Evolocumab

Evolocumab: Considerations for the Management of Hyperlipidemia

Barbara S. Wiggins 1 • Jeffrey Senfield2 • Helina Kassahun3 • Armando Lira3 • Ransi Somaratne4

Ⓒ Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.
Recent Findings PCSK9 inhibitors are a class of lipid-lowering agents that significantly reduce low-density lipoprotein choles- terol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia. Data from these studies show that evolocumab significantly reduces LDL-C levels. Treatment with evolocumab also significantly improves levels of other lipid parameters (e.g., apolipoproteins A1 and B, lipoprotein(a), non– high-density lipoprotein cholesterol, and triglycerides). Recent results indicate that LDL-C reduction with evolocumab signifi- cantly reduces the risk of cardiovascular events and is also associated with atherosclerotic plaque regression. From a safety standpoint, rates of adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between evolocumab and controls in clinical trials, and no increase in AEs was observed when evolocumab was used in combination with statins.
Summary Patients with elevated LDL-C benefit from evolocumab treatment, suggesting that evolocumab could help meet an unmet medical need in high-risk patient populations with atherosclerotic cardiovascular disease and hyperlipidemia that are unable to reduce LDL-C levels sufficiently with statin therapy alone.
Keywords Low-density lipoprotein cholesterol . PCSK9 . Statins . Evolocumab

Introduction

Pharmacological treatment for elevated low-density lipopro- tein cholesterol (LDL-C) is common in the USA, where

This paper is part of the Topical Collection on Statin Drugs

* Barbara S. Wiggins [email protected]

1 Department of Pharmaceutical Sciences, Pharmacy Clinical Specialist–Cardiology, Medical University of South Carolina, Charleston, SC, USA
2 Clinical Cardiac Electrophysiologist, Novant Health Heart and Vascular Institute, 1718 East 4th Street, Suite 607,
Charlotte, NC 28204, US
3 Clinical Research Medical Director, Amgen Inc., Thousand Oaks, CA, USA
4 Global Development Executive Medical Director, Amgen Inc., Thousand Oaks, CA, USA
approximately one in three adults aged ≥ 20 years (34%) have high LDL-C or are taking cholesterol-lowering therapies. From 2005 to 2008, 34 million adults were on a pharmaco- logic regimen for high LDL-C [1]. Lowering LDL-C has an established role in preventing deaths from coronary heart dis- ease (CHD) and reducing all-cause mortality, benefits that are independent of the therapy’s mechanism of action [2, 3].
Current management strategies for the treatment of patients with elevated blood cholesterol include 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitors (statins), which are considered standard first-line pharmacotherapy for hypercholesterolemia and have been extensively studied in randomized controlled trials [4, 5, 6••]. These agents have long been recognized for their LDL-lowering capability and ability to confer significant reductions in CHD-related and all- cause mortality [7]. Across 21 trials of statins versus control, there was a highly significant 22% reduction (P < 0.0001) in major vascular events per 1.0 mmol/L reduction in LDL cho- lesterol [2]. Statin therapy is generally well tolerated, but some patients are unable to tolerate these agents secondary to adverse effects [8, 9]. Additionally, some patients, although able to take statins, are unable to achieve desired LDL-C reductions with statin therapy alone, thus requiring combination therapy [10]. Therefore, research efforts have been ongoing to identify new classes of lipid-lowering agents to fill this unmet need. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in- hibitors are a class of drug approved for the treatment of hy- percholesterolemia. The PCSK9 inhibitor evolocumab (Repatha®, AMG 145) is also now indicated to reduce the risk of myocardial infarction, stroke, and coronary revascular- ization. Here, we discuss the mechanism of action and clinical trial data for the PCSK9 inhibitor evolocumab, focusing on results available from published phase II and III studies. Literature Review A literature search was conducted using MEDLINE to identify all phase II and III clinical trials published through July 19, 2017. The search strategy included the keywords “evolocumab” and “AMG 145” and was limited to articles written in English. In addition, ClinicalTrials.gov was used to identify all clinical trials involving evolocumab that have been completed or are currently in progress. Evolocumab: Mechanism of Action Evolocumab is a fully human immunoglobulin G (IgG) sub- class 2 monoclonal antibody directed against PCSK9. Its mechanism of action is to block PCSK9 from binding to the LDL receptor, thus increasing the uptake of LDL-C. In the liver, LDL receptors on hepatocytes mediate the uptake of LDL-C and facilitate its clearance from plasma [11, 12]. The enzyme PCSK9 regulates hepatic LDL receptor expression by binding to LDL receptors at the cell surface [13]. Internalization of the LDL receptor–PCSK9 complex results in degradation of the LDL receptor [14]. Thus, inhibition of this process results in increased LDL receptor surface expres- sion, allowing for increased uptake of LDL-C and lowering of LDL-C levels. Observations that PCSK9 gain-of-function mutations increase LDL-C [15] and loss-of-function mutations re- duce LDL-C [16] provided a strong rationale for using PCSK9 as a therapeutic target. This was strengthened by the recognition that statins upregulate both hepatic LDL receptors and PCSK9, suggesting therapeutic potential for PCSK9 inhibition among statin-treated patients [17]. Proof of principle was provided by preclinical experi- ments conducted in monkeys, in which evolocumab, when added to statin therapy, abrogated the PCSK9– LDL receptor interaction, increasing the expression of LDL receptors and the uptake of LDL-C [18]. Pharmacokinetics The clearance of monoclonal antibodies, including evolocumab, relies on both linear (reticuloendothelial system) and nonlinear (target-mediated disposition) pathways [19]. At low concentrations, evolocumab elimination occurs mostly via saturable binding to PCSK9; at higher concentrations, elimination of evolocumab occurs mostly through nonsaturable elimination by an endogenous IgG clearance mechanism [20]. Elimination of evolocumab is approximately linear for doses > 140 mg, including the two approved doses in the USA: 140 mg every 2 weeks (Q2W) and 420 mg monthly (QM). Maximum suppression of circulating PCSK9 occurs within 4 h of administration of evolocumab and is followed by a reduction of LDL-C from baseline. LDL-C nadir is reached by 14 days (140 mg) and 21 days (420 mg) [21]. As evolocumab dose and exposure increase, the clear- ance of evolocumab decreases. In phase II studies, pharmaco- kinetic (PK) results were similar to those observed in phase I studies, with approximately linear PK for doses ≥ 140 mg Q2W [22]. The half-life of evolocumab in patients is 11 to 17 days [20].

