Novel Incretin Therapies for the Treatment of T2DM Patricia - - PowerPoint PPT Presentation

Novel Incretin Therapies for the Treatment of T2DM

Patricia McDonald PhD Diabetes Coalition, Palm Beach County Symposium The Scripps Research Institute Jupiter Florida April 28nd 2017

Financial Disclosure Statement : “I do not have any financial relationships relative to the content of this program.” Diabetes Coalition, Palm Beach County Symposium The Scripps Research Institute Jupiter Florida April 28nd 2017

Patricia McDonald PhD

Basic Research

• Academic Departments

Infectious Diseases

• Molecular Medicine
• Neuroscience
• Chemistry
• Structural Biology

Technology Platforms Cell Based Screening RNA Genomics Proteomics Informatics Drug Discovery Discovery Biology uHTS/Lead ID Medicinal Chemistry DMPK In vivo Pharmacology Metabolics

Drug Discovery & Development

Scripps Florida

Advanced Technologies Drug Discovery

Drug Discovery & Development Process

Discovery Development

3-5 Years +7 Years +1.5 Years

‘Bench to Bedside’

Basic Research Done at the Bench Clinical Research Done in the Patient Translational Research Bench -to- Bedside

Natural Progression of T2DM

b-cell function continues to decline Reversible Permanent

Need to intervene early with disease modifying therapies!

Insulin Resistance b cell dysfunction Carbohydrate Digestion Loss of b cell mass

Hyperglycaemia

Metformin TZDs a-Glucosidase Inhibitors Sulphonylureas Insulin

Type 2 Diabetes - Standard Therapies

Incretin Mimetics /Enhancers SGLT2 Inhibitors

*Standard treatment options are limited to treating symptoms and not underlying cause.

Novel Incretin Therapies for the Treatment of T2DM

Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, even before blood glucose levels become elevated.

Intestine Secretion Insulin

In . cret . in

GLP-1: Glucagon Like Peptide -1

Peripheral and Central Actions of GLP-1

Action of GLP-1 and GLP-1R

Adapted from Deacon et al. Diabetes. 1995;44:1126.

Additional Actions

• f GLP-1/GLP-1R

(Observed in rodents) Ø Restores b cell function Ø Increases insulin biosynthesis Ø Promotes b-cell mass, b-cell differentiation

GLP-1R

Ø Enhances glucose-induced insulin secretion Ø Reduces circulating glucose levels Ø Inhibits glucagon secretion and hepatic glucose production Ø Slows gastric emptying Ø Promotes satiety

GLP-1/GLP-1R Actions that combine to control glycemia

Insulin

Current GLP-1 Targeted Therapies

• Enhances glucose-dependent

insulin secretion

• Reduces hepatic glucose output
• Regulates gastric emptying
• Promotes satiety
• Increase in β-cell mass?
• Nausea
• Vomiting
• Diarrhea/Constipation
• Abdominal Pain
• Patient Compliance

Short and Long Acting Injectables

• Compromised b cell

function

• Pancreatitis
• Pancreatic cancer
• Thyroid cancer

Current Approach: Target Specificity

• Byetta (Exendin 4)
• Trulicity (Dulaglutide)
• Victoza (Liraglutide)

Novel Approach: Signal Selectivity

b-Cell

?

Development of an Autocrine-Based System for Screening Large Combinatorial Peptide Libraries

~100 million peptides/month

GLP-1R

P5: The First Potent, Selective GLP-1R G-protein Biased Agonist

Gas

b-arrestin

GLP-1R

Peptide 1,2,3….

P5 Improves Glucose Tolerance and is Insulin Sparing

C57BL/6-DIO Acute GTT 8 hr Fasting

1 5 3 0 4 5 6 0 7 5 9 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 7 0 0

T im e (m in ) G lu c o s e (m g /d l)

c o n t r o l E x 4 (1 u g /k g ) P 5 (1 u g /k g )

** ** * * *

c o n tro l P 5 (1 0 u g /k g ) P 5 (1 u g /k g ) E x 4 (1 0 u g /k g ) E x 4 (1 u g /k g )

• 0 .6
• 0 .4
• 0 .2

0 .0 0 .2

D g ly c a te d H b A 1 c (% )

*

P5 has Superior Antihyperglycaemic Efficacy in DIO Mice GTT 8 hr Fasting in following 4wk treatment in DIO Chronic Study HbA1c

• 4
• 3
• 2
• 1

1 2 3 4 5 2 0 4 0 6 0 8 0 1 0 0 1 2 0

lo g [p e p tid e ] n M C e llu la r R e s p o n s e (% o f m a x )

P 5 E x 4 P 5 -F c

EC50=5 nM

In Vitro Characterization of Long-acting G-protein Biased Agonist P5-Fc

P5 a b c

NH2 NH2 COOH COOH

d a y s o f tre a tm e n t D a ily fo o d in ta ke (g )

5 1 0 1 5 2 0 2 5 0 .0 0 .5 1 .0 1 .5 2 .0 2 .5 3 .0 3 .5 4 .0 4 .5 5 .0

** * * * * **

2 0 4 0 6 0 8 0 1 0 0 1 2 0

C u m m u la tiv e fo o d in ta k e (% o f c o n tro l)

**

D a y s o f tre a tm e n t D W e ig h t (% )

5 1 0 1 5 2 0 2 5

• 3 0
• 2 5
• 2 0
• 1 5
• 1 0
• 5

5

C o n t ro l P 5 -F c d im e r (Q 3 D ) L Y 2 1 8 9 2 6 5 (Q 3 D )

** ** * * * * * *

• 6 0
• 5 0
• 4 0
• 3 0
• 2 0
• 1 0

D F a t m a s s (% )

**

P5-Fc Promotes Weight Loss

*

P5 and P5-Fc show Improved Outcomes

P5 Ex4 P5-Fc Dulaglutide Secretagogue activity √ √√√ √√√

nd

Decrease gastic emptying √ √ √ √ Lower blood glucose level √ √ √√√ √√√ Decrease HbA1c √ √ √√√

nd

Decrease food intake

ᵡ

√ √√√

ᵡ

Weight loss

ᵡ

√ √√√

ᵡ

Decrease steatosis √ √ √

nd

Malaise

ᵡ

√

ᵡ

nd

Efficacy Safety Long acting (QW) Short acting (QD)

Discovery Development 3-5 Years +7 Years +1.5 Years P5

McDonald lab

Emmanuel Sturchler Ainhoa Nieto Rachel Turn Richard Hawkins *

Lerner Lab

Hongkai Zhang Jia Xie Teresa Jones LinLing He

Acknowledgements

Dawson Lab

Philip Cistrone