Phase III Lp(a)HORIZON: Pelacarsen (Novartis) Reduces Lp(a), Not Cardiovascular Events

Basel – Novartis announced that the pelacarsen phase III Lp(a)HORIZON trial, a pioneering cardiovascular outcomes study, did not meet its primary endpoint of reducing the risk of cardiovascular events, a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, compared to placebo¹. Lower lipoprotein (a), Lp(a), levels were achieved with pelacarsen in this study population, which was receiving guideline-directed treatments, including lipid lowering and antihypertensive therapies^1,2. The findings provide important new evidence on the relationship between Lp(a) lowering and cardiovascular outcomes. Elevated Lp(a) is an inherited cardiovascular risk factor affecting approximately one in five people worldwide with no approved targeted treatment^1,3.

"Lp(a)HORIZON was a pioneering cardiovascular outcomes trial designed to answer one of the most important unanswered questions in cardiovascular medicine by evaluating whether lowering Lp(a) can reduce residual cardiovascular risk beyond optimized, guideline-directed care, when other major cardiovascular risk factors are already being managed," said Shreeram Aradhye, President, Development and Chief Medical Officer, Novartis. "Although lower Lp(a) levels were observed with pelacarsen, the findings did not demonstrate that this translated into reduced cardiovascular risk in the overall study population. These are not the results we hoped for, but they provide important evidence that advances scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes and may help inform future approaches to cardiovascular risk management. We thank the more than 8,000 trial participants and investigators who made this study possible, and remain committed to driving cardiovascular innovation."

The Lp(a)HORIZON trial data will be presented at an upcoming medical congress.

About Pelacarsen
Pelacarsen is an investigational antisense oligonucleotide (ASO) designed to potently inhibit lipoprotein (a), Lp(a), production at its source^4,5.

Novartis obtained global rights to develop, manufacture and commercialize pelacarsen under a license and collaboration agreement with Ionis Pharmaceuticals.

About Elevated Lp(a)
Elevated Lp(a) is an inherited, independent and causal cardiovascular disease (CVD) risk factor. Lp(a) levels are approximately 90% genetically determined and largely unaffected by diet or lifestyle⁶. Lp(a) can contribute to plaque buildup and inflammation in the arteries, which can lead to plaque rupture and cardiovascular events⁷. Approximately 20 percent of people worldwide, and nearly one-third of those with premature cardiovascular disease, have elevated Lp(a)^3,8. US and European guidelines recommend Lp(a) testing once in a lifetime for all adults^9,10.

About Lp(a)HORIZON
Lp(a)HORIZON (NCT04023552) is a Phase III, randomized, placebo-controlled, double-blind, parallel-group, multi-center global cardiovascular outcomes trial evaluating the effect of pelacarsen on the incidence of 4-point major adverse cardiovascular events (MACE) in 8,323 patients with elevated Lp(a) and established CVD. The primary endpoint is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, evaluated in the overall population (Lp(a) ≥70 mg/dL) and subpopulation (Lp(a) ≥90 mg/dL)¹¹.

References

1. Novartis data on file.
2. Cho L, Nicholls SJ, Nordestgaard BG, et al. 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). Am Heart J. 2025 2025;287:1-9. doi:10.1016/j.ahj.2025.03.019
3. Tsimikas S, Marcovina SM. Ancestry, Lipoprotein(a), and Cardiovascular Risk Thresholds: JACC Review Topic of the Week. J Am Coll Cardiol. 2022;80(9):934-946. doi:10.1016/j.jacc.2022.06.019
4. Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;386(10002):1472-1483. doi:10.1016/S0140-6736(15)61252-1
5. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388(10057):2239-2253. doi:10.1016/S0140-6736(16)31009-1
6. Wilson, DP, Jacobson, TA, Jones, PH, et al. (2019). Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol. 13(3), 374–392.
7. Boffa MB. Beyond fibrinolysis: the confounding role of Lp(a) in thrombosis. Atherosclerosis. 2022;349:72-81. doi:10.1016/j.atherosclerosis.2022.04.009
8. Byrne H, Sinha S, Pradhan H, et al. How common is elevated Lp(a) in premature ASCVD patients? A real-world study using a large US electronic health record database. Poster presented at: European Atherosclerosis Society (EAS) Congress; May 4-7, 2025; Glasgow, UK.
9. Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of dyslipidemia: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Published online March 13, 2026. doi:10.1161/CIR.0000000000001423
10. Mach F, Koskinas KC, Roeters van Lennep JE, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2025;46(42):4359-4378. doi:10.1093/eurheartj/ehaf190
11. ClinicalTrials.gov. NCT04023552. Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON). Available from: https://clinicaltrials.gov/study/NCT04023552 [Last accessed: July 2026].