LAPLACE-TIMI 57 Primary Results y A Double-blind, Randomized, - - PowerPoint PPT Presentation

LAPLACE-TIMI 57 Primary Results y

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

R b t P Gi li MD SM FAHA FACC Robert P. Giugliano, MD, SM, FAHA, FACC

TIMI Study Group, Cardiovascular Division Brigham and Women’s Hospital g p Harvard 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 lipoproteins pharmacokinetics/pharmacodynamics tolerability 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 Design

78 centers 5 countries

70 mg AMG 145 SC Q2W Placebo SC Q2W 78 Subjects

Screening and Placebo Run-in Period S b t

g 79 Subjects 105 mg AMG 145 SC Q2W 79 Subjects 140 mg AMG 145 SC Q2W 78 S bj t

Subcutaneous 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 S

Maximum 6 weeks

Day 1 Visits: Week 2 Week 8

Week 12

Week 6 Week 4 Week 10 Week 14

Q2W:

80 Subjects

Q4W: Primary Endpoint

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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: p Assessed

Major Entry Criteria

• Age 18–80 years

St bl d f t ti ± ti ib f 4 k

• Stable dose of statin ± ezetimibe for 4 wks
• Fasting LDL-C ≥ 85 mg/dL

Fasting 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)

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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 wks AMG 145 Reduced LDL-C at 12 wks

70 mg N = 79 105 mg N = 79 140 mg N = 78 280 mg N = 79 350 mg N = 79 420 mg N = 80

AMG 145 Q2W AMG 145 Q4W 20

• 10

t Week 12

N = 79 N = 79 N = 78 N = 79 N = 79 N = 80

* p < 0 0001 for each dose vs placebo

• 40
• 30
• 20

Placebo (SE) a

p < 0.0001 for each dose vs placebo

• 41.8
• 41.8
• 50.0
• 50.3
• 60
• 50

40

ge LDL-C vs P

• 60.2
• 66.1
• 80
• 70

% Chang

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 wks Mean (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 Subgroups AMG 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 subgroups Baseline Characteristics y g p y g p

All patients

• 66% (-71, -61)
• 50% (-56, -45)

*

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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

10

in

p < 0.0001 for weeks 2-12 for each dose vs placebo

–30 –20 –10

m Baseline i DL-C

–60 –50 –40 –30

Change from alculated LD

–90 –80 –70

Mean % C Ca

number of

patients 79 79 78 78 78 76 77 74 77 76 76 77 75 77 77 78 76 73 75 76 76 77 76 77 76 74 73 74

Study Drug Administration

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

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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

10

in

% Change in LDL C Through 12 Wks

–30 –20 –10

m Baseline i DL-C

p < 0.0001 for weeks 2-12 for each dose vs placebo

–60 –50 –40 –30

Change from alculated LD

–90 –80 –70

Mean % C Ca

79 79 77 75 70 71 77 78 77 74 72 76 77 76 75 74 74 75 78 77 76 number of patients

Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Study Week –100

9 80 69 8 78 76 6 74 76 77

Study Drug Administration

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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 Week 8 Week 9 Week 10 Week 11 Week 12 –30 –20

Calculated ean (SE)

–60 –50 –40

Change in C Placebo, Me

–80 –70 –60

ercentage C LDL-C vs. P

70 mg 105 mg n = 22 n = 7 n = 23 n = 16 n = 22 n = 25 n = 11 n = 28 n = 15 n = 28

Study Drug Administration

280 mg 350 mg n = 25 n = 6 n = 25 n = 16 n = 26 n = 27 n = 10 n = 26 n = 18 n = 27

Study Drug Administration

–100 –90

Pe L

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105 mg 140 mg n = 25 n = 11 n = 28 n = 15 n = 28 n = 29 n = 16 n = 30 n = 20 n = 27 350 mg 420 mg n = 27 n = 10 n = 26 n = 18 n = 27 n = 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 Doses with Top 2 AMG 145 Doses

33%

• 43%
• 33%
• 61%
• 48%
• 44%
• 32%
• 48%
• 36%
• 56%
• 42%
• 53%
• 43%

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P < 0.0001 versus placebo for all parameters Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error

Safety

Adverse Events, Patient Incidence,

Q2W Dose Groups Q4W Dose Groups

Placebo AMG 145 Placebo AMG 145 70 mg 105 mg 140 mg 280 mg 350 mg 420 mg Total n N=78 N=77 g N=79 g N=79 g N=78 g N=79 g N=79 g N=80 N=629 Adverse events 33 41 52 43 38 45 48 48 348 Serious AE 4 1 4 2 2 2 15 Lead to drug DC 2* 2 Drug related AEs 7 4 9 4 4 6 7 9 50↑ L d t d DC Lead to drug DC Injection site rxn 2 1 1 1 2 3 1 11 AST or ALT >3x ULN 1 1 CPK >5X ULN 1 1 1 1 4** CV events‡ 1 1 4 1 1 8 Death 1 1

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*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 k

• f 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 offers di f LDL C d ti th t t t ti 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 THE 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 safety Thank you to our investigators and coordinators, data safety committee members, clinical endpoint committee members, core laboratories, operational teams, monitors, and sponsor