Intranasal Administration of Exenatide in Patients with Type 2 Diabetes: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Erich Blase, Wei Deng, Brandon Walsh, Mark Fineman, Christopher A. Rhodes Amylin Pharmaceuticals, Inc., San Diego, CA
Presenter Disclosure Information Presenter Disclosure Information Erich Blase • Stockholder: Amylin Pharmaceuticals, Inc. • Employee: Amylin Pharmaceuticals, Inc. 2
Introduction Introduction • Exenatide, an incretin mimetic, has multiple mechanisms of action that improve glucose control in patients with type 2 diabetes: – Enhancement of glucose-dependent insulin secretion – Suppression of inappropriately elevated postprandial glucagon secretion – Slowing of gastric emptying – Reduction of food intake • Exenatide is currently administered twice daily via subcutaneous injection prior to major meals • Intranasal delivery of exenatide – Non-invasive mealtime dosing 3
Objective Objective • Examine the pharmacokinetics, pharmacodynamics, safety, and tolerability of intranasal administration of exenatide in patients with type 2 diabetes using at least one OAD 4
Study Design Study Design • Single-blind, dose-escalation, placebo-controlled study of intranasal administration of exenatide in subjects with type 2 diabetes – Single dose delivered (one to three 100- μ L nasal sprays) – Standardized breakfast given after medication – Blood samples prior to and during the 8 hours following medication Screening Treatment (visits occurred 2-8 days apart; 28 day maximum duration) Visit 1 2 3 4 5 6 7 Saline IN Exen IN Low Dose Placebo Exen IN Exen IN Exen IN 30 min Screening 200 mcg (n=12) IN 60 mcg 200 mcg 600 mcg (alt form) Exen SC 5 mcg Abbreviations: IN = intranasal; SC = subcutaneous 5
Study Design Study Design • Single-blind, dose-escalation, placebo-controlled study of intranasal administration of exenatide in subjects with type 2 diabetes – Single dose delivered (one to three 100- μ L nasal sprays) – Standardized breakfast given after medication – Blood samples prior to and during the 8 hours following medication Screening Treatment (visits occurred 2-8 days apart; 28 day maximum duration) Visit 1 2 3 4 5 6 7 Saline IN Low Dose Exen IN Exen IN Exen IN Exen IN 200 mcg Group 60 mcg 200 mcg 600 mcg (alt form) (n=12) 30 min Placebo Screening IN High Dose Exen IN Exen IN Exen IN Exen IN Group Exen SC 600 mcg 800 mcg 1200 mcg 1800 mcg (n=8) 5 mcg Abbreviations: IN = intranasal; SC = subcutaneous 6
Demographics and Baseline Characteristics Demographics and Baseline Characteristics All subjects (N=20) Sex, male/female (%) 65/35 Age (y) 55 ± 9 Body weight (kg) 93 ± 12 BMI (kg/m 2 ) 31 ± 3 A1C (%) 8.1 ± 1.3 FPG (mg/dL) 156.4 ± 34.6 Duration of diabetes (y) 9 ± 8 ITT Population. Data are mean ± SD, except for sex. 7
Disposition Disposition Total Enrolled (N=20) High Dose Cohort Low Dose Cohort Enrolled Enrolled (N=12) (N=8) Intent-to-Treat Intent-to-Treat (N=12) (N=8) Withdrew (AE) Evaluable Withdrew (AE) Evaluable (N=1) (N=11) (N=2) (N=6) 8
Pharmacokinetic Results Pharmacokinetic Results 60 mcg IN 3500 200 mcg IN Plasma Exenatide (pg/mL) 3000 600 mcg IN 800 mcg IN 2500 1200 mcg IN 1800 mcg IN 2000 1500 1000 500 0 0 60 120 180 240 300 360 420 480 Time (min) 9
Pharmacokinetic Results Pharmacokinetic Results 800 600 mcg IN Plasma Exenatide (pg/mL) 5 mcg SC 700 600 500 400 300 200 100 0 0 60 120 180 240 300 360 420 480 Time (min) 10
Serum Glucose Serum Glucose Placebo 240 Serum Glucose (mg/dL) 220 200 180 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 11
Serum Glucose Serum Glucose Placebo 240 5 mcg SC Serum Glucose (mg/dL) 220 200 180 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 12
Serum Glucose Serum Glucose Placebo 240 5 mcg SC Serum Glucose (mg/dL) 220 1800 mcg IN 200 180 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 13
Serum Glucose Serum Glucose Placebo 240 5 mcg SC Serum Glucose (mg/dL) 220 1800 mcg IN 1200 mcg IN 200 180 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 14
Serum Glucose Serum Glucose Placebo 240 5 mcg SC Serum Glucose (mg/dL) 220 1800 mcg IN 1200 mcg IN 200 800 mcg IN 180 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 15
Serum Glucose Serum Glucose Placebo 240 5 mcg SC Serum Glucose (mg/dL) 220 1800 mcg IN 1200 mcg IN 200 800 mcg IN 600 mcg IN 180 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 16
Serum Glucose Serum Glucose Placebo 240 5 mcg SC Serum Glucose (mg/dL) 220 1800 mcg IN 1200 mcg IN 200 800 mcg IN 600 mcg IN 180 200 mcg IN 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 17
Serum Glucose Serum Glucose Placebo 240 5 mcg SC Serum Glucose (mg/dL) 220 1800 mcg IN 1200 mcg IN 200 800 mcg IN 600 mcg IN 180 200 mcg IN 60 mcg IN 160 140 120 100 80 0 30 60 90 120 150 180 210 240 Time (min) Exenatide followed by breakfast 18
Serum Glucose and Insulin Serum Glucose and Insulin Serum Glucose Serum Insulin Placebo Placebo 240 80 600 mcg IN 600 mcg IN Serum Glucose (mg/dL) 220 Serum Insulin ( μ IU/mL) 70 200 60 180 50 160 40 140 30 120 20 100 10 80 0 0 30 60 90 120 150 180 210 240 0 30 60 90 120 150 180 210 240 Time (min) Time (min) Exenatide Exenatide followed by followed by breakfast breakfast 19
Safety and Tolerability Safety and Tolerability • The most frequent adverse events with intranasal exenatide administration were nausea (6 patients) and vomiting (5 patients) – Nausea and vomiting occurred at doses ≥ 600 mcg – Nausea also occurred in 1 patient with placebo • Sneezing occurred with intranasal administration of exenatide (2 patients) and placebo (1 patient) • Intranasal administration of exenatide was generally well tolerated with no serious adverse events or hypoglycemic events 20
Conclusion Conclusion • Intranasal administration of exenatide in patients with type 2 diabetes was well tolerated and resulted in: – Therapeutic plasma exenatide concentrations – Enhanced glucose-dependent insulin secretion – Improved PPG control • These data support the further development of intranasal exenatide delivery in the range of 600 mcg as a non-invasive treatment option for patients with type 2 diabetes 21
22 Additional Slides Additional Slides
Pharmacokinetic Results Pharmacokinetic Results 4000 AUC 0-tlast (pg ⋅ h/mL) 3000 2000 1000 0 0 200 400 600 800 1000 1200 1400 1600 1800 Exenatide IN Dose (mcg) 23
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