Efficacy of Evolocumab—Phase II Studies

Randomized, placebo-controlled, 12-week phase II trials assessed varying doses and treatment regimens in different hyperlipidemic patient populations, with some allowing use of ezetimibe (a cholesterol absorption–blocking agent that has been widely used in the setting of statin intolerance; Table 1 [23–29]). With the exception of the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER-1), all trials had the same primary endpoint, percentage change in LDL-C from baseline at week 12. The primary endpoint for OSLER-1 was the incidence of adverse events (AEs); the secondary endpoint was percentage change in LDL-C.
In phase II studies, evolocumab therapy resulted in improvements in primary and secondary efficacy out- comes in all patient populations examined, regardless of background lipid-lowering therapy or background cardio- vascular risk (Table 1). In key phase II studies, reductions in LDL-C at week 12 for evolocumab regimens adminis- tered biweekly at doses up to 140 mg ranged from 37 to 69% when corrected for control (Table 1). Similar reduc- tions were seen with monthly regimens administered at doses up to 420 mg (26–64%; Table 1). In most trials, significant improvements in the levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), non–HDL-

Table 1 Phase II studies of evolocumaba
Study population, N (randomized and treated) Treatments and doses LDL-C change at 12 weeks,b,c % (95% CI or SE)

MENDEL [23] N = 406
Fasting LDL-C ≥ 2.6 and < 4.9 mmol/L (≥ 100 and < 190 mg/dL); low cardiovascular risk (FRS < 10%); no concomitant lipid-lowering therapy LAPLACE-TIMI 57 [24] N = 629 History of hypercholesterolemia and fasting LDL-C concentration > 2.2 mmol/L (> 85 mg/dL) while on a stable dose of statin (with or without EZE) for ≥ 4 weeks

GAUSS [25] N = 157
Statin-intolerant with background EZE; LDL-C levels above risk-based goals per NCEP
⦁ EVO 70, 105, or 140 mg or PLC Q2W

⦁ EVO 280, 350, or 420 mg or PLC QM
⦁ EZE 10 mg QD

⦁ EVO 70, 105, or 140 mg or PLC Q2W

⦁ EVO 280, 350, or 420 mg or PLC QM

⦁ EVO 280, 350, or 420 mg QM

⦁ EVO 420 mg QM + EZE 10 mg QD
⦁ PLC QM + EZE 10 mg QD
•– 47 (− 55, − 40) to − 37 (− 45, − 30) (PLC-corrected)

⦁ − 53 (− 60, − 45) to − 44 (−5 1, − 36) (PLC-corrected)

⦁ − 66 (− 72, − 61) to − 42 (− 47, − 37) (PLC-corrected)

⦁ − 50 (− 56, − 44) to − 42 (− 48, − 36) (PLC-corrected)

⦁ − 36 (− 44, − 28) to − 26 (−34, − 18) (PLC + EZE-corrected)

⦁ − 47 (− 54, − 41) (PLC + EZE-corrected)

RUTHERFORD [26] N = 167
HeFH by Simon Broome criteria, and LDL-C
≥ 2.6 mmol/L (100 mg/dL) with triglycerides
≤ 4.5 mmol/L (400 mg/dL) despite at least 4 weeks of stable statin and other
lipid-lowering therapy

⦁ EVO 350 or 420 mg or PLC QM • − 44 (4) and − 56 (4) (PLC-corrected)

YUKAWA [27] N = 307
Japanese patients at high cardiovascular risk on background statins

⦁ EVO 70 or 140 mg or PLC Q2W

⦁ EVO 280 or 420 mg or PLC QM

⦁ − 53 (3) and − 69 (3) (PLC-corrected)

⦁ − 58 (3) and − 64 (3) (PLC-corrected)

TESLA (Part A) [28] N =8
Patients with HoFH by either genetic confirmation or clinical diagnosis (history of an untreated LDL-C > 13 mmol/L [500 mg/dL] plus either xanthoma before 10 years of age or evidence of HeFH in both parents).

OSLER [29] N = 1104
Patients who completed either LAPLACE-TIMI 57, GAUSS, RUTHERFORD, or MENDEL

⦁ EVO 420 mg QM, then EVO 420 mg Q2W • − 17 (SD, 19) and − 14 (SD, 27) (not PLC-corrected)

⦁ EVO 420 QM + SOC or SOC • − 52 (2) (not SOC-corrected; week 52)

