Canadian Journal of Cardiology 33 (2017) 350e357

Review
New Drugs for Atherosclerosis
Caroline S. Bruikman, MD, Robert M. Stoekenbroek, BSc, G. Kees Hovingh, MD, PhD, MBA,
and John P. Kastelein, MD, PhD, FESC
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

ABSTRACT 
RESUM 
E
Atherosclerosis, the underlying process that ultimately leads to clinical L’atheroscle
rose, le processus sous-jacent qui mène ultimement à la
cardiovascular disease (CVD), is caused by the multifactorial interac- maladie cardiovasculaire (MCV), est cause e par l’interaction multi-
tion of various conditions, and dyslipidemia is widely acknowledged as factorielle de diverses affections, et la dyslipide mie est largement
1 of the crucial risk factors in this process. Statin drugs have been reconnue comme l’un des facteurs de risque cruciaux dans le pro-
shown to decrease low-density lipoprotein cholesterol and CVD cessus. Il a e te
 de
montre que les me dicaments de la famille des
morbidity as well as mortality and are therefore pivotal in CVD pre- statines diminuent le cholesterol à lipoproteines de faible densite
 ainsi
vention. Despite the use of statin drugs, CVD remains a leading cause que la morbidite  et la mortalite
 lie
es à la MCV et qu’ils sont par con-
of mortality worldwide, which suggests that additional lipid-lowering sequent essentiels dans la pre vention de la MCV. En de pit de l’utili-
therapies are warranted. Several novel therapeutic agents, which are sation des me dicaments de la famille des statines, la MCV demeure
described in this review, are now well on their way in their respective l’une des causes principales de mortalite  dans le monde entier, ce qui
development paths and might revolutionize anti-atherosclerotic drug suggère que des traitements hypolipe miants additionnels sont
therapy. s. Plusieurs nouveaux agents the
justifie rapeutiques de crits dans la
presente revue sont en bonne voie dans leur processus d’e laboration
volutionner le traitement me
respectif et pourraient re dicamenteux de
roscle
l’athe rose.

Cardiovascular disease (CVD) is a leading cause of morbidity
and mortality worldwide.
Atherosclerosis, the underlying disease process in CVD, is
caused by a multiplicity of conditions, and dyslipidemia is 1 of
the most important risk factors. Large prospective epidemio-
logic studies have consistently shown that high levels of low-
density lipoprotein cholesterol (LDL-C) are predictive of
future CVD events, and the causal nature of this association
was bolstered by multiple studies showing that lowering
LDL-C levels results in reduced CVD risk.1
The effect of statin drugs on CVD outcomes is driven by
the extent of LDL-C lowering. High-intensity statin therapy,
defined as atorvastatin in 40- or 80-mg doses and rosuvastatin
in 20- or 40-mg doses, typically lower LDL-C and triglyceride
(TG) levels by approximately 50% and 30%, respectively, and
are therefore recommended in patients at high risk.2 Ezeti-
mibe can be added to this regimen, which will result in an
Received for publication August 17, 2016. Accepted September 8, 2016.
Corresponding author: John P. Kastelein, MD, PhD, FESC, Department
of Vascular Medicine, Academic Medical Centre, Meibergdreef 9, 1105 AZ
Amsterdam, The Netherlands. Tel.: þ31-20-566-6612; fax: þ31-20-566-
9343.
E-mail: j.j.kastelein@amc.uva.nl
See page 356 for disclosure information.
approximate further 20% lowering of LDL-C. The Improved
Reduction of Outcomes: Vytorin Efficacy International Trial
(IMPROVE-IT) showed a modest additional reduction of
events by adding ezetimibe to statin drugs.3
Other lipid-lowering therapies currently comprise fibrates,
which predominantly lower TG levels. The evidence that this
class has a beneficial effect on CVD outcome measures has not
been provided.4
Not all patients benefit from these therapies, because of either
side effects (ranging from mild myalgia to rhabdomyolysis,
diabetes mellitus) or central nervous system complaints.5
Therefore, extensive research is being carried out to expand
the therapeutic opportunities to treat dyslipidemia. We discuss
those novel lipid-lowering therapies that are currently evaluated.
Novel Pharmacologic Treatment to Decrease
Circulating LDL-C
Proprotein convertase subtilisin/kexin type 9 inhibitors
Of the various novel approaches to treat dyslipidemia,
proprotein convertase subtilisin/kexin type 9 (PCSK9) in-
hibition is the most advanced in clinical development.
