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PCSK9 inhibitors: A new era of lipid lowering therapy
Rahul Chaudhary, Jalaj Garg, Neeraj Shah, Andrew Sumner
Rahul Chaudhary, Department of Medicine, Sinai Hospital of
Baltimore, Johns Hopkins University, Baltimore, MD 21209,
United States
Jalaj Garg, Neeraj Shah, Andrew Sumner, Division of
Cardiology, Lehigh Valley Health Network, Allentown, PA 18103,
United States
Author contributions: Chaudhary R and Garg J contributed
equally to the paper; all authors contributed to this paper.
Conict-of-interest statement: All authors report no conicts
of interest.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/
Manuscript source: Invited manuscript
Correspondence to: Jalaj Garg, MD, FESC, Division of
Cardiology, Lehigh Valley Health Network, 1250 S Cedar Crest
Blvd, Allentown, PA 18103,
United States. garg.jalaj@yahoo.com
Telephone: +1-585-7660898
Fax: +1-610-4023225
Received: August 15, 2016
Peer-review started: August 16, 2016
First decision: September 6, 2016
Revised: November 23, 2016
Accepted: December 7, 2016
Article in press: December 9, 2016
Published online: February 26, 2017
Abstract
Hyperlipidemia is a well-established risk factor for
developing cardiovascular disease (CVD). The recent
American College of Cardiology and American Heart
Association guidelines on lipid management emphasize
treatment of individuals at increased risk for developing
CVD events with 3-hydroxy-3-methylglutaryl coenzyme
A reductase inhibitors (statins) at doses proven to
reduce CVD events. However, there are limited options
for patients who are either intolerant to statin therapy,
develop CVD despite being on maximally tolerated statin
therapy, or have severe hypercholesterolemia. Recently
the Food and Drug Administration approved two novel
medications for low-density lipoprotein (LDL)-cholesterol
reduction: Evolocumab and Alirocumab. These agents
target and inactivate proprotein convertase subtilsin-
kexin type 9 (PCSK9), a hepatic protease that attaches
and internalizes LDL receptors into lysosomes hence
promoting their destruction. By preventing LDL receptor
destruction, LDL-C levels can be lowered 50%-60%
above that achieved by statin therapy alone. This review
explores PCSK-9 biology and the mechanisms available
to alter it; clinical trials targeting PCSK9 activity, and the
current state of clinically available inhibitors of PCSK9.
Key words: Hyperlipidemia; Statins; Proprotein convertase
subtilsin-kexin type 9
© The Author(s) 2017. Published by Baishideng Publishing
Group Inc. All rights reserved.
Core tip: Hyperlipidemia is a well-established risk factor
for developing cardiovascular disease (CVD). However,
there are limited options for patients who are either
intolerant to statin therapy, develop CVD despite being
on maximally tolerated statin therapy, or have severe
hypercholesterolemia. The Food and Drug Administration
has approved two novel medications for low-density
lipoprotein (LDL)-cholesterol reduction in this patient
population: Evolocumab and Alirocumab. These agents
target and inactivate proprotein convertase subtilsin-
kexin type 9 (PCSK9), a hepatic protease that attaches
and internalizes LDL receptors into lysosomes hence
promoting their destruction. By preventing LDL receptor
destruction, LDL-C levels can be lowered 50%-60% above
that achieved by statin therapy alone. PCSK9 inhibitors are
REVIEW
Submit a Manuscript: http://www.wjgnet.com/esps/
DOI: 10.4330/wjc.v9.i2.76
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World J Cardiol 2017 February 26; 9(2): 76-91
ISSN 1949-8462 (online)
World Journal of
Cardiology
W J C
an exciting agent for reducing LDL-C and have ushered in
a new era of lipid lowering therapy.
Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new
era of lipid lowering therapy. World J Cardiol
2017; 9(2): 76-91
Available from: URL: http://www.wjgnet.com/1949-8462/full/v9/
i2/76.htm DOI: http://dx.doi.org/10.4330/wjc.v9.i2.76
INTRODUCTION
Hyperlipidemia is a well-established risk factor for develo-
ping cardiovascular disease (CVD)[1]. Multiple double
blind placebo controlled trials have shown that treatment
with HMG CoA Reductase inhibitors (statins) lowers
low-density lipoprotein (LDL)-C levels and reduces CVD
events in individuals with CVD or those at high risk for
developing it[2,3]. However, CVD events continue to occur
in some patients on statins, despite receiving maximal
tolerated therapy. Other patients develop side effects
from statins that limit their use. Hence, newer modalities
of treatment to lower LDL-C are needed in clinical
practice. Recently the Food and Drug Administration (FDA)
approved two medications which target a novel pathway
to reduce LDL-C. They are monoclonal antibodies that
inactivate proprotein convertase subtilsin-kexin type 9
(PCSK9). This review will explore the biology of PCSK 9,
clinical trials targeting PCSK9 activity, and the current
state of clinically available inhibitors of PCSK9.
LDL-CHOLESTEROL METABOLISM
LDL-C has been the target of therapy for improving
outcomes in patients at high risk for developing CVD
and has been considered a surrogate endpoint for
clinical events by the FDA[1]. Reviewing LDL cholesterol
metabolism is therefore important in understanding
therapeutic approaches to treat hyperlipidemia.
The lipid cycle begins with the release of immature
very low-density lipoprotein (VLDL) or nascent VLDL from
the liver. Nascent VLDL contains apolipoprotein-B100
(apoB-100), apolipoprotein E (apoE), apolipoprotein C1
(apoC1), cholesteryl esters, cholesterol, and triglycerides.
While circulating in blood, high-density lipoprotein (HDL)
donates apolipoprotein C-Ⅱ (apoC-Ⅱ) to nascent VLDL
that leads to its maturation. Mature VLDL interacts with
lipoprotein lipase (LPL) in the capillary beds of adipose
tissues, cardiac muscle and skeletal muscle cells, which
leads to extraction of triglycerides from VLDL for storage
or energy production in these tissues. VLDL combines
with HDL again and an interchange occurs where apoC-
Ⅱ is transferred back to HDL along with phospholipids
and triglycerides in exchange for cholesteryl esters via
cholesterylester-transfer protein (CETP). This exchange
and removal of triglycerides leads to conversion of VLDL
to intermediate-density lipoprotein (IDL)[4]. Half of IDLs
are recognized and endocytosed by liver cells due to
apoB-100 and apoE. The remaining IDL lose apoE, and
with an increased concentration of cholesterol compared
to triglyceride, transform into low-density lipoproteins
(LDL). LDL particles thus formed contain apoB-100,
which acts as a ligand for binding to LDL receptors
(LDLR). Once LDL binds to LDLR, LDL/LDLR complex is
internalized by endocytosis into clathrin coated vesicles.
In the cytosol, LDL and LDLR separate with recycling of
LDLR to the cell surface. LDLR recycling is a continuous
process and each receptor recycles up to 150 times after
which they are endocytosed and metabolized[5]. Statins
act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase, which is involved in intracellular
production of cholesterol. This lowers the levels of
intracellular cholesterol leading to increased expression of
LDLR on cell surfaces causing a reduction in serum LDL-
cholesterol[6].
Seidah and colleagues discovered that proprotein
convertase subtilisin/kexin type 9 (PCSK9) regulates
LDLR degradation and could potentially be a target for
modulating LDLR expression and consequently LDL-C
levels[7,8]. PCSK9 is a hepatic protease that attaches to
and internalizes LDLR into lysosomes hence promoting
their destruction[9]. Clinical studies have shown that
PCSK9 gain of function mutation is associated with
familial hypercholesterolemia and premature CVD[10,11].
