Pramlintide Therapy Part 1 of 2 n Pharmacodynamic

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

Pramlintide: Absolute and Percent Change in Weight Absolute Change in Weight (kg) Dose Esc No Drug Follow-up Maintenance Dose Esc 3. 5 kg * *P<0. 0001 †P<. 001 0 2 4 8 12 16 3. 6% * 24 † * *P<0. 0001 †P<. 001 * No Drug Follow-up Maintenance * † * “Evaluable Population” Percent Change in Weight 0 2 4 Time (wk) Placebo (n=48) Pramlintide (n=97) Weyer C, et al. Obes Rev. 2005; 6(Suppl 1): 21. Abstract O 050. 8 * 12 * 16 Time (wk) 24

Summary of Pramlintide Effects Mean (SE) Change in Hb. A 1 c Type 1, Recommended Dose Hb. A 1 c 0 Placebo + Insulin (n=393)* Pramlintide + Insulin (496)* -0. 1 -0. 2 -0. 3 -0. 4 -0. 5 -0. 6 -0. 7 0 13 26 39 52 Time (Weeks) 100 90 80 70 60 Incidence 50 (%) 40 30 20 10 0 Overall Nausea Severe Hypoglycemia 5 4 Event Rate/ 3 Subject Year 2 1 0 -4 4 -26 Time (Weeks) 26 -52 0 0 -4 4 -26 Time (Weeks) 26 -52

Pramlintide Phase 3 Studies Type 1 Diabetes Hb. A 1 c Effect for Total Population (ITT, 6 months) +0. 1 Pbo + Insulin 30/60 QID + Ins 137 -121 (US) 137 -117 (Eur) 137 -112 (US) n=147 90 BID + Ins 60 TID + Ins 90 TID + Ins Pbo + Insulin 60 TID + Ins 60 QID + Ins Mean (SE) D Hb. A 1 c (%) 0 Pbo + Insulin -0. 1 n=147 n=144 n=154 n=234 -0. 2 n=148 -0. 3 P=0. 007 -0. 4 -0. 5 -0. 6 n=243 n=161 n=164 P=0. 013 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 Hb. A 1 c in Type 1 Diabetes Placebo + Insulin Pram 60 TID + Insulin Pram 60 QID + Insulin 0. 2 0 Stable Insulin n=154 n=161 P=0. 011 -0. 2 P=0. 012 -0. 4 P=0. 001 -0. 6 Placebo + Insulin Pram 60 TID + Insulin Pram 60 QID + Insulin 0. 2 P=0. 012 -0. 8 -1 -1. 2 Hb. A 1 c Change from Baseline (%) Mean Hb. A 1 c Change from Baseline (%) ITT 0 n=36 n=30 -0. 2 P=0. 007 -0. 4 P=0. 015 -0. 6 P=0. 017 -0. 8 P=0. 003 -1 -1. 2 0 13 26 Weeks 39 52 0 Mean (SE) 13 26 39 Weeks Placebo + Insulin Pram 60 TID + Insulin Pram 60 QID + Insulin 137 -121 52

Pramlintide Therapy Results in Greater Reduction in Hb. A 1 c Than Insulin Alone in Type 1 Diabetes, Recommended Doses (Week 26) Improved 0 10 20 30 40 50 60 70 80 90 100 Cumulative Percent 100 90 80 70 60 50 40 30 20 10 0 -2 Worse -1. 5 Placebo -1 0. 5 Change in Hb. A Pramlintide 30/60 QID 0 1 C 0. 5 1 (%) From Baseline Pramlintide 60 TID 1. 5 2 Pramlintide 60 QID

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

Weight Effect Type 1 Diabetes, Week 26 137 -112 (US) Mean (SE) D Weight (lb) Pbo + Insulin 30/60 QID + Ins 137 -117 (Eur) Pbo + Insulin 90 BID + Ins 60 TID + Ins 137 -121 (US) 90 TID + Ins Pbo + Insulin 60 TID + Ins 60 QID + Ins 3 2 1 n=168 0 -1 n=104 n=119 n=174 n=86 n=99 -2 -3 P<0. 0001 -4 * -5 P=0. 0035 * n=113 n=106 n=90 P<0. 0001 * *

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