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

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

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

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

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

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

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

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

P9 Diabetes 1996,45: Lancet 1998;352: DCCT (Type 1) Retinopathy HbA 1c (%) Rate/100 Patient Years UKPDS (Type 2) HbA 1c (%) Incidence/100 Patient Years Retinopathy Lessons from the DCCT and UKPDS: Continuous Relationship Between Glycemia and Long-Term Complications No threshold effect – the lower the better

P HbA 1c (%) yrs HbA 1c (%) UKPDS (Type 2), Insulin Group Normal Baseline 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.

P11 Insulin Therapy and Glycemic Control in Young, Insulin-Treated Patients The Wisconsin Longitudinal Study Klein et al, Diabetes Care 1996, 19: % 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

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: % Klein et al, Diabetes Care 19: % Type 2 Patients, Hiss et al, ADA % Type 1 Patients, Hiss et al, ADA 2001

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

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

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: , Intensified Conventional Years from Randomization Major Episodes Incidence (%) Intensification with Insulin Pioglitazone NDA, 1998 Kelley et al, Diabetes Care 21: , % 8% 15% 22% 29%

P16 DCCT (Type 1)UKPDS (Type 2) Intensified Insulin Therapy Produces Weight Gain Diabetes Care 1988;11: JAMA 1998;280: Lancet 1998; 352: Conventional Intensified Quartile of Weight Gain Mean change in weight (kg) Intensified Conventional Change in weight (kg) Years from Randomization

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 A Systolic BP mm Hg 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile B Diastolic BP mm Hg 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile C Triglycerides mg/dL 1 st Quartile 2 nd Quartile 3 rd Quartile 4 th Quartile D Total Cholesterol mg/dL Purnell J, JAMA 1998;280:

P18 Polonsky KS, New Engl J Med, 1988; 318: Glucose Lowering Efficacy: Importance of Postprandial Hyperglycemia Glucose (mg/dL) DIABETIC CONTROL

P19 Target Range 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

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

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

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

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) amMidnight5 pm12 noon Time Amylin Insulin Adapted from Koda JE, et al. Diabetes Amylin: a Neuroendocrine Hormone

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

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

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

P27 Three Fluxes Control Blood Glucose GlucagonAmylin Insulin Meal Glucose

P28 Pramlintide Smoothes Glucose Profiles After Meals in Type 1 Diabetic Humans Minutes after Sustacal Change in glucose (mg/dL) Placebo 10 µg 30 µg 60 µg 100 µg 300 µg

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

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) Sustacal Insulin Sustacal Infusion p=0.005 Mean change in plasma glucagon (pg/mL) Injection Type 1 diabetes, SC injection Type 2 diabetes, IV infusion

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

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

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

P34 Gastric half- emptying time (hours) * p < vs. placebo 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.

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

P36 Amylin-Sensitive Neurons in Area Postrema are Almost All Glucose-Sensitive Minutes Spikes per sec 246 Glucose mM Amylin 10nM

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

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

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

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

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

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

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 (1273) 1970 (1179) Placebo (420) 581 (538)

P Duration of Exposure  1 Dose 2109  6 Months 1350  1 Year 261  2 Years Number of Subjects Duration of Exposure to Pramlintide All Studies, All Doses

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

P46 % Patients Type 1 Diabetes (n=1179) Type 2 Diabetes (n=1273) Antibiotics CV Medications Lipid Lowering Agents Oral Hypoglycemic Agents Prokinetic Agents Total Concomitant Medication Use Sulfonylureas Glitazones Biguanides  Glucosidase Inh

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

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

P49 Pramlintide Pharmacokinetic Profile Type 1 and Type 2 Diabetes Type 1 Diabetes Plasma Pramlintide Concentration (pmol/L) 1 x 30 µg Pramlintide 1 x 60 µg Pramlintide 1 x 90 µg Pramlintide 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

