本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2400201

摘要内容如下：

背景

家族性乳糜微粒血症综合征是一种与严重高甘油三酯血症和重症急性胰腺炎相关的遗传性疾病。Olezarsen通过减少肝脏载脂蛋白C-III的合成来降低血浆甘油三酯水平。

方法

在一项3期、双盲、安慰剂对照试验中，我们将确诊为家族性乳糜微粒血症综合征的患者随机分为两组，一组每4周皮下注射Olezarsen 80 mg或50 mg，另一组接受安慰剂，共53周。有两个主要终点:80 mg Olezarsen组和安慰剂组之间从基线到6个月的空腹甘油三酯水平百分比变化的差异，以及50 mg Olezarsen组和安慰剂组之间的差异（如果第一个差异显著，则进行评估）。次要终点包括载脂蛋白C-III水平相对于基线的平均百分比变化和独立判定的急性胰腺炎发作。

结果

共有66名患者接受了随机分组；22人被分配到80-mg Olezarsen组，21人被分配到50-mg Olezarsen组，23人被分配到安慰剂组。基线时，患者的平均（±SD）甘油三酯水平为2630±1315 mg/DL，71%的患者在过去10年内有急性胰腺炎病史。服用80mg剂量的Olezarsen后，6个月时的甘油三酯水平显著降低（-43.5%；95%置信区间[CI]，-69.1至-17.9；P<0.001），但50-mg剂量（-22.4%；95%可信区间为-47.2~2.5；P=0.08）。从基线到6个月，80 mg组与安慰剂组相比，载脂蛋白C-III水平的平均百分比变化差异为-73.7%（95%CI，-94.6至-52.8），50 mg组与安慰剂组相比，差异为-65.5%（95%CI，-82.6至-48.3）。到53周时，安慰剂组发生了11次急性胰腺炎发作，奥扎沙森组各发生了1次急性胰腺炎发作（比率[合并奥扎沙森组与安慰剂组]为0.12；95%置信区间，0.02至0.66）。80 mg Olezarsen组中有4名患者发生了试验中心的试验研究者认为与试验药物或安慰剂有关的中度严重不良事件。

结论

在家族性乳糜微粒血症综合征患者中，Olezarsen可能是一种降低血浆甘油三酯水平的新疗法。（由Ionis Pharmaceuticals资助；Balance ClinicalTrials.gov编号，NCT04568434。）

英文原文如下：

Abstracts

BACKGROUND  Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III.

METHODS  In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 53 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis.

RESULTS  A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen (-43.5%; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4%; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7% (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5% (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group.

CONCLUSIONS  In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).

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