J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 6 5 , N O . 2 4 , 2 0 1 5

ª 2 0 1 5 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N I S S N 0 7 3 5 - 1 0 9 7 / $ 3 6 . 0 0

P U B L I S H E D B Y E L S E V I E R I N C . h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 5 . 0 5 . 0 0 1

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Are PCSK9 Inhibitors the NextBreakthrough in the Cardiovascular Field?

Robert P. Giugliano, MD, SM, Marc S. Sabatine, MD, MPH

ABSTRACT

Fro

ha

pe

gra

Dia

Gla

Dia

Lis

Ma

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the low-density lipoprotein receptor, escorting it

to its destruction in the lysosome and thereby preventing the recirculation of the low-density lipoprotein receptor

to the hepatocyte cell surface. Both gain-of-function mutations in PCSK9 (causing marked increases in low-density

lipoprotein cholesterol [LDL-C] concentration and premature atherosclerosis) and loss-of-function mutations (causing

modest LDL-C reduction with low rates of coronary heart disease) have been described. Several monoclonal anti-

bodies to PCSK9 have achieved LDL-C reductions of 50% to 70% across various patient populations and back-

ground lipid therapies. Phase 2/3 trials have demonstrated good tolerability without clear drug-related toxicity,

although the number and duration of patients treated to date is modest. Currently, 4 phase 3 trials involving

>70,000 patients are testing whether these drugs reduce cardiovascular events. The U.S. Food and Drug Admin-

istration is currently reviewing the existing data to determine whether these agents could be made available prior

to the completion of these cardiovascular endpoint trials expected in 2018. (J Am Coll Cardiol 2015;65:2638–51)

© 2015 by the American College of Cardiology Foundation.

T wo separate lines of research—the firstexploring the structure and function of afamily of serine proteases, known as propro-

tein convertases, that activate a wide variety of pro-teins regulating several key cellular pathways inhumans and other organisms (1), and the secondinvestigating genetic causes of familial hypercholes-terolemia (FH) (2), were the parents of a potent newclass of low-density lipoprotein cholesterol (LDL-C)–lowering drugs known as the proprotein convertasesubtilisin/kexin type 9 (PCSK9) inhibitors. In 2001,scientists at Millennium Pharmaceuticals discoveredPCSK9 during studies of cerebellar neuron apoptosis,and the gene was characterized shortly thereafter, in2003 (3). In parallel, research by the French Network

m the Cardiovascular Division, Brigham and Women’s Hospital, Harvard M

s received grant support from Merck and AstraZeneca; grant support and

rsonal fees from Bristol-Myers Squibb, CVS Caremark, Pfizer, and Sanofi ou

nt support from Abbott Laboratories, Accumetrics, Critical Diagnostics, D

gnostics, Takeda, and Gilead; grant support and personal fees f

xoSmithKline, Intarcia, Merck, and Sanofi; and personal fees from Ae

gnostics, Vertex, Zeus Scientific, and CVS Caremark outside of the subm

ten to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Vale

nuscript received March 29, 2015; revised manuscript received April 29, 2

for Autosomal Dominant Hypercholesterolemia (4),and independently in Utah (5), identified a third FHlocus (the first 2 mutation loci map to the low-density lipoprotein receptor [LDL-R] and apolipopro-tein B genes). In 2003, Abifadel et al. (6) were the firstto describe mutations in the PCSK9 gene as a cause ofFH. Studies in families from Utah (7), Norway (8), andthe United Kingdom (9) provided confirmation thatPCSK9 mutations were responsible for FH.

These initial discoveries that gain-of-function mu-tations in PCSK9 could cause hypercholesterolemiawere quickly followed by reports that loss-of-functionmutations in PCSK9 caused a reduction in cholesterol(10). Themodest (15% to 28%), but lifelong, lowering ofLDL-C appeared to confer considerable protection

edical School, Boston, Massachusetts. Dr. Giugliano

personal fees from Amgen and Daiichi-Sankyo; and

tside the submitted work. Dr. Sabatine has received

aiichi-Sankyo, Eisai, Genzyme, Nanosphere, Roche

rom Amgen, AstraZeneca, Bristol-Myers Squibb,

gerion, Alnylam, Cubist, MyoKardia, Pfizer, Quest

itted work.

ntin Fuster.

015, accepted May 4, 2015.

AB BR E V I A T I O N S

AND ACRONYM S

CHD = coronary heart disease

FH = familial

hypercholesterolemia

HDL = high-density lipoprotein

LDL-C = low-density

lipoprotein cholesterol

LDL-R = low-density

lipoprotein receptor

MoAb = monoclonal antibody

PCSK9 = proprotein

convertase subtilisin/kexin

type 9

SC = subcutaneous

= standard of care

J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5 Giugliano and SabatineJ U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1 PCSK9 Inhibitors: The Next Breakthrough

2639

from the development of coronary heart disease (CHD)(11). Thus, the stage was set for the development oftherapies that could inhibit PCSK9, lower LDL-C, and,hopefully, reduce atherothrombotic events.

ROLE OF PCSK9 IN REGULATING

LDL-R METABOLISM

The principal route of clearance of circulating LDL-Cfrom the blood is via hepatocyte endocytosis—aprocess mediated by binding of LDL-C to LDL-Rs onthe hepatocyte cell membrane (Central Illustration).The typical LDL-R is able to recirculate back to thecell surface up to 150 times, with PCSK9 playinga critical role in LDL-R metabolism. The catalyticsubunit of PCSK9 binds to the epidermal growthfactor-like domain of the LDL-R and then escortsthe receptor to its degradation within the lysosome.Given the counter-regulatory role played by PCSK9,gain-of-function mutations in PCSK9 resulting in itsoverexpression lead to fewer functioning LDL-Rs andhigher levels of circulating LDL-C. Conversely, loss-of-function mutations in PCSK9 result in lowerLDL-C levels. PCSK9 can bind other proteins; appearsto play additional, lesser roles in lipid metabolism;and its expression can be modified by a number offactors (e.g., statins increase PCSK9 levels)—furtherdetails can be found elsewhere (1,2).

THERAPEUTIC INHIBITION OF PCSK9

Studies in PCSK9 knockout mice demonstrated a 2- to3-fold increase in LDL-Rs and a 25% to 50% decreasein circulating cholesterol (12). This led to the explo-ration of a number of methods to reduce PCSK9 levelsand/or inhibit its function, including both oral andparenteral therapies (2) (Central Illustration). Bothantisense oligonucleotides and small interferingribonucleic acids have been studied in pre-clinicaland phase 1 human studies. Mimetic peptides, LDL-Rantagonists, small molecules, and gene silencingapproaches to modulate PCSK9 are in earlier stages ofdevelopment. A number of approaches using novelsmall molecules have been described, including theuse of epidermal growth factor-A mimetics to blockPCSK9 binding of the LDL-R (13) and inhibitors of pro-PCSK9 autoprocessing and/or secretion (14); unfor-tunately, the PCSK9-LDL-R complex has a relativelyflat surface that makes binding by a small moleculeinhibitor challenging (15). However, parenteralmonoclonal antibodies (MoAbs) have been the mostsuccessful strategy to date and are now in late-stage(phase 3 clinical trials) testing (Table 1); thus, theyare the focus of this paper.

PCSK MONOCLONAL ANTIBODIES

The first studies in humans in healthy vol-unteers (16,17) were conducted with the fullyhuman PCSK9 MoAb REGN727 (hereafteralirocumab) and, shortly thereafter, with thefully human MoAb AMG145 (evolocumab [18])and the humanized MoAb RN316 (bococizu-mab [19]). These studies demonstrated dose-dependent reductions in unbound PCSK9levels beginning within hours after injectionwith top doses achieving unmeasurablePCSK9 levels for 2 weeks before returning tobaseline >6 weeks following a single injec-tion. Dose-dependent reduction in LDL-C (upto 70%), timing of nadir LDL-C (between 4

and 14 days), and delay in return to baseline LDL-C(2 to 8þ weeks) were observed with each of theseMoAbs. More recently, data were presented withLY3015014, a humanized MoAb with a unique epitopethat permits the normal proteolytic degradation ofPCSK9 (unlike other MoAbs), thereby resulting in amore sustained lowering of LDL-C (20).

PHASE 2 CLINICAL TRIALS

Both alirocumab and evolocumab have been exten-sively evaluated in more than a dozen phase 2 trialsexploring dose ranging and dose frequency, variouspatient populations, and adjunctive lipid-loweringtherapies, with fewer studies available with bococi-zumab (Table 2). The top doses being developedof alirocumab (150 mg subcutaneously [SC] every2 weeks) and evolocumab (140 mg SC every 2 weeks;420 mg SC every 4 weeks) administered for 12 weeksreduce LDL-C by approximately 60% to 70% (75 to85 mg/dl) at trough (17,18) and >90% (>100 mg/dl) atpeak (21). The vast majority (70% to 90%) of patientswith hyperlipidemia treated with statin therapy wereable to achieve an LDL-C <70 mg/dl with alirocumab(22) and evolocumab (23,24), demonstrating theability of these drugs to drive down levels of LDL-C toranges not possible with existing therapies. A phase 2trial with bococizumab in 351 patients with hyper-cholesterolemia reported LDL-C reductions of 53%(53 mg/dl) with 150 mg every 2 weeks and by 41%(45 mg/dl) with 300 mg every 4 weeks, adjusted forplacebo (19). A phase 2 trial comparing LY3015014with placebo in 527 patients with hypercho-lesterolemia treated with standard care (includingstatins) revealed reductions in LDL-C of up to 58%(w79 mg/dl) and 45% (w61 mg/dl) with adminis-tration every 4 and 8 weeks, respectively, adjustedfor placebo (25).

