1. P1 Joann L. Data, MD, PhD Senior VP, Regulatory Affairs & Quality Assurance Amylin Pharmaceuticals, Inc. Overview

2. P2 SYMLIN™ (Pramlintide Acetate) Amylin Pharmaceuticals, Inc.

3. P3 SYMLIN Injection Indication: Adjunctive therapy to insulin, to improve glycemic and metabolic control in people with type 1 or type 2 diabetes Administration: Injected subcutaneously approximately 15 minutes prior to a meal Presentations: Vials and cartridges

4. P4 Amylin’s Presentation Unmet Medical Need Kenneth Polonsky, MD Chairman, Department of Medicine Washington University Pramlintide Pharmacology Andrew Young, MD, PhD VP Research Amylin Pharmaceuticals Clinical Program Orville Kolterman, MD Senior VP Clinical Affairs Amylin Pharmaceuticals Risk/Benefit Summary Alain Baron, MD VP Clinical Research Amylin Pharmaceuticals

5. P5 Consultants Hugh E. Black, DVM, PhD Toxicology Consultant Hugh E. Black and Associates, Inc. Wayne Colburn, PhD Pharmacokinetics Consultant MDS Pharma Services Richard Dickey, MD Clinical Consultant Private Practice, Hickory, NC Kerry Hafner, PhD Statistical Consultant PRA International Kenneth Polonsky, MD Clinical Consultant Washington University

6. P6 Kenneth Polonsky, MD Adolphus Busch Professor of Medicine Chairman, Department of Medicine Washington University School of Medicine Unmet Medical Need

7. P7 Type 1 Insulin therapy 1920 200019001950 A Century of Diabetes Care Pump therapy Human insulin Insulin analogs NPH insulin Oral Agents Type 2 Insulin therapy 1920 200019001950

8. P8 Insulin Therapy Necessary When  -Cell Fails Type 1 diabetes -  -cell failure at outset –Insulin dependent Type 2 diabetes - Gradual  -cell deterioration –Diet and oral agents early stages of disease –Late-stage disease, insulin therapy necessary

9. P9 Diabetes 1996,45:1289-1298Lancet 1998;352:837-853 DCCT (Type 1) Retinopathy 16 12 8 4 0 56789101112 HbA 1c (%) Rate/100 Patient Years UKPDS (Type 2) HbA 1c (%) Incidence/100 Patient Years 8 6 4 2 0 567891011 Retinopathy Lessons from the DCCT and UKPDS: Continuous Relationship Between Glycemia and Long-Term Complications No threshold effect – the lower the better

10. P10 8.8 8.1 7.2 7.7 4 6 8 10 HbA 1c (%) 0 6 7 8 0246810 yrs HbA 1c (%) UKPDS (Type 2), Insulin Group Normal Baseline 06.5+ 4+ 6 yrs DCCTEDIC DCCT (Type 1) Lessons from the DCCT and UKPDS: Sustained Intensification of Therapy is Difficult UK Prospective Diabetes Study Group (UKPDS) 33: Lancet. 1998;352:837–853. DCCT/EDIC Study Group, Diabetes 2001 (Suppl. 1) 41: A63.

11. P11 Insulin Therapy and Glycemic Control in Young, Insulin-Treated Patients The Wisconsin Longitudinal Study Klein et al, Diabetes Care 1996, 19: 744-750 20% 60% 80% 100% Number of Injections 40% 0% 0410 yrs 20% 60% 80% 100% Type of Insulin 40% 0% 0410 yrs HbA 1c 0410 yrs 2% 6% 8% 10% 4% 0% Short Acting Short and Long Acting Long Acting 3 or more 2 1

12. P12 Lessons from the DCCT and UKPDS: Intervention Works, but is Difficult to Achieve Population data shows inadequate glycemic control in diabetes patients in the US ADA: recommended target Upper limit of normal range ADA: intensification advised 7% 8% 9% 6% HbA 1c 10% 8.8% El-Kebbi IM, Arch Intern Med 161: 1295-301 2001 9.1% Klein et al, Diabetes Care 19: 744-750 1996 9.6% Type 2 Patients, Hiss et al, ADA 2001 9.8% Type 1 Patients, Hiss et al, ADA 2001

13. P13 Our Ability to Achieve Tight Glycemic Control with Insulin Therapy is Limited by: Hypoglycemia Weight Gain Postprandial hyperglycemia

14. P14 Barriers to Achieving Glycemic Targets with Insulin in Type 1 Diabetes: Severe Hypoglycemia DCCT Research Group, Diabetes 1997;46:271-286 HbA 1c (%) During Study 100 80 60 40 20 0 567891011121314 Rate/100 Patient Years Conventional Intensified Intensified regimens result in 3- to 4-fold higher severe hypoglycemia event rates than conventional regimens

15. P15 Barriers to Achieving Glycemic Targets with Insulin in Type 2 Diabetes: Hypoglycemia Adjunct therapy to Insulin Pioglitazone Hypoglycemia incidence –Pbo –15mg QD –30mg QD Acarbose Hypoglycemia incidence –Pbo –25-100mg TID Lancet 352: 837-853, 1998 5 4 3 2 1 0 03691215 Intensified Conventional Years from Randomization Major Episodes Incidence (%) Intensification with Insulin Pioglitazone NDA, 1998 Kelley et al, Diabetes Care 21: 2056-61, 1998 5% 8% 15% 22% 29%

