Novartis’ pelacarsen lowered Lp(a) but failed to reduce cardiovascular events in the Phase III Lp(a)HORIZON trial of 8,323 patients.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
Investigational pelacarsen lowered lipoprotein(a) [Lp(a)] in the Phase III Lp(a)HORIZON trial (NCT04023552) but failed to achieve its primary goal of reducing major adverse cardiovascular events (MACE). The readout represents a major setback for one of the leading targeted approaches to this inherited cardiovascular risk factor and raises important questions about how Lp(a) reduction can address residual cardiovascular risk.
Pelacarsen Lowers Lp(a), But Misses Primary Endpoint
The randomized, double-blind, placebo-controlled Phase III Lp(a)HORIZON cardiovascular outcomes trial evaluated pelacarsen against placebo in 8,323 patients with elevated Lp(a) and established cardiovascular disease who were receiving guideline-directed therapy.
Pelacarsen failed to significantly reduce the trial’s four-point MACE primary composite, comprising cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization. The endpoint was assessed in both the overall study population with Lp(a) levels of at least 70 mg/dL and a prespecified subpopulation with levels of at least 90 mg/dL.
Despite lowering circulating Lp(a) levels, the biochemical effect did not translate into a statistically significant reduction in clinical events.
Understanding the Unmet Need in Lp(a)
Lp(a) is an independent, causal cardiovascular risk factor that can promote arterial inflammation and plaque formation. Circulating levels are approximately 90% genetically determined and remain largely unaffected by diet or lifestyle.
Elevated Lp(a) affects roughly one in five people worldwide, with a higher prevalence among people with premature cardiovascular disease. Yet no approved targeted therapy currently exists specifically for elevated Lp(a). Both US and European clinical guidelines recommend measuring Lp(a) at least once during adulthood to identify individuals with elevated inherited cardiovascular risk.
Targeting Lp(a) Synthesis at Its Source
Discovered by Ionis Pharmaceuticals and licensed globally to Novartis, pelacarsen is an investigational antisense oligonucleotide (ASO). It selectively targets messenger RNA encoding apolipoprotein(a) [apo(a)], the unique protein component that combines with apolipoprotein B to form Lp(a).
Pelacarsen uses an N-acetylgalactosamine (GalNAc) conjugate to promote targeted uptake into hepatocytes, where it triggers RNase H-mediated degradation of apo(a) mRNA. This suppresses apo(a) protein synthesis in the liver, reducing production and release of Lp(a) into the circulation.
Testing Residual Risk Beyond Standard Care
All participants in Lp(a)HORIZON were receiving guideline-directed treatment, including lipid-lowering and antihypertensive therapies. The trial sought to determine whether targeted Lp(a) reduction could provide additional cardiovascular benefit once other major risk factors were already being managed.
The negative topline result does not disprove the causal role of Lp(a) in atherosclerotic cardiovascular disease. Rather, it shows that pharmacologically lowering Lp(a) with pelacarsen did not further reduce the prespecified cardiovascular event composite in this optimized clinical trial population.
Full Dataset Presentation and Post-Trial Regulatory Horizon
“Lp(a)HORIZON was designed to answer a central question: whether Lp(a) lowering could address residual risk beyond optimized guideline-directed care,” said Shreeram Aradhye, M.D., President of Development and Chief Medical Officer at Novartis. The company said the findings add important evidence to the clinical understanding of the relationship between Lp(a) lowering and cardiovascular outcomes.
While detailed topline data have not yet been disclosed, Ionis reported that pelacarsen demonstrated an acceptable safety profile. Full efficacy, safety, event-rate, and prespecified subgroup analyses are expected to be presented at an upcoming medical congress.
These data will be important for determining whether treatment effects differed across patient subgroups and for clarifying the implications of the findings for future Lp(a)-lowering strategies.
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About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.