The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Evinacumab in Patients with Refractory

Hypercholesterolemia
Robert S. Rosenson, M.D., Lesley J. Burgess, M.D., Ph.D.,
Christoph F. Ebenbichler, M.D., Seth J. Baum, M.D., Erik S.G. Stroes, M.D., Ph.D.,
Shazia Ali, Pharm.D., Nagwa Khilla, M.S., Robert Hamlin, B.S., Robert Pordy, M.D.,
Yuping Dong, Ph.D., Vladimir Son, Ph.D., and Daniel Gaudet, M.D., Ph.D.​​

A BS T R AC T

BACKGROUND
Patients with refractory hypercholesterolemia, who have high low-density lipopro- From the Icahn School of Medicine at
tein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maxi- Mount Sinai, New York (R.S.R.), and Re-
generon Pharmaceuticals, Tarrytown
mum tolerated doses, have an increased risk of atherosclerosis. In such patients, (S.A., N.K., R.H., R.P., Y.D., V.S.) — both
the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human in New York; TREAD Research, Cardiolo-
monoclonal antibody against angiopoietin-like 3, are not known. gy Unit, Department of Internal Medi-
cine and Tygerberg Hospital, Parow,
South Africa (L.J.B.); the Department of
METHODS Internal Medicine I, Medical University
In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or Innsbruck, Innsbruck, Austria (C.F.E.);
without heterozygous familial hypercholesterolemia who had refractory hypercho- Excel Medical Clinical Trials, Department
of Integrated Medical Sciences, Charles
lesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher E. Schmidt College of Medicine, Florida
with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Atlantic University, Boca Raton (S.J.B.);
Patients were randomly assigned to receive subcutaneous or intravenous evinacumab the Department of Vascular Medicine,
Academic Medical Center, Amsterdam
or placebo. The primary end point was the percent change from baseline in the (E.S.G.S.); and the Clinical Lipidology
LDL cholesterol level at week 16 with evinacumab as compared with placebo. and Rare Lipid Disorders Unit, Depart-
ment of Medicine, Université de Montré-
RESULTS al Community Gene Medicine Center,
In total, 272 patients were randomly assigned to the following groups: subcutaneous Montreal, and ECOGENE-21 Clinical and
Translational Research Center, Chi-
evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), coutimi, QC — both in Canada (D.G.).
or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous Address reprint requests to Dr. Rosenson
evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 pa- at Icahn School of Medicine at Mount Si-
nai, 1425 Madison Ave., MC Level, New
tients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). York, NY 10029.
At week 16, the differences in the least-squares mean change from baseline in the
This article was published on November
LDL cholesterol level between the groups assigned to receive subcutaneous evinacu­ 15, 2020, at NEJM.org.
mab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and
DOI: 10.1056/NEJMoa2031049
the placebo group were −56.0, −52.9, and −38.5 percentage points, respectively Copyright © 2020 Massachusetts Medical Society.
(P<0.001 for all comparisons). The differences between the groups assigned to
receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per
kilogram and the placebo group were −50.5 percentage points (P<0.001) and −24.2
percentage points, respectively. The incidence of serious adverse events during the
treatment period ranged from 3 to 16% across trial groups.
CONCLUSIONS
In patients with refractory hypercholesterolemia, the use of evinacumab signifi-
cantly reduced the LDL cholesterol level, by more than 50% at the maximum dose.
(Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.)

