Cardiometab Syndr J. 2021 Mar;1(1):66-75 https://doi.org/10.51789/cmsj.2021.1.e5 pISSN 2734-1143·eISSN 2765-3749

View Point Emerging New Lipid-Lowering Therapies in the Statin Era

Albert Youngwoo Jang , MD1, Sang-Ho Jo , MD, PhD2, and Kwang Kon Koh, MD, PhD1

1Division of Cardiovascular Disease, Gachon Cardiovascular Research Institute, Gachon University Gil Hospital, Incheon, Korea 2Cardiovascular Center, Hallym University Sacred Heart Hospital, Anyang, Korea

Received: Dec 18, 2020 Revised: Jan 12, 2021 ABSTRACT Accepted: Jan 17, 2021 Statins have become the backbone of lipid-lowering therapy today by dramatically improving Correspondence to cardiovascular (CV) outcomes. Despite well-controlled low-density lipoprotein cholesterol Kwang Kon Koh, MD, PhD (LDL-C) through statins, up to 40% patients still experience CV diseases. New therapeutic Cardiometabolic Syndrome Unit, Division of Cardiology, Gachon University Gil Hospital, 774 agents to target such residual cholesterol risk by lowering not only LDL-C but triglyceride beon-gil 21, Namdong-daero, Namdong-gu, (TG), TG-rich lipoproteins (TRL), or lipoprotein(a) (Lp[a]) are being newly introduced. Incheon 21565, Korea. Proprotein convertase subtilisin/kexin type 9 (PCSK9) small interference RNA (siRNA) and E-mail: [email protected] bempedoic acid therapies adding to statin therapies have shown additional improvement

Copyright © 2021. Korean Society of in CV outcomes. Recent trials investigating eicosapentaenoic acid to patients with high CardioMetabolic Syndrome TG despite statin therapy have also demonstrated significant CV benefit. Antisense This is an Open Access article distributed oligonucleotide (ASO) therapies with hepatocyte-specific targeting modifications are now under the terms of the Creative Commons being newly introduced with promising lipid-lowering effects. ASOs targeting TG/TRL, such Attribution Non-Commercial License (https:// as angiopoietin-like 3 or 4 (ANGPTL3 or ANGPTL4), apolipoprotein C-III (APOC3), or Lp(a) creativecommons.org/licenses/by-nc/4.0/) have effectively lowered the corresponding lipids without requiring high or frequent doses. which permits unrestricted non-commercial use, distribution, and reproduction in any Clinical outcomes from such novel therapeutics are yet to be proven. In this article, we review medium, provided the original work is properly emerging therapeutics targeting LDL-C, TG, TRL, and Lp(a) to reduce the residual risk. cited. Keywords: Dyslipidemia; Cardiovascular disease; Residual risk; Treatment ORCID iDs Albert Youngwoo Jang https://orcid.org/0000-0002-8802-268X Sang-Ho Jo INTRODUCTION https://orcid.org/0000-0002-2063-1542

Funding Many investigators have demonstrated the beneficial effects of low-density lipoprotein This work was supported by a grant from the cholesterol (LDL-C) lowering statins on reducing coronary artery disease (CAD) events Korean Society of CardioMetabolic Syndrome. in patients with or without CV disease (CVD).1,2 Despite significant improvement in CV outcomes since the advent of statins, up to 40% of statin-treated patients continue to suffer Conflict of Interest from life-threatening CV events even with adequately controlled LDL-C targets by intensive The authors have no financial conflicts of 3,4 interest. Dr. Koh holds a certificate of patent, statin treatment. The remaining CV risk in such patients is called the ‘residual risk.’ In 10-1579656 (pravastatin+valsartan). this article, we review emerging therapeutics targeting LDL-C, triglyceride (TG), TG-rich lipoproteins (TRL), and lipoprotein(a) (Lp[a]) for residual cholesterol risk reduction. Author Contributions Conceptualization: Koh KK, Jang AW; Writing - original draft: Koh KK, Jang AW; Writing - review & editing: Koh KK, Jang AW, Jo SH. https://e-cmsj.org 66 New Lipid-Lowering Therapies

