Mean Fasting Plasma Glucose - Intarcia Therapeutics, Inc.

Comments

Transcription

Mean Fasting Plasma Glucose - Intarcia Therapeutics, Inc.
A Phase 1b Study of ITCA 650: Continuous Subcutaneous Delivery of Exenatide via DUROS Device
Lowers Fasting and Postprandial Plasma Glucose
®
Kenneth Luskey , MD John McNally , PhD Janice Dahms , MS Douglas Logan , MD Gilbert Weiner , DO Douglas Denham , DO Thomas Alessi , PhD
• To evaluate the safety and tolerability of ITCA 650 in subjects with type 2
diabetes mellitus.
Demographics
Semipermeable
Membrane
Osmotic
Engine
Actual Size: 4mm x 45mm
Piston
Drug
Reservoir
Exenatide
Day 8
20 mcg/day
Day 22
40 mcg/day
Day 29
-10.0
-20.0
-30.0
80 mcg/day
10 mcg/day
20 mcg/day
40 mcg/day
52.1
37-67
56.7
49-63
Sex (M/F)
8/4
7/4
4/6
7/4
Weight (kg)
Mean
Range
95.7
75.5-130.2
94.3
55.7-120.4
88.5
56.1-125.8
89.5
58.1-130.3
HbA1c (%)
Mean
Range
7.7%
6.5-10.2
7.9%
6.7-9.8
7.4%
6.5-9.4
7.4%
6.6-9.4
20.0%
80.0%
36.4%
45.4%
18.2%
8.3%
91.7%
90.9%
9.1%
8
-20.0
-40.0
-60.0
Group 1
10 mcg/day
Group 2
20 mcg/day
Group 3
40 mcg/day
Group 4
80 mcg/day
N
12
11
10
11
Completed the Study
11 (92%)
11 (100%)
10 (100%)
7 (64%)
1 (8%)
1
0
0 (0%)
0
0
0 (0%)
0
0
4 (36%)
2
2
7.5
7
6.5
6
10 mcg/day
20 mcg/day
40 mcg/day
80 mcg/day
Change in 2 hour Postprandial Glucose
Subject Disposition
HbA1c at Day -1 and Day 29
10 mcg/day
40 mcg/day
20 mcg/day
Day 29
57.4
47-70
Day 29
Day -1
56.4
44-68
80 mcg/day
Incidence of Nausea versus Time
Treatment Days
0.0
Day 5
Day 15
Week 1
Day 29
-40
-60
-80
A meal tolerance test was conducted on Days -1, 5, 15
and 29. The 2 hour postprandial value from these
tests were used in this analysis.
10 mcg/day
20 mcg/day
40 mcg/day
Week 2
Week 3
Week 4
None
Mild
Moderate
92%
8%
0%
100%
0%
0%
100%
0%
0%
100%
0%
0%
Group 2
20 mcg/day
None
Mild
Moderate
82%
9%
9%
100%
0%
0%
91%
9%
0%
91%
9%
0%
Group 3
40 mcg/day
None
Mild
Moderate
40%
60%
0%
100%
0%
0%
80%
20%
0%
100%
0%
0%
Group 4
80 mcg/day
None
Mild
Moderate
18%
55%
27%
78%
22%
0%
86%
14%
0%
86%
14%
0%
Group 1
10 mcg/day
-20
-100
-0.93
-1
-1.5
-2
-2.5
-2.91
-3
-3.5
20 mcg/day
40 mcg/day
80 mcg/day
80 mcg/day
Day 29
Age (years)
Mean
Range
0.0
Day 5
-0.31
Conclusions
Day -1
Group 4
80 mcg/day
-0.5
-0.28
-40.0
Day 29
Group 3
40 mcg/day
Treatment Days
Day 15
0
10 mcg/day
Day -1
Group 2
20 mcg/day
Subjects discontinued
Adverse events
Withdrew consent
Day 15
Treatment Days
Day 29
Change in Fasting Plasma Glucose
Group 1
10 mcg/day
• To characterize the effect of ITCA 650 on the pharmacodynamic measures of
glucose metabolism in subjects with type 2 diabetes mellitus
• Implantable osmotic mini -pump
• Steady-state delivery of drugs & biologics
• Dosing for up to 12 months with a single device
• Insertion/removal in a 10 to 15 minute in -office procedure
100.0
10 mcg/day
Previous Treatment
Diet and Exercise
Metformin
Metformin + TZD
Aim
120.0
HbA1c (%)
ITCA 650 represents a novel method to deliver exenatide for an extended period
of time with 100% compliance for the long-term treatment of type 2 diabetes.
140.0
Day 1
Mean Change in
Fasting Plasma Glucose (mg/dL)
Fasting plasma glucose decreased in all dose groups within 1-2 days of
initiation of treatment. In addition, the 2-hour postprandial glucose also
decreased in all groups during treatment. A decrease in hemoglobin A1c was
noted in all treatment groups. Lastly, weight loss was observed in all groups in a
dose-dependent manner. ITCA 650 was well tolerated primarily with
observations of anticipated mild bruising, itching and local pain at the insertion
site, as well as transient mild nausea and vomiting in a small number of
subjects that primarily occurred in the first week of treatment.