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 The n e w e ng l a n d j o u r na l
L
ifelong exposure to elevated low-
density lipoprotein (LDL) cholesterol levels
is associated with an increased risk of
atherosclerotic cardiovascular disease.1 In the
United States, approximately 7% of adults re-
ceive a diagnosis of severe hypercholesterolemia,
defined as having untreated LDL cholesterol levels
of 190 mg per deciliter (4.91 mmol per liter) or
higher.2 In one study, a familial hypercholester-
olemia mutation was present in 1.7% of 1386 pa-
tients with severe hypercholesterolemia.2 In a
meta-analysis involving 11 million adults, the
worldwide prevalence of familial hypercholester-
olemia among those with severe hypercholester-
olemia was 7.2%.3
Heterozygous familial hypercholesterolemia
is an autosomal dominant genetic disorder that is
most often caused by mutations in the LDL recep-
tor gene, resulting in decreased or absent he-
patic clearance of LDL cholesterol from the
circulation and in an elevated plasma LDL cho-
lesterol level.4-6 In the general population, the es-
timated prevalence of heterozygous familial hy-
percholesterolemia is 0.32%, which suggests that
1 in 313 people is affected.3 In the aforemen-
tioned meta-analysis, the worldwide prevalence
of heterozygous familial hypercholesterolemia
among people with atherosclerotic cardiovascu-
lar disease, premature atherosclerotic cardiovas-
cular disease, or severe hypercholesterolemia was
determined to be 10, 20, and 23 times as high,
respectively, as the prevalence in the general
population.3 Data from 1493 patients with het-
erozygous familial hypercholesterolemia in the
Spanish SAFEHEART registry showed that 22.1%
had atherosclerotic cardiovascular disease and
10.3% had cardiovascular events during a mean
follow-up of 3.9 years.7 As compared with the
risk of coronary artery disease in a reference
group of patients with LDL cholesterol levels of
less than 130 mg per deciliter (3.36 mmol per
liter) and no familial hypercholesterolemia mu-
tation, the risk was 6.0 times as high among
patients with LDL cholesterol levels of 190 mg
per deciliter or higher and no mutation and was
22.3 times as high among patients with LDL
cholesterol levels of 190 mg per deciliter or
higher and a mutation, findings that reflect the
detrimental effect of lifelong exposure to elevat-
ed LDL cholesterol levels.2 Familial hypercho-
lesterolemia mutations are associated with an
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of m e dic i n e
increase in the odds of early-onset (≤55 years of
age) myocardial infarction by a factor of 3.8.8
The 2019 European Society of Cardiology
(ESC)–European Atherosclerosis Society (EAS)
clinical guidelines recommend target LDL cho-
lesterol levels of less than 55 mg per deciliter
(1.42 mmol per liter), less than 70 mg per deci-
liter (1.81 mmol per liter), and less than 100 mg
per deciliter (2.59 mmol per liter) in patients
with very high, high, and moderate risk for ath-
erosclerotic cardiovascular disease, respectively.9
The 2018 American College of Cardiology (ACC)–
American Heart Association (AHA) guidelines
recommend that clinicians use an LDL choles-
terol threshold of 70 mg per deciliter or higher
to prompt intensification of lipid-lowering thera-
pies in patients with very high risk for athero-
sclerotic cardiovascular disease.10 These treatment
goals are difficult to achieve in some patients
with heterozygous familial hypercholesterolemia
despite treatment with a statin at a maximum
tolerated dose, ezetimibe, and a proprotein con-
vertase subtilisin–kexin type 9 (PCSK9) inhibitor.
Although additional lowering of the LDL choles-
terol level may be done with LDL apheresis, the
use of this invasive approach is restricted by lim-
ited accessibility to apheresis centers, high pro-
cedural costs, inconvenience to patients, the
lack of insurance coverage support, and adverse
events.4,11,12
Angiopoietin-like 3 (ANGPTL3) plays a prom-
inent role in the regulation of lipid metabolism
by inhibiting lipoprotein lipase and endothelial
lipase.13-17 Patients with loss-of-function variants
of ANGPTL3 have a hypolipidemic phenotype,
with substantially reduced levels of LDL choles-
terol, triglycerides, and high-density lipoprotein
(HDL) cholesterol.18 Moreover, the risk of coro-
nary artery disease among patients with ANGPTL3
loss-of-function variants is 41% lower than the
risk in the general population.18 Functional analy-
ses conducted in a phase 2 proof-of-concept study
suggest that evinacumab, a fully human mono-
clonal antibody against ANGPTL3, is effective in
lowering the LDL cholesterol level with a mecha-
nism independent of the LDL receptor.19-21 In the
phase 3 Evinacumab Lipid Studies in Patients
with Homozygous Familial Hypercholesterol-
emia (ELIPSE HoFH), involving 65 patients with
homozygous familial hypercholesterolemia, pa-
tients who received treatment with evinacumab
 Evinacumab in Refr actory Hypercholesterolemia
had a 47.1% reduction from baseline in the LDL
cholesterol level at week 24, whereas those who
received placebo had a 1.9% increase, resulting
in a between-group least-squares mean difference
of –49.0 percentage points (P<0.001); results
were similar even among those with null vari-
ants of homozygous familial hypercholesterol-
emia (<2% LDL receptor activity).22
In the phase 2 proof-of-concept study and the
phase 3 ELIPSE HoFH trial, evinacumab was
infused intravenously, over a period of 60 min-
utes, at a dose of 15 mg per kilogram of body
weight every 4 weeks. However, subcutaneous
administration of evinacumab can be more con-
venient for patients. In this trial, we assessed the
efficacy and safety of subcutaneous and intrave-
nous evinacumab, as compared with placebo, in
patients with refractory hypercholesterolemia
who had been treated with maximum tolerated
doses of statins and other lipid-lowering thera-
pies, including a PCSK9 inhibitor.
Me thods
Trial Oversight
This randomized, double-blind, placebo-con-
trolled, phase 2 trial was conducted at 85 sites
across 20 countries. The trial protocol, available
with the full text of this article at NEJM.org, was
approved by the institutional review board or
ethics committee at each participating site. The
trial was conducted in accordance with ethical
principles originating from the Declaration of
Helsinki and was consistent with International
Conference on Harmonisation Good Clinical
Practice guidelines and applicable regulatory re-
quirements. The principal investigators and spon-
sor (Regeneron Pharmaceuticals) designed the trial
protocol and selected the participating sites. Clini-
cal trial monitoring and site supervision were per-
formed by a contract research organization with
oversight by the sponsor. The sponsor was also
involved in the collection, analysis, and interpre-
tation of the data and checked the information
provided in the manuscript. The first author
wrote the first draft of the manuscript. All the
authors had unrestricted access to the trial data,
contributed to the first draft of the manuscript,
participated in revisions, and vouch for the ac-
curacy and completeness of the data and for the
fidelity of the trial to the protocol. Editorial sup-
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port for the writing of the manuscript was pro-
vided by Prime Global and paid for by the sponsor.
Trial Design and Patients
The trial included a run-in period of variable
duration for patients who were not receiving a
PCSK9 inhibitor or background lipid-lowering
therapy at a maximum tolerated dose on a regu-
lar basis. The run-in period was followed by a
2-week screening period, a double-blind treat-
ment period lasting 16 weeks for subcutaneous
treatment and 24 weeks for intravenous treat-
ment, a 48-week open-label treatment period for
intravenous treatment only, and a 24-week fol-
low-up period after the last dose of the trial drug
(Fig. S1 in the Supplementary Appendix, avail-
able at NEJM.org).
Patients 18 to 80 years of age were eligible for
inclusion in the trial if they had primary hyper-
cholesterolemia, defined as either heterozygous
familial hypercholesterolemia or non–heterozy-
gous familial hypercholesterolemia with clinical
atherosclerotic cardiovascular disease. The hyper-
cholesterolemia was refractory to treatment with
a PCSK9 inhibitor and a statin at a maximum
tolerated dose, with or without ezetimibe. A diag-
nosis of heterozygous familial hypercholesterol-
emia was based on genotyping or clinical criteria.
For patients who did not undergo genotyping,
the clinical diagnosis was based on the Simon
Broome criteria for definite familial hypercho-
lesterolemia or the World Health Organization–
Dutch Lipid Clinic Network criteria, with a score
of more than 8 points (range of possible scores,
0 to 32) indicating a certain diagnosis of het-
erozygous familial hypercholesterolemia (see the
Supplementary Appendix). Refractory hypercho-
lesterolemia was defined as an LDL cholesterol
level of 70 mg per deciliter or higher with clinical
atherosclerotic cardiovascular disease or a level
of 100 mg per deciliter or higher without clinical
atherosclerotic cardiovascular disease. The full
list of eligibility criteria is provided in the Sup-
plementary Appendix. Written informed consent
was obtained from each patient in the trial.
Randomization
Patients were randomly assigned to receive sub-
cutaneous treatment (one of three evinacumab