SOC

CENTRAL ILLUSTRATION PCSK9 Function and Potential Targets for Therapeutics

Giugliano, R.P. et al. J Am Coll Cardiol. 2015; 65(24):2638–51.

SREBP-2 in hepatocytes regulates transcription of several lipids and proteins, including the low-density lipoprotein receptor (LDL-R) and proprotein convertase

subtilisin/kexin type 9 (PCSK9) (step 1). PCSK9 is processed in the endoplasmic reticulum into a mature form (step 2) and undergoes packaging by the Golgi apparatus

(as does the LDL-R) before being secreted (step 3). The LDL-R binds circulating low-density lipoprotein cholesterol (LDL-C) (step 4), and the pair is internalized in

endosomes, where LDL-C can be shuttled for other use. Meanwhile, the LDL-R recirculates to the cell surface (step 5) up to 150 times, removing additional LDL-C from

the circulation. PCSK9 regulates the number of LDL-R by binding to and internalizing the LDL-R (step 6), escorting it to its destruction in the lysosome (step 7). This does

not permit the LDL-R to recirculate. Several methods to interfere with the function of PCSK9 are shown by the letters within red octagons. Small interfering ribonucleic

acids (siRNAs) (A) can block transcription of PCSK9 messenger ribonucleic acid, whereas small molecular inhibitors (B) can disrupt the processing of PCSK9—both

approaches reduce the production of functional PCSK9. Two extracellular approaches to inhibit PCSK9 function include monoclonal antibodies (MoAbs) (C) and

adnectins (D) that prevent binding of PCSK9 to the LDL-R. SREBP ¼ sterol-binding regulatory element-binding transcription factor.

Giugliano and Sabatine J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5

PCSK9 Inhibitors: The Next Breakthrough J U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1

2640

In phase 2 studies, LDL-C was significantly andsimilarly lowered with alirocumab and evolocumabcompared with placebo, whether patients were takingno, low-dose, or high-dose statins; taking ezetimibe; orhad heterozygous FH. The findings appear consistentacross major subgroups (e.g., age, sex, diabetes, risklevel) with no significant treatment–subgroup inter-actions consistently reported. Longer-term follow-up($1 year) demonstrated a persistent similar reductionin LDL-C as was observed in the 12-week studies.

In addition, evolocumab reduced LDL-C in themajority of patients with homozygous FH (26,27); theresponders had partially functioning (2% to 25%)LDL-R. Genetic analyses in patients who did notrespond to evolocumab demonstrated nonfunc-tioning LDL-Rs (<2% function) (26).

Both alirocumab and evolocumab also significantlyreduce apolipoprotein B, total cholesterol, tri-glycerides, and non–high-density lipoprotein choles-terol (HDL); lipoprotein(a) (22,24,28,29), HDL, and

TABLE 1 Trial Acronyms

DESCARTES Durable Effect of PCSK9 Antibody Compared with Placebo Study

EBBINGHAUS Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlthin High cardiovascUlar Risk Subjects

FOURIER Further Cardiovascular Outcomes Research With PCSK9 Inhibitionin Subjects With Elevated Risk

GAUSS Goal Achievement After Utilizing an Anti-PCSK9 Antibodyin Statin Intolerant Subjects

LAPLACE LDL-C Assessment with PCSK9 Monoclonal Antibody InhibitionCombined with Statin Therapy

MENDEL Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C inSubjects Currently Not Receiving Drug Therapy for Easing Lipid Levels

ODYSSEY LONGTERM

Long-term Safety and Tolerability of Alirocumab in High CardiovascularRisk Patients with Hypercholesterolemia Not Adequately Controlledwith Their Lipid Modifying Therapy

OSLER Open-Label Study of Long-Term Evaluation Against LDL-C

PROFICIO Program to Reduce LDL-C and Cardiovascular Outcomes FollowingInhibition of PCSK9 in Different Populations

RUTHERFORD Reduction of LDL-C with PCSK9 Inhibition in Heterozygous FamilialHypercholesterolemia Disorder

SPIRE Studies of PCSK9 Inhibition and the Reduction of vascular Events

TESLA Trial Evaluating PCSK9 Antibody in Subjects with LDL-ReceptorAbnormalities

TIMI Thrombolysis In Myocardial Infarction

YUKAWA Study of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibodyin Japanese Patients With Advanced Cardiovascular Risk

LDL-C ¼ low-density lipoprotein cholesterol; PCSK9 ¼ proprotein convertase subtilisin/kexin type 9.

J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5 Giugliano and SabatineJ U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1 PCSK9 Inhibitors: The Next Breakthrough

2641

apolipoprotein A are minimally (if at all) increased(<10%), as would be expected given the mechanismof action of these drugs. No reduction in C-reactiveprotein has been reported, but it should be noted thatthe populations studied would be expected to havenormal (or low) levels of C-reactive protein, andstudies in patients post-acute coronary syndromesare ongoing.

No clear drug-related toxicities have been reportedin the phase 2 studies, although the duration oftherapy was generally short (12 weeks) and low-frequency, but clinically relevant signals cannot beexcluded (30). One patient in an early phase 2 studyof alirocumab developed a leukocytoclastic reaction(31); however, this has not been seen in subsequenttrials. No neutralizing antibodies have been reportedin the trials to date. A placebo-controlled study ofevolocumab in patients who were intolerant of sta-tins has shown no excess in myalgias or other seriousadverse events compared with placebo (32). Othertheoretical safety concerns (33) on the basis of otherroles and targets of PCSK9 beyond LDL-R degrada-tion include an increased risk for viral infections(because some LDL-Rs function as viral entry re-ceptors), insulin resistance and glucose intolerance(reported in humans carrying the R46L PCSK9 loss-of-function-mutation [34]), and increased visceraladiposity, which is due to decreased free fatty acidclearance related to changes in other lipoproteinstargeted by PCSK9 (35). Overall, across the phase 2trials with a modest number of patient-years offollow-up, cardiovascular events were infrequent(30); longer-term safety experiences in a greaternumber of patients are discussed in the followingsection.

PHASE 3 AND LONGER-TERM

FOLLOW-UP STUDIES

Multiple larger phase 3 studies with alirocumab andevolocumab evaluating lipid endpoints and longer-term follow-up studies have been published or pre-sented (Table 3).

PCSK9 MONOTHERAPY. Similar to the phase 2 trialsdiscussed previously, larger phase 3 trials with these2 PCSK9 inhibitors have demonstrated consistent re-ductions in LDL-C across a variety of patients andbackground therapies. Both evolocumab and alir-ocumab have been studied as monotherapies versusezetimibe (36,37). In 614 patients with baseline LDL-C100 to 190 mg/dl, evolocumab reduced LDL-C at12 weeks by 55% to 57% (w80 mg/dl) on averagecompared with placebo, whereas ezetimibe achieved

an 18% to 19% (w26 mg/dl) reduction (36). Similarly,in a study of alirocumab monotherapy versus ezeti-mibe in 103 patients with a 1% to 5% 10-year risk offatal cardiovascular events, alirocumab reducedLDL-C by 47% (66 mg/dl) at 24 weeks, compared withonly 16% (22 mg/dl) for ezetimibe (37).

COMBINATION WITH STATIN. In 316 patients withestablished CHD or CHD risk equivalents and hy-percholesterolemia, alirocumab reduced LDL-C at24 weeks by 46% (46 mg/dl) more than placebo, with75% of patients achieving an LDL-C <70 mg/dl(compared with 9% with placebo) (38). In a similarpopulation of patients who were taking maximallytolerated statins, alirocumab reduced LDL-C by 30%(31 mg/dl) more than ezetimibe, permitted more pa-tients to achieve an LDL-C <70 mg/dl than ezetimibe(77% vs. 46%), and had a similar safety profile toezetimibe (39).

