8/13/2016

What is and What Does It Do? • Glucagon is a 29 aminoacid polypeptide • regulated by endocrine, paracrine, and autonomic Is Glucagon Ready For Prime Time? mechanisms • along with is principal regulator of homeostasis • it opposes insulin action George Grunberger, MD, FACP, FACE • under , pancreatic cells secrete glucagon —> - Chairman, Grunberger Institute, Bloomfield Hills, MI - Clinical Professor, Internal Medicine and Molecular Medicine & Genetics glycogen breakdown and raise glucose Wayne State University School of Medicine, Detroit, MI • under , pancreatic β cells secrete insulin —> - Professor, Internal Medicine stimulates glucose uptake from , glycogen formation Oakland University William Beaumont School of Medicine, Rochester, MI and lowers blood glucose - Visiting Professor, First Faculty of Medicine, Charles University, Prague, Czech Republic - Immediate Past President, American Association of Clinical Endocrinologists -Chancellor, American College of Endocrinology

Milestones in the Discovery and Renaissance of Glucagon

1922 Banting and Best administer Banting and Macleod awarded Nobel 1922 pancreatic extract to diabetic Prize for discovery of insulin treatment, 1923 dogs and observe decreased blood 1923 establishing its glucose; a transient increase in primary role in diabetes Relevant Disclosures blood glucose is noted

1923 Hyperglycemic substance in pancreatic extracts named 1957 “glucagon” 1957 Bromer identifies 1959 sequence, paving Valverde and Unger 1968 the way for commercially GLP-1 identify 2 distinct available glucagon glucagon-like & GIP 1959 Unger develops Research support: Eli Lilly, AstraZeneca 1975 glucagon radioimmunoassay Speakers’ bureau: Eli Lilly, , Sanofi, BI, Unger recognizes glucagon’s role as counterregulatory partner to Unger receives 2014 AstraZeneca insulin in Banting Lecture Rolf Luft Award from Karolinska Institutet International for work on glucagon Symposium 2008 2011 focuses on DeFronzo includes glucagon’s role 2014 alpha cell as part in diabetes of “Ominous Octet”

My objectives today

1. glucagon physiology in health and disease 2. glucagon as a therapeutic target in 3. glucagon as a therapeutic target in

1 8/13/2016

The Liver Is Glucagon’s Target Organ Cytoarchitecture of Human Islets Mouse Islet2 100 • Glucagon is the primary regulator of hepatic 80 1 • Human islets 60 glucose production, which consists of : – Alpha, beta, and delta cells are (%) 40 • Glycogenolysis – breakdown of stored glycogen intermingled throughout islet1,2 20 into glucose2

Islet Cell Population Cell Islet 0 – Fewer beta cells, more alpha InsulinGlucagon SST • Gluconeogenesis – glucose synthesis from non- 2 Magnification x 20 75% 19% 6% and delta cells Human Islet2 carbohydrate sources2 • Cytoarchitecture of human islet 100 suggests paracrine interactions1 80 60

40 (%) 20 0 Insulin Glucagon SST Islet Cell Population Cell Islet 54% 35% 11% Magnification x 40 1. Cabrera O et al. PNAS. 2006;103(7):2334-2339. 2. Brissova M et al. J Histochem Cytochem. 2005;53(9):1087-1097.

1. Ramnanan CJ et al. Diabetes Obes Metab. 2011;13(suppl 1):118-125. 2. Lin Y, Sun Z. J Endocrinol. 2010;204(1):1-11.

Crosstalk between α and β cells Glucagon and Type 1 Diabetes in the pancreatic islet

• in health: insulin/glucagon ratio strictly regulated, both reach liver via splanchnic circulation simultaneously • in T1DM: s.c. insulin first absorbed, then systemic circulation —> glucagon acts unopposed, lower insulin/glucagon ratio —> hyperglycemia • if injecting more s.c. insulin —> hypoglycemia • no cells but cells still there —> fasting + postprandial hyperglycemia

Glucagon and Type 1 Diabetes So, What Does This Have to with Diabetes and My Patients?

