ALPACA: lepodisiran 400 mg lowers Lp(a) by 94 percent from day 60 to 180, and by 95 percent over a year with a second dose (Nissen et al., NEJM 2025)

Original title: Lepodisiran - A Long-Duration Small Interfering RNA Targeting Lipoprotein(a)

N Engl J Med · 1 May 2025 · 9

Nissen SE, Ni W, Shen X, Wang Q, Navar AM, Nicholls SJ, Wolski K, Michael L, Haupt A, Krege JH, ALPACA Trial Investigators

320 participants with median Lp(a) of 254 nmol/L received lepodisiran 16, 96 or 400 mg at baseline and day 180, 400 mg then placebo, or placebo: placebo-adjusted time-averaged reductions from day 60 to 180 were 40.8, 75.2 and 93.9 percent, and from day 30 to 360 the 400 mg single dose gave 88.5 percent and two doses 94.8 percent, with mild injection-site reactions in up to 12 percent and no drug-related serious adverse events. Presented at ACC.25; the basis of the ACCLAIM-Lp(a) outcomes trial.

Original abstract

Background: Elevated lipoprotein(a) concentrations are associated with atherosclerotic cardiovascular disease. The safety and efficacy of lepodisiran, an extended-duration, small interfering RNA targeting hepatic synthesis of lipoprotein(a), are unknown.

Methods: We randomly assigned participants in a 1:2:2:2:2 ratio to receive lepodisiran at a dose of 16 mg, 96 mg, or 400 mg at baseline and again at day 180, lepodisiran at a dose of 400 mg at baseline and placebo at day 180, or placebo at baseline and at day 180, all administered by subcutaneous injection. Data from the two groups that received lepodisiran at a dose of 400 mg at baseline were pooled for the primary analysis. The primary end point was the time-averaged percent change from baseline in the serum lipoprotein(a) concentration (lepodisiran difference from placebo [i.e., placebo-adjusted]) during the period from day 60 to day 180.

Results: A total of 320 participants underwent randomization; the median baseline lipoprotein(a) concentration was 253.9 nmol per liter. The placebo-adjusted time-averaged percent change from baseline in the serum lipoprotein(a) concentration from day 60 to day 180 was -40.8 percentage points (95% confidence interval [CI], -55.8 to -20.6) in the 16-mg lepodisiran group, -75.2 percentage points (95% CI, -80.4 to -68.5) in the 96-mg group, and -93.9 percentage points (95% CI, -95.1 to -92.5) in the pooled 400-mg groups. The corresponding change from day 30 to day 360 was -41.2 percentage points (95% CI, -55.4 to -22.4), -77.2 percentage points (95% CI, -81.8 to -71.5), -88.5 percentage points (95% CI, -90.8 to -85.6), and -94.8 percentage points (95% CI, -95.9 to -93.4) in the 16-mg, 96-mg, 400-mg-placebo, and 400-mg-400-mg dose groups, respectively. Serious adverse events, none of which were deemed by investigators to be related to lepodisiran or placebo, occurred in 35 participants. Dose-dependent, generally mild injection-site reactions occurred in up to 12% (8 of 69) of the participants in the highest lepodisiran dose group.

Conclusions: Lepodisiran reduced mean serum concentrations of lipoprotein(a) from 60 to 180 days after administration. (Funded by Eli Lilly; ALPACA ClinicalTrials.gov number, NCT05565742.).

Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.