“Entolimod, an Innovative Medical Radiation

Countermeasure”

Michelle Ross, DVM, MS, Ph.D.

SVP Public Health and Government Affairs, Cleveland BioLabs, Inc. Email: mross@cbiolabs.com

Category: Development of new technologies and products for personal protection

Cleveland BioLabs, Inc. is an innovation-oriented,

clinical-stage, biopharmaceutical company

• Founded in 2003 based on technology from Cleveland

Clinic

• Comprises 20 employees with headquarters in Buffalo, NY

• Publically traded on NASDAQ under ‘CBLI’

• Funded through public and private investment and

government contract and grant support

• Developing novel drugs for radiation defense and oncology

• Entolimod (CBLB502)

• Medical radiation countermeasure

• Anticancer immunotherapeutic

• CBLB612

• Hematopoietic stem cell mobilizer

2

CBLI is led by an experienced drug development team

Chief Executive Officer & Co-Founder Chief Scientific Officer & Co-Founder

Yakov Kogan, PhD, MBA

• Member of executive team since co-founding CBLI in 2003

• Appointed CEO of CBLI in 2012

• Responsible for securing $41M in project-specific VC funding

and 9 grants valued at up to $36M

• Previously Dir. of Bus. Development at Integrated Genomics

Andrei Gudkov, PhD, DSci

• SVP of Basic Science, Chair of Dept. of Cell Stress Biology,

Roswell Park Cancer Institute

• Former Chair, Dept. Molecular Biology at Cleveland Clinic

• 30+ issued, >30 pending patents

• 200+ research publications

Chief Financial Officer Strategic Medical Advisor

Neil Lyons, CPA

• Over 20 years of financial executive experience, including

7 years in life sciences

• Advised on over $1B in equity, debt and M&A transactions

• Managed complex federal contracting operations in excess of

$300M annually

Langdon Miller, MD

• Medical oncologist with >20 years of clinical drug

development experience

• Major roles in development of drugs for hematological and

solid tumors, including Neupogen®, Leukine®, Camptosar®,

Aromasin®, Ellence®, Sutent®, and most recently, Zydelig™

• Previous senior roles at the NCI, Pharmacia,

PTC Therapeutics, Calistoga Pharmaceuticals, and

Gilead Sciences

EVP, Regulatory Affairs

Ann Hards, PhD

• Over 20 years of regulatory experience

• Multiple successful NDAs, MAAs, sNDAs, advisory committees

• Responsible for regulatory aspects of development and/or

approval of 14 major new drugs/new indication, including drugs

with combined annual peak sales of over $30B (including

Lipitor®, Plavix®, Avapro®)

SVP, Public Health and Government Affairs

Michelle Ross, DVM, MS, PhD

• 21 years of active service in US Army Med. Department

• Senior military officer involved in forming national defense

policy in chemical, biological and radiological / nuclear

(CBRN) threat countermeasures and public health strategies

in response to both infectious disease outbreaks and

counterterrorism

3

FEMA estimates that >100,000 people would develop ARS if

a 10-kt nuclear device was detonated in Washington, DC*

Exposure, Gy

People

Injured, N

Mean Mortality

with Available Medical Care

Mean Mortality

Without Available Medical Care

Without

Major Trauma

With

Major Trauma

Without

Major Trauma

With

Major Trauma

Low Radiation Exposure Risk (Mortality Primarily Dependent on Extent of Traumatic Injuries)

<1.25 175,293 0-1% 8% 0-5% 40%

Moderate to High Radiation Risk (Mortality Increasingly Dependent on Radiation Exposure)

1.25-3.0 59,684 8% 25% 25% 100%

3-5.3 33,939 45% 73% 73% 100%

5.3-8.3 18,506 87% 100% 98% 100%

8.3-15 24,782 100% 100% 100% 100%

>15 10,802 100% 100% 100% 100%

Total 147,713

Overall Total 323,006

Presuming limited major trauma,

~82,136 people with potentially

recoverable ARS would die

* Buddemeier et al. National capital region: Key response planning factors for the

aftermath of nuclear terrorism. http://www.fas.org/irp/agency/dhs/fema/ncr.pdf)

