ImportanceSevere hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains.ObjectiveTo determine the tolerability, efficacy, and dose of plozasiran, an APOC3-targeted small interfering–RNA (siRNA) drug, for lowering triglyceride and apolipoprotein C3 (APOC3, regulator of triglyceride metabolism) levels and evaluate its effects on other lipid parameters in patients with sHTG.Design, Setting, and ParticipantsThe Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2) was a placebo-controlled, double-blind, dose-ranging, phase 2b randomized clinical trial enrolling adults with sHTG at 74 centers across the US, Europe, New Zealand, Australia, and Canada from May 31, 2021, to August 31, 2023. Eligible patients had fasting triglyceride levels in the range of 500 to 4000 mg/dL (to convert to millimoles per liter, multiply by 0.0113) while receiving stable lipid-lowering treatment.InterventionsParticipants received 2 subcutaneous doses of plozasiran (10, 25, or 50 mg) or matched placebo on day 1 and at week 12 and were followed up through week 48.Main Outcomes and MeasuresThe primary end point evaluated the placebo-subtracted difference in means of percentage triglyceride change at week 24. Mixed-model repeated measures were used for statistical modeling.ResultsOf 229 patients, 226 (mean [SD] age, 55 [11] years; 176 male [78%]) were included in the primary analysis. Baseline mean (SD) triglyceride level was 897 (625) mg/dL and plasma APOC3 level was 32 (16) mg/dL. Plozasiran induced significant dose-dependent placebo-adjusted least squares (LS)–mean reductions in triglyceride levels (primary end point) of −57% (95% CI, −71.9% to −42.1%; P < .001), driven by placebo-adjusted reductions in APOC3 of –77% (95% CI, −89.1% to −65.8%; P < .001) at week 24 with the highest dose. Among plozasiran-treated patients, 144 of 159 (90.6%) achieved a triglyceride level of less than 500 mg/dL. Plozasiran was associated with dose-dependent increases in low-density lipoprotein cholesterol (LDL-C) level, which was significant in patients receiving the highest dose (placebo-adjusted LS-mean increase 60% (95% CI, 31%-89%; P < .001). However, apolipoprotein B (ApoB) levels did not increase, and non–high-density lipoprotein cholesterol (HDL-C) levels decreased significantly at all doses, with a placebo-adjusted change of −20% at the highest dose. There were also significant durable reductions in remnant cholesterol and ApoB48 as well as increases in HDL-C level through week 48. Adverse event rates were similar in plozasiran-treated patients vs placebo. Serious adverse events were mild to moderate, not considered treatment related, and none led to discontinuation or death.Conclusions and RelevanceIn this randomized clinical trial of patients with sHTG, plozasiran decreased triglyceride levels, which fell below the 500 mg/dL threshold of acute pancreatitis risk in most participants. Other triglyceride-related lipoprotein parameters improved. An increase in LDL-C level was observed but with no change in ApoB level and a decrease in non–HDL-C level. The safety profile was generally favorable at all doses. Additional studies will be required to determine whether plozasiran favorably modulates the risk of sHTG-associated complications.Trial RegistrationClinicalTrials.gov Identifier: NCT04720534

中文翻译：

---

Plozasiran (ARO-APOC3) 治疗严重高甘油三酯血症

重要性严重高甘油三酯血症 (sHTG) 会增加患动脉粥样硬化性心血管疾病 (ASCVD)、非酒精性脂肪性肝炎和急性胰腺炎的风险。尽管有可用的治疗方法，但 sHTG 引起的持续性 ASCVD 和急性胰腺炎相关发病率仍然存在。 目的确定 plozasiran 的耐受性、疗效和剂量。APOC3-靶向小干扰RNA (siRNA)药物，用于降低甘油三酯和载脂蛋白C3（APOC3，甘油三酯代谢调节剂）水平并评估其对sHTG患者其他血脂参数的影响。设计、设置和参与者评估ARO的研究- APOC3 治疗成人严重高甘油三酯血症 (SHASTA-2) 是一项安慰剂对照、双盲、剂量范围 2b 期随机临床试验，在美国、欧洲、新西兰、澳大利亚和加拿大的 74 个中心招募了患有 sHTG 的成人2021年5月31日至2023年8月31日。符合条件的患者在接受稳定降脂治疗的同时，空腹甘油三酯水平在500至4000 mg/dL（换算为毫摩尔每升，乘以0.0113）范围内。在第 1 天和第 12 周皮下注射 2 次 plozasiran（10、25 或 50 mg）或匹配的安慰剂，并随访至第 48 周。主要结果和措施主要终点评估减去安慰剂后甘油三酯百分比平均值的差异第 24 周时发生变化。使用混合模型重复测量进行统计建模。结果 229 名患者中，226 名（平均 [SD] 年龄，55 [11] 岁； 176 名男性 [78%]）被纳入初步分析。基线平均 (SD) 甘油三酯水平为 897 (625) mg/dL，血浆 APOC3 水平为 32 (16) mg/dL。 Plozasiran 诱导显着剂量依赖性安慰剂调整最小二乘法 (LS)——甘油三酯水平（主要终点）平均降低 -57%（95% CI，-71.9% 至 -42.1%；磷< .001），由安慰剂调整后的 APOC3 降低 –77% 驱动（95% CI，-89.1% 至 -65.8%；磷< .001）在第 24 周时使用最高剂量。在接受 plozasiran 治疗的患者中，159 名患者中的 144 名 (90.6%) 达到了低于 500 mg/dL 的甘油三酯水平。 Plozasiran 与低密度脂蛋白胆固醇 (LDL-C) 水平的剂量依赖性增加相关，这在接受最高剂量的患者中显着（安慰剂调整的 LS 平均增加 60%（95% CI，31%-89%） ;磷< .001）。然而，在所有剂量下，载脂蛋白 B (ApoB) 水平并未增加，非高密度脂蛋白胆固醇 (HDL-C) 水平显着下降，最高剂量下安慰剂调整后的变化为 -20%。到第 48 周，残余胆固醇和 ApoB48 也显着持续降低，HDL-C 水平增加。 与安慰剂治疗的患者相比，接受 plozasiran 治疗的患者的不良事件发生率相似。严重不良事件为轻度至中度，不被认为与治疗相关，并且没有导致停药或死亡。结论和相关性在这项针对 sHTG 患者的随机临床试验中，plozasiran 降低了甘油三酯水平，使其低于急性胰腺炎的 500 mg/dL 阈值大多数参与者都面临风险。其他甘油三酯相关的脂蛋白参数得到改善。观察到 LDL-C 水平升高，但 ApoB 水平没有变化，非 HDL-C 水平降低。所有剂量的安全性总体上都是有利的。需要进行更多研究来确定 plozasiran 是否能有利地调节 sHTG 相关并发症的风险。试验注册ClinicalTrials.gov 标识符：NCT04720534