r antibdies Greater ptency than viral vectrs in primates and in humans Cmbinatin vaccines pssible Develpment speed Ease f manufacture & strage Electrpratin is a key enabling technlgy eliminating the need fr cmplex viral r lipid vectrs Page 4 2

3 INO: Fulfilling the Prmise f DNA Vaccines N vectr induced respnses repeat bsts; multiple/cmbinatin vaccines Greater ptency than viral vectrs in primates and in humans Manufacturing advantages Page 5 Hw Electrpratin Delivers DNA Vaccines Electrpratin (electrical field)-based DNA delivery: Efficient: 1000X increase in DNA uptake N residual carrier/vectr t lead t txicity/vectr immunity Elicits T cell and antibdy immune respnses Page 6 3

4 SynCn DNA Vaccines + EP: Strng T-Cell & Antibdy Respnses SIV vaccine mdel (NHP) UPenn/Merck/Invi IFN-g Elispt Prliferatin DNA + EP Ad5 DNA + EP Ad5 Ref: Weiner et al. Mlecular Therapy, August 2010 Page 7 Key DNA Vaccine Develpment Prgrams Preclinical Prgrams Dengue fever, CHIKV Malaria: funded by MVI PATH (Gates Fund. NGO) Next-gen HCV (PA- CARE grant) HIV: NIH/DAIDS HVDDT Cntract Gvt./NGO Funding NIH/NIAID/DAIDS MVI DOD, CDMRP DTRA Page 8 4

5 Annual Cervical Disease Burden due t HPV in US 2 nd largest cancer killer amngst wmen wrldwide Cervical cancer HPV16/18+ CIN2/3 11,000 new cases/year (500,000 + ww) ~250K CIN2/3 HPV16/18+ ASCUS CIN risk ~500K ~1 millin ASCUS / HPV infectins Paps, HPV testing, Clpscpy 20+ Millin HPV Infected 50+ Millin Pap Smears ~3 millin Page 9 Therapeutic HPV Vaccines fr Cervical Cancer Treatment Prphylactic vaccines Aimed at inducing natural immunity against HPV infectin. They generate serum-neutralizing antibdies. Anti-L1-directed vaccines are designed fr preventive purpse (Merck; GSK) Therapeutic vaccines Fcused n wmen with active disease/hpv expsure. Aimed at eliminating r cntrlling existing infectin r disease prgressin. Inductin f strng cell-mediated respnses. HPV E6 and E7 prteins are gd targets fr therapeutic vaccines as they are expressed in mst f the HPV-related (pre) cancerus tumrs. A vaccine/therapeutic including types 16 and 18 culd ptentially treat 70+% f cervical cancers. 10 Page 10 5

6 Therapeutic HPV Vaccines fr Cervical Cancer Treatment Previus Studies: MVA based HPV E6/E7 vaccines Transgene/Rche: Phase IIa (n = 21) cmpleted; Phase IIb (n = 200) recruiting Ad5, SFV (Semliki Frest virus)-based HPV E6/E7 vaccines Prtein/Peptide-based vaccines Listeria-based vaccines DNA-based vaccines (TC Wu) Use gene gun techniques t intrduce HPV DNA vaccines directly int APCs. Hwever Safety and immune interference issues were reprted Vaccinatin with HPV DNA vaccines was able t induce lw HPV-specific CTL In E6/E7 transgenic mice culd nt vercme immune tlerance. Lw immune respnses bserved in human clinical trials - cultured elispts needed t see cellular respnses - n antibdy respnses induced. Page 11 Histrical Data: HPV16 E6 and E7-specific T cell respnses induced by a HPV DNA vaccine in humans IM injectin: 5/15 patients shwed E7-specific respnses, 2/15 patients shwed E6-specific respnses, the T cell immune respnses required several days f culture t be bserved. Vaccinatin did nt elicit antibdy respnses Trimble C L et al. Clin Cancer Res 2009;15: Page 12 6

