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CBLB502 Biodefense Update Investor Day - June 13, 2012
NASDAQ:CBLI
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Safe Harbor
This presentation includes forward-looking statements and predictions, including
statements about potential revenue-bearing transactions, the market potential of
CBLI’s technologies and product candidates, and the potential value of pipeline
products. These statements represent CBLI’s judgment as of the date of this
presentation and are subject to risks and uncertainties that could cause actual
results to differ materially from those expressed in such forward-looking
statements. In particular, CBLI faces risks and uncertainties that it may not be able
to sustain its business model, that revenues may be lower or expenses higher
than projected, that product sales may not increase, that development of product
candidates in the Company’s pipeline may not succeed or that commercial
transactions may not go forward as planned.
The factors that could cause actual results to differ are discussed in more detail in
CBLI’s filings with the Securities and Exchange Commission, including its latest
Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and Current
Reports on Form 8-K. These reports are available under the “Investors” tab on
CBLI’s website at www.cbiolabs.com.
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Scientific Update Andrei Gudkov, Ph.D., D. Sci., Chief Scientific Officer, CBLI;
SVP Basic Science, Roswell Park Cancer Institute
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Key attributes meet or exceed DoD and BARDA development
threshold requirements
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CBLB502 - Desirable Target Product Profile
• Demonstrated increased survival in animal models of lethal radiation:
• 3x survival of irradiated NHPs
• Significantly reduces incapacitation of survivors
• Reduces radiological damage in both HP and GI systems
• Single intramuscular injection with broad application time window
• From prior (24 hr) to & post (>48 hr) exposure
• Completed two Phase I safety trials in total of 150 healthy
volunteers
• cGMP drug product demonstrated stability at -200C for at least 4 years
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
FDA pathway to approve drugs where efficacy is unethical to test
in humans
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Animal Rule
• Efficacy in animal models that mimic human disease, with relevant
end-points
• Human safety in healthy volunteers
• Well understood mechanism of action to justify selection of objective
biomarkers of efficacy
• Well understood correlation of biomarker response between animal
models and human volunteers to calculate dose conversion
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Rhesus macaque as appropriate model for demonstrations of
pivotal efficacy and definitive dose conversion
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Comparison of Animal Models with Human
Characteristic Rhesus Dog Mouse Rat
ARS features
Sensitivity to radiation + + - -
Kinetics of ARS
development
+/- +/- - -
HP sub-syndrome + + +/- +/-
GI sub-syndrome + +/- - -
CBLB502 Efficacy
Biomarkers
G-CSF + NA + ND
IL-6 + +/- +/- ND
NEU + +/- - ND
CBLB502 Tolerability
ALT + +/- - +/-
AST + +/- - +/-
Phosphate +/- - - +/-
Blood pressure +/- ND ND ND
Genetic closeness + - - -
Total score 21 10 4 4
Total available score 24 20 22 16
Final score for similarity to humans, % 88% 50% 18% 25%
+ High similarity
+/- Moderate similarity
- Low similarity
ND No data
NA Not applicable
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
From Mechanism of Action to Human Response
NF-kappaB
IL8/KC
Neutrophils
G-CSF IL6
Thrombocytes
Apoptosis
SOD2
HSCs GI-SCs
ROS
survival mediators
pathology mediators
projected biomarkersAnimal Efficacy Animal Efficacy
Human PK Human Biomarkers
Animal PK Animal Biomarkers
Human Safety Human Safety
HumanHuman
EfficaciousEfficaciousDoseDose
Biomarkers Human response
CBLB502 TLR5 NF-kB
IAPs, Bcl2
SOD2, ferritin
S100, HAMP
Cytokines
Suppress apoptosis
Inactivate ROS
Inhibit infections
Promote regeneration
Reduced HP and GImorbidities
SURVIVAL
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Framework for prediction of efficacious human
dose
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Dose Conversion Methodology
Healthy(e.g., non-irradiated)
Diseased(e.g., irradiated)
Hu
man
sA
nim
als (
e.g.