16. P16 DCCT (Type 1)UKPDS (Type 2) Intensified Insulin Therapy Produces Weight Gain Diabetes Care 1988;11:567-573 JAMA 1998;280:140-146 Lancet 1998; 352:837-853 Conventional Intensified 30 25 20 15 10 5 0 -5 12 3 4 Quartile of Weight Gain Mean change in weight (kg) 03691215 7.5 5.0 2.5 0.0 Intensified Conventional Change in weight (kg) Years from Randomization

17. P17 Impact of Weight Gain on Cardiovascular Risk Factors Type 1 Patients on IIT (n=582), Stratified by Weight Change 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile 120 118 116 114 112 110 A Systolic BP mm Hg 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile 80 78 76 74 72 70 B Diastolic BP mm Hg 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile 90 85 80 75 70 65 C Triglycerides mg/dL 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile D Total Cholesterol mg/dL 195 190 185 180 175 170 Purnell J, JAMA 1998;280:140-146

18. P18 Polonsky KS, New Engl J Med, 1988; 318: 1231-1239. Glucose Lowering Efficacy: Importance of Postprandial Hyperglycemia 400 300 200 100 0600100014001800220002000600 Glucose (mg/dL) DIABETIC CONTROL

19. P19 Target Range 0 50 100 150 200 250 300 350 400 Glucose (mg/dL) Sensor Measurement Insulin Bolus Fingerstick Measurement Daily Log and Sensor Data (24 hrs) 8AM 12 Noon 7PM Midnight Age: 44 years HbA 1c 7.1% Type 1 Patient

20. P20 Current Opportunity to Achieve Glycemic Goals Control Postprandial Glucose Without Weight Gain Without Increasing Hypoglycemia

21. P21 Andrew Young, MD PhD Vice President, Research Amylin Pharmaceuticals, Inc. Pramlintide Pharmacology

22. P22 Pramlintide Pharmacology Comparison of amylin and pramlintide molecules Insulin, glucagon and amylin abnormalities in diabetes Glucose fluxes controlled by amylin/pramlintide “Glucose-dependence” of amylin/pramlintide action ~ 1700 scientific communications

23. P23 37-amino acid peptide Located almost entirely in  -cells Co-secreted with insulin during meals Receptor characterized in CNS Healthy subjects n = 6 Plasma insulin (pM) Plasma amylin (pM) 30 25 20 15 10 5 7 amMidnight5 pm12 noon Time Amylin Insulin 600 400 200 0 Adapted from Koda JE, et al. Diabetes 1995. Amylin: a Neuroendocrine Hormone

24. P24 Amylin Binding/Receptors in Rat Brain nucleus accumbens area postrema dorsal raphe

25. P25 Hormonal Disturbances in Diabetes Insulin Deficiency Amylin Deficiency Glucagon Excess Unger et al., J Clin. Invest. 1970 Dobbs et al., Science 1975. Fineman et al., Diabetologia 1996 Data on file Insulin-using Type 2 Time after liquid meal (min) 0 5 10 15 20 -300306090120150180 Non-diabetic Type 1 Plasma amylin (pM)

26. P26 Pramlintide: an Analog of Amylin Human amylin not pharmaceutically practical Pramlintide designed to be non-aggregating, soluble, stable Full spectrum of activity, equipotent, similar kinetics

27. P27 Three Fluxes Control Blood Glucose GlucagonAmylin Insulin - - + + - Meal Glucose

28. P28 Pramlintide Smoothes Glucose Profiles After Meals in Type 1 Diabetic Humans 0306090120150180 -50 -25 0 25 50 75 100 125 Minutes after Sustacal Change in glucose (mg/dL) Placebo 10 µg 30 µg 60 µg 100 µg 300 µg

29. P29 Glucoregulatory Actions of Amylin * * * In man Glucagon Secretion Amylin Glucose Insulin Satiety Gastric Emptying Digestion

30. P30 Pramlintide Suppresses Postprandial Glucagon Secretion Pram 30  g + Ins (N=14) P<0.05, incremental AUC Placebo + Ins (N=20) Mean change in plasma glucagon (pg/mL) 0 10 20 30 0 6090120150180 Sustacal 60 0 20 40 060120180240 Insulin Sustacal Infusion p=0.005 Mean change in plasma glucagon (pg/mL) Injection Type 1 diabetes, SC injection Type 2 diabetes, IV infusion

31. P31 Amylin Inhibits Nutrient-Stimulated, But Not Hypoglycemia-Stimulated Glucagon Secretion in Rats Glucose 6mM (clamped) 2mM (hypo) -60601802400120 0 100 200 300 Saline Amylin 500 1000 L-Arginine Minutes Glucagon (pM) Silvestre et al., Am. J. Physiol 2001.

32. P32 Pramlintide Does Not Affect Defenses Against Hypoglycemia in Humans Pramlintide does not suppress secretion of: –Glucagon –Growth Hormone –Cortisol –Epinephrine –Norepinephrine Pramlintide does not impede glucose response to glucagon intervention Study AP93-04, AP93-08

33. P33 Glucoregulatory Actions of Amylin * In man Amylin Glucose Insulin Digestion Glucagon Secretion Satiety Gastric Emptying * *

34. P34 Gastric half- emptying time (hours) * p < 0.004 vs. placebo 0 1 2 3 4 90 µg60 µg30 µg Placebo * * * Single SC doses (N = 11, crossover); Tc-99m labelled pancake; solid component measured ~1 hour delay Pramlintide Slows Gastric Emptying in Humans with Type 1 Diabetes Kong et al. Diabetologia 1998.

