Key Points
- Elevated lipoprotein(a) is associated with incident atherosclerotic cardiovascular disease and aortic stenosis
- The ALPACA trial randomized 320 patients with a serum lipoprotein(a) concentration ≥175 nmol/L in 1:2:2:2:2 ratio to receive lepodisiran 16 mg (baseline and 180 days), lepodisiran 96 mg (baseline and 180 days), lepodisiran 400 mg (baseline and 180 days), lepodisiran 400mg at baseline followed by placebo at 180 days, or placebo at both timepoints
- The placebo-adjusted time-averaged change in lipoprotein(a) from day 60 to day 180 was 94% for the pooled lepodisiran groups.
Epidemiological studies and Mendelian randomization analyses have demonstrated a strong association between elevated lipoprotein(a) and incident atherosclerotic cardiovascular disease and aortic stenosis. Currently, no pharmacologic therapies are approved by regulators for the treatment of elevated lipoprotein(a). Lepodisiran is a small interfering RNA (siRNA) that inhibits hepatic production of apolipoprotein(a).
The ALCAPA trial was a Phase II randomized clinical trial conducted in 66 centers in 10 countries undertaken to evaluate the safety and efficacy of leposidiran at various dosages. The trial enrolled individuals aged 40 years or older who had a serum lipoprotein(a) concentration ≥175 nmol/L. Women of childbearing potential were excluded, along with individuals with a recent cardiovascular event, moderate or severe heart failure, an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2, or hepatic enzyme levels more than three times the upper limit of the normal range. Participants were randomized in a 1:2:2:2:2 ratio, to receive subcutaneous lepodisiran 16 mg, 96 mg, or 400 mg at baseline and again at day 180, lepodisiran 400 mg at baseline and placebo at day 180, or placebo at baseline and at day 180. The primary end point was the time-averaged percent change from baseline in serum lipoprotein(a) concentration from day 60 to day 180. Primary results were presented at ACC 2025 with simultaneous publicacion in NEJM.
The average age of the study population was 63 years, approximately 43% were women, and the median lipoprotein(a) concentration was 254 nmol/L. The placebo-adjusted time-averaged percent change in the lipoprotein(a) concentration from day 60 to day 180 was −40.8% (95% CI, −55.8 to −20.6) in the 16-mg lepodisiran group and −75.2% (95% CI, −80.4 to −68.5) in the 96-mg group. The corresponding change in the pooled 400-mg group was −93.9% (95% CI, −95.1 to −92.5). Sustained reductions in lipoprotein(a) were observed out to day 540. No serious adverse events related to lepodisiran were reported.
In conclusion, lepodisiran significantly reduced time-averaged lipoprotein(a) from day 60 to 180 with reductions of 94% observed following a single dose of lepodisiran 400 mg. The investigators commented that “completion of ongoing Phase 3 cardiovascular outcome trials is now a critical research priority to determine whether these therapies can reduce cardiovascular morbidity and mortality”.