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AmandaBai98
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pelacarsen_pubmed-dataset

text stringlengths 138 2.25k	label stringlengths 138 2.25k
The purpose of this study was to assess the effect of pelacarsen on directly measured Lp(a)-C and LDL-C corrected for its Lp(a)-C content.	The purpose of this study was to assess the effect of pelacarsen on directly measured Lp(a)-C and LDL-C corrected for its Lp(a)-C content.
The authors evaluated subjects with a history of cardiovascular disease and elevated Lp(a) randomized to 5 groups of cumulative monthly doses of 20-80 mg pelacarsen vs placebo. Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apolipoprotein(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-C	The authors evaluated subjects with a history of cardiovascular disease and elevated Lp(a) randomized to 5 groups of cumulative monthly doses of 20-80 mg pelacarsen vs placebo. Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apolipoprotein(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-C
The baseline median Lp(a)-C values in the groups ranged from 11.9 to 15.6 mg/dL. Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs -29% to -67%; P = 0.001-<0.0001). Baseline laboratory-reported mean LDL-C ranged from 68.5 to 89.5 mg/dL, whereas LDL-C	The baseline median Lp(a)-C values in the groups ranged from 11.9 to 15.6 mg/dL. Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs -29% to -67%; P = 0.001-<0.0001). Baseline laboratory-reported mean LDL-C ranged from 68.5 to 89.5 mg/dL, whereas LDL-C
ranged from 55 to 74 mg/dL. Pelacarsen resulted in mean percent/absolute changes of -2% to -19%/-0.7 to -8.0 mg/dL (P = 0.95-0.05) in LDL-C	ranged from 55 to 74 mg/dL. Pelacarsen resulted in mean percent/absolute changes of -2% to -19%/-0.7 to -8.0 mg/dL (P = 0.95-0.05) in LDL-C
Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing therapies. The ineffectiveness of lifestyle modification, statins, and ezetimibe to lower Lp(a); the modest Lp(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors; the adverse effect profile and unclear cardiovascular benefit of pharmacotherapies such as niacin and mipomersen; and the impracticality of regular lipoprotein apheresis represent major challenges to currently available therapies. Nevertheless, emerging nucleic acid-based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects. Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials.	Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing therapies. The ineffectiveness of lifestyle modification, statins, and ezetimibe to lower Lp(a); the modest Lp(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors; the adverse effect profile and unclear cardiovascular benefit of pharmacotherapies such as niacin and mipomersen; and the impracticality of regular lipoprotein apheresis represent major challenges to currently available therapies. Nevertheless, emerging nucleic acid-based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects. Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials.
As Lp(a) levels are determined genetically, lifestyle interventions have no effect on Lp(a)-mediated ASCVD risk. While traditional low-density lipoprotein cholesterol (LDL-C) can now be effectively lowered in the vast majority of patients, current lipid lowering therapies have no clinically relevant Lp(a) lowering effect. There are multiple Lp(a)-directed therapies in clinical development targeting LPA mRNA that have shown to lower Lp(a) plasma levels for up to 90%: pelacarsen, olpasiran, and SLN360. Pelacarsen is currently investigated in a phase 3 cardiovascular outcome trial expected to finish in 2024, while olpasiran is about to proceed to phase 3 and SLN360's phase 1 outcomes were recently published. If proven efficacious, Lp(a) will soon become the next pathway to target in ASCVD risk management.	As Lp(a) levels are determined genetically, lifestyle interventions have no effect on Lp(a)-mediated ASCVD risk. While traditional low-density lipoprotein cholesterol (LDL-C) can now be effectively lowered in the vast majority of patients, current lipid lowering therapies have no clinically relevant Lp(a) lowering effect. There are multiple Lp(a)-directed therapies in clinical development targeting LPA mRNA that have shown to lower Lp(a) plasma levels for up to 90%: pelacarsen, olpasiran, and SLN360. Pelacarsen is currently investigated in a phase 3 cardiovascular outcome trial expected to finish in 2024, while olpasiran is about to proceed to phase 3 and SLN360's phase 1 outcomes were recently published. If proven efficacious, Lp(a) will soon become the next pathway to target in ASCVD risk management.
Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD.	Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD.
Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) and statins may not be protective in advanced CKD. The reasons for the limited efficacy of statins in advanced CKD are unclear, but statins may increase plasma levels of the highly atherogenic molecule lipoprotein(a), also termed Lp(a), as well as PCSK9 (protein convertase subtilisin/kexin type 9) levels. Lp(a) has also been linked to calcific aortic stenosis, which is common in CKD. Moreover, circulating Lp(a) levels increase in nephrotic syndrome with declining renal function and are highest in patients on peritoneal dialysis. Thus, the recent publication of the Phase 2 randomized controlled trial of pelacarsen [also termed AKCEA-APO(a)-LRx and TQJ230], a hepatocyte-directed antisense oligonucleotide targeting the	Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) and statins may not be protective in advanced CKD. The reasons for the limited efficacy of statins in advanced CKD are unclear, but statins may increase plasma levels of the highly atherogenic molecule lipoprotein(a), also termed Lp(a), as well as PCSK9 (protein convertase subtilisin/kexin type 9) levels. Lp(a) has also been linked to calcific aortic stenosis, which is common in CKD. Moreover, circulating Lp(a) levels increase in nephrotic syndrome with declining renal function and are highest in patients on peritoneal dialysis. Thus, the recent publication of the Phase 2 randomized controlled trial of pelacarsen [also termed AKCEA-APO(a)-LRx and TQJ230], a hepatocyte-directed antisense oligonucleotide targeting the
gene messenger RNA, in persons with CVD should be good news for nephrologists. Pelacarsen safely and dose-dependently decreased Lp(a) levels by 35-80% and a Phase 3 trial [Lp(a)HORIZON,	gene messenger RNA, in persons with CVD should be good news for nephrologists. Pelacarsen safely and dose-dependently decreased Lp(a) levels by 35-80% and a Phase 3 trial [Lp(a)HORIZON,
Mechanisms of action of pelacarsen, also known as AKCEA-APO(a)-LRx and TQJ230, among other names. Pelacarsen is a hepatocyte-directed antisense oligonucleotide targeting the mRNA transcribed from the	Mechanisms of action of pelacarsen, also known as AKCEA-APO(a)-LRx and TQJ230, among other names. Pelacarsen is a hepatocyte-directed antisense oligonucleotide targeting the mRNA transcribed from the
Patients with genetically associated elevated lipoprotein(a) [Lp(a)] levels are at greater risk for coronary artery disease, heart attack, stroke, and peripheral arterial disease. To date, there are no US FDA-approved drug therapies that are designed to target Lp(a) with the goal of lowering the Lp(a) level in patients who have increased risk. The American College of Cardiology (ACC) has provided guidelines on how to use traditional lipid profiles to assess the risk of atherosclerotic cardiovascular disease (ASCVD); however, even with the emergence of statin add-on therapies such as ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, some populations with elevated Lp(a) biomarkers remain at an increased risk for cardiovascular (CV) disease. Residual CV risk has led researchers to inquire about how lowering Lp(a) can be used as a potential preventative therapy in reducing CV events. This review aims to present and discuss the current clinical and scientific evidence pertaining to pelacarsen.	Patients with genetically associated elevated lipoprotein(a) [Lp(a)] levels are at greater risk for coronary artery disease, heart attack, stroke, and peripheral arterial disease. To date, there are no US FDA-approved drug therapies that are designed to target Lp(a) with the goal of lowering the Lp(a) level in patients who have increased risk. The American College of Cardiology (ACC) has provided guidelines on how to use traditional lipid profiles to assess the risk of atherosclerotic cardiovascular disease (ASCVD); however, even with the emergence of statin add-on therapies such as ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, some populations with elevated Lp(a) biomarkers remain at an increased risk for cardiovascular (CV) disease. Residual CV risk has led researchers to inquire about how lowering Lp(a) can be used as a potential preventative therapy in reducing CV events. This review aims to present and discuss the current clinical and scientific evidence pertaining to pelacarsen.
Single-stranded antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are two classes of RNA-targeted therapeutics that specifically target the LPA gene, which encodes for apolipoprotein(a), a dominant and rate-limiting component in the hepatic synthesis of Lp(a) particle. Pelacarsen (ASO), olpasiran (siRNA) and SLN360 (siRNA) are novel drugs that have demonstrated efficacy in lowering Lp(a) levels and excellent safety profiles.	Single-stranded antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) are two classes of RNA-targeted therapeutics that specifically target the LPA gene, which encodes for apolipoprotein(a), a dominant and rate-limiting component in the hepatic synthesis of Lp(a) particle. Pelacarsen (ASO), olpasiran (siRNA) and SLN360 (siRNA) are novel drugs that have demonstrated efficacy in lowering Lp(a) levels and excellent safety profiles.
Lp(a) is an independent risk factor for cardiovascular disease. RNA-directed therapies, pelacarsen, olpasiran and SLN360, have shown efficacy in dramatically lowering serum Lp(a) levels. Outcomes data will be the next frontier of Lp(a) trials.	Lp(a) is an independent risk factor for cardiovascular disease. RNA-directed therapies, pelacarsen, olpasiran and SLN360, have shown efficacy in dramatically lowering serum Lp(a) levels. Outcomes data will be the next frontier of Lp(a) trials.
Pelacarsen is a liver-targeted antisense oligonucleotide that potently lowers lipoprotein(a) [Lp(a)] levels. Its safety and efficacy in diverse populations has not been extensively studied.	Pelacarsen is a liver-targeted antisense oligonucleotide that potently lowers lipoprotein(a) [Lp(a)] levels. Its safety and efficacy in diverse populations has not been extensively studied.
A randomized double-blind, placebo-controlled, study was performed in 29 healthy Japanese subjects treated with single ascending doses (SAD) of pelacarsen 20, 40 and 80 mg subcutaneously or multiple doses (MD) of pelacarsen 80 mg monthly for 4 doses. The primary objective was to assess the safety and tolerability in healthy Japanese subjects; secondary objectives to assess the pharmacokinetics of pelacarsen; and exploratory objective to determine the effect of pelacarsen on plasma Lp(a) levels.	A randomized double-blind, placebo-controlled, study was performed in 29 healthy Japanese subjects treated with single ascending doses (SAD) of pelacarsen 20, 40 and 80 mg subcutaneously or multiple doses (MD) of pelacarsen 80 mg monthly for 4 doses. The primary objective was to assess the safety and tolerability in healthy Japanese subjects; secondary objectives to assess the pharmacokinetics of pelacarsen; and exploratory objective to determine the effect of pelacarsen on plasma Lp(a) levels.
