Efficacy and Tolerability of ITCA 650

Efficacy and Tolerability of ITCA 650 (Continuous Subcutaneous Exenatide)
in Poorly Controlled Type 2 Diabetes With Baseline A1C>10%
Robert R. Henry, MD; Julio Rosenstock, MD; Michelle A. Baron, MD
1
2
3
Section of Diabetes, Endocrinology, and Metabolism, Veterans Affairs San Diego Healthcare System, San Diego, CA; Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX; Intarcia Therapeutics, Boston, MA
1
Age, years
52.1 (10.2)
a
Age range, years
33 (55.0)
This Race, n (%)
METHODS
White
45 (75.0)
Black or African American
Design
• Interim analysis from an open-label, multicenter study (FREEDOM-1 HBL)
8 (13.3)
Other
21 (35.0)
–– Evaluate HbA1c, weight and safety data available at the end of 2013 for all patient who had
completed Week 13
BMI, kg/m2a
32.1 (4.9)
BMI ≥30 kg/m2, n (%)
39 (65.0)
• Included patients with T2DM who were screened for the Phase 3, double-blind, randomized, placebocontrolled study of ITCA 650 (FREEDOM-1), but were ineligible because of an initial HbA1c >10%
HbA1c (%)
10.7 (0.9)
• Patients were treated with open-label ITCA 650 20 mcg/day for 13 weeks and then 60 mcg/day for
26 weeks.
• Background antidiabetic medication was maintained throughout the study.
a
Fasting plasma glucose (mg/dL)a
248.4 (52.2)
Mean standard deviation.
• FREEDOM 1 is a double-blind, randomized, placebo-controlled, multicenter study in patients with an
HbA1c of 7.5% to 10.0% to evaluate the efficacy and safety of ITCA 650 in patients receiving diabetes
treatment. Patients who met all inclusion criteria for FREEDOM-1 but had HbA1c >10% but ≤12%
were enrolled in FREEDOM-1HBL (Figure 1).
ITCA 650
60 µg/day
Follow-up
Figure 1. Study Flow Chart
• Body mass index (BMI) ≥25 and ≤45 kg/m
2
Study Assessments for interim analysis
• Baseline Characteristics
• HbA1c
• Body weight
8.3
8
-2.5%
60
19 Weeks
6
3 Month ITCA 650
Mini-pump 20 mcg/d
100%
26 weeks
4 weeks
50
Endpoint
6 Month
ITCA 650 Mini-pumps 60 mcg/d
30
10%
2%
3%
4%
5%
HbA1c Reduction at Least
• HbA1C targets of ≤7% were achieved in 30% of subjects who had completed at least 13 weeks of
treatment.
6 Month
ITCA 650 Mini-pumps 60 mcg/d
• 22% of patients had HbA1c reductions of at least 4% (Figure 5).
• Only 2 patients were non-responders (decrease in HbA1c <0.5%) at the time of the interim analysis.
Figure 5. HbA1c for Individual Patients Achieving at Least 4% Change From
Baseline (number in bar represents HbA1c at endpoint)
Table 2. Study Discontinuations
ITCA 650 (N=60)
Hyperglycemia
1 (1.7%)
Adverse event
4 (6.7%)
Nausea/vomiting
2 (3.3%)
Diarrhea
1 (1.7%)
Sudden cardiac death*
1 (1.7%)
*Unrelated to study drug
Effect on HbA1c
• Interim assessment of patients completing each study interval is shown in (Figure 3).
• Mean reductions of HbA1c at Week 13 (n=50), Week 19 (n=39), and Week 26 (n=25) were –2.5%,
–2.9%, and –3.2%, respectively.
0.0
11 (18%)
Diarrhea
11 (18%)
Hypoglycemia – minor*
3 (5%)
10.4
10.4
-4.1
-4.1
10.9
CONCLUSIONS
• In this interim analysis, the addition of a single agent, ITCA 650 resulted in mean HbA1c reductions
>3% in patients who had reached 26 weeks of treatment.
• 30% of patients who had reached 13 weeks of treatment (n=50) achieved target HbA1c ≤7%.
