Pelacarsen
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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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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]
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]
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.[6]
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.[6] 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).[7]
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.[8]
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]
Administration
Pelacarsen is administered as a subcutaneous injection once monthly.[11] The drug has demonstrated good tolerability in clinical studies, with the ability to reduce lipoprotein(a) levels by up to 80%.[12]
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.[13] The drug was later licensed to Novartis, which assigned it the development code TQJ230.[13]
Regulatory status
Pelacarsen sodium (IONIS-APOALRx) is under development for the treatment of cardiovascular diseases, aortic valve stenosis and hyperlipoproteinemia.[14] The drug currently has investigational status and has not been approved by any regulatory agency for clinical use.
See also
References
- ^ a b c d Nurmohamed NS, Kaiser Y, Waissi F, Stroes ES (2020). "Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease". Clinical Kidney Journal. 13 (5): 753–759. doi:10.1093/ckj/sfaa024. PMC 7577764. PMID 33046992.
- ^ Yeang C, Karwatowska-Prokopczuk E, Su F, Dinh B, Xia S, Witztum JL, et al. (March 2022). "Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol". Journal of the American College of Cardiology. 79 (11): 1035–1046. doi:10.1016/j.jacc.2021.12.032. PMC 8972555. PMID 35300814.
- ^ Karwatowska-Prokopczuk E, Lesogor A, Yan JH, Hurh E, Hoenlinger A, Margolskee A, et al. (January 2023). "Efficacy and safety of pelacarsen in lowering Lp(a) in healthy Japanese subjects". Journal of Clinical Lipidology. 17 (1): 181–188. doi:10.1016/j.jacl.2022.12.001. PMID 36529659.
- ^ Dharma R (4 August 2023). "Ionis, Novartis to develop medicine for cardiovascular disease". Pharmaceutical Technology. Retrieved 23 November 2023.
- ^ a b c Tsimikas S, et al. (2025). "Design and Rationale of Lp(a)HORIZON Trial: Assessing the Effect of Lipoprotein(a) Lowering With Pelacarsen on Major Cardiovascular Events in Patients With CVD and Elevated Lp(a)". American Heart Journal. 287: 1–9. doi:10.1016/j.ahj.2025.03.019. PMID 40185318.
- ^ a b Pavanello C, et al. (2025). "Pelacarsen: Mechanism of action and Lp(a)-lowering effect". Journal of Clinical Lipidology. doi:10.1016/j.jacl.2025.06.004.
- ^ Tsimikas S, et al. (2022). "Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol". Journal of the American College of Cardiology. 79 (11): 1035–1046. doi:10.1016/j.jacc.2021.12.032. PMC 8972555. PMID 35300814.
- ^ Nakajima K, et al. (2023). "Efficacy and safety of pelacarsen in lowering Lp(a) in healthy Japanese subjects". Atherosclerosis. 363 (1): 9–18. doi:10.1016/j.atherosclerosis.2022.11.013. PMID 36529659.
- ^ Novartis Pharmaceuticals (4 July 2025). A Randomized Double-blind, Placebo-controlled, Multicenter Trial Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With Established Cardiovascular Disease (Report). clinicaltrials.gov.
- ^ "A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Progression of Calcific Aortic Valve Stenosis". Novartis. 11 July 2025. Archived from the original on 25 March 2025. Retrieved 20 August 2025.
- ^ "Lipoprotein(a): Progress on One of the Last Untreatable Frontiers of Cardiovascular Risk". Cleveland Clinic. 4 January 2024. Archived from the original on 26 March 2025. Retrieved 20 August 2025.
- ^ "Pelacarsen (AKCEA-APO(a)-LRx)". MedChemExpress. Retrieved 20 August 2025.
- ^ a b "Delving into the Latest Updates on Pelacarsen with Synapse". Synapse. Retrieved 20 August 2025.
- ^ "Pelacarsen sodium by Novartis for Cardiovascular Disease: Likelihood of Approval". Pharmaceutical Technology. 9 September 2024. Archived from the original on 18 March 2025. Retrieved 20 August 2025.
External links
- Lp(a)HORIZON Clinical Trial on ClinicalTrials.gov