tsx-v: sbm fse: zsb...tsx-v: sbm fse: zsb safety of sbm-tfc-1067 0 20 40 60 80 100 120 140 4.2 11.8...
TRANSCRIPT
TSX-V: SBM
FSE: ZSB
TM
TSX-V: SBM
FSE: ZSB
TSX-V: SBM
FSE: ZSB
Introduction and History
• Sirona Biochem was founded in 2009
• TFChem was acquired in 2011
Sirona Biochem (Parent Company)Vancouver, BC, Canada
TFChem (Wholly Owned Subsidiary)Cosmetic Valley, France
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Sirona’s Fluorination Chemistry Technology The Solution to Unstable Carbohydrate Molecules
Resulting in improved bioavailability and selectivity that translates into better safety and efficacy
Carbohydrate
molecules are
unstable by
nature
Our technology
stabilizes
carbohydrate
molecules
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Current Collaborations & Pipeline
Cosmetic Products
Therapeutic Area Compound Partnering Status
Skin lightening SBM-TFC-849 Valeant Pharmaceuticals
Skin lightening SBM-TFC-1067 Ready for licensing
Anti-aging SBM-TFC-837 Ready for licensing
Therapeutic Area Compound Partnering Status
Diabetes SBM-TFC-039 Partnered with Fosun Pharma in ChinaReady for licensing in ROW
Regenerative Medicine SBM-TFC-1165 Ready for licensing
Inflammatory Disease In development JV with Bloom Burton & Co
Pharmaceutical Products
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TM
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Skin Lightening Agent
SBM-TFC-1067
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The Problem
• Deoxyarbutin is a tyrosinase inhibitor that prevents melanin formation• Deoxyarbutin is unstable and is broken down in the body, releasing hydroquinone,
a known carcinogen• Hydroquinone is banned in the EU and restricted in USA• The problem is to develop the safest and most effective skin lightener in the world
Deoxyarbutin and arbutin are commonly used skin-lightening agents that have safety risks associated with their use
O O OH+
Hydroquinonetoxic
O HO
OH
breaks down into
Deoxyarbutin
OH
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SBM-TFC-1067
Superior safety and 8 times the efficacy of deoxyarbutin.
• Our goal was to develop a safer and more effective compound than Deoxyarbutin
• We have successfully developed a stabilized Deoxyarbutin, with zero hydroquinone released, thus eliminating potential adverse events
Sirona Biochem ’s Solution
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Global Skin Lightening Market
2015 2016 2017 2018
Japan 12.8 13.2 13.7 14.1
Asia-Pacific 4.1 4.5 4.8 5.2
US, EU, ROW 0.4 0.4 0.4 0.5
0.0
5.0
10.0
15.0
20.0
25.0
$ b
illio
ns
19.8
17.318.1 18.9
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Safety of SBM-TFC-1067
0
20
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60
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100
120
140
4.211.8
88.8
128.6
Hyd
roq
uin
on
e R
ele
ase
d (
%)
Deoxyarbutin SBM-TFC-1067
In vitro stability: percentage of hydroquinone released
Water RT 14 days
Bis Tris buffer RT 14 days
PBS RT 14 days
Ringer solution at pH 6.8 at RT 14 days
Ringer solution at pH 5.5 at 70°C 24H
Ringer solution at pH 8.5 at 70°C 24H
Fibroblasts RT 48H
Keratinocytes RT 48H
Human skin extract RT 48H
Synthetic perspiration RT 48H
SBM-TFC-1067 is stable and extremely safe, with zero hydroquinone released in all tested conditions (chemical, biological)
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Summary of Safety Evaluations
Genotoxicity Test(SOS Chromotest) • No genotoxicity between concentrations of 0 to 0.25%
Acute Toxicity Test(on keratinocytes) • MTT50: 66µg/ml
Ocular Irritation Test(on human reconstituted cornea)
• Low toxicity at a concentration of 0.14%• No toxicity at a concentration of 0.01%
Phototoxicity Test(on fibroblasts)
• No phototoxicity
Skin Irritation Test(on RHE)
• No irritation at a concentration of 0.05%
Sensitization Test• Non sensitizer (high flow, no haptenation, MTT75:
20µg/ml, no IL-18 induction)• Irritant on keratinocytes