regimens or placebo, assigned in a 1:1:1:1 ratio)
or intravenous treatment (one of two evinacu­
3
 The n e w e ng l a n d j o u r na l
mab regimens or placebo, assigned in a 1:1:1 ra-
tio). Randomization was stratified according to
the presence or absence of heterozygous familial
hypercholesterolemia (2:1 ratio) and to the re-
ceipt or nonreceipt of a high-intensity statin. The
subcutaneous regimens were evinacumab at a
dose of 450 mg weekly, 300 mg weekly, or 300 mg
every 2 weeks or placebo weekly. The intravenous
regimens were evinacumab at a dose of 15 mg per
kilogram of body weight every 4 weeks or 5 mg per
kilogram every 4 weeks or placebo every 4 weeks.
All patients who were assigned to the intravenous-
treatment groups entered the 48-week open-label
treatment period, in which they received intrave-
nous evinacumab at a dose of 15 mg per kilogram
every 4 weeks, regardless of their treatment as-
signment in the double-blind treatment period.
In this article, we present the results from the
double-blind treatment period.
End Points
The primary end point was the percent change
from baseline in the LDL cholesterol level at
week 16 with subcutaneous or intravenous evi-
nacumab as compared with placebo. The LDL
cholesterol level was calculated with the use of
the Friedewald formula.23 Secondary end points
included lipid levels. Safety was evaluated on the
basis of the incidence of adverse events that oc-
curred during the double-blind treatment period.
Lists of secondary end points and protocol-defined
adverse events of special interest are provided in
the Supplementary Appendix.
Statistical Analysis
We calculated that a sample of 36 patients per trial
group would provide the trial with 90% power to
detect a between-group difference in the mean
percent change in the LDL cholesterol level of 20
percentage points in any one pairwise compari-
son with the use of an independent group t-test
with a 0.05 two-sided significance level, under
the assumption of a common standard deviation
of 25%, with adjustment to account for a 5% drop-
out rate. The primary efficacy end point of the
percent change from baseline in the calculated
LDL cholesterol level at week 16 during the
double-blind treatment period was analyzed in
the intention-to-treat population with the use of
a mixed-effect model with a repeated-measures
approach. The model included the categorical
fixed effects of treatment (evinacumab or pla-
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of m e dic i n e
cebo), randomization strata (receipt of a high-
intensity statin [yes or no] and presence of het-
erozygous familial hypercholesterolemia [yes or
no]), time point up to week 16, strata-by-time point
interaction, and treatment-by-time point interac-
tion, as well as the continuous fixed covariates
of the calculated LDL cholesterol level at base-
line and baseline LDL cholesterol level-by-time
point interaction. The model provided baseline-
adjusted least-squares mean estimates at week
16 with corresponding 95% confidence intervals
and standard errors.
Four between-group comparisons were per-
formed with regard to the primary end point:
intravenous evinacumab at a dose of 15 mg per
kilogram every 4 weeks was compared with in-
travenous placebo, and each of the three doses
of subcutaneous evinacumab (450 mg weekly,
300 mg weekly, and 300 mg every 2 weeks) was
compared with subcutaneous placebo. The sta-
tistical testing of these four pairwise compari-
sons with regard to the primary end point was
performed with the use of a hierarchical inferen-
tial approach to adjust for multiplicity; testing
was to be performed in the order shown above,
with each subsequent test performed when the
primary end-point results were significant at an
alpha level of 0.05. The regimen of intravenous
evinacumab at a dose of 5 mg per kilogram ev-
ery 4 weeks was added to allow for an initial as-
sessment of the dose–response relationship with
the intravenous route of administration. Second-
ary efficacy end points and the comparison of
intravenous evinacumab at a dose of 5 mg per
kilogram with placebo were assessed descrip-
tively. Baseline and safety data were assessed
with the use of descriptive statistics. The statisti-
cal analysis plan did not include a provision for
correction for multiplicity in tests for secondary
or other outcomes; results for these outcomes are
reported as point estimates and 95% confidence
intervals. Because the widths of the confidence
intervals have not been adjusted for multiplicity,
they should not be used to infer definitive treat-
ment effects with regard to secondary outcomes.
R e sult s
Trial Groups
Overall, 272 patients were randomly assigned to
receive subcutaneous evinacumab or placebo (163
patients) or intravenous evinacumab or placebo
 Evinacumab in Refr actory Hypercholesterolemia
(109 patients) (Fig. S2). The subcutaneous regi-
mens were evinacumab at a dose of 450 mg
weekly (40 patients), 300 mg weekly (43 patients),
or 300 mg every 2 weeks (39 patients) or placebo
weekly (41 patients). The intravenous regimens
were evinacumab at a dose of 15 mg per kilo-
gram every 4 weeks (39 patients) or 5 mg per
kilogram every 4 weeks (36 patients) or placebo
every 4 weeks (34 patients). Six patients (3 as-
signed to a subcutaneous regimen and 3 assigned
to an intravenous regimen) did not receive the
trial agent. Thus, the intention-to-treat population
included 266 patients (160 assigned to a subcu-
taneous regimen and 106 assigned to an intrave-
nous regimen).
Patient Characteristics
Subcutaneous Evinacumab
The demographic and clinical characteristics of
the patients at baseline were generally well bal-
anced among the subcutaneous-treatment groups
(Table 1). In total, 116 patients (72%) had hetero-
zygous familial hypercholesterolemia and 44 (28%)
did not. The baseline mean (±SD) LDL choles-
terol level was similar among patients assigned
to receive evinacumab at a dose of 450 mg
weekly (146.3±84.6 mg per deciliter [3.78±2.19
mmol per liter]), evinacumab at a dose of 300 mg
weekly (159.1±73.0 mg per deciliter [4.11±1.89
mmol per liter]), and placebo (157.8±92.4 mg per
deciliter [4.08±2.39 mmol per liter]) but was lower
among patients assigned to receive evinacumab
at a dose of 300 mg every 2 weeks (136.2±70.2
mg per deciliter [3.52±1.82 mmol per liter]). All
the patients were receiving a PCSK9 inhibitor,
44% were receiving a high-intensity statin (with
all these patients receiving a maximum tolerated
dose of the statin), and 30% were receiving
ezetimibe.
Intravenous Evinacumab
The demographic and clinical characteristics of
the patients at baseline were also generally well
balanced among the intravenous-treatment groups
(Table 2). In total, 86 patients (81%) had hetero-
zygous familial hypercholesterolemia and 20 (19%)
did not. The baseline mean LDL cholesterol level
was similar among patients assigned to receive
evinacumab at a dose of 15 mg per kilogram
(143.1±54.4 mg per deciliter [3.70±1.41 mmol per
liter]), evinacumab at a dose of 5 mg per kilo-
gram (146.0±61.0 mg per deciliter [3.78±1.58
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mmol per liter]), and placebo (144.5±46.6 mg
per deciliter [3.74±1.21 mmol per liter]). Most of
the patients (96%) were receiving a PCSK9 in-
hibitor, 49% were receiving a high-intensity statin
(with all these patients receiving a maximum toler-
ated dose of the statin), and 38% were receiving
ezetimibe.
Primary Efficacy Analysis
Subcutaneous Evinacumab
At week 16, the change from baseline in the LDL
cholesterol level was −47.2% with subcutaneous
evinacumab at a dose of 450 mg weekly and
−44.0% with subcutaneous evinacumab at a dose
of 300 mg weekly, as compared with 8.8% with
placebo, with a least-squares mean difference (each
of these evinacumab regimens vs. placebo) of
–56.0 and −52.9 percentage points, respectively
(P<0.001 for both comparisons) (Fig. 1 and
Table 3). A smaller reduction from baseline in
the LDL cholesterol level at week 16 was ob-
served with subcutaneous evinacumab at a dose
of 300 mg every 2 weeks, with a least-squares
mean difference (vs. placebo) of −38.5 percentage
points (P<0.001) (Fig. 1 and Table 3). The reduc-
tion in the LDL cholesterol level with all three
subcutaneous-evinacumab regimens was observed
as early as the first postbaseline lipid assessment
(week 2) and was maintained through week 16.
Intravenous Evinacumab
At week 16, the change from baseline in the LDL
cholesterol level was –49.9% with intravenous
evinacumab at a dose of 15 mg per kilogram, as
compared with 0.6% with placebo, with a least-
squares mean difference of –50.5 percentage
points (P<0.001) (Fig. 1 and Table 3). The change
was –23.5% with intravenous evinacumab at a
dose of 5 mg per kilogram, with a least-squares
mean difference (vs. placebo) of –24.2 percent-
age points (Fig. 1 and Table 3). The reduction in
the LDL cholesterol level with the two intrave-
nous-evinacumab regimens was observed as early
as the first postbaseline lipid assessment (week 2)
and was maintained through week 16.
Secondary Efficacy Analysis
Lipid levels were substantially lower with subcu-
taneous and intravenous evinacumab than with
placebo (Tables S1 and S2). With the exception
of the lipoprotein(a) level, all atherogenic lipo-
protein levels decreased in a dose-dependent man-
5
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Demographic and Clinical Characteristics of the Patients in the Subcutaneous-Treatment Groups.*

