TCR-modified T cells

CORPORATE PRESENTATION
"Safe Harbor" Statement
This presentation contains forward-looking statements - that is,
statements related to future, not past, events. These statements
may be identified either orally or in writing by words as "expects",
"anticipates", "intends", "plans", "believes", "seeks", "estimates",
"will", "may" or words of similar meaning. Such statements are
based on our current expectations and assumptions, and
therefore are subject to various risks and uncertainties that could
cause the actual results, performance or achievements to differ
materially from any future results, performance or achievements
that may be expressed or implied by such forward-looking
statements. These factors include, without limitation, those
discussed in our public reports filed with the Frankfurt Stock
Exchange. The company does not assume any obligations to
update or revise any of these forward-looking statements, even if
new information becomes available in the future.
Medigene – clinical stage immunotherapies
Corporate strategy
Development focus
 World class immunotherapy company
 Indications with high medical need
focused on the treatment of cancer
 Strategy concentrated on proprietary
and partnered clinical development in
oncology
 Proprietary programs on hematological
malignancies and TCRs
 T cell directed immunotherapies
 Dendritic cell vaccines (DCs),
phase I/II
 T cell receptor modified T cells
(TCRs), late preclinical stage
 T cell-specific antibodies (TABs),
preclinical stage
Corporate information
 Headquartered in Munich (Germany), with offices in Washington, D.C. and San
Diego, California
 Team of approx. 70 experts in immunotherapy and pharmaceutical development
 Listed on Frankfurt Stock Exchange: MDG1; WKN: A1X3W0
3
Medigene is a full-fledged biopharmaceutical
company
Fully integrated company with expertise in Medical Affairs, CMC (QM, GMP, GLP, GCLP),
Quality Control, Regulatory Affairs, Business Development, Alliance Management, IP,
IR/PR and Administration
4
Immunotherapy ̶ the future of cancer therapy
activation of immune
system
2010 ff
1990 –
2010
treatment of
tumor
Before
1990
Classical
Mainstays
Cancer
Immunotherapies
Newer
Treatments
Hormone therapies
Stem cell transplantation
Small molecule
targeted therapies
Immune response modifiers
Antibody therapies
Surgery
Radiation
DC vaccines
Latest developments:
Adoptive cell therapies
CARs and TCRs
Chemotherapy
5
Immunotherapies’ time has come
Growth of the cancer immunotherapy space based on publications.*
*Source: GEN (March 2016): Cancer Immunotherapy 2016, En Bloc Analysis of the Publications Landscape
Uncovers Trends in the Space by Enal Razvi, Ph.D. and Gary Oosta, Ph.D.
6
Medigene’s platforms are linked synergistically –
to treat different kinds of cancer
Medigene's Immunotherapy Platforms
DC vaccines
TCRs
TABs
7
Medigene’s immunotherapies are tailored to
address different types and stages of cancer
DCs
TCRs
DC vaccines
TCR-modified
T cells
low
tumor
burden
Legend: tumor
; T cell
; DC vaccine
TABs
high
tumor burden
; TCR-modified T cell
; pathogenic T cell
T cell-specific
mabs
unwanted
T cells
8
IIT
Medigene
Medigene’s immunotherapy pipeline
and current IIT trials
PROJECT
INDICATION
DC Vaccine Study
AML
PRECLINICAL/
RESEARCH
PHASE I
PHASE II
PHASE III
0
TCR Study
undisclosed
2017
TCR Study
undisclosed
2018
TABs
T-cell leukemias
+ new applications
DC Vaccine Study
Prostate cancer*
DC Vaccine Study
AML**
TCR Study
Cancer***
2016/2017
* Investigator initiated trial (IIT) Oslo University Hospital
** Investigator initiated trial (IIT) Ludwig-Maximilians University Hospital
***Investigator initiated trial (IIT) with Medigene being part of the consortium, pending grant funding
9
Therapeutic dendritic cell (DC) vaccines
Dendritic cell (DC) vaccines:
induce the maturation of own, cancer-specific dendritic cells and
trigger both T cells and natural killer cells to attack the tumor
TCR-modified
TCR-modified
T cells
T cells
Adoptive T cell therapy with TCRs:
arms patient-derived T cells ex vivo with suitable T-cell receptors
that enable them to detect and efficiently kill cancer cells in vivo
TCR-modified
T cells
T cell-specific antibodies (TABs):
deplete unwanted T cells and track TCR-modified T cells
10
Personalized cancer treatment
with DC vaccines
www.footolia.de
University Hospital Oslo
Dendritic cells get isolated from the patients blood and individually treated in GMP cell culture laboratories.
