1. Bydureon ® Educate By Expert toolkit Scientific slides: GLP-1 receptor agonists and the discovery of exenatide GLP-1, glucagon-like peptide-1. Developed with the guidance and approval of an independent international editorial committee Date of preparation: Apri l 2014 150515

2. 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 HbA 1c 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.

3. 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

4. What is GLP-1? GLP-1 is an incretin hormone that is secreted by the L-cells in the gut 1 –Secreted in a nutrient-dependent manner 1 –Exerts multiple glucoregulatory properties 1 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 production 2 Suppresses postprandial glucagon secretion  decreased hepatic glucose production 2 Slows gastric emptying 1 Stimulates glucose-dependent insulin secretion 1 Improves first-phase insulin response 3 Reduces appetite and food intake 4 Slide is animated

5. 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

6. 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 diabetes 1 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 0101 0202 60 120 180 0 20 40 60 80 Time (min) Insulin (mU/L) * * * * * * * Oral glucose IV glucose Type 2 diabetes 0101 0202 60 120 180 0 20 40 60 80 Time (min) Insulin (mU/L) * * * Oral glucose IV glucose

7. 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 0 060120180240 Time (min) Mean (SE) GLP-1 (pmol/L) * * * * * * * * Meal Normal glucose tolerance subjects (n=33) Impaired glucose tolerance subjects (n=15) Type 2 diabetes patients (n=54)

8. 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

9. 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 04:0008:0012:0016:00 SnackLunch Breakfast Glucose (mmol/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

10. 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 –60060 120 180240 Insulin (pmol/L) Time (min) * * * * Liquid meal GLP-1 GLP-1 + erythromycin Placebo

11. 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

12. Exenatide: The first GLP-1 receptor agonist Exenatide is a synthetic version of exendin-4 that shares over 50% similarity with human GLP-1 1 –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 exerted 2,3 –The effects of exenatide when it binds to the GLP ‑ 1 receptor are equivalent to native GLP-1 4 Unlike native GLP-1, exenatide is not inactivated by the DPP4 enzyme, which means it remains active for longer 5 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.

13. Discovery and licensing of exenatide Placeholder for video 1Biv. Dr Orville Kolterman: Discovery and licensing of exenatide 13 i Expert sound bite

14. 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 10,000 100 0 10 0 1010 1 –1 01 2 3 4 567 Hours after injection Plasma exendin-4 (pM) 50 nmol 5 nmol 0.5 nmol 0.05 nmol Exendin-4

15. Persistent pharmacological effects of exenatide Placeholder for video 1Bv. Dr Orville Kolterman: Persistent pharmacological effects of exenatide 15 i Expert sound bite

16. 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 mg Placebo Meal 16:00 00:00 06:0012:00 2 0 4 6 8 12 Serum glucose (mmol/L) Time of day 16:00 10 14 * ** * * *** * ** * * * * * ** * * Meal

17. Postprandial effects of exenatide Placeholder for video 1Bvi. Dr Orville Kolterman: Postprandial effects of exenatide 17 i Expert sound bite

18. Exenatide restores the first-phase insulin response BID, twice daily. Fehse F, et al. J Clin Endocrinol Metab 2005;90:5991–7.

19. Exenatide suppresses inappropriately elevated postprandial glucagon concentrations BID, twice daily. DeFronzo RA, et al. Curr Med Res Opin 2008;24:2943–52.

20. Discovering the secondary benefits of exenatide Placeholder for video 1Bvii. Dr Orville Kolterman: Discovering the secondary benefits of exenatide 20 i Expert sound bite

21. 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

22. 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