4

N o n e G -C S F IL -1 2 E n to lim o d

0

2 0 ,0 0 0

4 0 ,0 0 0

6 0 ,0 0 0

8 0 ,0 0 0

1 0 0 ,0 0 0

E s t im a te d M o r ta lity b y

R a d ia t io n E x p o s u re a n d T re a tm e n t

M e d ic a l R a d ia t io n C o u n te rm e a s u r e

Nu

mb

er o

f A

RS

-Re

late

d F

ata

liti

es

8 6 ,7 4 58 2 ,6 1 4

6 4 ,4 3 9

4 5 ,4 3 8

In this scenario, entolimod could offer survival benefit to tens of

thousands of people with radiation exposures of 1.25-15 Gy

• Assumptions

• 10kT nuclear device is detonated in Washington,

DCa

• 136,911 people are exposed to 1.25-15 Gy of TBI

• No supportive care is available

• G-CSF survival advantage = -5%b

• IL-12 survival advantage = 22%b

• Entolimod survival advantage = 45%c

a Buddemeier et al. http://www.fas.org/irp/agency/dhs/fema/ncr.pdf b Gluzman-Poltorak et al. J Hematol Oncol. 2014 c Krivokrysenko et al. RS-23 study report. 2014

37,176 lives saved with entolimod

5

Historical ARS treatments have limitations

• Potassium iodide (KI)

• Effective against the long-term risk of cancer, ten to fifteen

years after exposure to certain types of radiation

• Prussian Blue

• Approved to reduce the net exposure to certain radioactive

elements

• Calcium and zinc diethylenetriaminepentaacetic acid

(DTPA)

• Chelating agents

None of these are effective in preventing or treating medical

conditions within either the hematopoietic or gastrointestinal

systems that arise from the acute effects of radiation exposure

6

Entolimod results compare favorably with those from

other drugs evaluated in NHP survival studies

A single dose of entolimod – administered without supportive care – provides substantial, statistically significant survival benefits and multi-

lineage hematological support

Drug Radiation

Exposure Dose Groups and N

Intensive

Supportive

Carea

Schedule Survival Benefit Euthanasia Hematology

Benefits

Filgrastimb

7.5 Gy

LD50/60

Control: 22

Filgrastim (10 μg): 24

Yes SC QD from 24 hours post-TBI until

ANC>1,000/μL for 3 days

Control vs Drug: 40.8% vs 79.2%

Improvement: 38.4%

(p<0.004)

Majority of

animals

ANC: Yes

PLT: No

Hgb: No

Filgrastimc 7.0 Gy

LD65/60

Control: 262

Filgrastim (10 μg): 26

No SC QD from 24 hours post-TBI for

18 days

Control vs Drug: 36% vs 31%

Improvement: -5%

(p=NS)

Data omitted ANC: Yes

PLT: No

Hgb: No

rHuIL-12d 7.0 Gy

LD90/60

Control: 26

rHuIL-12 (50, 100, 250, or

500 ng/kg): 18/group

No SC x 1 at 24 hours post-TBI Control vs Drug: 11% vs 33%, 39%,

39%, 50%

Improvement: 22%, 28%, 28%, 39%

(P<0.05)

Majority of

animals

ANC: Yes

PLT: 500 µg

Hgb: No

rHuIL-12c 7.0 Gy

LD65/60

Control: 26

rHuIL-12 (175 ng/kg): 36

No SC x 1 at 24 hours post-TBI Control vs Drug: 36% vs 58%

Improvement: 22%

(P=NS)

Data omitted ANC: Yes

PLT: Yes

Hgb: Yes

Entolimode

7.2 Gy

LD70/60

Control: 40

Entolimod (0.3, 1.0, 3.0,

6.6, 10, 40, or 120 μg/kg):

20/group

No IM x 1 at 25 hours post-TBI Control vs Drug: 27.5% vs 25.0%,

36.8%, 25%, 45%, 75%, 70%, 70%

Improvement: -2.5%, 9.3%, -2.5%,

17.5%, 47.5%, 42.5%, 42.5%

(P=0.0021, p<0.0001, p<0.0001)

Minimal

(2/179

animals)

ANC: Yes

PLT: Yes

Hgb: Yes

a. Transfusions, antibiotics, antidiarrheals, antiemetics, anti-inflammatories, antipyretics, anti-ulceratives, fluids, nutritional support

b. Farese et al. Radiat Res. 2013

c. Gluzman-Poltorak et al. J Hematol Oncol. 2014

d. Gluzman-Poltorak et al. Am J Hematol. 2014

e. Krivokrysenko et al. RS-23 Study Report. 2014

Abbreviations: ANC=absolute neutrophil count, EUA=Emergency Use Authorization, Hgb=hemoglobin, IM=intramuscular, LD=lethal dose, PLT=platelet count, SC=subcutaneous, TBI=total body

irradiation

7

Entolimod is a well-characterized medical

radiation countermeasure

• Derivative of Salmonella typhimurium

protein, FliC flagellin

• Protein with a molecular weight of

35 kilodaltons

• Produced by recombinant DNA technology

in Escherichia coli

• Acts as a highly potent and specific

agonist of Toll-like receptor 5 (TLR5)