35. P35 Enables oral rescue from hypoglycemia Gastric Actions of Amylin Over-ridden by Hypoglycemia in Rats

36. P36 Amylin-Sensitive Neurons in Area Postrema are Almost All Glucose-Sensitive 060120180 Minutes 0 2 4 12 Spikes per sec 246 Glucose mM Amylin 10nM

37. P37 Summary: Glucoregulatory Actions of Amylin/Pramlintide Inhibits nutrient stimulated glucagon secretion Regulates nutrient uptake from the meal Glucose-lowering actions over-ridden during hypoglycemia

38. P38 Summary: Rationale for Pramlintide Pramlintide replaces absent amylin Pramlintide restores control of glucose influx Complements insulin control of glucose efflux

39. P39 Orville G. Kolterman, MD Senior Vice President, Clinical Affairs, Amylin Pharmaceuticals, Inc. Adjunct Professor of Medicine University of California, San Diego Clinical Program

40. P40 Pramlintide Indication Adjunctive therapy to insulin, to improve glycemic and metabolic control in people with type 1 or type 2 diabetes

41. P41 ß-cell function Disease Progression Diet Exercise PLUS Oral agent Normal Absent Type 2 PLUS Combination Oral agents Type 1 Pramlintide Population Treatment population PLUS Insulin

42. P42 Pramlintide Therapy  Program Overview Pharmacodynamic Review Type 2 Diabetes Efficacy Safety Type 1 Diabetes Efficacy Safety

43. P43 TOTAL PATIENTS Number of Patients Included in Pramlintide Database Clin Pharm / Others Total Patient-Yr Exposure TOTAL PATIENTS Type 2 Diabetes -Long-term, controlled Type 1 Diabetes -Long-term, controlled Pramlintide 4493 1011 2727 1512 (1273) 1970 (1179) Placebo 1504 453 697 470 (420) 581 (538)

44. P44 4493 0 500 1000 1500 2000 2500 3000 3500 Duration of Exposure  1 Dose 2109  6 Months 1350  1 Year 261  2 Years 4000 4500 Number of Subjects Duration of Exposure to Pramlintide All Studies, All Doses

45. P45 Population Demographics Long-Term, Controlled Studies Age (mean years) Duration of diabetes (mean yrs) HbA 1c (mean %) BMI (mean kg/m 2 ) Type 1 Studies Type 2 Studies 40 17 8.9 26 57 12 9.2 32

46. P46 % Patients Type 1 Diabetes (n=1179) Type 2 Diabetes (n=1273) Antibiotics 35.339.4 CV Medications 32.065.5 Lipid Lowering Agents 6.424.5 Oral Hypoglycemic Agents 0.321.0 Prokinetic Agents 1.2 1.8 Total 56.382.2 Concomitant Medication Use Sulfonylureas Glitazones Biguanides  Glucosidase Inh. 13.2 0.5 11.9 0.2 21.0

47. P47 Pramlintide as Adjunctive Therapy to Insulin in Type 1 and Type 2 Diabetes Results in: Further improvement in glycemic control –Postprandial glucose –HbA 1c No increase in insulin use Weight loss

48. P48 Pramlintide Therapy Program Overview  Pharmacodynamic Review Type 2 Diabetes –Efficacy –Safety Type 1 Diabetes –Efficacy –Safety

49. P49 Pramlintide Pharmacokinetic Profile Type 1 and Type 2 Diabetes Type 1 Diabetes 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 012345 Plasma Pramlintide Concentration (pmol/L) 1 x 30 µg Pramlintide 1 x 60 µg Pramlintide 1 x 90 µg Pramlintide 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 012345 Plasma Pramlintide Concentration (pmol/L) Type 2 Diabetes Hours from Initial Dosing 1 x 60 µg Pramlintide 1 x 90 µg Pramlintide 1 x 120 µg Pramlintide

50. P50 Plasma Pramlintide Plasma Pramlintide (pM) N=15 0306090120150180 0 25 50 Time (min) Kolterman et al., Diabetologia 1996. Plasma Glucose Plasma Glucose (mg/dL) 100 150 200 250 300 0306090120150180 Time (min) Insulin only Pram (30 µg) + Insulin Meal Addition of Pramlintide to Regular Insulin Therapy Improves Postprandial Glucose Control Mean (SE) Type 1 Diabetes

51. P51 Time (minutes) -3003060120270360180240300420 Plasma Glucose (mg/dL) 90 120 150 240 180 210 270 Pramlintide 30 µg QID + Insulin (n=14) Placebo + Insulin (n=14) Study Drug + Insulin Study Drug + Insulin LunchBreakfast p=0.001 post-breakfast p=0.02 post-lunch 137-107 Preprandial Addition of Pramlintide Improves Postprandial Glucose Control Mean (SE) Type 1 Diabetes, 28 Day Study

52. P52 Pramlintide Reduces Postprandial Glucose Concentrations in a Dose-Related Manner 0306090120150180 -50 -25 0 25 50 75 100 125 Minutes after Sustacal Change in Glucose (mg/dL) Placebo 10 µg 30 µg 60 µg 100 µg 300 µg Type 1 Diabetes AP93-08, 137-104, 137-105

53. P53 0 10 20 30 40 50 60 70 80 90 100 Incidence of Nausea (%) Bar = Nausea Incidence Pramlintide Dose-Relationships -4000 -2000 0 2000 4000 6000 8000 10000 12000 14000 Mean Glucose Incremental AUC (mgmin/dL, 0-180 min) Dose (µg Pramlintide) Placebo n=107 10 n=43 30 n=189 60 n=42 100 n=65 300 n=21 AP93-08, 137-104, 137-105 Type 1 Diabetes Line = Mean Glucose AUC Dose Response Test: P = 0.012

