New Kids on the Block: The Promise of PCSK9 …...Proprotein convertase subtilisin—kexin type 9...

INDIANA PHARMACISTS ALLIANCE CONTINUING PHARMACY EDUCATION (CPE)

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]

Additional Author:

Taylor D. Steuber, PharmD, BCPS

PGY2 Pharmacotherapy Resident

Indiana University Health/Butler University

[email protected]

Additional Author:

Allison M. Boyd, PharmD Candidate


[email protected]

Additional Author:

Alexandra E. Foster, PharmD Candidate


[email protected]

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.

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.

3. Identify key efficacy and safety

outcomes of PCSK9 inhibitors in

the management of

hyperlipidemia.

4. Discuss the application and

potential place in therapy for

PCSK9 inhibitors.

Introduction

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 HMG-

CoA reductase inhibitors, more commonly

known as “statins,” and their importance in

both primary and secondary CVD

prevention through LDL-C reduction and

mailto:[email protected]




2016 ARTICLE 2

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 dose-

dependent 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

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 PCSK9-

directed 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


2016 ARTICLE 2

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

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


2016 ARTICLE 2


2016 ARTICLE 2

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, placebo-

or 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%

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 alirocumab-

treated 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 treatment-

emergent adverse events was similar among

patients receiving alirocumab and placebo in

all trials.16-26 Commonly reported adverse


2016 ARTICLE 2

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, placebo-

or 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

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, placebo-

controlled, 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 LDL-

C 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, placebo-

controlled 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


2016 ARTICLE 2

expected to be completed by February

2018.37

Safety Profile

Similar incidence of treatment-

emergent 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

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


2016 ARTICLE 2

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 LDL-

C, 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

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.


2016 ARTICLE 2

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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

• No relevant drug interactions

• Degraded to small peptides

• 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

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2016 ARTICLE 2

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eeks

N =

73

5 (R

and

om

ize

d 1

:2)

-SC

pla

ceb

o b

iwee

kly

-SC

alir

ocu

mab

biw

eekl

y

Max

imal

ly

tole

rate

d

stat

in ±

LLT

LDL-

C

No

n-H

DL

Ap

o-B

-51

.4 t

o -

57

.9

-45

.7 t

o -

52

.4

-39

.3 t

o -

45

.8

OD

YSSE

Y H

IGH

FH

24,2

5

NC

T01

617

655

[Stu

dy

com

ple

te]

Pa

tie

nt

Po

pu

lati

on

: ag

e 5

1 y

ears

, 47

% w

om

en, v

aryi

ng

CV

risk

, bas

elin

e LD

L-C

~1

97

mg/

dL

Du

rati

on

: 7

8 w

eeks

N =

10

7 (R

and

om

ize

d 1

:2)

-SC

pla

ceb

o b

iwee

kly

-SC

alir

ocu

mab

150

mg

biw

eekl

y

Max

imal

ly

tole

rate

d

stat

in ±

LLT

LDL-

C

No

n-H

DL

Ap

o-B

-39

.1

-35

.8

-30

.3

Pri

mar

y H

yper

cho

lest

ero

lem

ia o

r H

eFH

OD

YSSE

Y O

PTI

ON

S I20

,21

Ba

ys H

, et

al.

Pa

tie

nt

Po

pu

lati

on

: ag

e 6

3 y

ears

, 35

% w

om

en, h

igh

CV

risk

, 59

% C

HD

, bas

elin

e LD

L-C

~1

05

mg/

dL,

on

sta

tin

Du

rati

on

: 2

4 w

eeks

N =

35

5 (R

and

om

ize

d 1

:1:1

:1)

-P

O a

torv

asta

tin

en

try

do

se o

r d

ou

ble

do

se o

r ro

suva

stat

in ±

P

O e

zeti

mib

e 1

0 m

g d

aily

± a

liro

cum

ab b

iwee

kly

Ato

rvas

tati

n

20

mg

or

40

mg

± LL

T

LDL-

C

No

n-H

DL

Ap

o-B

-20

.9 t

o -

39

.8

-21

.6 t

o -

41

.1

-23

.6 t

o -

38

.4

OD

YSSE

Y O

PTI

ON

S II

20,2

2

NC

T01

730

053

[Stu

dy

com

ple

te]