No serious adverse events or clinically relevant abnormalities in any laboratory parameters were noted. In the MD cohort, mean plasma concentrations of pelacarsen peaked at ∼4 hours and declined in a bi-exponential manner thereafter. In the SAD cohorts, the placebo-corrected least-square mean (PCLSM) percent changes in Lp(a) at Day 30 were: -55.4% (p=0.0008), -58.9% (p=0.0003) and -73.7% (p<0.0001) for the 20 mg, 40 mg, and 80 mg pelacarsen-treated groups, respectively. In the MD cohort, the PCLSM at Days 29, 85, 113, 176 and 204 were -84.0% (p=0.0003), -106.2% (p<0.0001), -70.0 (p<0.0001), -80.0% (p=0.0104) and -55.8% (p=0.0707), respectively.	No serious adverse events or clinically relevant abnormalities in any laboratory parameters were noted. In the MD cohort, mean plasma concentrations of pelacarsen peaked at ∼4 hours and declined in a bi-exponential manner thereafter. In the SAD cohorts, the placebo-corrected least-square mean (PCLSM) percent changes in Lp(a) at Day 30 were: -55.4% (p=0.0008), -58.9% (p=0.0003) and -73.7% (p<0.0001) for the 20 mg, 40 mg, and 80 mg pelacarsen-treated groups, respectively. In the MD cohort, the PCLSM at Days 29, 85, 113, 176 and 204 were -84.0% (p=0.0003), -106.2% (p<0.0001), -70.0 (p<0.0001), -80.0% (p=0.0104) and -55.8% (p=0.0707), respectively.
Pelacarsen demonstrates an acceptable safety and tolerability profile and potently lowers plasma levels of Lp(a) in healthy Japanese subjects, including with the 80 mg monthly dose being evaluated in the Lp(a) HORIZON trial.	Pelacarsen demonstrates an acceptable safety and tolerability profile and potently lowers plasma levels of Lp(a) in healthy Japanese subjects, including with the 80 mg monthly dose being evaluated in the Lp(a) HORIZON trial.
Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%.	Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%.
Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic stroke risk in statin-treated patients with atherosclerosis without increasing hemorrhagic stroke, even with very low achieved low-density lipoprotein cholesterol levels. Icosapent ethyl reduces the risk of total and first ischemic stroke in patients with established cardiovascular disease or diabetes mellitus. Clinical outcome trials are underway for newer lipid-modifying agents, including inclisiran, bempedoic acid, and pemafibrate. New biologic agents including evinacumab, pelacarsen, olpasiran, and SLN360 are also discussed. In addition to statins and ezetimibe, PCSK9 inhibitors and icosapent ethyl reduce the risk of ischemic stroke without increasing the risk of hemorrhagic stroke. These therapies dramatically expand options for reducing stroke in high-risk settings.	Statins and ezetimibe reduce ischemic stroke risk without increasing hemorrhagic stroke risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors similarly reduce ischemic stroke risk in statin-treated patients with atherosclerosis without increasing hemorrhagic stroke, even with very low achieved low-density lipoprotein cholesterol levels. Icosapent ethyl reduces the risk of total and first ischemic stroke in patients with established cardiovascular disease or diabetes mellitus. Clinical outcome trials are underway for newer lipid-modifying agents, including inclisiran, bempedoic acid, and pemafibrate. New biologic agents including evinacumab, pelacarsen, olpasiran, and SLN360 are also discussed. In addition to statins and ezetimibe, PCSK9 inhibitors and icosapent ethyl reduce the risk of ischemic stroke without increasing the risk of hemorrhagic stroke. These therapies dramatically expand options for reducing stroke in high-risk settings.
We analyzed data from 4 clinical trials of the ASO pelacarsen targeting apolipoprotein(a) that included 455 patients. Common LPA genetic variants rs10455872 and rs3798220, major and minor isoform size, and changes in Lp(a), LDL-C, apoB, OxPL-apoB and OxPL-apo(a) were analyzed according to categories of baseline Lp(a).	We analyzed data from 4 clinical trials of the ASO pelacarsen targeting apolipoprotein(a) that included 455 patients. Common LPA genetic variants rs10455872 and rs3798220, major and minor isoform size, and changes in Lp(a), LDL-C, apoB, OxPL-apoB and OxPL-apo(a) were analyzed according to categories of baseline Lp(a).
The prevalence of carrier status for rs10455872 and rs3798220 combined ranged from 25.9% in patients with Lp(a) in the 75 - <125 nmol/L range to 77.1% at Lp(a) ≥375 nmol/L. The prevalence of homozygosity for rs3798220, rs10455872 and for double heterozygosity in category of Lp(a) ≥375 nmol/L was 6.3%, 14.6% and 12.5%, respectively. Isoform size decreased with increasing Lp(a) plasma levels, with 99.3% of patients with Lp(a) ≥175 nmol/L having ≤20 KIV repeats in the major isoform. The mean percent reduction from baseline in Lp(a), OxPL-apoB and OxPL-apo(a) in response to pelacarsen was not affected by the presence of rs10455872 and rs3798220, isoform size or baseline Lp(a) at all doses studied.	The prevalence of carrier status for rs10455872 and rs3798220 combined ranged from 25.9% in patients with Lp(a) in the 75 - <125 nmol/L range to 77.1% at Lp(a) ≥375 nmol/L. The prevalence of homozygosity for rs3798220, rs10455872 and for double heterozygosity in category of Lp(a) ≥375 nmol/L was 6.3%, 14.6% and 12.5%, respectively. Isoform size decreased with increasing Lp(a) plasma levels, with 99.3% of patients with Lp(a) ≥175 nmol/L having ≤20 KIV repeats in the major isoform. The mean percent reduction from baseline in Lp(a), OxPL-apoB and OxPL-apo(a) in response to pelacarsen was not affected by the presence of rs10455872 and rs3798220, isoform size or baseline Lp(a) at all doses studied.
