TARGETING LIPOPROTEIN(A): THE EMERGING ERA OF RNA-BASED THERAPIES IN CARDIOVASCULAR RISK REDUCTION

Résumé fourni par la source

ASCVD /CVD Risk Reduction Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, stroke, and aortic stenosis. Elevated Lp(a) affects up to 20% of the population, and no FDA-approved therapies currently exist to specifically target its reduction. Lepodisiran, a novel small interfering RNA (siRNA) agent, has emerged as a promising therapy for targeted Lp(a) lowering. This review aims to synthesize the available clinical evidence on lepodisiran, including data from Phase 1 and 2 trials, highlighting its efficacy, safety profile, and potential implications for cardiovascular risk management. A narrative synthesis of peer-reviewed studies evaluating lepodisiran in humans was conducted. Key outcomes included percent change in Lp(a) concentration, duration of effect, and safety findings. The Phase 1 randomized, placebo-controlled dose-escalation study (JAMA, 2023) included 48 participants with Lp(a) ≥75 nmol/L. Lepodisiran demonstrated a dose-dependent and sustained reduction in Lp(a) levels. The highest dose (608 mg) achieved a median 97% reduction in Lp(a), sustained through 48 weeks. No serious adverse events related to the drug were reported, and injection-site reactions were mild. The Phase 2 ALPACA trial (NEJM, 2025), a multicenter, randomized, placebo-controlled trial of 320 participants with elevated Lp(a), confirmed these findings. A single 400 mg dose resulted in an average 93.9% reduction in Lp(a) over a six-month period, with durable effects and a favorable safety profile. Dose-response relationships were evident, and the pharmacodynamic impact was consistent across subgroups. Lepodisiran shows robust, dose-dependent, and long-lasting reductions in Lp(a) concentrations, with a favorable safety profile. These findings position lepodisiran as a highly promising therapeutic candidate for individuals at elevated ASCVD risk due to high Lp(a) levels. Ongoing Phase 3 trials are expected to clarify whether Lp(a) lowering with lepodisiran translates to improved cardiovascular outcomes

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