Plozasiran reduces triglyceride levels in mixed hyperlipidemia

1. In this randomized controlled trial, among patients with mixed hyperlipidemia, plozasiran significantly reduced fasting triglyceride levels compared with placebo.

2. Compared with placebo, the plozasiran groups also saw reductions in apolipoprotein C3 (APOC3), non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B (apoB) levels. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Mixed hyperlipidemia is a common disorder with elevated triglyceride and low-density lipoprotein (LDL) cholesterol levels. A fasting triglyceride level greater than 150 mg/dL increases the risk of atherosclerotic cardiovascular disease (ASCVD). Current LDL cholesterol-lowering therapies have succeeded in reducing the risk of ASCVD among patients with mixed hyperlipidemia, but significant risk remains due to elevated triglyceride and cholesterol remnant levels. APOC3 is a glycoprotein that is a key regulator of triglyceride-rich lipoprotein metabolism. Plozasiran is a small interfering RNA designed to reduce APOC3 expression in the liver and has been shown in a phase one study to produce substantial reductions in APOC3 and triglyceride levels among healthy volunteers and patients with hypertriglyceridemia. The present trial assessed the efficacy and safety of plozasiran compared with placebo among patients with mixed hyperlipidemia. Compared to placebo, plozasiran resulted in significant reductions in fasting triglyceride levels at week 24 and commensurate reductions in APOC3, non-HDL cholesterol, and apo B levels. The study was limited by the demographic characteristics of its participants, 90% of whom were White, limiting the generalizability of the study findings. Additionally, the trial did not assess the effect of plozasiran on the risk of ASCVD, and as such, the impact of the drug on clinical outcomes remains unknown. Nevertheless, these findings have helped lay the necessary groundwork for a phase three trial examining the effect of plozasiran on ASCVD risk.

Click to read the study in NEJM

Relevant Reading: RNA interference therapy targeting apolipoprotein C-III in hypertriglyceridemia

In-Depth [randomized controlled trial]: This phase 2b, double-blind, randomized controlled trial compared the effects of plozasiran with those of placebo on fasting triglyceride, APOC3, non-HDL cholesterol, and apo B levels in patients with mixed hyperlipidemia. Adults aged 18 or older with a fasting triglyceride level of 150-499 mg/dL and an LDL cholesterol of ≥70 mg/dL or a non-HDL cholesterol of ≥100 mg/dL were included. The primary outcome was the mean percent change in the fasting plasma triglyceride level from baseline to week 24. A total of 324 patients completed the trial and were assigned in a 3:1 ratio to receive plozasiran or placebo, with 60 participants receiving 10 mg plozasiran quarterly (on day one and at week 12), 64 receiving 25 mg plozasiran quarterly, 61 receiving 50 mg plozasiran quarterly, 61 receiving 50 mg plozasiran half-yearly (on day one and at week 24), and 78 receiving volume-matched placebos. At week 24, the least-squares mean percent change in fasting triglyceride level from baseline, compared with placebo, was −49.8 percentage points (95% Confidence Interval [CI], −59.0 to −40.6) in the 10-mg-quarterly group, −56.0 percentage points (95% CI, −65.1 to −46.8) in the 25-mg-quarterly group, −62.4 percentage points (95% CI, −71.5 to −53.2) in the 50-mg-quarterly group, and −44.2 percentage points (95% CI, −53.4 to −35.0) in the 50-mg-half-yearly group. Commensurate reductions were observed in the APOC3 level, which showed strong, positive correlations with the changes in fasting triglyceride level (Pearson correlation coefficient, 0.85), as well as in non-HDL cholesterol and apo B levels. The safety of plozasiran was also assessed, and the incidence of adverse events throughout the trial period was found to be similar between the plozasiran and placebo groups. In summary, among patients with mixed hyperlipidemia, plozasiran was found to be safe and resulted in significant reductions in fasting triglyceride levels, as well as commensurate reductions in APOC3, non-HDL cholesterol, and apo B levels.

Image: PD

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