In patients randomized to Lp(a) lowering trials, LPA genetic variants are common, but a sizable proportion do not carry common variants associated with elevated Lp(a). In contrast, the major isoform size was almost uniformly ≤20 KIV repeats in patients with Lp(a) ≥175 nmol/L. The Lp(a) and OxPL lowering effects of pelacarsen were independent of both LPA genetic variants and isoform size.	In patients randomized to Lp(a) lowering trials, LPA genetic variants are common, but a sizable proportion do not carry common variants associated with elevated Lp(a). In contrast, the major isoform size was almost uniformly ≤20 KIV repeats in patients with Lp(a) ≥175 nmol/L. The Lp(a) and OxPL lowering effects of pelacarsen were independent of both LPA genetic variants and isoform size.
Pelacarsen decreases plasma levels of lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPL). It was previously reported that pelacarsen does not affect the platelet count. We now report the effect of pelacarsen on on-treatment platelet reactivity.	Pelacarsen decreases plasma levels of lipoprotein(a) [Lp(a)] and oxidized phospholipids (OxPL). It was previously reported that pelacarsen does not affect the platelet count. We now report the effect of pelacarsen on on-treatment platelet reactivity.
Subjects with established cardiovascular disease and screening Lp(a) levels ≥60 mg per deciliter (~ ≥150 nmol/L) were randomized to receive pelacarsen (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or placebo for 6-12 months. Aspirin Reaction Units (ARU) and P2Y12 Reaction Units (PRU) were measured at baseline and the primary analysis timepoint (PAT) at 6 months.	Subjects with established cardiovascular disease and screening Lp(a) levels ≥60 mg per deciliter (~ ≥150 nmol/L) were randomized to receive pelacarsen (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or placebo for 6-12 months. Aspirin Reaction Units (ARU) and P2Y12 Reaction Units (PRU) were measured at baseline and the primary analysis timepoint (PAT) at 6 months.
Of the 286 subjects randomized, 275 had either an ARU or PRU test, 159 (57.8%) were on aspirin alone and 94 (34.2%) subjects were on dual anti-platelet therapy. As expected, the baseline ARU and PRU were suppressed in subjects on aspirin or on dual anti-platelet therapy, respectively. There were no significant differences in baseline ARU in the aspirin groups or in PRU in the dual anti-platelet groups. At the PAT there were no statistically significant differences in ARU in subjects on aspirin or PRU in subjects on dual anti-platelet therapy among any of the pelacarsen groups compared to the pooled placebo group (p > 0.05 for all comparisons).	Of the 286 subjects randomized, 275 had either an ARU or PRU test, 159 (57.8%) were on aspirin alone and 94 (34.2%) subjects were on dual anti-platelet therapy. As expected, the baseline ARU and PRU were suppressed in subjects on aspirin or on dual anti-platelet therapy, respectively. There were no significant differences in baseline ARU in the aspirin groups or in PRU in the dual anti-platelet groups. At the PAT there were no statistically significant differences in ARU in subjects on aspirin or PRU in subjects on dual anti-platelet therapy among any of the pelacarsen groups compared to the pooled placebo group (p > 0.05 for all comparisons).
Lipoprotein(a) [Lp(a)] has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (∼50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid-targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering.	Lipoprotein(a) [Lp(a)] has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (∼50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid-targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering.