Curr Atheroscler Rep (2018) 20:17
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a CI confidence interval, LDL-C low-density lipoprotein cholesterol, MENDEL Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels, FRS Framingham Risk Score, EVO evolocumab, PLC placebo, Q2W every 2 weeks, QM monthly, QD once daily, EZE ezetimibe, LAPLACE-TIMI 57 LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy, GAUSS Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects, NCEP National Cholesterol Education Program, RUTHERFORD Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder, HeFH heterozygous familial hypercholesterolemia, YUKAWA Study of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients with Advanced Cardiovascular Risk, TESLA Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities, HoFH homozygous familial hypercholesterolemia; OSLER Open-Label Study of Long-Term Evaluation Against LDL-C, SD standard deviation, SE standard error, SOC standard of care
b Primary endpoint for all trials except OSLER, which was LDL-C at 52 weeks. Data presented are least squares mean normalized to control; background therapy varied by study: MENDEL: week 12 data reported corrected for placebo; patients received evolocumab monotherapy; LAPLACE: outcomes at week 12 are reported; data are placebo-corrected; YUKAWA: week 12 data are reported; data are versus placebo; 6.2% of patients received high-intensity statins; GAUSS: outcomes at week 12 are reported, difference is from baseline (not corrected for placebo); patients received evolocumab with or without ezetimibe
c For treatment differences, MENDEL and LAPLACE-TIMI 57 (P ≤ 0.0001 vs control), GAUSS, RUTHERFORD, and YUKAWA (all P ≤ 0.001 vs control), TESLA (Part A) (not significant vs baseline), and OSLER (P < 0.0001 vs baseline) C, very low-density lipoprotein cholesterol, apolipopro- tein B, apolipoprotein A1, and lipoprotein(a) were also observed (Table 2) [23–39]. Efficacy of Evolocumab—Phase III Studies Based on results from evolocumab phase II studies, phase III studies were conducted with the 140 mg Q2W and 420 mg QM doses because these two doses provided maximal and consistent reductions in LDL-C. In phase 3 studies, evolocumab treatment consistently resulted in reductions in LDL-C in a wide range of patient populations, regardless of background lipid-lowering treatment or baseline cardiovascu- lar risk. Primary endpoints and study durations varied across the randomized, placebo-, and/or ezetimibe-controlled phase III trials reported to date (Table 3) [31–40]. Across the phase III studies, reductions in LDL-C ranged from 37 to 76% versus control for patients treated with evolocumab 140 mg Q2W; reductions ranged from 38 to 75% versus control for patients treated with evolocumab 420 mg QM (Table 3). Significant improvements were also observed in other lipid parameters in phase III studies (Table 2). Table 3 outlines study name, study population, treat- ment doses, and change from baseline in LDL-C for all phase III studies of evolocumab published to date. Key global, phase III studies are described in more detail below. MENDEL-2 MENDEL-2 evaluated evolocumab monotherapy versus ezetimibe versus placebo in patients with hypercholesterol- emia [31]. In MENDEL-2 (the largest monotherapy trial for a PCSK9 inhibitor to date), there was a 57% reduction from baseline in LDL-C for patients receiving biweekly evolocumab versus < 1 and 18% reductions for patients re- ceiving placebo and ezetimibe, respectively (P < 0.001 for both); corresponding results for monthly evolocumab were 56 versus 1 and 19%, respectively (P < 0.001 for both) [31]. LAPLACE-2 LAPLACE-2 evaluated evolocumab versus ezetimibe versus placebo in patients with hypercholesterolemia who were re- ceiving stable doses of statins [32]. In LAPLACE-2, LDL-C reductions for biweekly regimens (66–75%; P < 0.05 vs pla- cebo) and monthly regimens (63–75%; P < 0.05 vs placebo) were greater for evolocumab added to moderate- or high- intensity statin therapy compared with placebo [32]. Furthermore, LDL-C reductions were greater with the addi- tion of evolocumab than with ezetimibe (17–24%) [32]. GAUSS-2 and GAUSS-3 GAUSS-2 evaluated evolocumab versus ezetimibe in statin- intolerant patients with hypercholesterolemia [35]. GAUSS-2 illustrated the benefit of evolocumab in patients who are statin intolerant, with LDL-C reductions of 37 and 39%, respective- ly, with biweekly and monthly dosing versus ezetimibe (P < 0.001 vs ezetimibe for both) [35]. This indicates that PCSK9-mediated LDL-C reduction operated independently from statin-mediated responses. GAUSS-3 was a longer phase III study that extended the findings of GAUSS-2 in statin- intolerant patients who underwent a blinded, placebo-con- trolled, 10-week statin rechallenge using 20 mg atorvastatin. The average reduction in LDL-C was 38% with monthly dos- ing when adjusted for ezetimibe (P < 0.001) [36]. RUTHERFORD-2 RUTHERFORD-2 evaluated evolocumab versus placebo in patients with heterozygous familial hypercholesterolemia (HeFH) despite statin therapy [40]. In RUTHERFORD-2, LDL-C reductions of 59 and 61% were seen with biweekly and monthly regimens, respectively (P < 0.0001 vs placebo for both), when corrected for placebo [40]. DESCARTES DESCARTES evaluated 52 weeks of evolocumab 420 mg QM versus placebo with background lipid-lowering therapy [34]. Evolocumab provided long-term reductions in LDL-C: the least squares mean LDL-C reduction from baseline for