Evolocumab was compared with placebo and withezetimibe in 2,067 patients with an LDL-C$150 mg/dl,all of whom were treated with either moderate orintensive statin therapy (40). For patients on a high-intensity statin (atorvastatin 80 mg or rosuvastatin40 mg), evolocumab reduced the mean LDL-Ccompared with placebo at 10 and 12 weeks by 66% to75% (56 to 70 mg/dl) with 140 mg every 2 weeks andby 63% to 75% (51 to 66 mg/dl) with 420 mg every4 weeks. In patients receiving moderate-dose statins

TABLE 2 Phase 2 Trial Results

Trial Name (Ref. #) N

Baseline LDL-CEntry Criteria,Median (mg/dl) Drug and Dosing (mg)

LDL-C Reductionvs. Placebo

In combination with statin

McKenney et al. (72) 183 $100, 127 Ali 50–150 Q2W 35%–67% at week 12

Ali 200–300 Q4W 38%–43% at week 12

Roth et al. (73) 92 >100, 123 Ali 150 Q2W 56% at week 8

LAPLACE-TIMI 57 (21) 631 $100, 123 Evo 70–140 Q2W 42%–66% at week 12

Evo 280–420 Q4W 42%–50% at week 12

YUKAWA (74) 310 $116, 143 Evo 70–140 Q2W 53%–69% at week 12

Evo 270–420 Q4W 58%–64% at week 12

Ballantyne et al. (75) 351 $80, 109 Boco 50–150 Q2W 35%–53% at week 12

Boco 200–300 Q4W 27%–41% at week 12

Kastelein et al. (25) 527 N/A, 135 LY3015014 20–300 Q4W 23%–58% at week 16

LY3015014 100–300 Q8W 23%–45% at week 16

Monotherapy

MENDEL (76) 406 100–190, 143 Evo 70–140 Q2W 37%–47% at week 12

Evo 280–420 Q4W 44%–53% at week 12

Statin intolerance

GAUSS (32) 160 >Goal, 193 Evo 280–420 Q2W 26%–36% at week 12

Evo 420 Q2W þezetimibe 10 QD

47% at week 12

Heterozygous familial hypercholesterolemia

Stein et al. (16) 77 $100, 155 Ali 150 Q2W 57% at week 12

Ali 150–300 Q4W 18%–32% at week 12

RUTHERFORD (77) 169 $100, 156 Evo 350–420 Q4W 44%–56% at week 12

Homozygous familial hypercholesterolemia

TESLA (26) 8 $130, 440 Evo 420 Q4W �17%* at week 12

Trials appear in order of publication date; abstracts/presentations are listed after publications. *Change for baseline (no placebo group was tested).

Ali ¼ alirocumab; Boco ¼ bococizumab; Evo ¼ evolocumab; LDL-C ¼ low-density lipoprotein cholesterol; NA ¼ not available (entry criteria specified diagnosis of highcholesterol); QD ¼ daily; Q2W ¼ biweekly; Q4W ¼ every 4 weeks; Q8W ¼ every 8 weeks; other abbreviations as in Table 1.

Giugliano and Sabatine J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5

PCSK9 Inhibitors: The Next Breakthrough J U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1

2642

(atorvastatin 10 mg, rosuvastatin 5 mg, or simvastatin40 mg), the corresponding reductions were 67% to70% (75 to 84 mg/dl) and 63% to 69% (78 to 80 mg/dl)with evolocumab dosed every 2 and 4 weeks,respectively. Reductions with ezetimibe were lessthan one-half of that achieved with evolocumab,regardless of the background statin. On a backgroundof high-intensity statin, the mean achieved LDL-Cwith evolocumab was 33 to 38 mg/dl, with >90%achieving an LDL-C <70 mg/dl.

COMBINATION WITH STATIN ± EZETIMIBE. In a52-week placebo-controlled randomized trial of evo-locumab in 901 patients with hypercholesterolemiatreated with diet alone, atorvastatin 10 mg, atorvas-tatin 80 mg, or atorvastatin 80 mg þ ezetimibe 10 mg(background therapy dependent upon Adult Treat-ment Panel 3 risk level), evolocumab reduced LDL-Cby 57% (57 mg/dl) on average compared with pla-cebo (range 49% to 62% across the various back-ground therapies) after 52 weeks of therapy (41). Themean achieved LDL-C at week 52 ranged from 45 to64 mg/dl with evolocumab, and the LDL-C wasreduced <70 mg/dl in 82% of patients (compared with

6% with placebo). Among 189 patients who receivedatorvastatin 80mgþ ezetimibe 10mg, themean LDL-Cvalues fell from 117 to 64 mg/dl with evolocumabversus 120 to 115 mg/dl with placebo, and 67% and11% had an LDL-C <70 mg/dl at week 52, respectively.

PATIENTS WITH STATIN INTOLERANCE. Two phase3 trials (42,43) in statin-intolerant patients havedemonstrated the efficacy and tolerability of PCSK9inhibitors in this challenging population. In a ran-domized placebo-controlled trial of 307 patientsintolerant to 2 or more statins whose LDL-Cs were notat goal as defined by Adult Treatment Panel 4, bothevolocumab 140 mg every 2 weeks and 420 mg every4 weeks reduced LDL-C at 12 weeks by 53% to 56% (99to 106 mg/dl) compared with 15% to 18% (30 to 36mg/dl) for ezetimibe (42). Preliminary results of aplacebo-controlled study of 314 patients with base-line LDL-C averaging 190 mg/dl who were intolerantof 2 or more statins (of which 1 was at a low dose) dueto myalgia randomized to alirocumab (75 mg every2 weeks with optional up-titration to 150 mg every2 weeks), ezetimibe 10 mg daily, or atorvastatin20 mg daily were reported at the 2014 American Heart

TABLE 3 Phase 3 and Long-Term Extension Trial Results

Trial Name N

Baseline LDL-CEntry Criteria,Median (mg/dl) Drug and Dosing (mg) LDL-C Reduction vs. Placebo

Monotherapy

MENDEL-2 (36) 614 100–190, 143 Evo 140 Q2W 57% and 39%* at 10–12 weeks†

Evo 420 Q4W 57% and 40%* at 10–12 weeks†

ODYSSEY MONO (78) 103 100–190, 140 Ali 75 Q2W‡ 32%* at week 24

In combination with statin

LAPLACE-2 (40) 2,067 $150, 109 Evo 140 Q2W 66%–75% and 44%–46%* at weeks 10–12†

Evo 420 Q4W 63%–75% and 39%–55%* at weeks 10–12†

ODYSSEY COMBO II (39) 720 $70, 108 Ali 75 Q2W‡ 30%* at week 12

ODYSSEY COMBO I (38) 316 $70, 97 Ali 75 Q2W‡ 46% at week 24

YUKAWA-2 (79) 404 $100, N/A Evo 140 Q2W 74%–75% at weeks 10–12†; 75%–76% at week 12

Evo 420 Q4W 66%–81% at weeks 10–12†; 61%–76% at week 12

In addition to diet alone, statin, or statin þ ezetimibe

DESCARTES (41) 901 $75, 104 Evo 420 Q4W 49%–62% at week 52

ODYSSEY CHOICE I (80) 803 >Goal, 122 Ali 75 Q2W

Ali 300 Q4W 52%–59% at week 24

Statin intolerance

GAUSS-2 (42) 307 >Goal, 193 Evo 140 Q2W 38%* at week 12; 38%* at weeks 10–12†

Evo 420 Q4W 38%* at week 12; 39%* at week 10–12†

ODYSSEY ALTERNATIVE (44) 314 >Goal, 191 Ali 75 Q2W‡ 30%* at week 24

ODYSSEY CHOICE II (80) 233 >Goal, 158 Ali 75 Q2W‡ 56% at week 24

Ali 150 Q4W§ 56% at week 24

Heterozygous familial hypercholesterolemia

RUTHERFORD-2 (45) 331 $100, 154 Evo 140 Q2W 59% at 12 weeks; 60% at weeks 10–12†

Evo 420 Q4W 61% at 12 weeks; 66% at weeks 10–12†

ODYSSEY FH I and II (47) 735 $160, 141 Ali 75 Q2W‡ 51%–58% at week 24

Homozygous familial hypercholesterolemia

TESLA Part B (27) 50 $130, 347 Evo 420 Q4W 31% at week 12

Long-term extension studies

OSLER-1 (48) and OSLER-2 (24) 1,359 $100, 120 Evo 420 Q4W 52% at week 52 (vs. standard of care)

ODYSSEY LONG TERM (22) 2,341 $70, 122 Ali 150 Q2W 62% at week 24

Trials appear in order of publication date; abstracts/presentations are listed after publications. See Table 1 for some trial acronyms. *Versus ezetimibe 10 mg QD. †Mean of thereductions at weeks 10 and 12. ‡Dose adjusted to 150 mg Q2W if LDL-C not at target (target either <70 or <100 mg/dl, depending on risk) at week 12. §Dose adjusted to 75 mgif LDL-C <25 mg/dl at weeks 8–12.

ODYSSEY ALTERNATIVE¼ Study of Alirocumab in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerantto Statins; ODYSSEY CHOICE ¼ Study to Evaluate the Efficacy and Safety of an Every Four Weeks Treatment Regimen of Alirocumab in Patients With Primary Hypercholes-terolemia; ODYSSEY COMBO ¼ Efficacy and Safety of Alirocumab Versus Placebo on Top of Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hyper-cholesterolemia; ODYSSEY FH ¼ Efficacy and Safety of Alirocumab Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous FamilialHypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy; ODYSSEY MONO ¼ Efficacy and Safety of Alirocumab Versus Ezetimibe in Patients WithHypercholesterolemia; other abbreviations as in Tables 1 and 2.

