Pelacarsen
Pelacarsen is an experimental antisense oligonucleotide drug designed to lower lipoprotein(a) levels in patients with cardiovascular disease. The drug targets the LPA gene that encodes apolipoprotein(a), a key component of lipoprotein. It was developed by Ionis Pharmaceuticals and Novartis.
As of August 2025, pelacarsen is undergoing Phase 3 clinical trials to evaluate its efficacy in reducing major cardiovascular events in patients with established cardiovascular disease and elevated Lp levels.
Mechanism of action
Pelacarsen is a second-generation, hepatocyte-directed antisense oligonucleotide that targets the messenger RNA transcribed from the LPA gene. The drug works by binding to the specific mRNA sequence, leading to its degradation through RNase H-mediated cleavage.The antisense oligonucleotide includes chemical modifications such as triantennary N-acetylgalactosamine conjugation, which improve biostability, decrease off-target toxicity compared with unmodified antisense oligonucleotides, and allow rapid, specific uptake by hepatocytes. This results in decreased apolipoprotein(a) production and consequently lower circulating Lp levels.
Clinical development
Phase 2 studies
In Phase 2 clinical trials, pelacarsen demonstrated significant reductions in Lp levels. The phase 2B trial was a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening Lp levels ≥60 mg/dL.Studies in healthy Japanese subjects showed dose-dependent reductions in Lp levels, with placebo-corrected reductions of 55.4%, 58.9%, and 73.7% for 20 mg, 40 mg, and 80 mg doses, respectively, at day 30.
Phase 3 trials
The primary Phase 3 study is the LpHORIZON trial, a global, multicenter, double-blind, placebo-controlled study conducted by Novartis. The trial enrolled 8,323 patients with established cardiovascular disease and elevated Lp levels of ≥70 mg/dL, testing the effect of pelacarsen on major cardiovascular events.Additional Phase 3 studies include the LpFRONTIERS CAVS trial, which is assessing the impact of Lp lowering with pelacarsen on the progression of calcific aortic valve stenosis.