{"id":"1c1f911bbd94","type":"article","url":"https://hartvaat.nl/2026/10/14/rna-therapieen-verlagen-lp-a-met-tot-97-procent-overzicht-nieuwe-remmers-en-fase/","title":"RNA-therapieën verlagen Lp(a) met tot 97 procent — overzicht nieuwe remmers en fase 3-resultaten","title_en":"RNA-Based Therapies for Lipoprotein(a) Reduction: Antisense Oligonucleotides, Small Interfering RNAs, and Emerging Platforms.","category":"cholesterol","category_label":"Cholesterol","professions":["apotheker","cardioloog","internist"],"tags":[],"journal":"Current atherosclerosis reports","doi":"10.1007/s11883-026-01474-4","source_url":"https://doi.org/10.1007/s11883-026-01474-4","authors":["Vibhu Parcha","Vera A Bittner"],"significance":7,"published":"2026-10-23","source_date":"2026-10-14","image":"","kennis":["https://hartvaat.nl/kennis/lipiden/lpa-meten-wanneer-waarom/","https://hartvaat.nl/kennis/lipiden/lp-a-verhoogd/"],"congress":"","summary_en":"This review summarizes the latest advances in RNA-based therapies targeting lipoprotein(a) [Lp(a)] in patients with genetically elevated levels. Phase 2 trials of antisense oligonucleotides and GalNAc-conjugated siRNAs demonstrate Lp(a) reductions of 79% to 97%, with favorable short-term safety profiles. Although the phase 3 HORIZON trial with pelacarsen missed its primary composite cardiovascular endpoint, two additional outcomes trials (OCEAN(a) and ACCLAIM-Lp) are ongoing, alongside promising data on oral small molecules and CRISPR-based approaches. These modalities represent a major step forward for managing Lp(a)-driven cardiovascular risk, with definitive clinical benefit still pending.","created":"2026-10-16T01:17:47Z","updated":"2026-10-16T01:17:52Z","licence":"Citeer vrij, met bronvermelding en een link naar hartvaat.nl (de url van het record). Samenvattingen zijn redactioneel werk van HartVaat; de oorspronkelijke publicaties blijven van hun uitgevers (doi). Geen medisch advies.","body_markdown":"Dit overzicht beschrijft de recente ontwikkelingen in RNA-gebaseerde therapieën die specifiek apolipoproteïne(a) remmen bij patiënten met een verhoogd Lp(a)-niveau. Fase 2-studies tonen aan dat antisense-oligonucleotiden en siRNA-conjugaten Lp(a) met 79 tot 97 procent kunnen verlagen, met een goed kortetermijnveiligheidsprofiel. Hoewel het fase 3 HORIZON-onderzoek met pelacarsen zijn primaire cardiovasculaire eindpunt niet haalde, blijven de uitkomststudies OCEAN(a) en ACCLAIM-Lp lopen. Deze therapieën bieden een veelbelovend perspectief voor de secundaire preventie bij patiënten met een genetisch bepaald hoog Lp(a) die niet reageren op standaard lipidendaling.","abstract_original":"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."}