👤 Lakshmi Kattamuri

Traditional risk reduction strategies like diet, exercise, and existing lipid- lowering medications have minimal impact on Lp(a) levels. Recent therapies targeting Lp(a) at the level of mRNA transcription of apo(a) or binding of apo(a) to apoB-100 have demonstrated substantial reductions of Lp(a). Lepodisiran is a GalNAc-conjugated small interfering RNA (siRNA) developed to inhibit LPA transcription, reducing apo(a) synthesis and circulating Lp(a) levels. This is an updated review of the mechanism of action, pharmacokinetics, clinical efficacy, and safety of Lepodisiran, as well as its effects on lipoprotein(a), with potential applications in treating patients with elevated cardiovascular risk. We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Lepodisiran," "small interfering RNA therapies," and "lipoprotein(a)". Lepodisiran demonstrated a dose-dependent and sustained reduction in Lp(a) levels, achieving a maximum reduction of up to 97% at the highest dose in a Phase 1 trial. A Phase 2 placebo-controlled trial similarly showed robust and durable decline in Lp(a) with a favorable safety profile. Lepodisiran is a promising therapy, with sustained Lp(a) reduction and good safety. Ongoing phase 3 trials are poised to provide robust data on its long-term safety, clinical efficacy, and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes. Lepodisiran demonstrates potent and sustained reductions in Lp(a) levels with a favorable safety profile, making it a promising therapeutic candidate for Lp(a)-mediated cardiovascular risk. Ongoing long-term outcome studies are essential to confirm its clinical benefit. Show less

Elevated levels of lipoprotein(a) have been linked to an increased risk of Atherosclerotic Cardiovascular Disease (ASCVD). Conventional lipid-lowering medications have modest to no impact on Lp(a) levels. Emerging RNA-based modalities significantly decrease Lp(a) by silencing the apo(a) mRNA at the post-transcriptional level. Pelacarsen (TQJ230) is a GalNAc-conjugated novel Antisense Oligonucleotide (ASO) that selectively inhibits apo(a) synthesis in hepatocytes. This updated review aims to elucidate the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of Pelacarsen (TQJ230), with a focused appraisal of its potential role in the prevention of Atherosclerotic Cardiovascular Disease (ASCVD). We conducted a literature search on PubMed, Google Scholar, and Scopus using keywords such as "Pelacarsen", "antisense oligonucleotide" OR "ASO", and "lipoprotein(a)" from inception to March 2025. Pelacarsen demonstrated a dose-dependent sustained reduction in Lp(a) levels, achieving up to a 97% reduction at the highest dose in Phase 1 and 2 trials. It was well-tolerated with a favorable safety profile. Phase 3 trials are underway to provide robust data on its long-term safety and impact on Atherosclerotic Cardiovascular Disease (ASCVD) outcomes. Pelacarsen (TQJ230) is a potent Lp(a)-lowering agent with promising efficacy and a favorable safety profile. However, its definitive role in reducing atherosclerotic cardiovascular events remains to be established. Ongoing Phase 3 trials will be critical in determining whether its lipid-lowering effects translate into meaningful long-term cardiovascular outcomes. Show less