Plozasiran: Groundbreaking RNA Interference Agent Targets APOC3 for Mixed Hyperlipidemia

The randomized, controlled trial (MUIR) involving participants with mixed hyperlipidemia showed that hyperlipidemia significantly reduced triglyceride levels at 24 weeks compared to placebo. The findings were published online in the New England Journal of Medicine on May 28, 2024.

Mixed hyperlipidemia poses a significant health risk, predisposing individuals to cardiovascular diseases, including heart attacks and strokes, due to an elevated non–high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. While conventional treatments such as statins have proven effective in managing lipid levels, they often fall short in adequately addressing mixed hyperlipidemia, leaving a treatment gap that Plozasiran aims to fill.

The clearance and metabolism of triglyceride-rich lipoproteins are down-regulated through APOC3–mediated inhibition of lipoprotein lipase. Christie M. Ballantyne, Baylor College of Medicine and the Texas Heart Institute, Houston, and colleagues conducted a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter).

The participants were assigned in a ratio of 3:1 to receive plozasiran or a placebo within each of the four cohorts (353 participants underwent randomization). In the first three cohorts, the participants received a subcutaneous plozasiran injection (10 mg, 25 mg, or 50 mg) or placebo on day one and week 12 (quarterly doses). In the fourth cohort, participants received 50 mg plozasiran or placebo on day one, and at week 24 (half-yearly dose).

The researchers pooled data from the participants who received a placebo. The primary endpoint was the percent change in fasting triglyceride level at week 24.

Based on the study, the researchers reported the following findings:

• At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of −49.8 percentage points with the 10-mg-quarterly dose, −56.0 percentage points with the 25-mg-quarterly dose, −62.4 percentage points with the 50-mg-quarterly dose, and −44.2 percentage points with the 50-mg-half-yearly dose.
• Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose.

In conclusion, Plozasiran emerges as a beacon of hope for individuals grappling with mixed hyperlipidemia, offering a promising avenue for more effective lipid management. As the journey towards its approval and adoption progresses, the medical community eagerly anticipates the potential impact of this groundbreaking RNA interference agent on improving cardiovascular outcomes and enhancing patient well-being.

Reference:

Ballantyne CM, et al “Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia” N Engl J Med 2024; DOI: 10.1056/NEJMoa2404143.