Carlsbad, California — September 4, 2026
Ionis Pharmaceuticals and partner Novartis reported topline results from the Phase 3 Lp(a)HORIZON cardiovascular outcomes study evaluating pelacarsen in patients with elevated lipoprotein(a) [Lp(a)] and established cardiovascular disease (CVD). The study did not meet its primary endpoint of reducing the risk of cardiovascular events compared with placebo, despite substantially lowering Lp(a) levels. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization. The outcome represents a significant development setback for pelacarsen, an investigational antisense oligonucleotide designed to inhibit Lp(a) production at its source. At the same time, the findings provide additional clinical evidence for researchers evaluating whether pharmacological reduction of genetically determined Lp(a) can translate into meaningful reductions in cardiovascular events.
Ionis and Novartis Evaluate Cardiovascular Outcomes
The Lp(a)HORIZON trial (NCT04023552) was a randomized, placebo-controlled, double-blind, multicenter global Phase 3 cardiovascular outcomes study involving approximately 8,323 patients with elevated Lp(a) and established CVD. Participants received guideline-directed cardiovascular care, including lipid-lowering and antihypertensive therapies, while the study assessed whether adding pelacarsen could reduce four-point major adverse cardiovascular events (MACE). Although pelacarsen achieved substantially lower Lp(a) levels, the reduction did not result in the expected decrease in cardiovascular events versus placebo. The trial was designed to address a major unresolved question in cardiovascular medicine: whether lowering Lp(a), an inherited and independent cardiovascular risk factor, can reduce residual risk in patients whose other major cardiovascular risk factors are already being managed. The full Lp(a)HORIZON dataset is expected to be presented at an upcoming medical congress
Pelacarsen Lowers Lp(a) but Misses Clinical Endpoint
Pelacarsen is an investigational antisense oligonucleotide (ASO) developed to potentially inhibit the production of Lp(a) at its source. Elevated Lp(a) is largely genetically determined, with levels estimated to be approximately 90% genetically determined, and is associated with plaque formation, arterial inflammation, and cardiovascular events. Approximately 20% of people worldwide are estimated to have elevated Lp(a). Ionis discovered pelacarsen and conducted its early development before Novartis exercised an option in February 2019 to license rights to develop and commercialize the therapy for targeted cardiovascular applications. Ionis said pelacarsen demonstrated an acceptable safety profile in the Phase 3 study. However, the failure to demonstrate cardiovascular risk reduction means that the clinical benefit of Lp(a) lowering with pelacarsen remains unproven in this established CVD population
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Ionis and Novartis Face Key Development Milestone
The Phase 3 outcome is important for both Ionis Pharmaceuticals and Novartis, as pelacarsen was designed to test whether targeting Lp(a) could establish a new approach to cardiovascular risk management. Recent reporting characterized the result as a setback for the companies and raised broader questions about the emerging class of Lp(a)-lowering therapies. Ionis CEO Brett P. Monia, PhD, said the results provide clarity that could meaningfully inform future cardiovascular care, while noting that the company continues to advance its broader RNA-targeted medicines pipeline. For Novartis, the findings represent a major late-stage development challenge for a program intended to address a substantial population with elevated inherited cardiovascular risk. The companies will now have the opportunity to evaluate the complete dataset when it is presented at a future medical congress, including additional analyses that may help clarify the relationship between Lp(a) reduction and cardiovascular outcomes.
Source: Ionis Pharmaceuticals, press relese