Conversely, individuals with loss of function mutations in
PCSK9 have been observed to have lower lifetime levels
of LDL-C and lower prevalence of CVD[12,13].
Since the discovery of PCSK9, results from preclinical
mice studies demonstrated that sterol regulatory ele-
ment binding protein-2 (SREBP-2) plays a key role in
regulating cholesterol metabolism. Low level of intra-
cellular cholesterol activates SREBP-2 and leads to LDLR
gene expression. This increases LDLR concentration
thus enhancing LDL clearance from circulation[8,14]. At
the same time SREBP-2 also induces the expression of
PCSK9, which promotes LDLR degradation. Thus, the
coordinated interplay of SREBP-2 induced transcription
of both LDLR and PCSK9 regulates circulating LDL
levels[15,16]. These discoveries resulted in the exploration
and development of therapeutic agents to lower LDL
levels by targeting PCSK9 activity.
FUNCTIONAL MECHANICS OF PCSK9
Hepatocytes are the predominant site for PCSK9
production, with other sites being intestines and kid-
neys[17,18]. PCSK9 reduces the number of LDLR in hepa-
tocytes by promoting their metabolism and subsequent
degradation[14]. PCSK9 has been shown to act both
intracellularly (playing a role as a chaperone) as well as a
secreted factor promoting LDLR internalization from the
hepatocellular surface. Under normal circumstances, the
LDL/LDLR complex is endocytosed by endosomes. The
acidic pH of the endosome reduces the affinity of LDL
for LDLR with rearrangement of the LDLR’s extracellular
domain into a hairpin structure, aiding in its recycling
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Chaudhary R
et al
. Review on PCSK9 inhibitors
back to plasma membrane. PCSK9 binding inhibits this
change and locks the LDLR in an open conformation
which prevents its recycling. The LDLR is then routed to
lysosomes for degradation (Figure 1)[19,20]. The secreted
form of PCSK9 circulates in the bloodstream and can
be inactivated by cleavage from proprotein convertase.
At a molecular level, the secretion of prodomain and
catalytically inactive PCSK9 promotes regular degradation
of LDLR implying that PCSK9 acts as a chaperone protein
rather than an active catalytic enzyme[21,22].
As described above, hepatic expression of PCSK9 and
LDLR are closely regulated by SREBP-2 and intracellular
levels of cholesterol[23,24]. Lipid lowering therapy with
statins[25-27], ezetimibe[28] and bile acid binding resins[29]
cause induction of SREBP-2 and hence co-induces both
PCSK9 and LDLR. The slight increase in PCSK9 activity
seen with statins does not negate their therapeutic eff-
ectiveness.
OTHER FUNCTIONS AND LOCATIONS OF
PCSK9
Apart from hepatocytes, PCSK9 is also expressed in
intestine, central nervous system, and mesenchymal
cells of the kidney. In vitro studies on human intestinal
epithelium have reported recombinant PCSK9 to enhance
cholesterol uptake in the human intestinal epithelial cells
(Caco-2/15 cell line) via the up regulation of the protein
expression of NPC1L1 and CD36 (involved in cholesterol
absorption in intestinal cells) along with an increased
expression of cholesterol transporters[30,31] and reduced
cholesterol synthesis (by reducing HMG-CoA reductase
activity)[32]. PCSK9 has been shown to have a role in the
metabolism of triglycerides and their accumulation in
visceral adipose tissue[33]. It also promotes chylomicron
secretion and helps regulate enterocyte cholesterol
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balance[32]. Studies have evaluated PCSK9 and their
association with increased susceptibility to hepatitis C
viral infection. Labonté et al[34] demonstrated a reduced
expression of CD81 (CD81 is a co-receptor for Hepatitis
C virus infection) by PCSK9 leading to protection against
infection by hepatitis C. Therefore, PCSK9 inhibitors
(Alirocumab) could increase CD81 expression resulting in
greater infectivity. However, in vitro and in vivo studies in
mice showed that PCSK9 did not reduce CD81 expression
and had no effect on HCV infectivity. Hence, the liter-
ature remains inconclusive about this potential effect
of PCSK9 inhibition[34]. Mbikay et al[35] demonstrated
that PCSK9 inhibition in mouse pancreatic islet β cells
led to hypoinsulinemia, hyperglycemia and glucose-
intolerance. Additionally the islet cells exhibited signs
of malformation, apoptosis and inflammation. Current
clinical data has failed to show this as a complication with
PCSK9 inhibition.
PCSK9 INHIBITION STRATEGIES
Preclinical studies demonstrate that statin-induced LDL
reduction occurs through increased LDLR expression on
hepatocytes along with increased LDL turnover, which leads
to its enhanced clearance from the circulation. However,
statins also induce PCSK9 expression, which dampens the
effective LDL clearing by promoting LDLR degradation[23].
Since PCSK9 is expressed both intracellularly and in the
circulation, multiple potential targets exist for its inhibition.
Various modalities to inhibit PCSK9 have been studied
including: (1) inhibition of production by gene silencing
through antisense oligonucleotides[36] or small interfering
RNA[37]; (2) prevention of PCSK9 binding to LDLR using
monoclonal antibodies[38], epidermal growth factor-like
repeat A (EGF-A), mimetic peptides[39] or adnectins; and (3)
inhibition of PCSK autocatalytic sites.
PCSK9 LDL-C
Endosome
LDL receptor
Lysosome PCSK9 bound LDL
receptor is digested in
lysosome Recycled LDL-receptor
LDL-cholesterol
incorporates into cell
Endosome
Figure 1 Mechanism and role of PCK9 in low-density lipoprotein-cholesterol metabolism. LDL: Low-density lipoprotein.
Chaudhary R
et al
. Review on PCSK9 inhibitors
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to statin therapy in patients with high atherosclerotic
cardiovascular risk with a follow up period of up to 12 wk.
SPIRE-1 (NCT01975376) and 2 (NCT01975389) have a
follow up period of up to 5 years collecting data on safety
and efficacy of this drug[49]. Recently, the preliminary
results of a study of Bococizumab delivery using an auto-
injector device (SPIRE-AI) reported successfully meeting
co-primary endpoints of percent change from baseline in
fasting LDL-C at week 12 and the delivery system success
rate, dened as the percent of patients whose attempts to
operate the pre-lled pen. SPIRE-AI is a 12-wk, double-
blind, placebo-controlled, randomized, parallel-group,
multicenter, phase Ⅲ clinical trial in 299 patients with
hyperlipidemia or mixed dyslipidemia receiving statin
therapy and whose LDL-C ≥ 70 mg/dL and assessed
the efcacy, safety, tolerability and subcutaneous admini-
stration of Bococizumab 150 mg and 75 mg with a pre-
lled pen[50].
Along similar lines, adnectins (also known as monobody)
and small peptide inhibitors have been investigated for LDL
reduction in phase
Ⅰ
clinical trials. The results in healthy
patients and those with hypercholesterolemia demonstrated
a maximal dose related reduction of LDL-C by up to
48%[51]. The advantage of developing adnectins is that they
are smaller than mAb, making them cheaper and easier to
produce. Their pharmacokinetics have been shown to be
favorable with a rapid onset of action in preclinical models,
further trials are awaited to see the development of this
agent[52].
Inhibition of autocatalytic site
This mechanism as a therapeutic target was first pro-
posed after discovering a loss of function mutation in the
autocatalytic cleavage site of PCSK9[53,54]. This approach
is still under preclinical investigational phase.
