Frederick Raal,1 Robert Dufour,2 Traci Turner,3 Fernando Civeira,4 Lesley Burgess,5 Gisle Langslet,6 Russell Scott,7 Anders G. Olsson,8 David Sullivan,9 Gerard K. Hovingh,10 Bertrand Cariou,11 Ioanna Gouni-Berthold,12 Ransi Somaratne,13 Ian

Bridges,14 Rob Scott,13 Scott M. Wasserman,13 and Daniel Gaudet15 for the RUTHERFORD-2 Investigators

1Carbohydrate & Lipid Metabolism Research Unit, University of Witwatersrand, Johannesburg, South Africa; 2Institut de Recherches Cliniques de Montreal, Universite de Montreal, Quebec, Canada; 3Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA; 4Hospital Universitario Miguel Servet, Zaragoza, Spain; 5TREAD Research, Cardiology Unit, Department of Internal Medicine, University of Stellenbosch, Parow, South Africa; 6Lipid Clinic, Oslo University Hospital, Oslo, Norway; 7Lipid and Diabetes Research Group, Christchurch, New Zealand; 8Linkoping University and Stockholm Heart Center, Stockholm, Sweden; 9Department of Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, Australia; 10Academisch Medisch Centrum, Vascular Medicine, Amsterdam, The Netherlands; 11Institut du Thorax, Nantes University Hospital, Nantes, France; 12Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany; 13Amgen Inc., Thousand Oaks, CA, USA; 14Amgen Ltd, Uxbridge, United Kingdom; 15ECOGENE-21, Dyslipidemia, Diabetes and Atherosclerosis Research Group, Department of Medicine, Université de Montréal, Chicoutimi, Québec, Canada

The Addition of Evolocumab (AMG 145) Allows the Majority of Heterozygous Familial Hypercholesterolemic Patients to Achieve Low-density Lipoprotein Cholesterol Goals - Results from the Phase 3 Randomized, Double-blind, Placebo-controlled Study

March 29, 2014, Featured Clinical Research Session 400American College of Cardiology, Washington DC

Background: Heterozygous Familial Hypercholesterolemia (HeFH)

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The RUTHERFORD-2 Study

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Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (NCT20110117)

Design: A 12-week, randomized, double-blind, placebo-controlled,

multicenter phase 3 study

Objective: To evaluate the efficacy and safety of evolocumab (AMG 145) 140 mg Q2W and 420 mg QM administered subcutaneously in a large cohort of HeFH patients unable to achieve an LDL-C < 100 mg/dL despite statin therapy with or without ezetimibe

RUTHERFORD-2 Study Design

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Screening Period

with Placebo Injection

Evolocumab 140 mg SC Q2WN = 111a

Placebo SC QMN = 55

Placebo SC Q2WN = 55aR

and

om

izat

ion

Day 1 Week 2 Week 4b Week 6b Week Week 10 Week 12 Week 14cMax. 6 weeks

Evolocumab or placebo SC Q2W

Evolocumab or placebo SC QM

Evolocumab 420 mg SC QMN = 110

En

d o

f S

tud

y

2:2:1:1

a N’s are number of patients randomized. One patient in each of the placebo Q2W and evolocumab Q2W groups did not receive any doses of the study drug and were not included in the analyses

b Injections at weeks 4 and 6 were done at homec Week 14 was a follow-up call for Q2W patients to capture adverse events and concomitant medications

Q2W, biweekly; QM, monthly; SC, subcutaneous

RUTHERFORD-2: Baseline Characteristics

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CharacteristicPlacebo Q2W

(N = 54)

Evolocumab 140 mg Q2W

(N = 110)

Placebo QM (N = 55)

Evolocumab 420 mg QM (N = 110)

Age (years), mean (SD) 51 (14) 53 (12) 47 (12) 52 (12)

Female, % 46 40 44 42

Race: white, % 93 90 89 89

PCSK9 (ng/mL), mean (SD) 431 (124) 458 (145) 441 (146) 436 (139)

HeFH classificationa, %

Definite 83 77 78 76

Probable 17 23 22 24

Statin use, % 100 100 100 100

Ezetimibe use, % 61 61 66 62

HeFH, heterozygous familial hypercholesterolemia; Q2W, biweekly; QM, monthly; SD, standard deviation

a Based on Simon Broome criteria

RUTHERFORD-2: Baseline Lipids

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CharacteristicPlacebo Q2W

(N = 54)

Evolocumab140 mg Q2W

(N = 110)

Placebo QM (N = 55)

Evolocumab 420 mg QM (N = 110)

LDL-Ca (mg/dL),mean (SD)

151 (37) 161 (51) 152 (43) 154 (43)

ApoB (mg/dL),mean (SD)

114 (30) 119 (31) 110 (22) 115 (26)

HDL-C (mg/dL),mean (SD)

53 (17) 50 (16) 49 (13) 52 (16)

ApoA1 (mg/dL),mean (SD)

145 (28) 142 (34) 135 (24) 143 (29)

Triglycerides (mg/dL), median (Q1, Q3)

96 (75, 143) 119 (87, 161) 102 (79, 151) 113 (85, 157)

Lp(a) (nmol/L), median (Q1, Q3)

44 (24, 105) 78 (29, 206) 87 (36, 219) 61 (17, 194)

a Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 40 mg/dL or triglyceride levels were > 400 mg/dL

Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein (a); Q2W, biweekly; QM, monthly; SD, standard deviation

RUTHERFORD-2: Mean % Change in LDL-Ca from Baseline to the Mean of Weeks 10 and 12, and Week 12 Alone