RESIDUAL CHOLESTEROL RISK DESPITE OF STATIN THERAPY

Total cholesterol is composed of high-density lipoprotein cholesterol (HDL-C) and atherogenic lipoproteins (LDL-C and TRL cholesterol [TRL-C]), which contain apolipoprotein B100 molecule (apoB) (Figure 1). Among LDL-C, small dense LDL is characterized as cholesterol-depleted LDL particles. Lp(a) is also an atherogenic lipoprotein that contains apoB. Lp(a) consists of a covalent link between apoB-containing LDL-like particle and apolipoprotein (a) (apo[a]).

Because the level of TG is significantly correlated with the amount of remnant cholesterol in TRLs, TG is a biomarker for circulating TRLs and their metabolic remnants.3,4 Recently, increased TRL-C levels were shown to be associated with increased CV risk.5,6 For these reasons, TRL-C may account, at least in part, for the residual cholesterol risk. Mendelian randomization studies demonstrated that genetic variants that mimic LDL-C- and TG- lowering therapies were associated with the same extent of reduction in atherosclerotic cardiovascular disease (ASCVD) risk as long as the per-unit decrease in apoB concentration was similar, regardless of the type of variant.2 These data strongly suggest that the risk of ASCVD is determined by the total concentration of circulating apoB particles irrespective of the lipid content they carry. Accordingly, the clinical benefit of any lipid-lowering therapy should be proportional to the absolute achieved reduction in apoB concentration regardless

n wa LDL ApoB o Lipolysis Trigger :LPL VLDL TRLs macrophage ApoB CE

CETP

TG Foam cell Production of nascent HDL Lipid exchange and formation and HDL Dysfunctional delivery of HDL inflammation→ HDL constituents atherosclerosis Endothelial junction

Lipolysis :LPL o TRLs Chylomicron ApoB

Figure 1. The production of TRLs, remnant cholesterol which induce formation of atherosclerosis. Because TG can be degraded by most cells, but cholesterol cannot be degraded by any cell, the cholesterol content of TRLs is more likely to be the cause of atherosclerosis and cardiovascular disease rather than raised TG per se. Indeed, remnant lipoproteins like LDL can enter the arterial intima. LPL activity at the surface of remnant particles, either at the surface of vascular endothelium or within the intima, leads to liberation of free fatty acids, monoacylglycerols, and other molecules for energy use and storage. Some apoB lipoproteins in LDL and TRLs can become trapped in the artery wall and cause local injury and inflammation. High triglyceride concentrations are a marker for raised TRLs, remnant cholesterol which, upon entrance into the intima, leads to low-grade inflammation, foam cell formation, atherosclerotic plaques, and ultimately cardiovascular disease and increased mortality. apoB = apolipoprotein B100 molecule; CE = cholesterol ester; CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; IDL = intermediate- density lipoprotein; LDL = low-density lipoprotein; LPL = lipoprotein lipase; VLDL = very low-density lipoprotein; TG = triglyceride; TRL = triglyceride rich lipoprotein.Reprinted with permission from Jang et al.19 https://e-cmsj.org https://doi.org/10.51789/cmsj.2021.1.e5 67 New Lipid-Lowering Therapies

of the corresponding decrease in LDL-C or TGs. In other words, targeting TRL-C and non- HDL-C is essential in patients with CV risk factors because it can be as effective as lowering LDL-C to very low concentrations for residual CV risk reduction.3,4,7

EMERGING LDL-C-LOWERING THERAPIES

PCSK9 small interference RNA The proprotein convertase subtilisin-kexin type 9 (PCSK9) small interference RNA (siRNA) decreases atherogenic lipoprotein levels, particularly LDL-C, through attenuation of LDL-C receptor degradation.

