Bydureon® Educate By Expert toolkit

Scientific slides: GLP-1 receptor agonists and the discovery of exenatide

GLP-1, glucagon-like peptide-1.

ENDORS

E

DDeveloped with the guidance and approval of an independent international editorial committee

Date of preparation: Apri l 2014 150515

Content guide

• These decks comprise a number of slides, arranged in story order. You may find that some slides are not relevant to your audience. Please hide these as you feel necessary

• Some slides are accompanied by a short sound bite video of an expert that you may wish to embed from the toolkit. These are marked with the ‘expert sound bite’ symbol

• All graphs have been created in PowerPoint to enable easy amends and translation

• HbA1c values and appropriate graphs include both DCCT (%) and IFFC (mmol/mol) units. Please delete where not appropriate for your market

i

Expert sound bite

DCCT, Diabetes Control and Complications Trial; IFFC, International Federation of Clinical Chemistry and Laboratory Medicine.

Executive summary

• This slide deck covers the following topics and contains speaker notes to assist presentation:

1. Introduction to Type 2 diabetes• Unmet needs and barriers to treatment

– Epidemiology of Type 2 diabetes

– Barriers to treatment (weight gain, hypoglycaemia, adherence to treatment)

• The Type 2 diabetes treatment pathway and individualised care– The place of GLP-1 receptor agonists and insulin in the treatment pathway

2. GLP-1 receptor agonists and the discovery of exenatide• GLP-1 mechanism of action and the incretin effect• The discovery of exenatide, the first GLP-1 receptor agonist

What is GLP-1?

• GLP-1 is an incretin hormone that is secreted by the L-cells in the gut1

– Secreted in a nutrient-dependent manner1

– Exerts multiple glucoregulatory properties1

Figure adapted from Drucker DJ, et al. 2006,1 Larsson H, et al. 1997,2 Quddusi S, et al. 2003,3 and Flint A, et al. 1998.4

GLP-1, glucagon-like peptide-1.1. Drucker DJ. Cell Metab 2006;3:153–65; 2. Larsson H, et al. Acta Physiol Scand 1997;160:413–22; 3. Quddusi S, et al. Diabetes Care 2003;26:791–8; 4. Flint A, et al. J Clin Invest 1998;101:515–20.

Fasting stateFed state

Suppresses glucagon secretion decreased hepatic glucose

production2

Suppresses postprandial glucagon secretion decreased

hepatic glucose production2

Slows gastric emptying1

Stimulates glucose-dependent insulin secretion1

Improves first-phase insulin response3

Reduces appetite and food intake4

Slide is animated

Pathophysiology of Type 2 diabetes and the incretin pathway

• Placeholder for video 1Bi. Professor Stephan Jacob: Pathophysiology of Type 2 diabetes and the incretin pathway

5

i

Expert sound bite

• The way in which oral glucose elicits a greater plasma insulin response than IV glucose is referred to as the ‘incretin effect’, which is reduced in patients with Type 2 diabetes1

The incretin effect is diminished in Type 2 diabetes

*p≤0.05 to the respective value after the oral load.IV, intravenous.Nauck M, et al. Diabetologia 1986;29:46–52.

Control

01 02 60 120 1800

20

40

60

80

Time (min)

Ins

uli

n (

mU

/L)

** * * * * *

Oral glucoseIV glucose

Type 2 diabetes

01 02 60 120 1800

20

40

60

80

Time (min)

Ins

uli

n (

mU

/L)

* **

Oral glucoseIV glucose

The production of GLP-1 is diminished in people with Type 2 diabetes

*p<0.05 between the Type 2 diabetes and the normal glucose tolerance groups.GLP-1, glucagon-like peptide-1; SE, standard error.Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001;86:3717–23.

• Postprandial GLP-1 levels are also reduced in subjects with impaired glucose tolerance and Type 2 diabetes

20

15

10

5

00 60 120 180 240

Time (min)

Me

an

(S

E)

GL

P-1

(p

mo

l/L

) * * * * ** *

*

Meal Normal glucose tolerance subjects (n=33)Impaired glucose tolerance subjects (n=15)Type 2 diabetes patients (n=54)

The effect of GLP-1 deficits on metabolic regulation

• Placeholder for video 1Bii. Professor Stephan Jacob: The effect of GLP-1 deficits on metabolic regulation

8

i

Expert sound bite

Replacement of GLP-1 can restore glucose homeostasis in patients with Type 2 diabetes

Healthy subjects, n=6; patients with Type 2 diabetes, n=7.GLP-1, glucagon-like peptide-1.Rachman J, et al. Diabetologia 1997;40:205–11.

0

2

4

6

8

10

12

14

16

00:00 04:00 08:00 12:00 16:00

SnackLunchBreakfast

Glu

co

se

(m

mo

l/L

)

Time of day

Type 2 diabetes: Saline (n=8)

Type 2 diabetes: Exogenous GLP-1 (n=7)

Healthy subjects (n=6)

20:00

Continuous GLP-1 infusion

GLP-1 delays gastric emptying and regulates insulin levels

*p<0.05.GLP-1, glucagon-like peptide-1.Meier JJ, et al. Diabetes 2005;54:2212–8.

