HARNESSING THE IMMUNE SYSTEM TO TREAT AND PREVENT DISEASE JANUARY 2014

HARNESSING THE IMMUNE
SYSTEM TO TREAT AND
PREVENT DISEASE
JANUARY 2014
CSE/OMX:BAVA, OTC:BVNRY
BAVARIAN NORDIC
CANCER IMMUNOTHERAPIES AND VACCINES FOR INFECTIOUS DISEASES
BAVARIAN NORDIC IN BRIEF
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•
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•
•
•
•
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Vertically integrated multinational biotech company
Revenue-generating
Leader in vector-based active immunotherapy – two technology platforms
First product approved in 2013
Two Phase 3 programs: Prostate cancer and smallpox
Ebola vaccine license and supply agreement with Janssen
Commercial scale cGMP manufacturing facility
Long-term contracts with the US government
REVENUES AND RESULTS, 5 YEARS
2009
1.000
500
0
-500
2
2010
2011
2012
2013
FACTS
2014E
• Founded 1994, IPO 1998
• Headquartered in Denmark
• Research centers in Mountain View, CA
and Munich, Germany
• Listed on NASDAQ OMX Copenhagen: BAVA
PIPELINE
Preclinical
IMVANEX®/ IMVAMUNE®
1-4)
Smallpox
PROSTVAC®
Prostate Cancer
IMVAMUNE® freeze-dried 1)
Smallpox
CV-301 Colon 1)
Colorectal Cancer
CV-301 Bladder
1)
Bladder Cancer
CV-301 Breast 1)
Breast Cancer
MVA-BN® PRO
Prostate Cancer
MVA-BN® HER2
Breast Cancer
MVA-BN® Brachyury
MVA-BN® Filo
5)
Metastatic Tumors
Filoviruses (Ebola/Marburg)
MVA-BN® RSV
MVA-BN® FMDV
1)
Respiratory Syncytial Virus
1)
MVA-BN® Anthrax
Foot-and-mouth Disease
1)
Anthrax
1) Government funded programs
2) Sold to government stockpiles
3) Approved in the European Union under the trade name IMVANEX® and in
Canada under the trade name IMVAMUNE®
4) Phase 3 registration studies are ongoing in the United States
5) Licensed to Janssen
3
Phase 1
Phase 1/2
Phase 2
Phase 3
Market
THE MVA-BN® VACCINE PLATFORM
MVA-BN
(IMVAMUNE)
Recombinant
MVA-BN
MVA-BN Antigen(s)
+
Vaccine Platform
 Approvals in EU and Canada
 Balanced Immune Response
 Strong IP Protection
4
Research & Development
 Construct Optimization
 Immune Enhancement
 Preclinical Analysis
Manufacturing
 Research Drug Product
 Clinical Batch Production
 Commercial Manufacturing
Immune Targets
(Antigens)
POXVIRUS TECHNOLOGY PLATFORM
PROSTVAC
CV-301
• Prostate cancer
• Colorectal, Breast, Lung,
Ovarian, Gastric, Bladder, Liver
and Renal cancer
PSA
CEA
TRICOM
TRIad of CO-stimulatory Molecules
Vectors
LFA-3
ICAM-1
Vaccinia + Fowlpox (VF)
(Prime)
GM-CSF can be used as adjuvant in both PROSTVAC ® and CV-301
5
B7.1
(Boost)
MUC-1
OUR
INFECTIOUS DISEASES
BUSINESS
6
IMVAMUNE® ADVANTAGES
TRADITIONAL SMALLPOX VACCINES
Traditional vaccines are based on a replicating vaccinia virus
• Dryvax®, ACAM2000, LC16m8, Elstree-BN
All have been shown to produce some/all of following serious side effects
• Myocarditis, pericarditis, encephalitis, progressive or generalized vaccinia, eczema
vaccinatum, inadvertent infection
Significant population should not receive replicating vaccines
• Congenital or acquired immunodeficiency, immunosuppresive medications,
exfoliative skin disorders (e.g. eczema)
IMVAMUNE®/IMVANEX®
Based on a non-replicating virus