Glucagon physiology is disturbed in both type 1 and type 2 diabetes

• patients have inappropriately elevated levels of glucagon, both in the fasting and postprandial states

• in addition to lack of insulin and/or excess glucagon also contributes to hyperglycemia

2 8/13/2016

Dasiglucagon (ZP4207) Ok, So What Can We Do With Glucagon in Type 1 Diabetes Now? • Glucagon analog • Phase II results support its potential for use in a ready-to-use rescue pen to treat severe hypoglycemia in diabetes Use for rescue in hypoglycemic emergencies • all subjects treated with or with the approved glucagon product achieved a blood glucose concentration of >70 Inhibit to lower hyperglycemia mg/dL within 30 minutes of dosing In dual hormone “bionic ” • time to clinically relevant plasma glucose increases of >20 mg/dL similar for dasiglucagon and approved glucagon with a median time of 9-10 minutes • dasiglucagon was well tolerated and had a similar safety profile compared to approved glucagon

August 11, 2016

Glucagon to the Rescue

Is This the Future of Glucagon Rescue?

Intranasal Glucagon (AMG504-1/Locemia Solutions)

T1D Exchange: 2 studies • 75 adults (mean age 33 years) • randomized, crossover trial (3 mg intranasal vs. 1 mg IM) • success = rise of glucose to 70 mg/dl or above within 30 min of nadir • mean time for intranasal 16 min, for IM 13 min • head/facial discomfort in 25% intranasal, 9% IM • 35 vs. 38% In children (4-17 years) • 48 participants • 3 mg intranasal vs. 1 mg IM • nadir 67-75 mg/dl In the midst of Phase 3 trials • all produced rise of 25 mg/dl + within 20 minutes The current emergency kit on the market involves dry powder in a vial that has to be • nausea 42% vs. 67% manually mixed up and is a 9-step process This one is premixed; take off the cap and press it against the skin and it delivers the Rickels et al. 2016 Diabetes Care 39:264-270 drug right away. Sherr et al. 2016 Diabetes Care 39:555-562

3 8/13/2016

Intranasal Glucagon (AMG504-1/Locemia Solutions)

Pramlintide Glucagon Inhibition in Type 1 Diabetes Treatment

(synthetic , on-label) GLP-1 receptor (off-label) DPP-4 inhibitors (off-label)

Suppressing Glucagon With Amylin Analog

Without Diabetes

Insulin-Using Type 2

Type 1

4 8/13/2016

Components of Bihormonal Bionic Pancreas The Beacon Hill Study Five Days of Usual Care vs. Bionic Pancreas

Russell et al. New Engl J Med 2014; 371:313-325

Dual hormone closed loop system Formulating Soluble Glucagon (insulin and glucagon) Towards Pumpable Glucagon for Artificial Pancreas

Insulin + Glucagon

JDRF Announces Two Partnerships to Develop Stable, Pumpable Glucagon to Support Advanced Generation Artificial Pancreas Systems Jun 20, 2013, 16:57 ET

5 8/13/2016

Multiple Dysfunctions Contribute to the Pathophysiology of Type 2 Diabetes Mellitus

Glucose β Insulin production secretion

Glucose Glucagon α secretion uptake Chronic hyperglycemia Lipolysis effect

Glucose Neurotransmitter reabsorption dysfunction

J Diabetes Sci Technol. 2015 Jan; 9(1): 8–16. Published online 2014 Oct 28. doi: 10.1177/1932296814555541 PMCID: PMC4495524 Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas DeFronzo RA. Diabetes. 2009;58(4):773-795

Hyperglycemia in Type 2 Diabetes Results from Abnormal Meal-Related Insulin and Glucagon Dynamics