PCSK9 inhibitors reduce circulating LDL-C by blocking
PCSK9-mediated degradation of the LDL receptor.6 Pro-
spective observational studies showed that individuals with

http://dx.doi.org/10.1016/j.cjca.2016.09.010
0828-282X/Ó 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

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Bruikman et al. 351
New Drugs for Atherosclerosis

Table 1. Therapeutic agents against atherosclerosis and their influence on the lipid profile
Group of drugs Low-density lipoprotein Triglycerides High-density lipoprotein Lipoprotein a Reference
PCSK9 inhibitors  >40%  <15% þ <15%  15-40% Navarese et al.8
Zhang et al.9
ASO against apoB-100  >40%  15%-40% No effect  15%-40% Raal et al.15-20
Carboxylase Ac-CoA e e e e
inhibitors
MTP inhibitor  >40%  >40% No effect  <15% Sirtori et al22
AMPK and ACL  15%-40% e No effect No effect Blom et al.25
modulators
CETP inhibitors  15%-40%  <15% þ >40%  15%-40% Glomset et al.28
Recombinant HDL-C e e e e
Viral vectors e  >40% e e Gaudet et al.45
ApoC3 antisense e  >40% e e Crosby et al.51-53
Lp(a) antisense No effect e e  >40% Gaudet et al.56,57
ACL, adenosine triphosphate-citrate lyase; apoC3, apolipoprotein C3; AMPK, adenosine monophosphateeactivated protein kinase; apoB-100, apolipoprotein
B-100; Ac-CoA, acetyl coenzyme A; ASO, antisense oligonucleotide; CETP, cholesterol ester transfer protein; HDL-C, high-density lipoprotein cholesterol; Lp(a),
lipoprotein a; MTP, microsomal transfer protein; PCSK9, proprotein convertase subtilisin/kexin type 9.

loss-of-function mutations in the PCSK9 gene exhibit
a reduced CVD risk compared with noncarriers.7 These
observations rapidly fueled interest in developing approaches
to pharmacologically inhibit PCSK9, which culminated in
the clinical development of monoclonal antibodies targeting
PCSK9. Alirocumab and evolocumab are now approved for
use in adults with primary hypercholesterolemia (heterozy-
gous familial and nonfamilial cases) or mixed dyslipidemia,
in combination with a statin drug or a statin drug with other
lipid-lowering therapies in patients unable to reach LDL-C
goals with the maximum tolerated dose and in patients at
risk of CVD who are statin intolerant or for whom a statin
drug is contraindicated.
A third PCSK9 inhibitor, bococizumab, will likely be approved
in the foreseeable future based on recently reported preliminary
reports from the phase III trial The Evaluation of Bococizumab
(PF-04950615; RN316) in Reducing the Occurrence of Major
Cardiovascular Events in High Risk Subjects (SPIRE-1).
The effects of PCSK9 inhibition have been demonstrated in
more than 20 phase II and III clinical trials. Recent meta-
analyses demonstrated mean LDL-C reductions of approxi-
mately 48%-62%.8 Notably, the lipid-lowering effects are
largely similar across treated populations (ie, statin intolerance,
inadequate lipid control, heterozygous familial hypercholester-
olemia [HeFH], or type 2 diabetes) and quite similar across the
different PCSK9 inhibitors at the highest dose.8,9 Furthermore,
high-density lipoprotein cholesterol (HDL-C) levels are
increased by a mean of 6%, whereas lipoprotein a (Lp[a]) levels
are decreased by approximately 26%. Significant LDL-C
lowering has also been demonstrated in patients with

Figure 1. Systems that are targeted by drugs described in this review. Yellow ¼ drugs described in this review; green ¼ cholesterol-containing
metabolites; and red ¼ substance targets. apoB, apolipoprotein B; apoC3, apolipoprotein C3; ASO, antisense oligonucleotide; CETP, choles-
terol ester transfer protein; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density li-
poprotein receptor; Lp(a) lipoprotein a; MTP, microsomal transfer protein; PCSK9, proprotein convertase subtilisin/kexin type 9; TG, triglyceride;
VLDL, very low-density lipoprotein.

