N Engl J Med

ACC 2025: Investigational drug dramatically lowers Lp(a) levels

April 1, 2025

Lepodisiran, a novel small interfering RNA (siRNA), could be a groundbreaking therapy for patients with elevated lipoprotein(a) [Lp(a)], according to results presented at American College of Cardiology (ACC).25. The substantial and sustained reduction in Lp(a) levels with a single injection highlights its potential to significantly mitigate cardiovascular risk in affected patients.

Study details: The phase 2 ALPACA study, conducted from November 2022 to April 2023 across 66 centers globally, evaluated the efficacy of lepodisiran in reducing Lp(a) levels. The study included 320 participants, with a median baseline Lp(a) concentration of 253.9 nmol/L. Participants were randomized to receive varying doses of lepodisiran or placebo.

Results: Lepodisiran significantly reduced Lp(a) levels in a dose-dependent manner. The 16-mg dose resulted in a 41% reduction, the 96-mg dose achieved a 75% reduction, and the 400-mg dose led to a 94% reduction in Lp(a) levels from baseline to days 60-180. The effect was sustained, with a 91% reduction at one year and 74% at 18 months.

Sources:

Nissen, S., et al. (2025, March 30). N Engl J Med. Lepodisiran – A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). https://www.nejm.org/doi/full/10.1056/NEJMoa2415818

(2025, March 30). American College of Cardiology. ALPACA: Single Injection of Novel Lepodisiran Reduces Lp(a) Concentration. https://www.acc.org/Latest-in-Cardiology/Journal-Scans/2025/03/24/16/30/sun-130pm-alpaca-acc-2025