On 18 November 2024, at the American Heart Association’s (AHA) 2024 Annual Scientific Sessions in Chicago, Illinois, US, during a late-breaking session on the topic of New Targets and New Treatments: Advances in Lipid Therapeutics, the results of the Phase II trial (NCT05537571) were presented. The study evaluated the effect of multiple doses of Silence Therapeutics’ zerlasiran in patients with elevated lipoprotein(a) (Lp[a]) who were at high risk of atherosclerotic cardiovascular disease.
Zerlasiran is a N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA being developed to target elevated levels of Lp(a). This investigational gene-silencing therapy is designed to temporarily block the expression of a specific gene to prevent undesirable effects. In this case, zerlasiran aims to silence the LPA gene, which encodes a protein unique to Lp(a). By inhibiting the LPA gene, zerlasiran lowers Lp(a) levels, which is expected to reduce the risk of heart disease, heart attacks and strokes.
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In the 60-week trial, participants were randomly assigned to one of the following treatment regimens: 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 chairman and chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic and professor of medicine at the Lerner College of Medicine, 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% to 5%. After multiple doses, each additional dose resulted in further reductions in Lp(a) levels, suggesting the possibility of less frequent dosing in Phase III. Zerlasiran was found to be well tolerated and no significant safety concerns were observed.
Key opinion leaders interviewed by GlobalData have emphasised the significant unmet need for therapies that specifically target Lp(a). Patients with elevated Lp(a) levels often have limited treatment options, as conventional therapies do not effectively lower Lp(a). Zerlasiran addresses this gap by providing a targeted approach to reduce this specific cardiovascular risk factor. The key benefit of zerlasiran’s approach is its ability to directly target and silence the gene responsible for Lp(a) production, enabling a precise and significant reduction in Lp(a) levels. High Lp(a) levels are a cardiovascular risk factor that conventional lipid-lowering drugs typically do not address. Additionally, the gene silencing mechanism with small interfering RNA allows for sustained reduction of Lp(a) levels with infrequent dosing, potentially improving patient adherence and enhancing long-term cardiovascular outcomes.
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