Metabolic dysfunctions become manifest in various tissues and organs that have complex, interrelated relationships. Crown Bioscience supports in vivo discovery research for obesity, diabetes, and cardiovascular disease with drug evaluation services in a wide range of models.

1. Clinically Relevant Models for
Type 2 Diabetes Research

2. Crown Bioscience
• A global platform technology company with
expertise in Oncology and Metabolic
Disorders
• Founded in 2006, headquartered in Santa
Clara, California, with research centers in
China, USA, and UK
• A team of 370 experts worldwide,
including highly trained PhD and MS
scientists, many with oversea experience
• A reliable partner to provide services to
the global pharmaceutical companies and
many biotech companies
Crown Bioscience Inc. │ Confidential – Not For Distribution 2

3. 12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 3
CrownBio:
Your Global Partner
Global capacity
>40,000 mice

4. Diabetes Facts and Figures
• Diabetes is a chronic, progressive, incurable disease
• 422 million people worldwide affected, 90% of which by the
Type 2 form (T2D)
• Characterized by hyperglycemia due to insufficient insulin
production and/or cellular insulin resistance
• Late stage disease includes complications such as
hypertension, increased cardiovascular risk, microvascular
complications such as eye, kidney, and nerve damage
• Current therapies have significant side effects, new agents
required with fewer risks, and to control diabetic
complications
• Appropriate technologies and models are needed to
enhance preclinical evaluation
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 4

5. CrownBio Models of Diabetes
• CrownBio provides the most clinically translatable
animal models in T2D research including:
– the world’s largest collection of spontaneously diabetic
NHPs
• Conventional rat or mouse models, allowing
consistency with historical data including:
– ZDF and ZSF-1 rats
– db/db and ob/ob mice
• Unique FATZO mouse and ZDSD rat polygenic
models of dysmetabolism
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 5

6. CrownBio Diabetes Technologies
and Resources
• CrownBio can perform a wide range of assays to test
key endpoints in diabetes research
• Typical study endpoints include:
– Insulin measurement (Chemiluminescence, MesoScale
Discovery)
– Glucose intolerance and impaired insulin response (GTT
or oGTT)
– Insulin resistance (ITT)
– Glucose disposition/insulin resistance (clamps)
– Continuous glucose monitoring (NovaBiomedical Stat
Strip® Xpress in rodents, DSI telemetry technology in
NHPs)
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 6

7. NHP Models of T2D
CrownBio

8. CrownBio Diabetic NHP Models
• CrownBio provides the largest collection of well-
characterized naturally diabetic NHPs including both
cynomolgus and rhesus monkeys
• Spontaneously diabetic NHPs mirror every aspect of the
human disease including disease progression, obesity, and
complications such as
– nephropathy
– neuropathy
– dyslipidemia
• Useful for metabolic dysfunction studies e.g. effects of HCD
on metabolism in diabetic and normoglycemic NHPs
• Models with such a close resemblance to human disease
provide the most reliable preclinical data to inform on clinical
trials
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 8

9. Clinical Symptom Presentation
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 9
• Characterized by hyperglycemia and changes in insulin levels

10. Progression of Diabetes
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 10

11. Metabolic Defect Validation
• Similar to humans,
spontaneously diabetic NHPs
have:
– impaired glucose tolerance and
pancreatic function measured
via glucose tolerance test
– reduced glucose disposition via
hyperglycemia clamp analysis
– insulin intolerance via insulin
tolerance test
– impaired insulin secretion rate
via graded glucose infusion test
– insulin resistance via euglycemia
clamp analysis
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 11

12. Blood Pressure Evaluation
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 12
• No correlation between blood glucose levels and blood pressure
in NHPs with or without diabetes
Tail cuff measurements used

13. NHP Models of Diabetes Response
to Antidiabetic Treatment
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 13

14. Responses to Rosiglitazone
(1mg/kg QD, PO, n=8)

15. Rodent Models of T2D
CrownBio

16. CrownBio Diabetic Rodent
Models and Technologies
• CrownBio can provide any commercially available rat
or mouse model for diabetes research
• Allows consistency with historical data
• We also provide the highly translatable FATZO mouse
and the ZDSD rat polygenic models of dysmetabolism
– spontaneously develop metabolic syndrome, obesity, and
diabetes
– intact leptin/leptin receptor pathway
– early development of hyperglycemia and insulin resistance
– similar disease progression to human patients, including late-
stage complications in the ZDSD rat
– response to antidiabetic treatments
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 16

17. The ZDSD Rat and FATZO Mouse
vs Conventional Models
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 17

18. Available Study Endpoints
• CrownBio can perform a
range of assays to test key
study endpoints in
diabetes research:
– single point glucose
determination
– continuous glucose
monitoring
– ELISA based assays to
quantify insulin levels
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 18
Continuous Monitoring of Diurnal Glucose Excursion
in the ZDSD Rat over 3 Days
Single point Glucose Determination in ZDSD and
SD Rats and in FATZO Mice

19. Available Study Endpoints
• CrownBio can perform a
range of assays to test key
study endpoints in diabetes
research:
– GTT: glucose tolerance tests
(i.v., i.p., or oral administration)
– ITT: insulin tolerance tests (i.p. or
s.c. administration)
– Glucose disposition/insulin
resistance (clamps)
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 19
Oral Glucose Tolerance Tests in the ZDSD
Rat, FATZO, and DIO Mice
Impaired Glucose Disposal in ZDSD Rat

20. Rodent Models of Diabetes
Response to Treatment
• CrownBio can evaluate the in
vivo response to antidiabetic
agents currently used in the clinic
• For a more thorough review of
the glucose response, CrownBio
can produce continuous glucose
curves during treatment
• Our highly translatable rodent
models respond similarly to
human patients to commonly
used glucose lowering
medications (metformin,
rosiglitazone, and exenatide)
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 20
Antidiabetic Drug Treatment Prevents Diabetes and
Weight Loss in ZDSD Rats
Metformin Glucose Lowering Effects Recorded by
Continuous Glucose Monitoring in ZDSD Rats

21. Summary
• Appropriate preclinical technologies and models required to further
preclinical diabetes research
• CrownBio provides conventional, as well as unique, highly translatable
models of T2D
– Spontaneously diabetic Non-Human Primates (NHPs)
– Polygenic Models: ZDSD rat, FATZO mouse
• Our service offering for diabetes research includes measurement of:
– Insulin levels (Chemiluminescence, MesoScale Discovery)
– Glucose tolerance and insulin response (GTT or oGTT)
– Insulin resistance (ITT)
– Glucose disposition (Clamps)
– Glucose fluctuations via continuous glucose monitoring (NovaBiomedical Stat
Strip® Xpress in rodents, DSI telemetry technology in NHPs)
• Customizable study designs to monitor multiple parameters and evaluate
new therapies
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 21

22. Connect with CrownBio
12/09/2016 Crown Bioscience Inc. │ Confidential – Not For Distribution 22
• Contact us at
busdev@crownbio.com
for full details on our
models and for access to
CVMD AppNotes and
model information