J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5 Giugliano and SabatineJ U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1 PCSK9 Inhibitors: The Next Breakthrough

2643

Association Scientific Sessions (44). Alirocumab notonly was significantly more effective in reducingLDL-C (absolute decline of 84 mg/dl compared with33 mg/dl for ezetimibe), but also had the lowest rateof muscle-related adverse events (33% vs. 41% ezeti-mibe [p ¼ 0.10] vs. 46% atorvastatin [p ¼ 0.04]).FAMILIAL HYPERCHOLESTEROLEMIA. Evolocumabhas completed separate phase 3 trials in patientswith heterozygous (45) and with homozygous FH(27); alirocumab has been studied in patients withheterozygous FH in phase 3 (46). A placebo-controlledtrial of 331 patients with heterozygous FH takingstatin � additional lipid-lowering agents demon-strated that both evolocumab 140 mg every 2 weeks

and 420 mg every 4 weeks significantly reducedLDL-C by approximately 60% (90 to 95 mg/dl)compared with placebo (45). Similar preliminaryfindings were reported with alirocumab at theEuropean Society of Cardiology Congress in 2014 (47).Analyses of 2 trials, enrolling a total of 732 patientswith heterozygous FH on a maximally-tolerateddose of statin � other lipid-lowering therapy, showed51% to 58% (66 to 85 mg/dl) reductions in LDL-C at24 weeks with alirocumab compared with placebo.The only phase 3 trial conducted in patients withhomozygous FH enrolled 50 patients with $4 weeksof a stable lipid regimen and demonstrated a 31%relative (93 mg/dl absolute) further reduction from

FIGURE 1 Cardiovascular Events in Long-Term PCSK9 Trials

3.3HR 0.52 [0.31, 0.90]

26/788

ODYSSEY LONG TERM OSLER-1 and OSLER-2

27/1,550 31/1,489 29/2,976

HR 0.47 [0.28, 0.78]

1.7

Placebo Alirocumuab SOC Evolocimuab

1.0

2.2

3

4

Even

t Rat

e (%

)

2

1

0

Rates of composite adjudicated cardiovascular events in the

ODYSSEY OUTCOMES (left) and OSLER (Open-Label Study of

Long-Term Evaluation Against LDL-C) 1 and 2 (right) trials. In the

ODYSSEY OUTCOME trial, the post-hoc cardiovascular endpoint

was a composite of coronary heart disease death, nonfatal

myocardial infarction, fatal or nonfatal ischemic stroke, and un-

stable angina requiring hospitalization, assessed after an average

follow-up of 65 weeks. In the OSLER trials, the pre-specified

cardiovascular endpoint was a composite of death, myocardial

infarction, unstable angina requiring hospitalization, coronary

revascularization, stroke, transient ischemic attack, and heart

failure requiring hospitalization, assessed after an average

follow-up of 11.1 months. Hazard ratios (HRs) are derived from

analyses of Kaplan-Meier event rates. PCSK9 ¼ proprotein

convertase subtilisin/kexin type 9; SOC ¼ standard of care.

Giugliano and Sabatine J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5

PCSK9 Inhibitors: The Next Breakthrough J U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1

2644

the baseline LDL-C with evolocumab compared withplacebo (27).LONGER-TERM TREATMENT. Larger and longer-termstudies provide further information regarding thedurability of lipid-lowering effects and safety ofPCSK9 inhibitors. In the OSLER I (Open-Label Studyof Long-Term Evaluation against LDL Cholesterol)study (48), 1,104 patients who completed 1 of 4 phase2 studies with evolocumab entered an open-labelcontrolled study comparing evolocumab 420 mgevery 4 weeks plus standard of care (SOC) to SOCalone. The LDL-C reduction with evolocumab þ SOC,as compared with SOC alone, remained constantat approximately 52% (w73 mg/dl) for the entire52-week period. More patients receiving evolocumabachieved LDL-C <100 mg/dl (96% vs. 32%), <70 mg/dl(83% vs. 4%), <50 mg/dl (56% vs. 0.5%), and<25 mg/dl (13% vs. 0%) (p < 0.001 for each compari-son with SOC alone). The tolerability of longer-termevolocumab was good (only 3.7% developed adverseevents that led to discontinuation of evolocumab),and serious adverse events occurred in a similarnumber of patients who received evolocumab þ SOC(7.1%) as with SOC alone (6.3%). Adverse events werenot increased among the 98 patients receiving evo-locumab who achieved an LDL-C <25 mg/dl comparedwith those achieving higher LDL-C levels or comparedwith patients receiving SOC only.

A pre-specified combined analysis of 4,465 pa-tients who completed 1 of 12 phase 2 or 3 studies ofevolocumab and who were then randomized to eitherevolocumab plus SOC versus SOC alone in an open-label extension study over an average of 11 months,was conducted across the OSLER 1 and 2 studies (24).Evolocumab 420 mg every 4 weeks reduced theaverage LDL-C by 61% from 120 to 48 mg/dl at 12weeks. Adverse events (the primary study endpoint)occurred in 69% of patients treated with evolocumabversus 65% in the SOC group, with no difference inthe rate of serious adverse events (7.5% in eachgroup). Only 2.4% of patients in the evolocumabgroup stopped treatment due to an adverse event.Neurocognitive events were reported morefrequently with evolocumab (0.9% vs. 0.3%), with noapparent relationship to the achieved LDL-C. Theongoing EBBINGHAUS (Evaluating PCSK9 BindingantiBody Influence oN coGnitive HeAlth in High car-diovascUlar Risk Subjects) study (NCT02207634) isprospectively evaluating this issue in a subgroup ofpatients with apparently normal cognitive functionenrolled in a phase 3 cardiovascular outcomes studywith evolocumab (49). The pre-specified compositeof death, myocardial infarction, hospitalization forunstable angina, coronary revascularization, stroke,

transient ischemic attack, and hospitalization forheart failure was reduced by 53% (95% confidenceinterval: 22% to 72%; p ¼ 0.003) (Figure 1). Althoughpromising, the modest number of cardiovascularevents (n ¼ 60), an exploratory, albeit adjudicated,endpoint in this analysis, requires confirmation in anadequately-powered trial.

In the ODYSSEY LONG TERM (Long-term Safetyand Tolerability of Alirocumab in High Cardiovas-cular Risk Patients with Hypercholesterolemia NotAdequately Controlled with Their Lipid ModifyingTherapy) placebo-controlled trial in 2,341 patientswith hyperlipidemia on maximally tolerated statinwho were at high risk for CHD, alirocumab reducedLDL-C by 62% at 24 weeks compared with placebo(achieved mean LDL-C 119 mg/dl with placebo vs. 48mg/dl with alirocumab) (22). More patients achievedan LDL-C <70 mg/dl at week 24 with alirocumabcompared with placebo (79% vs. 8%; p < 0.001).Patients in the alirocumab group had higher rates ofinjection-site reactions 5.9% vs. 4.2%), myalgia (5.4%vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), andophthalmologic events (2.9% vs. 1.9%) over a periodof 78 weeks. As was observed with evolocumab, ratesof adverse events among 575 (37%) patients who

J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5 Giugliano and SabatineJ U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1 PCSK9 Inhibitors: The Next Breakthrough

2645

achieved an LDL-C <25 mg/dl on at least 2 consecu-tive readings was similar to the overall alirocumabgroup. In a post-hoc analysis of selected cardiovas-cular events with alirocumab, the time to first adju-dicated major cardiovascular event (a composite ofCHD death, myocardial infarction, ischemic stroke, orunstable angina requiring hospitalization) was lessfrequent with alirocumab than with placebo (hazardratio: 0.52; 95% confidence interval: 0.31 to 0.90).Confirmation of these findings in a prospectivelydesigned cardiovascular outcomes trial is needed,given the small number of events (n ¼ 53) in thispost-hoc analysis.

It is of interest to compare the reduction in car-diovascular events observed, given the degree ofLDL-C reduction obtained with PCSK9 inhibitors, inthese 2 recent analyses in the context of the rela-tionship between LDL-C reduction and major vascularevents reported in the CTT (Cholesterol TreatmentTrialists) meta-analysis (50). The latter analysisdemonstrated a 22% reduction in major vascularevents for each 1 mmol/l reduction in LDL-C in ananalysis of >170,000 patients from 27 randomizedtrials of cholesterol lowering—a relationship thatremained consistent across a broad range of base-line LDL-C values. Given the LDL-C reduction (70 to72 mg/dl or 1.8 to 1.9 mmol/l) observed in the OSLER1 and 2 and ODYSSEY LONG-TERM analyses, theCTT meta-analysis would have predicted a reductionof just over 40% in major vascular events—a valuethat falls well within the confidence interval ofthe observed results. Ongoing phase 3 trials thatare adequately powered to examine cardiovascularevents are ongoing.

PHASE 3 CLINICAL OUTCOME TRIALS

There are 4 ongoing large, placebo-controlled phase3 trials in >70,000 patients investigating whetherPCSK9 inhibitors on a background of statin reducecardiovascular events (Figure 2). In the ODYSSEYOutcomes trial (51), 18,000 patients 1 to 12 monthspost–acute coronary syndrome treated withmaximally-tolerated atorvastatin or rosuvastatin arebeing randomized to subcutaneous alirocumab orplacebo every 2 weeks. All patients must have eitheran LDL-C $70 mg/dl, non-HDL total cholesterol$100mg/dl, or apolipoprotein B$80mg/dl. The initialdose of alirocumab is 75 mg, with drug discontinua-tion for LDL-C <15 mg/dl on repeated measurements,and up-titration to 150 mg for LDL-C $50 mg/dl.