Inclisiran is a newly developed drug using siRNA technology designed to inhibit PCSK9 production through neutralizing the messenger RNA of the PCSK9 gene (Table 1).8 Inclisiran is siRNAs conjugated to a triantennary N-acetylgalactosamine (GalNAc), designed to deliver the drug specifically to liver cells PCSK9 is mainly produced. Thus, a much lower amount of drug is required for liver cell-targeting therapeutics, maximizing drug efficacy and durability while reducing side effects.9 The impact of the drug is persisted for at least 180 days after initiation of treatment. This enables inclisiran to be administration every 3 or 6 months, compared with the PCSK9 mAbs injected every 2 or 4 weeks, although the LDL-C lowering effects are similar. Inclisiran successfully lowered LDL-C levels by 40 to 50% over 1.5 years in subjects with familial hypercholesterolemia (FH)10 or elevated LDL-C levels without FH.11 Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo; such reactions were generally mild, and none were severe or persistent. Phase 3 outcome studies are currently underway (ClinicalTrials.gov NCT03705234).

Bempedoic acid Bempedoic acid also reduces LDL-C levels by attenuating ATP citrate lyase, an enzyme upstream of HMG-CoA reductase, crucial in the biosynthesis of cholesterol. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial, enrolled

Table 1. A summary of clinical trials targeted on lowering LDL-C Trial name Drug and dose Sample Inclusion Duration Primary endpoint LDL-C reduction Outcome (95% CI) size (yr) (mg/dL) ORION-910 Inclisiran 284 mg SC n=482 FH patients on 1.5 1. Percent change from baseline in 58.7 58.7%* (PCSK9 siRNA) injection on day 1, maximal statin dose LDL-C at day 510 90, 270, and 450 with or without 2. Time-adjusted percent change 37.7% † ezetimibe from baseline in LDL-C between day 90 and day 540 ORION-10 AND Inclisiran 284 mg SC n=3,172 Elevated LDL-C 1.5 1. Percent change from baseline in 56.2/50.9 52.3%/49.9%* ORION-1111 injection on day 1, despite maximal LDL-C at day 510 (PCSK9 siRNA) 90, 270, and 450 statin dose 2. Time-adjusted percent change 53.8%/49.2%† from baseline in LDL-C between day 90 and day 540 CLEAR12 Harmony Bempedoic acid 180 n=2,230 CV disease and 1.0 Safety at 1 year* 19.2 Higher incidence of drug mg once daily heterozygous FH on discontinuation d/t adverse maximal statin dose events. Higher incidence of gout (1.2% vs. 0.3%) ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; CLEAR = the cholesterol lowering via bempedoic acid and ACL-inhibiting regimen; CV = cardiovascular; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; MI = myocardial infarction; LDL-C = low-density lipoprotein cholesterol; ORION = inclisiran for subjects with ASCVD or ASCVD-risk equivalents and elevated LDL-C. *Outcomes for primary endpoint 1. †Outcomes for primary endpoint 2. https://e-cmsj.org https://doi.org/10.51789/cmsj.2021.1.e5 68 New Lipid-Lowering Therapies

2,230 patients with underlying CVDs or heterozygous FH who were treated with maximal statin therapy (Table 1).12 In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo. At week 12, bempedoic acid reduced the mean LDL-C level by 19.2 mg/dL, representing a change of −16.5% from baseline. Although bempedoic acid was proven with its safety throughout a previous study, the uric acid levels and the incidence of gout were significantly higher.12 Further investigation is warranted to delineate the underlying mechanism of such findings.

