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2016 ARTICLE 2
New Kids on the Block: The Promise of PCSK9 Inhibitors in the
Management of Hyperlipidemia
Corresponding Author:
Sarah A. Nisly, PharmD, BCPS
Associate Professor of Pharmacy Practice
Butler University
[email protected]
Learning Objectives:
Upon completion of this article the learner
should be able to:
1.
Explain the role of PCSK9 in the
pathophysiology of
hyperlipidemia.
2.
Describe the mechanism of
action of PCSK9 inhibitors.
Additional Author:
Allison M. Boyd, PharmD Candidate
Indiana University Health/Butler University
[email protected]
3.
Identify key efficacy and safety
outcomes of PCSK9 inhibitors in
the management of
hyperlipidemia.
Additional Author:
Alexandra E. Foster, PharmD Candidate
Indiana University Health/Butler University
[email protected]
4.
Discuss the application and
potential place in therapy for
PCSK9 inhibitors.
Additional Author:
Taylor D. Steuber, PharmD, BCPS
PGY2 Pharmacotherapy Resident
Indiana University Health/Butler University
[email protected]
Introduction
ACPE no. 0120-0000-16-011-H04-P
1.5 Contact Hour (.15 CEU’s)
This is a knowledge based activity.
See the end of the article for CE details.
Target Audience: Pharmacists
Faculty Disclosure: Faculty have no
conflicts of interest to disclose
Goal:
The goal of this article is to review PCSK9
inhibitors and explore their potential role in
the pharmacologic management of
hyperlipidemia.
Cardiovascular disease (CVD)
remains the leading cause of mortality in the
Unites States, with approximately 1 in every
3 deaths attributed to cardiovascular causes.
Elevated low density lipoprotein cholesterol
(LDL-C) has been commonly associated
with an increased risk of CVD. The
American College of Cardiology
(ACC)/American Heart Association (AHA)
Task Force published joint guidelines in
2013 in an effort to prevent CVD and
promote cardiovascular health.1 The
committee emphasized the role of HMGCoA reductase inhibitors, more commonly
known as “statins,” and their importance in
both primary and secondary CVD
prevention through LDL-C reduction and
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other beneficial effects. With the publication
of these guidelines, it is estimated that over
45 million middle-aged Americans who do
not have CVD will be considered for statin
therapy, with an overall statin-eligible
population of 1 in every 3 American adults.2
Despite the potential increase in patients in
whom statin therapy would be beneficial,
there are barriers that exist in clinical
practice, namely statin intolerance or
resistance. Statin intolerance is dosedependent and has been reported anywhere
between 5-25% in the literature.3,4 A recent
review discussed a retrospective cohort
study that identified an alarming rate of
statin discontinuation, as high as 60%
among individuals in routine clinical
practice.5 Through either intolerance or
resistance, it is estimated that only 50% of
patients attain individualized LDL-C targets
with statins.6 Given the growing population
of patients eligible for statin therapy, along
with the challenges faced in clinical
practice, alternatives are necessary. The role
of additional lipid-lowering therapies
remains unclear; thus, there is a need for
new therapeutic agents. Proprotein
convertase subtilisin—kexin type 9
(PCSK9) inhibitors are new agents with
robust LDL-C lowering, reported between
50-70% in clinical trials.7 In this review, we
discuss clinical implications of PCSK9
inhibitors and evaluate potential benefits and
risks in patients with hyperlipidemia as well
as CVD.
General Overview of PCSK9 Inhibitors
PCSK9 inhibitors target the PCSK9
protein, which is most commonly expressed
in the liver, but also in the gastrointestinal
tract, kidneys, and nervous system. The
molecular target was discovered in 2003
when gene mutations were seen in French
families. Increased function mutations are
2016 ARTICLE 2
associated with familial
hypercholesterolemia and elevated LDL-C,
whereas decreased function mutations are
associated with lower LDL-C.7
Currently, two PCSK9 inhibitors
have been approved by the FDA: alirocumab
(Praluent®) which was approved in July
2015, followed shortly by evolocumab
(Repatha®) in August 2015. Table 1 lists
these agents, as well as additional PCSK9
inhibitors that are currently being studied in
clinical trials.8-10
There are several categories of PCSK9directed therapies that have been developed.