FDA APPROVAL STATUS OF PCSK9
INHIBITORS
The FDA approved Alirocumab (Praluent) in July 2015
for adult patients with heterozygous familial hyper-
cholesterolemia or in patients with clinically significant
atherosclerotic CVD requiring additional LDL lowering
after being on diet control and maximally tolerated statin
therapy. Evolocumab (Repatha) was also approved in
August, 2015 for use in adult patients with heterozygous
familial hypercholesterolemia, homozygous familial hyper-
cholesterolemia, or clinical atherosclerotic CVD requiring
additional lowering of LDL cholesterol after being on a
controlled diet and maximally-tolerated statin therapy.
Alirocumab (status: FDA approved)
Alirocumab has been studied in three phase
Ⅰ
trials. In
two of these trials, healthy volunteers were administered
Alirocumab intravenously (n = 40) or subcutaneously (n
= 32) which reduced LDL-C in a dose-dependent fashion
with a reduction of up to 65% at maximal doses[55]. The
Gene silencing via antisense oligonucleotides or small
interfering RNA
This approach targets intracellular PCSK9 activity by
utilizing antisense oligonucleotide to reduce intracellular
expression of PCSK9. Preclinical trials on hyperlipidemic
mice evaluating two such compounds were promising
with a reduction in LDL by 38% at six weeks of therapy
while doubling LDLR expression in the liver[38]. However,
the phase
Ⅰ
trials evaluating two of these agents were
terminated prematurely and further development of the
drug (BMS-84442) was not continued (NCT01082562).
Two additional drugs: SPC5001 and SPC4061 showed
successful reduction in LDL by 50% during preclinical
testing in primates[40]. However, the first phase
Ⅰ
trial
in healthy human subjects and individuals with familial
hypercholesterolemia were terminated early (NCT01
350960)[41,42]. SPC5001 was seen to cause mild to moder-
ate injection site reactions and renal tubular toxicity[43].
Further development of SPC4061 was discontinued for
undisclosed reasons.
Similarly, small interfering RNA (siRNA) administration
has been shown to significantly reduce plasma PCSK9
and LDL levels in cynomolgus monkeys[37,38,43]. ALN-PCS
is a siRNA, which was tested by delivery through second-
generation lipid nanoparticles. In a study by Fitzgerald
et al[44], ALN-PCS demonstrated a dose dependent
reduction in PCSK9 and LDL levels with a reduction of up
to 70% in PCSK9 levels and 40% in LDL levels at doses
of 0.4 mg/kg. This was the first study to demonstrate
intracellular PCSK9 inhibition translated into reduction of
circulating LDL levels.
Monoclonal antibodies
Utilization of monoclonal antibodies has been the most
effective approach thus far in inhibiting PCSK9 and re-
ducing LDL levels. Currently, at least six monoclonal
antibodies (mAb) have been or are being developed
and tested: Alirocumab (formerly called SAR236553/
REGN727), Evolocumab (formerly called AMG145), RG7
652[45], LGT209 (NCT01979601, NCT01859455), 1B20[46]
and Bococizumab (formerly called RN316/PF-049 50615).
Alirocumab and Evolocumab have recently been approved
by the FDA. The major clinical studies leading up to their
approval are outlined later in this paper.
Bococizumab is a unique mAb, which utilizes pH
sensitive binding to PCSK9 and was developed for a longer
serum half-life and duration of action on LDL reduction[47].
In phase
Ⅰ
studies, single intravenous or subcutaneous
dosages significantly reduced LDL in patients with
hypercholesterolemia, both with and without concomitant
atorvastatin therapy[48]. In a phase Ⅱ trial by Gumbiner
et al[48], patients on statin therapy not at target LDL-C
were enrolled and observed a 60% reduction in LDL-C
after 12 wk of therapy. Five phase Ⅲ trials are ongoing for
Bococizumab including SPIRE-HF (evaluating the efcacy
of this agent in heterozygous familial hypercholesterolemia
NCT01968980); SPIRE-HR (NCT01968954) and SPIRE-
LDL (NCT01968967) trials are comparing Bococizumab
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dose or switching to rosuvastatin. Atorvastatin at 20 mg
and 40 mg/d regimens reduced LDL by 44% and 54%
with addition of Alirocumab respectively vs 21% and 23%
with addition of ezetimibe respectively vs 5% and 5% with
doubling atorvastatin dose respectively compared to 21%
with switching to rosuvastatin 40 mg/d. In the OPTIONS
Ⅱ trial, rosuvastatin was studied using a similar protocol
and showed that the addition of Alirocumab had the most
significant reduction in LDL-C after 24 wk of therapy as
opposed to addition of ezetimibe or doubling the dose of
rosuvastatin[62,63]. Another study evaluating the efcacy of
Alirocumab as monotherapy (MONO study)[64] compared
to ezetimibe in patients with hypercholesterolemia and
moderate cardiovascular risk to monotherapy with
Alirocumab and found that Alirocumab reduced LDL-C 47%
vs 16% by ezetimibe after 24 wk of therapy (P < 0.0001).
CHOICE Ⅱ study evaluated Alirocumab in patients
intolerant to statin therapy. Two hundred and thirty
one patients with a history of statin intolerance were
shown to have a 56% reduction in LDL with Alirocumab
(vs placebo; P < 0.001)[59]. Another study evaluating
Alirocumab in patients intolerant to statin therapy is
the ODYSSEY ALTERNATIVE trial. Three hundred and
fourteen patients completed this randomized controlled
trial, which compared Alirocumab 75 mg every 2 wk (n
= 126) to ezetimibe 10 mg/d (n = 125) and atorvastatin
20 mg/d (n = 63) for 24 wk. At 24 wk, the data showed
a 45% reduction in LDL with Alirocumab as opposed
to 15% reduction in LDL with ezetimibe. This trial
demonstrated fewer skeletal muscle adverse events in
the Alirocumab group as compared to atorvastatin arm
[32.5% vs 46% respectively, HR = 0.61 (0.38-0.99; P =
0.042)], with no signicant difference when compared to
the ezetimibe group (41%) [HR 0.71 (0.47 to 1.06; P =
0.09)][65].
Alirocumab has also been shown to be effective
in lowering LDL-C in patients with familial hypercho-
lesterolemia. The FH
Ⅰ and FH Ⅱ studies evaluated a
total of 735 patients (n = 486 and 249 respectively) with
heterozygous familial hypercholesterolemia inadequately
controlled on lipid lowering therapy and found Alirocumab
to reduce LDL levels 48.8% (vs a 9.1% increase in
placebo: FH
Ⅰ study) and 48.7% (vs 2.8% increase
in LDL with placebo: FH Ⅱ study) from baseline[66].
ODYSSEY HIGH FH trial reported 105 patients with familial
hypercholesterolemia on maximally tolerated statin
therapy and LDL > 160 demonstrating a 46% reduction
of LDL (vs 7% with placebo) at 24 wk (P < 0.001)[67].
OLE trial (NCT01954394) is currently ongoing with results
anticipated by June 2017. This trial is recruiting patients
with heterozygous familial hypercholesterolemia who have
completed one of the other studies and evaluating for
safety parameters including adverse events, laboratory
data and vital signs.