EMERGING HYPERTRIGLYCERIDEMIA (TG, TRL-C, AND NON-HDL-C)-LOWERING THERAPIES Potent selective peroxisome proliferator-activated receptor α (PPARα) agonist High TG levels contribute to CVDs even when LDL-C is well controlled.13 Worldwide efforts to abrogate CV events in such patients, namely, those with residual CV risk, have been made by modulating non-LDL-C such as TG, TRL-C, or Lp(a).3,4,14 TG- or TRL-lowering strategies have been thoroughly tested for CVD reduction. Although fenofibrates have failed to significantly benefit those with T2DM, patients with T2DM and high TG showed improved CV outcomes in the posthoc analysis. When fairly reviewed, it is essential to acknowledge that none of these trials, selected based on hypertriglyceridemia, consistently showed benefit.3,4 This trend was also retained in subgroups with hypertriglyceridemia or mixed dyslipidemia (high TG and low HDL-C) in each of these trials.3,4 A meta-analysis demonstrated that TG levels significantly decreased in the pemafibrate group than in the placebo group, with a reduction effect similar to that exhibited by fenofibrate. Compared with the placebo group, the pemafibrate group also showed improvements in HDL-C and non-HDL-C levels as well as in homeostasis model assessment for insulin resistance. Total adverse events were significantly lower in the pemafibrate group than in the fenofibrate group. In contrast, the LDL-C level was significantly higher in the pemafibrate group than in the placebo and fenofibrate groups. However, actual clinical data as well as long-term efficacy and safety need to be investigated in the future.15 The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes (PROMINENT) study will test pemafibrate, a potent selective PPARα modulator, as one means to resolve this issue (NCT03071692) (Table 2).16

Omega-3 fatty acids Recently, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) showed that high doses (4 g per day) of eicosapentaenoic acid (EPA), icosapent ethyl, was associated with CV benefit Table( 2). A total of 8179 participants with high CV risk were recruited, among which 71% and 29% comprised a secondary and primary prevention cohort, respectively, and 58% had T2DM (Table 2).17 Baseline LDL-C levels were well-controlled with statins (median value, 75.0 mg/dL), while TG levels were moderately elevated (median value, 216.0 mg/dL). The primary endpoint was reduced by 25% in the EPA group. Interestingly, target TG attainment of 150 mg/dL did not affect the efficacy of EPA. The recently announced analysis of the REDUCE-IT data suggests that the increased EPA levels have mediated the benefit after administering omega-3 fatty acidshttps://www.acc. ( org/latest-in-cardiology/articles/2020/03/24/16/41/mon-1045-eicosapentaenoic-acid-levels-in- reduce-it-acc-2020).

