Twenty clinical trials map the Lp(a)-lowering therapeutic landscape across three drug classes, review (J Clin Med 2026)

Background/Objectives: Elevated lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor associated with atherosclerotic cardiovascular disease and calcific aortic valve disease. Historically, therapeutic options for reducing Lp(a) have been limited. This study aimed to characterize the clinical development landscape of emerging Lp(a)-targeted therapies, evaluate endpoint assessment strategies, and summarize available efficacy evidence from investigational agents. Methods: A qualitative clinical trial landscape review was conducted using ClinicalTrials.gov. Interventional Phase I-III studies evaluating therapies specifically targeting Lp(a) were identified through a structured registry search performed on 5 November 2025. Eligible studies were screened according to predefined inclusion and exclusion criteria. Extracted data included trial characteristics, therapeutic class, endpoint methodologies, and published efficacy outcomes. Data were synthesized narratively. Results: Twenty clinical trials met the eligibility criteria. Three therapeutic classes were identified: antisense oligonucleotides (ASOs), small interfering RNA (siRNA)-based therapies, and small-molecule inhibitors. Pelacarsen represented the sole ASO program, whereas siRNA-based therapies constituted the largest therapeutic category. Five studies were designed as cardiovascular outcomes trials. Percent change from baseline in circulating Lp(a) concentration was the most frequently used efficacy endpoint. Published data demonstrated substantial reductions in Lp(a) concentrations across all major therapeutic platforms. Available non-head-to-head published evidence showed substantial Lp(a) reductions across several investigational agents, including siRNA-based therapies, pelacarsen, and muvalaplin, although differences between studies preclude direct comparison between therapeutic platforms. Conclusions: The Lp(a) therapeutic landscape has rapidly evolved, with RNA-based therapies demonstrating unprecedented reductions in circulating Lp(a) concentrations. Ongoing cardiovascular outcomes trials will determine whether these reductions translate into meaningful cardiovascular benefits, establish Lp(a) as a therapeutic target in cardiovascular prevention and clarify the long-term safety and risk-benefit profile of Lp(a)-targeted therapies.