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 Womens Hospital
Harvard Medical School, Boston, MA
Supported by research grant from Amgen, Inc.
An Academic Research Organization of
Brigham and Womens 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 Womens 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 Womens Hospital and Harvard Medical School

Kohli P, et al. Clin Cardiol. 2012;35:385-391.

Major Entry Criteria

Age 1880 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 Womens 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%

Body mass index (kg/M2), mean (SD)

30 (5)

30 (6)

Coronary artery disease, %

27%

31%

450 (124)

443 (126)

Characteristic

LDL, mg/dL, mean (SD)

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
Brigham and Womens Hospital and Harvard Medical School

Primary Endpoint:
AMG 145 Reduced LDL-C at 12 wks
AMG 145 Q2W

% Change LDL-C vs Placebo (SE) at Week 12

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

-10
-20

* p < 0.0001 for each dose vs placebo

-30
-40
-50

-41.8

-41.8
-50.0

-60
-70

-50.3

-60.2
-66.1

-80
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 Womens 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 Womens 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

Brigham and Womens Hospital and Harvard Medical School

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)
An Academic Research Organization of
Brigham and Womens Hospital and Harvard Medical School

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
105 mg
140 mg

n = 22
n = 25
n = 29

An Academic Research Organization of

Brigham and Womens Hospital and Harvard Medical School

n=7
n = 11
n = 16

n = 23
n = 28
n = 30

n = 16
n = 15
n = 20

n = 22
n = 28
n = 27

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
100 280 mg
350 mg
420 mg

n = 25
n = 27
n = 27

An Academic Research Organization of

Brigham and Womens Hospital and Harvard Medical School

n=6
n = 10
n = 17

n = 25
n = 26
n = 26

n = 16
n = 18
n = 19

n = 26
n = 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 Womens Hospital and Harvard Medical School

-43%

-42%

-48%

-53%

Safety
Q2W Dose Groups
Adverse
Events, Patient
Incidence, n

Placebo

Q4W Dose Groups

140 mg
N=78

Placebo

N=78

70 mg
N=79

AMG 145
105 mg
N=79

N=77

280 mg
N=79

AMG 145
350 mg
N=79

420 mg
N=80

Total
N=629

Adverse events

33

41

52

43

38

45

48

48

348

Serious AE

15

Lead to drug DC

2*

50

Injection site rxn

11

AST or ALT >3x ULN

CPK >5X ULN

4**

CV events

Death

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 Womens 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 Womens 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