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Table 2. A summary of clinical trials targeted on lowering TG or TRL Trial name Type of drug Dose Sample size Inclusion Follow up Primary endpoint Outcome HR (95% CI) (phase) duration (yr) PROMINENT Pemafibrate 0.2 mg twice daily n=10,000 Mild to moderately high 3.75 Composite In progress (NCT03071692) TG and low HDL endpoint REDUCE-IT17 Icosapent ethyl 4 g daily n=8,179 Diabetes or established 4.9 Composite 0.75 (0.68–0.83) (phase 3) CVD, on statin with high endpoint TG STRENGTH Trial18 Omega-3 carboxyl 4 g daily n=13,086 High TG and low HDL 3.0 Composite 0.99 (0.90–1.09) acid (EPA and DHA) endpoint EVAPORATE Icosapent ethyl 4 g daily n=80 Coronary atherosclerosis 1.5 Change in low- −17% vs. +109% study20 on statin therapy with attenuation (p=0.006) high TG plaque volume Raal et al.23 ANGPTL3 mAb SAD: Evinacumab SC n=83 for SAD TG >150 but ≤450 mg/dL 0.5 Incidence Evinacumab was (phase 1) at 75/150/250 mg, or study; n=56 for and LDL ≥100 mg/dL and severity well-tolerated. IV at 5/10/20 mg/kg; MAD study of treatment- Lipid changes in MAD: SC 150/300/450 emergent adverse TG were similar to mg once weekly, events those observed with 300/450 mg every 2 ANGPTL3 loss-of- weeks, or IV at 20 mg/ function mutations kg once a month Gaudet et al.24 ANGPTL3 ASO Vupanorsen (AKCEA- n=105 T2DM patients with 0.5 Mean percentage 40 mg Q4W group: (phase 2) ANGPTL3-LRx) hepatic steatosis, and change in fasting 36% fasting TG levels >150 TG from baseline 80 mg Q4W group: mg/dL to 6 months 53% 20 mg QW group: 47% Witztum et al.25 APOC3 ASO Volanesorsen (ISIS n=66 Familial chylomicronemia 0.72 Percentage 77% mean TG (phase 3) 304801) 300 mg syndrome (52 wk) change in fasting decrease weekly or placebo TG at 3 months Alexander et al.26 APOC3 ASO GalNAc conjugated n=114 Established CVD or were 0.5 Mean percentage 10 mg Q4W group: (phase 2) Volanesorsen, 10 mg at high risk for CVD with change in fasting 23% Q4W, 15 mg Q2W, 10 fasting TG levels between TG levels from 15 mg Q2W: 56% mg QW, 50 mg Q4W ≥200 and ≤500 mg/dL baseline to 6 10 mg QW: 60% months 50 mg Q4W: 60% ANGPTL3 = angiopoietin-like 3; ANGPTL4 = angiopoietin-like 4; APOC3 = apolipoprotein C-III; ASO = antisense oligonucleotide; CI = confidence interval; CVD = cardiovascular disease; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; GalNAc = triantennary N-acetylgalactosamine; HDL = high-density lipoprotein; HR = hazard ratio; LDL = low-density lipoprotein; mAb = monoclonal antibody; MAD = multiple ascending dose; N/A = not available; REDUCE-IT = Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial; SAD = single ascending dose; SC = subcutaneous; T2DM = type 2 diabetes mellitus; TG = triglyceride; TRL = TG-rich lipoproteins; VLDL = very low-density lipoprotein.

These trials' results bring into question why the EPA only regimens had positive results while EPA + docosahexaenoic acid (DHA) regimens did not. A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh Cardiovascular Risk PatienTs With Hypertriglyceridemia (STRENGTH) trial was planned as a randomized, double-blind, placebo-controlled study to test 4 g omega-3 carboxylic acid (EPANOVA, 75% concentration of EPA and DHA) daily therapy as an add-on to a statin in high-risk patients with high TG and low HDL-C levels. This trial was expected to provide insight into two critical questions- low vs. high dosage and EPA vs. EPA+DHA combination. Unfortunately, however, the trial was terminated in January 2020.18 When 1,384 patients had experienced a primary end point event (of a planned 1,600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of 4 g omega-3 carboxylic acid vs the corn oil comparator. The results may suggest that CV benefits may be mediated by EPA but not DHA. Experimental studies have shown that the EPA does not raise LDL-C, reduces inflammation, enhances endothelial function, inhibits oxidation of apoB particles, and affects membrane stability and cholesterol organization, including crystal formation, unlike DHA.19 The effects of EPA on plaque progression over 9 to 18 months compared to placebo using serial computerized tomographic angiography in statin-treated patients with elevated TG were evaluated in the Effect of Vascepa on Improving Coronary Atherosclerosis in People With https://e-cmsj.org https://doi.org/10.51789/cmsj.2021.1.e5 70 New Lipid-Lowering Therapies

High Triglycerides Taking Statin Therapy (EVAPORATE) trial. Treatment of EPA 4 g once daily significantly reduced plaque quantity of multiple plaque components, including low attenuation plaque, compared with placebo.20 However, the results of such clinical studies can be quite confusing due to several reasons. Various doses (lower or high doses of omega-3 fatty acids) or substances (EPA alone or EPA plus DHA combination) were administered. Target populations were heterogeneous among each study; the presence of underlying statin therapy differed, let alone diverse statin doses. Very recently, placebos such as corn or mineral oil were also introduced. Therefore, these data should be interpreted with caution due to the several debatable issues above. Finally, regarding safety and adverse events, a larger percentage of patients in the EPA group in REDUCE-IT and EPA+DHA in STRENTH study than in the placebo group were hospitalized for atrial fibrillation or flutter, while serious bleeding events occurred in 2.7% of the patients in EPA group and in 2.1% in the placebo group. The significance of these observations is uncertain; however, the increased risk of bleeding, which is likely an effect of platelet aggregation, may be a critical mechanism by which EPA reduces CVD risk.

