Intranasal administration of exenatide in Type II diabetic patients

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
Erich Blase
• Stockholder: Amylin Pharmaceuticals, Inc.
• Employee: Amylin Pharmaceuticals, Inc.
2
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
• 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
• 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
Screening
Visit
1
Treatment
(visits occurred 2-8 days apart; 28 day maximum duration)
2
3
4
5
6
7
Placebo
IN
Exen IN
60 mcg
Exen IN
200 mcg
(alt form)
Exen IN
200 mcg
Exen IN
600 mcg
Saline IN
Low Dose
(n=12)
Screening
30 min
Exen SC
5 mcg
Abbreviations: IN = intranasal; SC = subcutaneous
5
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-μL nasal sprays)
– Standardized breakfast given after medication
– Blood samples prior to and during the 8 hours following medication
Screening
Visit
Low Dose
Group
(n=12)
High Dose
Group
(n=8)
1
Treatment
(visits occurred 2-8 days apart; 28 day maximum duration)
2
3
Saline IN
Screening
30 min
Placebo
IN
Exen SC
5 mcg
4
5
6
7
Exen IN
60 mcg
Exen IN
200 mcg
(alt form)
Exen IN
200 mcg
Exen IN
600 mcg
Exen IN
600 mcg
Exen IN
800 mcg
Exen IN
1200 mcg
Exen IN
1800 mcg
Abbreviations: IN = intranasal; SC = subcutaneous
6
Demographics and Baseline Characteristics
All subjects
(N=20)
Sex, male/female (%)
65/35
Age (y)
55 ± 9
Body weight (kg)
93 ± 12
BMI (kg/m2)
31 ± 3
A1C (%)
FPG (mg/dL)
8.1 ± 1.3
156.4 ± 34.6
Duration of diabetes (y)
9±8
ITT Population. Data are mean ± SD, except for sex.
7
Disposition
Low Dose Cohort
Total Enrolled
(N=20)
High Dose Cohort
Enrolled
(N=12)
Enrolled
(N=8)
Intent-to-Treat
(N=12)
Intent-to-Treat
(N=8)
Withdrew (AE)
(N=1)
Evaluable
(N=11)
Withdrew (AE)
(N=2)
Evaluable
(N=6)
8
Pharmacokinetic Results
60 mcg IN
200 mcg IN
600 mcg IN
800 mcg IN
1200 mcg IN
1800 mcg IN
Plasma Exenatide (pg/mL)
3500
3000
2500
2000
1500
1000
500
0
0
60
120
180
240
300
360
420
480
Time (min)
9
Pharmacokinetic Results
Plasma Exenatide (pg/mL)
800
600 mcg IN
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
Placebo
Serum Glucose (mg/dL)
240
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
Placebo
5 mcg SC
Serum Glucose (mg/dL)
240
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
Placebo
5 mcg SC
1800 mcg IN
Serum Glucose (mg/dL)
240
220
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
Placebo
5 mcg SC
1800 mcg IN
1200 mcg IN
Serum Glucose (mg/dL)
240
220
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
Placebo
5 mcg SC
1800 mcg IN
1200 mcg IN
800 mcg IN
Serum Glucose (mg/dL)
240
220
200
180
160
140
120
100
80
0
30
60
90
120
150
180
210
240
Time (min)
Exenatide
followed by
breakfast
15
Serum Glucose
Placebo
5 mcg SC
1800 mcg IN
1200 mcg IN
800 mcg IN
600 mcg IN
Serum Glucose (mg/dL)
240
220
200
180
160
140
120
100
80
0
30
60
90
120
150
180
210
240
Time (min)
Exenatide
followed by
breakfast
16
Serum Glucose
Placebo
5 mcg SC
1800 mcg IN
1200 mcg IN
800 mcg IN
600 mcg IN
200 mcg IN
Serum Glucose (mg/dL)
240
220
200
180
160
140
120
100
80
0
30
60
90
120
150
180
210
240
Time (min)
Exenatide
followed by
breakfast
17
Serum Glucose
Placebo
5 mcg SC
1800 mcg IN
1200 mcg IN
800 mcg IN
600 mcg IN
200 mcg IN
60 mcg IN
Serum Glucose (mg/dL)
240
220
200
180
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 Insulin
Serum Glucose
Placebo
600 mcg IN
220
200
180
160
140
120
100
Placebo
600 mcg IN
80
Serum Insulin (μIU/mL)
Serum Glucose (mg/dL)
240
70
60
50
40
30
20
10
0
80
0
30
60
90
120
150
180
210
240
0
30
Time (min)
Exenatide
followed by
breakfast
60
90
120
150
180
210
240
Time (min)
Exenatide
followed by
breakfast
19
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
• 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
Additional Slides
22
AUC 0-tlast (pg⋅h/mL)
Pharmacokinetic Results
4000
3000
2000
1000
0
0
200
400
600
800 1000 1200 1400 1600 1800
Exenatide IN Dose (mcg)
23

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