Transcript LDL-C Assessment with PCSK9 monoclonaL

LAPLACE-TIMI 57 Primary Results
A Double-blind, Randomized, Placebo-controlled, Dose-ranging Study to
Evaluate the Efficacy, Safety, and Tolerability of a Monoclonal Antibody to
PCSK9 in Combination with a Statin in Patients with Hypercholesterolemia
Robert P. Giugliano, MD, SM, FAHA, FACC
TIMI Study Group, Cardiovascular Division
Brigham and Women’s Hospital
Harvard Medical School, Boston, MA
Supported by research grant from Amgen, Inc.
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
PCSK9 Regulates the Surface Expression of LDLRs
by Targeting LDLRs for Lysosomal Degradation
LDL receptor
AMG 145, a fully human monoclonal antibody that binds PCSK9,
was well tolerated and lowered LDL in phase Ia and Ib studies
(Dias CS, JACC published online Oct 17, 2012. http://dx.doi.org/10.1016/j.jacc.2012.08.986)
Brown MS, et al. Proc Natl Acad Sci U S A. 1979;76:3330-3337.
Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547.
Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.
Qian YW, et al. J Lipid Res. 2007;48:1488-1498.
Horton JD, et al. J Lipid Res. 2009;50:S172-S177.
Zhang DW, et al. J Biol Chem. 2007;282:18602-18612.
Objectives
Objectives: To compare 12 weeks of AMG 145
(given SC Q2 or Q4 weeks) vs placebo in
stable patients with hypercholesterolemia on
a statin ± ezetimibe:
– Primary:
% change in LDL-C*
– Secondary:
changes in other lipoproteins
pharmacokinetics/pharmacodynamics
tolerability and safety
* measured using ultracentrifugation in a central core laboratory
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Study Design
78 centers
5 countries
Placebo SC Q2W
78 Subjects
70 mg AMG 145 SC Q2W
79 Subjects
105 mg AMG 145 SC Q2W
79 Subjects
Screening and
Placebo Run-in
Period
140 mg AMG 145 SC Q2W
78 Subjects
Subcutaneous
injection of
6 mL placebo
Placebo SC Q4W
77 Subjects
Fasting LDL-C
5-10 days
before
randomization
280 mg AMG 145 SC Q4W
79 Subjects
350 mg AMG 145 SC Q4W
79 Subjects
420 mg AMG 145 SC Q4W
80 Subjects
Maximum 6 weeks
Visits: Day 1
Week 2
Week 4
Week 6
Week 8
Q2W:
Q4W:
934 screened
631 random.
629 treated
Week 10
Week 12 Week 14
Primary
Endpoint
Assessed
( *2 subjects assigned placebo Q4W received no study drug)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Kohli P, et al. Clin Cardiol. 2012;35:385-391.
Major Entry Criteria
•
•
•
•
•
•
•
Age 18–80 years
Stable dose of statin ± ezetimibe for 4 wks
Fasting LDL-C ≥ 85 mg/dL
Fasting triglycerides ≤ 400 mg/dL
No other prescription lipid lowering therapy
No recent ACS, revascularization, stroke
No major comorbidities
Randomization stratified by: 1) Baseline LDL (<130 vs ≥130 mg/dL)
2) Use of ezetimibe at baseline
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Kohli P, et al. Clin Cardiol. 2012;35:385-391.
Baseline Characteristics
Placebo
(N=157)
AMG 145
(N=474)
Age, years, mean (SD)
60 (9)
61 (10)
Sex, female, %
54%
50%
Race, white, %
94%
87%
124 (29)
123 (27)
LDL < 130 mg/dL, %
66%
65%
Ezetimibe, %
10%
9%
Intensive statin regimen*, %
25%
31%
Diabetes mellitus, %
11%
18%
30 (5)
30 (6)
27%
31%
450 (124)
443 (126)
Characteristic
LDL, mg/dL, mean (SD)
Body mass index (kg/M2), mean (SD)
Coronary artery disease, %
Free PCSK9 (ng/mL), mean (SD)
P = NS
for all
comparisons
*rosuvastatin ≥20 mg, atorvastatin ≥40 mg, simvastatin 80 mg or ezetimibe + any statin
An Academic Research Organization of
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Primary Endpoint:
AMG 145 Reduced LDL-C at 12 wks
AMG 145 Q2W
70 mg
N = 79
105 mg
N = 79
AMG 145 Q4W
140 mg
N = 78
280 mg
N = 79
350 mg
N = 79
420 mg
N = 80
* p < 0.0001 for each dose vs placebo
LDL-C at 12 wks
Mean (mg/dL) 73
(SD)
(25)
53
44
69
60
58
(21)
(25)
(28)
(23)
(26)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
NOTE: LDL-C measured using ultracentrifugation in a central core laboratory
% Reduction in LDL with Top 2
AMG 145 Doses: Major Subgroups
140 mg Q2W dose of AMG 145
reduced LDL at 12 weeks ranging
from 56-74% in key subgroups
-66% (-71, -61)