Pa

tie

nt

Po

pu

lati

on

: ag

e 6

1 y

ears

, 39

% w

om

en, h

igh

CV

risk

, 63

% C

HD

, bas

elin

e LD

L-C

~1

11

mg/

dL,

on

sta

tin

Du

rati

on

: 24

wee

ks

N =

30

5 (R

and

om

ize

d 1

:1:1

)

-P

O r

osu

vast

atin

en

try

do

se o

r d

ou

ble

do

se d

aily

± P

O

ezet

imib

e 1

0 m

g d

aily

± a

liro

cum

ab b

iwee

kly

Ro

suva

stat

in

10

mg

or

20

mg

± LL

T

LDL-

C

No

n-H

DL

Ap

o-B

-20

.3 t

o -

36

.1

-18

.5 t

o -

31

.4

-17

.1 t

o -

29

.2

OD

YSSE

Y LO

NG

TER

M26

Ro

bin

son

JG

, et

al.

Pa

tie

nt

Po

pu

lati

on

: ag

e 6

1 y

ears

, 38

% w

om

en, h

igh

CV

risk

, 69

% C

HD

, 18

% H

eFH

, bas

elin

e LD

L-C

~12

2 m

g/d

L

Du

rati

on

: 7

8 w

eeks

N =

23

41 (

Ran

do

miz

ed

1:2

)

-SC

pla

ceb

o b

iwee

kly

-SC

alir

ocu

mab

150

mg

biw

eekl

y

Max

imal

ly

tole

rate

d

stat

in ±

LLT

LDL-

C

No

n-H

DL

Ap

o-B

-61

.9

-52

.3

-54

.0


2016 ARTICLE 2

Evo

locu

mab

(R

ep

ath

a®)

Clin

ical

Tri

al

Stu

dy

De

scri

pti

on

Tr

eatm

ent

Gro

up

s* B

ackg

rou

nd

stat

in o

r LL

T†

Ch

ange

in L

ipid

Pa

ram

eter

s‡ (

%)

Pri

mar

y H

yper

cho

lest

ero

lem

ia

Mo

no

ther

ap

y

MEN

DEL

-228

K

ore

n M

J, e

t a

l. P

ati

en

t P

op

ula

tio

n:

age

53

yea

rs, 6

9%

wo

men

, lo

w C

V r

isk,

no

CH

D, b

ase

line

LDL-

C ~

14

3 m

g/d

L

Du

rati

on

: 1

2 w

eeks

N =

61

5 (R

and

om

ize

d 1

:1:1

:1:2

:2)

-P

O p

lace

bo

dai

ly, S

C p

lace

bo

biw

eekl

y/m

on

thly

-

PO

eze

tim

ibe

10

mg

dai

ly, S

C p

lace

bo

biw

eek

ly/m

on

thly

-

PO

pla

ceb

o d

aily

, SC

evo

locu

mab

biw

eekl

y/m

on

thly

No

ne

#

LDL-

C¶

No

n-H

DL¶

Ap

o-B

¶

-56

.5 t

o -

57

.4

-39

.4 t

o -

39

.7

-48

.8 t

o -

53

.5

-35

.5 t

o -

35

.6

-47

.1 t

o -

50

.9

-33

.6 t

o -

34

.6

Co

mb

ina

tio

n T

her

ap

y

LAP

LAC

E-229

R

ob

inso

n J

G, e

t a

l.

Pa

tie

nt

Po

pu

lati

on

: age

60

yea

rs, 4

6%

wo

men

, hig

h C

V

risk

, 23

% C

HD

, bas

elin

e LD

L-C

~1

09

mg/

dL

Du

rati

on

: 1

2 w

eeks

N =

20

67

-M

od

erat

e-

or

hig

h-i

nte

nsi

ty s

tati

n¤

± P

O e

zeti

mib

e 1

0 m

g d

aily

± S

C e

volo

cum

ab b

iwee

kly/

mo

nth

ly

No

ne

#

LDL-

C

No

n-H

DL

Ap

o-B

-63

.0 t

o -

75

.0

-58

.0 t

o -

65

.0

-51

.0 t

o -

59

.0

Sta

tin

Into

lera

nt

Pa

tien

ts¥

GA

USS

-230

St

roes

E, e

t a

l.

