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 28 nd 2017

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

Scripps Florida Advanced Drug Basic Technologies Discovery Research Drug Discovery & Development • Academic Departments Technology Platforms Drug Discovery Infectious Diseases Cell Based Screening Discovery Biology • Molecular Medicine RNA uHTS/Lead ID • Neuroscience Genomics Medicinal Chemistry • Chemistry Proteomics DMPK • Structural Biology Informatics In vivo Pharmacology Metabolics

Drug Discovery & Development Process Discovery Development 3-5 Years +7 Years +1.5 Years

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

Natural Progression of T2DM b -cell function continues to decline Reversible Permanent Need to intervene early with disease modifying therapies!

Type 2 Diabetes - Standard Therapies Incretin Mimetics b cell Insulin /Enhancers Resistance dysfunction Sulphonylureas Metformin TZDs Hyperglycaemia a -Glucosidase Insulin Inhibitors Carbohydrate Loss of SGLT2 Inhibitors b cell mass Digestion *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. In . cret . in In testine Se cret ion In sulin

GLP-1: Glucagon Like Peptide -1 Peripheral and Central Actions of GLP-1

Action of GLP-1 and GLP-1R Additional Actions GLP-1/GLP-1R Actions that of GLP-1/GLP-1R combine to control glycemia (Observed in rodents) Enhances glucose-induced Ø Restores b cell Ø insulin secretion function Ø Reduces circulating glucose levels Ø Increases insulin biosynthesis Inhibits glucagon secretion and Ø hepatic glucose production Promotes b -cell mass, Ø b -cell differentiation Ø Slows gastric emptying Promotes satiety Ø GLP-1R Insulin Adapted from Deacon et al. Diabetes . 1995;44:1126.

Current GLP-1 Targeted Therapies Short and Long Acting Injectables Compromised b cell • function • Pancreatitis • Pancreatic cancer • Thyroid cancer • Enhances glucose-dependent • Nausea insulin secretion • Vomiting • Reduces hepatic glucose output • Diarrhea/Constipation • Regulates gastric emptying • Abdominal Pain • Promotes satiety • Patient Compliance • Increase in β-cell mass?

Current Approach: Novel Approach: Target Specificity Signal Selectivity b -Cell ? • Byetta (Exendin 4) • Trulicity (Dulaglutide) • Victoza (Liraglutide)

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 Peptide 1,2,3…. GLP-1R G a s b -arrestin

P5 Improves Glucose Tolerance and is Insulin Sparing Acute GTT 8 hr Fasting C57BL/6-DIO

P5 has Superior Antihyperglycaemic Efficacy in DIO Mice Chronic Study GTT 8 hr Fasting in following HbA1c 4wk treatment in DIO 7 0 0 0 .2 6 0 0 D g ly c a te d H b A 1 c (% ) G lu c o s e (m g /d l) 5 0 0 * 0 .0 ** * 4 0 0 * -0 .2 3 0 0 2 0 0 c o n t r o l -0 .4 ** E x 4 (1 u g /k g ) * 1 0 0 P 5 (1 u g /k g ) -0 .6 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 1 5 3 0 4 5 6 0 7 5 9 0 T im e (m in )

In Vitro Characterization of Long-acting G-protein Biased Agonist P5-Fc b a P5 NH 2 NH 2 EC 50 =5 nM c C e llu la r R e s p o n s e (% o f m a x ) 1 2 0 P 5 E x 4 1 0 0 P 5 -F c 8 0 6 0 4 0 COOH COOH 2 0 0 -4 -3 -2 -1 0 1 2 3 4 5 lo g [p e p tid e ] n M

P5-Fc Promotes Weight Loss C o n t ro l P 5 -F c d im e r (Q 3 D ) 5 L Y 2 1 8 9 2 6 5 (Q 3 D ) 0 0 -1 0 D W e ig h t (% ) -5 D F a t m a s s (% ) * * * ** * * * * -2 0 -1 0 -1 5 -3 0 -2 0 -4 0 ** -2 5 -5 0 ** -3 0 -6 0 0 5 1 0 1 5 2 0 2 5 D a y s o f tre a tm e n t 5 .0 1 2 0 4 .5 C u m m u la tiv e fo o d in ta k e D a ily fo o d in ta ke (g ) 4 .0 1 0 0 3 .5 (% o f c o n tro l) ** 8 0 3 .0 2 .5 * * 6 0 ** 2 .0 * 1 .5 4 0 * 1 .0 0 .5 2 0 ** 0 .0 0 0 5 1 0 1 5 2 0 2 5 d a y s o f tre a tm e n t

P5 and P5-Fc show Improved Outcomes Short acting (QD) Long acting (QW) P5 Ex4 P5-Fc Dulaglutide Secretagogue activity √ √√√ √√√ nd Decrease gastic emptying √ √ √ √ Lower blood glucose level √ √ √√√ √√√ Efficacy Decrease HbA1c √ √ √√√ nd ᵡ ᵡ Decrease food intake √ √√√ ᵡ ᵡ Weight loss √ √√√ Decrease steatosis √ √ √ nd ᵡ ᵡ Safety Malaise √ nd P5 Discovery Development 3-5 Years +7 Years +1.5 Years

Acknowledgements McDonald lab Lerner Lab Dawson Lab Hongkai Zhang Philip Cistrone Emmanuel Sturchler Ainhoa Nieto Jia Xie Rachel Turn Teresa Jones LinLing He Richard Hawkins *