54. P54 Pramlintide Dose-Relationships Mean Change in % HbA1c From Baseline Line = Mean HbA 1c Dose (µg) Pramlintide Placebo n=99 30 n=90 75 n=102 150 n=90 0 10 20 30 40 50 60 70 80 90 100 Incidence of Nausea (%) Bar = Nausea Incidence Type 2 Diabetes, Week 13 -0.8 -0.6 -0.7 -0.9 -1.1

55. P55 Doses Selected for Phase 3 Studies Type 2 diabetes range: 30 to 150 µg Type 1 diabetes range: 30 to 90 µg

56. P56 Phase 3 Clinical Trials Demonstration of efficacy Assessment of safety Guidance for clinical use

57. P57 Study Design Considerations No precedent for efficacy studies in insulin-treated subjects DCCT established HbA 1c as surrogate endpoint for glycemic control On-going debate regarding “threshold effect” Ancillary metabolic effects (weight, insulin use, lipid profile) not fully appreciated

58. P58 General Approach to Pramlintide Phase 3 Clinical Studies All subjects were treated with insulin All studies employed an “add-on” design –Pramlintide or placebo was added to existing therapies –Oral hypoglycemic agents were to be unchanged Sulfonylurea Metformin

59. P59 Approaches to Insulin Management Clinical Trial Setting Insulin should ideally remain constant to isolate effect of “add-on” drug Changes in insulin use during the study period confound data interpretation Clinical Practice Setting Involves frequent changes in insulin regimens –Patient safety (hypoglycemia) –Pursuit of glycemic targets

60. P60 Insulin Use in Pramlintide Phase 3 Clinical Studies Four studies  Consistent insulin dosing encouraged Two studies  No constraints on insulin dosing Allowed changes for patient safety Patients were not discontinued due to changes in insulin regimen Analysis plan pre-defined “stable insulin” subgroup –Total daily dose at baseline ± 10% –Isolates “true” drug effect

61. P61 Phase 3 Study Design Type 2 and Type 1 Diabetes Multicenter, randomized, placebo-controlled Primary endpoint –HbA 1c, week 26 or 52 Secondary endpoints –Weight –Insulin use –Safety parameters

62. P62 Pramlintide Therapy Program Overview Pharmacodynamic Review  Type 2 Diabetes  Efficacy Safety Type 1 Diabetes Efficacy Safety

63. P63 Type 2 Diabetes Phase 3 Program Metabolic Stability 137-123 PBO, Pram 90 BID, 90 TID or 120 BID N = 499 137-122 PBO, Pram 60 TID, 90 BID or 120 BID N = 656 Endpoint Assessments (Week) 401339262052 Randomization Placebo Lead-In 137-111 PBO, Pram * 30, 75, or 150 TID N = 538 * pH=4.7; lower bioavailabity, 150 µg  120 µg

64. P64 Summary of Pramlintide Effects Type 2, Recommended Dose HbA 1c 0 10 20 30 40 50 60 70 80 90 100 0-44-2626-52 Time (Weeks) Incidence (%) -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 013263952 Mean (SE) Change in HbA 1c 0 1 2 3 4 5 0-44-2626-52 Time (Weeks) Event Rate/ Subject Year Time (Weeks) Overall NauseaSevere Hypoglycemia Placebo + Insulin (n=207) * Pramlintide + Insulin (n=222) * * Evaluable Population

65. P65 90BID + Ins n=171 n=161 Pbo + Insulin P=0.002 * 120BID + Ins n=166 137-122 (US) Pramlintide Phase 3 Studies Type 2 Diabetes HbA 1c Effect for Total Population (ITT, 6 months) Mean (SE)  HbA 1c (%) 0 -0.4 -0.3 -0.2 -0.1 -0.5 -0.6 -0.7 -0.8 137-123 (Eur) 90TID + Ins n=129 90BID + Ins n=121 n=123 Pbo + Insulin 120BID + Ins n=126 P=0.029 Dosage Recommendation: 120 µg given 2-3 times/day 150TID + Ins n=144 P=0.010 * 75TID + Ins n=136 30TID + Ins n=122 Pbo + Insulin n=136 137-111 (US) P=0.004 *

66. P66 Addition of Pramlintide to Insulin Reduces HbA 1c in Type 2 Diabetes Stable InsulinITT Placebo + Insulin Pramlintide 120 BID + Insulin 137-122 Placebo + Insulin n=161 Pramlintide 120 BID + Insulin n=166 Placebo + Insulin n=55 Pramlintide 120 BID + Insulin n=70

67. P67 Pramlintide Therapy Results in Greater Reduction in HbA 1c Than Insulin Alone in Type 2 Diabetes, Recommended Dose (Week 26) 0 10 20 30 40 50 60 70 80 90 100 Cumulative Percent  100 90 80 70 60 50 40 30 20 10 0 -2012 Change in HbA 1C from Baseline PlaceboPramlintide 120 BID Worse Improved -1.50.5 1.5

68. P68 Pramlintide Facilitates Achievement of ADA Targets Type 2 Diabetes, Week 26 Placebo + Insulin Pramlintide 120 BID/150 TID + Insulin Achieved 8% or Less Achieved 7% or Less 21% 2% 35% 8% Pooled data