Pa

tie

nt

Po

pu

lati

on

: ag

e 6

2 y

ears

, 46

% w

om

en, v

aryi

ng

CV

risk

, 29

% C

HD

, bas

elin

e LD

L-C

~1

94

mg/

dL

Du

rati

on

: 1

2 w

eeks

N =

30

7 (R

and

om

ize

d 1

:1:2

:2)

-P

O e

zeti

mib

e 1

0 m

g d

aily

, SC

pla

ceb

o b

iwe

ekly

/mo

nth

ly

-P

O p

lace

bo

dai

ly, S

C e

volo

cum

ab b

iwee

kly/

mo

nth

ly

No

or

low

-

do

se s

tati

n ±

LLT

LDL-

C

No

n-H

DL

Ap

o-B

-36

.9 t

o -

38

.7

-31

.5 t

o -

34

.6

-32

.2 t

o -

35

.0

Lon

g-T

erm

Stu

die

s

DES

CA

RTE

S31

Blo

m D

J, e

t a

l. P

ati

en

t P

op

ula

tio

n:

age

56

yea

rs, 5

3%

wo

men

, var

yin

g C

V

risk

, 15

% C

HD

, bas

elin

e LD

L-C

~1

00

mg/

dL

Du

rati

on

: 5

2 w

eeks

N =

90

1 (1

:2)

-SC

pla

ceb

o m

on

thly

-

SC e

volo

cum

ab 4

20

mg

mo

nth

ly

No

ne

#

LDL-

C

No

n-H

DL

Ap

o-B

-48

.5 t

o -

61

.6

-41

.2 t

o -

54

.5

-37

.8 t

o -

47

.7

FOU

RIE

R37

N

CT0

176

463

3

[Stu

dy

on

goin

g]

Pa

tie

nt

Po

pu

lati

on

: cl

inic

ally

evi

den

t A

SCV

D a

t h

igh

ris

k fo

r

a r

ecu

rren

t ev

en

t

Du

rati

on

: 5

year

s

N =

27

,500

0

-St

and

ard

th

erap

y, S

C p

lace

bo

biw

eekl

y/m

on

thly

-

Stan

dar

d t

her

apy,

SC

evo

locu

mab

biw

eekl

y/m

on

thly

Stat

in

LDL-

C

No

n-H

DL

Ap

o-B

—

—

—

Fam

ilial

Hyp

erch

ole

ster

ole

mia

Het

ero

zyg

ou

s FH

RU

THER

FOR

D-2

34

Ra

al F

J, e

t a

l.

Pa

tie

nt

Po

pu

lati

on

: ag

e 5

1 y

ears

, 42

% w

om

en, h

igh

CV

risk

, 31

% C

HD

, bas

elin

e LD

L-C

~1

55

mg/

dL

Du

rati

on

: 1

2 w

eeks

N =

32

9 (R

and

om

ize

d 1

:1:2

:2)

-SC

pla

ceb

o b

iwee

kly/

mo

nth

ly

-SC

evo

locu

mab

biw

eekl

y/m

on

thly

Stab

le d

ose

stat

in ±

LLT

LDL-

C

No

n-H

DL

Ap

o-B

-60

.2 t

o -

65

.6

-49

.4 t

o -

55

.0

-56

.0 t

o -

60

.0

Ho

mo

zyg

ou

s FH

TESL

A P

art

B35

R

aa

l FJ,

et

al.

Pa

tie

nt

Po

pu

lati

on

: ag

e 3

1 y

ears

, 49

% w

om

en, h

igh

CV

risk

, 43

% C

HD

, bas

elin

e LD

L-C

~3

48

mg/

dL

Du

rati

on

: 1

2 w

eeks

N =

49

(Ran

do

miz

ed

1:2

)

-SC

pla

ceb

o m

on

thly

-

SC e

volo

cum

ab 4

20

mg

mo

nth

ly

Stab

le d

ose

stat

in ±

LLT

LDL-

C

No

n-H

DL

Ap

o-B

-31

.0

-29

.2

-22

.9

Pri

mar

y H

yper

cho

lest

ero

lem

ia o

r H

eFH

OSL

ER I

and

OSL

ER II

36∫

Sab

atin

e M

S, e

t a

l. P

ati

en

t P

op

ula

tio

n:

age

58

yea

rs, 4

9%

wo

men

, var

yin

g C

V

risk

, 20

% C

HD

, bas

elin

e LD

L-C

~1

20

mg/

dL

Du

rati

on

: 5

2 w

eeks

N =

44

65 (

Ran

do

miz

ed

1:2

)

-St

and

ard

th

erap

y al

on

e◊

-St

and

ard

th

erap

y◊, S

C e

volo

cum

ab b

iwee

kly/

mo

nth

ly

Stab

le d

ose

stat

in ±

LLT

LDL-

C

No

n-H

DL

Ap

o-B

-61

.0

-52

.0

-47

.2

* A

liro

cum

ab d

ose

d a

t 7

5 m

g b

iwee

kly

and

tit

rate

d t

o 1

50

mg

biw

eekl

y at

wee

k 1

2 if

LD

L-C

was

≥ 7

0 m

g/d

L u

nle

ss o

ther

wis

e sp

ecif

ied

. Evo

locu

mab

do

sed

14

0 m

g b

iwee

kly

or

42

0 m

g m

on

thly

.