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352 Canadian Journal of Cardiology
Volume 33 2017

homozygous familial hypercholesterolemia (HoFH) with re- and side effects suggests that PCKS9 inhibitors could revolu-
sidual LDL receptor activity.10 Although the trials were not tionize the treatment of patients at high risk for CVD.
powered to study clinical outcomes, 3 meta-analyses pooled trial
data on the incidence of myocardial infarction and demonstrated Antisense oligonucleotide against apoB-100
significant reductions.8,11,12 Another meta-analysis showed that
Apolipoprotein B (apoB) is the main structural and
evolocumab and alirocumab were safe and well tolerated.9 The
receptor-binding component of atherogenic lipoproteins in
most common side effects are injection site reactions. Available
the very low-density lipoprotein (VLDL) pathway, including
trial evidence indicates that neurocognitive adverse events may
LDL-C. Mipomersen is an antisense oligonucleotide (ASO)
occur (although they are not statistically significant) more
inhibitor of apoB that inhibits the protein translation at the
commonly in individuals receiving an antibody to PCSK9,12 but
mRNA level, thereby ultimately reducing LDL-C levels.15
these events are uncommon and have not been associated with
Inhibition of apoB 100 production could be particularly
LDL-C levels in patients receiving treatment. Moreover, it is
valuable in the treatment of patients with HoFH, who typi-
unclear to what extent closer monitoring of trial participants
cally respond suboptimally to statin drugs because of a lack of
allocated to PCSK9 inhibitors has led to an ascertainment bias.12
functional LDL receptors. In 2013, the US Food and Drug
Neurocognitive effects are now specifically observed in the
Administration (FDA) approved an apoB ASO called mipo-
Evaluating PCSK9 Binding Antibody Influence on Cognitive
mersen for the treatment of HoFH, partly based on the data
Health in High Cardiovascular Risk Subjects (EBBINGHAUS)
derived in a phase III study in which a 24.7% LDL-C
study, a substudy of the Further Cardiovascular Outcomes
reduction was observed in 34 patients with HoFH assigned
Research With PCSK9 Inhibition in Subjects With Elevated
to mipomersen. Moreover, apoB and Lp(a) levels were
Risk (FOURIER) trial (clinicaltrials.gov NCT02207634).
decreased significantly, by 26.8% and 31.1%, respectively.16
Large-scale cardiovascular outcome studies are currently
Adverse events were injection site reactions, flulike symp-
ongoing: the Study to Evaluate the Effect of Alirocumab on the
toms, and increased alanine aminotransferase (ALT) levels.17
Occurrence of Cardiovascular Events in Patients Who Have
Inherent to its mechanism of action, mipomersen increased
Experienced an Acute Coronary Syndrome (ODYSSEY Out-
hepatic fat content with corresponding increases in liver
comes) trial is investigating the efficacy of alirocumab vs placebo
transaminase levels. However, a limited number of hepatic
among 18,000 patients with a recent acute coronary syndrome
biopsy samples, obtained in patients with increased liver fat,
(clinicaltrials.gov NCT01663402); the FOURIER study aims
did not show significant fibrosis.18
to determine the clinical benefit of evolocumab compared with
Other studies have demonstrated similar efficacy of mipo-
statin drugs among 27,500 patients with dyslipidemia and
mersen in patients with HeFH when added to conventional
established CVD (clinicaltrials.gov NCT01764633). The third
lipid-lowering therapy.15 Weekly administration of mipomersen
PCSK9 antibody, bococizumab, is evaluated in the CVD
200 mg (83 patients) and placebo (41 patients) for 26 weeks
outcomes-SPIRE program (the evaluation of bococizumab in
among HeFH patients with coronary artery disease resulted in a
reducing the occurrence of major cardiovascular events in high-
28% reduction of LDL-C levels once it was added to maximally
risk subjects). In the SPIRE-1 trial, patients with CVD (or at
tolerated statin therapy.19 Sustained LDL-C reductions were
high risk) with an LDL-C > 70 mg/dL (1.8 mmol/L) were
observed among participants of a long-term extension trial. A
enrolled, whereas in SPIRE-2, patients with LDL-C levels >
phase III trial comprising 310 patients with HeFH (Mipo-
100 mg/dL (2.6 mmol/L) were enrolled (clinicaltrials.gov
mersen in Patients With Familial Hypercholesterolemia and
NCT01975389, NCT01975376) The estimated termination
Inadequately Controlled Low-Density Lipoprotein Cholesterol
date is set to occur in April 2017.