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20µg of compound at 100µg/mL (in 90% purified water/5% ethanol/ 5% DMSO) was deposited on human skin (exchange surface: 2cm2)
ResultsQuantity TFC-1067 per gram epidermis (ng/g)
SD (ng/g)
EPIDERMIS22278 1296
DERMIS 5142 831
With a high flux capacity and excellent efficacy, very low concentrations could be used in aqueous formulations
Flux SD
TFC-1067 0.12 µg/h/cm² 0.020
Deoxyarbutin 0.17 µg/h/cm² 0.041
SBM-TFC-1067 penetrates into the site of action (epidermis layer of the skin)
SBM-TFC-1067 0.01%
Transcutaneous Diffusion
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Efficacy of SBM-TFC-1067
0
0.1
0.2
0.3
0.4
SBM-TFC-1067 Deoxyarbutin
0.035 mM
0.272 mM
IC5
0 (
mM
)
Inhibition of Human Tyrosinase (300U/ml)
SBM-TFC-1067 has 8 times the efficacy of deoxyarbutin
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Safety and Efficacy Summary
EfficacySafety
• Superior safety profile over deoxyarbutinwith zero hydroquinone released
• No genotoxicity (0-0.25%)
• Very minor ocular irritation at 0.14%
• No ocular irritation at 0.01%
• No skin irritation at 0.05%
• No sensitization
• No phototoxicity
• 8 times the efficacy ofdeoxyarbutin
• High flux capacity to the site of action in the epidermis
• Antioxidant properties
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Synthesis of SBM-TFC-1067 and Patents
• The synthesis of SBM-TFC-1067 is a three
step process
• Scale-up and manufacturing would be
straightforward
• Patent: PCT application on 04/03/2015:
PCT/FR2015/050530
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TM
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Glycoprotein Program Anti-Aging and Regenerative Medicine
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Natural Anti-Freeze Glycoproteins (AFGPs)
…enable survival under freezing temperatures
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Data Illustrating Protection of Oocytes and Platelets From Cold Temperatures
Incubation of oocytes at 4°C during 24h
G.L.Fletcher; S.V.Goddard; Y.Wu; CHEMTECH 1999, 30(6), 17-28.
Naturally Occurring Antifreeze Glycoprotein
Protects Cells From Stressed Environment
Platelets preserved (not activated) at 4°C
F. Tablin; A. E. Olivier; N.J. Walker; L.M. Crowe; J.H. Crowe; J.
Cell. Physiol. 1996, 168, 305-313.
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Exciting Data Generated From First Generation of
Synthetic Antifreeze Glycoproteins
Etablissement Français du Sang, Strasbourg, Pr. J.P. Cazenave
Note: Unprotected platelets remain viable for
approximately 3-5 days
21 Day Study of Glycoprotein Protection Against Platelet Aggregation at 3 Temperatures.
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Data Continued - Skin Fibroblast Temperature Studies
ProteoCell biotechnologies, Canada, Dr. S. Hussein
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Data Continued - Skin Fibroblast Oxidative Stress Studies
ProteoCell biotechnologies, Canada, Dr. S. Hussein
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Data Continued - Stem Cell Preservation Studies
Johnson and Johnson, United States, S. Nelson
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Data Continued - β-Islet Cell Preservation Studies
Alberta University , Canada, Dr. Rajotte
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The Second Generation of Antifreeze Glycoproteins
We have successfully stabilized three patented antifreeze glycoproteins.
The first generation of these synthetic
antifreeze glycoproteins were very
effective at preserving cells against
stressed environments but they were
unstable and could not be used for
human applications…
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0
20
40
60
80
100
D0 D1 D2 D3 D4 D5 D6 D7 D10 D12
Cell v
iab
ilit
y (
%)
Viability of fibroblasts under stressed conditions of serum deprivation
Stresscontrol
Stress +TFC-837 at5mg/ml
At the conclusion of a 12 day study, 100% of the unprotected cells were dead whereas 75% of theglycoprotein-protected cells were fully viable.