In the FOURIER (Further Cardiovascular OutcomesResearch With PCSK9 Inhibition in Subjects WithElevated Risk) trial (52), 27,500 stable patients with

prior MI, ischemic stroke, or peripheral arterialdisease treated with optimal-dose statin are beingrandomized to SC evolocumab or placebo. All pa-tients must have either an LDL-C $70 mg/dl or non-HDL total cholesterol of $100 mg/dl. The dose ofevolocumab is 140 mg every 2 weeks or 420 mgevery 4 weeks; these 2 regimens achieve similarreductions of LDL-C over time (43). No adjustmentof the dose of evolocumab is permitted on thebasis of LDL-C values, although patients may selectwhether they prefer the every 2-week or every4-week regimen.

Two placebo-controlled phase 3 trials (53,54) inpatients at high risk for cardiovascular events areassessing whether bococizumab 150 mg SC every2 weeks reduces cardiovascular events. The entrycriteria are similar, except that SPIRE-1 (Studies ofPCSK9 Inhibition and the Reduction of vascularEvents-1) (53) is enrolling 17,000 patients with LDL-Cbetween 70 and 100 mg/dl, whereas in SPIRE-2 (54),9,000 patients with LDL-C $100 mg/dl are beingenrolled.

Completion of these 4 trials is projected for late2017. In the interim, the U.S. Food and Drug Admin-istration is currently evaluating both alirocumab andevolocumab on the basis of phase 2 and 3 studiescompleted through mid-2014. Thus, while we awaitthe results from the ongoing phase 3 outcomes trials,it is possible that PCSK9 inhibitors may be availablebefore then for use in selective high-risk patientswho are not able to achieve the desired LDL-C level(e.g., FH, statin-intolerant).

CLINICAL IMPLICATIONS

FOR INDIVIDUAL PATIENTS

Given the consistent effects on LDL-C that have beenreported with MoAbs to PCSK9 in a wide variety ofclinical scenarios, the most obvious benefit to indi-vidual patients is that a dramatically lower LDL-Clevel can be achieved, with a high likelihood ofreaching <70 mg/dl. A remarkable feature of theMoAb to PCSK9 is that the LDL-C reduction is sus-tained for 2 to 8 weeks after a single SC injection,depending on the dose and the MoAb binding it.

Patients with FH (recent estimates in the generalpopulation are 1 in 200 for heterozygous FH [55] andas many as 1 in 160,000 for homozygous FH [56])typically do not achieve recommended levels ofLDL-C with currently available oral therapies (57);thus, FH patients stand to benefit the most fromtreatment with a PCSK9 inhibitor. In addition, pa-tients with hypercholesterolemia who are intolerantto high doses of statin or have a less than expected

FIGURE 2 Phase 3 Designs for Cardiovascular Endpoint Trials

Population

Patients on maximumtolerated potent statins

n=9000

NCEP-ATPIII TLC diet or equivalent

Double-Blind Treatment Period (64 Weeks)

n=9000

Screening, Placebo Run-in,and Lipid Stabilization

Period

LDL-C

1° EP:

All-cause mortality

Stroke or TIADeath or CHF leading to hospitalization

CV death, MI, UA leading to hospitalization, stroke, coronary revascularization2° EP:

Evolocumab SC140 mg Q2W or 420 mg Q4W

~11,250 Subjects

Placebo SCQ2W or QM

~11,250 Subjects

F/U

aver

age

4 yr

s≥ 70 mg/dLor

≥ 100 mg/dLnon-HDL-C4 weeks stable on moderate

or high-intensity statin

Run-in

Screeningvisit

Injectiontrainingvisit

18,000 pts 4–52 weeks post-ACSAge >40 years

Ezetimibe can be added ifatorvastatin dose is maximal

R

atorvastatin 40–80 mg or rosuvastatin 20–40 mg

≥70 mg/dL (1.81 mmol/L) Composite of ––––

CHD deathNon-fatal MIIschemic strokeHigh-risk UA → hospitalization

On evidence-based medical Rx

LDL-C at EntryA

B 27,500 Stable patients with prior MI, ischemic stroke, or PADAge 40 to 85 years

At least 1 other high-risk feature

Alirocumab SC*

Placebo SC

Primary Endpoint

(A) Alirocumab. (B) Evolocumab. (C) Bococizumab.*75 mg subcutaneous (SC) every other week with titration (as necessary) to 150 mg SC every

other week, if low-density lipoprotein cholesterol (LDL-C)$50 mg/dl (1.29 mmol/l). ACS ¼ acute coronary syndrome(s); CHD ¼ coronary heart

disease; CHF ¼ congestive heart failure; CV ¼ cardiovascular; F/U ¼ follow-up; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial

infarction; NCEP-ATP III ¼ National Cholesterol Education Panel Adult Treatment Panel 3; PAD ¼ peripheral arterial disease; pts ¼ patients;

Q2W ¼ every other week; Q4W ¼ every 4 weeks; Rx ¼ treatment; SC ¼ subcutaneous; TIA ¼ transient ischemic attack; TLC ¼ therapeutic

lifestyle changes; UA ¼ unstable angina.

Continued on the next page

Giugliano and Sabatine J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5

PCSK9 Inhibitors: The Next Breakthrough J U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1

2646

response to statin would have a very high likelihood(>90% in some studies) of achieving an LDL-C<70 mg/dl. Only the rare patient with homozygousFH and <2% LDL-R activity (so-called null mutations)

have shown a lack of response to PCSK9 inhibitors;in such patients, other treatments (e.g., therapiesthat target hepatic secretion of apolipoprotein B) areneeded.

FIGURE 2 Continued

No. of Patients 17,000 9,000

SPIRE 1

LDL-C ≥70 to <100 mg/dL LDL-C ≥100 mg/dL

SPIRE 2

Bococizumab 150 mg Q2W SC vs. Placebo SC

Inclusion criteriaAge ≥18 and high risk of CV event

Must be on background lipid lowering therapy

Planned coronary revascularization

4-way composite endpoint of: CV death / non-fatal MI / non-fatal stroke / hospitalization forunstable angina needing urgent revascularization

Composite endpoint of CV death, non-fatal MI, and non-fatal stroke

Composite endpoint of all-cause death, non fatal MI, and non-fatal stroke

Hospitalization for unstable angina needing urgent revascularization

October 2013

June 2018 March 2018

October 2013

NYHA functional class IV CHF or LVEF <25%Creatinine clearance < 30 ml/min/1.73m2

Prior hemorrhagic stroke

Exclusion criteria

Entry lipid values

Treatment

Primary Endpoint

Secondary Endpoints

Study start

Study end

C

J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5 Giugliano and SabatineJ U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1 PCSK9 Inhibitors: The Next Breakthrough

2647

A second added benefit of PCSK9 inhibitors is theability to lower the lipoprotein(a) concentration and,hopefully, thereby also reduce the independent re-sidual risk associated with elevated lipoprotein(a)levels that has been demonstrated even among pa-tients who have low LDL-C on statin therapy (58).Statins and other commonly used oral lipid-loweringtherapies (other than nicotinic acid, which itself doesnot reduce cardiovascular events when added toa statin [59,60]) do not significantly affect lip-oprotein(a). Because lipoprotein(a) is not thought tobe cleared by the LDL-R but is mainly regulated byhepatic secretion (61), further work is needed toelucidate the mechanism through which PCSK9 in-hibitors reduce lipoprotein(a). In addition, ongoingstudies may provide additional insight as to whetherthe reduction in lipoprotein(a) obtained with PCSK9inhibitors will translate into added clinical benefit,above and beyond that attributable to achieving alower LDL-C.

IMPLICATIONS FOR POPULATION HEALTH

Atherosclerotic cardiovascular disease remains theleading cause of morbidity and mortality in devel-oped countries, while rates are rapidly increasing indeveloping regions. In the United States, the preva-lence of CHD is 15.5 million (6.2%) in adults age$20 years, with an estimated 635,000 new CHDevents occurring annually (62). In addition, there

are nearly 60 million Americans estimated to havean LDL-C $160 mg/dl (63)—a level at whichhigh-intensity statin may be necessary to achievethe desired 50% reduction in LDL-C. Yet even amongpatients with established atherosclerosis, an analysisin 2012 from a large U.S. managed-care databasedemonstrated that only 26% of patients werereceiving a high-intensity statin (64). This likelyexplains why only about one-third of very high-riskpatients achieve an LDL-C <70 mg/dl in surveysconducted both within (65) and outside of theUnited States (66). Whether the underutilization ofhigh-intensity statins is due to intolerance (which isestimated to be only 10% to 20% of patients) and/orpatient or physician preference, the acceptance ofhigh-dose statin therapy has been slow over thedecade since the PROVE IT TIMI 22 (Pravastatin orAtorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) study firstestablished its superiority over moderate-intensitystatin therapy in high-risk patients (67).

