Pelacarsen
Experimental antisense oligonucleotide drug for lowering lipoprotein(a)
From Wikipedia, the free encyclopedia
Pelacarsen is an experimental antisense oligonucleotide drug designed to lower lipoprotein(a) (Lp(a)) levels in patients with cardiovascular disease.[1] The drug targets the LPA gene that encodes apolipoprotein(a), a key component of lipoprotein(a).[1][2][3] It was developed by Ionis Pharmaceuticals and Novartis.[4]
- Investigational
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| Other names | AKCEA-APO(a)-LRx, IONIS-681257, TQJ230, IONIS-APO(a)-LRx, ISIS-APO(a)-LRx |
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| Formula | C296H439N71O163P20S13 |
| Molar mass | 8636.36 g·mol−1 |
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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(a) levels.[5] In September 2026, Novartis declared the drug had failed in clinical trials, to the shock of leading physicians, including Harlan Krumholz.[6]
Mechanism of action
Pelacarsen is a second-generation, hepatocyte-directed antisense oligonucleotide that targets the messenger RNA (mRNA) transcribed from the LPA gene.[1] The drug works by binding to the specific mRNA sequence, leading to its degradation through RNase H-mediated cleavage.[7]
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.[7] This results in decreased apolipoprotein(a) production and consequently lower circulating Lp(a) levels.[1]
Clinical development
Phase 2 studies
In Phase 2 clinical trials, pelacarsen demonstrated significant reductions in Lp(a) 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(a) levels ≥60 mg/dL (≥150 nmol/L).[8]
Studies in healthy Japanese subjects showed dose-dependent reductions in Lp(a) 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.[3]
Phase 3 trials
The primary Phase 3 study is the Lp(a)HORIZON trial (NCT04023552), a global, multicenter, double-blind, placebo-controlled study conducted by Novartis.[5] The trial enrolled 8,323 patients with established cardiovascular disease and elevated Lp(a) levels of ≥70 mg/dL (approximately 149 nmol/L), testing the effect of pelacarsen on major cardiovascular events.[5][9]
Additional Phase 3 studies include the Lp(a)FRONTIERS CAVS trial, which is assessing the impact of Lp(a) lowering with pelacarsen on the progression of calcific aortic valve stenosis.[10]
Other Lp(a)-lowering therapies
Pelacarsen is part of an emerging class of investigational therapies designed to lower Lipoprotein(a) by targeting its synthesis in the liver. While pelacarsen utilizes an antisense oligonucleotide (ASO) approach, other therapies in clinical development include small interfering RNAs (siRNAs) such as olpasiran, lepodisiran, and zerlasiran, which also target LPA messenger RNA. Additionally, oral small-molecule inhibitors like muvalaplin are being investigated for their ability to disrupt the assembly of the Lp(a) particle.[11]
Administration
Pelacarsen is administered as a subcutaneous injection once monthly.[12] The drug has demonstrated good tolerability in clinical studies, with the ability to reduce lipoprotein(a) levels by up to 80%.[13]
Development history
Pelacarsen was initially developed by Ionis Pharmaceuticals under various developmental names including ISIS-APO(a)-LRx, IONIS-APO(a)-LRx, and AKCEA-APO(a)-LRx.[14] The drug was later licensed to Novartis, which assigned it the development code TQJ230.[14]
Regulatory status
Pelacarsen sodium (IONIS-APOALRx) is under development for the treatment of cardiovascular diseases, aortic valve stenosis and hyperlipoproteinemia.[15] The drug currently has investigational status and has not been approved by any regulatory agency for clinical use.