CBLB502 Medical and Curaxins OverviewInvestor DayJune 8, 2011
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 the Company’s judgment as of the date of
this presentation and are subject to risks and uncertainties that could cause actual
results of events 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.
Safe-Harbor
2
Scientific and Clinical Program Goals
3
Support Animal Rule-driven development of CBLB502 for biodefense applications• Mechanism of action studies: rational choice of biomarkers
• Defining CBLB502 efficacy range
• Determination and validation of human dose
Moving CBLB502 to oncology clinic• Radiotherapy adjuvant (local irradiation models)
• Chemotherapy adjuvant
• Effect on tumors
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CBLB502 in Preclinical Model of Local Irradiation
Toll-like Receptor 5 Agonist Protects Mice from Dermatitis and Oral Mucositis Caused by Local Radiation: Implications for Head
and Neck Cancer Radiotherapy.
(Int. J. Rad. Onc. Biol. Phys., in press)
Goal:
• Justification of use of CBLB502 as a supporting care radioprotection adjuvant
Results:
• CBLB502 is efficacious against radiation-induced mucositis and dermatitis
Significance:
• Strong preclinical support of use of CBLB502 as radiotherapy adjuvant
• Justification of new application (protection from radiation-induced dermatitis)
Approval of “CBLB502 as supportive care” trial protocol in head and neck cancer patients by Scientific Review Committee of Roswell Park
Head and neck irradiation model in mice
Extending Indications of CBLB502Mitigation of chemotherapy side effects and direct anticancer action
Irinotecan and CBLB502 against Wart colon tumors in Fisher rats
CBLB502 displays both supportive care and direct antitumor activities in rat model of colon cancer
0 4 8 12 16 20 24 28 32Me
an
Tu
mo
r W
eig
ht
(mg
)
200
500
2000
5000
100
1000
10000
Antitumor activity and toxicity of Irinotecan ± CBLB502
in rats bearingadvanced Ward colorectal carcinoma
Time (Days)
0 4 8 12 16 20 24 28 32
Me
an
Bo
dy
We
igh
t (%
)
80
85
90
95
100
105
110
Control
CBLB502 0.2 mg/kg x 5
Irinotecan 200 mg/kg x 3
CBLB502 0.2 mg/kg(5) + Irinotecan 200 mg/kg
CBLB502 0.2 mg/kg(3) + Irinotecan 200 mg/kg
Irinotecan 200 mg/kg + CBLB502 0.2 mg/kg
"Toxicity"
"Antitumor Activity"
Irinotecan daily x3, 200 mg/kg i.v. +/- CBLB502
0 4 8 12 16 20 24 28 32 36 40 44 48 52Me
an
Tu
mo
r W
eig
ht
(mg
)
200
500
2000
5000
100
1000
10000
Indivadual rat bearing advanced Ward colorectal carcinoma
response to CBLB502 0.2 mg/kg/day by i.p. daily x 5
Time (Days)
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Me
an
Bo
dy
We
igh
t (%
)
90
95
100
105
110
115
Rat # 1
Rat # 2
Rat # 3
Rat # 4
"Toxicity"
"Antitumor Activity"
0
CBLB502, x3 daily, 0.2 mg/kg
Irinitecan+CBLB502
placebo
Irinitecan alone
(all dead from GI toxicity)
CBLB502 rescues animals from Irinotecan toxicity with no
interference with its antitumor activity
CBLB502 caused complete regression of tumors in part
of the animals
Granulocyte colony formation in vitro by mouse BM cells irradiated
in vivo in vitroCBLB502CBLB502
Radioprotective Effect of CBLB502 is Indirect
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Histological Atlas of CBLB502 ActivityIdentification of Target Organs
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-5
5
15
25
35
45
55
65
75
Liver Smallintestine
Largeintestine
Kidneys Lungs Brain Spleen
Lu
cif
era
se f
old
in
du
cti
on
CBLB502
LPS
80
NFkB reporter induction in various tissues
NFkB reporter mice
vehicle CBLB502liver
control CBLB502
NF-kB
DNA
Liver is the primary target
organ of CBLB502
Balb/C-Tg(IkBa-luc)Xen mice
NF-kB activation in livers
Inta
ct
CBLB
502
PBS
PBS
CBLB
502
CBLB
502
0
20000
40000
60000
80000No surgery
Liver isolation
Lu
cifera
se u
nit
s
NF-kB activation in livers
Inta
ct
CBLB
502
PBS
PBS
CBLB
502
CBLB
502
0
20000
40000
60000
80000No surgery
Liver isolation
Lu
cifera
se u
nit
s
Step 1. Occluding the hepatoduodenalligament containing hepatic artery and portal vein with a non-traumatic clamp.
