laplace-timi 57 primary resultsprimary endpoint an academic research organization of brigham and...

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


* 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



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)


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)

*


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


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


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


280 mg350 mg

n = 25 n = 6 n = 25 n = 16 n = 26n = 27 n = 10 n = 26 n = 18 n = 27


–100

–90Pe L


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%


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


*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


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

laplace-timi 57 primary resultsprimary endpoint an academic research organization of brigham and...

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