Genetic studies have paved the way for therapies that reduce translation of proteins that play causal roles in dyslipidemia and atherosclerosis like proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B-100 (apoB), apolipoprotein(a) [apo(a)], apolipoprotein C3 (apoC3), and angiopoietin-like 3 (ANGPTL3). Either antisense oligonucleotide (ASO) therapies and small interfering RNA (siRNA) molecules inhibit protein synthesis and consequently improve dyslipidemia. Most of these molecules contain N-acetylgalactosamine (GalNAc) moieties that have high specificity for hepatocytes and therefore reduce concentration in other tissues. Inclisiran, an siRNA for PCSK9, has shown robust LDL-C reductions, with good tolerability, in severe forms of hypercholesterolemia as well as in high cardiovascular disease patients with injections every 3 to 6 months. Pelacarsen is an ASO against apolipoprotein(a) that reduces Lp(a) up to 80% with good tolerability. Either inclisiran or pelacarsen is being tested to show it can prevent ASCVD. AMG 890, an siRNA compound aimed at reducing apo(a) synthesis, is also under investigation. Volanesorsen is an ASO against apoC3 that reduces triglyceride levels up to 70% and is being tested in severe hypertriglyceridemic patients. Vupanorsen is an ASO against ANGPTL3 that reduced triglyceride levels 36-53% among moderate hypertriglyceridemic individuals. Interestingly, it also reduces ApoC3 and non-HDL cholesterol and apoB; however, it lowers HDL cholesterol. RNA-targeted therapies are being extensively tested for dyslipidemia treatment with promising results.	Genetic studies have paved the way for therapies that reduce translation of proteins that play causal roles in dyslipidemia and atherosclerosis like proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein B-100 (apoB), apolipoprotein(a) [apo(a)], apolipoprotein C3 (apoC3), and angiopoietin-like 3 (ANGPTL3). Either antisense oligonucleotide (ASO) therapies and small interfering RNA (siRNA) molecules inhibit protein synthesis and consequently improve dyslipidemia. Most of these molecules contain N-acetylgalactosamine (GalNAc) moieties that have high specificity for hepatocytes and therefore reduce concentration in other tissues. Inclisiran, an siRNA for PCSK9, has shown robust LDL-C reductions, with good tolerability, in severe forms of hypercholesterolemia as well as in high cardiovascular disease patients with injections every 3 to 6 months. Pelacarsen is an ASO against apolipoprotein(a) that reduces Lp(a) up to 80% with good tolerability. Either inclisiran or pelacarsen is being tested to show it can prevent ASCVD. AMG 890, an siRNA compound aimed at reducing apo(a) synthesis, is also under investigation. Volanesorsen is an ASO against apoC3 that reduces triglyceride levels up to 70% and is being tested in severe hypertriglyceridemic patients. Vupanorsen is an ASO against ANGPTL3 that reduced triglyceride levels 36-53% among moderate hypertriglyceridemic individuals. Interestingly, it also reduces ApoC3 and non-HDL cholesterol and apoB; however, it lowers HDL cholesterol. RNA-targeted therapies are being extensively tested for dyslipidemia treatment with promising results.
Lipoprotein(a) (Lp(a)) is a low density lipoprotein particle that is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory and pro-oxidative properties. Traditional lipid-lowering therapy does not provide a sufficient Lp(a) reduction. For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. Another option is inclisiran, for which no outcome data are available yet. Lipoprotein apheresis acutely and in the long run decreases Lp(a) levels and effectively improves cardiovascular prognosis in high-risk patients who cannot be satisfactorily treated with drugs. New drugs inhibiting the synthesis of apolipoprotein(a) (an antisense oligonucleotide (Pelacarsen) and two siRNA drugs) are studied. Unlike LDL-cholesterol, for Lp(a) no target value has been defined up to now. This overview presents data of modern capabilities of cardiovascular risk reduction by lowering Lp(a) level.	Lipoprotein(a) (Lp(a)) is a low density lipoprotein particle that is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory and pro-oxidative properties. Traditional lipid-lowering therapy does not provide a sufficient Lp(a) reduction. For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. Another option is inclisiran, for which no outcome data are available yet. Lipoprotein apheresis acutely and in the long run decreases Lp(a) levels and effectively improves cardiovascular prognosis in high-risk patients who cannot be satisfactorily treated with drugs. New drugs inhibiting the synthesis of apolipoprotein(a) (an antisense oligonucleotide (Pelacarsen) and two siRNA drugs) are studied. Unlike LDL-cholesterol, for Lp(a) no target value has been defined up to now. This overview presents data of modern capabilities of cardiovascular risk reduction by lowering Lp(a) level.
Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density lipoprotein cholesterol (LDL-C) target cannot be achieved despite maximally tolerated statin. The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS. Fish oils reduce serum triglycerides by about 25 %. EPA (and not DHA) seems to have cardioprotective effects. Despite cardiovascular outcome benefits, bile-exchange resins have limited use due to poor tolerance. Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the enzyme microsomal triglyceride transfer protein (MTP) and approved for the treatment of adult patients with homozygous familial hypercholesterolemia (HoFH). Close monitoring for hepatotoxicity is required. Mipomersen is a single-stranded synthetic antisense oligonucleotide (ASO) that affects the production and secretion of apoB-containing lipoproteins with demonstrated efficacy in both homozygous and heterozygous FH patients. It is approved for restricted use due to risk of hepatotoxicity. Pelacarsen is an antisense oligonucleotide that reduces the production of apo(a) in the liver.	Non-statin drugs find utility in the management of dyslipidaemia in mixed dyslipidaemia, patients with statin intolerance, and when guidelines directed low-density lipoprotein cholesterol (LDL-C) target cannot be achieved despite maximally tolerated statin. The most definite indication of fenofibrate monotherapy is fasting serum triglyceride >500 mg/dl to reduce the risk of acute pancreatitis It offers a modest reduction in cardiovascular events. The statin-ezetimibe combination is commonly used for lipid lowering particularly after ACS. Fish oils reduce serum triglycerides by about 25 %. EPA (and not DHA) seems to have cardioprotective effects. Despite cardiovascular outcome benefits, bile-exchange resins have limited use due to poor tolerance. Bempedoic acid added to maximally tolerated statin therapy is approved to lower LDL-C in adults with primary hypercholesterolemia or mixed dyslipidaemias, HeFH, in patients with ASCVD who require additional lowering of LDL-C, and in patients who are statin-intolerant. Inclisiran is a long-acting double-stranded small interfering RNA (siRNA) that inhibits the transcription of PCSK-9 leading to a decrease in PCSK9 generation in hepatocytes and an increase in LDL receptor expression in the liver cell membrane leading to about 50 % reduction in serum LDL-C levels. Lomitapide lowers plasma levels of all ApoB-containing lipoproteins, including VLDL, LDL, and chylomicrons by inhibiting the enzyme microsomal triglyceride transfer protein (MTP) and approved for the treatment of adult patients with homozygous familial hypercholesterolemia (HoFH). Close monitoring for hepatotoxicity is required. Mipomersen is a single-stranded synthetic antisense oligonucleotide (ASO) that affects the production and secretion of apoB-containing lipoproteins with demonstrated efficacy in both homozygous and heterozygous FH patients. It is approved for restricted use due to risk of hepatotoxicity. Pelacarsen is an antisense oligonucleotide that reduces the production of apo(a) in the liver.
