abstract
background
Lipoprotein(a) is a suspected risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver.
methods
We conducted a randomized, double-blind, placebo-controlled, dose-ranging study in patients with established atherosclerotic cardiovascular disease and lipoprotein(a) levels greater than 150 nmol per liter. Patients were randomized to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary endpoint was percent change in lipoprotein(a) concentration from baseline through week 36 (expressed as placebo-adjusted mean percent change). Safety was also assessed.
Results
Among the 281 patients enrolled, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter and the median concentration of low-density lipoprotein-cholesterol was 67.5 mg per deciliter. At baseline, 88% of patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor. At 36 weeks, lipoprotein(a) concentrations had increased by an average of 3.6% in the placebo group, while olpasiran therapy had reduced lipoprotein(a) concentrations significantly and substantially in a dose-dependent manner, resulting in placebo-adjusted mean percentage changes of -70.5% for the 10 mg dose, -97.4% for the 75 mg dose, -101.1% for the 225 mg every 12 week dose and -100.5% for the 225 mg dose administered every 24 weeks (P<0.001 for all comparisons to baseline). The overall incidence of adverse events was similar in all study groups. The most common side effects associated with olpasiran were injection site reactions, mainly pain.
Conclusions
Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and more extensive studies will be needed to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.)