Subcutaneous
Placebo, Weekly Total
Characteristic Subcutaneous Evinacumab (N = 39) (N = 160)

450 mg Weekly 300 mg Weekly 300 mg Every 2 Wk

(N = 40) (N = 42) (N = 39)
Age — yr 54.5±15.1 54.0±12.2 55.0±13.0 52.4±12.7 54.0±13.2
Female sex — no. (%) 29 (72) 23 (55) 21 (54) 27 (69) 100 (62)
Race — no. (%)†
White 38 (95) 39 (93) 34 (87) 34 (87) 145 (91)
Black 1 (2) 0 0 3 (8) 4 (2)
Asian 0 0 2 (5) 1 (3) 3 (2)
Other 1 (2) 1 (2) 0 1 (3) 3 (2)
Not reported 0 2 (5) 3 (8) 0 5 (3)
Body-mass index‡ 27.9±4.4 29.3±4.9 28.0±4.4 29.1±5.2 28.6±4.7
Heterozygous familial hypercholesterolemia
status — no. (%)
Present 29 (72) 30 (71) 29 (74) 28 (72) 116 (72)
Diagnosed with genotyping 13 (32) 16 (38) 11 (28) 9 (23) 49 (31)
Diagnosed with clinical criteria 16 (40) 14 (33) 18 (46) 19 (49) 67 (42)
Absent 11 (28) 12 (29) 10 (26) 11 (28) 44 (28)
Calculated LDL cholesterol — mg/dl 146.3±84.6 159.1±73.0 136.2±70.2 157.8±92.4 150.0±80.2
Apolipoprotein B — mg/dl 112.4±43.1 123.2±42.1 107.8±43.8 120.6±51.1 116.1±45.1
HDL cholesterol — mg/dl 52.5±13.8 57.0±22.9 51.7±15.5 56.2±16.7 54.4±17.6
Non-HDL cholesterol — mg/dl 173.0±84.8 185.1±74.8 165.3±71.2 183.9±92.8 176.9±80.9
Total cholesterol — mg/dl 225.5±86.2 242.2±77.3 217.0±68.8 240.1±91.9 231.4±81.4
Median fasting triglycerides (IQR) — mg/dl 109.5 118.5 128.0 112.0 114.5
(82.0–183.5) (83.0–177.0) (87.0–167.0) (85.0–176.0) (85.5–176.5)
Median lipoprotein(a) (IQR) — nmol/liter 24.5 81.5 60.0 48.0 46.5
(15.5–97.5) (21.0–231.0) (16.0–128.0) (21.0–170.0) (17.0–154.0)
Coronary heart disease — no. (%) 22 (55) 21 (50) 22 (56) 21 (54) 86 (54)
Acute myocardial infarction 7 (18) 13 (31) 9 (23) 9 (23) 38 (24)
Silent myocardial infarction 1 (2) 2 (5) 0 0 3 (2)
Chronic stable or unstable angina 14 (35) 9 (21) 16 (41) 16 (41) 55 (34)
Coronary revascularization procedure 17 (42) 18 (43) 17 (44) 13 (33) 65 (41)
Risk equivalents of coronary heart disease 9 (22) 7 (17) 8 (20) 7 (18) 31 (19)
— no. (%)
Peripheral arterial disease 4 (10) 2 (5) 7 (18) 4 (10) 17 (11)
Ischemic stroke 5 (12) 2 (5) 2 (5) 2 (5) 11 (7)
Chronic kidney disease 0 0 0 1 (3) 1 (1)
Known history of type 1 or 2 diabetes 3 (8) 3 (7) 1 (3) 1 (3) 8 (5)
mellitus and ≥2 additional risk
factors§

