From the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, (E.S.G.S.); Ionis Pharmaceuticals, Carlsbad (V.J.A., E.K.-P., T.A.P., S.X., S.T.), and the Divisions of Endocrinology and Metabolism (J.L.W.) and Cardiovascular Medicine (S.T.), Department of Medicine, University of California, San Diego, La Jolla - both in California; the Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada (R.A.H.); the Department of Translational and Precision Medicine, Center for Rare Disorders of Lipid Metabolism, Sapienza University of Rome, Rome (M.A.); Baylor College of Medicine and the Texas Heart Institute, Houston (C.M.B.); the National Institute for Health Research and Wellcome Trust Clinical Research Facility, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom (H.S.); and the Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York (H.N.G.).
N Engl J Med. 2024 May 16;390(19):1781-1792. doi: 10.1056/NEJMoa2400201. Epub 2024 Apr 7.
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.
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 49 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.
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 as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 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 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (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.
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.).
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严重急性胰腺炎相关的遗传疾病。Olezarsen 通过降低载脂蛋白 C-III 的肝合成来降低血浆甘油三酯水平。
在一项 3 期、双盲、安慰剂对照试验中，我们随机分配经基因鉴定患有家族性乳糜微粒血症综合征的患者皮下注射 80mg 或 50mg 奥扎雷森或安慰剂，每 4 周一次，共 49 周。主要终点有两个：80mg 奥扎雷森组与安慰剂组相比，空腹甘油三酯水平从基线到 6 个月的变化百分比差异，以及（如果第一个显著）50mg 奥扎雷森组与安慰剂组相比的差异。次要终点包括载脂蛋白 C-III 水平从基线的平均百分比变化和独立裁决的急性胰腺炎发作。
共有 66 名患者接受了随机分组；22 名患者被分配到 80mg 奥扎雷森组，21 名患者被分配到 50mg 奥扎雷森组，23 名患者被分配到安慰剂组。在基线时，患者的平均（±SD）甘油三酯水平为 2630±1315mg/dL，71%的患者在过去 10 年内有急性胰腺炎病史。与安慰剂相比，80mg 奥扎雷森剂量在 6 个月时显著降低了甘油三酯水平（-43.5%；95%置信区间 [CI]，-69.1 至-17.9；P<0.001），但 50mg 奥扎雷森剂量则不然（-22.4%；95%CI，-47.2 至 2.5；P=0.08）。与安慰剂组相比，80mg 奥扎雷森组从基线到 6 个月载脂蛋白 C-III 水平的平均百分比变化差异为-73.7%（95%CI，-94.6 至-52.8），50mg 奥扎雷森组为-65.5%（95%CI，-82.6 至-48.3）。在第 53 周时，安慰剂组发生了 11 例急性胰腺炎发作，奥扎雷森组各发生了 1 例（ pooled olezarsen groups vs. placebo 的比值，0.12；95%CI，0.02 至 0.66）。site 的试验研究者认为与试验药物或安慰剂相关的中度严重程度的不良事件发生在 80mg 奥扎雷森组的 4 名患者中。
在家族性乳糜微粒血症综合征患者中，奥扎雷森可能代表一种降低血浆甘油三酯水平的新疗法。（由 Ionis 制药公司资助；Balance ClinicalTrials.gov 编号，NCT04568434）。