EMERGING NEW THERAPIES FOR TG-LOWERING

Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) are promising targets for CVD reduction. ANGPTLs inhibit lipoprotein lipase (LPL), which mediates lipolysis of TGs in TRLs (Figure 2).19,21 Dysfunctional ANGPTLs may translate to a higher level of TG, thereby leading to a higher risk of CVD. Accordingly, heterozygous carriers of ANGPTL4 loss-of-function mutations show a

Figure 2. Lipoprotein lipase is a central hub in metabolism of TRLs formation. The ANGPTL3 or ANGPTL4 is a promising target because ANGPTLs inhibit LPL, which mediates lipolysis of TGs in TRLs. Another key regulating protein for TRL metabolism is APOC3. APOC3 regulates TG levels through inhibiting LPL activity and hepatic TRL uptake in the liver. ANGPTL = angiopoietin-like; APOC3 = apolipoprotein C-III; FFA = free fatty acid; GPIHBP1 = glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1; LPL = lipoprotein lipase; TG = triglyceride; TRL = triglyceride rich lipoprotein. Reprinted with permission from Jang et al.19 https://e-cmsj.org https://doi.org/10.51789/cmsj.2021.1.e5 71 New Lipid-Lowering Therapies

19% reduction in CAD incidence.22 Pharmacological inhibition of these ANGPTLs, including ANGPTL3 mAb, called evinacumab,23 or ANGPTL3 antisense oligonucleotides (ASOs), called vupanorsen24 showed a similar reduction of TG, LDL-C, and very-low-density lipoprotein compared with genetic variants without safety issues. In patients with homozygous FH receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the TG and LDL-C level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 50% and 49% at 24 weeks, respectively Table( 2).23 The incidence of serious adverse events during the evinacumab treatment ranged from 3 to 16% across trial groups. The limitations of this trial include the small sample size and the short treatment duration. Thus, robust conclusions pertaining to the long-term safety of evinacumab cannot be established. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild.

Apolipoprotein C-III (APOC3) is another key regulating protein for TRL metabolism. APOC3 regulates TG levels through inhibiting LPL activity and hepatic TRL uptake (Figure 2). ASO therapy targeting APOC3 showed promising results (Table 2). Volanesorsen, an APOC3 ASO, was administered in 66 subjects with familial chylomicronemia syndrome.25 APOC3 levels decreased by 84%, with a concurrent 77% decrease in TG levels through a 52-week period. Thrombocytopenia and injection-site reactions were common adverse events. As APOC3 is mainly synthesized in the liver, GalNAc enabled the drug to be delivered with lower doses. GalNAc-conjugated volanesorsen was administered to established/high risk CV patients with high TG levels. The GalNAc-conjugated volanesorsen was administered with a lower dose and longer intervals, although it showed effective and prolonged TG-lowering effect.26 Whether reducing TG by inhibiting ANGPTL3, ANGPTL4, or APOC3 translates to better outcomes is to be investigated.