evolocumab at week 52 was 57% (P < 0.001 vs placebo), when adjusted for placebo [34]. This was consistent with the reduction seen in these patients at week 12 (58%) [34]. TESLA (Part B) The TESLA (Part B) study evaluated evolocumab therapy versus placebo in 50 patients with homozygous familial hypercholsterolemia (HoFH), a rare genetic condition charac- terized by extremely high levels of LDL-C [37]. In this ran- domized, placebo-controlled study, monthly treatment with evolocumab produced a 31% reduction in LDL-C, when ad- justed for placebo (P < 0.0001 vs placebo) [37]. Seven pa- tients in the study were < 18 years of age. In this population, evolocumab reduced LDL-C from baseline by 26%. This study also examined the effect of evolocumab in a pre- specified analysis of patients by LDL receptor mutation status. In patients with LDL receptor mutations in both alleles (of which at least one was defective), evolocumab reduced LDL-C by 41%. Patients with receptor-negative mutations in both LDL receptor alleles did not respond to evolocumab treatment and LDL-C levels instead increased slightly (3 to Curr Atheroscler Rep (2018) 20:17 Page 5 of 13 17 Table 2 Summary of non-low-density lipoprotein cholesterol lipid changes in evolocumab trialsa Study name Change from baseline versus placebo/control at end of study,b % (95% CI or SE) apoA1 apoB HDL-C Lp(a) Non-HDL-C Triglycerides Phase II studies MENDEL [23] 3 (− 3, 8) to 11 (5, 16)d − 44 (− 51, − 38) to − 32 (− 39, 3 (− 4, 10) to 10 (4, 17)d − 29 (− 40, − 18) to − 11 (− 22, 0)e − 47 (− 53, − 41) to − 35 (− 42, − 12 (− 25, 1) to − 2 (− 16, 13)h − 26)i − 29)i LAPLACE-TIMI 57 [24, 30] 0 (− 4, 4) to 5 (1, 9)d − 56 (− 61, − 52) to − 34 (− 40, − 29)i 2 (− 3, 6) to 8 (4, 13)d − 32 (4) to − 18 (4)c − 61 (− 66, − 56) to − 38 (− 43, − 33)i − 34 (− 46, − 22) to − 13 (− 25, − 2)e GAUSS [25] 6 (1, 12) to 8 (1, 15)f − 49 (− 56, − 42) to − 34 (− 40, − 27)c 6 (− 1, 12) to 12 (4, 20)d − 29 (− 42, − 16) to − 20 (− 29, − 11)f − 60 (− 67, − 52) to − 40 (− 47, − 19 (− 34, − 5) to − 10 (− 34, 15)h RUTHERFORD [26] 2 (2) to 2 (2)h − 46 (4) to − 35 (4)c 7 (3) to 8 (3)f − 32 (4) to − 23 (4)c − 54 (4) to − 42 (4)c − 20 (6) to − 15 (6)f YUKAWA [27] 4 (2) to 10 (2)d − 61 (3) to − 47 (3)c 4 (3) to 16 (3)d − 51 (5) to − 32 (5)c − 63 (3) to − 50 (3)c − 20 (6) to − 14 (6)e TESLA (Part A) [28] 1 (SD, 14) to5 (SD, 12)h − 15 (SD, 14) to − 13 (SD, 19)h − 1 (SD, 21) to 5 (SD, − 19 (SD, 12) to − 12 (SD, 11)h NR − 6 (SD, 16) to 6 (SD, 26)h OSLER-1 [29] 5 (1)g − 43 (1)g 9 (1)g − 30 (Q1, Q3; − 50, − 13)g − 46 (1)g − 9 (Q1, Q3; − 24, 14)g Phase III studies − 33)c 22)h MENDEL-2 [31] NR − 48 (− 52, − 44) to − 48 (− 52, − 45)c 6 (2, 10) to 9 (5, 13)f −20 (−28, −13) to −18 (−25, −11)c − 51 (− 55, − 48) to − 50 (− 53, − 18 (− 22, − 9) to − 6 (− 16, 4)d LAPLACE-2 [32] NR − 59 (− 67, − 52) to − 51 (− 57, − 45)e 4 (0, 8) to 10 (5, 15)d − 36 (− 43, − 28) to − 21 (− 28, − 13)e − 65 (− 74, − 57) to − 57 (− 64, − 50)e − 30 (− 41, − 19) to − 12 (− 22, − 3)d YUKAWA-2 [33] 7 (2) to 9 (2)f − 66 (2) to − 56 (2)c 10 (3) to 17 (3)c − 53 (6) to − 40 (5)c NR − 28 (10) to − 17 (7)e DESCARTES [34] NR − 48 (2) to − 38 (4)g 4 (2) to 11 (4)g − 29 (3) to − 10 (6)g − 55 (3) to − 41 (5)g − 23 (9) to − 4 (7)g GAUSS-2 [35] 3 (− 1, 7) to 6 (2, 9)h − 35 (− 40, − 30) to − 32 (− 37, − 28)c 5 (1, 10) to 6 (1, 10)h − 25 (− 34, − 17) to − 24 (− 31, − 17)c − 35 (− 39, − 31) to − 32 (− 36, − 6 (− 17, 4) to − 3 (− 11, 6)h GAUSS-3 [36] NR − 34 (− 38, − 30)c 6 (2, 10)e − 21 (− 28, − 15)c − 33 (− 37, − 29)c − 4 (− 14, 5)h RUTHERFORD-2 [37] 4 (− 2, 9) to 9 (4, 13)e − 49 (− 55, − 44) to − 49 (−56, – 43)i 9 (5, 14) to 9 (4, 15)e − 32 (− 39, − 24) to − 28 (− 36, − 21)i − 55 (− 61, − 49) to − 55 (− 62, − 20 (− 28, − 11) to − 12 (− 21, 2)e TESLA (Part B [37] NR −23 (−35, −12)c −0.1 (−9, 9)h −12 (−26, 2)h −30 (−42, −18)i 0.3 (− 15, 16)h − 46)c − 27)c − 48)i FOURIER [38•] 5c – 43c 8c – 27c – 52c – 16c GLAGOV [39••] J 5c – 41c 3c – 7c – 63c – 19c a MENDEL Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently not Receiving Drug Therapy for Easing Lipid Levels, LAPLACE-TIMI 57 LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy, GAUSS Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects, RUTHERFORD Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder, YUKAWA Study of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients with Advanced Cardiovascular Risk, TESLA Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities, OSLER Open-Label Study of Long-Term Evaluation Against LDL-C, DESCARTES Durable Effect of PCSK9 Antibody Compared with Placebo Study, apoA1 apolipoprotein A1, NR not reported, apoB apolipoprotein B, HDL-C high-density lipoprotein cholesterol, Lp(A) lipoprotein (a), Q quartile 17 Curr Atheroscler Rep (2018) 20:17 Page 6 of 13 b Data presented are least squares means normalized to control; values shown with interquartile ranges (Q1, Q3) are medians; background therapy varied by study: MENDEL: week 12 data reported corrected for placebo; patients received evolocumab monotherapy; LAPLACE: outcomes at week 12 are reported; data are placebo-corrected; YUKAWA: week. 12 data are reported; data are versus placebo; 6.2% of patients received high-intensity statins; GAUSS: outcomes at week 12 are reported; values are corrected for baseline (not placebo); P values shown are versus placebo + ezetimibe; RUTHERFORD: week 12 data are reported; 90% received intensive statin therapy; 64% received ezetimibe; TESLA (Part A): week 12 data are