First major trial of Lp(a) lowering fails to cut CV events

Clinical takeaway: Management does not change: measure Lp(a) at least once in adulthood. Intensify LDL lowering and management of other modifiable risk factors when levels are elevated. Outcomes trials of other agents targeting Lp(a) continue. 

A patient with LDL at goal, blood pressure controlled, no cigarettes, and a statin taken faithfully can still arrive in the emergency department with a myocardial infarction. Inherited lipoprotein(a), or Lp(a), is one of the reasons why. Roughly one in five people worldwide carries an elevated level, set almost entirely by genetics and largely unaffected by lifestyle. Clinicians can name that risk for a patient but cannot treat it directly, because no approved medication directly targets Lp(a). 

The genetic case for going after the particle is as strong as observational science gets. Lp(a) levels are approximately 90% genetically determined and track with cardiovascular events consistently enough that the particle looks causal. What genetics cannot establish is whether pushing levels down pharmacologically, decades into established disease, would prevent CV events. Several drugs capable of suppressing Lp(a) sharply are now in outcomes trials. The first phase 3 test of that strategy has just delivered a negative topline result that cardiologists largely may not have expected. 

In 8,323 patients with established cardiovascular disease and Lp(a) of 70 mg/dL or higher, treated with optimized standard-of-care therapy for cardiovascular disease, monthly pelacarsen did not significantly reduce the primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization requiring hospitalization compared with placebo. Patients on the drug did reach lower Lp(a) levels than those on placebo, so the trial tested what it set out to test: whether adding pelacarsen to contemporary secondary-prevention therapy reduces events. 

Novartis released topline findings only, with no effect estimate, no magnitude of Lp(a) reduction, no safety findings, and no result from the prespecified second primary-analysis population with Lp(a) of 90 mg/dL or higher. Detailed trial data will be presented at an upcoming medical conference. 

In earlier dose-ranging work in 286 patients with established cardiovascular disease, pelacarsen reduced Lp(a) by 72% with 60 mg every four weeks and by 80% with 20 mg weekly. The weekly regimen totaled 80 mg over four weeks, whereas the phase 3 trial used a single 80 mg injection every four weeks. Prior population modeling estimated that lowering Lp(a) by an absolute reduction of about 50 mg/dL for five years might reduce cardiovascular events by 20% in secondary prevention, though the estimate was imprecise, spanning roughly 27 to 138 mg/dL. Whether the trial achieved and sustained that reduction has not been disclosed. 

Known as Lp(a)HORIZON, the current trial randomized participants 1:1 to monthly subcutaneous pelacarsen 80 mg or matching placebo, double-blind, across a multicenter global design, with established cardiovascular disease defined as prior myocardial infarction, ischemic stroke, or symptomatic peripheral artery disease. The trial was event-driven, built to run until 993 adjudicated primary events had accrued, with a minimum follow-up of 2.5 years and an anticipated duration of roughly six years. 

A phase 3b study of Lp(a) lowering in US Black and Hispanic patients completed in March, a separate study is testing pelacarsen on background inclisiran, and a phase 2 trial is evaluating progression of calcific aortic valve stenosis. The topline release did not address these studies. 

This clinical strategy also gets retested with different candidates. Amgen's olpasiran, a small interfering RNA (siRNA), is in a phase 3 outcomes trial in patients with prior myocardial infarction or coronary revascularization and Lp(a) of at least 200 nmol/L, with primary completion expected in 2028. The strategy is also moving upstream: Amgen has opened a prevention trial of olpasiran in patients without a prior major atherothrombotic event, and Lilly's lepodisiran, an siRNA, is in a phase 3 trial extending to adults at risk of a first cardiovascular event, with primary completion expected in 2029. 

"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," said Shreeram Aradhye, MD, president of development and chief medical officer at Novartis. "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." 

Source: Novartis (2026 Sep 4) Novartis announces Lp(a)HORIZON Phase III topline results for pelacarsen in patients with elevated Lp(a) and established cardiovascular disease (CVD)