ODYSSEY LONG TERM trial was recently published
and is a 78-wk follow-up of 2341 patients with hyper-
cholesterolemia and LDL > 70 mg/dL on maximally
tolerated statins. The patients receiving 150 mg Aliro-
cumab every 2 wk were shown to have a 62% reduction
third trial evaluated patients with non-familial hyper-
cholesterolemia on atorvastatin and LDL > 100 mg/dL
or with LDL > 130 mg/dL being managed by diet alone.
Alirocumab reduced LDL-C up to 65% in patients on
statins and up to 60% in patients being managed on
diet alone. It was observed that Alirocumab remained
effective for a longer period of time in patients not on
statins[55].
Three phase Ⅱ trials[56-58] evaluated the efficacy of
Alirocumab in patients with familial hypercholesterolemia.
Stein et al[58] evaluated 77 patients on statin therapy
with LDL-C greater than 100 mg/dL and found that
Alirocumab reduced LDL-C in a dose-dependent manner
by up to 43% with a maximum dosage of 300 mg every
4 wk. However, the reduction was even greater (up
to 70%) at a dosage regimen of 150 mg every 2 wk.
Additionally, these patients had a signicant reduction in
apoB levels and non-high density lipoprotein cholesterol
and also had increases in HDL. McKenney et al[56], in
their study of 183 patients conrmed a dose dependent
reduction of LDL-C with the most efficacious regimen
being 150 mg every 2 wk (with LDL reduction up to
70%). Interestingly, different doses of atorvastatin did
not make a significant difference in LDL-C reduction.
These results were further corroborated by Roth et al[57]
in their study of 92 patients with LDL-C > 100 mg/dL.
They showed that there was signicant and comparable
LDL reduction irrespective of the dosage of atorvastatin
(10 mg vs 80 mg) when added to Alirocumab 150 mg
every 2 wk[57].
The phase Ⅲ randomized, double-blinded ODYSSEY
trials were designed to evaluate Alirocumab for long-
term safety, efficacy and adverse events (Table 1) and
include CHOICE
Ⅰ, CHOICE Ⅱ, OLE, LONG TERM,
COMBO
Ⅰ, COMBO Ⅱ, FH
Ⅰ, FH Ⅱ, HIGH FH, MONO,
ALTERNATIVE, OPTIONS
Ⅰ and OPTIONS Ⅱ. The dosage
of Alirocumab administered was 150 mg every 2 wk in
ODYSSEY LONG TERM and HIGH FH trials and 75 mg
(titrated up to 150 mg to reach pre-specied LDL goals)
in ODYSSEY ALTERNATIVE, OPTIONS
Ⅰ, OPTIONS Ⅱ and
COMBO
Ⅰ trials.
CHOICE
Ⅰ study evaluated Alirocumab vs placebo in
803 patients with poorly controlled hypercholesterolemia.
Alirocumab reduced LDL by 52% in statin-naïve patients
and by 59% in patients on maximally tolerated statins
as compared to placebo (P < 0.001)[59]. Similarly,
COMBO
Ⅰ and Ⅱ trials evaluated 316 patients and 720
patients respectively with LDL > 70 mg/dL and high
cardiovascular risk on maximally tolerated statin therapy.
COMBO
Ⅰ showed Alirocumab reduced LDL-C up to 50%
(vs 2% with placebo) after 24 wk of treatment. COMBO
Ⅱ compared ezetimibe to Alirocumab in patients on
background statin therapy and found a 50% LDL reduction
with Alirocumab vs 20% reduction with ezetimibe at
24 wk[60]. OPTIONS
Ⅰ trial[61] published in August 2015,
randomized 355 patients with hypercholesterolemia
and LDL > 70 and found the addition of Alirocumab
to atorvastatin had the greatest reduction in LDL as
compared to addition of ezetimibe, doubling atorvastatin
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Table 1 Summary of phase Ⅲ ODYSSEY trials with Alirocumab
Name of trial Ref. Allocation and
blinding
No. of
patients
Inclusion criteria Study arms
(with dosing)
Primary end point Results
LONG TERM
(NCT01507831)
Seidah et al[7];
Randomized
double blinded trial
2341 Either 1 or 2 below and who aren’t
adequately controlled with their LLT:
(1) Patients with heFH with or without
CHD or CHD risk equivalents
OR (2) Patients with HCL with
CHD or CHD risk equivalents
Alirocumab
(SC) (n = 1553)
vs Placebo
(SC) (n = 788)
both with
background
LLT
Percentage change
in calculated LDL
cholesterol level
from baseline to
week 24
-61.0% change with
Alirocumab vs +0.8% change
with placebo (CI: -64.3 to
-59.4; P < 0.001)
FH Ⅰ
(NCT01623115)
Kastelein et al[66];
Randomized
double blinded
486 Patients with heterozygous
familial hypercholesterolemia who
are not adequately controlled with
their lipid-modifying therapy
Alirocumab
(SC) vs Placebo
(SC) both with
background
LLT
Percent change in
calculated LDL-C at
week 24
-48.8% for Alirocumab
compared with 9.1% for
placebo (P < 0.0001)
FH Ⅱ
(NCT01709500)
Kastelein et al[66];
Randomized
double blinded
249 Patients with heFH who are not
adequately controlled with their
LLT
Alirocumab
(SC) vs Placebo
(SC) both with
background
LLT
Percent change in
LDL-C to week 24
-48.7% for Alirocumab
compared with 2.8% for
placebo (P < 0.0001)
HIGH FH
(NCT01617655)
Kastelein et al[67];
Randomized
double blinded
107 Patients with heterozygous
familial hypercholesterolemia who
are not adequately controlled with
their lipid-modifying therapy with
LDL > 160
Alirocumab
(SC) (n = 72) vs
Placebo (SC) (n
= 35) both with
background
LLT
Percent change in
calculated LDL-C at
week 24
Percent decrease from
baseline was 45.7% vs 6.6%,
difference 39.1, P < 0.0001
Absolute difference in values
of LDL-C at 24 wk 107 mg/
dL vs 182 mg/dL
COMBO Ⅰ
(NCT01644175)
Colhoun et al[60];
Randomized
double blinded
316 Patients with hypercholesterolemia
and estbl CHD or CHD risk
equivalents; not controlled with a
maximally tolerated LLT, both at
stable dose for at least 4 to 6 wk
prior to screening
Alirocumab
(SC) (n = 205) vs
Placebo (SC) (n
= 106)
Percent change in
calculated LDL-C at
week 24
-48.2% with Alirocumab (CI:
-52.0% to -44.4%) and -2.3%
with placebo (CI: -7.6% to
3.1%) for Alirocumab and
placebo, respectively, an
estimated mean difference of
-45.9% (CI: -52.5% to -39.3%)
(P < 0.0001)
COMBO Ⅱ
(NCT01644188)
Moriarty et al[65];
Randomized
double blind
720 Patients with hypercholesterolemia
and established CHD or CHD
risk equivalents who are not
adequately controlled with a
maximally tolerated daily dose of
statin at stable dose for at least 4
wk prior to the screening visit
Alirocumab
(SC) + placebo
(for ezetimibe)
orally +
background
statin therapy (n
= 467)
vs Placebo (SC)
+ ezetimibe
orally +
Background
statin therapy (n
= 240)
Percent change in
calculated LDL-C at
week 24
Reductions in LDL-C
from baseline were 50.6%
± 1.4% for Alirocumab vs
20.7% ± 1.9% for ezetimibe
(difference 29.8% ± 2.3%; P <
0.0001)
OPTIONS Ⅰ
(NCT01730053)