Efficacy of SBM-TFC-837
SBM-TFC-837 protects fibroblasts from the stressed condition of serum deprivation
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Efficacy of SBM-TFC-837
0
20
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120
no irradiation irradiation control irradiation + TFC-837 # TM0021-F4
(5 mg/mL)
irradiation + TFC-837 # TM0021-F4
(10mg/mL)
irradiation + TFC-837 # TM0021-F4
(15 mg/mL)
irradiation + TFC-1165 # TM0025
(5 mg/mL)
irradiation + TFC-1165 # TM0025
(10 mg/mL)
irradiation + TFC-1165 # TM0025
(15 mg/mL)
Fib
rob
last
Via
bili
ty (
%)
1H
3H
24H
Viability of fibroblasts after UVA irradiation (11J/cm2)
SBM-TFC-837 protects fibroblasts from the stressed condition of UV irradiation
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Sirona’s Glycoprotein program: Biomimicry
The potential opportunities are enormous
Sirona’s Glycoproteinprogram
Cosmetic Active Ingredients
Anti-agingProtection & Regeneration
Healing, Wound care,
Hypothermic protection,
Sunscreen
Post-sunburn/ radiotherapy
Adjuvants for biologicalmaterial preservation
Cells
Stem cells
Islet cells
Platelets
Red bloodcells
Adipocytes
Tissues
Skin explants, RHE,
Cornea
Organs
Transplant
RenalReperfusion
Living organisms
Vaccines
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Ongoing Development
• Evaluation in other stressed conditions
• Gene and protein expression
• Mechanism of action
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Synthesis and Patents
• Family of compounds with one
carbohydrate mimic and 1 to 3 amino
acids
• Patent: priority application of EP on
17/03/2014: EP 14305374.2; application of
PCT on 17/03/2015: PCT/EP2015/055577
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TM
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SGLT2 Inhibitor ProgramType 2 diabetes
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Diabetes2012 statistics from the International Diabetes Federation (www.idf.org)
More than 371 million people have diabetes.
By 2030, this will rise to 552 million.
In 2011, 4.8 million people died due to
diabetes and more than $471 billion US
was spent on related healthcare.
Global prevalence is drastically increasing.
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Market Segmentation
Total Type 2 Diabetes Therapeutics Market
Insulins Non-Insulin Therapeutics
Human Insulin Modern Insulin Standard of Care (SOC) Add-on to SOC
Biguinides
Sulfonylureas
Meglitinides
Glitazones
Incretins
SGLT2* Inhibitors
*Sodium-glucose co-transporter 2
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Emerging MarketsIndia & China Outpacing the USA
By 2030, experts predict that Type 2 Diabetes will grow by:US 25%, India 66%, and China 44%
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SGLT2 InhibitorsA New Class of Diabetes Drugs
The novel mechanism of action for SGLT2 inhibition is
blocking the re-uptake of glucose from the kidneys
and improving the obesity profile.
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Global SGLT2 inhibitor Market
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
2013 2014 2015 2016 2017 2018 2019 2020
$U
S m
illio
ns
Forxiga
Invokana
Lusefi
Suglat
Ertugliflozin
Farxiga
Jardiance
Invokana
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Competitive Lifecycle
2013 2017 2021 2025 2029 2033
New Product/ Indications Existing Competition
Canagliflozin (J & J, Mitsubishi Tanabe)
Dapagliflozin (AZ, Ono)
Empagliflozin (BI, Eli Lilly)
Ipragliflozin (Astellas)
Ertugliflozin (Pfizer)
Luseogliflozin (Taisho)
Tofogliflozin (Chugai, Sanofi, Kowa)
SBM-TFC-039 (Sirona, Fosun)
CPL-200-075 (Celon)
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TM
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SGLT2 Inhibitor ProgramSirona’s preclinical program for type 2 diabetes
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Head-to-head trial
• Six hours after administration, SBM-TFC-039 reduced blood glucose by 44% compared to 26% for Canagliflozin
• SBM-TFC-039 (1 mg/kg) proved to be more efficacious than Canagliflozin
0 2 4 6 80
5
10
15
20
25
Control Lean
Control Diabetic
SBM-TFC-039 1 mg/kg
Canagliflozin 1 mg/kg
Hrs
[Blo
od G
luco
se]
(mm
ol/L)
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SBM-TFC-039 Preclinical Study Results
0 4 8 12 16 20 240
5
10
15
20
25
Control Diabetic
1 mg/kg SBM-TFC-039
Control Lean
Time (hr)
[Blo
od G
luco
se]
(mm
ol/L)
• In an acute dosing study, SBM-TFC-039 reduced the blood glucose levels in diabetic rats to the level of lean rats within 6 hours.
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SBM-TFC-039 Preclinical Study Results
• In a 28-day chronic dosing study, SBM-TFC-039 reduced blood glucose levels by 71% in ZDF rats (fed state) compared to non-treated rats.
Day 0 Day 7 Day 14 Day 21 Day 280
10
20
30
Control Lean
Control Diabetic
1 mg/kg SBM-TFC-039
[Blo
od G
luco
se]
(mm
ol/L)
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SBM-TFC-039 Preclinical Study Results
• When challenged with glucose SBM-TFC-039 reduced blood glucose excursion by 89% in diabetic rats.
