Importance Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities.

Objectives To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a).

Design, Setting, and Participants Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023.

Interventions Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval.

Main Outcomes Measures The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations.

Results Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, −30% (IQR, −51% to −18%) for the 300 mg of zerlasiran group, and −29% (IQR, −39% to −7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, −17 to 28) nmol/L for the placebo group, −258 (IQR, −289 to −188) nmol/L for the 200 mg of zerlasiran group, −310 (IQR, −368 to −274) nmol/L for the 300-mg dose group, and −242 (IQR, −343 to −182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, −4% to 21%), −97% (IQR, −98% to −95%), −98% (IQR, −99% to −97%), and −99% (IQR, −99% to −98%), respectively, attenuating to 0.3% (IQR, −2% to 21%), −60% (IQR, −71% to −40%), −90% (IQR, −91% to −74%), and −89% (IQR, −91% to −76%) 201 days after administration.

Conclusions Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration.