1
Small Molecule Platform
Improving Radiation Treatment
SphingoGene, Inc.
Delaware C-Corporation
James S Norris PhD
Board President and Interim CEO
norrisjs@musc.edu
2
To obtain funding or partnerships in order to
complete preclinical development of SPG105
for IND filing
3
A family of lipids involved in cell
signaling
• Cell differentiation
• Proliferation
• Programmed cell death – apoptosis
4
Dysregulation of ceramide accumulation is a common
mechanism of resistance to therapies
5
• Alleviate resistance to
• Chemotherapy
• Radiation Therapy
• Synergistic killing with targeted therapies
(combination therapy)
• TKIs – imatinib, dasatinib, nilotinib,
sorafenib, sunitinib
• HDAC inhibitors – vorinostat
• mAbs – Rituximab, milatuzumab
6
Fingolimod (Gilenya, Novartis)
• First oral drug for Multiple Sclerosis
• $1.2B sales in 2012, up 147% from 2011
iSONEP (Lpath)
• Phase 2 clinical development for wet AMD (macular
degeneration)
• $500M partnerships with Pfizer
Others - in preclinical development
7
8
Rational for Our Drugs Mechanism of
Action:
Ceramide
Cancer
Cell
Death
Acid
Ceramidase
Radiation Therapy
Prevents ceramide accumulation
Allows escape from cell death
9
How our drugs work:
Ceramide
Cancer
Cell
Death
Acid
Ceramidase
SPG105
Radiation Therapy
Inhibits Acid Ceramidase
Prevents ceramide accumulation
And Potentiates Radiation
Allows escape from cell death
Induced Cancer Killing
10
Background on SphingoGene
• Founded in 2006 by scientist-entrepreneurs at
the Medical University of South Carolina (MUSC)
• Obtained exclusive worldwide rights to the
intellectual property from MUSC
11
Why Start with Prostate Cancer?
“My granddad died of prostate cancer. I have
dedicated my thesis work which has led to our
lead clinical compound to him.”
Joseph Cheng
MUSC MD/PhD candidate
SphingoGene Researcher
“Hurry up! The Baby Boom generation is getting
prostate cancer!”
Ken Burger
Author of “Baptized in Sweet Tea”
Prostate Cancer Patient, Charleston, S.C.
12
Death by Type
Occurrence by Type
Other
27%
Prostate
15%
Lung
28%
Other
30%
Breast
14%
Leukemia
3%
Thyroid
3%
Kidney
4%
Bladder
Lung
14%
4%
Melanoma
5%
Kidney
2%
Lymphoma
5%
Colon
6%
Colon
9%
Bladder
3%
Ovary
3%
Lymphoma
3%
Breast
7%
Leukemia
4%
Prostate
5%
Pancrease
6%
Source: Cancer Facts and Figures 2012
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf
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Prostate Cancer
• Forms in male prostate gland
• Most common cancer in men
• Risk increases with age
•In 2012:
 241,740 men will be diagnosed
 25,170 will die from the disease
14
How Our Platform Works
•Ceramide levels increase during radiation therapy; leads to cancer cell death
•Acid ceramidase (AC) and Sphingosine Kinase (SK) activity increase during radiation
therapy in cancer cells
•AC reduces ceramide levels, SK forms S1P, both permitting cancer cell survival
•Our compounds inhibit AC or SK or mimic ceramide making radiation or other
therapies more effective at inducing cancer cell death
15
Progress and Leads
•Clinical efficacy established in animal models of cancer at nM concentrations
•Dose Escalation: No toxicity observed at effective doses and 20 X higher doses
Lead Small Molecule Candidates (of 40):
Drug
Target
Stage of Development
SPG 105
AC Inhibitor
Clinical lead; efficacy established in rodent tumor xenograft
models and cell culture models of prostate and breast cancers
SPG 103
Ceramide-like Efficacy established in rodent tumor xenograft pancreatic
Drug
