The use of olpasiran therapy in patients with atherosclerotic cardiovascular disease significantly reduces lipoprotein(a) concentrations, according to new randomized trial results. These findings from the OCEAN(a)-DOSE trial were reported Sunday at the American Heart Association Scientific Sessions 2022 in Chicago by Michelle L. O’Donoghue, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School, Boston. O’Donoghue and colleagues also reported these results in a manuscript simultaneously published online in The New England Journal of Medicine. Patients who have higher levels of circulating lipoprotein(a) have an increased risk for developing atherosclerotic cardiovascular disease, as well as calcific vascular aortic stenosis. Despite these data, there are currently no drug treatments that dramatically reduce the amount of lipoprotein(a). The apolipoprotein(a) (LPA) gene regulates the expression of lipoprotein(a). The olpasiran siRNA molecule prevents the creation of lipoprotein(a) molecules in liver cells. The Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study (OCEAN[a]-DOSE) trial enrolled 281 patients who had more than 150 nmol per liter of lipoprotein(a) in their systems. Patients were randomly divided into five groups (placebo group: mean age=63.4 ± 9.6 years; olpasiran group: mean age=61.6 ± 9.6 years): placebo every 12 weeks (67% male, 89% white), 10 mg olpasiran every 12 weeks (79% male, 90% white), 75 mg of olpasiran every 12 weeks (60% male, 90% white), 225 mg of olpasiran every 12 weeks (73% male, 84% white) or 225 mg of olpasiran every 24 weeks (60% male, 89% white). Olpasiran was delivered subcutaneously. Prior medical histories of the patients included coronary artery disease, myocardial infarction, hypertension, heart failure and other various cardiac-related conditions. At baseline, the median concentration of lipoprotein(a) was 260.3 nmol per liter, the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter, 88% of patients were on a statin, 52% of patients were on ezetimibe and 23% were on a proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor. At the 36-week follow-up, placebo patients had a mean 3.6% increase in lipoprotein(a) concentration, while the olpasiran patients had decreased levels of lipoprotein(a) concentration that was dose-dependent. Adjusting for placebo, patients with the 10 mg olpasiran dose had −70.5% lipoprotein(a) concentration, 75 mg dose had −97.4%, 225 mg dose every 12 weeks had −101.1% and 225 mg dose every 24 weeks had −100.5% (P < 0.001 for all groups, compared to baseline). The investigators also addressed safety concerns throughout the study. Adverse events occurred similarly in all groups. The most common adverse event was pain at the injection site. There was one death in the placebo group, which was not related to cardiovascular issues. Though this study demonstrates a significant decrease in the concentration of lipoprotein(a) when patients are injected with olpasiran, the authors acknowledge that it is unclear whether olpasiran will decrease the risk of negative cardiovascular events. In her slide presentation, O’Donoghue concluded that a 75-mg or higher dose of olpasiran every 12 weeks reduces lipoprotein(a) concentration by more than 95% in patients with established atherosclerotic cardiovascular disease and that olpasiran “appears safe and well-tolerated.” “These findings set the foundation for phase 3 testing scheduled to commence later this year,” she said in her concluding slide. The OCEAN(a)-DOSE trial was funded by Amgen, the manufacturer of olpasiran. Source: O’Donoghue ML, Rosenson RS, Gencer B, et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med 2022 Nov 6. (Article in press)