P50 Plasma Pramlintide Plasma Pramlintide (pM) N= Time (min) Kolterman et al., Diabetologia Plasma Glucose Plasma Glucose (mg/dL) 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

P51 Time (minutes) Plasma Glucose (mg/dL) 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 Preprandial Addition of Pramlintide Improves Postprandial Glucose Control Mean (SE) Type 1 Diabetes, 28 Day Study

P52 Pramlintide Reduces Postprandial Glucose Concentrations in a Dose-Related Manner Minutes after Sustacal Change in Glucose (mg/dL) Placebo 10 µg 30 µg 60 µg 100 µg 300 µg Type 1 Diabetes AP93-08, ,

P Incidence of Nausea (%) Bar = Nausea Incidence Pramlintide Dose-Relationships Mean Glucose Incremental AUC (mgmin/dL, min) Dose (µg Pramlintide) Placebo n= n=43 30 n= n= n= n=21 AP93-08, , Type 1 Diabetes Line = Mean Glucose AUC Dose Response Test: P = 0.012

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= n= Incidence of Nausea (%) Bar = Nausea Incidence Type 2 Diabetes, Week

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

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

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

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

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

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

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

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

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

P64 Summary of Pramlintide Effects Type 2, Recommended Dose HbA 1c Time (Weeks) Incidence (%) Mean (SE) Change in HbA 1c Time (Weeks) Event Rate/ Subject Year Time (Weeks) Overall NauseaSevere Hypoglycemia Placebo + Insulin (n=207) * Pramlintide + Insulin (n=222) * * Evaluable Population

P65 90BID + Ins n=171 n=161 Pbo + Insulin P=0.002 * 120BID + Ins n= (US) Pramlintide Phase 3 Studies Type 2 Diabetes HbA 1c Effect for Total Population (ITT, 6 months) Mean (SE)  HbA 1c (%) (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= (US) P=0.004 *

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

P67 Pramlintide Therapy Results in Greater Reduction in HbA 1c Than Insulin Alone in Type 2 Diabetes, Recommended Dose (Week 26) Cumulative Percent  Change in HbA 1C from Baseline PlaceboPramlintide 120 BID Worse Improved

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

P69 Weight Effect Type 2 Diabetes, Week Mean (SE)  Weight (lb) n=97 n=90 P= * n=88 P< * n=100 P= * 150TID + Ins Pbo + Insulin 75TID + Ins 30TID + Ins (US) n=97 90BID + Ins n=103 P= * Pbo + Insulin 120BID + Ins (Eur) 90TID + Ins n=98 P= * n=100 P< * 90BID + Ins Pbo + Insulin 120BID + Ins (US) n=131 n=108 n=121 P= * P< *

P Change in % HbA 1c Week 4Week 13Week 26 Change in Weight (lb) Week 4Week 13Week 26 Change in Insulin Use (%) 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:

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

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 (1273) 1970 (1179) Placebo (420) 581 (538)

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)

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

P75 Vision/Retinal Disorder Adverse Events One study ( ) 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

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

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%) Pramlintide 76 (9%) Number of hypoglycemic events per one year of patient time , Combined (ITT)

P78 Severe Hypoglycemia Event Rates Type 2 Diabetes All Pramlintide vs. All Placebo 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 n=175

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

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

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

P82 Type 1 Diabetes Phase 3 Program Endpoint Assessments (Week) Randomization Placebo Lead-In PBO, Pram 30 QID Pram 30 QID / 60 QID Re-randomization N = PBO, Pram 60 TID, 60 QID or 90 TID N = PBO, Pram 60 TID, 90 BID or 90 TID N = 586 Metabolic Stability

P83 Summary of Pramlintide Effects Type 1, Recommended Dose Mean (SE) Change in HbA1c HbA 1c Overall NauseaSevere Hypoglycemia Time (Weeks) Event Rate/ Subject Year Time (Weeks) Incidence (%) Placebo + Insulin (n=393)* Pramlintide + Insulin (496)* Time (Weeks) * Evaluable Population

