At the American Heart Association's (AHA) 2024 Annual Scientific Sessions, Phase II trial results for Silence Therapeutics’ zerlasiran were presented, demonstrating significant reductions in lipoprotein(a) [Lp(a)] levels in patients at high risk of atherosclerotic cardiovascular disease. The study (NCT05537571) evaluated multiple doses of zerlasiran, an N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) designed to target elevated Lp(a).
Targeted Gene Silencing
Zerlasiran is an investigational gene-silencing therapy that temporarily blocks the expression of the LPA gene, which encodes a protein unique to Lp(a). By inhibiting the LPA gene, zerlasiran aims to lower Lp(a) levels, thereby reducing the risk of heart disease, heart attacks, and strokes. High Lp(a) levels are a cardiovascular risk factor that conventional lipid-lowering drugs typically do not address.
Study Design and Results
The 60-week trial randomized participants to various treatment regimens, including placebo and zerlasiran at different doses and intervals. Specifically, participants received either a subcutaneous placebo every 16 weeks for three doses (n=23), a placebo every 24 weeks for two doses (n=24), zerlasiran 300mg every 16 weeks for three doses (n=42), zerlasiran 300mg every 24 weeks for two doses (n=44), or zerlasiran 450mg every 24 weeks for two doses (n=45).
Dr. Steven Nissen, MD, from the Cleveland Clinic, reported that subcutaneous injections of 300mg or 450mg of zerlasiran, administered every 16 or 24 weeks, reduced time-averaged Lp(a) levels by 80% to 85% over a follow-up period of 36 to 60 weeks. Additionally, zerlasiran lowered time-averaged low-density lipoprotein cholesterol (LDL-C) by 25–30% and apoB by 10–15%. The data indicated that each additional dose resulted in further reductions in Lp(a) levels, suggesting the potential for less frequent dosing in Phase III trials. Zerlasiran was well-tolerated, with no significant safety concerns observed.
Addressing Unmet Needs
Key opinion leaders emphasize the significant unmet need for therapies specifically targeting Lp(a). Patients with elevated Lp(a) levels often have limited treatment options, as conventional therapies are not effective in lowering Lp(a). Zerlasiran addresses this gap by providing a targeted approach to reduce this specific cardiovascular risk factor. The gene silencing mechanism with siRNA allows for sustained reduction of Lp(a) levels with infrequent dosing, potentially improving patient adherence and enhancing long-term cardiovascular outcomes.
