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CBLB502 Biodefense Update Investor Day - June 13, 2012

NASDAQ:CBLI

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.

2


Scientific Update Andrei Gudkov, Ph.D., D. Sci., Chief Scientific Officer, CBLI;

SVP Basic Science, Roswell Park Cancer Institute

3


Key attributes meet or exceed DoD and BARDA development

threshold requirements

4

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


FDA pathway to approve drugs where efficacy is unethical to test

in humans

5

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


Rhesus macaque as appropriate model for demonstrations of

pivotal efficacy and definitive dose conversion

6

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


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

7


Framework for prediction of efficacious human

dose

8

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


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

9


Largest GLP NHP study ever conducted

10

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


GLP NHP Survival Results

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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


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


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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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


Regulatory Affairs Ann Hards, Ph.D., EVP Regulatory Affairs and Quality Assurance

18


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

19


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

20


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

21


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

22


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

23


Government Affairs Ed Martin, M.D., Ret. Rear Admiral, Martin Blanck & Associates

24


Q&A

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