• Developed under the FDA Animal Rule (21

CFR 601.90) which permits drug approval

based on demonstration of efficacy in

animals and safety in humans

8

Preserved tissue integrity, reduced hematopoietic and GI morbidities, increased anti-infective immunity

Survival

Entolimod mechanism of action

Entolimod TLR5 NFkB

IAPs, Bcl2

SOD2, ferritin

S100, HAMP

Cytokines

Suppress apoptosis

Inactivate ROS

Inhibit infections

Promote regeneration

Reduced HP and GI morbidities

SURVIVAL

Yoon SI, Kurnasov O, Natarajan V, Hong M, Gudkov AV, Osterman AL, Wilson IA. Structural basis of TLR5-flagellin recognition and signaling. Science 335:859-64. 2012.

9

# Agent/approach Action Prophylaxis Treatment

1 Anti-oxidants Reduction of severity of physical damage

2 Inhibitors of apoptosis

Reduction of cell loss in sensitive organs

3 Stimulators of regeneration

Accelerate recovery, reduce duration of disease

4 Anti-infectives Prevent and treat most common cause of death

5 Replacement therapy

Substitutes deficient function, buys time for regeneration

En

tolim

od

Power of a natural product: cumulative effect of multiple protective mechanisms mobilized by entolimod that mimics physiological

response to systemic Salmonella infection and enables both prophylactic and treatment use

Multiple mitigation strategies in one agent

10

Entolimod prevents radiation-related death in non-human

primates (randomized, blinded placebo-controlled study)

• A single dose of entolimod administered 25 hours after irradiation increased survival by ~3-fold (47.5% absolute improvement: from 27.5% to 75%)

• Animals received no other supportive care (eg, transfusions, intravenous fluids, antibiotics, or growth factors)

0 7 14 21 28 35 42 49 56 63

0

10

20

30

40

50

60

70

80

90

100

T im e , d a y s

Su

rv

iva

l, %

0 (N = 4 0 )

0 .3 (N = 2 0 )

1 .0 (N = 1 9 )

3 .0 (N = 2 0 )

6 .6 (N = 2 0 )

1 0 (N = 2 0 )

4 0 (N = 2 0 )

1 2 0 (N = 2 0 )

E n to l im o d D o s e , g /k g ( In it ia l N )

11

0

10

20

30

40

50

60

70

80

90

100

E n to lim o d D o s e , g /k g ( In it ia l N )

60

-Da

y S

urv

iva

l, %

9

5%

CI

0 (

N=

40)

0.3

 (N

=20)

1.0

(N

=19)

3.0

 (N

=20)

6.6

(N

=20)

10 (N

=20)

40 (

N=

20)

120 (

N=

20)

E m a x P re d ic t io n

P = .0 0 2 1

P < .0 0 0 1

P < .0 0 0 1

~3-fold

survival

increase

Entolimod induces hematological improvements in

neutrophils, platelets, and red blood cell parameters

Entolimod doses ≥10 μg/kg significantly reduced damage to various hematological

components necessary for survival and improved the overall proportion of days

alive and free of severe cytopenias and anemia (P<0.0001 for all tests)

0 7 1 4 2 1 2 8 3 5

1 0

4 2 4 9 5 6 6 3

A b s o lu te N e u tro p h il C o u n t

T im e , d a y s

Me

an

S

EM

, x

10

3/

L

0 (N = 4 0 )

0 .3 (N = 2 0 )

1 .0 (N = 1 9 )

3 .0 (N = 2 0 )

6 .6 (N = 2 0 )

1 0 (N = 2 0 )

4 0 (N = 2 0 )

1 2 0 (N = 2 0 )

E n to lim o d D o s e , g /k g ( In it ia l N )

0 .1

0 .5

1 .0

.0 1

0 7 1 4 2 1 2 8 3 5

1 0

1 0 0

4 2 4 9 5 6 6 3

P la te le t C o u n t

T im e , d a y s

Me

an

S

EM

, x

10

3/

L

0 (N = 4 0 )

