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Pramlintide

Pramlintide is an analog of amylin that helps overcome the limitations of human amylin. It has similar pharmacokinetic and pharmacodynamic properties to human amylin, and it reduces postprandial glucagon secretion, slows gastric emptying, and promotes satiety. Pramlintide has been shown to be effective in reducing caloric intake and improving glucose control in type 1 and type 2 diabetes. It is generally well-tolerated, although it may cause mild-to-moderate nausea during initiation.

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Pramlintide

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  1. Human amylin A Pramlintide (analog of amylin) T A A T T Q N L L C R F V N A T A H C A T T Q N L L C S R K F V N Y S H C L F T N S I G N K Amide N Amide Y S T L F T S V N A N P G S P S I N P G N T S V N G 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 Adapted from Young A, et al. Drug Dev Res 1996; 37:231-248Adapted from Westermark P, et al. Proc Natl Acad Sci 1990; 87: 5036-5040

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

  3. Placebo or 100 µg/h pramlintide infusion Placebo or 25 µg/h pramlintide infusion 0 1 2 3 4 5 Pramlintide Reduces Postprandial Glucagon Placebo Pramlintide T2DM, Late Stage T1DM Insulin Insulin Sustacal 30 Sustacal 60 20 50 10 Plasma Glucagon (pg/mL)  Plasma Glucagon (pg/mL) 0 40 -10 30 -20 0 1 2 3 4 5 Time (h) Time (h) T2DM, n = 12; AUC1-4 h: P = 0.005 T1DM, n = 9; AUC1-5 h: P<0.001; Data from: Fineman M, et al. Metabolism. 2002;51:636-641. Fineman M, et al. Horm Metab Res. 2002;34:504-508.

  4. Gastric Emptying Is Accelerated in T1DM Pramlintide Slowed Gastric Emptying-T1DM Insulin + Placebo Insulin + Pramlintide % Emptied per hr after breakfast Placebo 30 μg Pramlintide 60 μg Pramlintide Type 1 diabetes; single SC pramlintide doses: n = 11, crossover 99m Tc labelled pancake; solid component measuredCalculated from Kong MF, et al. Diabetologia 1998; 41:577-583 Nowak TV, et al. Gastroenterology 1990; 98:A378;

  5. Pramlintide Reduced Caloric Intakein Type 2 Diabetes Placebo Pramlintide 1250 -202 kcal (-23%) P <0.01 1000 750 CHO Ad-Libitum Caloric Intake (kcal) CHO 500 Fat Fat 250 Protein Protein 0 n = 11; subjects given buffet meal Pramlintide (single SC injection, 120 μg)Data from Chapman I, et al. Diabetologia 2005; 48:838-848

  6. Pramlintide Improved Postprandial Glucose TYPE 1 DIABETES Lispro Insulin Pramlintide 60 μg + Lispro Insulin 300 250 Mean (SE) Plasma Glucose (mg/dL) 200 150 100 0 60 120 180 240 Regular Insulin Pramlintide 60 μg + Regular Insulin 300 Mean (SE) Plasma Glucose (mg/dL) 250 200 150 100 0 60 120 180 240 Time Relative to Meal and Pramlintide (min) Evaluable; Mean (SE) Pramlintide + Lispro insulin, n = 20; Pramlintide + Regular insulin, n = 18 Data from Weyer C, et al. Diabetes Care 2003; 26:3074-3079; Pramlintide Acetate Prescribing Information, 2005

  7. Pramlintide Clinical Effects TYPE 1 DIABETES COMBINED PIVOTALS Placebo + Insulin 30 or 60 μg Pramlintide TID or QID + Insulin Δ Insulin Use (%) Δ Weight (kg) Δ A1C (%) Week 4 Week 13 Week 26 Week 4 Week 13 Week 26 Week 4 Week 13 Week 26 1 0 8 6 -0.2 0 4 * -0.4 2 *** *** -1 0 *** *** -0.6 *** ** -2 *** -0.8 -2 -4 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; 25:724-730; Ratner R, et al. Diabetic Med 2004; 21:1204-1212

  8. Pramlintide Reduced Fasting andPostprandial Glucose TYPE 1 DIABETES Baseline 6 Months 180 160 * Glucose (mg/dL) * 140 120 pre-bf post-bf pre-lu post-lu pre-di post-di bedtime N = 265; *P<0.5; Clinical-Practice Study: all pramlintide doses bf, breakfast; lu, lunch; di, dinner Data on file, Amylin Pharmaceuticals, Inc.

  9. >3-6 Months 1.0 Blinded Studies Open-LabelStudy 0.5 0.27 0.24 0.20 0.15 0.04 0 φ Ψ Ψ No InsulinReduction Insulin Reduction Insulin Reduction Medically Assisted Severe Hypoglycemia PRAMLINTIDE TYPE 1 DIABETES STUDIES Placebo Pramlintide 0-3 Months 1.0 Blinded Studies Open-LabelStudy 0.50 0.5 Event Rate/Patient Year 0.19 0.10 0.14 0.08 0 Ψ Ψ φ No Insulin Reduction Insulin Reduction Insulin Reduction ITT, Indicated doseφNo Pramlintide dose titration; Ψ Pramlintide dose titration Pramlintide Acetate Injection US Prescribing Information, 2005

  10. Pramlintide Safety and Tolerability in Type 1 Diabetes • 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 • 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 Pramlintide Acetate Injection US Prescribing Information, 2005

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