Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk.

The efficacy and safety of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III messenger RNA, have not been established in this population.

针对载脂蛋白C-III信使RNA的反义寡核苷酸olezarsen的疗效和安全性在这一人群中尚未确立。

Methods

We conducted two double-blind, randomized, placebo-controlledtrials (CORE-TIMI 72a and CORE2-TIMI 72b).

我们进行了两项双盲、随机、安慰剂对照试验（CORE-TIMI 72a 和 CORE2-TIMI 72b）

Patients with severe hypertriglyceridemia were assigned in a 1:1:1 ratio to receive olezarsen at a dose of 50 mg, olezarsen at a dose of 80 mg, or placebo monthly for 12 months.

严重高甘油三酯血症患者按1:1:1的比例分配，每月接受50毫克或80毫克的olezarsen治疗或安慰剂，持续12个月。

The primary outcome was the percent change in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group (placebo-adjusted change).

主要结果是6个月时甘油三酯水平的百分比变化，报告为每个olezarsen剂量组与安慰剂组之间的差异（安慰剂调整后的变化）。

Secondary lipid outcomes included the percent change in the triglyceride level at 12 months and in apolipoprotein C-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at 6 months and 12 months.

次要脂质结果包括12个月时甘油三酯水平的百分比变化，以及6个月和12个月时载脂蛋白C-III、残余胆固醇和非高密度脂蛋白（非HDL）胆固醇的百分比变化。

Acute pancreatitis events were assessed across both trials.

在两项试验中评估了急性胰腺炎事件。

Results

A total of 1061 patients were included in the primary analysis (617 in the CORE-TIMI 72a trial and 444 in the CORE2-TIMI 72b trial).

共有1061名患者纳入主要分析（CORE-TIMI 72a试验中617名，CORE2-TIMI 72b试验中444名）。

At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was -49.2 percentage points in the olezarsen 50-mg group and -54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (P<0.001 for all comparisons of olezarsen with placebo).

在6个月时，与安慰剂相比，CORE-TIMI 72a试验中olezarsen 50-mg组的甘油三酯水平从基线的平均变化为-62.9个百分点，olezarsen 80-mg组为-72.2个百分点；在CORE2-TIMI 72b试验中，olezarsen 50-mg组为-49.2个百分点，olezarsen 80-mg组为-54.5个百分点（所有olezarsen与安慰剂的比较P<0.001）。

Decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons).

与安慰剂相比，olezarsen在降低甘油三酯、载脂蛋白C-III、残余胆固醇和非HDL胆固醇水平方面效果更显著（所有比较P<0.001）。

The incidenceof acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001).

与安慰剂相比，急性胰腺炎的发生率在使用olezarsen的情况下较低（平均比率，0.15；95%置信区间，0.05至0.40；P<0.001）。

The incidenceof any adverse events appeared to be similar across trial groups.

任何不良事件的发生率在试验组之间似乎相似。

Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000 per microliter) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted.

使用80毫克剂量的olezarsen时，肝酶水平升高和血小板减少（血小板计数<100,000每微升）更为常见，并且观察到肝脏脂肪分数的剂量依赖性增加。

Conclusions

Among patients with severe hypertriglyceridemia, treatment with olezarsen led to a significantly greater reduction in the triglyceride level at 6 months and in the incidenceof acute pancreatitis than placebo.

对于严重高甘油三酯血症的患者，与安慰剂相比，olezarsen治疗在6个月时甘油三酯水平显著降低，并且急性胰腺炎的发生率也显著降低。

(Funded by Ionis Pharmaceuticals; CORE-TIMI 72a and CORE2-TIMI 72b ClinicalTrials.gov numbers, NCT05079919 and NCT05552326.).

(由Ionis Pharmaceuticals资助; CORE-TIMI 72a和CORE2-TIMI 72b临床试验注册号，NCT05079919和NCT05552326。)