69. P69 Weight Effect Type 2 Diabetes, Week 26 -5 -4 -3 -2 0 1 2 3 Mean (SE)  Weight (lb) n=97 n=90 P=0.0029 * n=88 P<0.0001 * n=100 P=0.0005 * 150TID + Ins Pbo + Insulin 75TID + Ins 30TID + Ins 137-111 (US) n=97 90BID + Ins n=103 P=0.0194 * Pbo + Insulin 120BID + Ins 137-123 (Eur) 90TID + Ins n=98 P=0.0002 * n=100 P<0.0001 * 90BID + Ins Pbo + Insulin 120BID + Ins 137-122 (US) n=131 n=108 n=121 P=0.0094 * P<0.0001 *

70. P70 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 Change in % HbA 1c Week 4Week 13Week 26 Change in Weight (lb) -3 -2 0 1 2 3 4 5 6 Week 4Week 13Week 26 Change in Insulin Use (%) -4 -3 -2 0 1 2 Week 4Week 13Week 26 Pramlintide Therapy Offers Unique Metabolic Benefits in Type 2 Diabetes All Patients, Recommended Dose Placebo + Insulin (N=284) Pramlintide Recommended Dose + Insulin (N=292) Baseline: 9.3 9.1

71. P71 Pramlintide Therapy Program Overview Pharmacodynamic Review Type 2 Diabetes Efficacy  Safety Type 1 Diabetes Efficacy Safety

72. P72 TOTAL PATIENTS Number of Patients Included in Pramlintide Database Clin Pharm / Others Total Patient-Yr Exposure TOTAL PATIENTS Type 2 Diabetes -Long-term, controlled Type 1 Diabetes -Long-term, controlled Pramlintide 4493 1011 2727 1512 (1273) 1970 (1179) Placebo 1504 453 697 470 (420) 581 (538)

73. P73 Placebo Cardiac Sudden Death Total 4 (0.75%) 1 (0.19%) 5 (0.94%) (n = 532) No Increase in Mortality Observed in Type 2 Diabetes Studies 10 deaths occurred among 2195 unique subjects in type 2 diabetes studies None classified as drug related Pramlintide Cardiac Total 5 (0.30%) (n = 1663)

74. P74 Adverse Event Profile for Type 2 Diabetes Frequent TEAEs (% of Subjects), Overall Incidence > 5%, Excluding Hypoglycemia % of Subjects Placebo N=420 Pramlintide N=1273 Nausea 14 (1 severe) 24 (2 severe) Anorexia38 Vomiting57 Abdominal pain68 Fatigue47 Dizziness46 Dyspepsia36

75. P75 Vision/Retinal Disorder Adverse Events One study (137-111) had an apparent increase in incidence of retinal disorder in the 150 µg treatment arm compared with placebo No apparent pramlintide-related increase in incidence of retinal disorder or other vision disorders at doses of 75 µg TID or 120 µg BID No safety concern

76. P76 Placebo Pramlintide Body as a Whole 3%2%Heart Rate & Rhythm 1%< 1% Type 2 Serious Treatment-Emergent Adverse Events Were Similar (  1% of Subjects) Body System: Central & Peripheral Nervous System <1%1% 2%1% Neoplasm Vascular (extra-cardiac) 1%2% Cardiac 4%3% Metabolic & Nutritional 1%2% 1%< 1% Platelets, Bleeding & Clotting Gastrointestinal1%2% Events different between pramlintide and placebo

77. P77 Severe Hypoglycemia (DCCT Definition) for Type 2 Diabetes Studies Number and incidence of patients with at least 1 hypoglycemia episode Patient exposure (years) Number of hypoglycemic events Placebo 17 (6%) 188 0.21 40 Pramlintide 76 (9%) 587 0.24 139 Number of hypoglycemic events per one year of patient time 137-122, 137-123 Combined (ITT)

78. P78 Severe Hypoglycemia Event Rates Type 2 Diabetes All Pramlintide vs. All Placebo 0.2 0.5 0.2 0.3 0.1 0 1 2 3 4 5 Mean (SE) Event Rate Per Subject Year Pram + InsPbo + Ins n=284n=871n=820n=267 Pram + InsPbo + InsPram + InsPbo + Ins n=576 Weeks 0-4Weeks 4-26Weeks 26-52 n=175

79. P79 Other Safety Observations Type 2 Diabetes No evidence of: –Serious events that are unusual in the absence of drug therapy –Cardiac toxicity –Hepatic toxicity –Renal toxicity No increase in frequency of clinically significant: –Lipid abnormalities –ECG changes –Changes in vital signs Systolic blood pressure Diastolic blood pressure –Laboratory abnormalities

80. P80 Pramlintide is Efficacious and Safe in Type 2 Diabetes Improves glycemic control No increase in insulin use Weight loss No safety issues Dosage recommendation: 120 µg given 2-3 times/day before meals

81. P81 Pramlintide Therapy Program Overview Pharmacodynamic Review Type 2 Diabetes Efficacy Safety Type 1 Diabetes  Efficacy Safety

82. P82 Type 1 Diabetes Phase 3 Program Endpoint Assessments (Week) 401339262052 Randomization Placebo Lead-In 137-112 PBO, Pram 30 QID Pram 30 QID / 60 QID Re-randomization N = 480 137-121 PBO, Pram 60 TID, 60 QID or 90 TID N = 651 137-117 PBO, Pram 60 TID, 90 BID or 90 TID N = 586 Metabolic Stability