Dyslipidaemia is a well-known risk factor for the development of cardiovascular disease, a leading cause of morbidity and mortality in developed countries. As a consequence, the medical community has been dealing with this problem for decades, and traditional statin therapy remains the cornerstone therapeutic approach. However, clinical trials have observed remarkable results for a few agents effective in the treatment of elevated serum lipid levels. Ezetimibe showed good but limited results when used in combination with statins. Bempedoic acid has been thoroughly studied in multiple clinical trials, with a reduction in LDL cholesterol by approximately 15%. The first approved monoclonal antibodies for the treatment of dyslipidaemia, PCSK9 inhibitors, are currently used as second-line treatment for patients with unregulated lipid levels on statin or statin combination therapy. A new siRNA molecule, inclisiran, demonstrates great potential, particularly concerning compliance, as it is administered twice yearly and pelacarsen, an antisense oligonucleotide that targets lipoprotein(a) and lowers its levels. Volanesorsen is the first drug that was designed to target chylomicrons and lower triglyceride levels, and olezarsen, the next in-line chylomicron lowering agent, is currently being researched. The newest possibilities for the treatment of dyslipidaemia are ANGPTL3 inhibitors with evinacumab, already approved by the FDA, and EMA for the treatment of familial hypercholesterolemia. This article provides a short summary of new agents currently used or being developed for lipid lowering treatment.	Dyslipidaemia is a well-known risk factor for the development of cardiovascular disease, a leading cause of morbidity and mortality in developed countries. As a consequence, the medical community has been dealing with this problem for decades, and traditional statin therapy remains the cornerstone therapeutic approach. However, clinical trials have observed remarkable results for a few agents effective in the treatment of elevated serum lipid levels. Ezetimibe showed good but limited results when used in combination with statins. Bempedoic acid has been thoroughly studied in multiple clinical trials, with a reduction in LDL cholesterol by approximately 15%. The first approved monoclonal antibodies for the treatment of dyslipidaemia, PCSK9 inhibitors, are currently used as second-line treatment for patients with unregulated lipid levels on statin or statin combination therapy. A new siRNA molecule, inclisiran, demonstrates great potential, particularly concerning compliance, as it is administered twice yearly and pelacarsen, an antisense oligonucleotide that targets lipoprotein(a) and lowers its levels. Volanesorsen is the first drug that was designed to target chylomicrons and lower triglyceride levels, and olezarsen, the next in-line chylomicron lowering agent, is currently being researched. The newest possibilities for the treatment of dyslipidaemia are ANGPTL3 inhibitors with evinacumab, already approved by the FDA, and EMA for the treatment of familial hypercholesterolemia. This article provides a short summary of new agents currently used or being developed for lipid lowering treatment.
Inclisiran, the most advanced siRNA-treatment targeting hepatic PCSK9, is well tolerated, producing a >30% reduction on LDL-C levels in randomized controlled trials. Pelacarsen is the most clinical advanced ASO, whereas olpasiran and SLN360 are the 2 siRNAs directed against the mRNA of the LPA gene. Evidence suggests that all Lp(a)-targeting agents are safe and well tolerated, with robust and sustained reduction in plasma Lp(a) concentration up to 70% to 90% in individuals with elevated Lp(a) levels.	Inclisiran, the most advanced siRNA-treatment targeting hepatic PCSK9, is well tolerated, producing a >30% reduction on LDL-C levels in randomized controlled trials. Pelacarsen is the most clinical advanced ASO, whereas olpasiran and SLN360 are the 2 siRNAs directed against the mRNA of the LPA gene. Evidence suggests that all Lp(a)-targeting agents are safe and well tolerated, with robust and sustained reduction in plasma Lp(a) concentration up to 70% to 90% in individuals with elevated Lp(a) levels.
Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.	Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.
