Lepodisiran, a long-duration small interfering RNA, reduces lipoprotein(a) levels

1. Lepodisiran, a long-duration small interfering RNA targeting lipoprotein(a) synthesis, reduced serum concentrations of lipoprotein(a) compared to placebo in adults with elevated levels.

2. Lepodisiran was associated with injection-site reactions, but no serious adverse events.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Elevated serum lipoprotein(a) levels are prevalent in worldwide populations and associated with an increased risk of atherosclerosis, cardiovascular disease, aortic stenosis, and increased mortality. Common lipid-modifying approaches, such as lifestyle management and statins, do not significantly impact lipoprotein(a) levels. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors could slightly reduce lipoprotein(a), but evidence is lacking in patients with elevated levels. No specific pharmacologic therapy has been approved. This study assessed the effect of lepodisiran, a small interfering RNA that inhibits hepatic production of apolipoprotein(a), which is the rate-limiting step in lipoprotein(a) synthesis. Among adults 40 years of age and older with serum lipoprotein(a) level ≥175nmol/L, lepodisiran administered 180 days apart, significantly reduced mean serum concentration of lipoprotein(a) 60-180 days after administration, compared to placebo. Lepodisiran was not associated with an increased risk of adverse events, compared to placebo. The study was limited to two doses of lepodisiran, and Black patients, among whom elevated lipoprotein(a) is more common, were underrepresented in the study. Nevertheless, these results provided early evidence that lepodisiran reduced serum concentrations of lipoprotein(a) and had an acceptable safety profile.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This was a clinical trial designed to evaluate the safety and efficacy of lepodisiran in reducing lipoprotein(a) concentrations. Adults aged 40 years or older with a baseline serum lipoprotein(a) concentration ≥175 nmol/L were eligible for inclusion. A total of 320 patients were enrolled and randomized. The primary outcome was the placebo-adjusted time-averaged percent change from baseline in serum lipoprotein(a). Overall, lepodisiran demonstrated significant dose-dependent reductions in Lipoprotein(a), with the placebo-adjusted time-averaged percent change from baseline (day 60-180) being -40.8 percentage points (pp) (95% confidence interval [CI] -55.8 to -20.6) for 16 mg, -75.2 pp (95% CI -80.4 to -68.5) for 96 mg, and -93.9 pp (95% CI -95.1 to -92.5) for the pooled 400 mg. The lipoprotein(a) lowering effect was durable. The placebo-adjusted time-averaged percent change from day 30 to day 360 was -94.8 pp (95% CI -95.9 to -93.4) in the 400mg-400mg group and -88.5 pp (95% CI -90.8 to -85.6) in the 400mg-placebo group. At day 540, the placebo-adjusted was -74.2 pp (95% CI -78.8 to -68.5) for the 400mg-400mg group, with dose-dependent attenuation in the lower-dose groups. Dose-dependent reductions in apoprotein B were also observed, with a maximal placebo-adjusted reduction of -15.5 pp (95% CI -21.0 to -9.6) at day 240 in the 400mg-400mg group. Lepodisiran was generally well-tolerated. Adverse events occurred in 74% of patients and were deemed to be related to lepodisiran or placebo in 10% of patients. Serious adverse events occurred in 11%, but none were deemed related to lepodisiran. These results demonstrated that lepodisiran provided durable reductions in lipoprotein(a) concentrations with a favorable safety profile over 540 days and prompted a need for further investigation into nucleic acid-based lipoprotein(a)-lowering therapies.

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