Intranasal Administration of Exenatide in Patients with Type 2 - - PowerPoint PPT Presentation

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

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Presenter Disclosure Information Presenter Disclosure Information Erich Blase

• Stockholder: Amylin Pharmaceuticals, Inc.
• Employee: Amylin Pharmaceuticals, Inc.

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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

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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

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Study Design Study Design

Screening Treatment (visits occurred 2-8 days apart; 28 day maximum duration) Visit Low Dose (n=12) Screening Saline IN Exen SC 5 mcg Placebo IN Exen IN 60 mcg Exen IN 200 mcg (alt form) Exen IN 200 mcg Exen IN 600 mcg 1 2 3 4 5 6 7

30 min

• 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-μL nasal sprays) – Standardized breakfast given after medication – Blood samples prior to and during the 8 hours following medication

Abbreviations: IN = intranasal; SC = subcutaneous

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Study Design Study Design

Screening Treatment (visits occurred 2-8 days apart; 28 day maximum duration) Visit Low Dose Group (n=12) High Dose Group (n=8) Exen IN 60 mcg Exen IN 200 mcg (alt form) Exen IN 200 mcg Exen IN 600 mcg Screening Saline IN Exen SC 5 mcg Placebo IN 1 2 3 4 5 6 7 Exen IN 600 mcg Exen IN 800 mcg Exen IN 1200 mcg Exen IN 1800 mcg

30 min

• 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-μL nasal sprays) – Standardized breakfast given after medication – Blood samples prior to and during the 8 hours following medication

Abbreviations: IN = intranasal; SC = subcutaneous

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Demographics and Baseline Characteristics Demographics and Baseline Characteristics

ITT Population. Data are mean ± SD, except for sex.

All subjects (N=20) Sex, male/female (%) 65/35 Age (y) 55 ± 9 Body weight (kg) 93 ± 12 BMI (kg/m2) 31 ± 3 A1C (%) 8.1 ± 1.3 FPG (mg/dL) 156.4 ± 34.6 Duration of diabetes (y) 9 ± 8

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Disposition Disposition

Total Enrolled (N=20) Enrolled (N=12) Intent-to-Treat (N=12) Withdrew (AE) (N=1) Evaluable (N=11) Enrolled (N=8) Intent-to-Treat (N=8) Evaluable (N=6) Withdrew (AE) (N=2)

Low Dose Cohort High Dose Cohort

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Pharmacokinetic Results Pharmacokinetic Results

60 120 180 240 300 360 420 480

500 1000 1500 2000 2500 3000 3500

600 mcg IN 60 mcg IN 200 mcg IN 800 mcg IN 1200 mcg IN 1800 mcg IN

Time (min) Plasma Exenatide (pg/mL)

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Pharmacokinetic Results Pharmacokinetic Results

60 120 180 240 300 360 420 480

100 200 300 400 500 600 700 800

600 mcg IN 5 mcg SC

Time (min) Plasma Exenatide (pg/mL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo

Exenatide followed by breakfast Time (min) Serum Glucose (mg/dL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo

Exenatide followed by breakfast

5 mcg SC

Time (min) Serum Glucose (mg/dL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo 1800 mcg IN

Exenatide followed by breakfast

5 mcg SC

Time (min) Serum Glucose (mg/dL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo 1200 mcg IN 1800 mcg IN

Exenatide followed by breakfast

5 mcg SC

Time (min) Serum Glucose (mg/dL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo 800 mcg IN 1200 mcg IN 1800 mcg IN

Exenatide followed by breakfast

5 mcg SC

Time (min) Serum Glucose (mg/dL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo 600 mcg IN 800 mcg IN 1200 mcg IN 1800 mcg IN

Exenatide followed by breakfast

5 mcg SC

Time (min) Serum Glucose (mg/dL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo 200 mcg IN 600 mcg IN 800 mcg IN 1200 mcg IN 1800 mcg IN

Exenatide followed by breakfast

5 mcg SC

Time (min) Serum Glucose (mg/dL)

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Serum Glucose Serum Glucose

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo 60 mcg IN 200 mcg IN 600 mcg IN 800 mcg IN 1200 mcg IN 1800 mcg IN

Exenatide followed by breakfast

5 mcg SC

Time (min) Serum Glucose (mg/dL)

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Serum Glucose and Insulin Serum Glucose and Insulin

30 60 90 120 150 180 210 240 80 100 120 140 160 180 200 220 240

Placebo 600 mcg IN

Serum Glucose

Exenatide followed by breakfast Time (min) Serum Glucose (mg/dL)

30 60 90 120 150 180 210 240 10 20 30 40 50 60 70 80

Placebo 600 mcg IN

Serum Insulin

Exenatide followed by breakfast Time (min) Serum Insulin (μIU/mL)

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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

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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

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Additional Slides Additional Slides

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Pharmacokinetic Results Pharmacokinetic Results

200 400 600 800 1000 1200 1400 1600 1800 1000 2000 3000 4000

Exenatide IN Dose (mcg) AUC 0-tlast (pg⋅h/mL)