RNA therapeutics
RNA-directed therapies lower Lp(a) by up to 97% in phase 2 trials, while phase 3 pelacarsen missed its primary endpoint (Curr Atheroscler Rep 2026)
Original title: RNA-Based Therapies for Lipoprotein(a) Reduction: Antisense Oligonucleotides, Small Interfering RNAs, and Emerging Platforms
This narrative review summarises the biology and clinical evidence for RNA-directed therapies targeting hepatic apo(a) synthesis. Phase 2 trials of pelacarsen, olpasiran, zerlasiran, and lepodisiran show placebo-adjusted Lp(a) reductions of 79% to 97% with favourable short-term safety. The recently released phase 3 Lp(a) HORIZON trial for pelacarsen achieved substantial biochemical lowering but did not meet its primary composite cardiovascular endpoint. Two additional outcomes trials for olpasiran and lepodisiran remain ongoing, alongside phase 2 data for the oral agent muvalaplin and early feasibility data for CRISPR-Cas9 gene editing. Whether the observed biochemical reductions translate into meaningful cardiovascular event reductions remains undetermined.
Original abstract
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. 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.
lepodisiranolpasiranpelacarsenRNA therapeuticstherapyzerlasiran
Summary written by lp-a.org from the published abstract; figures as published. Page updated 16 October 2026. Methods.