Both of the approved PCSK9 inhibitors are
monoclonal antibodies that bind to PCSK9
and prevent interaction with LDL receptors
(LDL-R). Additional mechanisms of
PCSK9-targeted therapies previously
studied have not made it to phase 2 clinical
trials.7
Normal PCSK9 protein physiology
and mechanism of action of PCSK9
inhibitors are illustrated in Figure 1.11-13
PCSK9 is synthesized in the nucleus of
hepatocytes and binds to LDL-R in
conjunction with LDL-C on the surface of
the cell. The presence of PCSK9 enhances
LDL-R degradation. This phenomenon also
occurs in organs such as the intestines,
kidneys, lungs, pancreas and adipose tissue,
but to a lesser extent. When PCSK9
inhibitors are administered, they bind to
circulating PCSK9 and prevent its
interaction with LDL-R, leading to an
increase in the number of LDL-R recycled
to the surface of the cell instead of being
degraded in the lysosome. This eventually
results in a higher removal of LDL-C from
the circulation. Overall, there is an inverse
relationship between plasma PCSK9
concentrations and LDL-R.12
Several researchers have investigated
the effect of statins on PCSK9 in both
human and animal models. Results have
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shown that statins increase the concentration
of PCSK9 by 14-47% in a dose-dependent
manner. Statins decrease synthesis of
cholesterol within the cell. This leads to
increased concentrations of sterol regulatory
element binding protein-2 (SREBP-2).
SREBP-2 is a transcription factor for both
2016 ARTICLE 2
PCSK9 and LDL-R, leading to increased
amounts of both proteins. Researchers then
theorized that silencing PCSK9 would result
in enhanced LDL-C lowering beyond that of
a statin alone, leading to several treatment
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options being developed and tested.12,13
Upregulation of PCSK9 through statin
therapy or gene mutations may also partly
explain why some patients remain resistant
to statins despite being on a maximally
tolerated dose, making this protein an
attractive target for drug therapy.
Comparative pharmacokinetics for
alirocumab and evolocumab are displayed in
Table 2.14,15
Efficacy and Safety Clinical Trial
Discussion of PCSK9 Inhibitors
Table 3 in the supplementary appendix
summarizes available clinical trial data
Alirocumab
Primary Hypercholesterolemia
Randomized, double-blind, placeboor ezetimibe-controlled, phase III trials have
examined the efficacy, safety, and
tolerability of alirocumab in patients with
primary hypercholesterolemia, defined as
fasting LDL-C from ≥ 70 to ≥ 100 mg /dL,
depending on the criteria outlined in each
trial. The primary efficacy endpoint, percent
reduction in LDL-C from baseline, was
measured at week 24. Trials were conducted
with alirocumab as monotherapy, in patients
on maximally tolerated statins, in statin
intolerant patients, or patients unable to
achieve adequate LDL-C lowering with
statin therapy alone.18-22
Alirocumab had similar LDL-C
lowering effects in this patient population
despite being used as monotherapy or in
conjunction with other medications, namely
statins. An LDL-C lowering of 45 to 50.5%
has been observed in published clinical
trials. All results were statistically
significant when compared to placebo or
ezetimibe, which had approximately 15%
2016 ARTICLE 2
additional LDL-C lowering at most. An
additional study with alirocumab in patients
with primary hypercholesterolemia and on
background statin therapy is ongoing, but
preliminary results indicate an LDL-C
reduction of 36.3 to 50.6% in alirocumabtreated patients, a significant reduction
compared to other treatment arms.22
Familial Hypercholesterolemia (FH)
Three randomized, double-blind,
placebo-controlled phase III trials
investigated the efficacy, safety, and
tolerability of alirocumab added to
background statin therapy in patients with
heterozygous familial hypercholesterolemia
(HeFH). Two completed phase III studies
have shown an LDL-C decrease of nearly
49% from baseline, which was significant
compared to placebo. Similarly, an
additional study currently in progress
showed preliminary results demonstrating
LDL-C reductions of 45.7% from baseline
in alirocumab-treated patients.22-25
Long-Term Efficacy and Safety Data
Long-term efficacy and safety of
alirocumab was established in ODYSSEY
LONG TERM, a 78 week randomized,
double-blind, placebo-controlled, parallel
group phase III trial. In this study, LDL-C
decreased by 61% from baseline in patients
treated with alirocumab at week 24, and this
reduction was sustained through week 78.