cancer models and cell lines
SK1 Inhibitor Clinical Efficacy in vitro and in vivo pending
SPG 104
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In Vivo Efficacy
•SG105 (clinical lead) Significantly Reduces Tumor Size;
in vivo mouse Xenograft Prostate Tumor Model
Log2
size
Log
2 xenograft
Log
2 Tumor Size
(% of initial volume)
(% of initial volume)
10
10
9
9
8
8
7
7
6
6
5
5
4
4
0
10
20
203030 40 50 60 70 80 90 100
DaysDays
Control (6)
IR only
(10)
Control
(n=6)
Control
(6)
Radiation
(Rad)
IRVehicle
only (10)
(8) Only (n=10)
Vehicle
Only
Vehicle
(8) (n=8)
Veh+IR
(10)
Vehicle
Veh+IR+ Rad
(10)(n=10)
SPG105
Only
(n=10)
LCL521
(10)
LCL521
(10)
SPG105
+ Rad
(n=10)
LCL+IR
LCL+IR(10)
(10)
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In Vivo Efficacy
•SPG105 Significantly Reduces Mortality; in vivo mouse
Xenograft Prostate Tumor Model
Percent survival
Percent Survival
100
75
Control
Ctl+IR
Vehicle
Veh+IR
LCL521
LCL+IR
50
25
0
0
25
50
Days
75
100
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Percentage of Weight change (ip every other day x5, n=3)
NT
35
0mg/kg
30
12.5mg/kg
25
25mg/kg
20
50mg/kg
15
75mg/kg
100mg/kg
10
150mg/kg
5
200mg/kg
0
250mg/kg
-5
-10
1
3
5
8
10
12
15
19
24
31
290mg/kg
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There is No Significant Toxicity Observed in Blood Chemical Test in Animal
after Multiple Injections (150mg/kg ip every other day x5)
Un-treated
n=4
Cremophore
LCL521
Un-treated
Cremophore
LCL521
Mode
Means
SD
Means
SD
Means
SD
Mode
Means
SD
Means
SD
Means
SD
ALB(g/DL)
3.38
0.40
3.50
0.12
3.23
0.25
WBC(10/L)
5.54
1.46
7.30
2.50
7.29
3.23
ALP(U/L)
98.25
7.76
89.50
10.38
88.50
13.08
LYM (10/L)
4.57
1.07
5.36
0.19
5.50
1.81
ALT(U/L)
97.00
32.59
92.50
85.02
81.75
57.38
MON (10/L)
0.20
0.18
0.30
0.27
0.26
0.24
AMY(U/L)
1065.50
42.26
955.75
37.53
946.25
40.36
GRA (10/L)
0.77
0.52
1.64
2.25
1.56
1.37
TBIL(mg/DL)
0.28
0.05
0.30
0.00
0.28
0.05
LY %
83.30
7.91
78.80
20.63
77.90
10.83
BUN(mg/DL)
23.50
2.52
20.25
2.87
17.50
2.38
MO %
3.28
2.09
3.55
2.02
3.35
2.14
CA++(mg/DL)
10.85
0.29
10.45
0.30
10.70
0.12
GR %
13.45
8.00
17.68
18.70
18.80
10.03
PHOS(mg/DL)
6.95
1.02
7.35
0.26
7.90
0.93
RBC (12/L)
12.30
0.37
12.00
0.67
11.98
0.37
CRE (mg/DL)
0.20
0.00
0.20
0.00
0.20
0.00
HGB (g/DL)
14.78
0.52
14.10
0.61
14.35
0.26
GLU (mg/DL)
140.75
20.04
134.50
17.75
127.50
21.44
HCT %
51.69
1.64
50.49
2.70
51.12
2.07
NA+ (MMO/L
155.75
1.26
154.25
0.96
156.25
2.99
MCV ( fl )
42.00
0.00
42.00
0.00
42.75
1.26
K+ (MMO/L)
6.05
0.81
6.63
0.40
7.85
0.37
MCH (pg)
12.00
0.28
11.78
0.19
11.98
0.21
TP (g/DL)
5.88
0.21
5.63
0.22
5.78
0.22
MCHC (g/DL)
28.55
0.47
27.95
0.44
28.05
1.40
GLOB (g/DL)
2.50
0.45
2.13
0.13
2.55
0.06
RDWc %
15.95
0.56
16.20
0.42
17.00
0.63
PLT (10/L)
386.75
251.67
562.00
76.68
630.25
47.41
PCT %
0.25
0.17
0.36
0.05
0.41
0.03
MPV ( fl )
6.35
0.37
6.45
0.19
6.48
0.25
PDWc %
28.80
0.35
28.63
0.71
29.75
0.68
n=4
Toxicity Study
Percentage of weight change (150mg/kg ip
every other day x5)
20
150mg/kg
15
10
5
0
1
-5
3
5
8
10
12
15
19
24
31
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Our Value Proposition
• Enhances Radiotherapy leading to more effective cancer
treatment
• Fewer side effects
Achieve same clinical benefit with reduced radiation
• Better quality of life
• Greater preservation of sexual function
• Reduce incidence of relapse = Reduced overall treatment
costs and reduced death rate
• Small Molecules = Easy manufacturing and delivery
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More effective radiotherapy of