† LL

T, e

xclu

din

g ez

eti

mib

e, u

nle

ss o

ther

wis

e sp

ecif

ied

.

‡ P

erce

nt

chan

ge in

lip

id p

aram

ete

rs in

inte

rven

tio

n g

rou

p r

ela

tive

to

co

mp

arat

or

gro

up

s at

wee

k 2

4 (a

liro

cum

ab)

or

at m

ean

of

wee

ks 1

0 a

nd

12

(evo

locu

mab

) st

atis

tica

lly s

ign

ific

ant.

#

No

ad

dit

ion

al s

tati

n o

r LL

T o

the

r th

an s

tud

y in

terv

enti

on

s.

¥ St

atin

into

lera

nt

def

ined

as u

nab

le t

o t

ole

rate

an

y d

ose

or

do

se la

rger

th

an t

he

sm

alle

st a

vaila

ble

tab

let

stre

ngt

h d

ue

to

into

lera

ble

mu

scle

-rel

ated

AEs

. ¶

Rep

ort

ed

as

per

cen

t ch

ange

re

lati

ve t

o (

1) p

lace

bo

an

d (

2) e

zeti

mib

e.

¤ M

od

erat

e-i

nte

nsi

ty s

tati

n t

her

apy—

ato

rvas

tati

n 1

0 m

g d

aily

, ro

suva

stat

in 5

mg

dai

ly, s

imva

stat

in 4

0 m

g d

aily

; h

igh

-in

ten

sity

sta

tin

th

erap

y—at

orv

asta

tin

80

mg

dai

ly, r

osu

vast

atin

40

mg

dai

ly.

∫ Ex

ten

sio

n o

f th

e p

are

nt

tria

ls:

Ph

ase

2—

MEN

DEL

-1, L

AP

LAC

E-TI

MI 5

7, G

AU

SS-1

, RU

THER

FOR

D-1

, YU

KA

WA

; P

has

e 3

—M

END

EL-2

, LA

PLA

CE-

2, G

AU

SS-2

, RU

THER

FOR

D-2

, DES

CA

RTE

S, T

HO

MA

S-1

, TH

OM

AS-

2.

◊ S

tan

dar

d t

her

apy

def

ine

d a

s th

erap

y b

ased

on

cu

rre

nt

guid

elin

es f

or

LDL-

C m

anag

em

ent.

A

bb

revi

atio

ns:

AC

S, a

cute

co

ron

ary

syn

dro

me;

Ap

o-B

, ap

olip

op

rote

in B

; A

SCV

D, a

ther

osc

lero

tic

card

iova

scu

lar

dis

ease

; C

HD

, co

ron

ary

hea

rt d

isea

se;

CV

, car

dio

vasc

ula

r; F

H, f

amil

ial h

yper

cho

lest

ero

lem

ia;

HeF

H, h

eter

ozy

gou

s fa

mili

al h

yper

cho

lest

ero

lem

ia;

LDL-

C, l

ow

-de

nsi

ty li

po

pro

tein

ch

ole

ster

ol;

LLT,

lip

id-l

ow

erin

g th

erap

y; N

on

-HD

L, n

on

-hig

h-d

ensi

ty li

po

pro

tein

; P

O, b

y m

ou

th;

SC, s

ub

cuta

neo

us


2016 ARTICLE 2

Table 4. Summarized comparison of available agents

Agent Dosing Scheme Major considerations Cost (WAC)

Alirocumab 75 mg SC once every 2 weeks

Note: may increase to max

dose of 150 mg SC once every

2 weeks if needed

No dose adjustment for hepatic

or renal insufficiency

$560/injection

$14,600/year

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

No dose adjustment for hepatic

or renal insufficiency

$542.31/injection

$14,100/year

SC-subcutaneous


2016 ARTICLE 2

References

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2016 ARTICLE 2

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