reported; data are versus baseline; OSLER-1: week 52 data versus baseline are reported (not corrected versus standard of care); 63% received statins. MENDEL-2: week 12 data reported; patients received evolocumab monotherapy; LAPLACE-2: mean week 10/12 data reported; patients received 80 or 10 mg atorvastatin, 40 or 5 mg rosuvastatin, or 40 mg simvastatin daily: YUKAWA-2: week 12 data reported; patients received 5 or 20 mg atorvastatin daily; DESCARTES: week 52 data reported; versus standard of care; patients were also randomized to diet alone or in combination with 10 mg, 80 mg atorvastatin, or 80 mg atorvastatin plus 10 mg ezetimibe daily; GAUSS-2: mean weeks 10 and 12; data are versus ezetimibe; GAUSS-3: mean weeks 22/24 reported; patients received evolocumab monotherapy; RUTHERFORD-2: 87% received intensive statin therapy, often in combination with ezetimibe (62%) or other lipid-modifying drugs; data are versus placebo; TESLA (Part B): 94% received high-intensity statin therapy; 92% also had ezetimibe; week 12 data reported; data are versus placebo; FOURIER: week 48 data corrected for placebo, all are mean except triglycerides and Lp(a), 69% received high-intensity statins, 30% received moderate-intensity statins, < 1% received low/no intensity statins, or had no data; GLAGOV: week 48 data are placebo-corrected absolute change, all are mean except triglycerides and Lp(a), reported; data are versus placebo; 58.9% were receiving high-intensity statin therapy and 39.4% moderate-intensity therapy, with 1.4% of patients not treated witha statin. Lp(a) SE values from the LAPLACE-TIMI-57 study were estimated based on Figure 1 from reference [29] c P ≤ 0.001 versus control; only the numerically largest P value for the range is reported d Not significant in at least 1 arm e P ≤ 0.05 versus placebo and/or ezetimibe or control; only the numerically largest P value for the range is reported f P ≤ 0.01 g Significance versus control not reported h Not significant in any arm i P < 0.0001 versus control; only the numerically largest P value for the range is reported 10%) from baseline to end of study. These results confirm that the effects of evolocumab correlate with the genetic cause of the individual’s HoFH, and that patients with two defective LDL receptors (and thus some receptor functionality) show a greater percentage reduction in LDL-C than do those with one or both LDL receptor-negative mutation(s) [37]. OSLER-2 OSLER-2 is an ongoing study monitoring long-term efficacy and safety of patients who completed an evolocumab phase III parent study. A combined analysis of OSLER-1 and -2 has been published. In the 4465 patients included in the analysis, LDL-C was reduced by 58% compared with standard of care (SOC) at 48 weeks (P < 0.001) [41]. In the 2979 patients en- rolled in OSLER-2 only, LDL-C was reduced by 64% relative to SOC alone at 12 weeks [41]. FOURIER Cardiovascular events were evaluated in the evolocumab cardiovascular outcomes study, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER), which was conducted in 27,564 patients and had a median duration of follow-up of 2.2 years. FOURIER was designed to assess whether evolocumab, in combination with optimized stable lipid- lowering therapy, decreased the risk of the primary compos- ite endpoint of cardiovascular death, myocardial infarction, stroke, coronary vascularization, or hospitalization for un- stable angina in patients with clinically evident cardiovas- cular disease [42]. At 48 weeks, the mean percentage reduc- tion in LDL-C was 59% to a median of 30 mg/dL. The primary composite endpoint occurred in 9.8% of patients in the evolocumab group and 11.3% of patients in the pla- cebo group. Evolocumab treatment significantly reduced the risk of the primary composite endpoint relative to pla- cebo (HR = 0.85; 95% CI, 0.79–0.92; P < 0.001) [38•]. The percentage of patients reaching the secondary endpoint was 5.9% in the evolocumab group and 7.4% in the placebo group (HR = 0.80; 95% CI, 0.73–0.88; P < 0.001) [38•]. The magnitude of risk reduction increased over time for both endpoints, respectively, from 12 and 16% in the first year to 19 and 25% beyond the first year. Furthermore, in the FOURIER study, consistency across baseline LDL-C levels was observed, and even patients with lower baseline LDL-C levels (median 74 mg/dL) saw a reduction in risk of the primary and key secondary composite endpoints. A pre- specified subanalysis of the FOURIER study in 3642 pa- tients with peripheral artery disease (PAD) showed that evolocumab treatment significantly reduced the primary composite endpoint (cardiovascular death, myocardial in- farction, stroke, coronary vascularization, or hospitalization J Values are placebo-correct absolute changes Table 3 Phase III studies of evolocumaba Study population, N (randomized and treated) Treatments and doses LDL-C change at end of studyb,c % (95% CI or SE) Curr Atheroscler Rep (2018) 20:17 Page 7 of 13 17 MENDEL-2 [31] N = 614 LDL-C ≥ 100 and < 190 mg/dL (≥ 2.6 and < 4.9 mmol/L); low cardiovascular risk (FRS < 10%) No concomitant lipid-lowering therapy LAPLACE-2 [32] N = 1896 LDL-C ≥ 150 mg/dL (≥ 3.9 mmol/L), no statin at screening; LDL-C ≥ 100 mg/dL (≥ 2.6 mmol/L), non-intensive statin at screening; or ≥ 80 mg/dL (≥ 2.1 mmol/L), intensive statin at screening; fasting triglyceride levels ≤ 400 mg/dL (≤ 4.5 mmol/L) GAUSS-2 [35] N = 307 LDL-C higher than NCEP goal and with a prior tolerance to ≥ 2 statins GAUSS-3 [36] N = 