[FOCUS FH]) was completed in February 2016. This trial
Other approaches to inhibit PCSK9 are also in clinical
investigated a different dosing regimen (3 times a week) in
development. Notably, ALN-PCSsc, which reduces PCSK9
addition to a once-weekly regimen. Preliminary results indicate
synthesis by interfering with RNA translation, resulted in
that the primary end point of sustained LDL-C reductions after
sustained reductions in LDL-C and Lp(a) at 6 months after a
60 weeks was met and that the safety profile was comparable to
single injection.13
the previous phase III trials of the drug (www.clinicaltrials.gov
Currently recruiting is the ORION trial (to evaluate the ef-
NCT01475825).
fect of ALN-PCSSC treatment on LDL-C). This phase II study
A meta-analysis that included data from 8 trials including
is randomizing 480 participants with atherosclerotic CVD and
462 patients with dyslipidemia showed mean LDL-C and TG
elevated LDL-C despite a maximum tolerated dose of LDL-Ce
reductions of approximately 32% and 36%, respectively.20 It
lowering therapies to evaluate the efficacy, safety, and tolerability
is unlikely that mipomersen will receive a broader indication
of ALN PCSSC injections. The estimated study completion date
than HoFH.
is December 2016 (clinicaltrials.gov NCT02597127).
In 2016, a simulation model in the United States tried to
Carboxylase Ac-CoA inhibitor
estimate the cost-effectiveness of PCSK9 inhibitors. Adding
PCSK9 inhibitors to statin drugs in HeFH was estimated to Carboxylase acetyl coenzyme A (Ac-CoA) inhibitor
prevent 316,300 major adverse cardiovascular events. Because (gemcabene) is a dicarboxylic acid for which the mechanism of
of current costs for these monoclonal antibodies, acceptable action has not yet been fully elucidated. The compound ap-
cost-effectiveness thresholds were not met.14 It should be noted pears to reduce the production of hepatic TGs and cholesterol
that in this model, a comparison was made between adding besides enhancing the clearance of VLDL.
PCSK9 inhibitors and adding ezetimibe; however, treatment of A phase II trial included 161 patients with HDL-C levels
HeFH adding ezetimibe usually is not sufficient. In conclusion, < 35 mg/dL who were randomized to 1 of 4 doses of gem-
irrespective of the costs, the beneficial balance between efficacy cabene or placebo for 12 weeks. Higher doses of gemcabene

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Bruikman et al. 353
New Drugs for Atherosclerosis

reduced LDL-C levels by 15%-25%, irrespective of baseline
TG levels. Among patients with baseline TG levels of 200 mg/
dL or more, lower doses of gemcabene significantly increased
HDL-C levels by 18% and reduced TG levels by 27%-39%.
The study showed no significant adverse events compared with
the placebo group and was well tolerated.21 The Efficacy and
Safety of Gemcabene in Patients With Homozygous Familial
Hypercholesterolemia on Stable, Lipid-Lowering Therapy
(COBALT-1) trial will assess the efficacy, tolerability, and
safety of gemcabene in patients with HoFH. A 12-Week, Phase
II Study in Patients With Severe Hypercholesterolemia
(ROYAL-1) will assess the efficacy and safety of gemcabene in
patients with hypercholesterolemia who are receiving high-
intensity stable statin therapy with or without ezetimibe in
212 patients with hypercholesterolemia (www.clinicaltrials.gov,
NCT02722408 and NCT02634151).
Microsomal transfer protein inhibitor
Microsomal transfer protein (MTP) is expressed in hepa-
tocytes and enterocytes and has a role in assembling and
secreting apoB-containing lipoproteins in the liver and intes-
tine. MTP inhibitors reduce both circulating cholesterol and
TG levels by interfering with the transfer of TGs to nascent
apoB-containing particles and chylomicrons in the liver and
intestine. This can result in the development of a fatty liver
and elevated transaminase levels, and development of the first
MTP inhibitor, implitapide, was stopped for this reason.22
The orally administered MTP inhibitor lomitapide has
been approved by the FDA for the treatment of HoFH.
Approval was based on the results of an open-label, single-
arm, phase III study that enrolled 29 patients with HoFH.
Participants received lomitapide in addition to their usual
lipid-lowering therapy in a dose escalation from 5 mg up to 60
mg (median dose was 40 mg). Mean LDL-C reductions were
approximately 50% after 26 weeks of treatment and 38% in
patients who completed 78 weeks of treatment. Also, apoB
and TG levels were significantly reduced by 49% and 45%,
respectively. Nineteen patients entered an extension study,
which confirmed that the beneficial effects on LDL-C and
other lipid outcomes persisted at 126 weeks of treatment.