83. P83 Summary of Pramlintide Effects Type 1, Recommended Dose -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 013263952 Mean (SE) Change in HbA1c HbA 1c Overall NauseaSevere Hypoglycemia 0 1 2 3 4 5 0-44-2626-52 Time (Weeks) Event Rate/ Subject Year 0 10 20 30 40 50 60 70 80 90 100 0-44-2626-52 Time (Weeks) Incidence (%) Placebo + Insulin (n=393)* Pramlintide + Insulin (496)* Time (Weeks) * Evaluable Population

84. P84 137-121 (US) n=154 Pbo + Insulin 60TID + Ins n=164 P=0.012 * n=161 60QID + Ins P=0.013 * -0.2 0 -0.4 -0.3 -0.1 -0.5 Mean (SE)  HbA 1c (%) -0.6 +0.1 Pramlintide Phase 3 Studies Type 1 Diabetes HbA 1c Effect for Total Population (ITT, 6 months) 137-112 (US) 30/60QID + Ins n=243 n=234 Pbo + Insulin P<0.001 * 137-117 (Eur) 60TID + Ins n=148 n=147 Pbo + Insulin 90TID + Ins n=147 90BID + Ins n=144 P=0.007 Dosage Recommendation: Initiate at 30 µg 3-4 times/day Maintenance 30 or 60 µg 3-4 times/day

85. P85 Addition of Pramlintide to Insulin Reduces HbA 1c in Type 1 Diabetes Stable InsulinITT Placebo + Insulin Pram 60 TID + Insulin Pram 60 QID + Insulin 137-121 Mean (SE) Placebo + Insulin n=154 Pram 60 TID + Insulin n=164 Pram 60 QID + Insulin n=161 P=0.011 P=0.001 -1.2 -0.8 -0.6 -0.4 -0.2 0 0.2 013263952 Weeks P=0.012 Mean HbA 1c Change from Baseline (%)

86. P86 Change in HbA 1C (%) From Baseline PlaceboPramlintide 30/60 QIDPramlintide 60 TIDPramlintide 60 QID Pramlintide Therapy Results in Greater Reduction in HbA 1c Than Insulin Alone in Type 1 Diabetes, Recommended Doses (Week 26) 0 10 20 30 40 50 60 70 80 90 100 Cumulative Percent  100 90 80 70 60 50 40 30 20 10 0 Worse Improved -2012-1.50.5 1.5

87. P87 Pramlintide Facilitates Achievement of ADA Targets Type 1 Diabetes, Week 26 Pooled data Placebo + Insulin Pramlintide Recommended Doses Achieved 8% or Less Achieved 7% or Less 28% 7% 47% 14%

88. P88 Weight Effect Type 1 Diabetes, Week 26 -5 -4 -3 -2 0 1 2 3 Mean (SE)  Weight (lb) Pbo + Insulin n=168 30/60QID + Ins n=174 P<0.0001 * 137-112 (US) Pbo + Insulin 60TID + Ins n=99 P<0.0001 * 60QID + Ins n=106 P<0.0001 * 137-121 (US) n=104 Pbo + Insulin n=119 60TID + Ins n=113 P<0.0001 * 90TID + Ins n=90 P<0.0001 * 90BID + Ins P=0.0035 * 137-117 (Eur) n=86

89. P89 Pramlintide Therapy Offers Unique Metabolic Benefits in Type 1 Diabetes All Patients, Recommended Doses in Type 1 Change in % HbA 1c -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0 Week 4Week 13Week 26 Change in Weight (lb) -3 -2 0 1 2 3 4 5 6 7 Week 4Week 13Week 26 Change in Insulin Use (%) -3.0 -2.5 -2.0 -1.5 -0.5 0 0.5 1.0 1.5 2.0 2.5 Week 4Week 13Week 26 Placebo + Insulin (N=538) Pramlintide Recommended Doses + Insulin (N=716) Baseline: 9.0 8.9

90. P90 Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control 0 2 4 6 Change in Insulin Use (%) Insulin Use 02468101214161820222426 Time (Weeks) 7.2 7.4 7.6 7.8 8 Pramlintide (n=243) Placebo (n=173) Change in Weight (lb) -3 -2 0 1 Weight Mean HbA 1C (%)

91. P91 Pramlintide Therapy Program Overview Pharmacodynamic Review Type 2 Diabetes Efficacy Safety Type 1 Diabetes Efficacy  Safety

92. P92 TOTAL PATIENTS Number of Patients Included in Pramlintide Database Clin Pharm / Others Total Patient-Yr Exposure TOTAL PATIENTS Type 2 Diabetes -Long-term, controlled Type 1 Diabetes -Long-term, controlled Pramlintide 4493 1011 2727 1512 (1273) 1970 (1179) Placebo 1504 453 697 470 (420) 581 (538)

93. P93 PlaceboPramlintide Cardiac Total 2 (0.22%) Cardiac Inflicted Injury Alcohol Total 2 (0.08%) 1 (0.04%) 5 (0.19%) (n = 904) (n = 2573) No Increase in Mortality Observed in Type 1 Diabetes Studies 7 deaths occurred among 3477 unique subjects 1 classified as “possibly drug related” Multi-Organ Failure1 (0.04%)

94. P94 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 Annual Event Rate per Patient-Year (±95% CI) Motor Vehicle Accidents/Injuries, All and Hypoglycemia-Related Type 1 Diabetes, Annual Event Rate per Patient-Year Placebo (2 of 904 pts) Hypo-Related 0.10 0.00 Pramlintide (28 of 2573 pts) All Placebo (7 of 904 pts) Pramlintide (17 of 2573 pts) p=0.13p=0.56

