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期刊来源：JAMA

原文链接：https://doi.org/10.1001/jama.2024.4504

摘要内容如下：

重要性

脂蛋白（a）是动脉粥样硬化性心血管疾病（ASCVD）和钙化性主动脉瓣狭窄的致病危险因素，尚无监管机构批准的药物治疗。

目标

评估Zerlasiran（一种靶向肝脏载脂蛋白（a）合成的短干扰RNA）的安全性和耐受性，以及对血清脂蛋白（a）浓度的影响。

设计、设置和参与者

2020年11月18日至2023年2月8日期间，在美国、荷兰、英国和澳大利亚的7个研究中心分别对血清脂蛋白（a）浓度大于150 nmol/L的健康参与者和稳定型ASCVD患者进行了单次和多次剂量研究，最后一次随访时间为2023年8月23日。

干预措施

受试者随机接受（1）单次皮下注射安慰剂（n=8）、泽拉西兰300 mg（n=6）或600 mg（n=6）；或（2）2剂安慰剂（n=9），泽拉西兰200 mg（n=9）间隔4周或300 mg（n=9）或450 mg（n=9）间隔8周。

主要成果和措施

主要结果是安全性和耐受性。次要结果包括泽拉西兰的血清水平和对脂蛋白（a）血清浓度的影响。

结果

在多次给药组的37名患者中（平均年龄，56[SD，10.4]岁；15名[42%]女性），36名完成了试验。在单剂量给药后延长随访的14名参与者中，13名完成了试验。无严重不良事件发生。多次给药组的中位基线脂蛋白（a）浓度为288（IQR，199-352）nmol/L。单次给药后365天脂蛋白（a）浓度的中位变化为：安慰剂组为14%（IQR，13%-15%），泽拉西兰组为-30%（IQR，-51%-18%），泽拉西兰组为-29%（IQR，-39%至-7%）。2次给药后，安慰剂组脂蛋白（a）浓度的最大中位变化为19（IQR，-17至28）nmol/L，200 mg泽拉西兰组为-258（IQR，-289至-188）nmol/L，300 mg剂量组为-310（IQR，-368至-274）nmol/L，450 mg剂量组为-242（IQR，-343至-182）nmol/L。最大中位数百分比变化分别为7%（IQR，-4%至21%）、-97%（IQR，-98%至-95%）、-98%（IQR，-99%至-97%）和-99%（IQR，-99%至-98%），衰减至0.3%（IQR，-2%至21%）、-60%（IQR，-71%至-40%），给药201天后-90%（IQR，-91%至-74%）和-89%（IQR，-91%至-76%）。

结论

泽拉西兰具有良好的耐受性，并能降低脂蛋白（a）浓度，且给药频率较低。

试用注册

ClinicalTrials.gov标识符：NCT04606602。

英文原文如下：

Abstracts

Importance  Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities.

Objectives  To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a).

Design, Setting, and Participants  Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023.

Interventions  Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval.

Main Outcomes Measures  The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations.

Results  Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, -30% (IQR, -51% to -18%) for the 300 mg of zerlasiran group, and -29% (IQR, -39% to -7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, -17 to 28) nmol/L for the placebo group, -258 (IQR, -289 to -188) nmol/L for the 200 mg of zerlasiran group, -310 (IQR, -368 to -274) nmol/L for the 300-mg dose group, and -242 (IQR, -343 to -182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, -4% to 21%), -97% (IQR, -98% to -95%), -98% (IQR, -99% to -97%), and -99% (IQR, -99% to -98%), respectively, attenuating to 0.3% (IQR, -2% to 21%), -60% (IQR, -71% to -40%), -90% (IQR, -91% to -74%), and -89% (IQR, -91% to -76%) 201 days after administration.

Conclusions  Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration.

Trial Registration  ClinicalTrials.gov Identifier: NCT04606602.

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