120 Meal 90 Insulin (µU/mL) 60 30 0 Healthy (n=11)

140 130 T2DM (n=12) 120 Glucagon (pg/mL) 110 100 90

360 330 300 Glucose 270 (mg/dL) 240

110 80 -60 0 60 120 180 240

J Diabetes Sci Technol. 2015 Jan; 9(1): 8–16. Time (min) Published online 2014 Oct 28. doi: 10.1177/1932296814555541 PMCID: PMC4495524 Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas Müller WA, et al. N Engl J Med. 1970;283:109-115

Pramlintide Glucagon as Target in Type 2 Diabetes

Glucagon suppression • pramlintide (alongside meal-time insulin injections) • incretin effect • DPP-4 inhibition • GLP-1 receptor agonism antagonism

6 8/13/2016

Enhancing Incretin Effects Glucose Control With (DPP-4 inhibitor)

GLP-1 effect is diminished in type 2 diabetes Natural GLP-1 has short half-life (1-2 min)

Injection Oral Sit

Add GLP-1 Block DPP-4, the 8.9 0. with longer that 0. half-life degrades GLP-1 0. • and GIP -0.5 -0.4 -0.6 • • -0.67 -0.7 -0.66 -0.7 A1C(%)

•  -1. • -1. • -1.1 * * • Sitagliptin † • -1.5 -1.4 -1.4 • -2. -1.9

Pharmacologic (supraphysiologic) GLP-1 Levels Physiologic * *P<0.001 vs active comparator monotherapy. †P<0.001 vs active comparator dual therapy. 1. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 2. Goldstein BJ, et al. Diabetes Care. 2007;30:1979-1987. 3. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 4. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. Drucker DJ, Nauck MA. Lancet. 2006;368:1696-1705 5. Derosa G, et al. Metab Clin Exp. 2010;59:887-895. 6. Sitagliptin prescribing information. Whitehouse Station, NJ: Merck & Co. Inc. 2010.

GLP-1 Receptor Agonists on the U.S. Market GLP-1 receptor agonists Exenatide, Liraglutide, Albiglutide, Dulaglutide Glucose  Glucose uptake (Resist degradation by DPP-4) Ingestion of dependent by peripheral food  Insulin tissue Pancreas

Release of active GLP-1 and GIP Beta cells  Blood glucose in GI tract Alpha cells fasting and postprandial states DPP-4 inhibitors DPP-4 Sitagliptin enzyme Glucose- Saxagliptin dependent Linagliptin Alogliptin  Glucagon Vildagliptin  Hepatic glucose Inactive Inactive production GLP-1 GIP

Drucker DJ and Nauck MA. Lancet. 2006;368:1696-1705.

Glucose Control With Liraglutide (GLP-1 RA)

0.5 0.23 0.09 0.

-0.24 -0.5 -0.51 -0.44 -0.5 A1C(%) -1. -0.9  -0.98 -1.00 -1.14 * -1.13 -1.09 -1.5 -1.33 * -1.50 -1.50 -2. * ** ** *** ** ** *P<0.0001 vs monotherapy. **P<0.0001 vs dual therapy. ***P<0.01 vs glargine. From: Treatment of Type 2 Diabetes: Role of GLP-1 Analogues and DPP-4 Inhibitors †All liraglutide dosages shown are 1.8 mg QD. by Ralph A. DeFronzo, MD; downloaded from Medscape, June 24, 2016 1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-279. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1232. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

7 8/13/2016

Glucagon Receptor Antagonism

Thank You!

LY2409021 decreases serum glucose by preventing glucagon receptor activation and alleviating excess gluconeogenesis. CNS, central nervous system; GABA, γ-aminobutyric acid. Pearson et al. 2016 Diabetes Care 39:1075-1077

Glucagon Receptor Antagonism (LY2409021) Pearson et al. 2016 Diabetes Care 39:1075-1077 Study 1: 12 weeks Study 2: 24 weeks

So, Is Glucagon Ready For Prime Time?

Glucagon physiology is disturbed in both type 1 and type 2 diabetes Glucagon is being used as a therapeutic target in type 1 diabetes Glucagon is being used as a therapeutic target in type 2 diabetes

You be the judge!

8