• These effects were achieved with almost 100% adherence with ITCA 650.
22%
25
3 Month ITCA 650
Mini-pump 20 mcg/d
Vomiting
• The type and incidence of AEs of special interest was consistent with other GLP-1 receptor agonists.
40%
20
0
17 (28%)
• Attenuation of expected weight loss is consistent with the correction of glucosuria in this High
Baseline population as glycemic control is restored.
50%
0%
10
Nausea
• ITCA 650 treatment was accompanied by weight loss at Week 26, the magnitude of which was
attenuated compared to that seen previously in Phase 2 (Henry et al, 2013).
78%
60%
39
40
1 (1.7%)
–– 69% were on OAD medications
-3.2%
20%
Lost to follow up
–– 31% were on diet and exercise
-2.9%
Patients With at Least 13 Weeks of Treatment
80%
50
• Adverse events of special interest
• At baseline
7.7
• HbA1C reductions ≥2% were achieved by 78% of subjects who completed at least 13 weeks of
treatment; 50% achieved >3% and 22% achieved ≥4% reductions (Figure 4).
26 Weeks
Reason for Discontinuation
• Baseline characteristics were consistent with a patient population having long standing T2DM
(Table 1).
7.8
ITCA 650 (N=60)
*Minor hypoglycemia was defined as symptoms suggestive of hypoglycemia with a plasma glucose level <60 mg/dL.
% of Patients
13 Weeks
• The average duration of T2DM was 9 years.
13 weeks
9
Figure 4. Proportion of Patients Achieving Specific HbA1c Reduction
• Proportion of patients with at least 13 Weeks with HbA1c ≤7%
RESULTS
Baseline
10
Figure 2. Patient Disposition at the Time of the Interim Analysis
• Adverse events
Study Endpoints for Interim Analysis
• Change in HbA1c and body weight from baseline at each time point for patients who had reached
Week 13, Week 19, and Week 26
10.9
Table 3. Adverse Events of Special Interest
Adverse Event
Patient Disposition
• Number of patients who had completed each study interval at the time of the interim analysis are
shown in Figure 2.
–– On a stable (≥3 months at the same dose) and optimal or near-optimal dose of:
• Glycosylated hemoglobin (HbA1c) >10.0% and ≤12.0%
• The majority of AEs were of mild or moderate severity.
a
–– Diet and exercise alone OR
§§ Metformin, sulfonylurea (SU) or thiazolidinedione (TZD) monotherapy or Combinations
of these OADs
Safety
• ITCA 650 was well generally well tolerated (Table 2).
26 Weeks
N=25
10.7
7
Change in HbA1c (%)
• ITCA 650 is an injection-free GLP-1 receptor agonist that can provide continuous SC exenatide for up
to 12 months from a single sub-dermal placement.
• On a stable (≥3 months prior to Screening) treatment regimen
19 Weeks
N=39
10.8
11
5 (11.7)
Hispanic or Latino, n (%)
13 Weeks
N=50
12
25 - 70
Male, n (%)
Number of Patients
• Nevertheless, a large segment of the T2DM population remains poorly controlled, even with 3 or more
OAD’s.1 Treatment with GLP-1 agonists or combinations of metformin and DPP-4 inhibitors in these
patients result in HbA1c reductions of approximately 2%.2-6 Enrolling patients with High Baseline
HbA1c who would otherwise have qualified for the double blind, placebo-controlled core study to
receive open-label study drug provides a robust opportunity to evaluate treatment response in this
patient population.
Patient Screening
Characteristic
ITCA 650
60 mcg/day
(N=60)
Figure 3. Mean Baseline HbA1c and Mean Change From Baseline
at Each Interval
• Diagnosis of type 2 diabetes for ≥3 months prior to Screening
• Type 2 diabetes mellitus (T2DM) is a progressive illness that often requires combinations of oral
antidiabetic drugs (OAD’s) and insulin to achieve adequate glycemic control. ADA and EASD treatment
guidelines recommend that treatment be individualized for each patient based on prognosis,
preferences, and co-morbidities.