http://fineartamerica.com/
healthmedicalinfohmi.blogspot.com
www.the-scientist.com
Re-injected dendritic cells activate the body‘s own T cells, to find and attack tumor cells.
11
Medigene’s “new generation” DCs mature fast and
show optimal immunotherapeutic potential
5-7 days
2-3 days
Maturation cocktail (2nd generation)
GM-CSF
+ IL-4
monocytes
2nd generation
7-10-day mature
DCs
1st generation
immature DCs
IL-12high
IL-10low
2 days
GM-CSF
+ IL-4
monocytes
1 day
“New generation”
maturation
cocktail
with TLR 7/8
agonist
mDC
New generation
3-day “polarized”
mature DCs
Optimised
interleukin (IL)
secretion
pattern for
innate and
adaptive
immunotherapy
12
Our lead indication acute myeloid leukemia (AML) High medical need
Disease characteristics:
Most common type of leukemia in adults
About 20,830 cases in USA*
Median age at diagnosis: 63 years
5-year survival rate - adults < 65 years of age: 20 - 50%
adults > 65 years of age: 2 - 10%
*Source: NIH, SEER Stat Fact Sheets: Acute Myeloid Leukemia (AML)
13
Medigene’s DC vaccines provide new therapy
options for older AML patients
Consolidation
therapy and
potential cure
Intense induction
chemotherapy
Allogeneic
stem cell
transplantation
Potential
cure
AML
Evaluation of the patient:
age/co-morbidity/ genetic
profile of leukemia
MRD or
Relapse
Therapy with
Medigene’s
“new generation”
DC vaccines
Relapse
Potential
cure
Long-term
remission
14
Investigator driven studies use Medigene’s
DC vaccine technology to treat AML
Lead indication AML trials
Sponsor
Status
Clinical Study, Investigator-initiated
• AML, intermediate and high-risk pts.
• Phase I/IIa
• Opened: Q1/2014
• 13 of 20 patients enrolled (Q4 2015)
Prof. M. Subklewe
Ludwig-MaximiliansUniversity Munich
NCT01734304
Phase I completed
Phase II opened
Data presented at:
• CRI-CIMT-EATI-AACR 9/2015
• ASH 12/2015
• CIMT 5/2016
Compassionate Use
• 5 patients with AML (Q4 2015)
Prof. G. Kvalheim
Dept. of Cellular Therapy
Oslo University Hospital
Data presented at:
• AACR 4/2015
• PIVAC 9/2015
• ASH 12/2015
• CIMT 5/2016
15
Results from Phase I IIT* and
Compassionate Use** Treatment in AML patients
(presented at ASH 2015 conference by external collaborators)
High success rate for GMP generation of DC vaccines
Efficient logistics for DC vaccine delivery
Vaccine antigens demonstrate immunogenicity
T cell responses as potential biomarkers of DC activity
Excellent safety profile of DC vaccines
*IIT at Ludwig-Maximilians-University Munich; **CU Patients at Oslo University Hospital
16
Medigene’s own DC trial in AML: Phase II part
started in April 2016
Trial design:
Phase I/II: open-label, prospective, non-randomized trial
20 AML patients: 6 phase I + 14 phase II, complete remission after
chemotherapy, not eligible for allo-transplantation
Patients selected with AML expressing the vaccine antigens:
WT-1 with or without PRAME (expressed on LIC/LSC)
Persistent vaccination for 50 weeks and a follow-up period of one year
or until progression
Primary objectives: feasibility and safety
Secondary objectives: induction of immune responses; control of
minimal residual disease (MRD); clinical response: time to progression
(TTP)
ClinicalTrials.gov Identifier: NCT02405338
17
Treatment scheme of Medigene’s DC trial
PHASE I
6 patients
PHASE II
14 patients
DSMB approval
Phase II
started in April
2016
Treatments with Medigene‘s DC vaccines
week 1-4
w6
w 10
w 14
w 18
w 22
w 26
w 30
w 34
w 38
w 42
w 46
w 50
18
Medigene’s DC vaccine technology is also used in
other cancer indications by investigators
