1. Olpasiran significantly and substantially reduced lipoprotein(a) concentration in patients with atherosclerotic cardiovascular disease compared to placebo.

2. Olpasiran reduced low-density lipoprotein (LDL) cholesterol concentration in patients with atherosclerotic cardiovascular disease compared to placebo. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Elevated lipoprotein(a) concentrations have been associated with an increased risk of atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA (siRNA) molecule that stops the expression of lipoprotein(a) via the apolipoprotein(a) gene (LPA). At baseline, the characteristics of both treatment and placebo groups were well matched. No significant mean percent change in lipoprotein(a) concentration was seen in the placebo group, but a significant reduction was seen in all doses of olpasiran groups at 36 weeks. A reduction of lipoprotein(a) was observed in all prespecified subgroups. Olpasiran also reduced concentrations of LDL cholesterol and LPA at 36 weeks. Participants that had a lipoprotein(a) concentration at the prespecified endpoint appeared to have a dose-response. Similar rates of adverse events and serious adverse events were seen in both the treatment and placebo groups. No patients died from cardiovascular-related events in this trial in either treatment or placebo groups. Although a significant reduction of lipoprotein(a) concentrations was observed in this study, there were no other primary endpoints to determine whether treatment confers any clinical benefits such as cardiovascular outcomes, morbidity, or mortality. Additionally, a large cohort of study participants were on statin therapy, ezetimibe, and proprotein convertase subtilisin-kexin type 9 inhibitors which may be a confounding factor when examining the clinical benefit of olpasiran.

Click to read the study in NEJM

Relevant Reading: Genetic variants associated with Lp(a) lipoprotein level and coronary disease

In-Depth [randomized controlled trial]: This phase two OCEAN(a)-DOSE trial (Olpasiran trials of cardiovascular events and lipoprotein[a] reduction-dose finding study) evaluated the efficacy and safety of different doses of olpasiran in patients with cardiovascular disease. Participants were randomized to receive one of four doses of olpasiran subcutaneously (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or placebo for a 48-week treatment period. A total of 281 patients were randomized to olpasiran (227 patients) or placebo (52 patients) groups. The median lipoprotein(a) concentration at baseline was 260.3 nmol per liter and LDL cholesterol concentration was 67.5 mg per deciliter. At 36 weeks, those in the placebo group saw a mean increase in lipoprotein(a) concentration of 3.6% (95% Confidence interval [CI], -0.1 to 7.3). The olpasiran treatment saw a significant reduction in mean lipoprotein(a) levels in all dosage groups at 36 weeks. The placebo-adjusted mean percent change in lipoprotein(a) concentration was the following: -70.5% (95% CI, -75.1 to -65.9) in the 10-mg dose group, -97.4% (95% CI, -102.0 to -92.8) in the 75-mg dose group, -101.1% (95% CI, -105.8 to -96.5) in the 225-mg dose every 12 weeks group, and -100.5% (95% CI, -105.2 to -95.8) in the 225-mg dose every 24 weeks group (p<0.001 for all groups compared to baseline). The placebo-adjusted mean percentage in LDL cholesterol concentration was -22.6% to -24.8% across all olparisan dose groups. The incidence of adverse events leading to discontinuation in both the placebo and treatment groups was 2%. Three patients in the placebo group and two patients in the treatment group experienced a primary cardiovascular event during the study. Overall, the present study suggests that olparisan may help prevent the development of atherosclerotic cardiovascular disease.

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