No significant differences in individual
cardiovascular events were observed.
ODYSSEY OUTCOMES is an ongoing trial
currently investigating the benefit of
alirocumab in occurrence of cardiovascular
events over the course of 5 years, with an
estimated completion date of December
2017.26-27
Safety Profile
The overall incidence of treatmentemergent adverse events was similar among
patients receiving alirocumab and placebo in
all trials.16-26 Commonly reported adverse
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events occurring in ≥ 5% of patients treated
with alirocumab and occurring more
frequently than placebo include
nasopharyngitis (11.3%), injection site
reactions (7.2%), and influenza (5.7%).14
Similar rates of neurocognitive events were
reported in patients receiving alirocumab or
placebo (0.8% vs. 0.7%).14
Evolocumab
Primary Hypercholesterolemia
Randomized, double-blind, placeboor ezetimibe-controlled studies have
examined the efficacy, safety, and
tolerability of evolocumab in patients with
primary hypercholesterolemia, defined as
fasting LDL-C varying from ≥ 75 to ≥ 150
mg /dL, depending on the criteria outlined in
each trial, and triglycerides ≤ 400 mg/dL.
The co-primary efficacy endpoints in a
majority of these trials were the percent
change of LDL-C from baseline at the mean
of weeks 10 and 12 and at week 12.28-30 One
study measured the primary endpoint at
week 52.31 Trials were conducted with
evolocumab as monotherapy, in patients on
maximally tolerated statins, in statin
intolerant patients, or patients unable to
achieve adequate LDL-C lowering with
statin therapy alone.28-31
Evolocumab has demonstrated
significant LDL-C lowering effects, as
monotherapy or in combination therapy with
statins and other lipid lowering therapies, in
published clinical trials. An LDL-C
lowering of 46.7 to 65% was observed in
patients receiving evolocumab, a statistically
significant difference as compared to
placebo or ezetimibe, which resulted in an
LDL-C lowering of 19.2% at most.28-31 Two
device trials have studied the ability of
patients with primary hypercholesterolemia
to self-administer in-home injections of
evolocumab in a pre-filled syringe (PFS) or
autoinjector pen (AI/pen). In one trial, 96%
of patients in the PFS group and 89.2% of
2016 ARTICLE 2
patients in the AI/pen group reported “full
in-home administration” of evolocumab at
both weeks 2 and 4; however, the difference
was not found to be statistically significant.