Non-haematological
diseases
Non-hematological
diseases
Lead indication
Sponsor
Sponsor
Sponsor
Status
Status
Status
Compassionate Use
• Different tumors and stages
• 6 patients with solid tumors
Prof. G. Kvalheim
Dept. of Cellular Therapy
Oslo University Hospital
Data presented at:
• AACR 4/2015
• PIVAC 9/2015
Clinical Study, Investigator-initiated
• Prostate cancer
• Phase II
• Opened: Q2/2014
• 20 patients recruited, 8 already
completed three years of treatment
Oslo University Hospital
NCT01197625
Patient treatment ongoing
Data presented at:
• PIVAC 9/2014
• AACR 4/2015
• AACR 4/2016
19
Medigene’s “new generation” DC vaccines
overcome the weakness of other DC vaccines
Medigene’s DC vaccines are high quality, fully characterized with >85%
mature polarized DCs
The special DC manufacturing process is patient-oriented, time-saving, costefficient and logistically simplified:
No tumor tissue from patient needed
Only one leukapheresis per patient
Manufacturing time just three days
High quantity yield of dendritic cells for more than 10 vaccinations
Over two years shelf-life of frozen cells
Can be administered to the patient as required
20
TCR-modified adoptive T cell therapy
Dendritic cell (DC) vaccines:
induce the maturation of own, cancer-specific dendritic cells and
trigger both T cells and natural killer cells to attack the tumor
TCR-modified
TCR-modified
T cells
T cells
Adoptive T cell therapy with TCRs:
arms patient-derived T cells ex vivo with suitable T cell receptors
that enable them to detect and efficiently kill cancer cells in vivo
TCR-modified
T cells
T cell-specific antibodies (TABs):
deplete unwanted T cells and track TCR-modified T cells
21
Medigene’s unique TCR platform for high tumor
burdens
2 Isolation of
patient T cells
4
Patient T cells are isolated from
blood samples and activated
2
Appropriate TCR is selected from
off-the-shelf library of
characterized TCRs
3
Anti-tumor TCR is introduced
using a viral vector into patient
T cells
4
Modified T cells are expanded to
large numbers in 10-15 days
5
TCR-modified T cells are
reinfused into patient
1
5
3
1
viral-vector
mediated
TCR transfer
TCR-modified
patient T cells with anti-tumor
specificity
22
Medigene is building up its unique
TCR library of “stress-tested” lead candidates
Library of therapeutic TCRs (as recombinant vectors)
TCR-1
TCR-2
TCR-3
TCR-4
TCR-5
TCR-6
TCR-7 TCR-8
TCR is selected with an HLA-peptide
specificity appropriate for
the patient and the tumor type
TCR-modified patient T cells
Liquid
cancers
Solid
cancers
23
Medigene established a full-scope TCR technology
platform
1. Prime T cells in vitro
2. Identify tumor-specific T cells
3. Isolate TCR sequences
off-the-shelf TCR library
mDC
…
4. Quality test TCRs
…
Specificity
MHC-restriction
Peptide sensitivity
CD8+ & CD4+T cell priming
with mDCs
5. Select TCR for clinical indication
Efficacy
Tumour cell recognition
Cytokine profile
TCR expression
…
6. GMP production & treatment
Patient TCRmodified T cell
therapeutic
Safety
Epitope analysis
Self-peptide library
HLA allo cell panel
On/off-target toxicity
In vivo mouse models
Patient blood
sample
24
Clinical development for TCRs in preparation –
A new treatment option for progressed hematological
diseases
“Cured”: no detectable
disease / molecular
remission
Adoptive T cell therapy
with TCRs
relapsed/
refractory
hematological
diseases
living with minimal residual
disease / chronic state
Relapse
25
Medigene‘s TCR studies in preparation
IIT (Charité/Berlin), pending grant funding (2016):