Robinson et al[63];
Randomized
double-blinded
355 Patients with prior CV disease +
LDL-C ≥ 70 mg/dL, or CV risk
factors + LDL-C ≥ 100 mg/dL
Alirocumab
with
atorvastatin
20 mg vs
Ezetimibe with
atorvastatin
20 mg vs
Atorvastatin 40
mg
Alirocumab
with
atorvastatin
40 mg vs
ezetimibe with
atorvastatin
40 mg vs
atorvastatin
80 mg vs
rosuvastatin 20
mg
Percent change in
calculated LDL-C to
week 24
Percent reduction from
baseline 44.1% (Alirocumab)
vs 20.5% (ezetimibe) vs 5.0%
(atorvastatin 40); P < 0.0001
Percent reduction from
baseline 54% (Alirocumab)
vs 22.6% (Ezetimibe) vs 4.8%
(Atorvastatin 80) vs 21.4%
(rosuvastatin 40); P < 0.0001
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at 24 wk. These results persisted at 78 wk. In a post-in LDL as opposed to a 1% increase in LDL with placebo
OPTIONS Ⅱ Robinson et al[63];
Randomized
double-blinded
305 Patients with prior CV disease +
LDL-C ≥ 70 mg/dL, or CV risk
factors + LDL-C ≥ 100 mg/dL
Alirocumab
with
rosuvastatin 10
mg
vs ezetimibe
with
rosuvastatin 10
vs rosuvastatin
20
Alirocumab
with
rosuvastatin
20 mg vs
ezetimibe with
rosuvastatin 20
vs Rosuvastatin
40
Percent change in
calculated LDL-C to
wk 24
Percent reduction from
baseline 50.6% (Alirocumab)
vs 14.4% (ezetimibe) vs 16.3%
(rosuvastatin 20); P < 0.0001
Percent reduction from
baseline 36.3% (Alirocumab)
vs 11.0% (Ezetimibe) vs
20.3% (rosuvastatin 40); P <
0.0001
ALTERNATIVE
(NCT01709513)
Moriarty et al[65];
Randomized
double-blinded
314 Primary heFH with moderate,
high or very high CV risk and
history of statin intolerance
Alirocumab +
oral placebo
vs ezetimibe
(10 mg/d) +
sc placebo vs
atorvastatin
(20 mg/d) + sc
placebo
Percent change in
calculated LDL-C to
week 24 in intention
to treat group
Percent reduction from
baseline 45% (Alirocumab)
vs 14.6% (Ezetimibe) with a
mean difference of -30.4%; P
< 0.0001
CHOICE Ⅰ
(NCT01926782)
Stroes et al[78];
Randomized,
double-blinded
803 Patients not having
adequate control of their
hypercholesterolemia based on
their individual level of CVD risk
Alirocumab
at q4 week
regimen vs
Placebo
Percent change
in LDL from
baseline to week
24 for Alirocumab
q4w vs placebo
in patients with
hypercholesterolemia
at moderate, high, or
very high CVD risk
with concomitant
statin therapy (n =
547)
Percent change
in LDL from
baseline to week
24 for Alirocumab
q4w vs placebo
in patients with
hypercholesterolemia
not on concomitant
statin therapy (n =
256)
LDL was reduced by 58.7%
with Alirocumab in patients
on maximally tolerated
statins (P < 0.001)
LDL was reduced by 52.4%
with Alirocumab in statin
naïve patients vs placebo (P
< 0.001)
CHOICE Ⅱ
(NCT02023879)
Stroes et al[78];
Randomized,
double-blinded
231 Patients with primary
hypercholesterolemia (heFH
or non-FH) not adequately
controlled with their non statin
lipid modifying therapy or diet
and statin intolerance
Alirocumab
(SC) vs placebo
(SC)
The percent change in
LDL-C from baseline
to week 24
Alirocumab reduced LDL-C
by 56.4% (P < 0.0001) vs
placebo
LONG TERM
(NCT01507831)
Robinson et al[62];
Randomized,
double-blinded
2341 Either A or B below and who are
not adequately controlled with
their LLT: (1) Patients with heFH
with or without established CHD
or CHD risk equivalents
OR
(2) Patients with
hypercholesterolemia together
with established CHD or CHD
risk equivalents
Alirocumab
(SC) 150 mg
every 2 wk vs
placebo (SC)
every 2 wk
Percentage change
in calculated LDL
cholesterol level from
baseline to week 24,
analyzed with the
use of an intention-
to-treat approach
150 mg Alirocumab every
2 wk had a 62% reduction
in LDL as opposed to a 1%
increase in LDL with placebo
at 24 wk
SC: Subcutaneous; LLT: Lipid lowering therapy; heFH: Heterozygous familial hypercholesterolemia; CHD: Coronary heart disease; HCL: Hyper-
cholesterolemia; MACE: Major adverse cardiovascular events; MI: Myocardial infarction; UA: Unstable angina; HR: Hazards ratio; CI: Condence interval.
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patients intolerant to statins (GAUSS-2 and GAUSS-3);
standalone in hyperlipidemia (MENDEL-2); heterozygous
familial hypercholesterolemia (RUTHERFORD-2 and
TAUSSIG); homozygous familial hypercholesterolemia
(TESLA and TAUSSIG); with primary hyperlipidemia or
mixed cholesterol disorder (THOMAS-1 and THOMAS-2:
Device trials). Also, long-term safety and efficacy
data is being evaluated by the five following studies:
DESCARTES; FOURIER; OSLER-2 trial; GLAGOV trial and
TAUSSIG study.
In LAPLACE-2 study 1896 patients with fasting LDL
≥ 150 (when not on statins) or LDL ≥ 100 (on non-
intense regimen of statins) or LDL ≥ 70 (on intensive
statin therapy) were randomized to a daily moderate
or high-intensity statin regimen and after 4 wk, further
randomized to receive Evolocumab, ezetimibe or
placebo. Evolocumab was shown to reduce LDL levels
by 66% to 75% (on every 2 wk regimen) and by 63%
to 75% (on once monthly regimen) when compared
to placebo in moderate- and high intensity statin
groups. In moderate and high intensity statin groups,
Evolocumab led to signicant reduction in absolute LDL
values in both regimens of Evolocumab (every 2 wk and
monthly). Adverse events reported were comparable in all
groups[75]. YUKAWA-2 study showed a similar reduction
in LDL in 404 Japanese patients when Evolocumab
regimens (140 mg once every 2 wk and 420 mg once
a month) were compared to placebo on 2 regimens of
low-dose background statin therapy (5 mg/d and 20
mg/d atorvastatin). Interestingly, the reduction in LDL
appeared to be similar irrespective of statin dosage (in
combination with Evolocumab) and showed a 67%
to 76% LDL reduction at 12 wk[76]. MENDEL-2 trial
compared the efcacy of Evolocumab with ezetimibe and
placebo in 614 patients with LDL between 100 mg/dL
and 190 mg/dL and low risk on Framingham scale (≤
10%). Evolocumab was shown to reduce LDL by up to
57% more than placebo and 40% more than ezetimibe
after 12 wk of therapy[77].
GAUSS-2 trial evaluated 307 patients with statin
intolerance and compared the 2 regimens of Evolocumab
(140 mg once every 2 wk and 420 mg once a month)
to daily oral or subcutaneous placebo (both placebo
groups on ezetimibe). At 12 wk, Evolocumab group
showed a reduction in LDL by 56% vs 39% in the other
groups (placebo + ezetimibe arm)[78]. Along similar lines,
GAUSS-3 trial evaluated the efficacy of Evolocumab in
218 statin intolerant patients compared to ezetimibe.