Similarly, there was no significant
difference in LDL-C reduction in the study
groups.32 A longer-term device study is
currently in progress.33
Familial Hypercholesterolemia (FH)
Two randomized, placebocontrolled, multicenter phase III trials have
investigated the utility of evolocumab added
to background statin therapy in patients with
heterozygous and homozygous familial
hypercholesterolemia (HoFH). At the mean
of weeks 10 and 12 and at week 12, patients
with HeFH demonstrated an LDL-C
lowering of 55.7 to 63.3%. This result was
statistically significant as compared to
placebo, which demonstrated approximately
1.1% LDL-C lowering at most.34 An LDL-C
lowering of 25.2% was observed in patients
with HoFH, as compared to an increase in
LDL-C of nearly 6% in patients receiving
placebo.35
Long-Term Efficacy and Safety Data
OSLER-I and OSLER-II were 2
open-label, randomized, controlled,
multicenter phase III studies that
investigated the long term efficacy and
safety of evolocumab. At 12 weeks, patients
receiving evolocumab experienced an LDLC lowering of 61%, as compared to standard
therapy alone. A significantly lower rate of
cardiovascular events was also observed in
patients receiving evolocumab (0.95% in
evolocumab group vs. 2.18% in standard
therapy group, RRR = 56.4, ARR 1.23,
NNT = 82, p = 0.003).36 FOURIER is an
ongoing double-blind, randomized, placebocontrolled multicenter trial (NCT 01764633)
investigating the cardiovascular benefit of
evolocumab in patients with a history of
clinically evident cardiovascular disease.
The study began in January 2013 and is
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expected to be completed by February
2018.37
Safety Profile
Similar incidence of treatmentemergent adverse events was demonstrated
among patients treated with evolocumab and
placebo.28-31,34-36 Adverse events occurring
in ≥ 5% of patients treated with evolocumab
and occurring more frequently in patients
receiving placebo include nasopharyngitis
(10.5%), upper respiratory tract infections
(9.3%), influenza (7.5%), back pain (6.2%),
and injection site reactions (5.7%).15 Similar
rates of neurocognitive events were reported
in patients treated with evolocumab as
compared to patients receiving placebo (≤
0.2% in both groups).15
Discussion
Perhaps one of the largest barriers to
the use of PCSK9 inhibitors is the cost
associated with these agents. The U.S.
Wholesale Acquisition Cost (WAC) of
alirocumab is approximately $14,600 per
year, with each biweekly dose costing $560
per injection. Similarly, the WAC of
evolocomab is $542.31 for one 140 mg
syringe, or approximately $14,100 annually
for the biweekly injection.38,39
There are several additional barriers
to the use of PCSK9 inhibitors for the
treatment of hypercholesterolemia. First,
these agents are injectable. This is an
inconvenience to many patients who
experience a phobia of needles when there
are other oral alternatives available. While
these medications are injectable, they also
only need administered once monthly or
bimonthly. This could be a potential
advantage for those patients who struggle to
take an oral medication on a daily basis.
Additional studies are needed to assess the
adherence of these agents in the general
population. Furthermore, the long term
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efficacy and safety of PCSK9 inhibitors has
not been fully established. Studies aimed at
evaluating the drugs for prevention of
cardiovascular events are currently
underway, but results are not expected until
around 2017. Without proof of reduction in
major cardiovascular morbidity and
mortality, it is difficult to justify the high
costs associated with these agents. Table 4
in the supplementary appendix summarizes
the dosing, cost, and major considerations of
the available agents.38
Additionally, several barriers should
be noted in regards to the previously
discussed clinical trials. While some trials
for both alirocumab and evolocumab do
evaluate the presence of coronary heart
disease, some are focused more on healthy
individuals (see Table 3 for details). This
does not accurately reflect the population
these drugs would likely be used in, as most
patients on statin therapy requiring
significant LDL-C lowering concomitantly
have coronary heart disease. This limits the
generalizability of the results. Perhaps the
most significant limitation of the discussed
trials is the lack of long term data. Without
this data, it is difficult to predict the efficacy
and safety outcomes compared to current
standards of care long-term. The clinical
trials only assessed adult patients with
familial hypercholesterolemia, but it is
important to keep in mind familial
hypercholesterolemia often presents in
childhood or early adolescence, a population
not evaluated by the current literature.