0

100

200

300

400

500

–60 0 60 120 180 240

Ins

uli

n (

pm

ol/

L)

Time (min)

*

*

*

*

Liquid meal

GLP-1GLP-1 + erythromycinPlacebo

Benefits of targeting the GLP-1 pathway in Type 2 diabetes

• Placeholder for video 1Biii. Professor Stephan Jacob: Benefits of targeting the GLP-1 pathway in Type 2 diabetes

11

i

Expert sound bite

Exenatide: The first GLP-1 receptor agonist

• Exenatide is a synthetic version of exendin-4 that shares over 50% similarity with human GLP-11

– Isolated from the Gila monster lizard saliva

• Exenatide and GLP-1 bind to the GLP-1 receptor with equal affinity, which is where their effects are exerted2,3

– The effects of exenatide when it binds to the GLP‑1 receptor are equivalent to native GLP-14

• Unlike native GLP-1, exenatide is not inactivated by the DPP4 enzyme, which means it remains active for longer5

• Exenatide is now available in BID (Byetta®) and QW (Bydureon®) formulations

BID, twice daily; DPP4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; QW, once weekly.1. Nielsen LL, et al. Regul Pept 2004;117:77–88; 2. Raufman JP. Regul Pept 1996;61:1–18; 3. Fehmann HC, et al. Peptides 1994;15:453–6; 4. Göke R, et al. J Biol Chem 1993;268:19650–5; 5. Baggio LL, et al. Gastroenterology 2007;132:2131–57.

Discovery and licensing of exenatide

• Placeholder for video 1Biv. Dr Orville Kolterman: Discovery and licensing of exenatide

13

i

Expert sound bite

Exendin-4 (exenatide) is a GLP-1 receptor agonist with a prolonged half-life

Graphs show plasma concentrations of exending-4 or GLP-1 after administration by subcutaneous bolus.GLP-1, glucagon-like peptide-1.Parkes D, et al. Drug Devel Res 2001;53:260–7.

100,000

10,000

1000

100

10

1

–1 0 1 2 3 4 5 6 7Hours after injection

Pla

sma

exen

din

-4 (

pM

)

50 nmol5 nmol0.5 nmol0.05 nmol

Exendin-4 100,000

10,000

1000

100

10

1

–1 0 1 2 3 4 5 6 7Hours after injection

Pla

sma

GL

P-1

(p

M) 50 nmol

5 nmol0.5 nmol0.05 nmol

GLP-1

Persistent pharmacological effects of exenatide

• Placeholder for video 1Bv. Dr Orville Kolterman: Persistent pharmacological effects of exenatide

15

i

Expert sound bite

Exenatide significantly reduces PPG when given before meals

Graph shows the 24-hour glucose profiles comparing exenatide and placebo after 2 weeks. *p<0.05 versus placebo.FPG, fasting plasma glucose; PPG, postprandial glucose.Schwartz SL, et al. Clin Ther 2008;30:858–67.

Exenatide 10 mgPlacebo

Meal Meal

16:00 00:00 06:00 12:00

2

0

4

6

8

12

Se

rum

glu

co

se

(m

mo

l/L

)

Time of day

16:00

10

14

*****

***************

Meal

Postprandial effects of exenatide

• Placeholder for video 1Bvi. Dr Orville Kolterman: Postprandial effects of exenatide

17

i

Expert sound bite

Exenatide restores the first-phase insulin response

BID, twice daily.Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991–7.

0

10

20

30

–180 0 20 30 60 120

Time (min)

Ins

uli

n s

ec

reti

on

(p

mo

l/k

g/m

in)

10 90

p=0.0029

p=0.0002p=0.0002Type 2 diabetes + exenatide vs Type 2 diabetes + saline

Type 2 diabetes + exenatide vs healthy controls + saline

Type 2 diabetes + exenatide 10 µg BID (n=13)Type 2 diabetes + saline (n=13)Healthy controls + saline (n=12)

Exenatide suppresses inappropriately elevated postprandial glucagon concentrations

BID, twice daily.DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943–52.

Meal

Baseline

Exenatide BID (n=61)

120

110

100

90

80

70Pla

sm

a g

luc

ag

on

(p

g/m

L)

–30 0 30 60 90 120 150 180 210 240Time (min)

275

250

200

175

150

125

Pla

sm

a g

luc

os

e (

mg

/dL

)

225

Discovering the secondary benefits of exenatide

• Placeholder for video 1Bvii. Dr Orville Kolterman: Discovering the secondary benefits of exenatide

20

i

Expert sound bite

Physiological differences between replacement of GLP-1 and DPP4 inhibitors in the treatment of Type 2 diabetes

• Placeholder for video 1Bviii. Professor Stephan Jacob: Physiological differences between replacement of GLP-1 and DPP4 inhibitors in the treatment of Type 2 diabetes

21

i

Expert sound bite

Summary: GLP-1 and exenatide

• GLP-1 is a gut-derived incretin hormone that regulates glucose homeostasis

– GLP-1 production and the incretin effect are suppressed in Type 2 diabetes

– Replacement of GLP-1 restored the insulin response and glucose homeostasis in patients with Type 2 diabetes

• Exenatide was the first GLP-1 receptor agonist to be developed for the treatment of Type 2 diabetes and is now available in two formulations:

BID, twice daily; GLP-1, glucagon-like peptide-1; QW, once-weekly.Byetta. Summary of Product Characteristics; 2 Bydureon. Summary of Product Characteristics.

Exenatide 5 or 10 µg twice daily

Exenatide 2 mg once weekly