Clinical indication selected
T cell receptor selected
Viral vector produced by EUFETS
Developments needed to start Medigene’s clinical TCR studies:
Identification of TCRs and pre-clinical work
GMP-conform patient treatment processes
Medigene‘s first company sponsored trial (2017):
Additional viral vector production capacities secured at EUFETS
Selection of commercial manufacturing partner
26
Compared to CARs, Medigene’s TCRs target a
broader spectrum of tumor targets
HER2
CD19
Minor
histocompatibility
antigens
Differentiation
antigens
Mesothelin
CD38
CARs target surface proteins:
App. 30% of human proteome
Limited to cell surface antigens, only tens of
options
Recognition is MHC*-independent
Higher risks of side effects
*MHC: Major Histocompatibility Complex
Universal
antigens
Cancer-germline
antigens
Viral
antigens
Mutations
TCRs target intracellular proteins:
App. 70% of human proteome
Recognize intracellular targets, with many
thousands of options
Recognition is MHC-restricted
Lower risk for side effects if TCRs are natural, nonmutated structures
27
Medigene’s technology delivers natural
optimal-affinity TCRs
Development of a comprehensive library of recombinant T cell receptors
No need for patient samples
Can address so far undruggable targets
In contrast to CAR technology, TCR technology has more starting points
available for recognizing tumor cells:
TCR platform can deliver specific T cell receptors for a large number of
tumor antigens
Non-mutated, fully-human T cell receptors with potential higher efficacy
and tolerability
A wide range of cancers and broad patient populations (diverse MHC
classes) can be reached
28
T cell-specific monoclonal antibodies
Dendritic cell (DC) vaccines:
induce the maturation of own, cancer-specific dendritic cells and
trigger both T cells and natural killer cells to attack the tumor
TCR-modified
TCR-modified
T cells
T cells
Adoptive T cell therapy with TCRs:
arms patient-derived T cells ex vivo with suitable T cell receptors
that enable them to detect and efficiently kill cancer cells in vivo
TCR-modified
T cells
T cell-specific antibodies (TABs):
deplete unwanted T cells and track TCR-modified T cells
29
TABs – Medigene’s unique T cell-specific
antibodies
Full-scope platform for antibody isolation
Unique animal models to assess MoA and clinical efficacy
Proof-of-principle of technology is established
Removal of unwanted T cells:
T-cell leukemia
TCR-modified T cells:
 T cell tracking ex vivo
 T cell removal in vivo
Status quo:
Ongoing studies establish proof-of-concept in pre-clinical models
30
Status of Medigene‘s TABs development process
Complete TCR sequences in vector libraries available
High throughput cellular screening systems have been established and
validated
Prototype antibodies have been isolated using standard methods
TABs can specifically target certain T cells
to deplete certain T cells in T cell malignancies
to mark certain T cells for diagnostic applications
but will preserve the patient’s natural immune defense
31
Corporate & financial highlights 2015
2015 – Highlights at a glance
Immunotherapies moved into clinical stage
Own phase I/II trial with
DC vaccines started for the
treatment of acute myeloid
leukemia (AML)
Successful capital increase
completed to finance the
immunotherapy programs
Clinical data on DC vaccines
presented at AACR and ASH
by our academic partners
Patent portfolio
strengthened for our
immunotherapies
EndoTAG® sold in its
entirety to SynCore
Spin-off Catherex Inc.
sold to Amgen Inc.