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 Evinacumab in Refr actory Hypercholesterolemia

Table 1. (Continued.)

Subcutaneous
Placebo, Weekly Total
Characteristic Subcutaneous Evinacumab (N = 39) (N = 160)

450 mg Weekly 300 mg Weekly 300 mg Every 2 Wk

(N = 40) (N = 42) (N = 39)
Lipid-lowering therapy — no. (%)
Any statin 24 (60) 24 (57) 24 (62) 27 (69) 99 (62)
High-intensity statin¶ 17 (42) 21 (50) 14 (36) 19 (49) 71 (44)
Ezetimibe 7 (18) 15 (36) 12 (31) 14 (36) 48 (30)
PCSK9 inhibitor 40 (100) 42 (100) 39 (100) 39 (100) 160 (100)

* Plus–minus values are means ±SD. Data are shown for the intention-to-treat population. Percentages may not total 100 because of round-
ing. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles per
liter, multiply by 0.01129. HDL denotes high-density lipoprotein, IQR interquartile range, LDL low-density lipoprotein, and PCSK9 proprotein
convertase subtilisin–kexin type 9.
† Race was reported by the patient.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Risk factors include a history of an ankle–brachial index of 0.9 or lower, a history of hypertension, a history of microalbuminuria or macroal-
buminuria, a history of proliferative diabetic retinopathy, and a known family history of coronary heart disease.
¶ High-intensity statin was defined as rosuvastatin at a dose of 20 mg or 40 mg daily, atorvastatin at a dose of 40 mg or 80 mg daily, or simv-
astatin at a dose of 80 mg daily (if the patient had been receiving this regimen for >1 year).

ner. At week 16, the change from baseline in the
HDL cholesterol level was −27.9%, −30.3%, and
−19.5% with subcutaneous evinacumab at a dose
of 450 mg weekly, 300 mg weekly, and 300 mg
every 2 weeks, respectively, as compared with
−1.7% with subcutaneous placebo. In addition,
at week 16, the change from baseline in the mean
HDL cholesterol level was −31.4% and −14.9%
with intravenous evinacumab at a dose of 15 mg
per kilogram and 5 mg per kilogram, respec-
tively, as compared with 1.9% with intravenous
placebo.
Safety
During the double-blind treatment period, adverse
events occurred in 68%, 67%, and 82% of the pa-
tients who received subcutaneous evinacumab
at a dose of 450 mg weekly, 300 mg weekly, and
300 mg every 2 weeks, respectively, as compared
with 54% of the patients who received subcuta-
neous placebo (Table 4). Adverse events that oc-
curred in at least 5% of the patients in the sub-
cutaneous-treatment groups are described in
Table S3. Adverse events that occurred in at least
5% of the patients who received subcutaneous
evinacumab (any of the three regimens) and oc-
curred more frequently with subcutaneous evi-
nacumab than with subcutaneous placebo in-
cluded urinary tract infection (11% vs. 8%),
injection-site erythema (6% vs. 3%), arthralgia
(5% vs. 3%), and myalgia (5% vs. 0%).
During the double-blind treatment period,
adverse events occurred in 84% and 75% of the
patients who received intravenous evinacumab at
a dose of 15 mg per kilogram and 5 mg per ki-
logram, respectively, as compared with 70% of
the patients who received intravenous placebo
(Table 4). Adverse events that occurred in at least
5% of the patients who received intravenous
evinacumab (either of the two regimens) and
occurred more frequently with intravenous evi-
nacumab than with intravenous placebo includ-
ed abdominal pain (6% vs. 0%), back pain (7%
vs. 6%), dizziness (7% vs. 0%), fatigue (7% vs.
6%), pain in an arm or leg (7% vs. 6%), nausea
(7% vs. 0%), and nasopharyngitis (12% vs. 6%).
In patients who received subcutaneous or in-
travenous evinacumab, few high-grade adverse
events were observed. Overall, there were no clini-
cally significant differences between the subcu-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Demographics and Clinical Characteristics of the Patients in the Intravenous-Treatment Groups.*