Baseline
Characteristics
All patients
420 mg Q4W dose of AMG 145
reduced LDL at 12 weeks ranging
from 38-57% in key subgroups
-50% (-56, -45)
*
UC = Ultra centrifugation
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
* Pinteraction = 0.048, all others >0.05
AMG 145 Q2W Dose Response:
% Change in LDL-C Through 12 Wks
Mean % Change from Baseline in
Calculated LDL-C
10
0
–10
–20
p < 0.0001 for weeks 2-12 for each dose vs placebo
–30
–40
–50
–60
–70
–80
–90
–100
Study Drug
Administration
number of
patients
78
79
79
78
74
78
76
77
77
77
76
76
78
75
77
77
Baseline
Week 2
Week 4
Week 6
Placebo Q2W (n = 78)
AMG145 105 mg Q2W (n = 79)
An Academic Research Organization of
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76
76
73
75
Week 8
77
76
77
76
74
76
74
73
Week 10
Week 12
AMG145 70 mg Q2W (n = 79)
AMG145 140 mg Q2W (n = 78)
LDL-C calculated using the Friedewald equation
AMG 145 Q4W Dose Response:
% Change in LDL-C Through 12 Wks
Mean % Change from Baseline in
Calculated LDL-C
10
0
–10
–20
p < 0.0001 for weeks 2-12 for each dose vs placebo
–30
–40
–50
–60
–70
–80
–90
–100
Study Drug
Administration
number of
patients
77
79
79
80
71
75
70
69
77
77
78
78
76
74
72
76
Baseline
Week 2
Week 4
Week 6
Study Week
Placebo Q4W (n = 77)
AMG145 350 mg Q4W (n = 79)
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75
77
76
74
Week 8
75
74
74
76
Week 10
76
78
77
77
Week 12
AMG145 280 mg Q4W (n = 79)
AMG145 420 mg Q4W (n = 80)
LDL-C calculated using the Friedewald equation
AMG 145 Dose Response:
% Change in LDL-C Wks 8-12 (placebo adjusted)
0
Percentage Change in Calculated
LDL-C vs. Placebo, Mean (SE)
–10
Week 8
Week 9
Week 10
Week 11
Week 12
–20
–30
–40
–50
–60
–70
–80
Study Drug
Administration
–90
–100
70 mg
280
mg
105 mg
350
140 mg
420
22
n = 25
25
n = 27
29
n = 27
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
7
n=6
11
n = 10
16
n = 17
23
n = 25
28
n = 26
30
n = 26
n = 16
15
n = 18
20
n = 19
22
n = 26
28
n = 27
27
n = 28
LDL-C calculated using the Friedewald equation
Secondary Results at 12 Wks
with Top 2 AMG 145 Doses
-33%
-32%
-43%
-48%
-44%
-61%
-36%
-56%
P < 0.0001 versus placebo for all parameters
Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
-43%
-42%
-48%
-53%
Safety
Q2W Dose Groups
Adverse Events,
Patient Incidence,
n
Placebo
AMG 145
105 mg
N=79
Q4W Dose Groups
140 mg
N=78
Placebo
N=77
280 mg
N=79
AMG 145
350 mg
N=79
420 mg
N=80
Total
N=629
N=78
70 mg
N=79
Adverse events
33
41
52
43
38
45
48
48
348
Serious AE
4
0
1
4
0
2
2
2
15
Lead to drug DC
0
0
0
2*
0
0
0
0
2
7
4
9
4
4
6
7
9
50↑
0
0
0
0
0
0
0
0
0
Injection site rxn
2
1
1
0
1
2
3
1
11
AST or ALT >3x ULN
1
0
0
0
0
0
0
0
1
CPK >5X ULN
0
1
1
1
0
0
0
1
4**
CV events‡
1
1
0
4
0
1
1
0
Death
0
0
0
1
0
0
0
0
Drug related AEs
Lead to drug DC
8
1
*Both events were reported as non-serious by the investigators.
†All 50 were reported as non-serious by the investigator and none led to discontinuation of drug
** All were asymptomatic
‡Acute coronary syndrome, coronary revascularization, TIA, congestive heart failure requiring hospitalization, or death
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Summary & Conclusion
In patients with hypercholesterolemia on a stable regimen
of statin ± ezetimibe, SC AMG 145 for 12 weeks:
• Reduced LDL-C (ultracentrifugation) by up to 66% at the end of the
dosing interval compared to placebo
• Reduced calculated LDL-C by up to 85% 1 week post dose
• Reduced total and non-HDL cholesterol, apo B, TC/HDL, Apo B/A1
• Well-tolerated with no dose-related increase in adverse events
PCSK9 inhibition with AMG 145 offers
a new paradigm for LDL-C reduction that warrants testing
in a large, phase III cardiovascular outcomes trial
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
THE LANCET
Lancet 2012:380 (online first).
Available on line at www.thelancet.com
Thank you to our investigators and coordinators, data safety
committee members, clinical endpoint committee members, core
laboratories, operational teams, monitors, and sponsor