Until the long-term data is released,
it is likely that PCSK9 inhibitors will have a
limited place in therapy. Statins will likely
remain the gold standard for treating
hypercholesterolemia, and PCSK9 inhibitors
will likely be utilized when a statin is not
tolerated or patients are unable to reach
individualized LDL-C goals at maximally
tolerated doses of statin therapy. These cases
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will likely be limited to those patients who
have cardiovascular disease, or have a
genetic condition such as familial
hypercholesterolemia who require additional
lowering of LDL-C despite maximally
tolerated statin therapy.38
Although clinical trials have not shown
significant adverse events with PCSK9
inhibitors, it is important to keep in mind the
potential long-term outcomes. It is known
that these agents significantly reduce LDLC, but the question remains whether or not
this reduction is associated with
cardiovascular benefits. LDL-C reduction
was the basis for FDA approval of lovastatin
in 1987, which took place 7 years prior to
the publication of the Scandinavian
Simvastatin Survival Trial. This was the first
trial to provide definitive evidence of a
statin’s clinical benefit and there have been
several subsequent trials demonstrating
statin efficacy coinciding with LDL-C
reduction. In addition, the IMPROVE-IT
trial demonstrated an LDL-C lowering
benefit of ezetimibe plus simvastatin over
simvastatin alone. However, this only
resulted in a marginal 2% decrease in death
from cardiovascular causes. While results of
these trials suggest LDL-C reduction will
reduce cardiovascular risk regardless of a
drug’s mechanism of action, several other
clinical trials involving non-statin
medications such as ILLUMINATE and
HPS2-THRIVE have demonstrated
significant LDL-C reductions with no
apparent cardiovascular benefits. Therefore,
the use of LDL-C reduction as a surrogate
marker for the approval of non-statin drugs
is controversial and predictions regarding
the long-term efficacy of PCSK9 inhibitors
should not be made without conclusive
2016 ARTICLE 2
data.39
Despite the discussed limitations
regarding the risks and benefits of PCSK9
inhibitors, the FDA advisory committee
voted 13 to 3 to approve alirocumab and 11
to 4 to approve evolocumab. The reasons for
approval include a potential benefit to
patients with very high risk of disease before
large cardiovascular outcome trials are
completed. While the committee members
acknowledged that LDL-C may be
unreliable for predicting cardiovascular
benefit, they agreed that the potential
benefits in patients currently outweigh the
potential risks associated with therapy
known at this time.8
Conclusion
PCSK9 inhibitors demonstrate a
novel mechanism of action for lipid
lowering therapy and have the potential to
significantly lower a patient’s LDL-C level,
with long-term studies currently
investigating cardiovascular benefits.
Results of the efficacy, safety, and
tolerability of alirocumab and evolocumab
support the potential role of PCSK9
inhibitors in the management of LDL-C in
patients with primary hypercholesterolemia
or familial hypercholesterolemia unable to
achieve adequate LDL-C lowering on
standard therapy alone. It is important to
note, however, that both alirocumab and
evolocumab lack long-term safety and
efficacy data with regard to cardiovascular
benefit. As more long-term outcomes data
becomes available, it is important for the
clinician to re-evaluate the clinical utility of
these agents in practice in order to maximize
patient safety and optimize cardiovascular
outcomes.
