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Zerlasiran was associated with deep reductions in lipoprotein a (Lp(a)) levels, decreasing further with each subsequent dose in patients with elevated Lp(a) levels and risk for atherosclerotic cardiovascular disease-related events. Further investigation of zerlasiran in a phase 3 trial is warranted.

In a phase 2 study, Stephen Nissen, MD, from the Cleveland Clinic, MD, in Ohio, and his team tested the small interfering RNA molecule zerlasiran as a Lp(a) targeting agent among patients with an elevated Lp(a) level (i.e. ≥125 nmol/L) and an increased risk for atherosclerotic cardiovascular disease-related events¹. The 178 participants were randomly assigned 1:1:2:2:2 to one of the placebo arms, to zerlasiran 300 mg, every 16 weeks (three doses), zerlasiran 300 mg, every 24 weeks (two doses), or zerlasiran 450 mg, every 24 weeks (two doses). Zerlasiran was administered intravenously. The primary endpoint was the time-averaged Lp(a) concentration from baseline to week 36.

For the 450 mg arm, the authors observed a drop of Lp(a) of approximately 95% after 4 weeks, increasing slowly to a reduction from baseline of 57.7%, after which the second dose was administered (at week 24). At week 28, the Lp(a) level had dropped to -97.2% from baseline, rising to a reduction from baseline of 71.7% at week 48. “Thus, the Lp(a) level remains lower for a longer time after the second dose, which is an important finding of this study,” emphasized Dr. Nissen. These findings were consistent for the other two active arms. The time-averaged changes in Lp(a) from baseline to week 36 were between -80% and -85% in the active arms. Furthermore, the corresponding results for LDL-cholesterol levels were around -25% and -32%; for ApoB they were between -10% and -15%. According to Dr. Nissen, no major safety or tolerability issues emerged.

These promising results support further investigation of zerlasiran in a phase 3 study. “We also need to study the effects of zerlasiran in Black patients, who tend to have higher Lp(a) levels,” mentioned Dr. Nissen.

Medical writing support was provided by Robert van den Heuvel.

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