Lepodisiran Demonstrates Sustained Lipoprotein(a) Reduction in Phase 2 Trial.

A phase 2 study published in The New England Journal of Medicine evaluated the safety and efficacy of lepodisiran, a long-acting small interfering RNA (siRNA) targeting hepatic synthesis of lipoprotein(a) [Lp(a)], a genetically determined and prevalent risk factor for atherosclerotic cardiovascular disease. Conducted across 66 global centers, the trial randomized 320 adults with elevated Lp(a) (≥175 nmol/L) into five groups receiving different doses of lepodisiran or placebo via subcutaneous injection.

The primary endpoint was the placebo-adjusted time-averaged percent change in serum Lp(a) from baseline to day 180. The highest dose (400 mg) led to a 93.9% reduction (95% CI, −95.1 to −92.5). After a second 400-mg dose at day 180, the reduction remained substantial at day 360 (−94.8%) and day 540 (−74.2%), highlighting the drug's prolonged action.

Secondary endpoints reinforced these findings, with consistent dose-dependent reductions in apolipoprotein B and high-sensitivity C-reactive protein. Injection-site reactions, the most frequent adverse event, were generally mild and occurred in up to 12% of patients in the highest-dose group. No serious adverse events were attributed to lepodisiran.

These results suggest that lepodisiran can achieve and maintain profound reductions in Lp(a) levels with infrequent dosing, a key advantage in long-term cardiovascular risk management. A phase 3 trial evaluating cardiovascular outcomes (NCT06292013) is underway to determine whether Lp(a) reduction with lepodisiran translates into clinical benefit.

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