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LAPLACE-TIMI 57 Primary ResultsyA 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
R b t P Gi li MD SM FAHA FACCRobert P. Giugliano, MD, SM, FAHA, FACCTIMI Study Group, Cardiovascular Division
Brigham and Women’s Hospitalg pHarvard Medical School, Boston, MA
S t d b h t f A I
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
Supported by research grant from Amgen, Inc.
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.
(Dias CS, JACC published online Oct 17, 2012. http://dx.doi.org/10.1016/j.jacc.2012.08.986)
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 ( i SC Q2 Q4 k ) l b i(given SC Q2 or Q4 weeks) vs placebo in stable patients with hypercholesterolemia on a statin ± ezetimibe:a statin ± ezetimibe: – Primary: % change in LDL-C*
– Secondary: changes in other lipoproteinspharmacokinetics/pharmacodynamicstolerability and safety
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
* measured using ultracentrifugation in a central core laboratory
Study Design78 centers5 countries
70 mg AMG 145 SC Q2W
Placebo SC Q2W 78 Subjects
Screening and Placebo Run-in
Period
S b t
g79 Subjects
105 mg AMG 145 SC Q2W 79 Subjects
140 mg AMG 145 SC Q2W 78 S bj tSubcutaneous
injection of 6 mL placebo
Fasting LDL-C 5-10 days
78 Subjects
280 mg AMG 145 SC Q4W
Placebo SC Q4W 77 Subjects
5-10 days before
randomization
Maximum 6 weeks
280 mg AMG 145 SC Q4W 79 Subjects
350 mg AMG 145 SC Q4W 79 Subjects
420 mg AMG 145 SC Q4W SMaximum 6 weeks
Day 1Visits: Week 2 Week 8 Week 12Week 6Week 4 Week 10 Week 14
Q2W:
80 Subjects
Q4W:Primary
Endpoint
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Kohli P, et al. Clin Cardiol. 2012;35:385‐391.
934 screened 631 random. 629 treated( *2 subjects assigned placebo Q4W received no study drug)
Q4W: pAssessed
Major Entry Criteria
• Age 18–80 yearsSt bl d f t ti ± ti ib f 4 k• Stable dose of statin ± ezetimibe for 4 wks
• Fasting LDL-C ≥ 85 mg/dLFasting triglycerides ≤ 400 mg/dL• Fasting triglycerides ≤ 400 mg/dL
• No other prescription lipid lowering therapy• No recent ACS revascularization stroke• 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
Characteristic Placebo(N=157)
AMG 145(N=474)
Age, years, mean (SD) 60 (9) 61 (10)
Sex, female, % 54% 50%
Race white % 94% 87%Race, white, % 94% 87%
LDL, mg/dL, mean (SD) 124 (29) 123 (27)
LDL < 130 mg/dL, % 66% 65%
P = NS for all comparisons
Ezetimibe, % 10% 9%
Intensive statin regimen*, % 25% 31%
Diabetes mellitus, % 11% 18%
co pa so s
Body mass index (kg/M2), mean (SD) 30 (5) 30 (6)
Coronary artery disease, % 27% 31%
Free PCSK9 (ng/mL) mean (SD) 450 (124) 443 (126)
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
Free PCSK9 (ng/mL), mean (SD) 450 (124) 443 (126)
*rosuvastatin ≥20 mg, atorvastatin ≥40 mg, simvastatin 80 mg or ezetimibe + any statin
Primary Endpoint: AMG 145 Reduced LDL-C at 12 wksAMG 145 Reduced LDL-C at 12 wks
70 mgN = 79
105 mgN = 79
140 mgN = 78
280 mgN = 79
350 mgN = 79
420 mgN = 80
AMG 145 Q2W AMG 145 Q4W
20
-10
0
t Wee
k 12
N = 79 N = 79 N = 78 N = 79 N = 79 N = 80
* p < 0 0001 for each dose vs placebo
-40
-30
-20
Plac
ebo
(SE)
a p < 0.0001 for each dose vs placebo
-41.8 -41.8-50.0 -50.3-60
-50
40
ge L
DL-
C v
s P
-60.2-66.1
-80
-70
% C
hang
LDL C at 12 wks
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
LDL-C at 12 wksMean (mg/dL)
(SD)73 (25)
53 (21)
44 (25)
69 (28)
60 (23)
58 (26)
% Reduction in LDL with Top 2 AMG 145 Doses: Major SubgroupsAMG 145 Doses: Major Subgroups
140 mg Q2W dose of AMG 145 reduced LDL at 12 weeks ranging
from 56-74% in key subgroups
420 mg Q4W dose of AMG 145 reduced LDL at 12 weeks ranging
from 38-57% in key subgroupsBaseline
Characteristicsy g p y g p
