Clinically Relevant In Vivo Models for Type 2 Diabetes Research

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

02/05/2023 3Crown Bioscience Inc. │ Confidential – Not For Distribution

CrownBio: Your Global Partner

Global capacity>40,000 mice

02/05/2023 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


02/05/2023 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


02/05/2023 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)


NHP Models of T2D

CrownBio

02/05/2023 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


02/05/2023 9

Clinical Symptom Presentation


• Characterized by hyperglycemia and changes in insulin levels

02/05/2023 10

Progression of Diabetes


02/05/2023 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


02/05/2023 12

Blood Pressure Evaluation


• No correlation between blood glucose levels and blood pressure in NHPs with or without diabetes

Tail cuff measurements used

02/05/2023 13

NHP Models of Diabetes Response to Antidiabetic Treatment


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

Rodent Models of T2D

CrownBio

02/05/2023 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


02/05/2023 17

The ZDSD Rat and FATZO Mouse vs Conventional Models


02/05/2023 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


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

02/05/2023 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)


Oral Glucose Tolerance Tests in the ZDSD Rat, FATZO, and DIO Mice

Impaired Glucose Disposal in ZDSD Rat

02/05/2023 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)


Antidiabetic Drug Treatment Prevents Diabetes and Weight Loss in ZDSD Rats

Metformin Glucose Lowering Effects Recorded by Continuous Glucose Monitoring in ZDSD Rats

02/05/2023 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


02/05/2023 22

Connect with CrownBio


• Contact us at [email protected] for full details on our models and for access to CVMD AppNotes and model information

Science

Clinically Relevant In Vivo Models for Type 2 Diabetes Research