Most common adverse events were gastrointestinal disor-
ders in 27 of 29 patients, which decreased with a low-fat diet
(< 20% calories from fat). Nevertheless, 3 patients dis-
continued the study at the 12-week mark. Liver steatosis,
a feared effect of agents affecting apoB synthesis,23 increased
from 1.0% to 8.6% in the first 26 weeks but remained stable
thereafter. Elevations of ALT levels were observed in 4 pa-
tients and could be resolved with dose reduction or temporary
interruption of treatment. No patients had to discontinue the
study because of hepatic adverse effects.24
To further evaluate the long-term safety and effectiveness
of lomitapide in clinical practice, the Lomitapide Observa-
tional Worldwide Evaluation Registry (LOWER) is enrolling
at least 300 patients with HoFH and following them for at
least 10 years.25
Adenosine monophosphateeactivated protein kinase
and adenosine triphosphateecitrate lyase modulators
ETC-1002 (bempedoic acid) is an oral drug that is adminis-
tered once daily. It simultaneously inhibits adenosine
triphosphateecitrate lyase (ACL) and activates adenosine
monophosphateeactivated protein kinase (AMPK). This results
in a reduction of hepatic cholesterol synthesis and increased LDL
receptor expression. Furthermore, AMPK activation probably has
beneficial effects on cardiometabolic parameters by virtue of its
anti-inflammatory properties.26 Bempedoic acid is metabolized
to its active form in liver only and not in muscle, which would
imply beneficial effects for patients with statin drug intolerance.
A number of clinical trials were conducted. A total of 348
patients with hypercholesterolemia with or without statin
drug intolerance were randomized to daily ETC-1002 120 mg
or 180 mg with or without ezetimibe. After 12 weeks of
treatment, mean LDL-C reductions were 27% in the 120-mg
group, 30% in the 180-mg group, 21% in the ezetimibe-only
group, and 43% and 48% in the groups receiving both eze-
timibe and ETC-1002 at the 2 doses, respectively. Moreover,
C-reactive protein levels decreased by approximately 30%-
40% in the 2 groups receiving ETC-1002 monotherapy.27
Overall, a favorable side effect profile was observed. The
frequency of muscle-related side effects and liver enzyme el-
evations was not statistically different in patients receiving
ETC-1002 and those receiving placebo.27
In conclusion, ETC-1002 has been shown to favorably
affect lipid profiles in short-term studies on different back-
ground lipid-lowering therapies. The dual mechanism of ac-
tion suggests that the drug could be beneficial for a wide
variety of patients, and phase III trials are required to
establish the drug’s long-term safety and efficacy. In January
2016, a phase III trial was initiated to investigate long-term
safety, tolerability, and efficacy of bempedoic acid 180 mg
in approximately 900 patients with statin-intolerant hyper-
lipidemia and a high cardiovascular risk that was not
adequately controlled by their lipid-modifying therapy to
assess treatment-related adverse events (clinicaltrials.gov
NCT02666664). In addition, we eagerly await the results
of the phase III CVD outcome trial (The Global Cholesterol
Lowering via BEmpedoic Acid, an ACL-inhibiting Regimen
Outcomes [CLEAR-OUTCOMES]).
Treatment to Increase HDL-C
Prospective epidemiologic studies have shown that plasma
HDL-C levels are inversely associated with a risk for future
CVD events. Reverse cholesterol transport, a process
involving the transport of cholesterol from macrophages in
the arterial wall to the liver, is considered to be the main
mechanism by which HDL exerts its antiatherogenic prop-
erties.28 Based on observations, raising HDL-C levels has
been the goal in many drug development programs. However,
data from both mendelian randomization and clinical inter-
vention studies have resulted in doubts about whether agents
to increase HDL-C will result in CVD risk reduction.29,30
For example, niacin did not reduce the incidence of CVD
events in 2 large trials, and the development of several
cholesterol ester transfer protein (CETP) inhibitors has been
halted because of futility.31 Despite these drawbacks, interest
in HDL as a means of improving CVD outcomes remains
substantial. However, focus has shifted from merely
increasing circulating HDL-C levels to increasing the ability
of HDL particles to promote cholesterol efflux from macro-
phages. It is speculated that the futility of oral drugs to raise

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354
HDL-C levels is attributable to a lack of improvement in
HDL function.32
Cholesterol ester transfer protein inhibitors
The physiological role of CETP is to exchange cholesterol
esters for TGs between HDL and TG-rich lipoproteins and
thereby reduce HDL-C levels. Unsurprisingly, inhibition of
CETP leads to a rise in HDL-C levels and a decrease of TG and
LDL-C levels.33 The development of 3 CETP inhibitors has been
terminated because of adverse effects or lack of efficacy.30,34,35
Currently, 2 more CETP inhibitors are in clinical devel-
opment. First, anacetrapib is being evaluated in patients with
familial hypercholesterolemia (FH) and patients with non-
FH. The Determining the Efficacy and Tolerability of
CETP Inhibition With Anacetrapib (DEFINE) trial included
306 patients with HeFH who were randomized to anacetrapib
100 mg or placebo for 52 weeks in addition to their lipid-
lowering therapy.36 Lipid changes of similar magnitude were
observed after 76 weeks in the DEFINE trial, which enrolled
1623 individuals with established CVD or CVD risk equiv-
alents.37 Anacetrapib was well tolerated in both studies, and
no safety concerns emerged. The question of if these effects
will translate into clinical benefit will be answered in the
Randomized Evaluation of the Effects of Anacetrapib
Through Lipid-Modification (REVEAL) trial, which enrolled
30,624 individuals with established CVD who will receive
anacetrapib for 4 years in addition to statin drugs. The study
is expected to conclude in 2017.