95. P95 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 Other Accidents/Injuries (Non-MVA), All and Hypoglycemia-Related Type 1 Diabetes, Annual Event Rate per Patient-Year (10/2573 pts) (2 of 904 pts) (197/2573 pts)(53/904 pts) Hypo-Related Accidents/Injuries All Accidents/Injuries Annual Event Rate per Patient-Year (±95% CI) PlaceboPramlintidePlaceboPramlintide p=1.00p=0.59

96. P96 Adverse Event Profile for Type 1 Diabetes Frequent TEAEs (% of Subjects), Overall Incidence > 5%, Excluding Hypoglycemia Nausea Anorexia Vomiting Abdominal pain Fatigue Dizziness Dyspepsia Placebo N=538 17 (1 severe) 2 7 7 4 4 3 Pramlintide N=1179 51 (7 severe) 18 13 8 7 4 4

97. P97 Most Nausea is Mild to Moderate Pramlintide-Treated Type 1 Patients in Long-Term Controlled Trials No nausea 49% Mild 22% Moderate 22% Severe 7%

98. P98 Nausea is Dose Dependent Type 1 Diabetes Long-Term Controlled Studies Pramlintide Dose Incidence of Nausea (%) 0 10 20 30 40 50 60 0 (Placebo)30/60 µg60 µg90 µg 70 80 90 100

99. P99 Nausea Dissipates Over Time Type 1 Diabetes, Long-Term Controlled Studies Incidence (%) ITT 0 10 20 30 40 Weeks 0 to 4Weeks 4 to 26Weeks 26 to 52 Placebo + Insulin Pramlintide + Insulin 50 60 70 80 90 100

100. P100 Serious Treatment-Emergent Adverse Events (  1% of Subjects) Placebo Pramlintide Body as a Whole 1%2% Gastrointestinal 2%1% Cardiac 1%<1% Type 1 Body System: Central & Peripheral Nervous System 0%1% <1% Respiratory 1%<1% Urinary Cardiovascular 1%<1% 1%<1% Resistance Mechanism Metabolic & Nutritional 6%10% Events different between pramlintide and placebo

101. P101 Assessment of Severe Hypoglycemia in Long-Term Controlled Trials Objective endpoints employed (DCCT) –Requiring the assistance of another individual (including aid in ingestion of oral carbohydrate) -or- –Requiring the administration of glucagon injection or intravenous glucose Sponsor’s intent was to have severe hypoglycemia reported as Serious Adverse Events

102. P102 Severe Hypoglycemia Annual Event Rate Type 1 Diabetes 1.1 0 1 2 3 4 5 Mean (SE) Event Rate per Subject Year Pram + InsPbo + Insulin n=538n=1179

103. P103 Severe Hypoglycemia Annual Event Rate Type 1 Diabetes Excluding Outlier 1.1 0 1 2 3 4 5 Mean (SE) Event Rate per Subject Year Pram + InsPbo + Insulin n=538n=1179

104. P104 Placebo + Insulin n=502 Severe Hypoglycemia Annual Event Rate over Time Type 1 Diabetes 1.6 3.2 1.1 1.0 0.6 0 1 2 3 4 5 Mean (SE) Event Rate per Subject Year Pramlintide + Insulin n=1179 Placebo + Insulin n=538 Pramlintide + Insulin n=1025 Pramlintide + Insulin n=641 Placebo + Insulin n=359 Weeks 0-4Weeks 4-26Weeks 26-52

105. P105 Severe Hypoglycemia Annual Event Rate by Dose Type 1 Diabetes Weeks 0-4 5 4 3 2 1 0 Placebo + Ins Pram 30 QID + Ins Pram 60 TID + Ins Pram 60 QID + Ins Pram 90 BID + Ins Pram 90 TID + Ins Mean (SE) Event Rate Per Subject Year

106. P106 Risk for Severe Hypoglycemia Decreases over Time Type 1 Diabetes, All Patients Risk 0.00 0.01 0.02 0.03 0.04 0.05 0.06 Weeks 246810121416182022242628303234363840424446485052 Placebo + Insulin Pramlintide + Insulin RT O’Neill Drug Information Journal; 21: 9-20, 1987.

107. P107 Risk for Severe Hypoglycemia Decreases over Time Type 1 Diabetes, 30 µg QID Placebo Pramlintide RT O’Neill Drug Information Journal; 21: 9-20, 1987.

108. P108 Pramlintide Alone Does Not Cause Hypoglycemia Normal volunteers did not become hypoglycemic following 10,000 µg dose 80x maximum recommended dose

109. P109 Pramlintide Does Not Alter the Response to Hypoglycemia In Type 1 Diabetes Pramlintide did not inhibit the counter-regulatory response to hypoglycemia –Time to counter-regulatory hormone release and time to glucose recovery unaffected No impact on hypoglycemia awareness –Catecholamine responses preserved –Perception of symptoms not diminished

110. P110 Risk of Hypoglycemia upon Initiation of Pramlintide Therapy in Type 1 Diabetes is Manageable Plasma Glucose Glucose DisposalFood Intake Self Blood Glucose Monitoring Insulin Dose Nausea/Satiety Start with 10-20% Prandial Insulin Dose Reduction Educate Patients, Diabetes Educators and Physicians Initiate Therapy Type 1: 30 µg or lower

