Zerlasiran, an investigational gene-silencing therapy developed by Silence Therapeutics, has demonstrated promising results in a Phase II trial for patients with elevated lipoprotein(a) (Lp[a]) at high risk of atherosclerotic cardiovascular disease. The trial results, presented at the American Heart Association's (AHA) 2024 Annual Scientific Sessions, indicate that zerlasiran significantly reduces Lp(a) levels, a key cardiovascular risk factor often unaddressed by conventional lipid-lowering drugs.
The 60-week trial (NCT05537571) involved random assignment of participants to various treatment regimens, including placebo and different doses of zerlasiran (300mg or 450mg) administered subcutaneously every 16 or 24 weeks. According to Dr. Steven Nissen, MD, chairman and chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic, zerlasiran reduced time-averaged Lp(a) levels by 80% to 85% over a follow-up period of 36 to 60 weeks.
Impact on Lipid Levels and Safety
Beyond its effect on Lp(a), zerlasiran also demonstrated a reduction in other key lipid parameters. The trial showed that zerlasiran lowered time-averaged low-density lipoprotein cholesterol (LDL-C) by 25–30% and apoB by 10% to 15%. Importantly, zerlasiran was found to be well-tolerated, with no significant safety concerns observed during the study.
Addressing Unmet Needs in Lp(a) Management
Key opinion leaders emphasize the significant unmet need for therapies specifically targeting Lp(a). Conventional therapies often fail to effectively lower Lp(a) levels, leaving patients with elevated Lp(a) at increased cardiovascular risk. Zerlasiran's mechanism of action, which involves silencing the LPA gene responsible for Lp(a) production, offers a targeted approach to reduce this specific risk factor.
The gene-silencing mechanism of zerlasiran, utilizing small interfering RNA, allows for sustained reduction of Lp(a) levels with infrequent dosing. This has the potential to improve patient adherence and enhance long-term cardiovascular outcomes. The Phase II data suggests that each additional dose of zerlasiran resulted in further reductions in Lp(a) levels, raising the possibility of even less frequent dosing in future Phase III trials.
