泊扎西然用于管理持续性乳糜微粒血症和胰腺炎风险。

Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk.

作者信息

Watts Gerald F, Rosenson Robert S, Hegele Robert A, Goldberg Ira J, Gallo Antonio, Mertens Ann, Baass Alexis, Zhou Rong, Muhsin Ma'an, Hellawell Jennifer, Leeper Nicholas J, Gaudet Daniel

机构信息

From the School of Medicine, University of Western Australia, and the Department of Cardiology, Royal Perth Hospital - both in Perth, Australia (G.F.W.); the Metabolism and Lipids Program, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai (R.S.R.), and New York University (NYU) Grossman School of Medicine, NYU Langone Health (I.J.G) - both in New York; Robarts Research Institute, London, ON (R.A.H.), and the Department of Medicine, McGill University, and the Genetic Dyslipidemia Clinic, Montreal Clinical Research Institute (A.B.) and Université de Montréal and ECOGENE-21 (D.G.), Montreal - all in Canada; Sorbonne University, INSERM UMR1166, Lipidology and Cardiovascular Prevention Unit, Department of Nutrition, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris (A.G.); the Department of Endocrinology, University Hospitals Leuven-KU Leuven, Leuven, Belgium (A.M.); and Arrowhead Pharmaceuticals, Pasadena (R.Z., M.M., J.H.), and Stanford University, Palo Alto (N.J.L.) - both in California.

出版信息

N Engl J Med. 2025 Jan 9;392(2):127-137. doi: 10.1056/NEJMoa2409368. Epub 2024 Sep 2.

DOI:10.1056/NEJMoa2409368

PMID:39225259

Abstract

BACKGROUND

Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides.

METHODS

In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis.

RESULTS

At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline.

CONCLUSIONS

Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).

摘要

背景

持续性乳糜微粒血症是一种常染色体隐性疾病，典型病因是家族性乳糜微粒血症综合征（FCS），但也有多种致病因素。该疾病与复发性急性胰腺炎风险相关。泊扎司然是一种小干扰RNA，可降低肝脏载脂蛋白C-III的生成及循环甘油三酯水平。

方法

在一项3期试验中，我们将75例持续性乳糜微粒血症患者（无论是否有基因诊断）随机分组，每3个月皮下注射泊扎司然（25mg或50mg）或安慰剂，共12个月。主要终点是10个月时空腹甘油三酯水平相对于基线的中位数变化百分比。关键次要终点包括空腹甘油三酯水平从基线到10个月和12个月平均值的变化百分比、空腹载脂蛋白C-III水平从基线到10个月和12个月的变化，以及急性胰腺炎的发生率。

结果

基线时，甘油三酯水平中位数为每分升2044mg。10个月时，25mg泊扎司然组空腹甘油三酯水平相对于基线的中位数变化（主要终点）为-80%，50mg泊扎司然组为-78%，安慰剂组为-17%（P<0.001）。关键次要终点在泊扎司然组的结果优于安慰剂组，包括急性胰腺炎的发生率（比值比，0.17；95%置信区间，0.03至0.94；P = 0.03）。各组不良事件风险相似；最常见的不良事件是腹痛、鼻咽炎、头痛和恶心。与安慰剂相比，泊扎司然导致的严重和重大不良事件较少见。基线时患有糖尿病前期或糖尿病的部分患者使用泊扎司然后出现高血糖。