Adults with elevated levels of lipoprotein (a)—Lp (a)—and established cardiovascular disease, saw their levels of the cholesterol-carrying lipoprotein drop by around 78% when taking the drug pelacarsen (Novartis) as part of the Lp(a)HORIZON clinical trial, but use of the investigational antisense oligonucleotide (ASO) did not result in a lower risk of major adverse cardiovascular events than placebo at a median follow-up of 4.7 years.
Results of the trial were presented at the American Heart Association (AHA) 2026 scientific session (6–9 November, Chicago, USA) and simultaneously published in the New England Journal of Medicine (NEJM), with investigators reporting that the trial’s primary endpoint, major adverse cardiovascular events (MACE), defined as a composite of death from cardiovascular causes, non-fatal myocardial infarction (MI), non-fatal stroke, or urgent coronary revascularisation, occurred in 12.3% of patients in the pelacarsen treatment group and 12.1% in the placebo group.
“Although the results are disappointing, neutral trials also provide scientific insights that help inform future research efforts,” said senior author Steven Nissen (Cleveland Clinic, Cleveland, USA) of the result. “A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a) as a strategy to reduce cardiovascular risk.”
The double-blind, randomised, placebo-controlled trial involved patients from 797 sites in 42 countries and included patients 18–80 years old who had prior cardiovascular disease and a Lp(a) level of greater than or equal to 70mg/dL. From December 2019 through July 2022, 8,322 patients were randomly assigned to receive pelacarsen 80mg or matching placebo via a self-administered injection every month.
Patients were followed for a median of 57 months (4.7 years) for both treatment groups.
Established cardiovascular disease was defined as a prior heart attack or a stroke occurring between three months and 10 years prior to enrolment, or symptomatic peripheral arterial disease. Patients received secondary prevention therapies before enrolment, including maximally tolerated lipid-lowering treatment according to local guidelines.
Key secondary endpoints included time to death from any cause and the change in Lp(a) levels after one year. The study also looked at two narrower combinations of heart events: one excluding urgent procedures and another focusing specifically on coronary-related heart events instead of stroke.
The reduction from baseline in Lp(a) after one year was 3.2% in the placebo group and 78.4% in the pelacarsen group with an estimated treatment difference of 77.7% percentage points.
After one year, LDL cholesterol fell to 62.3mg/dL with pelacarsen, but rose to 71.2mg/dL with the placebo. Overall, pelacarsen lowered LDL by 13.3 percentage points compared to placebo.
Serious adverse events occurred in 37.3% of patients in the pelacarsen group and in 41.1% of the placebo group. Adverse events were more common in the pelacarsen group, including flu-like symptoms, injection site reactions and other events that led to permanent study drug discontinuation.
“The HORIZON trial is not the end of the story,” added Nissen. “Ongoing trials are studying different populations, such as primary prevention or aortic stenosis, and different therapies such as small interfering RNA (siRNA) that silences specific genes by breaking down complementary messenger RNA. We look forward to their results.”
The study was funded by Novartis Pharmaceuticals Corporation.