0 .3 (N = 2 0 )

1 .0 (N = 1 9 )

3 .0 (N = 2 0 )

6 .6 (N = 2 0 )

1 0 (N = 2 0 )

4 0 (N = 1 9 )

1 2 0 (N = 2 0 )

E n to lim o d D o s e , g /k g ( In it ia l N )

2 0

5 0

5 0 0

0 7 1 4 2 1 2 8 3 5

7 0

8 0

9 0

1 0 0

1 1 0

1 2 0

1 3 0

4 2 4 9 5 6 6 3

H e m o g lo b in

T im e , d a y s

Me

an

S

EM

, g

/L

0 (N = 4 0 )

0 .3 (N = 2 0 )

1 .0 (N = 1 9 )

3 .0 (N = 2 0 )

6 .6 (N = 2 0 )

1 0 (N = 2 0 )

4 0 (N = 1 9 )

1 2 0 (N = 2 0 )

E n to lim o d D o s e , g /k g ( In it ia l N )

0 7 1 4 2 1 2 8 3 5

1 0

1 0 0

4 2 4 9 5 6 6 3

A b s o lu te R e tic u lo c y te C o u n t

T im e , d a y s

Me

an

S

EM

, x

10

3/

L

0 (N = 4 0 )

0 .3 (N = 2 0 )

1 .0 (N = 1 9 )

3 .0 (N = 2 0 )

6 .6 (N = 2 0 )

1 0 (N = 2 0 )

4 0 (N = 1 9 )

1 2 0 (N = 2 0 )

E n to lim o d D o s e , g /k g ( In it ia l N )

5 0

5

12

Entolimod increased pharmacodynamic biomarkers

(G-CSF and IL-6) in non-human primates

Dose-dependent effects on both biomarkers were highly predictive of entolimod effects

on survival (Spearman rank correlation coefficient for each biomarker = 0.84)

0 .0 1

0 .1

1

1 0

1 0 0

1 ,0 0 0

1 0 ,0 0 0

1 0 0 ,0 0 0

P la s m a G -C S F A d jA U C 0 -2 4

E n to lim o d D o s e , g /k g (N )

Ad

jAU

C0

-24,

Me

an

R

an

ge

, h

r

pg

/mL

0 (

N=37)

0.3

 (N

=20)

1.0

(N

=19)

3.0

 (N

=20)

6.6

(N

=20)

10 (N

=20)

40 (

N=19)

120 (

N=20)

E m ax

P < 0 .0 0 0 1

1 0 0

1 ,0 0 0

1 0 ,0 0 0

1 0 0 ,0 0 0

1 ,0 0 0 ,0 0 0

P la s m a IL -6 A d jA U C 0 -2 4

E n to lim o d D o s e , g /k g (N )

Ad

jAU

C0

-24,

Me

an

R

an

ge

, h

r

pg

/mL

0 (

N=40)

0.3

 (N

=20)

1.0

(N

=19)

3.0

 (N

=20)

6.6

(N

=20)

10 (N

=20)

40 (

N=19)

120 (

N=20)

E m ax

P < 0 .0 0 0 1

Abbreviations: AdjAUC0-24=background adjusted area under the curve from 0 to 24 hours, G-CSF=granulocyte colony-stimulating factor, IL-6=interleukin-6.

13

Entolimod increased pharmacodynamic biomarkers

(G-CSF and IL-6) in human subjects

The dose-dependent changes in these biomarkers in non-human primates

and in humans supports their utility for dose conversion between species

Abbreviations: AdjAUC0-24=background adjusted area under the curve from 0 to 24 hours, G-CSF=granulocyte colony-stimulating factor, IL-6=interleukin-6.

1 0 0

1 ,0 0 0

1 0 ,0 0 0

1 0 0 ,0 0 0

P la s m a IL -6 A d jA U C 0 -2 4 - - A b s o lu te D o s in g

E n to lim o d D o s e , g (N )

Ad

jAU

C0

-24,

Me

dia

n

Ra

ng

e,

hr

pg

/mL

2 (

N=6)

6 (

N=6)

12 (

N=6)

25 (

N=31)

30 (

N=36)

35  (N

=31)

40 (

N=5)

50 (

N=3)