, NH
P)
• Establish efficacious drug dose range (survival)
• Validate PD biomarkers as surrogate biomarkers for survival (quantify treatment effects)
• Identify treatment effect on PD biomarkers in animal model
• Identify treatment effect on PD biomarkers in humansN/A
1 2
3
Convert dose from healthy animals to healthy humans
Show equivalence
0.1
1
10
100
1000
10000
100000
0.01 0.1 1 10 100Trea
tmen
t eff
ect [
G-C
SF: A
UC(
0-24
) inc
reas
e, p
g*hr
/mL]
CBLB502 dose, ug/kg
Graphical Illustration of Dose Conversion
NHP response Human response
A
BC
D
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Estimation of human dose based on biomarker
response
Projected full efficacious
dose in NHP
Projected
human dose
human
Rhesus
macaque
3/3 independent biomarkers predict similar human dose
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Largest GLP NHP study ever conducted
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GLP/GCP Study in Non-Human Primates
• 179 NHPs (~1:1 males/females)
• 8 groups: 7 different doses of CBLB502 and 1 placebo
• Randomized, blind study
• TBI LD70 (7.5 Gy)
• Drug/placebo administration: i.m., 25 hrs post TBI
• Monitoring: physiological parameters, biomarkers
• Observation period: 60 days post-irradiation
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
GLP NHP Survival Results
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
GLP NHP Study - Major Endpoints Reached
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Survival 95% Confidence
CBLB502 Overall Unadjusted Adjusted odds ratio Interval on
Dose Survival P-value P-value (vs vehicle) odds ratio
0.0 11 / 40 ( 27.5) . n/a .
0.3 5 / 20 ( 25.0) 0.5817 0.5817 0.9 ( 0.2, 3.4)
1.0 7 / 19 ( 36.8) 0.2580 0.4473 1.5 ( 0.4, 5.6)
3.0 5 / 20 ( 25.0) 0.4473 0.4473 0.9 ( 0.2, 3.4)
6.6 9 / 20 ( 45.0) 0.1439 0.1439 2.2 ( 0.6, 7.6)
10.0 15 / 20 ( 75.0) 0.0021 0.0021 * 7.9 ( 2.0, 33.6)
40.0 14 / 20 ( 70.0) <.0001 <.0001 * 6.2 ( 1.6, 24.2)
120.0 14 / 20 ( 70.0) <.0001 n/a 6.2 ( 1.6, 24.2)
• Half maximal effective concentration (EC50) established
• Pattern of dose dependence determined
• Significant piece of BLA package
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
None of above observed in healthy volunteer studies
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Addressing FDA Safety Concern: Cytokine storm
Definition
A potentially fatal immune reaction consisting of a positive feedback loop
between cytokines and immune cells, with highly elevated levels of
various cytokines (http://medical-dictionary.thefreedictionary.com/Cytokine+Storm)
Symptoms
Prolonged hypotension, disseminated intravascular coagulation, multiple
organ failure (respiratory failure, renal impairment, long-lasting
transaminase increase) - based on toxicity profile of CD28 agonist
TGN1412 (Suntharalingam et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N
Engl J Med. 2006 Sep 7;355(10):1018-28.)
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved. 14
Cytokine Storm Mechanism and Drivers
Inducers and
amplifiers
Cytotoxic
“executors”
Pro-inflammatory (flu-
like syndrome) Others
TNFa, IL-1b IL-2, IL-12, IFNg IL-6, IFNa, IFNb, IL-8 G-CSF, IL-10
Chain reaction of NFkB-mediated activation of
NFkB-inducing and cytotoxic factors
NFkB
Agent NFkBTNFaIL-1b
NFkB
TNFaIL-1bIL-2IL-12IFNg
NFkB
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Cytokines tested
G-CSF MCP-1
IL-1a MIP-1
IL-1b IP-10
IL-2 GM-CSF
IL-3 IFN-g
IL-4 FGF2 basic
IL-6 FLT3
ligand
IL-8 VEGF
IL-10 SCF
IL-12 KGF
MCP-1 TPO
TNFa
0
5000
10000
15000
20000
25000
30000
G-CSF IL-6 IL-8 IL-10 TNF IL-2 IL-1b
AU
C(0
-24
), p
g*h
r/m
l
NHPs, 10 ug/kg CBLB502 i.m.
Humans, 0.45 ug/kg CBLB502 i.m.
• Cytokine induction patterns are similar between NHPs and humans
• Only four cytokines show sizable induction
• No induction of cytokine storm-generating cytokines
Cytokines induced by CBLB502
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Induced cytokine content is cardinally different between CBLB502
and cytokine-storm-inducing agent
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
G-CSF IL-6 IL-8 IL-10 TNFa IL-1b IFNg
AU
C,
pg
-hr/
mL
Humans, CBLB502, 0.45 ug/kg i.m.
NHPs, CBLB502, 10 ug/kg i.m.
Humans, TGN1412, 100 ug/kg i.v.