EMERGING ASO THERAPIES FOR LP(A)-LOWERING

Lp(a) consists of apoB covalently bound to apo(a). The Lp(a), thus, simultaneously inherits atherogenic properties of apoB within LDL-C and thrombotic and pro-inflammatory characteristics of apo(a).14 Recently, two clinical trials that evaluated ASO technology for directly inhibiting the apo(a) synthesis reported promising results (Table 3). The first trial examined the

safety and efficacy of the ASO IONIS-APO(a)Rx (previously ISIS-APO[a]Rx) in subjects with high Lp(a) levels. Subjects with 125–437 nmol/L and ≥438 nmol/L showed 62.8% and 67.7% drop in Lp(a) concentrations compared with the placebo group, respectively (Table 3).27

Table 3. A summary of clinical trials targeted on lowering Lp(a) Type of Intervention Type of trial Sample Baseline Lp(a) concentration Lp(a) % reduction Outcome Randomized to IONIS- Randomized, double- n=64 (Cohort A: Lp(a) of Cohort A (>80th Cohort A: 62.8% vs. N/A APO(a)Rx [ASO targeting blind, placebo-controlled, 125-437 nmol/L, Cohort B: percentile): 261.4 placebo; Cohort B: 67.7% apo(a)] or placebo27 dose-titration, phase 2 Lp(a) >438 nmol/L) nmol/L; Cohort B (>99th vs. placebo trial percentile): 457.6 nmol/L Randomized to AKCEA- Randomized, double- n=286 (patients with 224.3 nmol/L (median of 20-mg monthly dose: 35; N/A APO(a)-LRx (ASO targeting blind, placebo-controlled, established CVD with pool population) 20-mg weekly dose: 80; apo[a] bound to GalNac) or dose-ranging phase 2 trial Lp(a) >60 mg/dL [150 Control: 6 placebo28 nmol/L]) APO = angiopoietin; ASO = antisense oligonucleotide; CVD = cardiovascular disease; Lp(a) = lipoprotein(a); N/A = not available.

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Despite the Lp(a) lowering of IONIS-APO(a)Rx, frequent injections and high cumulative doses were necessary for delivering the drug into the hepatocytes, where apo(a) production mainly

occurs. The GalNAc-conjugated IONIS-APO(a)Rx, named AKCEA-APO(a)Rx-LRx, enhanced the potency by 30-fold with a mean of 92.49% reduction in Lp(a) concentrations. A subsequent randomized, double-blind, placebo-controlled, dose-ranging trial was published recently investigating the reduction of Lp(a) levels in different doses and intervals of AKCEA-APO(a) 28 Rx-Lrx (Table 3). The highest cumulative dose (20 mg weekly) reduced Lp(a) by a mean

of 80%. AKCEA-APO(a)Rx-Lrx effectively lowered Lp(a) up to 99% within a tolerable dose (Table 3). There were no significant differences between any APO(a)-LRx dose and placebo concerning platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. The phase 3 outcome trials with these agents are currently underway (ClinicalTrials.gov NCT04023552).

PERSPECTIVE AND CONCLUSION

New therapeutic agents in lowering not only LDL-C but TG, TRL, or Lp(a) have shown promising results. Novel siRNA and ASO technology have opened new doors to reduce the expression of target genes effectively. The introduction of GalNAc into ASOs has pushed boundaries even further to reduce cumulative drug doses by precisely delivering the drugs to hepatic cells, where most lipid metabolism occurs. Drugs that substantially decrease LDL-C, TG/TRLs, or Lp(a) profiles using such technology, such as inclisiran (PCSK9 siRNA), GalNAc conjugated ASO therapies for ANGPTL3 or 4, APOC3, or Lp(a) may potentially revolutionize the paradigm of lipid lowering therapy. Concerning omega-3 fatty acids, high doses of the EPA seem to be effective and promising; however several aspects such as the placebo issue should be solved before becoming more convincing.