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Weeks 10 and 12

a Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 40 mg/dL or triglyceride levels were > 400 mg/dL

b P < 0.001; placebo-adjusted treatment difference analyzed using repeated measures model which included treatment group, stratification factors (from IVRS), scheduled visit and the interaction of treatment with scheduled visit as covariates

LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly; SE, standard error

Ad

jus

ted

Me

an

Pe

rce

nt

Ch

an

ge

± S

E f

rom

B

as

eli

ne

Placebo Q2W (N = 54) Placebo QM (N = 55) Evolocumab 140 mg Q2W (N = 110) Evolocumab 420 mg QM (N = 110)

-1%

-60%b

-61%

2%

-63%

-66%b -59%b -61%b

-2%

6%

-56%-61%

Week 12

RUTHERFORD-2: LDL-Ca Goal Achievement < 70 mg/dL

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a Determined by the Friedewald formula with reflexive testing via preparative ultracentrifugation when calculated LDL-C was < 40 mg/dL or triglyceride levels were > 400 mg/dL

b P < 0.001; analyzed using CMH test, stratified by the stratification factorsLDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly

Pro

po

rtio

n o

f P

atie

nts

(%

)

Weeks 10 and 12 Week 12

2%

67%

80%

2% 2%

68%

2%

63%

Placebo Q2W (N = 54) Placebo QM (N = 55) Evolocumab 140 mg Q2W (N = 110) Evolocumab 420 mg QM (N = 110)

61%b65%b

79%b

66%b

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RUTHERFORD-2: Placebo-adjusted Treatment Differences in Other Lipids from Baseline to Week 12

HDL-C

TriglyceridesApoB

ApoA1

Lp(a)

All evolocumab vs. placebo treatment differences were statistically significant at the P < 0.001 level (except for ApoA1, which was not part of the testing hierarchy); adjusted for multiplicity

No notable difference were observed between the means of Weeks 10 and 12 and Week 12 alone

Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; Lp(a), lipoprotein (a); SE, standard error

Evolocumab 140 mg Q2W vs. placeboEvolocumab 420 mg QM vs. placebo

Tre

atm

ent

Dif

fere

nce

% M

ean

± S

E

-49% -49%

9%

9%

4%

-20%

-12%

-32%-28%

9%

Tre

atm

ent

Dif

fere

nce

% M

ean

± S

ET

reat

men

t D

iffe

ren

ce%

Mea

n ±

SE

Tre

atm

ent

Dif

fere

nce

% M

ean

± S

ET

reat

men

t D

iffe

ren

ce%

Mea

n ±

SE

RUTHERFORD-2: Safety and Tolerability

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Adverse events (AEs), n (%)Placebo(N = 109)

Evolocumab (N = 220)

Treatment-emergent AEs 53 (48.6) 124 (56.4)Most common AEs in Evolocumab Patientsa

Nasopharyngitis 5 (4.6) 19 (8.6)Headache 4 (3.7) 9 (4.1)Contusion 1 (0.9) 9 (4.1)Back pain 1 (0.9) 8 (3.6)Nausea 1 (0.9) 8 (3.6)Arthralgia 2 (1.8) 8 (3.6)

Serious AEs 5 (4.6) 7 (3.2)AEs leading to discontinuation of study drug 0 (0.0) 0 (0.0)Deaths 0 (0.0) 0 (0.0)Potential injection-site reactionsb 4 (3.7) 13 (5.9)

Neurocognitive AEsc 0 (0.0) 0 (0.0)Muscle-related SMQd 1 (0.9) 10 (4.5)Anti-evolocumab antibodies,e % - 0.0

a Occurring in ≥ 3.5% of evolocumab-treated patientsb Reported using high-level term grouping, which includes injection site (IS) rash, IS inflammation, IS pruritus, IS reaction, and IS urticariac Searched HLGT terms: Deliria (incl confusion); cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and perception; mental impairment disorders.d Standard Medical Dictionary for Regulatory Activities (MedDRA) Queries. e Binding or neutralizing

RUTHERFORD-2: Key Laboratory Results

11ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; ULN, upper limit of normal

Laboratory ResultsPlacebo(N = 109)

Evolocumab (N = 220)

ALT or AST > 3 × ULN at any post-baseline visit, %

0.0 0.0

CK > 5 × ULN at any post-baseline visit, %

1.8 0.0

CK > 10 × ULN at any post-baseline visit, %

0.9 0.0

RUTHERFORD-2: Conclusions Evolocumab administered either biweekly or monthly yielded

significant reductions in LDL-C in HeFH patients on statins with or without ezetimibe. The mean reduction of LDL-C at Week 12 was 61% in the 140 mg Q2W and

56% in the 420 mg QM evolocumab dose groups, respectively.

The mean reduction of LDL-C at the mean of Weeks 10 and 12 was 61% in the 140 mg Q2W and 63% in the 420 mg QM evolocumab dose groups, respectively.

Evolocumab 140 mg biweekly and 420 mg monthly dosing regimens were clinically equivalent.

The majority of patients achieved LDL-C targets.

Evolocumab treatment resulted in favorable changes in other lipoproteins.

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RUTHERFORD-2: Conclusions

Evolocumab was well tolerated, with no notable difference in the AE profile compared with placebo.

The rate of nasopharyngitis and muscle-related adverse events (AEs) was higher in the evolocumab group.• The imbalance in the overall set of muscle-related AEs was not due to

significant imbalances in any individual muscle-related event (i.e., creatine kinase).

Evolocumab may offer a new and effective treatment option to further reduce LDL-C in HeFH patients.

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