218 LDL-C ≥ 100 mg/dL and CHD, OR LDL-C ≥ 130 without CHD, and able to tolerate atorvastatin 10 mg and any other statin at any dose or, alternatively, three or more statins, with one at the lowest average daily starting dose and two other statins at any dose. RUTHERFORD-2 [40] N = 329 HeFH according to Simon Broome criteria and taking a stable dose of a statin with or without other approved lipid-modifying therapy YUKAWA-2 [33] N = 404 Japanese patients at high cardiovascular risk on background statins ⦁ EVO 140 mg Q2W + PLC PO QD ⦁ EZE 10 mg QD + PLC SC Q2W ⦁ PLC PO Q2W + PLC SC QD ⦁ EVO 420 mg + PLC PO QM ⦁ EZE 10 mg QD + PLC SC QM ⦁ PLC PO QM + PLC SC QD ⦁ EVO 140 mg Q2W + PLC QD PO ⦁ EZE QD PO + PLC SC Q2W ⦁ PLC PO + PLC SC Q2W ⦁ EVO 420 mg QM + PLC QD PO ⦁ EZE QD PO + PLC SC QM ⦁ PLC PO + PLC SC QM ⦁ EVO 140 mg Q2W + PLC QD PO ⦁ PLC Q2W + EZE QD PO ⦁ EVO 420 mg QM + PLC QD ⦁ PO PLC QM + EZE QD PO ⦁ EVO 420 mg QM + PLC QD PO ⦁ PLC QM + EZE QD PO ⦁ EVO 140 mg or PLC Q2W ⦁ EVO 420 mg or PLC QM ⦁ EVO 140 mg or PLC Q2W ⦁ EVO 420 mg or PLC QM ⦁ − 57 (− 61, − 53) (PLC-corrected) ⦁ − 55 (− 59, − 51) (PLC-corrected) ⦁ − 75 (− 85, − 65) to − 66 (− 73, − 58) (PLC-corrected, high statin); − 70 (− 75, − 65) to − 67(− 73, − 61) (PLC-corrected, moderate statin) ⦁ − 75 (− 83, − 67) to − 63 (− 71, − 55) (PLC-corrected, high statin); − 69 (− 77, − 60) to − 63 (− 69, − 57) (PLC-corrected, moderate statin) ⦁ − 37 (− 42, − 32) (PLC+ EZE-corrected) ⦁ − 39 (− 43, − 34) (PLC + EZE-corrected) ⦁ − 38 (− 42, − 33) (PLC + EZE-corrected ⦁ − 59 (− 65, − 53) (PLC-corrected) ⦁ − 61 (− 69, − 54) (PLC-corrected) ⦁ − 76 (4) to − 75 (3) (PLC-corrected) ⦁ − 70 (2) to − 67 (3) (PLC-corrected) Table 3 (continued)  Study population, N (randomized and treated) Treatments and doses LDL-C change at end of studyb,c % (95% CI or SE) DESCARTES [34] N = 901 LDL-C ≥ 75 mg/dL (≥ 1.9 mmol/L) and < 100 mg/dL (< 2.6 mmol/L) in patients with CHD or < 130 mg/dL (< 3.4 mmol/L) in patients without CHD, and fasting triglycerides ≤ 400 mg/dL (≤ 4.5 mmol/L) TESLA (Part -B) [37] N = 50 HoFH diagnosed either by genetic analysis or clinical criteria FOURIER [38••] N = 27,525 CHD and LDL-C ≥ 70 mg/dL or non-HDL ≥ 100 mg/dL while on optimized lipid-lowering therapy (≥ 20 mg atorvastatin or equivalent) GLAGOV [39] N = 968 ≥ 1 epicardial coronary stenosis ≥ 20% ⦁ EVO 420 mg or PLC QM • − 58 (2) (wk 12; PLC-corrected) ⦁ − 57 (2) (wk 52, PLC-corrected) ⦁ EVO 420 mg QM • − 31 (− 44, − 18) (PLC-corrected) ⦁ EVO or PLC 140 mg Q2W or 420 mg QM • − 59 (− 58, − 60) (PLC-corrected) ⦁ EVO or PLC 420 mg QM • − 57 (− 60, − 53) (PLC-corrected; absolute change) 17 Curr Atheroscler Rep (2018) 20:17 Page 8 of 13 a MENDEL Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels, LDL-C low-density lipoprotein cholesterol, EVO evolocumab, FRS Framingham Risk Score, Q2W every 2 weeks, PLC placebo, PO oral, QD once daily, EZE ezetimibe, SC subcutaneous, QM monthly, LAPLACE LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With |Statin Therapy, GAUSS Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects, NCEP National Cholesterol Education Program, RUTHERFORD Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder, HeFH heterozygous familial hypercholesterolemia, YUKAWA Study of LDL-Cholesterol Reduction Using a Monoclonal PCSK9 Antibody in Japanese Patients with Advanced Cardiovascular Risk, ATOR atorvastatin, DESCARTES Durable Effect of PCSK9 Antibody Compared with Placebo Study, CHD coronary heart disease, TESLA Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities, HoFH homozygous familial hypercholesterolemia, FOURIER Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; GLAGOV Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound b Data presented are normalized to control; background therapy varied by study: MENDEL-2: week 12 data reported; data are versus placebo, as patients received evolocumab monotherapy; LAPLACE-2: mean weeks 10/12 data reported; data are versus placebo; patients received 80 or 10 mg atorvastatin, 40 or 5 mg rosuvastatin, or 40 mg simvastatin daily; YUKAWA-2: week 12 data reported; data are versus placebo; patients received 5 or 20 mg atorvastatin daily; DESCARTES: week 52 data reported; data are versus standard of care; patients were also randomized to diet alone or in combination with 10 or 80 mg atorvastatin or 80 mg atorvastatin plus 10 mg ezetimibe daily; GAUSS-2: mean weeks 10/12 data reported; data are versus ezetimibe; GAUSS-3: mean weeks 22/24 reported; patients received evolocumab monotherapy; data are versus ezetimibe; RUTHERFORD-2: week 12 data reported; data are versus placebo; 87% received intensive statin therapy, often in combination with ezetimibe (62%) or other lipid-modifying drugs; TESLA-B: week 12 data reported; 94% received high-intensity statin therapy; 92% also had ezetimibe; FOURIER: week 48 data reported; data are versus placebo; all received ≥ 20 mg atorvastatin or equivalent with or without ezetimibe; GLAGOV: week 76 data reported; data are versus placebo; 59% were receiving high-intensity statin therapy and 39% moderate- intensity therapy with 1% of patients not treated with a statin c For treatment differences, RUTHERFORD-2 and TESLA (Part B) (P ≤ 0.0001 vs control), MENDEL-2, GAUSS-2, GAUSS-3, YUKAWA-2, DESCARTES, FOURIER, GLAGOV (all P ≤ 0.001), and LAPLACE-2 (all P < 0.05) Table 4 Adverse events occurring in > 1% of evolocumab-treated patients and more frequently than with placebo in pooled 12-week studies [20]