Intravenous Placebo,
Every 4 Wk Total
Characteristic Intravenous Evinacumab (N = 33) (N = 106)
15 mg/kg Every 4 Wk 5 mg/kg Every 4 Wk
(N = 38) (N = 35)
Age — yr 52.1±12.1 55.7±9.6 56.2±10.9 54.6±11.0
Female sex — no. (%) 19 (50) 22 (63) 18 (55) 59 (56)
Race — no. (%)†
White 35 (92) 32 (91) 27 (82) 94 (89)
Black 0 0 2 (6) 2 (2)
Asian 0 1 (3) 1 (3) 2 (2)
Other 3 (8) 2 (6) 3 (9) 8 (8)
Body-mass index‡ 29.3±4.9 28.8±4.6 28.8±5.2 29.0±4.9
Heterozygous familial hypercholesterolemia
status — no. (%)
Present 31 (82) 29 (83) 26 (79) 86 (81)
Diagnosed with genotyping 10 (26) 11 (31) 11 (33) 32 (30)
Diagnosed with clinical criteria 21 (55) 18 (51) 15 (45) 54 (51)
Absent 7 (18) 6 (17) 7 (21) 20 (19)
Calculated LDL cholesterol — mg/dl 143.1±54.4 146.0±61.0 144.5±46.6 144.5±54.0
Apolipoprotein B — mg/dl 112.6±32.4 113.4±33.8 116.7±27.0 114.1±31.1
HDL cholesterol — mg/dl 51.5±17.4 58.2±16.8 55.4±18.0 54.9±17.4
Non-HDL cholesterol — mg/dl 169.4±54.2 170.6±61.5 176.2±48.0 171.9±54.5
Total cholesterol — mg/dl 220.9±56.8 228.8±60.2 231.6±50.4 226.8±55.7
Median fasting triglycerides (IQR) — mg/dl 126.5 (89.0–166.0) 102.0 (86.0–156.0) 147.0 (104.0–200.0) 122.0 (92.0–171.0)
Median lipoprotein(a) (IQR) — nmol/liter 34.0 (15.0–157.0) 27.0 (18.0–80.0) 33.0 (16.0–154.0) 31.0 (17.0–127.0)
Coronary heart disease — no. (%) 21 (55) 20 (57) 25 (76) 66 (62)
Acute myocardial infarction 13 (34) 10 (29) 14 (42) 37 (35)
Silent myocardial infarction 0 0 0 0
Chronic stable or unstable angina 13 (34) 16 (46) 16 (48) 45 (42)
Coronary revascularization procedure 19 (50) 15 (43) 20 (61) 54 (51)
Risk equivalents of coronary heart disease — 10 (26) 4 (11) 7 (21) 21 (20)
no. (%)
Peripheral arterial disease 8 (21) 2 (6) 1 (3) 11 (10)
Ischemic stroke 2 (5) 1 (3) 2 (6) 5 (5)
Chronic kidney disease 0 0 1 (3) 1 (1)
Known history of type 1 or 2 diabetes mel- 2 (5) 2 (6) 4 (12) 8 (8)
litus and ≥2 additional risk factors§
Lipid-lowering therapy — no. (%)
Any statin 33 (87) 27 (77) 28 (85) 88 (83)
High-intensity statin¶ 23 (61) 17 (49) 15 (45) 55 (52)
Ezetimibe 13 (34) 15 (43) 12 (36) 40 (38)
PCSK9 inhibitor 37 (97) 33 (94) 32 (97) 102 (96)

* Plus–minus values are means ±SD. Data are shown for the intention-to-treat population. Percentages may not total 100 because of round-
ing. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for triglycerides to millimoles
per liter, multiply by 0.01129.
† Race was reported by the patient.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Risk factors include a history of an ankle–brachial index of 0.9 or lower, a history of hypertension, a history of microalbuminuria or macroal-
buminuria, a history of proliferative diabetic retinopathy, and a known family history of coronary heart disease.
¶ High-intensity statin was defined as rosuvastatin at a dose of 20 mg or 40 mg daily, atorvastatin at a dose of 40 mg or 80 mg daily, or simv-
astatin at a dose of 80 mg daily (if the patient had been receiving this regimen for >1 year).

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 Evinacumab in Refr actory Hypercholesterolemia

Intravenous evinacumab, 15 mg/kg every 4 wk Subcutaneous evinacumab, 450 mg weekly

Intravenous evinacumab, 5 mg/kg every 4 wk
Intravenous placebo, every 4 wk
21
Least-Squares Mean Change from Baseline
Subcutaneous evinacumab, 300 mg weekly
Subcutaneous evinacumab, 300 mg every 2 wk
Subcutaneous placebo, weekly

14
7
in LDL Cholesterol Level (%)

0
−7
−14
−21
−28
−35
−42
−49
−56
Baseline 2 4 6 8 10 12 14 16
Week

Figure 1. Least-Squares Mean Percent Change from Baseline in the Calculated Low-Density Lipoprotein Cholesterol
Level at Week 16.
The least-squares mean and standard errors are taken from a mixed-effect model with a repeated-measures ap-
proach, with the categorical fixed effects of treatment (evinacumab or placebo), randomization strata (receipt of a
high-intensity statin [yes or no] and presence of heterozygous familial hypercholesterolemia [yes or no]), time point
up to week 16, treatment-by-time point interaction, and strata-by-time point interaction, as well as continuous fixed
covariates of the calculated low-density lipoprotein (LDL) cholesterol level at baseline and baseline LDL cholesterol
level-by-time point interaction. I bars indicate standard errors.

Table 3. Change from Baseline in the Calculated LDL Cholesterol Level at Week 16 in Patients with Refractory
Hypercholesterolemia.*

No. of Change from Baseline Difference vs. Placebo

Trial Group Patients in LDL Cholesterol Level (95% CI) P Value

percent percentage points

Subcutaneous regimen
Evinacumab
450 mg weekly 40 –47.2±6.2 –56.0±9.0 (–73.7 to –38.3) <0.001
300 mg weekly 42 –44.0±6.3 –52.9±9.0 (–70.7 to –35.1) <0.001
300 mg every 2 wk 39 –29.7±6.4 –38.5±9.1 (–56.5 to –20.6) <0.001
Placebo, weekly 39 8.8±6.4 — —
Intravenous regimen
Evinacumab
15 mg/kg every 4 wk 38 –49.9±6.1 –50.5±9.0 (–68.4 to –32.6) <0.001
5 mg/kg every 4 wk 35 –23.5±6.6 –24.2±9.3 (–42.6 to –5.7)† —
Placebo, every 4 wk 33 0.6±6.6 — —

* Plus–minus values are least-squares means ±SE. Data are shown for the intention-to-treat population.
† The width of the 95% confidence interval has not been adjusted for multiplicity and cannot be used to infer treatment
effects.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 4. Overall Safety Profile of Subcutaneous and Intravenous Evinacumab during the Double-Blind Treatment Period
in Patients with Refractory Hypercholesterolemia.*

≥1 Adverse
Event Resulting Any Adverse
No. of Any Adverse ≥1 Serious in Treatment Event Resulting
Trial Group Patients Event Adverse Event Discontinuation in Death

number of patients (percent)