7 Tumr size (mm) Tumr size (mm) VGX-3100: SynCn Immungen Design CnE6E7 (16CnE6E7) IgELS HPV-16 E6 HPV- * * * Endprtelytic cleavage site 18CnE6E7 IgELS HPV- Endprtelytic cleavage site HPV- * * * * Deletins r mutatins imprtant fr p53 binding and degradatin Mutatins in Rb binding site Page 13 Vaccinatin with pcne6e7 delays/prevents tumr grwth pvax pcne6e7 pe7 Yan et al (2009) Vaccine Prphylactic mdel - mice pv A X 18 pc ne 6 E 7 16 pe 7 14 Grups 1. pvax 2. pcne6e7 3. pe Days after tumr implantatin Therapeutic mdel - mice Nte: TC1 Challenge mdel - Lung Epit. Cell line with HPV-16 E6, E7 Page 14 7

8 High Cncentratin, High Purity Frmulatins VGX-3100 (HPV) Test pgx3001 pgx3002 Nucleic Acid Cncentratin 6.0 mg/ml 6.0 mg/ml Purity (A260/280) Hst-Cell RNA 0.1% 1% Hst-Cell Prtein 0.1% 0.1% Hst-Cell DNA 0.001% 0.001% Endtxin 0.1 EU/mg 0.1 EU/mg Micrbial Limits Absent Absent VGX-3400 (Influenza) pgx2001 pgx2002 pgx mg/ml 8.1 mg/ml 8.5 mg/ml % 0.08% 0.07% 0.03% 0.04% 0.04% 0.001% 0.001% 0.001% 1.1 EU/mg 1.2 EU/mg 1.9 EU/mg Absent Absent Absent Nw rutinely achieve upwards f 10+ mg/ml t supprt multiplasmid frmulatins Page 15 HPV Distributin in Invasive Cervical Cancer HPV types 16 r 18 accunt fr > 70% ICC and > 55% HSIL wrldwide Ref: Smith et al Int. J. Cancer (2007) Page 16 8

9 HPV-001: Phase 1 Study - Safety & Immungenicity Cmbinatin f HPV DNA vaccine delivered IM using Cellectra EP device HPV 16, 18 (E6 + E7) Study Ppulatin: Patients with a histry f CIN 2/3 previusly treated by LEEP prcedure Sites: Nrth Carlina, Pennsylvania, Puert Ric Chrt Number f Patient Dse(mg) 0.3 X 2 Plasmids 1 X 2 Plasmids 3 X 2 Plasmids Sampling Vaccinatin Mnth Patients were vaccinated 3x at 0, 1, 3 m. Serum and PBMC samples cllected at multiple time pints befre and pst immunizatin t evaluate immune respnses. Page 17 HPV-001 Summary f AEs by Grade and Chrt Injectin Site Reactins (Subject Cunt) Adverse Events (Subject Cunt) Grade Chrt 1 (0.6mg) (n=6) Vaccinatin a 0 Vaccinatin Vaccinatin b 0 Chrt 2 (2mg) (n=6) Vaccinatin Vaccinatin Vaccinatin Chrt 3 c (6mg) (n=6) Vaccinatin d 0 Vaccinatin Vaccinatin a Grade 3 tensin headache assessed by investigatr as nt related t study drug b Grade 3 gastrenteritis viral assessed by investigatr as nt related t study drug c All data is current thrugh September, 2010 with n subjects in Chrt 3 having received vaccinatin 3 d Grade 3 wrist fracture assessed by investigatr as nt related t study drug Page 18 9

10 C1 D0 C1 PD2 C1 PD3 C2 D0 C2 PD2 C2 PD3 C3 D0 C3 PD2 C3 PD3 C1 D0 C1 PD2 C1 PD3 C2 D0 C2 PD2 C2 PD3 C3 D0 C3 PD2 C3 PD3 OD 450 OD 450 HPV 16 & Abs by Chrt and Vaccinatin 2.5 HPV (1:150) ELISA Data 2.5 HPV (1:150) Representative Western Blt (Chrt 2) Overall: 15/18 Ab psitive t > 1 Ag (mst > 2) Respnses persist t > 9 mnths Page 19 HPV16, Western Blt Sercnversin in 14/15 Evaluable Samples Page 20 10