Whether the safety and tolerability profile of thePCSK9 MoAbs will continue to be as favorable as re-ported in the phase 2 and early phase 3 studies re-mains to be seen. However, their introduction intoclinical practice could result in a major shift in theLDL-C population distribution (Figure 3) and hasthe potential to have a large effect on futureatheroembolic events. As seen in the Mendelianrandomization studies of loss-of-function mutations

FIGURE 3 Shift in Distribution of LDL-C in a Population of High-Risk Individuals With

Use of PCSK9 Inhibitor

Population EffectNCEP High-risk Pts in

LAPLACE-TIMI 57 Treatedwith 140mg Q2W Evolocumab

Mean (SD): 47 (30) mg/dL% pts

25 50

??Physiologic

LDL-C

NCEP Goalfor High-Risk Pts

75 100LDL-Cholesterol (mg/dl)

125 150 175 200 225

NCEP High Risk Patients in LAPLACE-TIMI 57 at Baseline mean (SD):

123 (30) mg/dL

Effect of PCSK9 MoAb

In the LAPLACE-TIMI 57 (LDL-C Assessment with Proprotein Convertase Subtilisin Kexin

Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy-Thrombolysis In

Myocardial Infarction 57) trial, the mean LDL-C among stable, high-risk patients with

hypercholesterolemia was 123 mg/dl, a value that is similar to the average reported in

several surveys of the U.S. general population (23). With administration of 140 mg

every 2 weeks of evolocumab, the average LDL-C was reduced to a mean of 47 mg/dl, with

>90% of patients achieving an LDL-C <70 mg/dl. The majority of patients thus achieved

an LDL-C of 25 to 60 mg/dl, a range labeled as physiological for humans by Brown and

Goldstein in their 1985 Nobel Lecture. HDL-C ¼ high-density lipoprotein cholesterol;

revasc ¼ revascularization; other abbreviations as in Figures 1 and 2.

Giugliano and Sabatine J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5

PCSK9 Inhibitors: The Next Breakthrough J U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1

2648

in PCSK9, even a modest (15% to 28%) lifelongreduction in LDL-C translates into a large (47% to88%) reduction in CHD events (11). This raises thepossibility of a dramatic alteration in the populationburden of atherosclerosis if potent PCSK9 inhibitioncould be safely and economically (e.g., at a pricesimilar to other currently available lipid therapies)initiated earlier in life (i.e., primary prevention).Although event rates in a primary prevention popu-lation are considerably lower than in secondary pre-vention, the CTT meta-analysis (50) of more intensiveLDL-C lowering observed a 25% reduction in majorvascular events for each 1 mmol/l (38.7 mg/dl)reduction in LDL-C in patients without vascular dis-ease. Moreover, among individuals at apparently lowrisk clinically, genetics and other novel risk factorscould be used to identify subsets with higher risk(68). If the relationship between LDL-C reduction andclinical benefit observed in the primary preventiontrials with statins holds true for PCSK9 inhibitors(50), a 36% reduction in major vascular events wouldbe expected with PCSK monotherapy, comparedwith placebo. This is comparable to the decline inrates of CHD death or first MI reported in a surveyof 4 U.S. communities over a 10-year period(69), a trend that has been attributed to reduced

rates of smoking, wider use of aspirin, and bettercontrol of CHD risk factors, in particular morefrequent use of statins. However, the authors wishto caution against excessive exuberance pendingthe results of the ongoing cardiovascular outcometrials. Furthermore, given increasing constraints onhealth care spending and higher bars being set bythe Centers for Medicare and Medicaid Services forcoverage determination of novel therapies (70),we anticipate the availability of MoAbs to PCSK9will be limited initially to those patients who areat high cardiovascular risk, with an LDL-C that isnot well controlled despite intensive therapy withstatin þ ezetimibe, or who cannot tolerate statintherapy.

SUMMARY

In the 12 years since mutations in the PCSK9 genewere identified as the third locus for FH, dozens ofclinical trials have demonstrated that potent reduc-tion in LDL-C is possible with MoAbs directed againstthe PCSK9 protein. In addition, these therapiesreduce a number of other atherogenic lipoproteins,including apolipoprotein B, non-HDL total choles-terol, and lipoprotein(a). The safety and tolerabilityprofile of the 2 most extensively studied MoAbs(alirocumab, evolocumab) for periods of up to 2 yearsappears promising; however, longer exposure isnecessary to more completely evaluate potentiallydelayed adverse effects, such as neurocognitiveimpairment and cancer. Given the reduction in LDL-Cobserved in phase 2 and 3 trials to date and the ana-lyses of cardiovascular events in longer-term studies,major vascular events could be reduced by 40% to50% in high-risk patients if the benefits follow asimilar relationship as that observed with statins.This degree of clinical benefit ought to be easilywithin the reach of ongoing phase 3 cardiovascularoutcome studies with 3 PCSK9 MoAbs in a total of>70,000 patients. Although the annals of clinical tri-als are rife with “can’t miss” therapies that subse-quently proved to be failures, the notion that bothstatins and PCSK9 MoAbs result in an increase inLDL-R activity on the hepatocyte surface (71) leads usto conclude that PCSK9 inhibitors are well positionedto become 1 of the next major breakthroughs in car-diovascular therapeutics.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Robert P. Giugliano, TIMI Study Office, Brigham andWomen’s Hospital, 350 Longwood Avenue, FirstFloor Offices, Boston, Massachusetts 02115. E-mail:rgiugliano@partners.org.

J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5 Giugliano and SabatineJ U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1 PCSK9 Inhibitors: The Next Breakthrough

2649

RE F E RENCE S

1. Artenstein AW, Opal SM. Proprotein convertasesin health and disease. N Engl J Med 2011;365:2507–18.

2. Abifadel M, Elbitar S, El Khoury P, et al.Living the PCSK9 adventure: from theidentification of a new gene in familial hyper-cholesterolemia towards a potential new classof anticholesterol drugs. Curr Atheroscler Rep2014;16:439.

3. Seidah NG, Benjannet S, Wickham L, et al. Thesecretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regenera-tion and neuronal differentiation. Proc Natl AcadSci U S A 2003;100:928–33.

4. Varret M, Rabes JP, Saint-Jore B, et al. A thirdmajor locus for autosomal dominant hypercho-lesterolemia maps to 1p34.1-p32. Am J Hum Genet1999;64:1378–87.

5. Hunt SC, Hopkins PN, Bulka K, et al. Geneticlocalization to chromosome 1p32 of the third locusfor familial hypercholesterolemia in a Utahkindred. Arterioscler Thromb Vasc Biol 2000;20:1089–93.

6. Abifadel M, Varret M, Rabes JP, et al. Mutationsin PCSK9 cause autosomal dominant hypercho-lesterolemia. Nat Genet 2003;34:154–6.

7. Timms KM, Wagner S, Samuels ME, et al.A mutation in PCSK9 causing autosomal-dominanthypercholesterolemia in a Utah pedigree. HumGenet 2004;114:349–53.

8. Leren TP. Mutations in the PCSK9 genein Norwegian subjects with autosomal dominanthypercholesterolemia. Clin Genet 2004;65:419–22.

9. Sun XM, Eden ER, Tosi I, et al. Evidence foreffect of mutant PCSK9 on apolipoprotein Bsecretion as the cause of unusually severe domi-nant hypercholesterolaemia. Hum Mol Genet2005;14:1161–9.

10. Cohen J, Pertsemlidis A, Kotowski IK, et al.Low LDL cholesterol in individuals of Africandescent resulting from frequent nonsense muta-tions in PCSK9. Nat Genet 2005;37:161–5.

11. Cohen JC, Boerwinkle E, Mosley TH Jr., et al.Sequence variations in PCSK9, low LDL, and pro-tection against coronary heart disease. N Engl JMed 2006;354:1264–72.

12. Rashid S, Curtis DE, Garuti R, et al. Decreasedplasma cholesterol and hypersensitivity to statinsin mice lacking Pcsk9. Proc Natl Acad Sci U S A2005;102:5374–9.

13. Zhang Y, Eigenbrot C, Zhou L, et al. Identifi-cation of a small peptide that inhibits PCSK9protein binding to the low density lipoprotein re-ceptor. J Biol Chem 2014;289:942–55.

14. Seidah NG, Prat A. The biology and therapeutictargeting of the proprotein convertases. Nat RevDrug Discov 2012;11:367–83.

15. Seidah NG. PCSK9 as a therapeutic target ofdyslipidemia. Expert Opin Ther Targets 2009;13:19–28.

16. Stein EA, Gipe D, Bergeron J, et al. Effect ofa monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein

cholesterol in patients with heterozygous familialhypercholesterolaemia on stable statin dose withor without ezetimibe therapy: a phase 2 rando-mised controlled trial. Lancet 2012;380:29–36.

17. Lunven C, Paehler T, Poitiers F, et al.A randomized study of the relative pharmacoki-netics, pharmacodynamics, and safety of alir-ocumab, a fully human monoclonal antibody toPCSK9, after single subcutaneous administrationat three different injection sites in healthy sub-jects. Cardiovasc Ther 2014;32:297–301.

18. Dias CS, Shaywitz AJ, Wasserman SM, et al.Effects of AMG 145 on low-density lipoproteincholesterol levels: results from 2 randomized,double-blind, placebo-controlled, ascending-dosephase 1 studies in healthy volunteers and hyper-cholesterolemic subjects on statins. J Am CollCardiol 2012;60:1888–98.

19. Ballantyne CM, Neutel J, Cropp A, et al.Results of bococizumab, a monoclonal antibodyagainst proprotein convertase subtilisin/kexin type9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hy-percholesterolemia. Am J Cardiol 2015;115:1212–21.