Subcutaneous regimen
Evinacumab
450 mg weekly 40 27 (68)† 3 (8) 0 0
300 mg weekly 42 28 (67)‡ 3 (7) 0 1 (2)
300 mg every 2 wk 39 32 (82)§ 2 (5) 2 (5) 1 (3)
Placebo, weekly 39 21 (54)¶ 3 (8) 2 (5) 0
Intravenous regimen
Evinacumab
15 mg/kg every 4 wk 37 31 (84)‖ 6 (16) 2 (5) 0
5 mg/kg every 4 wk 36 27 (75)** 2 (6) 2 (6) 0
Placebo, every 4 wk 33 23 (70)†† 1 (3) 1 (3) 0

* Data are shown for the double-blind safety analysis population, which included 266 patients.
† The most common adverse events that occurred with subcutaneous evinacumab at a dose of 450 mg weekly were
diarrhea (8%), headache (10%), influenza-like illness (8%), injection-site erythema (10%), nausea (10%), nasophar-
yngitis (10%), and urinary tract infection (10%).
‡ The most common adverse events that occurred with subcutaneous evinacumab at a dose of 300 mg weekly were
chest pain (7%), fall (7%), headache (7%), injection-site hemorrhage (7%), injection-site hematoma (7%), back pain
(10%), nasopharyngitis (10%), oropharyngeal pain (10%), and urinary tract infection (10%).
§ The most common adverse events that occurred with subcutaneous evinacumab at a dose of 300 mg every 2 weeks
were arthralgia (8%), back pain (8%), myalgia (8%), constipation (10%), nausea (10%), nasopharyngitis (10%), and
urinary tract infection (13%).
¶ The most common adverse events that occurred with subcutaneous placebo were diarrhea (8%), fatigue (8%),
nausea (8%), urinary tract infection (8%), headache (10%), back pain (13%), dizziness (13%), and nasopharyngitis
(15%).
‖ The most common adverse events that occurred with intravenous evinacumab at a dose of 15 mg per kilogram every
4 weeks were asthenia (8%), dizziness (8%), hypertension (14%), and nasopharyngitis (16%).
** The most common adverse events that occurred with intravenous evinacumab at a dose of 5 mg per kilogram every
4 weeks were influenza-like illness (8%), pain in an arm or leg (8%), nasopharyngitis (8%), fatigue (11%), and myal-
gia (11%).
†† The most common adverse events that occurred with intravenous placebo were arthralgia (9%), influenza-like illness
(9%), myalgia (12%), and headache (18%).

taneous-treatment groups and the intravenous-
treatment groups with respect to serious adverse
events, adverse events resulting in treatment dis-
continuation, or adverse events of special interest
that occurred during the double-blind treatment
period.
In the subcutaneous-treatment groups, the
only adverse event resulting in treatment discon-
tinuation that was considered by the investigator
to be related to the trial drug was dyspnea, which
occurred with subcutaneous evinacumab at a
dose of 300 mg every 2 weeks and resolved fully.
Adverse events resulting in death occurred in
one patient who was treated with subcutaneous
evinacumab at a dose of 300 mg weekly (heart
failure or cardiogenic shock) and one patient who
was treated with subcutaneous evinacumab at a
dose of 300 mg every 2 weeks (sudden cardiac
death). These events occurred in patients with
underlying heart disease and were not consid-
ered by the investigator to be related to the trial
drug. In the intravenous-treatment groups, the
only adverse event resulting in treatment discon-
tinuation that was considered by the investigator
to be related to the trial drug was anaphylactic
reaction (an adverse event of special interest),
which occurred with the second dose of intrave-
nous evinacumab at a dose of 15 mg per kilo-