Step 2. CBLB502/PBS injections.
Step 3. The blood supply occluded for 30 minutes then clamp released and blood circulation restored.
Step 4. Mice were irradiated immediately after the surgery with 10 Gy TBI.
Step 5. Bone marrow cells isolated from femura and total colony formation estimated using MethoCult media and standard protocol for CFU assay.
Assessing Role of Hepatocytes in Radioprotection:surgical exclusion of liver from blood circulation
Step 1. Occluding the hepatoduodenalligament containing hepatic artery and portal vein with a non-traumatic clamp.
Step 2. CBLB502/PBS injections.
Step 3. The blood supply occluded for 30 minutes then clamp released and blood circulation restored.
Step 4. Mice were irradiated immediately after the surgery with 10 Gy TBI.
Step 5. Bone marrow cells isolated from femura and total colony formation estimated using MethoCult media and standard protocol for CFU assay.
No liver = No radioprotection of bone marrow
Liver is the source of endogenous HP-protecting factors mobilized by CBLB502
BMC-CFU
0
20
40
60
80
100
No surgery
Liver isolation
Co
lon
y n
um
be
r
BMC-CFU
0
20
40
60
80
100
No surgery
Liver isolation
Co
lon
y n
um
be
r/ 5
x1
04
BM
Cs
10
TLR5 Activation Protects Liver from Fas
11
TLR5 Agonist Protects Mice from Fas
Caspase activation
0
20000
40000
60000
80000
100000
120000
Intact Fas CBLB502 CBLB502+Fas
Ca
sp
ase
3,7
activity
Liver enzymes
0
50
100
150
200
250
300
350
400
Intact CBLB502
Se
rum
AL
T (
U/L
)
0
50
100
150
200
250
300
350
400
Intact CBLB502Fas
Se
rum
AL
T (
U/L
)
CBLB502
+Fas
0 5 10 15 20 25 300
20
40
60
80
100
Days
Anim
al s
urv
ival (
%)
Mouse survival
PBS (n=16)
CBLB502, 0.5 h (n=16)
CBLB502, 2 hs (n=10)
CBLB502, 6 hs (n=10)
Liver condition
12
Intact
Anti-Fas
CBLB502 + anti-Fas
con
tro
lC
BLB
50
2
• CT26, TLR5-negative syngeneiccolon cancer, was grown as liver metastases in Balb/c mice
• Tumor growth was monitored using luminometer imager (tumors express luciferase)
• Tumor suppressive effect of CBLB502 is associated with tumor infiltration with immunocytes
CBLB502 against liver metastases of colon cancer in mice
livermetastase
liver
metastase
Control (no drug) CBLB502, 5hrs post injection
CT26 tumor-free mice (liver)
0 20 40 600
20
40
60
80
100 Intact, n=15
CBLB502, n=19log rank p=0.0067
Days
Perc
en
t su
rviv
al
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Direct Anti-tumor Effects of CBLB502
healthy
TLR5- tumors in liver
TLR5+ tumors in liver
TLR5+ tumors
TLR5- tumors
CB
LB5
02
No toxicity
Tumor suppression
Tumor suppression
Tumor suppression
No antitumor effect
TLR5-negative tumors
TLR5-positive tumors
• Identification of target tissues enables rational choice of indications and regimens
• Phase I/II “CBLB502 as a single agent” trial protocol was approved by Scientific Review Committee of Roswell Park
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CBLB502 as Direct Antitumor Agent
• Has direct suppressive effect in several animal models of TLR5-positive tumors (lung, colon cancer, melanoma)
• Effective against liver metastases regardless of TLR5 status of the tumor
• Acts by mobilizing antitumor immunity
• Expected to provide anti-tumor vaccination
• Fits several clinical trial scenarios, including liver metastasis of colon cancer, liver cancer, bladder cancer, H&N cancer, etc.
