Pramlintide – An analog of amylin that overcomes the tendency of human amylin to: Aggregate, form insoluble particles Adhere to surfaces – Pharmacokinetic and pharmacodynamic properties similar to human amylin Human amylinPramlintide (analog of amylin) Amide S S A Y T N S G V N T TT T N A A A L I K S S C C Q R L N N N F G F L V H P P P Y T N S G V N T TT T N A A A L I K S S C C Q R L N N N F G F L V H Adapted from Young A, et al. Drug Dev Res 1996; 37: Adapted from Westermark P, et al. Proc Natl Acad Sci 1990; 87:

Pramlintide Mimicked Three Important Actions of Amylin That Impact Glucose Appearance       Amylin*Pramlintide Slows gastric emptying Promotes satiety and reduces caloric intake Inhibits inappropriately high postprandial glucagon secretion *All amylin studies were performed in animals Pramlintide Acetate Injection US Prescribing Information, 2005

Pramlintide Reduces Postprandial Glucagon T1DM Time (h) Placebo Pramlintide Placebo or 25 µg/h pramlintide infusion Insulin Sustacal T2DM, Late Stage Time (h) Plasma Glucagon (pg/mL) Insulin Sustacal Placebo or 100 µg/h pramlintide infusion  Plasma Glucagon (pg/mL) T2DM, n = 12; AUC 1-4 h : P = T1DM, n = 9; AUC 1-5 h : P<0.001; Data from: Fineman M, et al. Metabolism. 2002;51: Fineman M, et al. Horm Metab Res. 2002;34:

% Emptied per hr after breakfast Placebo 30  g Pramlintide 60  g Pramlintide Pramlintide Slowed Gastric Emptying- T1DM Insulin + Placebo Insulin + Pramlintide Type 1 diabetes; single SC pramlintide doses: n = 11, crossover 99m Tc labelled pancake; solid component measured Calculated from Kong MF, et al. Diabetologia 1998; 41: Gastric Emptying Is Accelerated in T1DM Nowak TV, et al. Gastroenterology 1990; 98:A378;

Pramlintide Reduced Caloric Intake in Type 2 Diabetes Protein CHO Fat CHO Fat Protein -202 kcal (-23%) P <0.01 Ad-Libitum Caloric Intake (kcal) Placebo Pramlintide n = 11; subjects given buffet meal Pramlintide (single SC injection, 120  g) Data from Chapman I, et al. Diabetologia 2005; 48:

Pramlintide Improved Postprandial Glucose Time Relative to Meal and Pramlintide (min) Mean (SE) Plasma Glucose (mg/dL) Mean (SE) Plasma Glucose (mg/dL) Lispro Insulin Pramlintide 60  g + Lispro Insulin Regular Insulin Pramlintide 60  g + Regular Insulin TYPE 1 DIABETES Evaluable; Mean (SE) Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18 Data from Weyer C, et al. Diabetes Care 2003; 26: ; Pramlintide Acetate Prescribing Information, 2005

Pramlintide Clinical Effects *** ** * *** Week 4Week 13Week 26Week 4Week 13Week 26 Week 4Week 13Week 26 Δ Insulin Use (%) Δ A1C (%) Δ Weight (kg) Placebo + Insulin 30 or 60  g Pramlintide TID or QID + Insulin TYPE 1 DIABETES COMBINED PIVOTALS ITT; Mean (SE); *P<0.05, **P<0.01, ***P<0.0001; Placebo + insulin, N = 538, Baseline A1C = 9.0% ; Pramlintide + insulin, N = 716, Baseline A1C = 8.9% Pramlintide Acetate Injection US Prescribing Information, 2005; Data on file, Amylin Pharmaceuticals, Inc. Data from: Whitehouse FW, et al. Diabetes Care 2002; 25: ; Ratner R, et al. Diabetic Med 2004; 21:

Pramlintide Reduced Fasting and Postprandial Glucose pre-bfpost-bfpre-lupost-lupre-dipost-dibedtime Glucose (mg/dL) Baseline 6 Months * * TYPE 1 DIABETES N = 265; * P<0.5; Clinical-Practice Study: all pramlintide doses bf, breakfast; lu, lunch; di, dinner Data on file, Amylin Pharmaceuticals, Inc.

Medically Assisted Severe Hypoglycemia Blinded Studies Event Rate/Patient Year No Insulin Reduction Insulin Reduction Insulin Reduction Open-Label Study  Placebo Pramlintide 0-3 Months  Blinded StudiesOpen-Label Study No Insulin Reduction Insulin Reduction Insulin Reduction  >3-6 Months PRAMLINTIDE TYPE 1 DIABETES STUDIES ITT, Indicated dose  No Pramlintide dose titration;  Pramlintide dose titration Pramlintide Acetate Injection US Prescribing Information, 2005

Pramlintide Safety and Tolerability in Type 1 Diabetes Nausea: – Mostly mild-to-moderate nausea. Occurred more frequently during initiation and then decreased with time but can increase risk of hypoglycemia. – Nausea reduced by dose titration – Could increase risk of insulin-induced severe hypoglycemia due to reduced food intake Insulin-Induced Severe Hypoglycemia: –More common in type 1 diabetes; risk reduced by appropriate patient selection, careful patient instruction and insulin dose adjustments as stated in the Boxed Warning Pramlintide Acetate Injection US Prescribing Information, 2005