P (US) n=154 Pbo + Insulin 60TID + Ins n=164 P=0.012 * n=161 60QID + Ins P=0.013 * Mean (SE)  HbA 1c (%) Pramlintide Phase 3 Studies Type 1 Diabetes HbA 1c Effect for Total Population (ITT, 6 months) (US) 30/60QID + Ins n=243 n=234 Pbo + Insulin P<0.001 * (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

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 Mean (SE) Placebo + Insulin n=154 Pram 60 TID + Insulin n=164 Pram 60 QID + Insulin n=161 P=0.011 P= Weeks P=0.012 Mean HbA 1c Change from Baseline (%)

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) Cumulative Percent  Worse Improved

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%

P88 Weight Effect Type 1 Diabetes, Week Mean (SE)  Weight (lb) Pbo + Insulin n=168 30/60QID + Ins n=174 P< * (US) Pbo + Insulin 60TID + Ins n=99 P< * 60QID + Ins n=106 P< * (US) n=104 Pbo + Insulin n=119 60TID + Ins n=113 P< * 90TID + Ins n=90 P< * 90BID + Ins P= * (Eur) n=86

P89 Pramlintide Therapy Offers Unique Metabolic Benefits in Type 1 Diabetes All Patients, Recommended Doses in Type 1 Change in % HbA 1c Week 4Week 13Week 26 Change in Weight (lb) Week 4Week 13Week 26 Change in Insulin Use (%) Week 4Week 13Week 26 Placebo + Insulin (N=538) Pramlintide Recommended Doses + Insulin (N=716) Baseline:

P90 Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control Change in Insulin Use (%) Insulin Use Time (Weeks) Pramlintide (n=243) Placebo (n=173) Change in Weight (lb) Weight Mean HbA 1C (%)

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

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 (1273) 1970 (1179) Placebo (420) 581 (538)

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%)

P 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 Pramlintide (28 of 2573 pts) All Placebo (7 of 904 pts) Pramlintide (17 of 2573 pts) p=0.13p=0.56

P 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

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= (1 severe) Pramlintide N= (7 severe)

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%

P98 Nausea is Dose Dependent Type 1 Diabetes Long-Term Controlled Studies Pramlintide Dose Incidence of Nausea (%) (Placebo)30/60 µg60 µg90 µg

P99 Nausea Dissipates Over Time Type 1 Diabetes, Long-Term Controlled Studies Incidence (%) ITT Weeks 0 to 4Weeks 4 to 26Weeks 26 to 52 Placebo + Insulin Pramlintide + Insulin

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

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

P102 Severe Hypoglycemia Annual Event Rate Type 1 Diabetes Mean (SE) Event Rate per Subject Year Pram + InsPbo + Insulin n=538n=1179

P103 Severe Hypoglycemia Annual Event Rate Type 1 Diabetes Excluding Outlier Mean (SE) Event Rate per Subject Year Pram + InsPbo + Insulin n=538n=1179

P104 Placebo + Insulin n=502 Severe Hypoglycemia Annual Event Rate over Time Type 1 Diabetes 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

P105 Severe Hypoglycemia Annual Event Rate by Dose Type 1 Diabetes Weeks 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

P106 Risk for Severe Hypoglycemia Decreases over Time Type 1 Diabetes, All Patients Risk Weeks Placebo + Insulin Pramlintide + Insulin RT O’Neill Drug Information Journal; 21: 9-20, 1987.

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.

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

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

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

P111 Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control Time (Weeks) Mean HbA 1C (%) Event Rate Per Subject Year Weeks 0-4 Weeks 4-26 Severe Hypoglycemia Change in Weight (lb) Weight Change in Insulin Use (%) Insulin Use Pramlintide (n=243) Placebo (n=173)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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