Pramlintide Therapy Part 1of 2 Pharmacodynamic Review Type 1 Diabetes Efficacy Safety

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.

Summary of Pramlintide Effects Type 1, Recommended Dose HbA1c Placebo + Insulin (n=393)* Pramlintide + Insulin (496)* -0.1 -0.2 -0.3 Mean (SE) Change in HbA1c -0.4 -0.5 -0.6 -0.7 13 26 39 52 Time (Weeks) 100 Overall Nausea Severe Hypoglycemia 90 80 70 5 60 Incidence 4 50 (%) Event 40 Rate/ 3 30 Subject 2 20 Year 10 1 0-4 4-26 26-52 0-4 4-26 26-52 Time (Weeks) Time (Weeks) * Evaluable Population

Pramlintide Phase 3 Studies Type 1 Diabetes HbA1c Effect for Total Population (ITT, 6 months) 137-112 (US) 137-117 (Eur) 137-121 (US) +0.1 Pbo + Insulin 30/60QID + Ins 90BID + Ins 60TID + Ins 90TID + Ins Pbo + Insulin 60TID + Ins 60QID + Ins n=147 Pbo + Insulin n=147 -0.1 n=144 n=154 n=234 -0.2 n=148 n=161 Mean (SE) D HbA1c (%) -0.3 P=0.007 n=164 -0.4 n=243 P=0.013 -0.5 -0.6 P<0.001 Dosage Recommendation: Initiate at 30 µg 3-4 times/day Maintenance 30 or 60 µg 3-4 times/day

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

Pramlintide Therapy Results in Greater Reduction in HbA1c Than Insulin Alone in Type 1 Diabetes, Recommended Doses (Week 26) Worse Improved 100 90 10 80 20 70 30 60 40 Cumulative Percent  Cumulative Percent  50 50 40 60 30 70 20 80 10 90 100 -2 -1.5 -1 0.5 0.5 1 1.5 2 Change in HbA (%) From Baseline 1C Placebo Pramlintide 30/60 QID Pramlintide 60 TID Pramlintide 60 QID

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

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

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