4 weeks
• The objectives of this High Baseline study were the same as the primary study, but provided the
opportunity to evaluate the efficacy, safety, and tolerability of ITCA 650 in very poorly controlled
patients with T2DM which represent a population with high unmet need and often with limited
treatment options. In addition the data presented in this interim analysis is the first available that
demonstrates the performance of both 3 and 6 month ITCA 650 devices (low and high doses).
Patient Selection
• Men and women between ages 18 and 80 years inclusive
INTRODUCTION
ITCA 650
20 µg/day
Table 1. Baseline Demographic and Clinical Characteristics
OBJECTIVES
ITCA 650, the injection-free GLP-1 receptor agonist that provides continuous SC exenatide for up to
12 months from a single sub-dermal placement, is undergoing extensive clinical evaluation in multiple
Phase 3 double-blind studies. This report represents the first 6 month, open-label experience with ITCA
650 mini-pumps from an ongoing multicenter study in subjects with type 2 diabetes who did not meet
enrollment criteria for the double-blind placebo controlled trial because of A1C >10%. Entrance criteria
for this open-label trial were: A1C >10% to ≤12%, age 18-80 years, BMI 25-45 kg/m2, and on stable
(≥3 months) diet and exercise and/or monotherapy or any combination of metformin, sulfonylurea, and
thiazolidinedione. Treatment was initiated by placing a 3-month ITCA 650 mini-pump delivering
20 mcg/day, which was then replaced by a 6-month ITCA 650 mini-pump delivering 60 mcg/day for
26 weeks. Pre-study oral antidiabetic agents (OADs) were maintained unchanged for the 39 week of
treatment. The primary endpoint was change in A1C from baseline to week 39. At the time of this initial
interim analysis, 50, 39, and 25 of the 60 subjects enrolled had completed 13, 19, and 26 weeks of
treatment; respectively. Mean baseline characteristics for the entire cohort (n=60) were A1C 10.7%, age
52.1 yrs, BMI 32.1 kg/m2, duration of diabetes 8.9 yrs, OADs use 69%. Mean reductions of A1C at Weeks
13 (n=50), 19 (n=39), and 26 (n=25) were -2.5%, –2.9%, and –3.2%, respectively. A1C reductions
≥2% were achieved by 78% of subjects who completed at least 13 weeks of treatment; 50% achieved
>3% and 22% achieved ≥4% reductions. A1C targets of ≤7% were achieved in 30% of subjects who
had completed at least 13 weeks of treatment. Adverse events were consistent with previous trials with
ITCA 650. In conclusion, ITCA 650 has the potential to markedly improve glycemic control in patients with
severe hyperglycemia and longstanding diabetes.
3
Mean HbA1c (%)
ABSTRACT
2
11.0
11.1
11.2
11.3
11.4
11.4
11.8
12.0 Baseline
-5.9
-6.2
-1.0
• ITCA 650 has the potential to markedly improve glycemic control in patients with severe
hyperglycemia and longstanding diabetes.
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initial therapy in type 2 diabetes mellitus (T2DM) with severe hyperglycemia. Poster 1059 presented
at the 73rd American Diabetes Association Annual Meeting, June 24, 2013.
3. Haak T, Meinicke T, Jones R, Weber S, von Eynatten M, Woerle HJ. Initial combination of linagliptin
and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebocontrolled study. Diabetes Obes Metab. 2012;14:565-74.
4. Henry RR, Murray AV, Nauck MA, et al. Response to dapagliflozin by baseline HbA1c in head-to-head
comparisons. Poster 1116 presented at the 73rd American Diabetes Association Annual Meeting, June
24, 2013.
5. Invokana Package Information, Janssen Pharmaceuticals, Inc., Titusville, NJ.
6. Janumet Prescribing Information, Merck & Co., Inc., Whitehouse Station, NJ.
-2.0
-3.0
-4.0
-5.0
-6.0
-7.0
-4.6
-4.7
-5.6
-4.7
-4.4
-4.0
-5.0
22% of Patients had HbA1c Reductions of at Least 4%
• Mean weight loss was 1.1 kg at 26 weeks.
Presented at the 74th Scientific Sessions of the American Diabetes Association, June 13-17, 2014,
San Francisco, CA.

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