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Table 1. PCSK9 inhibitor therapies currently in development
Manufacturer
Drug
Phase
Sanofi/Regeneron
Alirocumab
3 (approved)
Amgen
Evolocumab
3 (approved)
Pfizer/Rinat
Bococizumab
3 (ongoing)
Novartis
LGT-209
2
Genentech
MPSK3169A, RG7652
2
Table 2. Pharmacokinetics of currently approved PCSK9 inhibitors, alirocumab and evolocumab
Alirocumab
Evolocumab
Tmax
3-7 days
3-4 days
Absolute Bioavailability
85%
72%
Volume of Distribution
0.04 – 0.05 L/kg
3.3 L
Metabolism
 Degraded to small peptides
 Degraded to small peptides
 No relevant drug interactions
 No relevant drug interactions
Half-Life
17-20 days; 12 days with statin
11-17 days
Elimination
Saturable binding or protelysis
Saturable binding or proteolysis
Patient Population: ACS event occurring 4 to 52 weeks
prior to randomization
Duration: maximum 280 weeks
Patient Population: age 63 years, 45% women, moderate
to high CV risk, 46% CHD, baseline LDL-C ~183 mg/dL
Duration: 24 weeks
Patient Population: age 63 years, 34% women, high CV
risk, 78% CHD, baseline LDL-C ~103 mg/dL
Duration: 52 weeks
Patient Population: age 61 years, 26% women, high CV
risk, 90% CHD, baseline LDL-C ~108 mg/dL
Duration: 104 weeks
Patient Population: age 60 years, 47% women, moderate
CV risk, baseline LDL-C ~140 mg/dL
Duration: 24 weeks
Study Description
Kasatelein JJ, et al.
Patient Population: age 53 years, 45% women, varying CV
risk, 43% CHD, baseline LDL-C ~140 mg/dL
Duration: 78 weeks
ODYSSEY HIGH FH24,25
Patient Population: age 51 years, 47% women, varying CV
NCT01617655
risk, baseline LDL-C ~197 mg/dL
[Study complete]
Duration: 78 weeks
Primary Hypercholesterolemia or HeFH
ODYSSEY OPTIONS I20,21
Patient Population: age 63 years, 35% women, high CV
Bays H, et al.
risk, 59% CHD, baseline LDL-C ~105 mg/dL, on statin
Duration: 24 weeks
ODYSSEY OPTIONS II20,22
Patient Population: age 61 years, 39% women, high CV
NCT01730053
risk, 63% CHD, baseline LDL-C ~111 mg/dL, on statin
[Study complete]
Duration: 24 weeks
ODYSSEY LONG TERM26
Patient Population: age 61 years, 38% women, high CV
Robinson JG, et al.
risk, 69% CHD, 18% HeFH, baseline LDL-C ~122 mg/dL
Duration: 78 weeks
Familial Hypercholesterolemia
HeFH
ODYSSEY FH I and FH II23,24
NCT01663402
[Recruiting participants]
Long Term Studies
ODYSSEY OUTCOMES27
Moriarty PM, et al.
Statin Intolerant Patients¥
ODYSSEY ALTERNATIVE19
Cannon CP, et al.
ODYSSEY COMBO II18
Kereiakes DJ, et al.
Combination Therapy
ODYSSEY COMBO I17
Roth EM, et al.
Primary Hypercholesterolemia
Monotherapy
ODYSSEY MONO16
Clinical Trial
Alirocumab (Praluent®)
Maximally
tolerated
statin ± LLT
Maximally
tolerated
statin ± LLT
Atorvastatin
20 mg or 40
mg ± LLT
Rosuvastatin
10 mg or 20
mg ± LLT
Maximally
tolerated
statin ± LLT
N = 355 (Randomized 1:1:1:1)
- PO atorvastatin entry dose or double dose or rosuvastatin ±
PO ezetimibe 10 mg daily ± alirocumab biweekly
N = 305 (Randomized 1:1:1)
- PO rosuvastatin entry dose or double dose daily ± PO
ezetimibe 10 mg daily ± alirocumab biweekly
N = 2341 (Randomized 1:2)
- SC placebo biweekly
- SC alirocumab 150 mg biweekly
Highintensity
statin ± LLT
± LLT
Maximally
tolerated
statin ± LLT