Lipid-driven cardiovascular disease (CVD) risk is caused by atherogenic apolipoprotein B (apoB) particles containing low-density lipoprotein cholesterol (LDL-C), triglycerides and lipoprotein(a) [Lp(a)] and resembles a large and modifiable proportion of the total CVD risk. While a surplus of novel lipid-lowering therapies has been developed in recent years, management of lipid-driven CVD risk in the Netherlands remains suboptimal. To lower LDL‑C levels, statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibiting antibodies are the current standard of therapy. With the approval of bempedoic acid and the silencing RNA inclisiran, therapeutic options are expanding continuously. Although the use of triglyceride-lowering therapies remains a matter of debate, post hoc analyses consistently show a benefit in subsets of patients with high triglyceride or low high-density lipoprotein cholesterol levels. Pemafibrate and novel apoC-III could be efficacious options when approved for clinical use. Lp(a)-lowering therapies such as pelacarsen are under clinical investigation, offering a potent Lp(a)-lowering effect. If proven effective in reducing cardiovascular endpoints, Lp(a) lowering holds promise to be the third axis of effective lipid-lowering therapies. Using these three components of lipid-lowering treatment, the contribution of apoB-containing lipid particles to the CVD risk may be fully eradicated in the next decade.	Lipid-driven cardiovascular disease (CVD) risk is caused by atherogenic apolipoprotein B (apoB) particles containing low-density lipoprotein cholesterol (LDL-C), triglycerides and lipoprotein(a) [Lp(a)] and resembles a large and modifiable proportion of the total CVD risk. While a surplus of novel lipid-lowering therapies has been developed in recent years, management of lipid-driven CVD risk in the Netherlands remains suboptimal. To lower LDL‑C levels, statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibiting antibodies are the current standard of therapy. With the approval of bempedoic acid and the silencing RNA inclisiran, therapeutic options are expanding continuously. Although the use of triglyceride-lowering therapies remains a matter of debate, post hoc analyses consistently show a benefit in subsets of patients with high triglyceride or low high-density lipoprotein cholesterol levels. Pemafibrate and novel apoC-III could be efficacious options when approved for clinical use. Lp(a)-lowering therapies such as pelacarsen are under clinical investigation, offering a potent Lp(a)-lowering effect. If proven effective in reducing cardiovascular endpoints, Lp(a) lowering holds promise to be the third axis of effective lipid-lowering therapies. Using these three components of lipid-lowering treatment, the contribution of apoB-containing lipid particles to the CVD risk may be fully eradicated in the next decade.
Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA, which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%.	Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA, which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%.
Lipoprotein(a) [Lp(a)] is a source of residual risk in patients with atherosclerotic cardiovascular disease (ASCVD). Clinical trials of fully human monoclonal antibodies targeting proprotein convertase subtilisin kexin 9 have shown that reductions in Lp(a) concentrations may be a predictor of event reduction with this class of cholesterol-lowering therapy. With the advent of selective therapies targeting Lp(a) such as antisense oligonucleotides, small-interfering RNA-based therapies, and gene editing, lowering of Lp(a) may lead to reduction in ASCVD. The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering with TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently testing the effect of pelacarsen, an antisense oligonucleotide, on ASCVD risk. Olpasiran is a small-interfering RNA that is in a phase 3 clinical trial. As these therapies enter clinical trials, challenges in trial design will have to be addressed to optimize patient selection and outcomes.	Lipoprotein(a) [Lp(a)] is a source of residual risk in patients with atherosclerotic cardiovascular disease (ASCVD). Clinical trials of fully human monoclonal antibodies targeting proprotein convertase subtilisin kexin 9 have shown that reductions in Lp(a) concentrations may be a predictor of event reduction with this class of cholesterol-lowering therapy. With the advent of selective therapies targeting Lp(a) such as antisense oligonucleotides, small-interfering RNA-based therapies, and gene editing, lowering of Lp(a) may lead to reduction in ASCVD. The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering with TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently testing the effect of pelacarsen, an antisense oligonucleotide, on ASCVD risk. Olpasiran is a small-interfering RNA that is in a phase 3 clinical trial. As these therapies enter clinical trials, challenges in trial design will have to be addressed to optimize patient selection and outcomes.
Atherosclerotic cardiovascular diseases (ASCVD) are a very important cause of premature death. The most important risk factor for ASCVD is lipid disorders. The incidence of lipid disorders and ASCVD is constantly increasing, which means that new methods of prevention and treatment of these diseases are still being searched for. In the management of patients with lipid disorders, the primary goal of therapy is to lower the serum LDL-C concentration. Despite the available effective lipid-lowering therapies, the risk of ASCVD is still increased in some patients. A high level of serum lipoprotein (a) (Lp(a)) is a risk factor for ASCVD independent of serum LDL-C concentration. About 20% of Europeans have elevated serum Lp(a) levels, requiring treatment to reduce serum Lp(a) concentrations in addition to LDL-C. Currently available lipid lowering drugs do not sufficiently reduce serum Lp(a) levels. Hence, drugs based on RNA technology, such as pelacarsen, olpasiran, SLN360 and LY3819469, are undergoing clinical trials. These drugs are very effective in lowering the serum Lp(a) concentration and have a satisfactory safety profile, which means that in the near future they will fill an important gap in the armamentarium of lipid-lowering drugs.	Atherosclerotic cardiovascular diseases (ASCVD) are a very important cause of premature death. The most important risk factor for ASCVD is lipid disorders. The incidence of lipid disorders and ASCVD is constantly increasing, which means that new methods of prevention and treatment of these diseases are still being searched for. In the management of patients with lipid disorders, the primary goal of therapy is to lower the serum LDL-C concentration. Despite the available effective lipid-lowering therapies, the risk of ASCVD is still increased in some patients. A high level of serum lipoprotein (a) (Lp(a)) is a risk factor for ASCVD independent of serum LDL-C concentration. About 20% of Europeans have elevated serum Lp(a) levels, requiring treatment to reduce serum Lp(a) concentrations in addition to LDL-C. Currently available lipid lowering drugs do not sufficiently reduce serum Lp(a) levels. Hence, drugs based on RNA technology, such as pelacarsen, olpasiran, SLN360 and LY3819469, are undergoing clinical trials. These drugs are very effective in lowering the serum Lp(a) concentration and have a satisfactory safety profile, which means that in the near future they will fill an important gap in the armamentarium of lipid-lowering drugs.
