RNA therapeutics
Review details how pelacarsen's GalNAc-conjugated antisense design achieved an 80% or greater Lp(a) reduction in phase 2b, now being tested for outcomes in Lp(a)HORIZON (J Clin Lipidol 2025)
Original title: Pelacarsen: Mechanism of action and Lp(a)-lowering effect
This review examines pelacarsen, a second-generation antisense oligonucleotide targeting hepatic apo(a) production, against the backdrop of Lp(a) affecting more than 1.4 billion people worldwide at levels of 125 nmol/L (50 mg/dL) or above, for whom no pharmacological Lp(a)-lowering therapy is currently approved in the United States and existing PCSK9 inhibitors achieve only modest reductions short of a clinically meaningful 50 to 100 mg/dL. Pelacarsen's triantennary N-acetylgalactosamine conjugation improves biostability, reduces off-target toxicity relative to unmodified antisense oligonucleotides, and enables rapid, liver-specific uptake. A phase 2b study showed an 80% or greater reduction in Lp(a) with a favourable safety profile in patients with established atherosclerotic cardiovascular disease. The ongoing phase 3 Lp(a)HORIZON trial is now testing whether this magnitude of Lp(a) lowering translates into fewer major cardiovascular events.
Original abstract
Background: Lipoprotein(a) (Lp[a]) is an apolipoprotein B100 (apoB)-containing lipoprotein with a single apolipoprotein(a) (apo[a]) covalently bound to apoB via a disulfide bond and oxidized phospholipids linked to apoB and apo(a), which is associated with proinflammatory, prothrombotic, and proatherogenic mechanisms. Elevated Lp(a) (≥125 nmol/L [≥50 mg/dL]) is an independent, causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD), affecting >1.4 billion individuals worldwide.
Sources Of Material: There are no pharmacological Lp(a)-lowering therapies approved in the United States; however, lipoprotein apheresis may be considered under certain circumstances. Germany is the only country where apheresis is approved for patients with elevated Lp(a) and progressing ASCVD.
Abstract Of Findings: Existing lipid-lowering therapies including proprotein convertase subtilisin/kexin type 9 inhibitors have shown modest effects on Lp(a) levels but fallen short of clinically meaningful reductions of >50 to 100 mg/dL. Several Lp(a)-lowering, RNA-targeted agents are in development, including antisense oligonucleotides (ASOs) and small interfering RNAs. Pelacarsen is a second-generation ASO that targets the production of apo(a) and includes chemical modifications such as triantennary N-acetylgalactosamine that improve biostability, decrease off-target toxicity compared with unmodified ASOs, and allow rapid, specific uptake by hepatocytes, the site of apo(a) synthesis. A phase 2b study of pelacarsen showed ≥80% reduction in Lp(a) concentration with a favorable safety profile in patients with established ASCVD.
Conclusion: The ongoing phase 3 Lp(a)HORIZON study is evaluating whether the Lp(a)-lowering effects of pelacarsen translate into reductions in the incidence of major cardiovascular events, also in patients with established ASCVD. Herein, we review the mechanism of action of pelacarsen and evidence for its Lp(a)-lowering effects.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.