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
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
March 29, 2014, Featured Clinical Research Session 400
American College of Cardiology, Washington DC
Background: Heterozygous Familial
Hypercholesterolemia (HeFH)
 HeFH is characterized by markedly elevated low-density
lipoprotein cholesterol (LDL-C), and if untreated, is
associated with significant premature cardiovascular
morbidity and mortality.1
 HeFH is most commonly caused by loss-of-function
mutations in the LDLR gene.2
 Although current treatments (e.g., statins +/- ezetimibe,
bile acid sequestrants and/or niacin) can produce
reductions in LDL-C of 50% – 65%, many HeFH patients
are still unable to achieve recommended LDL-C targets.3
1. Eur Heart J 2013;34:3478-90
2. Ann Human Genet. 2008;72:485-98.
3. J Clin Lipidol. 2007;1:280-6.
2
The RUTHERFORD-2 Study
 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
3
RUTHERFORD-2 Study Design
Evolocumab 420 mg SC QM
N = 110
End of Study
Screening
Period
with
Placebo
Injection
Randomization
Evolocumab 140 mg SC Q2W
N = 111a
2:2:1:1
Placebo SC Q2W
N = 55a
Placebo SC QM
N = 55
Max. 6 weeks
Day 1
Week 2
Week 4b
Week 6b
Week
Week 10
Week 12
Week 14c
Evolocumab or placebo SC Q2W
Evolocumab or placebo SC QM
a
b
c
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
Injections at weeks 4 and 6 were done at home
Week 14 was a follow-up call for Q2W patients to capture adverse events and concomitant medications
Q2W, biweekly; QM, monthly; SC, subcutaneous
4
RUTHERFORD-2: Baseline Characteristics
Placebo Q2W
(N = 54)
Evolocumab
140 mg Q2W
(N = 110)
Placebo QM
(N = 55)
Evolocumab
420 mg QM
(N = 110)
51 (14)
53 (12)
47 (12)
52 (12)
Female, %
46
40
44
42
Race: white, %
93
90
89
89
431 (124)
458 (145)
441 (146)
436 (139)
Definite
83
77
78
76
Probable
17
23
22
24
Statin use, %
100
100
100
100
Ezetimibe use, %
61
61
66
62
Characteristic
Age (years), mean (SD)
PCSK9 (ng/mL), mean (SD)
HeFH classificationa, %
a
Based on Simon Broome criteria
HeFH, heterozygous familial hypercholesterolemia; Q2W, biweekly; QM, monthly; SD, standard deviation
5
RUTHERFORD-2: Baseline Lipids
Characteristic
Placebo Q2W
(N = 54)
Evolocumab
140 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
6
RUTHERFORD-2: Mean % Change in LDL-Ca from Baseline
to the Mean of Weeks 10 and 12, and Week 12 Alone
Adjusted Mean Percent Change ± SE from Baseline
Weeks 10 and 12
10
Week 12
20
2%
0
-10
6%
10
0
-1%
-10
-20
-2%
-20
-30
-30
-40
-40
-50
-50
-60
-60
-61%
-70
-60%b
-63%
-66%b
-61%
-70
-59%b
-56%
-61%b
Placebo Q2W (N = 54)
Placebo QM (N = 55)
Evolocumab 140 mg Q2W (N = 110)
Evolocumab 420 mg QM (N = 110)
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
7
LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly; SE, standard error
RUTHERFORD-2: LDL-Ca Goal Achievement
< 70 mg/dL
Weeks 10 and 12
Week 12
79%b
66%b
61%b
65%b
90
80
80%
Proportion of Patients (%)
80
68%
70
63%
67%
70
60
60
50
50
40
40
30
30
20
20
10
10
2%
0
2%
2%
2%
0
Placebo Q2W (N = 54)
Placebo QM (N = 55)
Evolocumab 140 mg Q2W (N = 110)
Evolocumab 420 mg QM (N = 110)
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 factors
8
LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly
RUTHERFORD-2: Placebo-adjusted Treatment Differences
in Other Lipids from Baseline to Week 12
Treatment Difference
% Mean ± SE
Treatment Difference
% Mean ± SE
-14
-24
-34
-44
-54
HDL-C
Triglycerides
-4
-49%
-49%
9%
9%
14
12
10
8
6
4
2
0
Treatment Difference
% Mean ± SE
ApoA1
0
-5
-10
-15
-25
Lp(a)
9%
-5
-10
-15
-20
-25
-30
-35
6
4
2
0
-32%
-28%
Evolocumab 140 mg Q2W vs. placebo
Evolocumab 420 mg QM vs. placebo
10
8
-20%
0
-40
12
-12%
-20
-30
Treatment Difference
% Mean ± SE
Treatment Difference
% Mean ± SE
ApoB
4%
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), 9
lipoprotein (a); SE, standard error
RUTHERFORD-2: Safety and Tolerability
Adverse events (AEs), n (%)
Treatment-emergent AEs
Most common AEs in Evolocumab Patientsa
Nasopharyngitis
Headache
Contusion
Back pain
Nausea
Arthralgia
Serious AEs
AEs leading to discontinuation of study drug
Deaths
Potential injection-site reactionsb
Neurocognitive AEsc
Muscle-related SMQd
Anti-evolocumab antibodies,e %
Placebo
(N = 109)
Evolocumab
(N = 220)
53 (48.6)
124 (56.4)
5 (4.6)
4 (3.7)
1 (0.9)
1 (0.9)
1 (0.9)
2 (1.8)
5 (4.6)
0 (0.0)
0 (0.0)
4 (3.7)
0 (0.0)
1 (0.9)
-
19 (8.6)
9 (4.1)
9 (4.1)
8 (3.6)
8 (3.6)
8 (3.6)
7 (3.2)
0 (0.0)
0 (0.0)
13 (5.9)
0 (0.0)
10 (4.5)
0.0
Occurring in ≥ 3.5% of evolocumab-treated patients
Reported using high-level term grouping, which includes injection site (IS) rash, IS inflammation, IS pruritus, IS reaction, and IS urticaria
c 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
10
a
b
RUTHERFORD-2: Key Laboratory Results
Laboratory Results
ALT or AST > 3 × ULN at any
post-baseline visit, %
CK > 5 × ULN at any
post-baseline visit, %
CK > 10 × ULN at any
post-baseline visit, %
Placebo
(N = 109)
Evolocumab
(N = 220)
0.0
0.0
1.8
0.0
0.9
0.0
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; ULN, upper limit of normal
11
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
12
lipoproteins.
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.
13