Entolimod, an Innovative Medical Radiation · 2016-05-26 · “Entolimod, an Innovative Medical...
Transcript of Entolimod, an Innovative Medical Radiation · 2016-05-26 · “Entolimod, an Innovative Medical...
“Entolimod, an Innovative Medical Radiation
Countermeasure”
Michelle Ross, DVM, MS, Ph.D.
SVP Public Health and Government Affairs, Cleveland BioLabs, Inc. Email: [email protected]
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
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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)
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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
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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
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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
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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.
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# 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
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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.
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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
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