Pelacarsen, an investigational monthly injection meant to lower lipoprotein(a), cut those blood levels by 78% but did not change how soon adults with established heart disease had a major cardiovascular event compared with placebo, the American Heart Association said Saturday².

Lp(a) HORIZON was a Phase III, double-blind, randomized trial at 797 sites in 42 countries². Researchers screened 14,249 adults and enrolled 8,323 with a prior cardiovascular event and Lp(a) of at least 70 mg/dL (about 148 nmol/L), a range the AHA said covers the highest fifth of the global population². Mean age was 60 years; 27% were women².

Participants received pelacarsen 80 mg or placebo as a monthly shot under the skin after a run-in to meet blood-pressure and cholesterol guidelines if needed². About 75% already met those criteria; nearly all were on antiplatelet drugs and 77-78% were on high-intensity statins². Median baseline Lp(a) was 109 mg/dL².

The primary comparison was time to first nonfatal heart attack, stroke, urgent procedure to open clogged heart arteries, or death from any cardiovascular cause². The AHA said that time did not change in the full cohort or in a subgroup with Lp(a) of 90 mg/dL or higher². Extended analyses of other event combinations, all-cause death and subgroups were also unchanged between drug and placebo².

Steven E. Nissen of Cleveland Clinic, senior author, said the results were completely neutral across multiple analyses². He said the finding does not mean Lp(a) is irrelevant and that people in other Lp(a) trials should not drop out². Three other cardiovascular outcome trials of different Lp(a)-targeting compounds are underway, he said².

Serious adverse events were reported in 37.3% on pelacarsen and 41.1% on placebo². Flu-like symptoms, injection-site reactions and acute allergic reactions were more common with the drug². Anaphylaxis occurred in 19 patients on pelacarsen and none on placebo; the AHA said none of those allergic reactions were fatal². About 21% on pelacarsen and more than 7% on placebo stopped the study drug because of adverse reactions². Novartis funded the trial².

Limitations included possible COVID-related events during the 2019-2026 study window and a sample that was 78% white, with less than 4% of African ancestry, a group the authors said has higher average Lp(a)². The trial was secondary prevention only². Results appeared in the New England Journal of Medicine and NEJM Evidence². Not medical advice.