Olpasiran markedly reduces lipoprotein(a) in atherosclerotic cardiovascular disease: NEJM

Lipoprotein(a) is a speculated risk factor for ASCVD. Olpasiran is a small interfering RNA (siRNA) that lowers the synthesis of Lp(a) in the liver. Michelle L. O'Donoghue and colleagues conducted a double-blind, randomized, dose-finding, placebo-controlled trial that included patients with established atherosclerotic cardiovascular disease and an Lp(a) concentration of more than 150 nmol per liter.

Two hundred eighty-one enrolled patients were randomly allocated to receive one of four olpasiran doses (75 mg every 12 weeks, 10 mg every 12 weeks, 225 mg every 24 weeks, or 225 mg every 12 weeks) or a matching placebo which was administered subcutaneously. Percent change in the LP(a) concentration from baseline to week 36 was reported as the placebo-adjusted mean percent change (primary endpoint). Also, safety was assessed.

The authors reported the following findings:

• At baseline, the median concentration of lipoprotein(a) among the 281 enrolled patients was 260.3 nmol per liter, and the median low-density lipoprotein cholesterol (LDL-C) concentration was 67.5 mg per deciliter.
• 88% of the people were taking statin therapy at baseline, 23% were taking a PCSK9 (proprotein convertase subtilisin–kexin type 9) inhibitor, and 52% were taking ezetimibe.
• The lipoprotein(a) concentration increased by a mean of 3.6% in the placebo group at 36 weeks.
• Olpasiran therapy significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of −70.5% with the 10-mg dose, −97.4% with the 75-mg dose, −101.1% with the 225-mg dose administered every 12 weeks, and −100.5% with the 225-mg dose administered every 24 weeks.
• The overall incidence of adverse events was comparable across the trial groups.
• The most common olpasiran-related adverse events were injection-site reactions, primarily pain.

To conclude, olpasiran therapy notably reduced the concentrations of lipoprotein(a) in patients with established ASCVD.

"Larger and longer trials will be needed to determine the effect of olpasiran therapy on cardiovascular disease," the researchers wrote.

Reference:

The study, "Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease," was published in the New England Journal of Medicine.

DOI: 10.1056/NEJMoa2211023