A fifth CETP inhibitor, TA8995, exerted potent effects on
both proatherogenic and antiatherogenic lipoprotein particles
in a phase I study, without the off-target effects of torcetrapib.
Therefore, the Cholesterol Ester Transfer Protein Inhibition
by TA-8995 in Patients With Mild Dyslipidaemia (TULIP)
study assessed the safety and efficacy of TA8995 as mono-
therapy and combined with statin drugs in patients with mild
dyslipidemia. After 12 weeks of treatment, LDL-C levels were
reduced by 45% at the highest dose in the TA8995 group and
by 63% in the combined group. In TULIP, TA-8995 was also
shown to increase cholesterol efflux and pre-beta HDL levels,
both measures of HDL functionality. Also HDL-C levels
increased by 157.5%.38 Currently, clinical end point trials are
in the planning stages.
Recombinant HDL-C
Apolipoprotein A1 (apoA1) is a major protein component
of HDL particles in plasma and promotes cholesterol efflux
from macrophages to pre-beta HDL particles through its
interaction with ABCAI. Intriguingly, 40 inhabitants of a
small village in Italy presented with very low HDL-C levels
and paradoxically appeared to be at a low risk for athero-
sclerosis. They are all carriers of a genetic variant of apoA1,
apoA1 Milano, which is considered a “superior apoA1.” A
formulation containing recombinant apoA1 Milano com-
plexed with phospholipids (ETC-2016) was formed and, in a
phase II clinical trial, was infused in patients with acute cor-
onary syndrome (ACS). Intravascular ultrasonography showed
that repeated infusion induced coronary plaque regression.39
A renewed formulation (MDCO-2016) will be tested in A
Placebo-Controlled, Double-Blind, Randomized Trial to
Compare the Effect of Treatment on Plaque Burden as
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Canadian Journal of Cardiology
Volume 33 2017
Determined by Intravascular Ultrasound and to Evaluate the
Efficacy, Pharmacokinetics, Safety, and Tolerability of
MDCO-216 Given as Multiple Weekly Infusions in Subjects
With a Recent Acute Coronary Syndrome (MILANO-PI-
LOT) clinical trial. This is a double-blind placebo-controlled
trial enrolling a total of 120 patients with ACS who will
receive weekly infusions of MDCO-2016 over a 5-week
period (www.clinicaltrials.gov NCT02678923) The primary
outcome measure is the change in atheroma volume, as
assessed using intravascular ultrasonography.
CER-001 is another drug that is a lipoprotein complex
consisting of phospholipid and recombinant human apoA1
that mimics the structure and function of HDL. However,
because it is negatively charged, it is not an exact copy of
naturally occurring nascent HDL particles. The Effect of
CER-001 on Atherosclerosis in Acute Coronary Syndrome
PatientsdEfficacy and Safety: The CHI SQUARE Trial
(CHI-SQUARE) was 1 of the first large trials infusing CER-
001 in 507 patients with recent ACS. Patients were ran-
domized to receive 6 weekly infusions of placebo or 3, 6, or 12
mg/kg CER-001. The primary outcome parameter showed no
reduction in coronary atherosclerosis compared with pla-
cebo.40 However, post hoc analysis did show a decrease in
plaque burden in patients with a baseline atheroma volume of
more than 30% who got the lowest dose of CER-001.41
The Modifying Orphan Disease Evaluation (MODE)
study evaluated the effect of biweekly infusions with CER-001
on carotid artery wall dimensions in patients with HoFH.
