The novel extended-duration small interfering RNA lepodisiran reduced mean serum concentrations of lipoprotein(a) (Lp[a]) from 60 to 180 days after being administered subcutaneously, according to results presented from the ALPACA study during a Featured Clinical Research session at ACC.25 in Chicago and simultaneously published in the NEJM.

In the phase 2 ALPACA study, conducted at 66 centers across Europe, Asia and the Americas from November 2022 to April 2023, 320 participants were randomized to one of five regimens of lepodisiran: 16 mg, 96 mg or 400 mg at baseline; 400 mg or placebo at day 180; or placebo at both time points. The mean age of patients was 62.7 years and 43% were women, and their median baseline concentration of Lp(a) was 253.9 nmol/liter. A total of 312 patients were included in the present analysis.

Among the participants, 68% were at high risk of a cardiovascular event, 48% had coronary artery disease and 31% had a previous myocardial infarction. A majority were on concomitant medications: 74% on statins, 33% on ezetimibe and 6% on PCSK9 inhibitors.

For the primary outcome of placebo-adjusted time-averaged percent change from baseline to days 60-180 in Lp(a) concentration, the reduction was –41 percentage points in the 16 mg lepodisiran group and –75 percentage points in the 96 mg lepodisiran group.

In the pooled analysis that included the group that received lepodisiran 400 mg at baseline and day 180 and in the group that received 400 mg of the drug and placebo at day 180, the change in the primary outcome was –94 percentage points. After a second dose of lepodisiran 400 at day 180, the change in Lp(a) was –95 percentage points from baseline to days 30-360, and at day 60 the reduction was sustained at –91 percentage points and at day 540 at –74 percentage points.

The authors note that a single 400 mg dose of lepodisiran was associated with a reduction of 88.5 percentage points in the primary outcome from day 30 to day 360.

Severe adverse events occurred in 35 participants, but none were attributed to lepodisiran; 0-12% of participants overall reported a mild, dose-dependent injection site reaction. One participant in the 16mg/16mg arm died during the study due to chronic cardiomyopathy.

"In the absence of effective therapeutic options, the global health burden of elevated [Lp(a)] concentrations makes development of these therapies an important research priority," write trial authors Steven E. Nissen, MD, MACC, et al.

A trial limitation was the low representation of Black participants, a population that more commonly has elevated Lp(a) than White participants.

In a related editorial comment, Daniel J. Rader, MD, notes that Lp(a)-lowering therapies are currently being studied in several large trials assessing cardiovascular outcomes. "Whether intervention to substantially reduce [Lp(a)] levels will reduce the risk of cardiovascular events to a clinically relevant degree is one of the biggest questions in cardiovascular medicine – and the answer will determine whether a new class of drugs that addresses a major cardiovascular risk factor will eventually be approved and become part of the recommended treatment regimen," he adds.