Many of these trials enable assessment of both supportive care and direct anti-tumor activity of CBLB502
Prospective Clinical Trials of CBLB502 in Cancer Patients
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• Reducing severity of mucositis and enhancing efficacy of radiotherapy of H&N
cancer
• Reducing severity of bowel toxicity and enhancing efficacy of radiotherapy of
pancreatic cancer
• Reducing severity of diarrhea in colon cancer patients treated with Irinotecan
• Treating primary hepatocellular carcinoma (liver cancer)
• Treating liver metastasis of colon cancer
• Treating liver metastasis of breast cancer
• Pre-operational treatment of prostate cancer
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CBLB502: Major Scientific and Clinical Updates
Demonstration of CBLB502 efficacy in preclinical model of local irradiation• Approval of Phase I/II “CBLB502 as supportive care” trial in head and neck cancer
patients by Scientific Review Committee of Roswell Park
Discovery of direct anticancer action of CBLB502: from “supportive care only” drug to combined “supportive care and anticancer” drug• Approval of Phase I/II “CBLB502 as a single agent” trial by Scientific Review
Committee of Roswell Park
Demonstration of radiomitigating efficacy of CBLB502 against GI manifestation of acute radiation syndrome in primates that received extremely high radiation doses• Critical result for justifying extended indications of CBLB502
Building of Histological Atlas of CBLB502 activity, identification of target organs• Path to optimal indications and regimens
Completion of Phase Ib human dose validation trial
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CuraxinsAnticancer drugs
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Curaxin’s Targets р53, NF-kB, HSF1 in Cancer
Normal cell response
to stressesinfection
DNA damage
t0
death survival
CANCER
target for activation (doxorubicin, 5FU, cisplatin, etc.)
target for inhibition (bortezomib)
target for inhibition (geladanomycin)
survival
survival
death or
arrest
Normal cell response
to stressesinfection
DNA damage
t0
death survival
CANCER
target for activation (doxorubicin, 5FU, cisplatin, etc.)
target for inhibition (bortezomib)
target for inhibition (geladanomycin)
survival
survival
death or
arrest
Curaxins Target FACT-dependent Transcription
+ Curaxin
Trap of FACT on chromatin blocks FACT-dependent transcription and
causes CK2-mediated p53 activation
NF-kB-dependent transcription requires FACT
Gasparian et al., Science Translational Research, in final revision
Curaxinactivator
inhibitor
inhibitor
live tumor cell dead tumor cell
Non-genotoxic anticancer drug candidates with triple
mechanism of action suitable for use in combinations with
conventional drugs
Antitumor Effects of Curaxins
Curaxins: Safe Multi-targeted Drugs
p53 activation
NF-kB inhibition
Heat shock inhibition
Genotoxicity
CuraxinsConventional
drugsProperty
p53 activation
NF-kB inhibition
Heat shock inhibition
Genotoxicity
CuraxinsConventional
drugsProperty
yes
no
no
yes
yes YES
no yes
Curaxins in Cancer Prophylaxis
50% reduction in breast tumor incidence in transgenic MMTV-neumice that were maintained on drinking water with non-toxic doses of curaxinCBLC137 during 10 months
Lack of genotoxicity, combined with p53 activation and NF-kBand HSF1 suppression, opens the opportunity of using
Curaxins as cancer preventing agents
Appearance of palpable tumors
in mice of different groups
0
0.2
0.4
0.6
0.8
1
1.2
Age (weeks)
tum
or-
free a
nim
als
(p
rop
ort
ion)
Control
CBL137, 0.1mg/ml
CBL137, 0.2mg/ml
p=10-5
p=0.0001
23
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Curaxins
Synthetic small molecules with proprietary structure
Unique mechanism of action: simultaneously affect multiple molecular targets in cancer cell
Efficacious in a broad spectrum of preclinical tumor models
Mechanism of action enables additional clinical indications beyond cancer treatment (anti-inflammatory, anti-infective)
First generation Curaxin CBLC102 is in clinical trial in patients with liver metastases
New generation Curaxin CBLC137 is at advanced stage of preclinical development
24
24
Incuron – JV for Curaxin Development
50/50 joint venture with Bioprocess Ventures, Moscow
~$18M to reach Phase II for new generation of Curaxins in US and Russia and conduct human trials in liver cancer in Russia for CBLC102
CBLI oversees mechanistic studies and formal development
Phase Ib trial for CBLC102 in liver started October 2010
IND-enabling studies for new generation of Curaxins on track for IND
Demonstrates feasibility of model combining advantages of US and Russian development platforms
25
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Milestones
• Start of pivotal animal efficacy studies for CBLB502 defense
• Start of definitive safety/dose validation trial in healthy volunteers for CBLB502 defense
• Start of CBLB502 Phase I/II trial in head and neck cancer patients for supportive care indication
• Start of CBLB502 Phase I/II trial in advanced liver metastases patients for safety/antitumor effect
• Completion of CBLC102 trial in liver cancer patients in Russia
• Filing of IND for studies of new generation curaxins
• Top level peer reviewed publications