The initial phase of the study included administration of
atorvastatin (20 mg) for 10 wk and placebo randomized
in a 1:1 fashion, followed by a 2-wk washout period
and crossover to alternate therapy for another 10 wk.
The patients who experienced muscle related adverse
effects while on statin therapy and not on placebo were
further enrolled in the second phase of the study, which
was a 24 wk double blinded randomized controlled
trial to compare Evolocumab (420 mg/mo divided in 3
doses) with ezetimibe (10 mg/d). At 24 wk, LDL-C was
hoc analysis, the reduction in LDL was also associated
with reduction in the combined end-point of death from
coronary artery disease, nonfatal myocardial infarction,
fatal or nonfatal ischemic stroke or unstable angina
requiring hospitalization (1.7% with Alirocumab vs
3.3% with placebo; HR = 0.52; 95%CI: 0.31-0.9; P =
0.02)[68]. The ODYSSEY Outcomes trial (NCT01663402)
is ongoing is closed to recruitment, and will assess the
effects of Alirocumab on CVD events in 18000 patients on
maximally tolerated statin therapy. Results of this trial are
expected in February 2018.
Evolocumab (status: FDA approved)
Evolocumab has been studied in two phase
Ⅰ studies.
Dias et al[69] evaluated healthy volunteers in phase
Ⅰa
and showed a short-term dose-dependent reduction in
LDL by up to 65% and after 6 to 8 wk of therapy by up
to 75% with a maximally administered dose of 420 mg
subcutaneously/intravenously. Phase
Ⅰb trial similarly
demonstrated up to 75% reduction in LDL as compared
to placebo over 1 to 4 wk in healthy volunteers.
Four phase Ⅱ trials were subsequently performed
that continued to show the benets of Evolocumab with
a dose-dependent reduction of LDL (maximal dosing up
to 420 mg) when added to maximally tolerated statin
therapy in patients with hypercholesterolemia (including
familial hypercholesterolemia)[70-72]. In LAPLACE-TIMI57
trial[70], Evolocumab was tested at varying doses ranging
from 70 to 140 mg every 2 wk or 280 to 420 mg every
4 wk in 631 patients on stable statin therapy and LDL
more than 85 mg/dL. LDL reduction up to 65% was
observed with the every two-week regimen as compared
to approximately 50% LDL reduction with the every
4-wk regimen. Evolocumab has also been studied as
monotherapy in 160 patients with hypercholesterolemia
and intolerance to statins in the GAUSS trial[73]. At doses
of 420 mg every 4 wk, it was shown to reduce LDL
by 40% to 50%. Furthermore, addition of ezetimibe
reduced LDL by up to 65%. Subsequently, the MENDEL
trial[71] showed a similar efcacy in LDL-C lowering when
Evolocumab was used as monotherapy in 406 patients
with hypercholesterolemia. Based on these trials, the
optimal frequency of Evolocumab therapy was determined
to be twice monthly to achieve a 50% to 60% reduction
in LDL in combination with statins. However, when used
as a monotherapy therapy, a frequency of once every
4 wk would be acceptable. Stein et al[74] evaluated 8
patients with homozygous familial hypercholesterolemia,
and found Evolocumab (at 420 mg every 2 wk) to reduce
LDL by approximately 25% vs 20% when used every 4
wk.
Evolocumab has further been evaluated in PROFICIO
(Program to reduce LDL-C and cardiovascular outcomes
following inhibition of PCSK9 in different populations)
phase Ⅲ trials (Table 2). The PROFICIO program
includes 14 trials where Evolocumab is being evaluated
in patients with hyperlipidemia in combination with
statins (LAPLACE-2 and YUKAWA-2); hyperlipidemic
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Table 2 Summary of important phase Ⅲ PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition
of PCSK9 In Different Populations) trials with Evolocumab
Name of trial Ref. Allocation
and blinding
No. of
patients
Inclusion criteria Study arms (with dosing) Primary end
point
Results
LAPLACE-2
(NCT01763866)
Robinson et al[75];
Randomized
double blinded
trial
1896 Individuals with LDL
> 150 mg/dL (not
on statin); or LDL >
100 mg/dL (on non-
intensive statin); or
LDL ≥ 80 mg/dL (with
intensive statin therapy)
Initially randomized to
daily moderate or high
intensity atorvastatin
for 4 wk. Patients were
again randomized to
Evolocumab (sc) vs
ezetimibe vs placebo
Percentage
change in
calculated LDL
cholesterol level
from baseline to
week 12
Evolocumab q2w and
qmonthly: 63% to 75%
reduction in LDL vs
placebo
Ezetimibe 19% to 32%
reduction in LDL vs
placebo
YUKAWA-2
(NCT01953328)
Kiyosue et al[76];
Randomized
double blinded
404 Japanese patients with
LDL > 70 on stable dose
statins for > 4 wk and
high cardiovascular risk
Initially randomized to
daily atorvastatin of 5 mg
or 20 mg for 4 wk. They
were further randomized
to Evolocumab (sc) at q2
week and qmonthly vs
placebo
Percent change
in calculated
LDL-C from
baseline at week
12
-67.0% to -76% reduction
with Evolocumab
compared to placebo (P
< 0.0001)
GAUSS-2
(NCT01763905)
Stroes et al[78];
Randomized
double blinded
307 Patients with LDL not at
goal according to their
cardiovascular risk and
not on statin or low dose
statin due to history of
statin intolerance (> 2
statins) with stable LLT
> 4 wk
Evolovumab (SC) at
q2 week and qmonthly
dosing vs Placebo (SC)
+ Ezetimibe (10 mg/d)
daily
Percent change
in LDL-C from
baseline at the
mean of weeks
10 and 12 and at
week 12
Change from
baseline LDL at
week 12
-55.3% to -56.1% for
Evolocumab compared
with -16.6% to -19.2% for
ezetimibe (P < 0.0001)
-103.6 to -105.4
(Evolocumab) vs -33 to
-39 (mg/dL)
MENDEL-2
(NCT01763827
Koren et al[77];
Randomized
double-blinded
614 NCEP ATP Ⅲ
Framingham risk score
of < 10%
Fasting LDL-C ≥ 100
mg/dL and <
190 mg/dL
Oral placebo to SC
placebo; ezetimibe to SC
placebo and oral placebo
to SC Evolocumab at
dosing regimens of 140
mg biweekly and 420 mg
monthly
Percent change
from baseline
in LDL-C level
averaged at
weeks 10 and 12
Percent change
from baseline in
LDL-C level at
week 12
Percent LDL change from
baseline averaged at
weeks 10 and 12 in the:
Once per 2 wk
arm: -56.9% (with
Evolocumab) vs -17.5
(with ezetimibe) vs -0.4%
(placebo)
For monthly arm:
-58.8% (with
evolocumab) vs -19.1
(with ezetimibe) vs -1.4%
(placebo)
Percent LDL change
from baseline averaged
at weeks 12: Once per
2 wk arm: -57% (with
Evolocumab) vs -17.8
(with ezetimibe) vs 0.1%
(placebo)
For monthly arm: -56.1%
(with Evolocumab) vs
-18.6 (with ezetimibe) vs
-1.3% (placebo)
RUTHERFORD-2
(NCT01763918)
Raal et al[72];
Randomized
double blinded
329 Patients with
heterozygous familial
hypercholesterolemia
who are on stable LLT
for 4 wk and LDL > 100
mg/dL
Evolocumab (SC) at 140
mg q2 weeks vs placebo
SC q2w AND
Evolocumab SC
qmonthly vs Placebo
(SC)
Percent change
from baseline
in LDL-C level
averaged at
weeks 10 and 12
Percent change
from baseline in
LDL-C level at
week 12
Percent LDL change
from baseline averaged
at weeks 12 in the: Once
per 2 wk arm: -61.2%
(with Evolocumab) vs
-1.1% (with placebo)
For monthly arm: -63.3%
(with evolocumab) vs
2.3% (with placebo)
Percent LDL change
from baseline averaged
at weeks 10 and 12 in
the: Once per 2 wk
arm: -61.3% (with
Evolocumab) vs -2%
(with placebo)
For monthly arm: -55.7%
(with Evolocumab) vs
5.5% (with placebo)
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in LDL with both regimens: 140 mg every 2 wk led to
59.2% reduction (CI: 53.4% to 65.1%) and 420 mg
once a month led to LDL reduction by 61.3% (CI: 53.6%
to 69%) as compared to placebo after 12 wk (P < 0.001
for all)[81]. The TESLA trial examined 50 patients with
homozygous familial hypercholesterolemia on stable lipid
lowering therapy and evaluated monthly Evolocumab
(420 mg) vs placebo therapy for 12 wk. Addition of
Evolocumab led to a signicant reduction in LDL-C by up
to 31% (CI: -44% to -18%; P < 0.0001)[82].
