Zerlasiran-A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Genetics

Background:

• Elevated lipoprotein(a) is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.
• Targeting hepatic synthesis of apolipoprotein(a) offers a potential therapeutic strategy to lower lipoprotein(a) levels.

Purpose of the Study:

• To evaluate the efficacy of zerlasiran, a small-interfering RNA (siRNA) therapeutic, in reducing serum lipoprotein(a) concentrations.
• To assess the safety and tolerability of zerlasiran in patients with established ASCVD.

Main Methods:

• A multicenter, randomized trial involving patients with stable ASCVD and elevated lipoprotein(a) (≥125 nmol/L).
• Participants received subcutaneous placebo or varying doses of zerlasiran (300 mg or 450 mg) every 16 or 24 weeks for up to 3 doses.
• The primary outcome was the time-averaged percent change in lipoprotein(a) from baseline to 36 weeks.

Main Results:

• Zerlasiran treatment resulted in substantial reductions in lipoprotein(a) levels, with time-averaged changes ranging from -81.3% to -85.6% compared to placebo.
• Median percent reductions at 36 weeks were notable, reaching up to -96.4% in the zerlasiran groups.
• The therapy was well-tolerated, with the most common adverse events being mild injection site reactions; no serious adverse events were deemed related to the study drug.

Conclusions:

• Zerlasiran effectively and significantly reduces lipoprotein(a) concentrations in patients with ASCVD.
• The siRNA therapy demonstrates a favorable safety profile, suggesting its potential as a treatment for managing cardiovascular risk associated with elevated lipoprotein(a).