Approved in EU and Canada
More than 7,500 individuals have been vaccinated
• Well tolerated – even in immune-compromised patients
• No reports of the serious adverse events reported with the use of replicating vaccinia
vaccines in the smallpox eradication campaign
7
SUCCESSFUL PARTNERSHIP WITH THE U.S. GOVERNMENT
CONTRACTS AWARDED TO-DATE EXCEED US$ 1BN
Developing freeze-dried vaccine
2003
2004
RFP-1
IMVAMUNE
Smallpox Vaccine
MVA-BN
Marburg
Vaccine
MVA-BN
Foot-andmouth disease
MVA-BN
Burkholderia
US$ 55m
US$ 18m
US$ 1m
US$ 500k
BARDA
NIH
DHS
DOD DTRA
RFP Freeze Dried
IMVAMUNE
Smallpox Vaccine
RFP Freeze Dried
Expansion
US$ 40m
BARDA
2005
2006
RFP-2
IMVAMUNE
Smallpox Vaccine
US$ 14m
US$ 100m
NIH
NIH
2007
2008
MVA-BN
Ebola/Marburg
Early research
2009
2010
2011
2012
2013
2014
Delivery contract
IMVAMUNE
Smallpox Vaccine
RFP-3
IMVAMUNE
Smallpox Vaccine
RFP-2 Expansion
IMVAMUNE
Smallpox Vaccine
RFP-3 Expansions
IMVAMUNE
Smallpox Vaccine
US$ 500m
US$ 16m
US$ 49m
US$ 228m
BARDA
NIH
BARDA
BARDA
Developing, producing, supplying liquid-frozen IMVAMUNE®
8
Expanding MVA-BN® platform
GROWING THE IMVAMUNE BUSINESS WITH FREEZE-DRIED
Ongoing US$ 95m contract with BARDA to develop a freeze-dried
IMVAMUNE
BENEFITS
•
•
Anticipated shelf life of greater than 10 years
Easier logistics and storage
TIMELINES
•
•
Ongoing transfer of FD process to commercial
scale facility
Phase 2 ongoing; anticipated EUA in 2016, which
allows for federal stockpiling
POTENTIAL
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First wave of replenishment could replace 20M
expiring doses in stockpile
Long term stated goal of US Government calls for
non-replicating vaccine for 66M US citizens
EBOLA/MARBURG VACCINE AGREEMENT WITH JANSSEN
Supply agreement
US$ 99m
BN to manufacture and supply ~2 million vaccine doses
• US$ 70m upfront
• US$ 29m pro rata with deliveries in 2015
License agreement
US$ 45m
BN grants exclusive license to Janssen for its MVA-BN Filovirus vaccine
(Ebola Zaire, Ebola Sudan and Marburg)
Janssen will cover development costs
• US$ 25m upfront
• US$ 20m in development and regulatory milestones
Equity investment
Johnson & Johnson Development Corporation has subscribed for 1.3
million new BN shares through private placement
10
US$ 43m
EBOLA - CLINICAL TRIALS
• Ongoing safety and immunogenicity trials of MVA-BN Filo in prime-boost
regimen with Janssen and GSK
• MVA-BN Filo/AdVac (Janssen)
• Phase 1 (n=72) initiated January 2015 in UK
• Full recruitment anticipated by end of January
• Additional trials starting soon in US and Africa
• MVA-BN/cAd EBO Z (GSK)
• Phase 1 (n=60) - 30 subjects will receive a booster of MVA-BN Filo
11
JANSSEN COLLABORATION
ADDITIONAL COMMERCIAL INFECTIOUS DISEASE TARGETS
• Subsequent to the Ebola collaboration, BN and Janssen have agreed to collaborate on
three additional infectious disease targets
• Bavarian Nordic will develop MVA-BN constructs for scientific evaluation
• Janssen will have an exclusive window to decide if they wish to enter into licensing
agreements
MVA/ADVAC – PRIME-BOOST RATIONALE
•
All adenoviruses require a separate boost to be an effective vaccination regime.