Maximally
tolerated
statin
None#
Background
statin or LLT†
N = 735 (Randomized 1:2)
- SC placebo biweekly
- SC alirocumab biweekly
N = 107 (Randomized 1:2)
- SC placebo biweekly
- SC alirocumab 150 mg biweekly
N = 18,000
- SC placebo biweekly
- SC alirocumab 75 to 150 mg biweekly
N = 314 (Randomized 1:2:2)
- PO atorvastatin 20 mg daily, SC placebo biweekly
- PO ezetimibe 10 mg daily, SC placebo biweekly
- PO placebo daily, SC alirocumab biweekly
N = 316 (Randomized 1:2)
- SC placebo biweekly
- SC alirocumab biweekly
N = 720 (Randomized 1:2)
- PO ezetimibe 10 mg daily, SC placebo biweekly
- PO placebo daily, SC alirocumab biweekly
N = 103 (Randomized 1:1)
- PO ezetimibe 10 mg daily, SC placebo biweekly
- PO placebo daily, SC alirocumab biweekly
Treatment Groups*
Table 3. Summary of relevant clinical trial data with lipid-lowering or cardiovascular outcomes
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
-20.9 to -39.8
-21.6 to -41.1
-23.6 to -38.4
-20.3 to -36.1
-18.5 to -31.4
-17.1 to -29.2
-61.9
-52.3
-54.0
-51.4 to -57.9
-45.7 to -52.4
-39.3 to -45.8
-39.1
-35.8
-30.3
—
—
—
-30.4
-25.6
-25.1
-45.9
-37.5
-35.8
-29.7
-22.9
-22.4
-31.6
-25.5
-25.8
Change in Lipid
Parameters‡ (%)
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Patient Population: age 51 years, 42% women, high CV
risk, 31% CHD, baseline LDL-C ~155 mg/dL
Duration: 12 weeks
Patient Population: age 56 years, 53% women, varying CV
risk, 15% CHD, baseline LDL-C ~100 mg/dL
Duration: 52 weeks
Patient Population: clinically evident ASCVD at high risk for
a recurrent event
Duration: 5 years
Patient Population: age 62 years, 46% women, varying CV
risk, 29% CHD, baseline LDL-C ~194 mg/dL
Duration: 12 weeks
Patient Population: age 60 years, 46% women, high CV
risk, 23% CHD, baseline LDL-C ~109 mg/dL
Duration: 12 weeks
Patient Population: age 53 years, 69% women, low CV risk,
no CHD, baseline LDL-C ~143 mg/dL
Duration: 12 weeks
Study Description
N = 329 (Randomized 1:1:2:2)
- SC placebo biweekly/monthly
- SC evolocumab biweekly/monthly
N = 901 (1:2)
- SC placebo monthly
- SC evolocumab 420 mg monthly
N = 27,5000
- Standard therapy, SC placebo biweekly/monthly
- Standard therapy, SC evolocumab biweekly/monthly
N = 307 (Randomized 1:1:2:2)
- PO ezetimibe 10 mg daily, SC placebo biweekly/monthly
- PO placebo daily, SC evolocumab biweekly/monthly
N = 2067
- Moderate- or high-intensity statin¤ ± PO ezetimibe 10 mg
daily ± SC evolocumab biweekly/monthly
N = 615 (Randomized 1:1:1:1:2:2)
- PO placebo daily, SC placebo biweekly/monthly
- PO ezetimibe 10 mg daily, SC placebo biweekly/monthly
- PO placebo daily, SC evolocumab biweekly/monthly
Treatment Groups*
Stable dose
statin ± LLT
Statin
None#
No or lowdose statin ±
LLT
None#
None#
Background
statin or LLT†
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
LDL-C
Non-HDL
Apo-B
Apo-B¶
Non-HDL¶
LDL-C¶
-60.2 to -65.6
-49.4 to -55.0
-56.0 to -60.0
-48.5 to -61.6
-41.2 to -54.5
-37.8 to -47.7
—
—
—
-36.9 to -38.7
-31.5 to -34.6
-32.2 to -35.0
-63.0 to -75.0
-58.0 to -65.0
-51.0 to -59.0
-56.5 to -57.4
-39.4 to -39.7
-48.8 to -53.5
-35.5 to -35.6
-47.1 to -50.9
-33.6 to -34.6
Change in Lipid
Parameters‡ (%)
Raal FJ, et al.