REFERENCES

1. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-1681. PUBMED | CROSSREF 2. Ference BA, Kastelein JJ, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-373. PUBMED | CROSSREF 3. Han SH, Nicholls SJ, Sakuma I, Zhao D, Koh KK. Hypertriglyceridemia and cardiovascular diseases: revisited. Korean Circ J 2016;46:135-144. PUBMED | CROSSREF 4. Cho KI, Yu J, Hayashi T, Han SH, Koh KK. Strategies to overcome residual risk during statins era. Circ J 2019;83:1973-1979. PUBMED | CROSSREF 5. Vallejo-Vaz AJ, Fayyad R, Boekholdt SM, Hovingh GK, Kastelein JJ, Melamed S, et al. Triglyceride-rich lipoprotein cholesterol and risk of cardiovascular events among patients receiving statin therapy in the TNT trial. Circulation 2018;138:770-781. PUBMED | CROSSREF 6. Duran EK, Aday AW, Cook NR, Buring JE, Ridker PM, Pradhan AD. Triglyceride-rich lipoprotein cholesterol, small dense LDL cholesterol, and incident cardiovascular disease. J Am Coll Cardiol 2020;75:2122-2135. PUBMED | CROSSREF

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7. Huh JH, Kang DR, Jang JY, Shin JH, Kim JY, Choi S, et al. Metabolic syndrome epidemic among Korean adults: Korean survey of Cardiometabolic Syndrome (2018). Atherosclerosis 2018;277:47-52. PUBMED | CROSSREF 8. Koh KK. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:e38. PUBMED | CROSSREF 9. Nair JK, Willoughby JL, Chan A, Charisse K, Alam MR, Wang Q, et al. Multivalent N-acetylgalactosamine- conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 2014;136:16958-16961. PUBMED | CROSSREF 10. Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med 2020;382:1520-1530. PUBMED | CROSSREF 11. Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507-1519. PUBMED | CROSSREF 12. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-1032. PUBMED | CROSSREF 13. Lawler PR, Kotrri G, Koh M, Goodman SG, Farkouh ME, Lee DS, et al. Real-world risk of cardiovascular outcomes associated with hypertriglyceridaemia among individuals with atherosclerotic cardiovascular disease and potential eligibility for emerging therapies. Eur Heart J 2020;41:86-94. PUBMED | CROSSREF 14. Jang AY, Han SH, Sohn IS, Oh PC, Koh KK. Lipoprotein(a) and cardiovascular diseases - revisited. Circ J 2020;84:867-874. PUBMED | CROSSREF 15. Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol 2019;18:38. PUBMED | CROSSREF 16. Pradhan AD. A new beginning for triglyceride-lowering therapies. Circulation 2019;140:167-169. PUBMED | CROSSREF 17. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22. PUBMED | CROSSREF 18. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020;324:2268-2280. PUBMED | CROSSREF 19. Jang AY, Lim S, Jo SH, Han SH, Koh KK. New trends in dyslipidemia treatment. Circ J. Forthcoming 2020. PUBMED | CROSSREF 20. Budoff MJ, Bhatt DL, Kinninger A, Lakshmanan S, Muhlestein JB, Le VT, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J 2020;41:3925-3932. PUBMED | CROSSREF 21. Graham MJ, Lee RG, Brandt TA, Tai LJ, Fu W, Peralta R, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017;377:222-232. PUBMED | CROSSREF 22. Dewey FE, Gusarova V, O'Dushlaine C, Gottesman O, Trejos J, Hunt C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med 2016;374:1123-1133. PUBMED | CROSSREF 23. Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJ, Rubba P, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020;383:711-720. PUBMED | CROSSREF 24. Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, Hurh E, Kingsbury J, Bartlett VJ, et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J 2020;41:3936-3945. PUBMED | CROSSREF 25. Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019;381:531-542. PUBMED | CROSSREF https://e-cmsj.org https://doi.org/10.51789/cmsj.2021.1.e5 74 New Lipid-Lowering Therapies

26. Alexander VJ, Xia S, Hurh E, Hughes SG, O'Dea L, Geary RS, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J 2019;40:2785-2796. PUBMED | CROSSREF 27. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo- controlled, dose-ranging trials. Lancet 2016;388:2239-2253. PUBMED | CROSSREF 28. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244-255. PUBMED | CROSSREF

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