Adverse event Placebo % Evolocumaba %
n = 1224 n = 2052
Nasopharyngitis 3.9 4.0
Back pain 2.2 2.3
Upper respiratory tract infection 2.0 2.1
Arthralgia 1.6 1.8
Nausea 1.2 1.8
Fatigue 1.0 1.6
Muscle spasms 1.2 1.3
Urinary tract infection 1.2 1.3
Cough 0.7 1.2
Influenza 1.1 1.2
Contusion 0.5 1.0
a 140 mg every 2 weeks and 420 mg once monthly combined

for unstable angina; HR = 0.79; 95% CI, 0.66–0.94; P = 0.0098). The absolute risk reduction for the primary endpoint in patients with PAD was 3.5% (with PAD) and 1.6% (without PAD). There was also a strong relationship between lower achieved LDL-C and a lower risk of major adverse limb events (acute limb ische- mia, major amputation, or urgent peripheral revascularization for ischemia [P = 0.026 for the beta coefficient]) [43].

GLAGOV

The GLAGOV study evaluated the effects of evolocumab on coronary atherosclerosis as assessed with intravascular
ultrasound in patients with coronary artery disease on optimal background statin therapy. At week 78, patients in the evolocumab group demonstrated a 0.95% reduction in percent atheroma volume; patients in the placebo group had an in- crease of 0.05%, for a mean difference of − 1.0% (95% CI,
− 1.8 to − 0.64%; P < 0.001). Total atheroma volume de- creased 0.91 mm3 for patients on placebo and 5.8 mm3 for patients on evolocumab, for a difference of − 4.9 mm3 (95% CI, − 7.3 to − 2.5; P < 0.001). A greater proportion of patients on evolocumab (64.3%) had plaque regression compared with those on placebo (47.3%); the difference was 17.0% (95%CI, 10.4 to 23.6%; P < 0.001) for percent atheroma volume. Similarly, the proportion of patients with plaque regression per total atheroma volume was 61.5vs 48.9% for patients on evolocumab and placebo, respectively (difference, 12.5%; 95% CI, 5.9 to 19.2%; P < 0.001) [39••]. Favorable effects in percent atheroma volume were also seen following treat- ment with evolocumab versus placebo inpatients with baseline LDL-C levels below 70 mg/dL (− 1.97 vs − 0.35%; P < 0.001) [39••]. Safety The safety profile of evolocumab from phase II and III studies suggests that evolocumab is safe and well tolerated in patients with familial hypercholesterolemia (heterozygous and homo- zygous), primary hyperlipidemia, and mixed dyslipidemia. The safety profile is consistent regardless of background lipid-lowering therapy, baseline cardiovascular risk, or patient Table 5 Adverse events occurring in ≥ 3% of monoclonal Adverse event Placebo, % Evolocumab, % antibody-treated patients and more frequently than with Evolocumab—52-week trial (DESCARTES) [34] n = 302 n = 599 placebo Nasopharyngitis 9.6 10.5 Upper respiratory tract infection 6.3 9.3 Influenza 6.3 7.5 Back pain 5.6 6.2 Injection site reactiona 5.0 5.7 Cough 3.6 4.5 Urinary tract infection 3.6 4.5 Sinusitis 3.0 4.2 Headache 3.6 4.0 Myalgia 3.0 4.0 Dizziness 2.6 3.7 Musculoskeletal pain 3.0 3.3 Hypertension 2.3 3.2 Diarrhea 2.6 3.0 Gastroenteritis 2.0 3.0 DESCARTES Durable Effect of PCSK9 Antibody Compared with Placebo Study a Erythema, pain, and bruising population. A pooled analysis of seven 12-week phase II and III trials reported the most common AE to be nasopharyngitis, occurring in 4.0% of patients on evolocumab and 3.9% of patients on placebo (Table 4 [20]) [44]. In patients treated with evolocumab monotherapy in the phase III MENDEL-2 study, incidences of AEs were comparable between patients treated with evolocumab and placebo (44% in each arm) [23]. Few patients in either treatment group in MENDEL-2 experienced serious AEs (1.3% evolocumab, 0.6% placebo). The rate of discontinuation due to AEs was relatively low: 2.3% across the evolocumab groups and 3.9% across the placebo groups [23]. Injection site reactions occurred in 5% of patients in the evolocumab and control arms. No increase in AEs has been observed when statins were used in combination with evolocumab in the LAPLACE com- bination trials [24, 32]. In the longer-term DESCARTES study, AE rates were comparable between evolocumab (75%) and placebo (74%), as were rates of serious AEs (6 vs 4%) [34]. In total, 2% of patients receiving evolocumab and 1% of patients receiving placebo discontinued treatment be- cause of an AE. The most common AEs reported in the DESCARTES study and in key 12-week clinical trials of evolocumab that occurred in ≥ 3% of evolocumab groups and were more frequent in evolocumab- than in placebo- treated patients are shown in Table 5 [34]. Adverse event data from the large FOURIER study (medi- an duration of follow-up 2.2 years; 69% were taking high- intensity statin therapy) showed no significant difference be- tween evolocumab and placebo groups, including serious AEs (24.8 vs 24.7%), drug-related withdrawals (1.6 vs 1.5%), al- lergic reaction (3.1 vs 2.9%), muscle-related events (5.0 vs 4.8%), adjudicated new-onset diabetes (8.1 vs 7.7%), neurocognitive events (1.6 vs 1.5%), aminotransferase levels > 3× the upper limit of normal (both 1.8%), and creatine ki- nase levels > 3× the upper limit of normal (both 0.7%) [38•]. The incidence of injection site reactions (2.1 vs 1.6%; P < 0.001) was significantly higher in the evolocumab group than in the placebo group. At present, two open-label exten- sion studies of the FOURIER trial are ongoing (NCT03080935 and NCT02867813), and are designed to as- sess the extended longer-term safety of evolocumab in ap- proximately 6600 patients. Neurocognitive events have been a potential concern with statins [45]. Although the presence of the blood-brain barrier is thought to preclude such effects from monoclonal antibod- ies such as evolocumab, neurocognitive events linked to statin treatment are of theoretical concern, and have been monitored in the evolocumab clinical trial program. The EBBINGHAUS study enrolled a subset of patients from the FOURIER study and prospectively collected data on neurocognitive function in patients receiving evolocumab versus placebo [46]. Unlike other neurocognitive data collected to date on evolocumab, this study employed an objective test battery that is validated to look for neurocognitive changes in drug trials. No signifi- cant between-group differences were found in the raw score for spatial working memory index of executive function (P < 0.001 for noninferiority; P = 0.85 for superiority), work- ing memory, episodic memory, or psychomotor speed. In ad- dition, there was no difference in the FOURIER study be- tween evolocumab and control groups in the rates of investigator-reported neurocognitive AEs (1.9 vs 1.3%) [46]. Patients with diabetes have a greater risk of developing atherosclerotic cardiovascular disease than do those without diabetes; thus, control of lipid levels is a critical component of disease management for these patients. Recent studies dem- onstrate that evolocumab effectively lowers LDL-C in patients with diabetes [47–49]. Although patients with diabetes are at increased risk of having a cardiovascular event, evolocumab treatment significantly reduces cardiovascular risk in these patients [50]. Evolocumab