Mechanism of action of SLN360, olpasiran, LY3819469 and pelacarsen [11,15,48]. ASGPR—asialoglycoprotein receptor; ASO—antisense oligonucleotides; siRNA—small interfering RNA; LPA—lipoprotein (a) gene; LDL—low density lipoprotein; ASCVD—atherosclerotic cardiovascular disease; Lp(a)—lipoprotein (a); apo (a)—apolipoprotein (a); RICS—RNA-induced silencing complex. The following was used in the preparation of the figure:	Mechanism of action of SLN360, olpasiran, LY3819469 and pelacarsen [11,15,48]. ASGPR—asialoglycoprotein receptor; ASO—antisense oligonucleotides; siRNA—small interfering RNA; LPA—lipoprotein (a) gene; LDL—low density lipoprotein; ASCVD—atherosclerotic cardiovascular disease; Lp(a)—lipoprotein (a); apo (a)—apolipoprotein (a); RICS—RNA-induced silencing complex. The following was used in the preparation of the figure:
Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient. Expected final online publication date for the	Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient. Expected final online publication date for the
Lipoprotein(a) (Lp(a)) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD), independent of other conventional risk factors. High Lp(a) levels are also independently associated with an increased risk of aortic stenosis progression rate. Plasma Lp(a) levels are primarily genetically determined by variation in the LPA gene coding for apo(a). All secondary prevention trials have demonstrated that the existing hypolipidemic therapies are not adequate to reduce Lp(a) levels to such an extent that could lead to a substantial reduction of ASCVD risk. This has led to the development of new drugs that target the mRNA transcript of LPA and efficiently inhibit Lp(a) synthesis leading to potent Lp(a) reduction. These new drugs are the ASO pelacarsen and the siRNAs olpasiran and SLN360. Recent pharmacodynamic studies showed that all these drugs potently reduce Lp(a) up to 98%, in a dose-dependent manner. Ongoing clinical trials will determine the Lp(a)-lowering efficacy, tolerability, and safety of these drugs as well as their potential effectiveness in reducing the ASCVD risk attributed to high plasma Lp(a) levels. We are not ready today to significantly reduce plasma Lp(a). Emerging therapies potently decrease Lp(a) and ongoing clinical trials will determine their effectiveness in reducing ASCVD risk in subjects with high Lp(a) levels.	Lipoprotein(a) (Lp(a)) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD), independent of other conventional risk factors. High Lp(a) levels are also independently associated with an increased risk of aortic stenosis progression rate. Plasma Lp(a) levels are primarily genetically determined by variation in the LPA gene coding for apo(a). All secondary prevention trials have demonstrated that the existing hypolipidemic therapies are not adequate to reduce Lp(a) levels to such an extent that could lead to a substantial reduction of ASCVD risk. This has led to the development of new drugs that target the mRNA transcript of LPA and efficiently inhibit Lp(a) synthesis leading to potent Lp(a) reduction. These new drugs are the ASO pelacarsen and the siRNAs olpasiran and SLN360. Recent pharmacodynamic studies showed that all these drugs potently reduce Lp(a) up to 98%, in a dose-dependent manner. Ongoing clinical trials will determine the Lp(a)-lowering efficacy, tolerability, and safety of these drugs as well as their potential effectiveness in reducing the ASCVD risk attributed to high plasma Lp(a) levels. We are not ready today to significantly reduce plasma Lp(a). Emerging therapies potently decrease Lp(a) and ongoing clinical trials will determine their effectiveness in reducing ASCVD risk in subjects with high Lp(a) levels.
An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.	An increase in blood lipoprotein (a) [Lp(a)] levels, mostly genetically determined, has been identified as an independent risk factor of atherosclerotic cardiovascular disease. No drug has yet been approved that markedly lowers Lp(a) and thereby reduces residual cardiovascular risk. The aim of this article was to critically review the evidence from clinical development studies to date on the efficacy and safety of new RNA-based therapeutics for targeted lowering of Lp(a). PubMed/MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov were searched without any language or date restriction up to November 5, 2022, and a total of 12 publications and 22 trial records were included. Several drugs were found that are currently in various stages of clinical development, such as the antisense oligonucleotide pelacarsen and the small interfering RNA molecule olpasiran and drugs coded as SLN360 and LY3819469. Among them, pelacarsen has progressed the most, currently reaching phase 3. All these drugs have so far shown satisfactory pharmacokinetic properties, consistently high and stable, dose-dependent efficacy in lowering Lp(a) even by more than 90%, with an acceptable safety profile in subjects with highly elevated Lp(a). In addition, reports of early clinical trials with pelacarsen imply a promising suppressive effect on key mechanisms of atherogenesis. Future research should focus on confirming these beneficial clinical effects in patients with lower average Lp(a) levels and clearly demonstrating the association between lowering Lp(a) and reducing adverse cardiovascular outcomes.