In the Open-Label Study of Long-Term Evaluation
Against LDL-C (OSLER) 1 and 2 trials 4465 patients
were enrolled who had completed 1 of the phase 2 or
phase 3 studies of Evolocumab (MENDEL-1, LAPLACE
TIMI 57, GAUSS-1, RUTHERFORD-1, YUKAWA-1,
MENDEL-2, LAPLACE-2, GAUSS-2, RUTHERFORD-2,
DESCARTES, THOMAS-1 or THOMAS-2) and randomized
to receive either Evolocumab (420 mg/mo in OSLER-1
and 140 mg every 2 wk or 420 mg once a month in
OSLER-2 trial) plus standard therapy (n = 2976) or
standard therapy (n = 1489). The median follow-up
was 11.1 mo. This study showed a 61% reduction in
LDL-C with Evolocumab compared to standard therapy
(95%CI: 59% to 63%; P < 0.001). Overall adverse
events were in 69% of patients in Evolocumab group
compared to 65% in standard therapy group. Of note,
the neurocognitive adverse events were low, but were
more frequent in Evolocumab group and appeared
reduced by 53% with Evolocumab compared to 17%
with ezetimibe. Muscle-related side effects were reported
in 21% patients on Evolocumab compared to 29% with
ezetimibe with stoppage of drug administration due to
muscle symptoms in 1% of patients in Evolocumab and
7% of patients on ezetimibe[79].
DESCARTES trial[80] evaluated 901 patients with
hyperlipidemia, comparing Evolocumab (420 mg once
a month subcutaneous) plus background lipid lowering
therapy vs placebo plus background lipid lowering
therapy for a period of 52 wk. Background lipid lowering
therapy included: Diet alone, low intensity atorvastatin
(10 mg), high intensity atorvastatin (80 mg) or ator-
vastatin 80 mg/d. All patients had fasting LDL-C > 75
mg/dL on background lipid lowering therapy. Addition
of Evolocumab resulted in LDL reduction by 51% to
60% in diet alone group, 59% to 64% in patients on
10 mg atorvastatin, 51% to 62% in patients on 80
mg atorvastatin and 43% to 54% in patients with
atorvastatin 80 mg/d and ezetimibe 10 mg/d (P < 0.001
for all).
Evolocumab has also been shown to be efficacious
in patients with heterozygous and homozygous familial
hypercholesterolemia. In the RUTHERFORD-2 trial, 329
patients with heterozygous familial hypercholesterolemia
were randomized to receive Evolocumab (140 and 420
mg respectively) or placebo at two weekly and monthly
regimens. Evolocumab showed a significant reduction
TESLA
(NCT01588496)
Raal et al[82];
Randomized
double-blinded
50 Homozygous familial
hypercholesterolemia,
on stable lipid-regulating
therapy for at least 4 wk,
LDL cholesterol ≥ 130
mg/dL (3.4 mmol/L);
Triglyceride ≤ 400
mg/dL (4.5 mmol/L);
Body weight of ≥ 40 kg
at screening,
and not receiving
lipoprotein apheresis
Evolocumab (SC) 420 mg
every 4 wk vs placebo (SC)
Percentage
change in
ultracentrifugation
LDL cholesterol
from baseline at
week 12 compared
with placebo,
analyzed by
intention-to-treat
Percent change from
baseline in LDL-C
at week 52
Evolocumab
signicantly reduced
ultracentrifugation LDL
cholesterol at 12 wk by
30.9% (95%CI: -43.9%
to -18.0%; P < 0.0001) vs
placebo
DESCARTES
(NCT01516879)
Blom et al[80];
Randomized,
double-blinded
901 Fasting LDL ≥ 75
mg/dL and meeting
the following on
background LLT: (1) <
100 mg/dL for subjects
with diagnosed CHD or
CHD risk equivalent; (2)
< 130 mg/dL for subjects
without diagnosed CHD
or CHD risk equivalent;
(3) on maximal
background LLT dened
as atorvastatin 80 mg PO
QD and ezetimibe 10 mg
PO QD
Fasting triglycerides ≤
400 mg/dL
Evolocumab (SC) 420
mg every 4 wk with diet
alone vs placebo with diet
Evolocumab (SC) 420
mg every 4 wk with diet
+ atorvastatin 10 mg/d
vs placebo with diet and
atorvastatin 10 mg/d
Evolocumab (SC) 420 mg
every 4 wk + atorvastatin
80 mg/d vs placebo +
atorvastatin 80 mg/d
Evolocumab (SC) 420 mg
every 4 wk + atorvastatin
80 mg/d + ezetimibe
10 mg/d vs placebo +
atorvastatin 80 mg/d +
ezetimibe 10 mg/d
Addition of Evolocumab
resulted in LDL
reduction by: (1) 51% to
60% in diet alone group;
(2) 59% to 64% in patients
on 10 mg atorvastatin
(3) 51% to 62% in patients
on 80 mg atorvastatin
(4) 43% to 54% in patients
with atorvastatin 80
mg/d and ezetimibe 10
mg/d (P < 0.001 for all)
SC: Subcutaneous; LLT: Lipid lowering therapy; heFH: Heterozygous familial hypercholesterolemia; CHD: Coronary heart disease; HCL: Hyper-
cholesterolemia; MACE: Major adverse Cardiovascular Events; MI: Myocardial infarction; UA: Unstable angina; HR: Hazards ratio; CI: Condence
interval.
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No data are available in patients with severe renal and
hepatic impairment.
Evolocumab
The pharmacokinetic and pharmacodynamics properties
of Evolocumab[83] demonstrate non-linear pharmacokin-
etics in absorption at doses below 140 mg; however,
between doses of 140 to 420 mg linear pharmacokinetics
is observed. The time to reach maximum concentration
is 3 to 4 d after a single dose. After a single 420 mg
dosage, its volume of distribution has been estimated
to be 3.3 L ± 0.5 L. A steady state in serum is observed
after about 12 wk of dosing. The t1/2 of Evolocumab is
between 11 to 17 d. The maximum reduction of LDL after
therapy was similar after dosing of 140 mg every 2 wk
or 420 mg once a month with effect within 14 d. Clinical
studies have not revealed a difference in pharmacokinetics
of Evolocumab in mild or moderate renal and hepatic
impairment. However, subjects with severe renal and
hepatic impairment have not been studied.