prostate cancer means:
• Same clinical benefit with reduced radiation
▫ Fewer side effects
▫ Greater preservation of sexual function and continence
issues
▫ Reduced incidence of relapse
▫ Targets mechanism of radioresistance
• Reduced death rates
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Market opportunity
• United States: 241,740 cases/year
• Worldwide:
903,500 cases/year
• @50% of patients will receive IR therapy. 21-44%
of these patients will relapse. In a couple of
studies 50% of patients relapsed and 51% of them
had local disease (not metastatic) making local
control relevant to survival. Our preclinical
indication is that SPG105/IR therapy will reduce
relapse and improve survival.
25
Financial Assumptions and Forecast
• Based on annual estimated US prostate cancer cases
treated with radiation therapy
• Market penetration expected similar to other cancer
therapeutics
• No increase in cases, no relapses
• $8000 per treatment per patient (drug cost)
Estimated worldwide market projected in billions
26
Other Markets
Platform applicable to the majority of solid tumors and
any cancer for which patients receive radiation therapy,
including internal radiotherapy (brachytherapy).
Approximate Incidence of other cancer markets (cases/year):
•Lung:
1,600,000
•Breast:
1,380,000
•Pancreatic:
220,000
•Oral cavity:
263,900
•Brain:
237,913
Total:
3,701,813 cases/year
Estimated worldwide market projected in billions
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3.5M new cases/yr; 2.5M death/yr
Top 10 Cancers Occurrence
Thyroid
2%
Lung
19%
Other
24%
Stomach
13%
Bladder
2% Lymph
2%
Pancreas
3%
Breast
7%
Esophagus
8%
Liver
10%
Colorectal
10%
Top 10 Cancer Death
Brain and
central
nervous Lymph
2%
system
2%
Leukemia
2%
Other
16%
Lung
25%
Breast
3%
Pancreas
4%
Colorectal
8%
Esophagus
9%
Source: The National Cancer Registry under the Ministry of Health
http://www.chinadaily.com.cn/china/2013-01/10/content_16100330.htm
Liver
15%
Stomach
14%
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Radiation Therapy for Other Cancers –
Candidates for SPG105
• Lung 60-70 Gy in 30-35 fractions
• Breast 50.4 - 60 Gy in 28-33 fractions
• Pancreas 50.4-54 Gy in 28-30 fractions
• Melanoma 36-60 Gy in 6-30 fractions (big variability)
• Head and Neck 60-70 Gy in 30-35 fractions.
Potential: If clinical trials successfully model the preclinical data then
SPG105 has the potential to become a standard of care
blockbuster drug in the radiation treatment industry.
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Competing Radiosensitizer
Drugs
• The first annual workshop for preclinical and clinical development of radiosensitizers
took place at the NCI in August 2012 (JNCI, pages 1-8, 2012 advanced access).
• Summary:
• There are ongoing trials many of which are focused on biomarker indicators to
improve patient selection.
• A partial use of drugs being studied include standard chemotherapeutic drugs such
as Gemcitabine, 5-Fu, Cisplatin while others are kinase inhibitors such as; Erlotinib,
Bevacizumab as examples.
• Other categories of drugs include ER inhibitor Tamoxifen and Her-2 inhibitors like
Trastuzumab.
• Two potential drugs that inhibit aspects of the ceramide-S1P rheostat with an
unknown value in the radiation therapy domain include Fingolimod and ASONEP.
Both of these drugs act downstream of SPG105.
• A recent preclinical publication demonstrated rapamycin might be useful as a
radiosensitizer.
