Document 6607426

Phase Ib Study of Icosabutate, A Novel Structurally Enhanced Fatty Acid, in Subjects with Hypercholesterolemia
Authors: Yan Qin , Jonas Hallén , Tore Skjæret , Erling Odden , David Fraser , Hilde Nyheim , Karen Cornelissen , Joseph Chiesa , Svein Olaf Hustvedt
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Pronova BioPharma Norge AS – part of BASF, Oslo, Norway, Covance Clinical Research Unit, Leeds, UK
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• INTRODUCTION:
• SAFETY:
Icosabutate, an orally active structurally enhanced fatty acid (SEFA),
has demonstrated reduction in triglycerides (TG) and cholesterol in
several rodent models of dyslipidemia and diabetes. In clinical single and
multiple dose studies icosabutate was well tolerated and significantly
lowered LDL-C, non- HDL-C and TG in subjects with mixed dyslipidemia.
The number of subjects reporting adverse events (AEs) were balanced
between the treatment arms (Table 2).
Baseline
Table 1:Baseline Lipid Values, Geometric Mean
This phase 1b study explored the lipid lowering effects of icosabutate
in subjects with hypercholesterolemia.
HDL-C
TC
• METHODS:
TG
Randomized double blind, placebo controlled study of icosabutate
600mg OD. Subjects with hypercholesterolemia treated with a statin
for at least 3 months were screened (Figure 1). Statins were temporarily discontinued for at least 28 days prior to dosing, and for the duration
of the study. Lipids were sampled at 3 screening visits, baseline (day -1),
and at days 1, 7, 14, 21, 28, and 29. The exploratory analyses considered
changes from baseline to day 28.
Icosabutate (n
(n=18)
18)
mmol/L
4.5
4.3
mg/dL
174
165
mmol/L
l/L
05
0.5
04
0.4
mg/dL
21
14
mmol/L
5.3
4.6
mg/dL
205
179
mmol/L
1.2
1.3
mg/dL
g/d
48
8
49
9
mmol/L
6.4
6.0
mg/dL
242
231
mmol/L
22
2.2
15
1.5
mg/dL
190
134
250
150
100
Non-HDL-C
Total-C
HDL-C
RANDO
OMIZATION
N
3:1
SCREENING visit 1
35-28 days prior to first dose
> Statin withdrawal
SCREENING visit 2
6 days prior to first dose
SCREENING visit 3
3 days prior to first dose
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Apo B*
Icosabutate 600 mg
N = 18
Placebo
N=6
LDL-C, VLDL-C,
Total-C, TG,
HDL-C
HDL-C,
Non-HDL-C,
apo C3, apo B,
PCSK-9
-6%
-3%
-4%
-7%
10%
-10%
-2%
-16%
-35%
-29%
-29%
-35%
5
-41%
Placebo
Icosabutate
Placebo Corrected
0
Baseline Day 28
Baseline Day 28
Pl
Placebo
b
For details please refer to “Comment to values” at the bottom of poster
I
Icosabutate
b
4 WEEKS
1. On statin medication > 3 months, stable dose
at least > 4 weeks
2. LDL-C > 2.5 mmol/L (97 mg/dL) and an
increase of > 20 % at visit 2 following
withdrawal of statin
PCSK-9
LDL-C
Figure 3: Time Curve of Mean LDL-C (mg/dL)
Statin washout
80
Double-blind
Double
blind treatment period
200
180
160
140
120
100
80
60
40
20
0
Figure 6: Change (%) in LS Means from Baseline to Day 28,
95% CI on Placebo Corrected Bar
60
Ch
hange (%)
mg/dL
24 white, male subjects with an average age of 55 (33-65) and BMI of
27,9 kg/m2 (24.7-32.2) were randomized to icosabutate, 600 mg OD,
(n=18) or placebo (n=6). Baseline lipid values were well-balanced
between the groups (Table 1). Efficacy results are shown in Figures 2-6.
Icosabutate significantly reduced TG, non-HDL-C, LDL-C, Total-C,
apo B compared to placebo. Apo C3 was significantly reduced from
baseline and PCSK-9 was significantly increased compared to placebo.
%
50
n
13
%
72
Mild
3
50
13
72
Moderate
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17
3
17
Severe
0
0
0
0
No subjects reported serious AEs or discontinued treatment due to AE.
• CONCLUSION:
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-50
• RESULTS:
Total
n
3
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* Apo B was only sampled on day 29, 24 hours after last dose
KEY INCLUSION CRITERIA
Icosabutate (n=18)
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-30
-40
40
Placebo (n=6)
Icosabutate
Figure 5: LS Mean Apo C3 (μg/mL) Levels at Baseline and Day 28.
SD included on bars
0
EXPLORATORY
ENDPOINTS
Table 2: Treatment Emergent Adverse Events
Apo
p C3
10
-20
DOUBLE-BLIND
TREATMENT
-20
-50
Placebo
μg
g/mL
Figure 1
-10
-40
0
20
% Change
LS Mean -10
10
There were no other findings of clinical importance in the clinical
laboratory evaluations, vital signs, 12-lead ECGs, telemetry, physical
examinations, or body weight observed during the study.
-30
50
Figure 2: Change (%) in LS Means from Baseline to Day 28
(95 % CI)
TG
Figure 4b: Change (%) of
Mean TG from Baseline
0
200
Changes in Lipids and Lipoproteins
LDL-C
Study
y Design
g
Figure 4a: Absolute TG values
((Mean)) at Baseline and
During Treatment (mg/dL)
% Change
Non-HDL-C
Placebo (n
(n=6)
6)
mg/dL
LDL-C
VLDL-C
• AIM:
Triglycerides
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In this exploratory phase Ib study in hypercholesterolemic subjects
temporarily withdrawn from statin, 28 days treatment with icosabutate
showed promising results
ICOSABUTATE :
• Reduced Total-C, LDL-C, non-HDL-C, TG, and apo B
compared to placebo
• Reduced plasma apo C3 substantially from baseline
• Increased plasma PCSK-9 levels compared to placebo
• Appeared safe and well tolerated
The results extend and confirm pre-clinical data on icosabutate and
suggest a unique pharmacological profile with large, robust reductions
in both LDL-C and TGs.These explorative data indicate that icosabutate
may be an important novel lipid-lowering agent in several patient populations. The results await confirmation in designated efficacy studies.
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Screening 1 Baseline
Day 1 Placebo
Day 7
Day 14
Day 21
0
Day 28
Icosabutate
Placebo
Icosabutate
Placebo Corrected
• AUTHOR’S DISCLOSURE:
This study was in whole sponsored by Pronova BioPharma Norge ASpart of BASF. Authors not employed by Pronova BioPharma/BASF have
no conflict of interest.
• COMMENT TO VALUES:
There is a slight variance in values presented in the abstract and those presented in this poster: – The values in the abstract are reported as median percentage change from baseline (average of visit 2-4) to 24 hours after last dose (day 29) – The values in this poster are reported in line with the clinical study report as LS mean change from baseline (day-1) to day 28.