Twenty-three patients received 12 biweekly infusions with
CER-001, and a significant reduction in carotid plaque mean
vessel wall area was shown, implying that CER-001 may
reverse atherogenic changes in the arterial wall. No adverse
events were reported, except a single drug-related adverse
eventda urticarial reaction.42
The efficacy and safety of CER-001 has been investigated
in different populations, including patients with familial
hypoalphalipoproteinemia in the phase III CER-001Therapy
As a Novel Approach to Treat Genetic Orphan Diseases
(TANGO) study (www.clinicaltrials.gov NCT02697136). In
addition, the CER-001 Atherosclerosis Regression ACS Trial
(CARAT) will evaluate the ability of CER-001 to reduce
plaque volume in 292 patients with ACS; the results are ex-
pected in 2017 (www.clinicaltrials.gov NCT02484378).
CSL112 is a new formulation of human apoA1 being
developed to reduce cardiovascular events after ACS. CSL112
particles consist of 2 molecules of apoA1 and phosphatidyl-
choline, which makes it more potent than native HDL at
enhancing cholesterol efflux. The phase 2 AEGIS-I (A Phase
2b Study of CSL112 in Subjects With Acute Myocardial
Infarction) trial evaluated the safety and tolerability of
CSL112 infusion in the setting of acute myocardial infarction.
Patients were randomized to receive either 1 or 2 doses of
CSL112. More than 1200 patients were included, and the
final data collection date for the primary outcome measure
was in December 2015. Results were presented at The
American Heart Association’s Scientific Sessions in November
2016.43 The AEGIS-I study met its co-primary safety end-
points, showing that CSL112 does not cause significant
changes in liver or kidney function and demonstrating that it
is well-tolerated when administered in the acute myocardial
infarction setting. The study also provided confirmation of
Bruikman et al.
New Drugs for Atherosclerosis
CSL112’s mechanism of action, cholesterol efflux enhance-
ment, as demonstrated by an immediate, up to four-fold in-
crease in cholesterol efflux capacity, compared to baseline.
Treatment to Decrease Hypertriglyceridemia
Gene therapy
Advances in gene technology have enabled the development
of gene therapies for a variety of conditions. Alipogene tipar-
vovec (Glibera) is the first gene therapy approved by the Eu-
ropean Medicines Agency as an orphan drug for clinical use and
targets congenital lipoprotein deficiency.44 Lipoprotein defi-
ciency is a rare autosomal recessive disease that causes extremely
elevated plasma TG levels (10- to 100-fold). It often presents in
childhood with repeated episodes of pancreatitis, eruptive
xanthomas, lipaemia retinalis, and hepatosplenomegaly. More
than 70 different mutations have been described.45
Alipogene tiparvovec is administered through 40-60
intramuscular injections during a single procedure using spi-
nal anesthesia. The adeno-associated viral vector introduces
episomal copies of a functional lipoprotein gene variant into
the muscle tissue.45 In 1 study comprising 14 lipoprotein-
deficient patients, a reduction of TG levels up to 60% was
observed at 12 weeks. The treatment is well tolerated, and
most frequent adverse reactions consisted of intramuscular
injection-associated local reactions.46 Long-term benefits were
confirmed in a recent retrospective analysis: a 50% reduction
in pancreatitis-adjudicated events after 6 years, irrespective of
the percentage of TG decrease.47 Findings in a mendelian
randomization study of blood lipids for coronary heart disease
support a causal effect of TGs and remnant particles on CVD
risk.48 Ongoing studies include the creation of vectors
expressing gain-of-function human low-density lipoprotein
receptor variants that enhance hepatic low-density lipoprotein
receptor protein abundance. Studies with mice showed
promising results, and this form of therapy is currently being
investigated in patients with HoFH.49
Apolipoprotein C3 antisense
Apolipoprotein C3 (ApoC3) is synthesized in the liver and
can be found on TG-rich lipoproteins such as chylomicrons
and VLDL but also on HDL. The protein inhibits lipoprotein
activity, enhances hepatic VLDL synthesis, and inhibits liver
clearance of TG-rich lipoproteins. Carriers of heterozygous
loss-of-function variants in ApoC3 are characterized by
reduced TG levels and reduced CVD risk.50 Volanesorsen
(formerly known as ISIS-APOCIIIRx) is a second-generation
ASO that reduces the synthesis of the ApoC3 protein. In
preclinical animal models, as well as in a phase I study with
healthy volunteers, volanesorsen robustly decreased TG
levels.51 In 3 patients with familial chylomicronemia syn-
drome included in the phase II study, TG levels were reduced
by 56%-86%. Most common adverse events were injection
site reactions and mild gastrointestinal complaints.52
In a phase II study, volanesorsen was administered to pa-
tients with high TG levels. A decrease of TG levels of 31.3%
and 70.9%, respectively, was found in the patients on mon-
otherapy and those receiving therapy with a fibrate back-
ground.53 Ongoing phase III studies are The COMPASS
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355
Study: A Study of Volanesorsen (formerly ISIS-APOCIIIRx)
in Patients With Hypertriglyceridemia (COMPASS) and
The APPROACH Study: A Study of Volanesorsen (Formerly
ISIS-APOCIIIRx) in Patients With Familial Chylomicrone-
mia Syndrome (APPROACH) study (www.clinicaltrials.gov,
NCT02211209 and NCT02300233).
