美国德州贝勒医学院Christie M. Ballantyne团队研究了靶向APOC3的RNA干扰剂Plozasiran治疗混合性高脂血症的疗效与安全性。相关论文发表在2024年5月28日出版的《新英格兰医学杂志》上。

混合型高脂血症患者有患动脉粥样硬化性心血管疾病的风险，这是由于富含甘油三酯的脂蛋白中残余胆固醇导致的非高密度脂蛋白（HDL）胆固醇水平升高。富含甘油三酯的脂蛋白的代谢和清除通过载脂蛋白C3（APOC3）介导的脂蛋白脂酶抑制而下调。

研究组进行了一项为期48周的2b期双盲、随机、安慰剂对照试验，评估了Plozasiran（一种肝细胞靶向APOC3小干扰RNA）在混合型高脂血症患者中的安全性和有效性（即甘油三酯水平为150至499 mg/dL，低密度脂蛋白胆固醇水平≥70 mg/dL或非高密度脂蛋白水平≥100 mg/dL）。参与者以3:1的比例在四个队列中的每一个队列中接受Plozasiran或安慰剂治疗。在前三组中，参与者在第1天和第12周（季度剂量）皮下注射Plozasiran（10 mg、25 mg或50 mg）或安慰剂。在第四组中，参与者在第1天和第24周（半年剂量）接受了50 mg Plozasiran或安慰剂。来自接受安慰剂治疗的参与者的数据被汇集在一起。主要终点是第24周空腹甘油三酯水平的百分比变化。

共有353名参与者接受了随机分组。在第24周，研究组观察到Plozasiran的空腹甘油三酯水平显著降低，与安慰剂相比，10 mg季度剂量的最小二乘平均百分比变化为−49.8个百分点（95%置信区间[CI]，−59.0至−40.6），25 mg季度剂量为−56.0个百分点（95%CI，所有比较中−65.1至−46.8）。安慰剂组10%的参与者、10mg Plozasiran季度剂量组12%的参与者、25mg季度剂量组7%的参与者、50mg季度剂量组20%的参与者、50mg半年剂量组21%的参与者观察到血糖控制恶化。

研究结果表明，在这项涉及混合性高脂血症参与者的随机对照试验中，与安慰剂相比，Plozasiran在24周时显著降低了甘油三酯水平。临床结果试验是有必要的。

附：英文原文

Title: Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia

Author: Christie M. Ballantyne, Szilard Vasas, Masoud Azizad, Peter Clifton, Robert S. Rosenson, Ting Chang, Stacey Melquist, Rong Zhou, Ma’an Mushin, Nicholas J. Leeper, Jennifer Hellawell, Daniel Gaudet

Issue&Volume: 2024-05-28

Abstract:

BACKGROUND

Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non–high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)–mediated inhibition of lipoprotein lipase.

METHODS

We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy 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 low-density lipoprotein [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 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24.

RESULTS

A total of 353 participants underwent randomization. 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 (95% confidence interval [CI], 59.0 to 40.6) with the 10-mg-quarterly dose, 56.0 percentage points (95% CI, 65.1 to 46.8) with the 25-mg-quarterly dose, 62.4 percentage points (95% CI, 71.5 to 53.2) with the 50-mg-quarterly dose, and 44.2 percentage points (95% CI, 53.4 to 35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). 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.

CONCLUSIONS

In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted.

DOI: NJ202405280000007

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2404143