20. Eacho P, Schroeder K, Beyer T, et al. Novelmechanism for the sustained durability of pro-protein convertase subtilisin-kexin type 9 mono-clonal antibody LY3015014 (abstr). J Am CollCardiol 2015;65 Suppl 10:A1577.

21. Giugliano RP, Desai NR, Kohli P, et al., for theLAPLACE-TIMI 57 Investigators. Efficacy, safety,and tolerability of a monoclonal antibody to pro-protein convertase subtilisin/kexin type 9 incombination with a statin in patients with hyper-cholesterolaemia (LAPLACE-TIMI 57): a rando-mised, placebo-controlled, dose-ranging, phase2 study. Lancet 2012;380:2007–17.

22. Robinson JG, Farnier M, Krempf M, et al., forthe ODYSSEY LONG TERM Investigators. Efficacyand safety of alirocumab in reducing lipids andcardiovascular events. N Engl J Med 2015;372:1489–99.

23. Desai NR, Giugliano RP, Zhou J, et al. AMG 145,a monoclonal antibody against PCSK9, facilitatesachievement of National Cholesterol EducationProgram-Adult Treatment Panel III low-densitylipoprotein cholesterol goals among high-risk pa-tients: an analysis from the LAPLACE-TIMI 57 trial(LDL-C assessment with PCSK9 monoclonal anti-body inhibition combined with statin therapy-thrombolysis in myocardial infarction 57). J AmColl Cardiol 2014;63:430–3.

24. Sabatine MS, Giugliano RP, Wiviott SD, et al.,for the Open-Label Study of Long-Term Evalua-tion against LDL Cholesterol (OSLER) In-vestigators. Efficacy and safety of evolocumab inreducing lipids and cardiovascular events. N Engl JMed 2015;372:1500–9.

25. Kastelein J, Nissen S, Rader D, et al. Safety andefficacy of LY3015014, a new monoclonal anti-body to proprotein convertase subtilisin/kexintype 9 (PCSK9) with an inherently longer durationof action, in patients with primary hypercholes-terolemia: a randomized, placebo-controlled,

dose-ranging, phase 2 study (abstr). J Am CollCardiol 2015;65 Suppl 10:A1591.

26. Stein EA, Honarpour N, Wasserman SM, et al.Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in ho-mozygous familial hypercholesterolemia. Circula-tion 2013;128:2113–20.

27. Raal F, Honarpour N, Blom D, et al., for theTESLA Investigators. Inhibition of PCSK9 withevolocumab in homozygous familial hyper-cholesterolaemia (TESLA Part B): a randomised,double-blind, placebo-controlled trial. Lancet2015;385:341–50.

28. Desai NR, Kohli P, Giugliano RP, et al. AMG145,a monoclonal antibody against proprotein con-vertase subtilisin kexin type 9, significantly re-duces lipoprotein(a) in hypercholesterolemicpatients receiving statin therapy: an analysis fromthe LDL-C Assessment with Proprotein ConvertaseSubtilisin Kexin Type 9 Monoclonal Antibody In-hibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57trial. Circulation 2013;128:962–9.

29. Gaudet D, Kereiakes DJ, McKenney JM, et al.Effect of alirocumab, a monoclonal proproteinconvertase subtilisin/kexin 9 antibody, on lip-oprotein(a) concentrations (a pooled analysis of150 mg every two weeks dosing from phase 2trials). Am J Cardiol 2014;114:711–5.

30. Stein EA, Giugliano RP, Koren MJ, et al. Effi-cacy and safety of evolocumab (AMG 145), a fullyhuman monoclonal antibody to PCSK9, in hyper-lipidaemic patients on various background lipidtherapies: pooled analysis of 1359 patients in fourphase 2 trials. Eur Heart J 2014;35:2249–59.

31. Stein EA, Mellis S, Yancopoulos GD, et al. Ef-fect of a monoclonal antibody to PCSK9 on LDLcholesterol. N Engl J Med 2012;366:1108–18.

32. Sullivan D, Olsson AG, Scott R, et al. Effect of amonoclonal antibody to PCSK9 on low-density li-poprotein cholesterol levels in statin-intolerantpatients: the GAUSS randomized trial. JAMA2012;308:2497–506.

33. Seidah NG, Awan Z, Chretien M, et al. PCSK9: Akey modulator of cardiovascular health. Circ Res2014;114:1022–36.

34. Awan Z, Delvin EE, Levy E, et al. Regionaldistribution and metabolic effect of PCSK9 insLEUand R46L gene mutations and apoE genotype. CanJ Cardiol 2013;29:927–33.

35. Poirier S, Mayer G, Benjannet S, et al. Theproprotein convertase PCSK9 induces the degra-dation of low density lipoprotein receptor (LDLR)and its closest family members VLDLR andApoER2. J Biol Chem 2008;283:2363–72.

36. Koren MJ, Lundqvist P, Bolognese M, et al.,for the MENDEL-2 Investigators. Anti-PCSK9monotherapy for hypercholesterolemia: theMENDEL-2 randomized, controlled phase III clin-ical trial of evolocumab. J Am Coll Cardiol 2014;63:2531–40.

37. Roth EM, Taskinen MR, Ginsberg HN, et al.Monotherapy with the PCSK9 inhibitor alir-ocumab versus ezetimibe in patients with

Giugliano and Sabatine J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5

PCSK9 Inhibitors: The Next Breakthrough J U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1

2650

hypercholesterolemia: results of a 24 week,double-blind, randomized phase 3 trial. Int JCardiol 2014;176:55–61.

38. Kereiakes DJ, Robinson JG, Cannon CP, et al.Efficacy and safety of the proprotein convertasesubtilisin/kexin type 9 inhibitor alirocumab amonghigh cardiovascular risk patients on maximallytolerated statin therapy: The ODYSSEY COMBO Istudy. Am Heart J 2015 Apr 30 [E-pub ahead ofprint].

39. Cannon CP, Cariou B, Blom D, et al. Efficacyand safety of alirocumab in high cardiovascularrisk patients with inadequately controlled hyper-cholesterolaemia on maximally tolerated dosesof statins: the ODYSSEY COMBO II randomizedcontrolled trial. Eur Heart J 2015;36:1186–94.

40. Robinson JG, Nedergaard BS, Rogers WJ,et al., for the LAPLACE-2 Investigators. Effect ofevolocumab or ezetimibe added to moderate- orhigh-intensity statin therapy on LDL-C lowering inpatients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014;311:1870–82.

41. Blom DJ, Hala T, Bolognese M, et al., for theDESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.N Engl J Med 2014;370:1809–19.

42. Stroes E, Colquhoun D, Sullivan D, et al., forthe GAUSS-2 Investigators. Anti-PCSK9 antibodyeffectively lowers cholesterol in patients withstatin intolerance: the GAUSS-2 randomized,placebo-controlled phase 3 clinical trial of evolo-cumab. J Am Coll Cardiol 2014;63:2541–8.

43. Moriarty PM, Jacobson TA, Bruckert E, et al.Efficacy and safety of alirocumab, a monoclonalantibody to PCSK9, in statin-intolerant patients:design and rationale of ODYSSEY ALTERNATIVE, arandomized phase 3 trial. J Clin Lipidol 2014;8:554–61.

44. Moriarty PM, Thompson PD, Cannon CP, et al.ODYSSEY ALTERNATIVE: Efficacy and safety ofthe proprotein convertase subtilisin/kexin type 9monoclonal antibody, alirocumab, versus ezeti-mibe, in patients with statin intolerance as definedby a placebo run-in and statin rechallenge arm(abstr). Circulation 2014;130:2108–9.

45. Raal F, Stein EA, Dufour R, et al.,RUTHERFORD-2 Investigators. PCSK9 inhibitionwith evolocumab (AMG 145) in heterozygousfamilial hypercholesterolaemia (RUTHERFORD-2):a randomised, double-blind, placebo-controlledtrial. Lancet 2015;385:331–40.

46. Kastelein JJ, Robinson JG, Farnier M, et al.Efficacy and safety of alirocumab in patients withheterozygous familial hypercholesterolemia notadequately controlled with current lipid-loweringtherapy: design and rationale of the ODYSSEYFH studies. Cardiovasc Drugs Ther 2014;28:281–9.

47. Kastelein JP, Ginsburg HN, Langslet G, et al.Efficacy and safety of alirocumab in patients withheterozygous familial hypercholesterolaemia notadequately controlled with current lipid-loweringtherapy: results of ODYSSEY FH I and FH IIstudies. Paper presented at: European Societyof Cardiology Congress 2014; August 31, 2014;Barcelona, Spain.

48. Koren MJ, Giugliano RP, Raal FJ, et al.,for the OSLER Investigators. Efficacy and safetyof longer-term administration of evolocumab(AMG 145) in patients with hypercholesterole-mia: 52-week results from the Open-LabelStudy of Long-Term Evaluation Against LDL-C(OSLER) randomized trial. Circulation 2014;129:234–43.

49. Amgen. Evaluating PCSK9 Binding antiBodyInfluence oN coGnitive HeAlth in high cardiovas-cUlar Risk Subjects (EBBINGHAUS). 2014. Avail-able at: https://www.clinicaltrials.gov/ct2/show/NCT02207634?term¼NCT02207634&rank¼1.Accessed April 30, 2015.