All patients-66% (-71, -61) -50% (-56, -45)
*
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
UC = Ultra centrifugation* Pinteraction = 0.048, all others >0.05
AMG 145 Q2W Dose Response:% Change in LDL-C Through 12 Wks% Change in LDL C Through 12 Wks
0
10
in
p < 0.0001 for weeks 2-12 for each dose vs placebo–30
–20
–10
0
m B
asel
ine
iD
L-C
–60
–50
–40
–30
Cha
nge
from
alcu
late
d LD
–90
–80
–70
Mea
n %
C Ca
number ofpatients
797978
78787677
74777676
77757777
78767375
76767776
77767473
74
Study DrugAdministration
Placebo Q2W (n = 78) AMG145 70 mg Q2W (n = 79)
Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12–100
78 77 76 77 75 76 73
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
Placebo Q2W (n = 78) AMG145 70 mg Q2W (n = 79)AMG145 105 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
0
10
in
% Change in LDL C Through 12 Wks
–30
–20
–10
0
m B
asel
ine
iD
L-C p < 0.0001 for weeks 2-12 for each dose vs placebo
–60
–50
–40
–30
Cha
nge
from
alcu
late
d LD
–90
–80
–70
Mea
n %
C Ca
7979
777570
717778
777472
767776
757474
757877
76
number ofpatients
Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12Study Week
–1009
800
698
78 766
74 76 77
Study DrugAdministration
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School LDL-C calculated using the Friedewald equation
Placebo Q4W (n = 77) AMG145 280 mg Q4W (n = 79)AMG145 350 mg Q4W (n = 79) AMG145 420 mg Q4W (n = 80)
AMG 145 Dose Response:% Change in LDL-C Wks 8-12 (placebo adjusted)% Change in LDL C Wks 8 12 (placebo adjusted)
–10
0Week 8 Week 9 Week 10 Week 11 Week 12
–30
–20
Cal
cula
ted
ean
(SE
)
–60
–50
–40
Cha
nge
in C
Pla
cebo
, Me
–80
–70
–60
erce
ntag
e C
LDL-
C v
s. P
70 mg105 mg
n = 22 n = 7 n = 23 n = 16 n = 22n = 25 n = 11 n = 28 n = 15 n = 28
Study DrugAdministration
280 mg350 mg
n = 25 n = 6 n = 25 n = 16 n = 26n = 27 n = 10 n = 26 n = 18 n = 27
Study DrugAdministration
–100
–90Pe L
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
105 mg140 mg
n = 25 n = 11 n = 28 n = 15 n = 28n = 29 n = 16 n = 30 n = 20 n = 27
350 mg420 mg
n = 27 n = 10 n = 26 n = 18 n = 27n = 27 n = 17 n = 26 n = 19 n = 28
LDL-C calculated using the Friedewald equation
Secondary Results at 12 Wks with Top 2 AMG 145 Doseswith Top 2 AMG 145 Doses
33%-43%
-33%
-61%
-48% -44%-32%
-48%-36%
-56%
-42%-53%
-43%
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
P < 0.0001 versus placebo for all parametersQ2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error
Safety
Adverse Events, Patient Incidence,
Q2W Dose Groups Q4W Dose Groups
PlaceboAMG 145
PlaceboAMG 145
70 mg 105 mg 140 mg 280 mg 350 mg 420 mg Totaln N=78 N=77
gN=79
gN=79
gN=78
gN=79
gN=79
gN=80 N=629
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
Drug related AEs 7 4 9 4 4 6 7 9 50↑
L d t d DC 0 0 0 0 0 0 0 0 0Lead to drug DC 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 8
Death 0 0 0 1 0 0 0 0 1
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
*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
Summary & Conclusion
In patients with hypercholesterolemia on a stable regimen f t ti ± ti ib SC AMG 145 f 12 kof 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• Well-tolerated with no dose-related increase in adverse events
PCSK9 inhibition with AMG 145 offersdi f LDL C d ti th t t t tia 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 LANCETTHE LANCET
Lancet 2012:380 (online first)Lancet 2012:380 (online first). Available on line at www.thelancet.com
Thank you to our investigators and coordinators data safetyThank you to our investigators and coordinators, data safety committee members, clinical endpoint committee members, core
laboratories, operational teams, monitors, and sponsor