礼来公司Giacomo Ruotolo团队的一项最新研究提出，solbinsiran（一种靶向ANGPTL3的GalNAc偶联siRNA）在混合性血脂异常成年人中的耐久性和有效性（PROLONG-ANG3）：一项双盲、随机、安慰剂对照的2期试验。这一研究成果发表在2025年3月31日出版的国际学术期刊《柳叶刀》上。

背景：混合性血脂异常血症，以循环甘油三酯和低密度脂蛋白胆固醇（LDL- c）浓度升高为特征，与动脉粥样硬化性心血管疾病的风险增加有关。Solbinsiran是一种galnac偶联的靶向肝血管生成素样蛋白3 （ANGPTL3）的小干扰RNA，在一项1期研究中降低了甘油三酯和LDL-C浓度。本研究旨在评估索宾西兰降低成人混合性血脂异常患者致动脉粥样硬化脂蛋白浓度的持久性和有效性。

方法：这项双盲、平行组、随机、安慰剂对照的2期试验在7个国家的41个临床研究单位招募了患有混合性血脂异常的成年人（年龄≥18岁）。患者接受中等或高强度他汀类药物治疗，空腹甘油三酯浓度在1.69 ~ 5.64 mmol/L之间，LDL-C至少为1.81 mmol/L，非高密度脂蛋白胆固醇至少为3.36 mmol/L。使用交互式网络反应系统，患者被随机分配（1:2:2:2）接受solbinsiran 100 mg， solbinsiran 400 mg， solbinsiran 800 mg或安慰剂，在第0天和第90天皮下注射。患者随访至少270天。主要结局是与安慰剂相比，solbinsiran从基线到第180天载脂蛋白B （apoB）浓度的百分比变化，在疗效评估下进行分析（在接受至少一剂研究药物的患者中）。

发现：在585名筛选的患者中，205名患者在2022年7月20日至2024年3月4日期间入组研究。其中女性111例（54%），男性94例（46%）；中位年龄为57岁[IQR 49-65])的患者被随机分配接受solbinsiran 100 mg （n=30）、solbinsiran 400 mg （n=58）、solbinsiran 800 mg （n=59）或安慰剂（n=58）。基线时，载脂蛋白ob的中位浓度为111 mg/dL (IQR 96-130)，甘油三酯的中位浓度为2.64 mmol/L (2.06 - 3.29)， LDL-C的中位浓度为3.16 mmol/L（2.57 - 3.82）。经安慰剂调整后，第180天载脂蛋白ob浓度较基线变化百分比为- 2.8% (95% CI - 15.5 ~ 11.9；索宾西兰100 mg组P =0.69)；- 14.3% (- 23.6 ~ - 3.9；P =0.0085)；- 8.3% (- 18.3 ~ 2.9；solbinsiran 800 mg的P =0.14)。索宾西兰耐受良好，不良事件发生率低。solbinsiran 100 mg组30例患者中有18例（60%）出现治疗不良事件，solbinsiran 400 mg组58例患者中有30例（52%）出现不良事件，solbinsiran 800 mg组59例患者中有26例（44%）出现不良事件，安慰剂组57例患者中有37例（65%）出现不良事件。

研究结果表明，Solbinsiran 400mg可降低混合性血脂异常患者的载脂蛋白B水平，且通常耐受性良好。solbinsiran对心血管结局的影响仍有待研究。

附：英文原文

Title: Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3):a double-blind, randomised, placebo-controlled, phase 2 trial

Author: Kausik K Ray, Ena Oru, Robert S Rosenson, Jeremiah Jones, Xiaosu Ma, Jennie Walgren, Axel Haupt, Subodh Verma, Daniel Gaudet, Stephen J Nicholls, Giacomo Ruotolo

Issue&Volume: 2025-03-31

Abstract: Background

Mixed dyslipidaemia, characterised by elevated concentrations of circulating triglycerides and LDL cholesterol (LDL-C), is associated with an increased risk of atherosclerotic cardiovascular disease. Solbinsiran, a GalNAc-conjugated small interfering RNA targeting hepatic angiopoietin-like protein 3 (ANGPTL3), reduced triglycerides and LDL-C concentrations in a phase 1 study. This study aimed to assess the durability and efficacy of solbinsiran in reducing concentrations of atherogenic lipoproteins in adults with mixed dyslipidaemia.

Methods

This double-blind, parallel-arm, randomised, placebo-controlled, phase 2 trial enrolled adults (aged ≥18 years) with mixed dyslipidaemia at 41 clinical research units across seven countries. Patients receiving moderate-intensity or high-intensity statins, and with concentrations of fasting triglycerides between 1·69 mmol/L and 5·64 mmol/L, LDL-C of at least 1·81 mmol/L, and non-HDL cholesterol of at least 3·36 mmol/L were included. Using an interactive web-response system, patients were randomly assigned (1:2:2:2) to receive either solbinsiran 100 mg, solbinsiran 400 mg, solbinsiran 800 mg, or placebo, by subcutaneous injection on days 0 and 90. Patients were followed up for at least 270 days. The primary outcome was percent change in apolipoprotein B (apoB) concentration from baseline to day 180 with solbinsiran compared with placebo, analysed under an efficacy estimand (in patients who received at least one dose of the study drug). This trial is completed and registered with ClinicalTrials.gov, NCT05256654.

Findings

Of 585 patients screened, 205 patients were enrolled in the study between July 20, 2022, and March 4, 2024. Patients (111 [54%] female and 94 [46%] male; median age 57 years [IQR 49–65]) were randomly assigned to receive solbinsiran 100 mg (n=30), solbinsiran 400 mg (n=58), solbinsiran 800 mg (n=59), or placebo (n=58). At baseline, median concentrations were 111 mg/dL (IQR96–130) for apoB, 2·64 mmol/L (2·06–3·29) for triglycerides, and 3·16 mmol/L (2·57–3·82) for LDL-C. The placebo-adjusted percent change in apoB concentration from baseline at day 180 was –2·8% (95% CI –15·5 to 11·9; p=0·69) for solbinsiran 100 mg; –14·3% (–23·6 to –3·9; p=0·0085) for solbinsiran 400 mg; and –8·3% (–18·3 to 2·9; p=0·14) for solbinsiran 800 mg. Solbinsiran administration was well tolerated, with a low incidence of adverse events. The number of patients with treatment-emergent adverse events was 18 [60%] of 30 patients in the solbinsiran 100 mg group, 30 [52%] of 58 patients in the solbinsiran 400 mg group, 26 [44%] of 59 patients in the solbinsiran 800 mg group, and 37 [65%] of 57 patients in the placebo group.

Interpretation

Solbinsiran 400 mg reduced apoB in patients with mixed dyslipidaemia and was generally well tolerated. The impact of solbinsiran on cardiovascular outcomes remains to be investigated.

DOI: 10.1016/S0140-6736(25)00507-0

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)00507-0/abstract