111. P111 Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control 7.2 7.4 7.6 7.8 8 02468101214161820222426 Time (Weeks) Mean HbA 1C (%) 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Event Rate Per Subject Year Weeks 0-4 Weeks 4-26 Severe Hypoglycemia Change in Weight (lb) -3 -2 0 1 Weight 0 2 4 6 Change in Insulin Use (%) Insulin Use Pramlintide (n=243) Placebo (n=173)

112. P112 Other Safety Observations Type 1 Diabetes No evidence of: –Serious events that are unusual in the absence of drug therapy –Cardiac toxicity –Hepatic toxicity –Renal toxicity No increase in frequency of clinically significant: –Lipid abnormalities –ECG changes –Changes in vital signs Systolic blood pressure Diastolic blood pressure –Laboratory abnormalities

113. P113 Pramlintide is Efficacious and Safe in Type 1 Diabetes Improves glycemic control Weight loss Increased insulin-induced hypoglycemia only during initiation of therapy –No increase in insulin-induced hypoglycemia after initiation of therapy No other safety issues Dosage recommendation: –Initiate at 30 µg 3-4 times/day before meals –Maintenance 30 or 60 µg 3-4 times/day before meals

114. P114 Guidelines for Initiation of Therapy Initial Dose –Type 2: 120 µg –Type 1: 30 µg or lower Dose Frequency –Determined by meal pattern –Administered within 15 minutes before a meal Insulin Reduction –10%-20% of preprandial, short-acting insulin dose

115. P115 Guidelines for Chronic Therapy Pramlintide Dose –Type 2: 120 µg –Type 1: 30 or 60 µg Insulin Dose –Adjusted according to standard clinical practice –Guided by self blood glucose monitoring

116. P116 Pramlintide as Adjunctive Therapy to Insulin Type 2 Diabetes Efficacious Safe Dosage recommendation: 120 µg given 2-3 times/day before meals Type 1 Diabetes Efficacious Safe Dosage recommendation: Initiate at 30 µg 3-4 times/day before meals Maintenance 30 or 60 µg 3-4 times/day before meals

117. P117 Alain Baron, MD Vice President, Clinical Research, Amylin Pharmaceuticals, Inc. Professor of Medicine Indiana University, School of Medicine Risk/Benefit Summary

118. P118 Risk and Barriers to Current Insulin Therapy Hypoglycemia Inadequate postprandial control –associated glycemic swings Weight gain Novel delivery and monitoring devices and insulin analogs are valuable therapeutic advances but still fall short of overcoming these barriers WE NEED NEW TOOLS

119. P119 Risk of Current Insulin Therapy % HbA 1c Reduction Insulin Dose Hypoglycemia Weight Gain Insulin Alone

120. P120 Type 2 Diabetes Pramlintide offers clear benefits outweighing expected, well recognized and manageable risks

121. P121 Type 2 Diabetes — Adjunctive to Insulin Therapy Risk Nausea –Mild, infrequent and transient Severe Hypoglycemia –No overall increased risk Management –Good clinical care –Adjustment of insulin dose Pramlintide is safe

122. P122 Pramlintide Overcomes Barriers and Challenges to Insulin Therapy in Type 2 Diabetes Barriers Postprandial hyperglycemia Weight gain Hypoglycemia Hyperinsulinemia Benefits –Reduced postprandial glucose excursions –Weight loss –No overall increased risk –Permits reduction of insulin dose

123. P123 Type 1 Diabetes Pramlintide offers clear benefits outweighing expected, well recognized and manageable risks

124. P124 Risk Nausea –Mild-moderate-severe –Dose-dependent and transient Management –Start therapy at 30 µg or less Type 1 Diabetes — Adjunctive to Insulin Therapy Severe Hypoglycemia –Increased risk upon initiation –Increased nausea/satiety –Dose-dependent –Start therapy at 30 µg or less –Adjustment of insulin dose Pramlintide can be used safely

125. P125 Pramlintide Overcomes Barriers and Challenges to Insulin Therapy in Type 1 Diabetes Barriers Hypoglycemia Weight gain Postprandial hyperglycemia and glycemic swings Benefits –No overall increased risk –Possible reduction of risk post-initiation –Weight loss particularly in overweight patients –Reduces postprandial glucose excursions

126. P126 Is the Reduction in HbA 1c Obtained with Pramlintide Worthwhile? Average reductions in HbA 1c of 0.3 – 0.7% vs. insulin alone and 0.5 – 1.0% vs. baseline are worthwhile According to DCCT data a 0.5% reduction in HbA 1c leads to ~ 30% decrease in risk of retinopathy

127. P127 Benefit of Pramlintide Therapy in Addition to Insulin To further reduce HbA 1c and attain glycemic goals To control postprandial hyperglycemia and associated glycemic swings Minimize weight gain

128. P128 Benefits of Pramlintide Therapy in Addition to Insulin Unique Mode of Action Limits postprandial glycemic excursions by: –Suppressing postprandial glucagon secretion (not achievable by exogenous insulin therapy), and –Modulating the rate of nutrient delivery Both effects are complementary and additive to the actions of insulin to limit postprandial glycemic excursions

129. P129 Advantages of Addition of Pramlintide to Insulin Therapy % HbA 1c Reduction Insulin Dose Hypoglycemia Weight Gain Pramlintide + Insulin Insulin Alone

130. P130 The complementary actions of insulin and pramlintide form a potent binary therapeutic tool to lower postprandial plasma glucose

131. P131 Conclusion Amylin replacement with pramlintide represents a novel and unique therapeutic advance that fulfills a need for patients with diabetes treated with insulin