Cytokine Response to CBLB502 vs Real Cytokine
Storm
Suntharalingam et al. Cytokine storm in a phase 1 trial of the anti-CD28
monoclonal antibody TGN1412. N Engl J Med. 2006 Sep 7;355(10):1018-28
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved. 17
Why is CBLB502 so different from other TLR
agonists? • Specific cell type expression of TLR5: CBLB502 induces NFkB mainly in non-
immune cells (i.e., hepatocytes, study CBL1.1-U-01-Rs-20) that cannot express
cytokine storm-inducing cytokines, while endotoxin target TLR4 is expressed in
macrophages and T-cells that are involved in cytokine response amplification
• Differences in molecular mechanisms of TLR4 and TLR5 signaling: TLR5
agonist induces only Myd88-mediated signal transduction pathway, while TLR4
agonist endotoxin activates additional pathways (i.e., TRIF-mediated) modifying
downstream response
intact LPS CBLB502
Small intestine (NFkB nuclear translocation)
intact LPS CBLB502
Small intestine (NFkB nuclear translocation)
intact LPS CBLB502
Small intestine (NFkB nuclear translocation)vehicle CBLB502 LPS
Sm. intestine
Liver
p65
DAPI
u/t CBLB502 LPS
Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Regulatory Affairs Ann Hards, Ph.D., EVP Regulatory Affairs and Quality Assurance
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Completed /Recent Regulatory Actions
• Fast-Track designation - July 18, 2010
• Orphan Drug designation – November 23, 2010
• Type C meeting on operational aspects of pivotal studies – February 9, 2011
Change in FDA review Division
• Type A meeting to respond to safety questions – July 5, 2011
• Type C meeting to provide new Division with background on MOA and
proposed dose conversion algorithm – September 29, 2011
• Written response to FDA questions resulting from Summer 2011 interactions
– December 29, 2011
• Type C meeting on animal model strategy – April 17, 2012 (canceled as
FDA’s pre-meeting comments were sufficient to plan an animal protocol
meeting)
• Type C meeting on clinical safety protocol design – April 18, 2012
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
FDA Requests from April 18, 2012 FDA Clinical Protocol
Meeting
• A revised protocol as discussed during the meeting
• A plan for comprehensive assessment of safety events, particularly CV function
• A specified minimum time interval between treatment of subjects
• Statement of study stopping rules
• A revised investigator’s brochure
• A summary of the factors differentiating CBLB502 from products that
elicit cytokine storm
• Evaluation of the results of the ongoing GLP animal efficacy study
prior to clinical protocol submission
• Top level results evaluated and submitted
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Written Conclusions from FDA
Requirement to understand MOA - [21CFR601.91(a)(1)]
• The mechanism of potentially lethal irradiation is reasonably well understood
• The mechanisms of CBLB502-induced radioprotection are reasonable
• The mechanisms of the putative harmful effects of CBLB502 are not well understood and not predicted by animal models therefore the preclinical toxiocology program is complete
• Additional safety observations must be performed in clinical trial(s)
Requirement to demonstrate efficacy in one or more animal models- [21CFR601.91(a)(2)]
• The NHP and mouse show evidence of the cellular and physiologic effects of CBLB502 similar to those in humans
• The monkey and mouse are acceptable animal models for demonstration of efficacy
• Pivotal program must be discussed, agreed and performed under GLP
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Written Conclusions from FDA (cont.)
Requirement for an endpoint of mortality or major morbidity - [21CFR601.91(a)(3)]
• The target indication for “reducing the risk of death following total body
irradiation” “appears reasonable”
Requirement for information that allows selection of an efficacious human dose - [21CFR601.91(a)(4)]
• The proposed dose conversion scheme is most likely the only one possible and therefore acceptable
• G-CSF and IL-6 play important roles in the mechanism and consequently can be used as biomarkers for dose conversion
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Planned Regulatory Actions Before End 2012
• Submit detailed clinical protocol to FDA for final agreement prior
to implementation
Addresses remaining Animal Rule MOA/safety requirements
• Request an EOPII (Type B) meeting to discuss pivotal animal trial designs and overall program strategy
Addresses remaining Animal Rule efficacy/dose conversion requirements
• Tentatively (dependent on agreements at EOPII meeting) request Type C meeting as bridge to Pre-BLA meeting to discuss operational details of data collection, etc. for the pivotal animal program
Addresses requirements outlined in Animal Rule guidance on harmonization of Animal Rule study operations with non-Animal Rule clinical study operations
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Government Affairs Ed Martin, M.D., Ret. Rear Admiral, Martin Blanck & Associates
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Copyright 2012 © Cleveland BioLabs, Inc. All rights reserved.
Q&A
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