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 Evinacumab in Refr actory Hypercholesterolemia
gram. This event, which occurred in a patient
with a relevant medical history of asthma and
seasonal allergies, involved multiple symptoms,
including dizziness, chest pressure, tingling in
the arms and legs, shortness of breath, pruritus,
decreased blood pressure, and increased heart
rate. The evinacumab infusion was discontinued
and the event resolved on the same day after treat-
ment with oral diphenhydramine. No patients
who received intravenous treatment had adverse
events resulting in death.
Discussion
In this phase 2 trial, we found that the use of
evinacumab reduced levels of LDL cholesterol and
atherogenic lipoproteins in patients with refrac-
tory hypercholesterolemia. The response to treat-
ment, or reduction in the LDL cholesterol level,
with subcutaneous and intravenous evinacumab
was observed as early as the first postbaseline
lipid assessment (week 2) and was maintained
through week 16. Serious adverse events were ob-
served in 3 to 16% of patients across trial groups.
To reduce the risk of atherosclerotic cardio-
vascular disease, patients who have heterozygous
familial hypercholesterolemia are typically treat-
ed with lipid-lowering therapies, which may in-
clude a statin, ezetimibe, and a PCSK9 inhibitor.9
Although each standard-of-care therapy contrib-
utes to overall lowering of the LDL cholesterol
level, there remains a residual unmet need among
patients who have a high baseline LDL choles-
terol level.24,25 This is particularly relevant in the
context of the 2019 ESC–EAS lipid-management
guidelines, which specify a target LDL choles-
terol level of less than 55 mg per deciliter for
patients with very high risk for atherosclerotic
cardiovascular disease9; the 2016 ESC–EAS guide-
lines and the 2018 ACC–AHA guidelines recom-
mended a target LDL cholesterol level of less than
70 mg per deciliter in patients with very high risk
for atherosclerotic cardiovascular disease.10,26 In
addition, some patients with heterozygous famil-
ial hypercholesterolemia may have adverse events
associated with standard-of-care lipid-lowering
therapies, which limit the optimization of treat-
ment regimens.25,27,28 Data from a pooled analysis
of eight phase 3 ODYSSEY trials involving 4629
patients with hypercholesterolemia (with or with-
out heterozygous familial hypercholesterolemia)
showed that 41% were not receiving a high-dose
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statin, with a frequent investigator-assessed rea-
son (in 32% of cases) being statin-associated
muscle symptoms, an increased creatine kinase
level, or both.29
The use of PCSK9 inhibitors in combination
with other lipid-lowering therapies reduces the
risk of major adverse cardiovascular events and
reduces the LDL cholesterol level by 50 to 60%.30,31
However, a real-world study involving 204 patients
with heterozygous familial hypercholesterolemia
and very high risk for cardiovascular disease
showed that only 39% had an LDL cholesterol
level of less than 55 mg per deciliter despite treat-
ment with PCSK9 inhibitors.25 Of the 143 patients
who were receiving triple therapy (a high-inten-
sity statin, ezetimibe, and a PCSK9 inhibitor),
45% had an LDL cholesterol level of less than
55 mg per deciliter.25 Given the significant reduc-
tion in levels of LDL cholesterol and atherogenic
lipoproteins observed in our trial, the addition of
evinacumab to standard-of-care lipid-lowering
therapies that include PCSK9 inhibitors in pa-
tients with refractory hypercholesterolemia may
potentially facilitate a greater number of patients
attaining guideline-defined target LDL choles-
terol levels and, in doing so, reduce the risk of
cardiovascular events and overall mortality. In
contrast to cholesterylester transfer protein and
apolipoprotein C3 inhibition, which results in a
small reduction in the apolipoprotein B level as
compared with the reduction in the LDL choles-
terol level, ANGPTL3 inhibition lowers both the
LDL cholesterol level and the apolipoprotein B
level substantially.32,33 In view of the strong ge-
netic data supporting a decrease in the risk of
cardiovascular disease proportional to the reduc-
tion in the apolipoprotein B level,34 the results of
this trial support a potential cardiovascular-dis-
ease benefit of ANGPTL3 inhibition.
Treatment with subcutaneous or intravenous
evinacumab prompted a reduction in the HDL
cholesterol level. Reduction in the HDL choles-
terol level has been observed in dyslipidemic or
normolipidemic mouse models after targeted
inactivation of ANGPTL3; this reduction is due
to derepression of endothelial lipase, which is a
consequence of ANGPTL3 blockade.15,21 In the
phase 3 ELIPSE HoFH trial involving patients
with homozygous familial hypercholesterolemia,
there was a 29.6% decrease in the HDL choles-
terol level after inhibition of ANGPTL3 with
evinacumab, as compared with a 0.8% increase
11
 The n e w e ng l a n d j o u r na l of m e dic i n e

with placebo.22 The importance of the reduction
in the HDL cholesterol level observed with evi-
nacumab remains to be fully elucidated, but in
patients with a naturally occurring genetic
ANGPTL3 deficiency, low HDL cholesterol levels
are not associated with an increased risk of car-
diovascular disease.18
Elevated levels of triglycerides have been re-
ported to be an independent risk factor for ath-
erosclerotic cardiovascular disease.35 Many stud-
ies show that PCSK9 inhibitors induce moderate
reductions in levels of triglycerides that are not
always statistically significant.36 Our trial shows
that the use of subcutaneous or intravenous evi-
nacumab could potentially lead to a clinically
significant reduction in the risk of cardiovascu-
lar disease by substantially reducing levels of
LDL cholesterol and triglycerides.
The reductions in the LDL cholesterol level
observed with subcutaneous evinacumab (450 mg
weekly and 300 mg weekly) were similar to the
reduction seen with intravenous evinacumab at a
dose of 15 mg per kilogram every 4 weeks. The
efficacy of this intravenous evinacumab regimen
has been shown previously in the pivotal phase
3 ELIPSE HoFH trial.22 Because intravenous ad-
ministration occurs in a health care setting, it
ensures greater adherence to treatment. However,
subcutaneous administration may be a viable al-
ternative, given that some patients may prefer to
administer the treatment at home despite the
increased frequency of dosing, in order to prevent
loss of work productivity and personal time.37,38
Moreover, subcutaneous administration is often
preferred by health care providers, because it low-
ers health care costs related to drug delivery.37
The limitations of this trial include the small
sample size and the short treatment duration.
Moreover, the racial backgrounds of the patients
were not as diverse as we had intended. Thus,
robust conclusions pertaining to the long-term
safety of evinacumab cannot be established. In
addition, we noted that the percentage of pa-
tients who were taking ezetimibe appeared to be
low, both among those assigned to receive sub-
cutaneous treatment (30%) and among those
assigned to receive intravenous treatment (38%).
The percentage of patients who were taking
ezetimibe in our trial was higher than the per-
centage of patients who were taking ezetimibe at
baseline (24%) in the ODYSSEY HIGH FH trial,
which assessed alirocumab in patients with het-
erozygous familial hypercholesterolemia, but was
lower than the percentage of patients with severe
heterozygous familial hypercholesterolemia who
were taking ezetimibe (62%) in TAUSSIG (Trial
Assessing Long-Term Use of PCSK9 Inhibition in
Subjects with Genetic LDL Disorders), which as-
sessed evolocumab in patients with familial hy-
percholesterolemia.39,40
In conclusion, results of this trial and previ-
ous studies suggest that evinacumab is effective
in lowering LDL cholesterol levels in patients
with refractory hypercholesterolemia, including
homozygous familial hypercholesterolemia,19,22
refractory heterozygous familial hypercholester-
olemia, and hypercholesterolemia of an undeter-
mined cause.
Supported by Regeneron Pharmaceuticals.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank the patients and their families who were involved in
the trial; Andrew Gewitz, Ph.D., of Regeneron Pharmaceuticals
for his contributions to the pharmacokinetic and pharmacody-
namic analyses; and Michele Damo, Pharm.D., and Atif Riaz,
Ph.D., of Prime Global (Knutsford, United Kingdom) for provid-
ing medical-writing assistance and editorial support on earlier
drafts of the manuscript under the direction of the authors.
This article is dedicated to the memory of Daniel A. Gipe,
M.D., who died prematurely and unexpectedly and to whom we
are all profoundly indebted, not only for his contributions to
this manuscript but also for his significant personal contribu-
tions to the recent advancements in the fields that are described
here.

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