Novartis announced pelacarsen did not meet its primary endpoint in the phase 3 Lp(a)HORIZON cardiovascular outcomes trial despite Lp(a) lowering.
The phase 3 Lp(a)HORIZON trial evaluating pelacarsen did not meet its primary endpoint of reducing major adverse
Pelacarsen, a GalNAc-conjugated antisense oligonucleotide designed to suppress hepatic Lp(a) production at its source, was evaluated in a phase 2, randomized, double-blind, placebo-controlled, dose-ranging trial published in the New England Journal of Medicine in 2020, which enrolled 286 patients with established cardiovascular disease and screening Lp(a) levels of at least 60 mg/dL. The phase 2 trial demonstrated dose-dependent Lp(a) reductions of up to 80% with the 20-mg weekly dose, with injection-site reactions as the most common adverse event, supporting advancement into the phase 3 outcomes trial.1,2
Did pelacarsen meet its primary endpoint in Lp(a)HORIZON?
No. Despite achieving lower Lp(a) levels than placebo, pelacarsen did not significantly reduce the composite cardiovascular endpoint in the overall study population.
What is pelacarsen's mechanism of action?
Pelacarsen is a GalNAc-conjugated antisense oligonucleotide that suppresses hepatic Lp(a) production, previously demonstrating up to 80% Lp(a) reduction in phase 2 dose-finding studies.
“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, MD, president of development and chief medical officer, Novartis.1
Lp(a)HORIZON (NCT04023552) is a phase 3, randomized, placebo-controlled, double-blind, multicenter global cardiovascular outcomes trial enrolling 8323 patients with elevated Lp(a) and established CVD2. The primary endpoint is a composite 4-point major adverse cardiovascular events (MACE) outcome, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization requiring hospitalization, evaluated in the overall population (Lp[a] ≥70 mg/dL) and a subpopulation (Lp[a] ≥90 mg/dL). Participants received guideline-directed treatments including lipid-lowering and antihypertensive therapies throughout the trial.
According to the company, pelacarsen achieved lower Lp(a) levels compared with placebo, but this reduction did not translate into a significant decrease in the composite cardiovascular endpoint in the overall study population. Full trial data have not yet been released and are planned for presentation at an upcoming medical congress.1
“Although lower Lp(a) levels were observed with pelacarsen, the findings did not demonstrate this translated into reduced cardiovascular risk in the overall study population,” said Aradhye.1 “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.”
The topline miss arrives as several other Lp(a)-lowering nucleic acid therapies remain in ongoing phase 3 trials.
Investigators presenting phase 2 ALPACA data on lepodisiran, an extended-duration small interfering RNA (siRNA) targeting Lp(a), at ESC Congress 2026 reported reductions in Lp(a)-bound oxidized phospholipids of up to 94% at the highest studied dose, though they emphasized this biomarker effect does not itself establish clinical benefit.3 Zerlasiran, another siRNA in phase 2 development, has similarly demonstrated substantial Lp(a) reductions sustained through 48 weeks.4
Novartis did not indicate whether the Lp(a)HORIZON result will affect the regulatory pathway for pelacarsen or the design of ongoing phase 3 substudies, including trials in Black, African American, and Hispanic populations and in patients with recent acute coronary syndrome.
