Efficacy and safety of inclisiran in adolescents with heterozygous familial hypercholesterolaemia (ORION-16): a two-part, randomised, multicentre clinical trial.

The ORION-16 study aimed to evaluate the efficacy and safety of inclisiran treatment in adolescents with HeFH.

ORION-16研究旨在评估Inclisiran治疗在携带HeFH的青少年中的疗效和安全性。

Methods

ORION-16 was a two-part (1-year double-blind, 1-year open-label), randomised, phase 3 trial at 51 sites across 26 countries.

ORION-16 是一项在 26 个国家的 51 个地点进行的为期两年（1 年双盲，1 年开放标签）的随机、III 期临床试验。

In Part 1, adolescents (aged 12 to <18 years) with HeFH and elevated LDL cholesterol on maximally tolerated statin treatment with or without other lipid-lowering therapy were randomly assigned 2:1 (via interactive response technology) to either inclisiran sodium 300 mg subcutaneously or placebo (administered on days 1, 90, and 270); in Part 2, all patients received inclisiran (days 360 [only patients previously assigned to receive placebo], 450, and 630).

在第一部分中，12 至 <18 岁的青少年，患有杂合子家族性高胆固醇血症（HeFH），在最大耐受剂量的他汀类药物治疗下，无论是否使用其他降脂治疗，均按 2:1 的比例（通过交互式响应技术）随机分配到 inclisiran 钠 300 mg 皮下注射或安慰剂（分别在第 1、90 和 270 天给药）；在第二部分中，所有患者均接受 inclisiran 注射（仅限之前被分配接受安慰剂的患者在第 360 天，以及第 450 和 630 天）。

The primary endpoint was the percentage change in LDL cholesterol from baseline to day 330, assessed in all randomly assigned patients.

主要终点是基线至第330天低密度脂蛋白胆固醇的百分比变化，评估所有随机分配的患者。

Safety was assessed in all patients who received at least one dose of study drug.

安全性评估包括所有至少接受一次研究药物剂量的患者。

Endpoints in Part 2 were analysed in all patients who entered and received at least one dose of study drug in Part 2.

第二部分的终点是在所有进入第二部分并至少接受了一剂研究药物的患者中进行分析的。

ORION-16 is registered at ClinicalTrials.gov (NCT04652726) and is completed.

ORION-16已在ClinicalTrials.gov注册（NCT04652726），并已完成。

Results

Between Feb 17, 2021, and Dec 14, 2022, 141 patients were randomly assigned (93 to inclisiran, 48 to placebo; median age 15·1 years [IQR 13·4-16·8]; 75 [53%] female; 128 [91%] White).

在2021年2月17日至2022年12月14日期间，共有141名患者被随机分配（inclisiran组93人，安慰剂组48人；中位年龄15.1岁[四分位数间距13.4-16.8]；75名[53%]女性；128名[91%]为白人）。

In Part 1, the least squares mean percentage change in LDL cholesterol from baseline to day 330 was -27·1% in the inclisiran group and 1·4% in the placebo group, with a between-group difference of -28·5% (95% CI -35·8 to -21·3; p<0·0001).

在第一部分研究中，从基线到第330天，inclisiran组的LDL胆固醇的最小二乘平均百分比变化为-27.1%，而安慰剂组为1.4%，两组之间的差异为-28.5%（95%置信区间-35.8至-21.3；p<0.0001）。

In Part 2, at day 720, a mean percentage change in LDL cholesterol from baseline of -33·7% (SD 24·0) was observed.

在第二部分研究中，第720天时，观察到基线低密度脂蛋白胆固醇的平均百分比变化为-33.7%（标准差24.0）。

Inclisiran was well tolerated, with a safety profile comparable to studies in adults.

Inclisiran耐受性良好，其安全性与成人研究中的情况相当。

Injection site reactions were more frequent with inclisiran (15 [16%] of 93 patients) than with placebo (three [6%] of 48) in Part 1 (13 [9%] of 139 in Part 2); all were mild and did not lead to study drug discontinuation.

在第一部分中，与安慰剂（48名患者中有3名[6%]）相比，inclisiran（93名患者中有15名[16%]）注射部位反应更频繁（第二部分139名患者中有13名[9%]）；所有反应均为轻度，未导致研究药物停药。

There were no treatment-related serious adverse events, and no deaths during the study.

研究期间没有与治疗相关的严重不良事件，也没有死亡事件。

interpretation

In adolescents with HeFH, inclisiran was effective in lowering LDL cholesterol, with sustained efficacy over 2 years, and was well tolerated.

在患有家族性高胆固醇血症（HeFH）的青少年中，inclisiran能有效降低低密度脂蛋白胆固醇（LDL-C），其疗效在2年内持续，并且耐受性良好。

These results support inclisiran as a potentially useful addition for the treatment of adolescents with HeFH, providing an infrequent dosing regimen.

这些结果支持inclisiran作为治疗HeFH青少年的潜在有用补充，提供了一种不频繁的给药方案。

funding

Novartis Pharma.

诺华制药