Inclusion/Exclusion Criteria
• 30 to 70 years of age
• diagnosis of type 2 diabetes mellitus for >6 months prior to screening
• stable treatment regimen of diet and exercise alone or in combination with
metformin monotherapy, thiazolidinedione (TZD) monotherapy, or metformin
plus TZD combination therapy
• hemoglobin A1c (HbA1c) >6.5% and <10%
• fasting plasma glucose (FPG) <270 mg/dL
• fasting C-peptide >0.8 ng/mL
160.0
Day 5
0.0
Change in Body Weight at Day 29
Treatment Days
Day 15
180.0
Randomized, open-label study
10-12 subjects/group
4 dose groups – 10, 20, 40 and 80 mcg/day
28 day treatment with ITCA 650
7-day follow-up
1
Change in Fructosamine
Fasting Plasma Glucose versus Time
Mean Change in 2 Hour
Postprandial Glucose (mg/dL)
A phase 1b study to evaluate the safety and tolerability of ITCA 650 treatment
was conducted in subjects with inadequately controlled type 2 diabetes. In this
study, subjects were randomized to receive either 10, 20, 40 or 80 mcg/day of
exenatide via DUROS device for 28 days.
4
Day 29
•
•
•
•
•
3
Day -1
Exenatide is a proven effective treatment for type 2 diabetes that improves
glucose control and induces weight loss. However, use of exenatide has been
limited due to the twice-daily self-injection schedule and frequent nausea which
may be associated with peak concentrations of drug. The DUROS® technology is
a subcutaneous continuous delivery system that has been utilized in the Viadur®
device, an FDA-approved therapy for prostate cancer. It is an osmotic delivery
device consisting of a small sterile titanium cylinder (4mm x 45 mm) that is
placed subcutaneously for extended periods of time. ITCA 650 is a DUROS device
engineered to deliver exenatide at a continuous and consistent rate for treatment
durations of 3 to 12 months and over a broad range of dose levels. Preclinical
studies have shown that ITCA 650 delivers exenatide at a consistent rate for >6
months with preserved stability of the drug product.
2
Change in Fructosamine (umol/L)
Study Design
1
Mean Fasting Plasma Glucose (mg/dL)
Abstract
1
Mean Change in Weight (kg)
1
No severe nausea was observed in any subjects
80 mcg/day
• Therapy with ITCA 650 at doses of 10, 20 and 40 mcg/day was well
tolerated for 28 days of therapy
• Mild nausea and vomiting were observed in the first week, but
diminished with time
• Decreases in fasting plasma glucose were observed in 1-2 days and were
maintained throughout the 28-day treatment period in all treatment groups
• Decreases in postprandial glucose, fructosamine and HbA1c were also noted
in all treatment groups
• Body weight decreased in all treatment groups
• Despite mild and moderate nausea in week 1, impressive weight loss
at 80 mcg/day suggests further investigation of high doses may be
warranted
• ITCA 650 has the potential to provide for continuous delivery of exenatide and
provide the following potential benefits:
• highly effective control of glucose
• reduction in frequency, severity and persistence of side effects
• elimination of need for self-injection
• significant weight-loss
• 100% compliance to prescribed therapy
Institutions:
1. Intarcia Therapeutics Inc., Hayward, CA, United States
2. Medpace, Cincinnati, OH, United States
3. Cetero Research, Miami Gardens, FL, United States
4. Cetero Research, San Antonio, TX, United States
Presented at the American Diabetes Association's 69th Scientific Sessions
June 5-9, 2009, in New Orleans, LA.
This work was supported in part by a research grant from Intarcia Therapeutics, Inc.
DUROS is a registered trademark of ALZA Corporation licensed to Intarcia Therapeutics, Inc.
VIADUR is a registered trademark of ALZA Corporation.