Download Taking Immunotherapy to the Next Level

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.
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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
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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)
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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
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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
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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
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*
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
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IHC Staining: CD8 +
Phase II Achieves Primary and Secondary Endpoints
Groups
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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
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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
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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
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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
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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
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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
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Design
Alternative Technologies
DNA
Manufacturing
Alternative Technologies
Management & Financials
Management
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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INTERNALLY
FUNDED
Cancer Programs
Phase I
Phase II
EXTERNALLY FUNDED
Infectious Disease
Programs
Phase III