• One of the best boost platforms that has been used in combination with adenoviruses
(of all species, human or chimp) is MVA.
•
As it relates to Ebola, the combination of adenovirus and MVA improves the induction of
strong immune responses in the short term (due to the highly immunogenic adenovirus), and
provides long-term protection, due to the properties of MVA-BN.
12
RSV: RESPIRATORY SYNCYTIAL VIRUS
RSV
• Major cause of upper & lower respiratory tract
infections in adults and children
• No approved vaccine; high unmet medical need
• Immunity wanes and recurrent infections are
common, particularly in individuals with respiratory
& circulatory diseases
Mortality Rate Per 100,000
person by years
LARGE UNMET MEDICAL NEED: CHILDREN & ELDERLY
40
35
30
25
20
15
10
5
0
<1
1-4
5-49
50-64
≥65
Age Bracket
SERIOUS HEALTH RISK FOR ELDERLY
LEADING CAUSE OF INFANT HOSPITALIZATION
• 177,000 hospitalizations and 14,000 deaths
annually among US adults older than 65 years
• Up to 176,000 hospitalizations in the US
annually in children under 5
• Infection rate in adults ranges between 5-10%
per year, 70-80% get respiratory symptoms,
10-20% are hospitalized, and 2-5% die
• 1.5 million outpatient visits in the US
annually in children under 5
• High levels of transmission in nursing homes
increase disease burden in these facilities
• 90% of infants contract RSV infection by 2
years of age, infants < 6 months of age are
most at risk for severe disease
• Major risk factor for adults with chronic
pulmonary conditions
• Children are major source of disease
transmission
13
MVA-BN RSV VACCINE CANDIDATE
MVA-BN RSV
• Highly immunogenic – inducing strong mucosal and serological immunity (antibodies & T cells)
• No enhanced disease in animal models
• Protection against both RSV subtypes (A&B) in animal models
• Flexible administration options: intranasal or intramuscular
• Received NIH support (animal efficacy)
• Favorable pre-IND – Phase 1 planned Q1 2015
MVA-BN: IDEAL RSV VACCINE PLATFORM
• Licensed platform
• Extraordinary safety profile
• Vector tested safely in elderly and
children
DEVELOPMENT STRATEGY
Elderly +
Adults at risk
Children >5yrs
14
Phase 1
2015
Second indication
OUR
CANCER IMMUNOTHERAPY
BUSINESS
15
PROSTVAC CLINICAL DEVELOPMENT PROGRAM
PROSTVAC has a robust clinical data package providing rationale for:
• Phase 3 trial as monotherapy in late-stage prostate cancer
• Combination and sequencing studies
• PROSTVAC plus anti-androgens
• PROSTVAC plus immune checkpoint inhibitors
• Early prostate cancer indications
12 ongoing or completed PROSTVAC clinical trials
Completed
Ongoing
Phase 1
4
-
Phase 2
4
4
Phase 3
-
1
Total
8
5
300+
1,400+
Total
patients
16
PROSTVAC PHASE 2 RESULTS
MOST PRONOUNCED SURVIVAL TO DATE IN PROSTATE CANCER
Significantly extended
overall survival
100
N
Deaths
Median
OS
Control
40
37
16.6
PROSTVAC
82
65
25.1
80
survival
(% of patients)
25.1
months
60
40
Δ 8.5 months improvement in OS
16.6
months
Hazard ratio
0.56 (95% CI 0.37–0.85)
p=0.0061
20
0
0
12
24
36
48
60
months
Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based
PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer
Kantoff et al., Journal of Clinical Oncology, January 2010
17
Pivotal data of approved agents:
Provenge®: ΔOS = 4.1 mo (AS/MS mCRPC)
Zytiga®: ΔOS = 5.2 mo (pre-chemo mCRPC)
Xtandi®: ΔOS = 2.2 mo (pre-chemo mCRPC)
Reference
Package insert Sipuleucel-T, enzalutamide and abiraterone
PROSTVAC PHASE 3: FULLY ENROLLED DECEMBER 2014
• Primary endpoint is overall survival
• Either one of the treatment arms must be
superior to placebo
PROSPECT
A Randomized, Double-blind, Global
Phase 3 Efficacy Trial of PROSTVAC in
Metastatic Castration-Resistant Prostate
Cancer
1,200 patients
• Each comparison requires 534 deaths for
the final analysis
• Interim analysis plan
• Pre-specified interim data analyses will evaluate
whether the trial should continue as planned or
potentially be stopped early for efficacy or futility
Phase 2 results:
Demonstrated hazard ratio
0.56 = 44% reduction in risk of
death
18
SPA terms for Phase 3:
Required hazard ratio 0.82 or
less = 18% reduction in risk of
death
Enrolled at 214 sites in 15 countries
Australia, Belgium, Canada, Denmark,
Estonia, France, Germany, Iceland,
Israel, Netherlands, Poland, Russia,
Spain, UK & US
3 study arms
PROSTVAC + GM-CSF
PROSTVAC
Placebo
PROSTVAC - PATIENT CASE HISTORY (“FRANK”)
PUBLISHED 2013 CASE REPORT IN CLINICAL GENITOURINARY CANCER
PSA
1.000,0
Radical
Prostatectomy
External
Beam Radiation
Vaccine
Treatment
Second Vaccine
Treatment
100,0
10,0
1,0
0,1
61
62
63
64
65
66
67
68
69
70
71
72
73
74
Gleason grade: 4 + 3 = 7
Trend before radical prostatectomy ( )
Trend after radical prostatectomy. External beam radiation
Trend after first vaccine trial ( )
Trend after second vaccine trial ( )
19
( )
5.8 months DT (doubling time)
9.6 months DT
28.6 months DT
75
76
77
78
79
80
81
82
Age
COMBINATION RATIONALE
POXVIRUS-BASED IMMUNOTHERAPY
Other
Anti-cancer Therapy
Combination Benefits
• Enhance tumor
immunogenicity
• Significant synergy of
therapeutic benefit
Targeted Therapies
BN Poxvirus-Based
Immunotherapy
Immune Checkpoint
Inhibitors
Radiation Therapy
20
• Accelerate timing to
anticancer immune
response
• Long duration of anticancer
response post-therapy
• Minimal-to-no added side
effects from
immunotherapy
• Potential for dose reduction
of systemic anticancer
therapy
EARLY RESULTS COMBINING PROSTVAC WITH
IPILIMUMAB APPEAR PROMISING
Median Halabi
Predicted Survival*
(months)
% Chemo Naïve
Median Overall
Survival
(months)
Δ OS
(months)
Alive at 24
months
PROSTVAC
alone
(n=32)1
17.2
100%
26.3
+ 9.1
53%
Ipilimumab
alone
(n=71)2
–
56.3%
17.1
–
–
PROSTVAC +
Ipilimumab
(n=30)3
18.5
80%
34.4
+15.9
73%
Phase 1 dose escalation trial; subjects with metastatic castration resistant prostate
cancer (mCRPC)
*Halabi et al., JCO 2003; 1Gulley et al, Cancer Immunol Immunother, 2010
2Madan et al, Lancet Oncology, 2012; 3Slovin et al, Annals Onc, 2013
21
MVA-BN BRACHYURY
NOVEL IMMUNOTHERAPY CANDIDATE WITH BROAD POTENTIAL- NCI FUNDED
• Brachyury is a tumor-associated antigen which is overexpressed in major
solid tumor indications
• Brachyury is reported to play a key role in the metastasis and progression of tumors
• Tumors which overexpress Brachyury are believed to be highly resistant to current
therapies and are associated with decreased survival rates
• Brachyury highly expressed in ultra-orphan Chordoma indication
• A Phase 1 study of MVA-BN Brachyury TRICOM initiated in patients with