0 30 60 90 1200
5
10
15
20
25
Control Diabetic
1 mg/kg SBM-TFC-039
Control Lean
Time (min)
[Blo
od G
luco
se]
(mm
ol/L)
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• SBM-TFC-039 triggered glucose excretion in a dose dependent manner
Con
trol
1mg/
kg
3m
g/kg
10m
g/kg
0
200
400
600
800
1000
UG
E (
mg/2
4hr/
100g b
ody w
eig
ht)
SBM-TFC-039 Preclinical Study Results
• SBM-TFC-039 was well tolerated
Primate Study
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SBM-TFC-039 Specifications
Test concentration
(M)
Solubility(µM)
1st 2nd Mean
Flags
Aqueous solubility (PBS, pH 7.4)
SBM-TFC-039 2.0E-04 249.93 248.10 200 ADJ
Test concentration
(M)
Weighted Average
of Three Replicates
Partition Coefficient (logD, n-octanol/PBS, pH 7.4)
SBM-TFC-039 1.0E-04 2.68
ADJ Adjusted. When the observed mean of solubility is greater than 200µM, the mean value is adjusted to the maximum assay concentration which is 200µM
• Synthesis in 11 steps / performed at a lab level / max 7.5g with 2.4%overall yield. Scale-up and optimization yet to be performed.
• Solubility
• Partition coefficient
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Intellectual Property – SGLT Inhibitor
• European patent protecting structure, process and use filed May 2011
• Expansion through PCT process May 2012
• National phase in all major markets in 2013
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SBM-TFC-039 Development Status
Study Description Status
Multi-gram synthesis Complete
Efficacy in mice Complete
Tolerability in rodents (MTD in mice, CVS and CNS safety pharmacology)
Complete
Pharmacokinetics in rats Complete
Metabolic profiling in rats (in vitro and in vivo) Complete
Efficacy in normal and diabetic rats Complete
Ancillary pharmacology (ADME-Tox, in vitro metabolism and pharmacology)
Complete
In vitro selectivity (SGLT2 vs. SGLT1) Complete
Efficacy in normal monkeys Complete
Pharmacokinetics in monkeys Complete
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SBM-TFC-039 Summary
SBM-TFC-039 Reduced glycemia with a long duration of action
• A highly selective and potent SGLT2 inhibitor
• Triggered glycosuria in a dose-dependent manner
• Glucosuria lasted 24 hours
• Reduced blood glucose levels following glucose challenge
• Reduced blood glucose level in obese diabetic rats and normalized diabetes in a 28-day chronic study
• Well tolerated and orally bioavailable
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TM
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SGLT2 Inhibitor ProgramFosun Pharma’s preclinical program for type 2 diabetes
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SBM-TFC-039 Ongoing Development
Milestone Status
Upfront payment Complete
Preclinical Studies (first line tests)• Urinary Glucose Excretion (UGE)• Oral glucose tolerance test (OGTT)• Pharmacokinetic study in rats• Batch production of 80g of compound• 14 day toxicology study with repeated administration
in Sprague Dawley (SD) rats
Complete (06/2014)Complete (06/2014)Complete (07/2014)Complete (12/2014)Complete (02/2015)
Milestone payment for completion of toxicology study Expected in March 2015
Preclinical studies (second line tests)
Investigational New Drug (IND)
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SBM-TFC-039 14 Day Rat Toxicity Study
Group Treatment Dose (mg/kg/day)
Animal Numbers & Sex
1 SBM-TFC-039 0 3M + 3F
2 SBM-TFC-039 100 3M + 3F
3 SBM-TFC-039 300 3M + 3F
4 SBM-TFC-039 800 3M + 3F
5 Canagliflozin 300 3M + 3F
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 1 2 3 4 5 6 7Days
14 Days Repeated Oral Administration and Toxicokinetic observation 7 Days Recovery
Same schema for toxicity and toxicokinetic studies
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Results of the 14 Day Toxicology Study
0
100
200
300
400
500
600
700
800
900
SBM-TFC-039 Canagliflozin
mg
/kg/
day
Maximum Tolerated Dose
• Efficacy study dosing: 3 mg/kg/day• Pharmacokinetics study dosing: 10mg/kg/day PO and 1 mg/kg/ day IV
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Summary
• Sirona Biochem is a development stage biotechnology company that is the leader in commercializing carbohydrate chemistry
• The opportunity exists to:
o License our glycoprotein for anti-aging and regenerative medicine
o License our SGLT2 inhibitor for type 2 diabetes / NASH
o License our skin lightener
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TM
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www.sironabiochem.com