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

Pramlintide: Absolute and Percent Change in Weight “Evaluable Population” Absolute Change in Weight (kg) Percent Change in Weight Dose Esc No Drug Follow-up Dose Esc No Drug Follow-up Maintenance Maintenance 3.5 kg 3.6% * * * * Pramlintide: Absolute and Percent Change in Weight Pramlintide is a related drug for the treatment of type 1 and type 2 diabetes that is being developed as an obesity treatment. In its phase 2 trial, individuals, who were not diabetic patients, experienced a 3.5 kg reduction in body weight using this injectible compound in various doses without behavioral intervention over a 16-week period. Therefore, the compound alone was able to achieve weight loss in this situation. Much more research on pramlintide needs to be completed to assure that these results are repeatable and consistent. Reference: Weyer C, Aronne L, Fujioka K, et al. Safety, dose-tolerance, and weight-related effects of pramlintide in obese subjects with or without type 2 diabetes. Obes Rev. 2005;6(Suppl 1):21. Abstract O050. † † * * * * *P<0.0001 †P<.001 *P<0.0001 †P<.001 * * 2 4 8 12 16 24 2 4 8 12 16 24 Time (wk) Time (wk) Placebo (n=48) Pramlintide (n=97) Weyer C, et al. Obes Rev. 2005;6(Suppl 1):21. Abstract O050.

Addition of Pramlintide to Insulin Reduces HbA1c in Type 1 Diabetes ITT Stable Insulin Placebo + Insulin n=154 Pram 60 TID + Insulin n=164 Pram 60 QID + Insulin n=161 P=0.011 P=0.001 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0.2 13 26 39 52 Weeks P=0.012 Mean HbA1c Change from Baseline (%) Weeks -1.2 -1 -0.8 -0.6 -0.4 -0.2 0.2 P=0.015 P=0.003 P=0.007 P=0.017 HbA1c Change from Baseline (%) 13 26 39 52 Placebo + Insulin n=36 Pram 60 TID + Insulin n=30 Pram 60 QID + Insulin n=30 Mean (SE) Placebo + Insulin Pram 60 TID + Insulin Pram 60 QID + Insulin 137-121

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

Pramlintide (n=243) Placebo (n=173) Time (Weeks) Insulin Use Weight Pramlintide Benefits are Seen in Patients with Type 1 Diabetes Targeting Optimal Glycemic Control 8 7.8 Mean HbA1C (%) 7.6 7.4 7.2 Pramlintide (n=243) Placebo (n=173) 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (Weeks) 2 4 6 Change in Insulin Use (%) Insulin Use Change in Weight (lb) -3 -2 -1 1 Weight Severe Hypoglycemia 4.5 4.0 3.5 3.0 Event Rate Per Subject Year 2.5 2.0 1.5 1.0 0.5 Weeks 0-4 Weeks 4-26

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

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

SYMLIN Boxed Warning DISCUSSION POINTS: SLIDE BACKGROUND: Symlin_PI_and_Med_Guide2005_p1.pdf