11 Cellular Respnses Induced by VGX3100/EP 0.3 mg/plasmid 16 E6 1 mg/plasmid 16 E6 16 E6 16 E6 16 E mg/plasmid 16 E6 16 E6 16 E Overall 13/18 (72%) Fully interpretable 13/16 (81%) E6 13/18 (72%) E7 9/18 (50%) Bth HPV16 & 18 11/18 (61%) Respnses frequently persist 6 mnths pst final immunizatin High Backgrund Page 21 VGX-3100 Phase I Study Cnclusins IM administratin f VGX-3100 by EP with CELLECTRA device was safe and generally well tlerated. N SAEs r study related grade 3 r 4 AEs reprted All subjects cmpleted 3 dse regimen VAS (tlerability scres) averaged 6.2/10 immediately after vaccinatin and decreased t 1.4/10 within 10 min Vaccine induced antigen specific cellular respnses t HPV 16 & 18 and E6 and E7 bserved 13/18 (72%) psitive by IFN-g ELISpt (> 50 SFU/10 6 PBMC) Magnitude increased with dse upt > 2500 SFU/10 6 PBMC fr a single antigen and > 5,670 SFU/10 6 PBMC fr all 4 antigens 4 subjects respnded t all 4 Ags Respnses persist t >9 mnths Vaccine induced Ag specific Ab respnses bserved against all 4 antigens High titers measured in 15/18 (83%) subjects Respnses persist t > 9 mnths Phase 2 study in untreated subjects with CIN 2/3 planned Page 22 11

12 Visual Analg Scale (VAS) Scre (Cm) CELLECTRA EP Device Tlerability Scres (IM, MID) IDEP 7.0 IMEP Minimally Invasive Device 3.0 Mean +/- sem EP: Electrpratin Cllectin Time After EP (Min) ID-EP IM-EP Time (Min) Mean 95% CI Range Mean 95% CI Range (-0.21) (-0.16) (-0.01) (-0.01) Page 23 ID & MID: Next Generatin DNA Delivery Systems fr B-cell Targets and Prphylactic Vaccinatin Prtable Crdless System Prtable Tethered System Flu Malaria Dengue CHIKV RSV Smallpx Surface EP System Page 24 12

13 NHP Challenge: Impact n Viral Replicatin 8 Plasmid Small Px Antigen Frmulatin High cncentratin; 1 mg/plasmid Mnkeypx challenge iv infused with 2 x 10 7 PFU f mnkeypx virus NR-523 Neuts by M. Slifka lab DNA cmpared t Dryvax Hira et al. J. Infect. Diseases (in press) Page 25 NHP Challenge: Impact n Clinical Disease Mrbidity (% Weight Lss) Lesins pvax1 IM ID Trs Hand Hira et al. J. Infect. Diseases (in press) Page 26 13

14 Cnclusins: Enhanced DNA Vaccines Cncerted develpment f vaccine, frmulatins, and delivery is critical. SynCn DNA vaccines delivered via Invi EP drives imprved humral and cellular immune respnses in many imprtant species Respnses mimic r can be superir t thse induced by live vaccine vectrs CTL and Antibdies Immune phentypes induced appear diverse and manipulatable allwing targeting f multiple pathgens and disease states SynCn - EP platfrm impacts disease r infectin in mdels f SIV, mnkeypx, malaria, chikungunya, cancer and influenza Preliminary data frm universal influenza and therapeutic HPV vaccines is prmising Page Acknwledgements Invi Amir Khan Kate Brderick Maria Wang Steve Kemmerer Xuefei Shen Feng Lin Janice Mendza Jay McCy Jessica Lee Mary Giffear Mark Bagarazzi J. Jseph Kim University f Pennsylvania Jian Yan Matthew Mrrw Devn Shedlck Jean Byer Karuppiah Muthumani David Weiner BIOQUAL, Inc. Mark Lewis Hanne Andersn VGXI, Inc. Henry Hebel Ying Cai SRI Peter Silvera Funding: NIH/NIAID/DAIDS; MVI-PATH DTRA; CDMRP Public Health Agency f Canada Gary Kbinger Ami Patel, Shane Jnes Page 28 14

15 Invi Bimedical Develping the next generatin f vaccines t prevent and treat cancers and infectius diseases investr.relatins@invi.cm NYSE Amex: INO Page 29 15