33
Management aligned to Medigene’s transformation
Prof. Dolores J. Schendel
CEO/CSO
Dave Lemus
COO
Supported by three Senior Vice Presidents
Dr. Dr. Olav Zilian as
SVP
Corporate Development
Dr. Kai Pinkernell as
SVP
Chief Medical Officer
Dr. Markus Dangl as
SVP
Research & Pre-Clinical
Development
34
Values from legacy pipeline realized - further
focus on core business
EndoTAG® sold in its entirety to SynCore
First payment of €1 m received in Q1-2016
Medigene receives €5 m from SynCore in five annual instalments and is
eligible for milestone payments and royalties for EndoTAG-1
Medigene spin-off Catherex, Inc. sold to Amgen Inc.:
Medigene is entitled to approximately 40% of all payments
Upfront payment of USD10.5 m, milestone and net sales payments for
Amgen's drug ImlygicTM
In Q1-2016, Medigene received its part of the upfront payment and a milestone
payment of USD1.2 m
35
Strong cash position
Gross proceeds of €46.4 m from capital increase in July 2015
Cash position at 31 Dec 2015 of €46.8 m (31 Dec 2014: €15.0 m)
Operative cash usage increased to €10.6 m (2014: €8.8 m)
Average monthly cash outflow of €0.9 m (2014: €0.7 m)
April 2016: Medigene sold of 50% of its' stake in the private
biotech company Immunocore for approximately GBP4.9 million
(approx. € 6.1 million).
36
The share and the shareholder structure
16%
QVT
08%
04%
03%
63%
03%
04%
Key share information
Aviva
Listed on the FSE
(Prime Standard)
SynCore
Number of shares: 19.7 m
Ridgeback
Current market cap of
approx. ~ €165 m
DJS Montana
RTW Master Fund
Freefloat (inkl. Morgan
Stanley 2,3%) *
Market capitalisation
increased from €52 m to
€171 m in 2015
Shares issued increased
from 13.9 m to 19.7 m in
2015
May 2016
Numbers based on last voting right notifications
*shareholding below 3%
37
Outlook for Medigene’s clinical programs
DCs:
Continuation of Phase I treatment to completion of all patients at 50 weeks
Sequential initiation of observation period for Phase I as patients complete
treatment
Progression to Phase II recruitment and treatment of DC vaccinated AML
patients at Oslo University Hospital
TCRs:
Pioneering first TCR trial in Germany as IIT at Charité Hospital Berlin in
2016
Commence two Medigene-sponsored clinical trials in 2017 and 2018
Isolate and further characterize novel TCRs for Medigene’s TCR library
38
The Medigene Investment Case
Medigene’s immunotherapy programs are deeply rooted in world-class
science
Led by inventors of Medigene’s immunotherapies and experienced
management team with sound industry background
Up-scalable technology platforms for fueling continual development of
candidates for the pipeline – for Medigene and partners
Unique knowledge and speed on TCR discovery and validation
Clinical studies ongoing and in preparation
Established and experienced company for biopharmaceutical product
development from research to market approval
Well funded
39
Medigene AG
MediGene
AG
Lochhamer Straße 11
82152 Planegg/Martinsried
Planegg / Martinsried
Germany
Listed on Frankfurt Stock Exchange (MDG1,
(MDG, Prime
PrimeStandard)
Standard)
T +49 - 89 - 20 00 33 - 0
F +49 - 89 - 20 00 33 - 2920
[email protected]
www.medigene.com

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