ADVERSE EFFECTS AND
CONTRAINDICATIONS
The following side effects have been reported by data
gathered from over 7000 patients (n = 2476 for Aliro-
cumab and n = 5416 for Evolocumab) evaluated in
the clinical trials mentioned above. Major side effects
observed for Alirocumab and Evolocumab are described
below.
Alirocumab
Alirocumab is contraindicated in patients who develop
serious hypersensitivity reactions like hypersensitivity
vasculitis or allergic reactions requiring hospitalization with
its usage. The most common adverse effects observed
with Alirocumab include nasopharyngitis (11.3% vs 11.1%
in placebo), injection site reactions (erythema, itchiness,
swelling, pain or tenderness) (7.2% vs 5.1% in placebo),
influenza (5.7% vs 4.6% in placebo), urinary tract
infection (4.8% vs 4.6% in placebo), diarrhea (4.7% vs
4.4% in placebo), bronchitis (4.3% vs 3.8% in placebo),
myalgia (4.2% vs 3.4% in placebo), muscle spasms (3.1%
vs 2.4% in placebo), sinusitis (3% vs 2.7% in placebo),
cough (2.5% vs 2.3% in placebo), contusion (2.1% vs
1.3% in placebo) and musculoskeletal pain (2.1% vs
1.6% in placebo). The most common adverse events that
lead to drug discontinuation were allergic reactions (0.6%
for Alirocumab vs 0.2% for placebo) and elevated liver
enzymes (0.3% in Alirocumab vs < 0.1% in placebo).
Evolocumab
Contraindications for Evolocumab are similar to Aliro-
cumab. The overall incidence of adverse effects with
Evolocumab 140 mg every 2 wk as compared to placebo
were 43.6% vs 41% respectively. The most common
adverse effects were nasopharyngitis (5.9% vs 4.8% in
placebo), upper respiratory tract infection (3.2% vs 2.7%
to be unrelated to LDL level at the time of treatment.
Composite adverse cardiovascular events (all-cause
death, coronary events including myocardial infarction,
unstable angina requiring hospitalization, or coronary
revascularization, cerebrovascular events including stroke
or transient ischemic attack, and heart failure requiring
hospitalization) were signicantly lower in patients with
Evolocumab compared to standard therapy (HR = 0.47;
95%CI: 0.28 to 0.78; P = 0.003)[83,84].
The TAUSSIG trial (NCT01624142) is evaluating
Evolocumab therapy in 300 patients with severe familial
hypercholesterolemia to determine its efcacy and side
effect profile. The results of this study are anticipated
by March 2020. Preliminary results reported by Stein et
al[74] on 8 patients with LDLR-negative or LDLR defective
homozygous familial hypercholesterolemia on stable
drug therapy when treated with Evolocumab at 420 mg
monthly for ≥ 12 wk, followed by 420 mg every 2 wk for
another 12 wk showed LDL reduction by 14% to 16% at
12 wk with 2 wk and 4 wk dosing regimens respectively
with no serious adverse events reported[75]. Finally, the
preliminary results of GLAGOV study (NCT01813422)
evaluating 950 patients with coronary artery disease on
lipid lowering therapy undergoing cardiac catheterization
for changes in percentage atheroma volume after 78
wk of Evolocumab therapy met primary and secondary
endpoints and nal results are to be reported in American
Heart Association (AHA) conference in November, 2016.
PHARMACOKINETICS AND
PHARMACODYNAMICS
The pharmacokinetic and pharmacodynamics parameters
of PCSK9 inhibitors are described below[85,86].
Alirocumab
The time taken to reach maximum serum concentration
is 3-7 d with similar serum concentration - time proles
between abdomen, upper arm or thigh as the sites of
injection. Steady state concentrations are reached at
an average of 3 to 4 doses. The volume of distribution
following intravenous administration is 0.04 to 0.05 L/kg.
The median half-life (t1/2) observed was between 17
to 20 d at 75 or 150 mg dosing every 2 wk. Alirocumab
is eliminated in two phases depending upon its plasma
concentration. The predominant mode of elimination
at lower concentrations is via saturation of the targets
(PCSK9) bound to the antibodies; however, at higher
concentrations it is primarily through proteolytic path-
ways[81]. There have been no metabolism studies
conducted since it has been previously demonstrated that
reticuloendothelial system is responsible for metabolizing
antibodies to small peptides and amino acids[87]. The
maximum reduction in free plasma PCSK9 levels and LDL
was observed within 3 and 15 d respectively, after drug
administration with no difference noted between different
sites. No dose adjustment is needed for patients with
mild or moderately impaired renal or hepatic function.
Chaudhary R
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mendations.
PCSK9 inhibitors are especially beneficial in the
treatment of familial hypercholesterolemic patients who
are intolerant to statins or have an elevated LDL-C level
despite being on maximally tolerated statin therapy.
Intuitively, addition of a PCSK9 inhibitor to low dose
statin therapy will be more effective in lowering LDL and
avoiding the side effects of statins, since low dose and
high dose statin regimens have yielded similar efficacy
when combined with PCSK9 inhibitors.
Several potential barriers exist that may impede the
widespread use of these medicines. First, statins have
a proven effectiveness that has been demonstrated in
multiple long-term studies. Statins have been shown to
reduce cardiovascular mortality by 30% and incidence of
stroke by 20% in multiple long-term studies[91,92]. PCSK9
inhibitors are effective in reducing LDL-C levels but
currently lack data demonstrating their use reduces CVD
events. Trials evaluating the effect of PCSK9 inhibitors
on long-term CVD events, however, are currently under-
way: FOURIER (Further cardiovascular outcomes
research with PCSK9 inhibition in subjects with elevated
risk; n = 22500) for Evolocumab (NCT01764633) and
ODYSSEY-OUTCOMES (ODYSSEY outcomes: Evaluation
of cardiovascular outcomes after an acute coronary
syndrome during treatment with alirocumab SAR236553)
(NCT01663402) for Alirocumab. However, their data will
not be available until December 2017 (for Alirocumab)
and February 2018 (for Evolocumab).
Another potential barrier to widespread use of
PCSK9 inhibitors is their cost. The Institute for Clinical
and Economic Review (ICER) reported that the number
needed to treat for 5 years to avoid one major adverse
cardiovascular event (NNT5) is 28. However, a list price
of $ 14350 per year generates a cost-effectiveness
ratio which far exceeds the accepted threshold of $
100000/quality-affected life-years[93]. To achieve cost-
effectiveness at this threshold would require a price
reduction by 60% to 65% of the current price. At
the conclusion of their report, the ICER suggested a
reduction by 85% to an annual cost of $2177 might be
required to avoid excessive cost burdens to the health
care system[94]. It should be noted that since there are
limited data on clinical adverse cardiovascular events,
cost effectiveness data might change once results from
ongoing CVD endpoint studies are available.
PCSK9 therapy is a welcome treatment option for
statin intolerant patients who require treatment of their
hyperlipidemia. It will be important that busy practitioners
do not under-prescribe statins nor be dissuaded from
attempting to find a dose of and statin agent that is
tolerated by the patient because PCSK9 inhibitors are
available. Despite these obstacles, PCSK9 inhibitors are
an exciting agent for reducing LDL-C hyperlipidemia and
have ushered in a new era of lipid lowering therapy.
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