Patient Population: age 31 years, 49% women, high CV
N = 49 (Randomized 1:2)
Stable dose
LDL-C
-31.0
statin ± LLT
risk, 43% CHD, baseline LDL-C ~348 mg/dL
Non-HDL
-29.2
- SC placebo monthly
- SC evolocumab 420 mg monthly
Duration: 12 weeks
Apo-B
-22.9
Primary Hypercholesterolemia or HeFH
OSLER I and OSLER II36∫
Patient Population: age 58 years, 49% women, varying CV
N = 4465 (Randomized 1:2)
Stable dose
LDL-C
-61.0
Sabatine MS, et al.
statin ± LLT
risk, 20% CHD, baseline LDL-C ~120 mg/dL
Non-HDL
-52.0
- Standard therapy alone◊
- Standard therapy◊, SC evolocumab biweekly/monthly
Duration: 52 weeks
Apo-B
-47.2
* Alirocumab dosed at 75 mg biweekly and titrated to 150 mg biweekly at week 12 if LDL-C was ≥ 70 mg/dL unless otherwise specified. Evolocumab dosed 140 mg biweekly or 420 mg monthly.
† LLT, excluding ezetimibe, unless otherwise specified.
‡ Percent change in lipid parameters in intervention group relative to comparator groups at week 24 (alirocumab) or at mean of weeks 10 and 12 (evolocumab) statistically significant.
# No additional statin or LLT other than study interventions.
¥ Statin intolerant defined as unable to tolerate any dose or dose larger than the smallest available tablet strength due to intolerable muscle-related AEs.
¶ Reported as percent change relative to (1) placebo and (2) ezetimibe.
¤ Moderate-intensity statin therapy—atorvastatin 10 mg daily, rosuvastatin 5 mg daily, simvastatin 40 mg daily; high-intensity statin therapy—atorvastatin 80 mg daily, rosuvastatin 40 mg daily.
∫ Extension of the parent trials: Phase 2—MENDEL-1, LAPLACE-TIMI 57, GAUSS-1, RUTHERFORD-1, YUKAWA; Phase 3—MENDEL-2, LAPLACE-2, GAUSS-2, RUTHERFORD-2, DESCARTES, THOMAS-1, THOMAS-2.
◊ Standard therapy defined as therapy based on current guidelines for LDL-C management.
Abbreviations: ACS, acute coronary syndrome; Apo-B, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; CV, cardiovascular; FH, familial hypercholesterolemia;
HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; Non-HDL, non-high-density lipoprotein; PO, by mouth; SC, subcutaneous
Homozygous FH
TESLA Part B35
Raal FJ, et al.
Familial Hypercholesterolemia
Heterozygous FH
RUTHERFORD-234
NCT01764633
[Study ongoing]
FOURIER37
Blom DJ, et al.
Long-Term Studies
DESCARTES31
Stroes E, et al.
Statin Intolerant Patients¥
GAUSS-230
Robinson JG, et al.
Combination Therapy
LAPLACE-229
Koren MJ, et al.
Primary Hypercholesterolemia
Monotherapy
MENDEL-228
Clinical Trial
Evolocumab (Repatha®)
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Table 4. Summarized comparison of available agents
Agent
Dosing Scheme
Major considerations
Cost (WAC)
Alirocumab
75 mg SC once every 2 weeks
No dose adjustment for hepatic
or renal insufficiency
$560/injection
No dose adjustment for hepatic
or renal insufficiency
$542.31/injection
Note: may increase to max
dose of 150 mg SC once every
2 weeks if needed
Evolocumab
140 mg SC once every 2 weeks
OR
420 mg SC once monthly
Note: 420 mg SC once
monthly preferred in patients
with homozygous familial
hypercholesterolemia
SC-subcutaneous
$14,600/year
$14,100/year
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