Article Impact Level: HIGH Data Quality: STRONG Summary of New England Journal of Medicine, NEJMoa2415818. https://doi.org/10.1056/NEJMoa2415818 Dr. Steven E. Nissen et al.
Points
- This study tested lepodisiran, an RNA-based drug targeting liver production of lipoprotein(a), and found significant reductions in Lp(a) levels compared to placebo across all tested doses.
- Among 320 participants with elevated baseline Lp(a), the highest dose of lepodisiran (400 mg) achieved a reduction of nearly 94 percent, sustained for up to 360 days post-injection.
- The drug demonstrated a clear dose-response effect, with higher doses yielding greater and longer-lasting decreases in Lp(a), a known risk factor for atherosclerotic cardiovascular disease.
- Safety outcomes were favorable, with no serious adverse events linked to lepodisiran and only mild injection-site reactions in a small percentage of high-dose participants.
- These findings support lepodisiran as a promising therapy for lowering Lp(a) in patients at risk for cardiovascular disease, warranting further clinical investigation and development.
Summary
This study aimed to evaluate the efficacy and safety of lepodisiran, a small interfering RNA targeting hepatic synthesis of lipoprotein(a) (Lp(a)), in reducing serum Lp(a) concentrations in individuals at risk for atherosclerotic cardiovascular disease. Participants were randomized to receive lepodisiran at doses of 16 mg, 96 mg, or 400 mg, or placebo, administered subcutaneously at baseline and again at day 180. The primary endpoint was the time-averaged percent change from baseline in serum Lp(a) concentrations from day 60 to day 180, comparing lepodisiran to placebo.
320 participants were enrolled, with a median baseline Lp(a) concentration of 253.9 nmol/L. In the primary analysis, the placebo-adjusted reduction in serum Lp(a) was significant across all treatment groups. The 16 mg dose reduced Lp(a) by −40.8 percentage points (95% CI, −55.8 to −20.6), the 96 mg dose by −75.2 percentage points (95% CI, −80.4 to −68.5), and the pooled 400 mg dose by −93.9 percentage points (95% CI, −95.1 to −92.5). The effect was maintained over a longer period, with reductions from day 30 to day 360 of −41.2 (95% CI, −55.4 to −22.4), −77.2 (95% CI, −81.8 to −71.5), and −94.8 (95% CI, −95.9 to −93.4) percentage points, respectively.
Safety assessments revealed serious adverse events in 35 participants, but none were related to lepodisiran or placebo. Dose-dependent, mild injection-site reactions were observed in up to 12% of participants in the 400 mg dose group. These results suggest that lepodisiran effectively reduces Lp(a) levels, with a favorable safety profile, supporting its potential as a therapeutic option for individuals with elevated Lp(a) and atherosclerotic cardiovascular disease risk.
Link to the article: https://www.nejm.org/doi/10.1056/NEJMoa2415818
References Nissen, S. E., Ni, W., Shen, X., Wang, Q., Navar, A. M., Nicholls, S. J., Wolski, K., Michael, L., Haupt, A., & Krege, J. H. (2025). Lepodisiran—A long-duration small interfering rna targeting lipoprotein(A). New England Journal of Medicine, NEJMoa2415818. https://doi.org/10.1056/NEJMoa2415818
