RNA-Based Therapies for Lipoprotein(a) Reduction: Antisense Oligonucleotides, Small Interfering RNAs, and Emerging Platforms

Purpose of Review Lipoprotein(a) [Lp(a)] is an independent, genetically determined, and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. Elevated Lp(a) affects approximately 20% of the global population and is not meaningfully modified by lifestyle intervention or existing lipid-lowering pharmacotherapy. This review summarizes the biology of Lp(a) as a therapeutic target, evaluates the efficacy of currently available lipid-lowering agents against this target, and describes the mechanistic principles, clinical evidence, and unresolved questions associated with RNA-based and emerging small-molecule and gene-editing approaches to Lp(a) reduction. Recent Findings Four RNA-directed agents targeting hepatic apolipoprotein(a) [apo(a)] synthesis have entered phase 2/3 development. This includes pelacarsen, an antisense oligonucleotide (ASO), and olpasiran, zerlasiran, and lepodisiran, which are N-acetylgalactosamine (GalNAc)-conjugated small interfering RNAs (siRNAs). Phase 2 data demonstrate Lp(a) reductions ranging from 79% to approximately 97% on a placebo-adjusted basis, approaching the practical limit of apo(a) suppression, with favorable short-term safety profiles. A fifth, structurally distinct siRNA conjugated with GalNAc at both strand termini has recently completed first-in-human testing, sustaining reductions up to 97% through 48 weeks after a single dose without injection-site reactions. Recently, the topline results of phase 3 Lp(a) HORIZON (pelacarsen) were released and demonstrate a substantial Lp(a) reduction without meeting the trial’s primary composite cardiovascular endpoint. Two further outcomes trials, OCEAN(a)-Outcomes (olpasiran) and ACCLAIM-Lp(a) (lepodisiran), remain ongoing. An oral small molecule, muvalaplin, achieved comparable reductions in phase 2 testing. Lastly, early non-human primate data, together with a completed phase 1 trial of an analogous CRISPR-Cas9 construct targeting a related hepatic lipid gene, support the feasibility of a CRISPR-Cas9-based gene-editing approach capable of durable apo(a) suppression from a single administration. Summary The pharmacology of Lp(a) suppression is now well characterized across three distinct therapeutic modalities. Whether the magnitude of biochemical reduction observed translates into a meaningful and safe reduction in cardiovascular events across different populations remains undetermined and will be addressed by the ongoing outcomes trials.