Article Impact Level: HIGH Data Quality: STRONG Summary of New England Journal of Medicine, NEJMoa2404143. https://doi.org/10.1056/NEJMoa2404143 Dr. Christie Ballantyne et al.
Points
- Plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, was evaluated in a 48-week, phase 2b trial for its safety and efficacy in patients with mixed hyperlipidemia.
- The study included 353 participants with triglyceride levels ranging from 150 to 499 mg per deciliter and either a low-density lipoprotein (LDL) cholesterol level of ≥70 mg per deciliter or a non–high-density lipoprotein (HDL) cholesterol level of ≥100 mg per deciliter.
- Significant reductions in fasting triglyceride levels were observed with plozasiran at week 24, with differences from placebo of -49.8 to -62.4 percentage points for the various dosages, all statistically significant (P<0.001 for all comparisons).
- Worsening glycemic control was noted in a subset of participants across different dosage groups, with 10% of those receiving a placebo and varying percentages in the plozasiran groups experiencing this adverse effect.
- The findings suggest the potential of plozasiran as a therapeutic intervention for addressing elevated triglyceride levels in patients with mixed hyperlipidemia while highlighting the need for further investigation through a clinical outcomes trial.
Summary
In a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial, the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, were evaluated in patients with mixed hyperlipidemia. The study included 353 participants with triglyceride levels ranging from 150 to 499 mg per deciliter and either a low-density lipoprotein (LDL) cholesterol level of ≥70 mg per deciliter or a non–high-density lipoprotein (HDL) cholesterol level of ≥100 mg per deciliter. The participants were assigned to receive plozasiran or placebo in a 3:1 ratio within four cohorts, with varying dosages and injection schedules. The primary endpoint was the percent change in fasting triglyceride level at week 24.
The results demonstrated significant reductions in fasting triglyceride levels with plozasiran compared to placebo at week 24. The least-squares mean percent change from baseline showed differences 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, all of which were statistically significant (P<0.001 for all comparisons). However, the study also observed worsening glycemic control in a subset of participants across the different dosage groups, with 10% of those receiving placebo, 12% of the 10-mg-quarterly dose group, 7% of the 25-mg-quarterly dose group, 20% of the 50-mg-quarterly dose group, and 21% of the 50-mg-half-yearly dose group experiencing this adverse effect.
In conclusion, the trial demonstrated that plozasiran significantly reduced triglyceride levels at 24 weeks in participants with mixed hyperlipidemia. The findings suggest the potential of plozasiran as a therapeutic intervention for addressing elevated triglyceride levels in this patient population while highlighting the need for further investigation through a clinical outcomes trial.
Link to the article: https://www.nejm.org/doi/10.1056/NEJMoa2404143
References Ballantyne, C. M., Vasas, S., Azizad, M., Clifton, P., Rosenson, R. S., Chang, T., Melquist, S., Zhou, R., Mushin, M., Leeper, N. J., Hellawell, J., & Gaudet, D. (2024). Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia. New England Journal of Medicine, NEJMoa2404143. https://doi.org/10.1056/NEJMoa2404143