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SPG105 is clean, unlike Gilenya which has multiple
effects (“dirty drug”):
It inhibits Acid Ceramidase by specifically targeting
acidic compartments (lysosomes) and functioning in
lysosomes to inhibit lysosomal enzyme.
Investigations have not found actions anywhere
else.
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SPG105 can be used in resistance of different
therapies that involve ceramide pathway.
• Chemotherapy
• TKI targeted therapies
• HDACI therapies
• mAb therapies
32
Patent Position
• SphingoGene has filed broad patents around targets
and various classes of compounds which can affect
their targets
• Lead Compounds:
Worldwide Patent pending for SPG105 (clinical lead); US
2011/0251197 A1
Issued patent for SPG103; US8,093,393 B2
Patent pending for SPG104; US 2012/0035268 A1
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Regulatory Path and Timelines
Investigational New Drug Application (IND) Filing in US:
•Phase I: Prostate Cancer Patients undergoing primary radiotherapy
•Primary Endpoint: Safety/Tolerability
•Phase IIa: Prostate Cancer Patients undergoing primary radiotherapy
•Primary Endpoint: Safety/Tolerability
•Second Endpoint: Efficacy/biochemical relapse
Overall Timeline to Exit:
34
Company Funding to Date
• NIH/NCI (University) Program Project Grant:
$1.6million
• NIH Small Business Technology Transfer (STTR) Grant:
$432,000
• ARRA stimulus package: $180,000
• South Carolina Research Authority (SCRA) start-up
funds and SBIR match: $125,000
Total: $2.34 Million of Non-dilutive funding
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• GMP synthesis
• Formulation
• Toxicity testing (rats, nonhuman privates
36
Anticipated Funding
• Phase I/II Small Business Innovative Research (SBIR)
Grant (CA174027-01): $2,115,479
• Phase I STTR (CA177006-01): $346,792
• Up to $200,000 (SCRA)
Total: $2.6 Million of Non-dilutive Funding
37
Anticipated Financial Needs
Projected cost for each milestone
GMP Synthesis (SBIR)
Formulation
$149,400
$79,100
Toxicity Testing (rats, non human primates)
$1,618,649
Phase I Trial (Hollings Cancer Center)
$1,100,000
Phase II Trial (Hollings Cancer Center)
$3,640,000
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Management Team & Advisors
• James Norris, PhD, Chairman of the board and Interim CEO
▫ Professor, Department of Microbiology & Immunology
▫ Medical University of South Carolina (MUSC)
• David Haselwood, Board Member & Business Advisor
▫ Experienced life science VC, entrepreneur & operator
▫ Burrill & Co, Roche, Proventys, Pharmasset, Primera
• Yusuf Hannun, MD, Director of the Stony Brook University Cancer
Center
▫ Joel Kenney Professor of Medicine, and the Vice Dean for Cancer Medicine
▫ World famous expert in sphingolipid biochemistry
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Advisors:
• Allen Conger, MBA University of Chicago
Experienced investment banker
• Andrew Barkan, BBA in management /finance Georgia State
University.
Asset Management & Investment Banking background. Work
in asset management with Wells Fargo, as vice president,
Oppenheimer & Company as director, and Morgan Stanley as
senior vice president
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Scientific Advisors and Collaborators
• Besim Ogretmen, Ph.D., Key expert on sphingolipid
metabolism
• Xiang Liu, MD, PhD, Key scientist and expert on acid
ceramidase in cancer
• Alicja Bielawska, Ph.D., Key chemist
• Zdzislaw M. Szulc, PhD key chemist
41
Clinical Advisors
• Thomas Keane, MD, Chairman of Urology, Medical
University of SC
• Michael Lilly, MD, Professor Department of
Medicine, Hem-Onc, Medical University of SC
• David Marshall, MD, Associate Professor, Radiation
Oncology, Medical University of SC
• Carolyn Britten, MD, Associate Professor,
Department of Medicine, Hem-Onc, Medical
University of SC
42
http://www.postandcourier.com/article/20130429/PC05/130429267/
1165/seeking-a-cure-musc-biotech-spinoff-wages-its-own-small-waron-cancer
http://www.postandcourier.com/article/20130429/PC05/130429270/
1010/improved-prognosis-tech-transfer-at-musc