Lp(a) antisense
Lp(a) is a plasma lipoprotein that consists of a central
LDL-like core containing a single molecule of apoB 100
linked by a disulfide bridge to a protein called apo(a).54 Many
prospective epidemiologic studies have reported positive as-
sociations of baseline Lp(a) concentration with CVD inde-
pendent of LDL-C.55
In a phase I study in healthy individuals with Lp(a) levels
> 25 nmol/L, IONIS-APO(a)-LRx (formerly known as
ISIS-APO(a)Rx) was administered in 50-, 100-, 200-, and
300-mg doses, or a placebo was given. Plasma Lp(a) con-
centration decreased from 39.6% in the 100-mg group to
77.8% in the group receiving 300 mg.56
Recently, the results of a phase II study were presented, in
which 2 cohorts of patients with elevated Lp(a) received
IONIS-APO(a)-LRx in different dosages. In the combined
cohorts, Lp(a) was reduced by a mean 72% (up to 94%) vs a
mean reduction of 3% in the placebo group.57
Conclusions
Statin drugs have been the cornerstone of treatment of
dyslipidemia for decades. However, despite the efficacy of
statin drugs, a significant amount of residual CVD risk re-
mains. Some patients are unable to tolerate statin drugs at
adequate doses or do not respond sufficiently. A large number
of novel targets have been investigated in recent years and are
summarized in Table 1 and Figure 1.
For some drugs, is it not clear what the future will bring.
The occurrence of adverse events and lack of tolerability make
it unlikely that mipomersen will ever be approved for any
group beyond the extremely rare unfortunate individuals with
homozygous FH. CETP inhibitors struggle to overcome the
adverse effects of the class and finding the right population to
show efficacy.
In contrast, PCSK9 inhibitors have shown a beneficial
balance between efficacy and side effects, suggesting a bright
future for these compounds for the treatment of high-risk
CVD. Also, bempedoic acid shows potential with a favor-
able side effect profile in statin-intolerant individuals, which
will possibly be confirmed in an ongoing phase III trial.
Carboxylase Ac-CoA inhibitors have proved to be well toler-
ated in phase II studies, but phase III trials still have to be
concluded.
Although the benefits of many novel drugs regarding
improving lipid profiles have been shown, some drugs, sur-
prisingly, have failed in late-stage trials. Ongoing event studies
are required to formally test whether these effects translate
into improved clinical outcomes.
Funding Sources
G. Kees Hovingh is holder of a Vidi grant [016.156.445]
from the Netherlands Organisation for Scientific Research
356
(NWO) and is supported by a grant from the CardioVascular
Research Initiative [CVON2011-19; Genius] and the Euro-
pean Union [TransCard: FP7-603091-2].
Disclosures
G. Kees Hovingh or his institution received honoraria for
consultancy, ad boards, received research support and/or
conduct of clinical trials from: AMGEN, Aegerion, Pfizer,
Astra Zeneca, Sanofi, Regeneron, KOWA, Ionis pharmaceu-
ticals, Synageva and Cerenis. John J.P. Kastelein is a recipient
of the Lifetime Achievement Award of the Netherland Heart
Foundation (NHS, project number 2010T082) and received
consulting fees or honoraria from Aegerion, Amgen, Astra-
Zeneca, Boehringer Ingelheim, Catabasis, Cerenis, Cymabay,
CSL Behring, Dezima Pharmaceuticals, Eli Lilly, Esperion,
Gemphire, ISIS, The Medicines Company, MSD, Novartis,
Pfizer, Pronova, Regeneron, Sanofi, and UniQur. S. Tsimikas
holds a dual appointment at UCSD and Ionis Pharmaceuti-
cals. Caroline S. Bruikman and Robert M. Stoekenbroek have
no conflicts of interest to disclose.
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