Silence Therapeutics recently unveiled end-of-treatment data from its Phase 2 ALPACAR-360 study of zerlasiran, an siRNA therapy, in individuals with atherosclerotic cardiovascular disease (ASCVD) and high lipoprotein(a) [Lp(a)] levels. The findings were presented at the American Heart Association Scientific Sessions 2024 and concurrently published in JAMA.
The study explored the efficacy of various zerlasiran dosages and intervals (300 mg every 16 weeks, 300 mg every 24 weeks, and 450 mg every 24 weeks). Results demonstrated significant reductions in Lp(a) concentrations. Over 36 weeks, all three regimens achieved mean time-averaged placebo-adjusted reductions exceeding 80% from baseline. Notably, this study marks the first to employ time-averaged Lp(a) analysis, providing a more comprehensive assessment of treatment effects over time. Maximum Lp(a) reductions even surpassed 90%. Importantly, Lp(a) reductions were sustained 60 weeks after the initial dose, with no new safety concerns identified.
This data will inform the selection of the optimal dose and dosing frequency for forthcoming Phase 3 zerlasiran trials. Elevated Lp(a) affects at least 20% of the global population and represents a substantial contributor to cardiovascular morbidity and mortality. As a genetic risk factor previously untreatable, gene-silencing therapies like zerlasiran offer promising new avenues for patient care.
The ALPACAR-360 study reinforces the potential of zerlasiran, particularly its durable Lp(a) reduction with infrequent dosing. The Phase 2 data suggest zerlasiran’s promise as a novel treatment for individuals with high Lp(a), paving the way for Phase 3 investigations.
Lp(a) is a genetically determined and independent risk factor for cardiovascular disease. While a definitive threshold for high Lp(a) remains to be established, approximately 20% of adults have Lp(a) levels exceeding 125 nmol/L. Increasing evidence points to the role of high Lp(a) in myocardial infarction, stroke, and peripheral arterial disease.
The ALPACAR-360 program aims to evaluate zerlasiran’s ability to reduce cardiovascular event risk in ASCVD patients with high Lp(a). This multicenter, randomized, double-blind, placebo-controlled Phase 2 study included 178 participants with ASCVD and Lp(a) levels ≥125 nmol/L (baseline Lp(a) concentration: 213 nmol/L). Patients were randomly allocated to one of the three zerlasiran doses mentioned earlier or a placebo. The primary endpoint was the time-averaged Lp(a) change from baseline to 36 weeks. Secondary endpoints encompassed time-averaged LDL-C changes and time-averaged Lp(a) changes to 48 and 60 weeks.
Silence Therapeutics, a clinical-stage biotechnology company, is dedicated to developing precision-engineered siRNA therapies to address a range of diseases. Their proprietary mRNAi GOLDâ„¢ platform facilitates the creation of siRNAs targeting disease-associated genes in the liver. The company’s pipeline focuses on areas of high unmet medical need, including cardiovascular disease, hematology, and rare diseases. Silence also collaborates with AstraZeneca and Hansoh Pharma, among other partners, on research and development initiatives.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