does not appear to have an effect on glucose homeostasis over 1 year of open-label treatment [49]. A pre-specified secondary analysis from the FOURIER study demonstrates that evolocumab does not increase the risk of new-onset diabetes in patients without diabetes; in this study, the majority of patients who developed diabetes during the study were prediabetic at baseline [50]. One theoretical concern with respect to therapeutic proteins is that they carry the potential for immunogenicity, which has been closely monitored in evolocumab clinical trials. However, thus far, the incidence of binding antibody develop- ment with evolocumab has been low (0.1%), with no reports of neutralizing antibodies. Furthermore, there has been no reported impact of binding antibodies on the clinical efficacy, safety, or PK of evolocumab. Results from up to 4 years from the open-label OSLER-1 extension study indicated that the development of anti-drug antibodies was low; only four tran- sient occurrences were observed, and no neutralizing antibod- ies were detected [51]. Because lipoproteins are involved in vitamin E transport ⦁ and cholesterol is required for steroidogenesis, levels of these compounds in patients who experienced very low LDL- C levels are of interest [53]. Data from the DESCARTES study were analyzed to determine whether evolocumab affects levels of vitamin E and cholesterol [54]. In all patients receiv- ing evolocumab, absolute vitamin E levels decreased by a mean of 16%; however, cholesterol-normalized vitamin E levels increased by a mean of 19%. No correlation was found between changes in cortisol, testosterone, or estradiol and the change in LDL-C from baseline among evolocumab-treated patients [54]. Vitamin E changes were consistent between pa- tients with very low LDL-C concentrations (defined as < 15, < 25, and < 40 mg/dL) and those with higher LDL-C concen- trations (≥ 40 mg/dL). In a subsequent pre-specified secondary analysis from the FOURIER study, there was no association between achieved LDL-C levels and any safety outcome [55], suggesting that achievement of very low levels of LDL-C does not impact patient risk for adverse events. These data add to a growing body of evidence suggesting that there is no plateau in benefit at low LDL-C levels. Dosage and Administration Dosing of evolocumab depends on indication. Evolocumab is approved in the USA to be administered subcutaneously at a dosage of 140 mg Q2W or 420 mg QM for patients with primary hyperlipidemia with established atherosclerotic car- diovascular disease or HeFH. For patients with HoFH, the approved dose in the USA is 420 mg QM. No dose adjustment of evolocumab is necessary for patients with mild to moderate renal impairment. Other than a small (N = 18), phase 1 study recently presented demonstrating that the safety profile of evolocumab in patients with severe renal impairment is simi- lar to that of patients with normal renal function [56], no published data are available in patients with severe renal impairment. Self-administration is approved for use in appropriately trained patients. There are currently two options for subcuta- neous self-administration: the Pushtronex® system for QM dosing, and the SureClick® autoinjector for Q2W dosing. Evolocumab can be stored refrigerated (2–8 °C) for up to 24 months. Once removed from the refrigerator, the drug may be stored at room temperature (25 °C) for up to 30 days. Place in Therapy Evolocumab is indicated for use as an adjunct to diet, as an adjunct to maximally tolerated statin therapy for treatment of adults with HeFH or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C, and as an adjunct to other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with HoFH who require additional lowering of LDL-C. Evolocumab is also indicated to reduce the risk of myocardial infarction, stroke, and coro- nary revascularization [20]. The maximally tolerated statin dose may vary depending on a patient’s tolerance. For patients with statin intolerance, the maximally tolerated dose could be no statin whereas for others it could mean high- or low-dose statin therapy in addition to evolocumab to sufficiently lower LDL-C and cardiovascular risk. Although these differences remain, data from LAPLACE-2 showed similar LDL-C– lowering efficacy in patients taking high-, moderate-, or low-dose statins, indicating that evolocumab was beneficial irrespective of the statin therapy dose [32]. The FOURIER study evaluated the ability of evolocumab to lower cardiovascular risk in combination with other lipid- lowering agents and showed a significantly reduced risk of the primary composite endpoint of cardiovascular death, myocar- dial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The reduction in risk for the pri- mary and secondary endpoints increased over time. Previous studies with other lipid-lowering drugs have also shown addi- tional cardiovascular risk reduction when added to a statin (e.g., the Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]) [57]. The FOURIER study demonstrates that reduction of LDL-C by evolocumab leads to a reduction in cardiovascular events. The observation in the GLAGOV study that evolocumab treatment reduces atherosclerotic plaque burden may provide a plausible biological explanation for the reduction in cardio- vascular events seen in FOURIER. Together, these data sug- gest that high-risk cardiovascular patients who do not have adequately controlled LDL-C levels despite maximally toler- ated statin therapy may benefit from the addition of a PCSK9 inhibitor, such as evolocumab. Conclusions Evolocumab is a PCSK9 inhibitor that increases LDL receptor expression and LDL-C uptake by hepatocytes, leading to in- creased clearance of LDL-C and lower serum LDL-C levels. Evolocumab has shown clinical efficacy in a diverse patient population in phase II and III studies, including patients with familial hypercholesterolemia (heterozygous and homozy- gous) and those who are statin intolerant. To date, no safety or tolerability differences have been detected among doses, dose frequencies, or patient subpopulations. Importantly, the cardiovascular outcomes trial FOURIER demonstrated a re- duced risk of cardiovascular events; ongoing open-label ex- tension studies will provide data on longer-term safety and efficacy of evolocumab. Acknowledgments The authors acknowledge Meghan Johnson, PhD, of Complete Healthcare Communications, LLC, whose work was funded by Amgen, and Annalise M. Nawrocki, PhD, of Amgen Inc., for writing and editorial assistance. Funding Information This work was supported by Amgen Inc. Compliance with Ethical Standards Conflict of Interest Barbara S. Wiggins has served as a consultant for Amgen Inc. Helina Kassahun, Armando Lira, and Ransi Somaratne are employees of Amgen Inc. and hold Amgen stock and/or stock options. Ransi Somaratne is an inventor on at least one pending patent application owned by Amgen Inc. relating to evolocumab. 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