50. Cholesterol Treatment Trialists’ (CTT) Collab-oration. Efficacy and safety of more intensivelowering of LDL cholesterol: a meta-analysis ofdata from 170,000 participants in 26 randomisedtrials. Lancet 2010;376:1670–81.

51. Schwartz GG, Bessac L, Berdan LG, et al. Effectof alirocumab, a monoclonal antibody to PCSK9,on long-term cardiovascular outcomes followingacute coronary syndromes: rationale and design ofthe ODYSSEY outcomes trial. Am Heart J 2014;168:682–9.

52. Amgen. Further Cardiovascular OutcomesResearch With PCSK9 Inhibition in Subjects WithElevated Risk (FOURIER). 2015. Available at:https://www.clinicaltrials.gov/ct2/results?term¼NCT01764633&Search¼Search. Accessed April30, 2015.

53. Pfizer. The Evaluation of Bococizumab(PF-04950615;RN316) in Reducing the Occur-rence of Major Cardiovascular Events in High RiskSubjects (SPIRE-1). 2015. Available at: https://www.clinicaltrials.gov/ct2/results?term¼NCT01975376&Search¼Search. Accessed April 30, 2015.

54. Pfizer. The Evaluation of Bococizumab(PF-04950615; RN316) in Reducing the Occur-rence of Major Cardiovascular Events in High RiskSubjects (SPIRE-2). 2015. Available at: https://www.clinicaltrials.gov/ct2/results?term¼NCT01975389&Search¼Search. Accessed April 30, 2015.

55. Nordestgaard BG, Chapman MJ, Humphries SE,et al., for the European Atherosclerosis SocietyConsensus Panel. Familial hypercholesterolaemiais underdiagnosed and undertreated in the generalpopulation: guidance for clinicians to preventcoronary heart disease: consensus statement ofthe European Atherosclerosis Society. Eur Heart J2013;34:3478–3490a.

56. Sjouke B, Kusters DM, Kindt I, et al. Homozy-gous autosomal dominant hypercholesterolaemiain the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. EurHeart J 2015;36:560–5.

57. Watts GF, Gidding S, Wierzbicki AS, et al. In-tegrated guidance on the care of familial hyper-cholesterolaemia from the International FHFoundation. Int J Cardiol 2014;171:309–25.

58. Khera AV, Everett BM, Caulfield MP, et al.Lipoprotein(a) concentrations, rosuvastatin ther-apy, and residual vascular risk: an analysisfrom the JUPITER trial (Justification for the Useof Statins in Prevention: an Intervention TrialEvaluating Rosuvastatin). Circulation 2014;129:635–42.

59. AIM-HIGH Investigators. Niacin in patientswith low HDL cholesterol levels receiving inten-sive statin therapy. N Engl J Med 2011;365:2255–67.

60. The HPS2-THRIVE Collaborative Group. Effectsof extended-release niacin with laropiprant inhigh-risk patients. N Engl J Med 2014;371:203–12.

61. Rader DJ, Cain W, Ikewaki K, et al. The inverseassociation of plasma lipoprotein(a) concentra-tions with apolipoprotein(a) isoform size is not dueto differences in Lp(a) catabolism but to differ-ences in production rate. J Clin Invest 1994;93:2758–63.

62. Mozaffarian D, Benjamin EJ, Go AS, et al., forthe American Heart Association Statistics Com-mittee and Stroke Statistics Subcommittee. Heartdisease and stroke statistics—2015 update: areport from the American Heart Association. Cir-culation 2015;131:e29–322.

63. Go AS, Mozaffarian D, Roger VL, et al., for theAmerican Heart Association Statistics Committeeand Stroke Statistics Subcommittee. Heart diseaseand stroke statistics—2014 update: a report fromthe American Heart Association. Circulation 2014;129:e28–292.

64. Rodriguez F, Olufade T, Heithoff K, et al.Frequency of high-risk patients not receiving high-potency statin (from a large managed care data-base). Am J Cardiol 2015;115:190–5.

65. Rosenson RS, Kent ST, Brown TM, et al. Un-derutilization of high-intensity statin therapy afterhospitalization for coronary heart disease. J AmColl Cardiol 2015;65:270–7.

66. Ray KK, Kastelein JJ, Boekholdt SM, et al. TheACC/AHA 2013 guideline on the treatment ofblood cholesterol to reduce atherosclerotic car-diovascular disease risk in adults: the good the badand the uncertain: a comparison with ESC/EASguidelines for the management of dyslipidaemias2011. Eur Heart J 2014;35:960–8.

67. Cannon CP, Braunwald E, McCabe CH, et al.,for the Pravastatin or Atorvastatin Evaluation andInfection Therapy–Thrombolysis in MyocardialInfarction 22 Investigators. Intensive versus mod-erate lipid lowering with statins after acute coro-nary syndromes. N Engl J Med 2004;350:1495–504.

68. Mega JL, Stitziel NO, Smith JG, et al. Geneticrisk, coronary heart disease events, and the clinicalbenefit of statin therapy: an analysis of primaryand secondary prevention trials. Lancet 2015Mar 3 [E-pub ahead of print].

69. Rosamond WD, Chambless LE, Heiss G, et al.Twenty-two-year trends in incidence of myocar-dial infarction, coronary heart disease mortality,and case fatality in 4 US communities, 1987–2008.Circulation 2012;125:1848–57.

70. Chambers JD, Chenoweth M, Cangelosi MJ,et al. Medicare is scrutinizing evidence moretightly for national coverage determinations.Health Aff (Millwood) 2015;34:253–60.

71. Stein EA, Raal FJ. New therapies for reducinglow-density lipoprotein cholesterol. EndocrinolMetab Clin North Am 2014;43:1007–33.

72. McKenney JM, Koren MJ, Kereiakes DJ, et al.Safety and efficacy of a monoclonal antibody to

J A C C V O L . 6 5 , N O . 2 4 , 2 0 1 5 Giugliano and SabatineJ U N E 2 3 , 2 0 1 5 : 2 6 3 8 – 5 1 PCSK9 Inhibitors: The Next Breakthrough

2651

proprotein convertase subtilisin/kexin type 9serine protease, SAR236553/REGN727, in patientswith primary hypercholesterolemia receivingongoing stable atorvastatin therapy. J Am CollCardiol 2012;59:2344–53.

73. Roth EM, McKenney JM, Hanotin C, et al.Atorvastatin with or without an antibody to PCSK9in primary hypercholesterolemia. N Engl J Med2012;367:1891–900.

74. Hirayama A, Honarpour N, Yoshida M, et al.Effects of evolocumab (AMG 145), a mono-clonal antibody to PCSK9, in hypercholes-terolemic, statin-treated Japanese patients athigh cardiovascular risk–primary results fromthe phase 2 YUKAWA study. Circ J 2014;78:1073–82.

75. Ballantyne CM, Neutel JM, Cropp A, et al.Efficacy and safety of bococizumab (RN316/PF-04950615), a monoclonal antibody againstproprotein convertase subtilisin/kexin type 9 instatin-treated hypercholesterolemic subjects: re-sults from a randomized, placebo-controlled,

dose-ranging study (NCT: 01592240) (abstr).J Am Coll Cardiol 2014;63 Suppl 12:A1374.

76. KorenMJ, ScottR, KimJB, et al. Efficacy, safety,and tolerability of a monoclonal antibody to pro-protein convertase subtilisin/kexin type 9 as mon-otherapy in patients with hypercholesterolaemia(MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012;380:1995–2006.

77. Raal F, Scott R, Somaratne R, et al. Low-den-sity lipoprotein cholesterol-lowering effects ofamg 145, a monoclonal antibody to proproteinconvertase subtilisin/kexin type 9 serine proteasein patients with heterozygous familial hypercho-lesterolemia: the Reduction of LDL-C with PCSK9Inhibition in Heterozygous Familial Hypercholes-terolemia Disorder (RUTHERFORD) randomizedtrial. Circulation 2012;126:2408–17.

78. Roth EM, Taskinen M-R, Ginsberg HN, et al.Monotherapy with the PCSK9 inhibitor alirocumabversus ezetimibe in patients with hypercholester-olemia: results of a 24 week, double-blind,

randomized Phase 3 trial. International J Cardiol2014;176:55–61.

79. Kiyosue A, Honarpour N, Xue A, et al. Effectsof evolocumab (AMG 145) in hypercholesterol-emic, statin-treated, Japanese patients at highcardiovascular risk: results from the phase IIIYUKAWA 2 study (abstr). J Am Coll Cardiol 2015;65 Suppl 10:A1369.

80. Stroes ESG, Guyton J, Farnier M, et al. Ef-ficacy and safety of different dosing regimens ofalirocumab (starting doses of 75 mg every twoweeks and 150 mg every four weeks) versusplacebo in patients with hyperchoelsterolemianot treated using statins: The ODYSSEY CHOICE Iand II studies. Paper presented at: AmericanCollege of Cardiology 64th Annual ScientificSessions and Expo 2015; March 14, 2015; SanDiego, CA.

KEY WORDS cholesterol, lipids,low-density lipoprotein