6 0 0 ,0 0 0

S p line

1 0 0

1 ,0 0 0

1 0 ,0 0 0

1 0 0 ,0 0 0

P la s m a G -C S F A d jA U C 0 -2 4 - - A b s o lu te D o s in g

E n to lim o d D o s e , g (N )

Ad

jAU

C0

-24,

Me

dia

n

Ra

ng

e,

hr

pg

/mL

2 (

N=6)

6 (

N=6)

12 (

N=6)

25 (

N=31)

30 (

N=36)

35  (N

=31)

40 (

N=5)

50 (

N=3)

6 0 0 ,0 0 0

S p line

1 0 0

1 ,0 0 0

1 0 ,0 0 0

1 0 0 ,0 0 0

P la s m a G -C S F A d jA U C 0 -2 4 -- B o d y -W e ig h t-A d ju s te d D o s in g

E n to lim o d D o s e , g /k g (N )

Ad

jAU

C0

-24,

Me

dia

n±

Ra

ng

e,

hr·p

g/m

L

<10 (

N=11)

10-1

9 (

N=6)

20-2

9 (

N=16)

30-3

9 (

N=50)

40-4

9 (

N=28)

50-5

9  (N

=6)

60-6

9 (

N=4)

70 (

N=3)

6 0 0 ,0 0 0

S p line

1 0 0

1 ,0 0 0

1 0 ,0 0 0

1 0 0 ,0 0 0

P la s m a IL -6 A d jA U C 0 -2 4 -- B o d y -W e ig h t-A d ju s te d D o s in g

E n to lim o d D o s e , g /k g (N )

Ad

jAU

C0

-24,

Me

dia

n±

Ra

ng

e,

hr·p

g/m

L

<10 (

N=11)

10-1

9 (

N=6)

20-2

9 (

N=16)

30-3

9 (

N=50)

40-4

9 (

N=28)

50-5

9  (N

=6)

60-6

9 (

N=4)

70 (

N=3)

6 0 0 ,0 0 0

S p line

14

Entolimod safety and pharmacology has been

documented in 150 healthy subjects and 25 patients

with advanced cancer

• Participant characteristics

• Men (N=141) and women (N=34)

• Age range: 18 to 82 years

• Body weights 45.9 to 117.3 kg (91.8 to 258.0 lbs)

• Doses: 2 to 50 μg (0.02 µg/kg to 1.09 µg/kg)

• Safety profile showed transient, self-limiting, IL-6-mediated events*

• Flu-like symptoms (headache, fever, chills, malaise, myalgia), and

gastrointestinal symptoms (eg, nausea, vomiting) lasting <24 hours and

improved by symptomatic intervention (400 mg of ibuprofen)

• Asymptomatic serum ALT and AST elevations, hyperglycemia, and

hypophosphatemia peaking at 8 hours and resolving by 24 hours

• Decreases in blood pressure and increases in pulse rate, peaking at 4 hours and

resolving by 24 hours

• No induction of “cytokine storm” mediators (eg, IL-1α, IL-1β, IL-2, interferon-α or

interferon–γ)

• No changes in serum bilirubin, creatinine, BUN

*Weber et al. Tumor Immunol. 1994

15

Entolimod has achieved pivotal development

status under the FDA animal rule

• Completion of a pivotal efficacy study in non-human primates

• Characterization of safety in 150 healthy subjects and

25 patients with advanced cancers

• Completion of formal animal-to-human dose conversion to select a

human dose (reviewed with FDA)

• Development of a high-yield cGMP manufacturing process

• Manufacturing of drug substance for >1,000,000 doses

• Demonstration of prolonged drug stability

• Formulation in single-use vials suitable for stockpiling

16

Entolimod regulatory summary

• The FDA agreed that there is sufficient data and justification to review

a pre-EUA submission for entolimod

• Submission targeted for 2Q’2015

• The pre-EUA application will include all required manufacturing,

nonclinical, and clinical reports and summaries, draft package insert,

patient information/consent document, and CRF

• CBLI plans to complete remaining full licensure studies for a

Biologics License Application (BLA) submission to the FDA with

funding assistance from the US govt.

• US DoD funding for some additional animal and clinical studies is being

negotiated

• Other requests for support are pending

17

Entolimod is well positioned to address the

challenge of treating ARS

• Demonstrated survival benefit with little to no supportive

care

• Protects both hematopoeitic and gastrointestinal systems

• Single administration

• Well characterized mechanism of action

• Established safety profile

• cGMP manufacturing process fully developed

• Pre-EUA submission and evaluation pending

18