Treatment of Lp(a): Is It the Future or Are We Ready Today?

Abstract

Purpose of Review The goal of this review is to present the pharmacodynamic effectiveness as well as the clinical efficacy and safety of investigational antisense oligonucleotides (ASOs) and small interference RNAs (siRNAs) drugs that specifically target lipoprotein(a) (Lp(a)). The review will discuss whether the existing lipid-lowering therapies are adequate to treat high Lp(a) levels or whether it is necessary to use the emerging new therapeutic approaches which are based on the current RNA technologies. Recent Findings 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. Summary 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) and cerebrovascular disease

“…Their results are eagerly awaited, as they are expected to provide invaluable information regarding the optimal therapeutic management of hyperlipoproteinemia (a), which would also lead to the development of updated, evidence-based guidelines tailored toward the effective secondary prevention of ASCVD, including cerebrovascular accidents. 5,6,61 Promising short-interfering RNA agents aimed at preventing Lp(a) formation are currently undergoing testing. Examples include zerlasiran or SLN360 and lepodisiran, which inhibit the synthesis of apo(a), and muvalaplin, which blocks the apo(a)-apoB-100 interaction while avoiding interaction with plasminogen.…”

“…Their results are eagerly awaited, as they are expected to provide invaluable information regarding the optimal therapeutic management of hyperlipoproteinemia (a), which would also lead to the development of updated, evidence-based guidelines tailored toward the effective secondary prevention of ASCVD, including cerebrovascular accidents. 5 , 6 , 61 …”

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?

“…Recent advancements in RNA interference (RNAi) technology have opened up new perspectives for developing treatments targeting apo(a) messenger ribonucleic acid (mRNA) degradation prior to translation. Potential therapeutic approaches involve nucleic acid therapeutics, which are designed to specifically target gene expression and can be delivered via ASOs or siRNA molecules [ 9 ]. In addition to nucleic acid-based therapies, muvalaplin, a small molecule inhibitor of Lp(a) particle formation, has shown promising results in reducing serum Lp(a) levels.…”

Estimating the Prevalence and Characteristics of Patients Potentially Eligible for Lipoprotein(a)-Lowering Therapies in a Real-World Setting

“…Actually, all these new drugs targeting Lp(a) are very promising and also overall safe, as far as their cost-effectiveness will be definitively established as part of streamlining the health investments in ASCVD prevention [12]. Moreover, phase III pivotal CV outcome trials (CVOTs)-OCEAN(a) with olpasiran and Lp(a)HORIZON with pelacarsen-are ongoing to evaluate their efficacy in the secondary prevention of major ASCV events in patients with elevated Lp(a) [13].…”