advanced cancer
• Open label trial enrolling patients with advanced cancer into three cohorts (6
patients per dose cohort) with dose escalation of MVA-BN Brachyury
• The objective is to determine the safety and tolerability of escalating doses of
MVA-BN Brachyury and to evaluate immunologic responses as measured by an
increase in Brachyury-specific T cells
22
COMPANY SUMMARY &
FINANCIALS
23
SELECTED MILESTONES
• Manufacture and deliver MVA-BN Filo (Ebola/Marburg) vaccine; targeting 2
million doses (2015)
• Investigational New Drug submission for MVA-BN RSV followed by initiation
of Phase 1 study (2015)
• Complete Phase 2 study of freeze-dried IMVAMUNE to support a pre-EUA
submission (requirement for stockpiling) (2015)
• Secure IMVANEX/IMVAMUNE orders from rest of world
• Advance clinical studies exploring the therapeutic potential of PROSTVAC in
combination with checkpoint inhibitors
• Interim analyses of PROSTVAC
24
FINANCIAL OUTLOOK
2014
Revenue
EBIT
Cash preparedness at year-end
$215m
$0m
$175m
Assumptions:
Deliver and revenue recognize 6.5 million doses
of IMVAMUNE to the U.S. Strategic National Stockpile
R&D costs - GROUP
Infectious Disease Division, EBIT
Cancer Immunotherapy Division, EBIT
All numbers are approximate
* R&D costs include approximately USD $17.5 million in contract expenses (stated under production
costs in the P&L statement) as well as USD $8 million capitalized in the balance sheet
25
* $105m
$70m
($70m)
SUMMARY AND CONTACTS
INVESTOR RELATIONS CONTACTS
Rolf Sass Sørensen/EU
+45 3326 8383 / [email protected]
Seth Lewis/USA
+1 978 298 5654 / [email protected]
BAVARIAN NORDIC (CSE/OMX:BAVA)
• Approved product; validated platform
• Two Phase 3 programs:
• Prostate cancer and smallpox
•
•
•
•
26
Diversified pipeline drawing from distinct technologies
Commercial manufacturing capability
Long-term R&D and delivery contracts with the US government
Revenue-generating
SHAREHOLDER INFORMATION
SHARE INFORMATION
Share price (Jan 8, 2015)
High/low 52 weeks
Market cap
Volume (3m, daily average)
No. of shares, 100% free-float
No. of registered
shareholders
DKK 213
91/ 220
USD $940M
225,000
27.7m
22,000
Largest shareholders
ATP (> 10%)
A.J. Aamund A/S (> 5%)
220
12%
10%
200
15%
180
63%
Denmark
US
UK
RoW
9%
Institutional
28%
63%
Private
Non-registered
160
FINANCIAL CALENDAR
140
120
100
80
Dec-13
27
Jan-14
Feb-14
Mar-14
Apr-14
May-14
Jun-14
Jul-14
Aug-14
Sep-14
Oct-14
Nov-14
Dec-14
2014 Annual Report
Annual General Meeting
2015 First Quarterly Report (Q1)
2015 Half-year Report (Q2)
2015 Third Quarterly Report (Q3)
11-Mar-15
23-Apr-15
05-May-15
25-Aug-15
03-Nov-15
This presentation includes "forward-looking statements" that involve risks, uncertainties and other
factors, many of which are outside of our control, that could cause actual results to differ
materially from the results discussed in the forward-looking statements. Forward-looking
statements include statements concerning our plans, objectives, goals, future events, performance
and/or other information that is not historical information. We undertake no obligation to publicly
update or revise forward-looking statements to reflect subsequent events or circumstances after
the date made, except as required by law.