Response to PCSK9 Inhibition Based on LDL Receptor Function in Familial Hypercholesterolemia: A Nonrandomized Clinical Trial.

Background

To evaluate the reduction in LDL-C achieved with PCSK9 inhibition according to FH genotype in a large cohort of patients with HeFH.

为了评估在一组HeFH患者中，根据FH基因型，PCSK9抑制治疗所实现的LDL-C降低程度。

DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized clinical trial reports on a predefined, pooled subanalysis of participants with HeFH requiring additional lipid-lowering therapy in the open-label worldwide phase 3 study of the PSCK9 inhibitor lerodalcibep.

设计、设置和参与者：本项非随机化临床试验报告了一项预先定义的、汇总分析，涉及在开放标签的全球第三阶段研究中，需要额外降脂治疗的杂合子家族性高胆固醇血症（HeFH）患者，该研究针对的是PCSK9抑制剂lerodalcibep。

This study included participants randomized to 5 phase 3 studies with the plasma PSCK9 inhibitor lerodalcibep and who participated in the open-label extension study from December 2020 to May 2025.

该研究包括了被随机分配到5项第三阶段研究中的参与者，这些参与者使用了血浆PCSK9抑制剂lerodalcibep，并且从2020年12月至2025年5月参与了开放标签的扩展研究。

Data were analyzed from March 2025 to February 2026.

数据分析的时间范围是从2025年3月至2026年2月。

intervention

All participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks.

所有参与者每月皮下注射300毫克lerodalcibep，持续72周。

main_outcome_and_measures

The co-primary efficacy end points were LDL-C reduction at weeks 48 and 72.

主要疗效终点是第48周和第72周的低密度脂蛋白胆固醇（LDL-C）降低。

Secondary and exploratory end points included LDL-C response according to FH genotype and the achievement of currently recommended LDL-C goals.

次要和探索性终点包括根据家族性高胆固醇血症（FH）基因型的低密度脂蛋白胆固醇（LDL-C）反应以及达到目前推荐的低密度脂蛋白胆固醇（LDL-C）目标。

Results

Among 703 included participants (mean [range] age, 53.8 [18-80] years; 372 male [52.9%]), 86 (12.2%) were Black, South Asian, or multiracial and 617 (87.8%) were White; 217 participants (72.3%) had atherosclerotic cardiovascular disease (ASCVD) or were at very high risk for ASCVD and 195 participants (27.7%) were at high risk for ASCVD.

在纳入的703名参与者中（平均年龄[范围]为53.8[18-80]岁；372名男性[52.9%]），86名（12.2%）为黑人、南亚人或多种族，617名（87.8%）为白人；217名参与者（72.3%）患有动脉粥样硬化性心血管疾病（ASCVD）或处于极高风险中，195名参与者（27.7%）处于高风险中。

Despite most participants receiving treatment with statins or ezetimibe, the mean (SD) baseline LDL-C was 144.9 (61.9) mg/dL.

尽管大多数参与者接受了他汀类药物或依折麦布的治疗，基线低密度脂蛋白胆固醇（LDL-C）的平均值（标准差）为144.9（61.9）mg/dL。

Mean (SD) reductions in LDL-C associated with lerodalcibep were 50.3% (28.9%) and 50.3% (28.7%) (mean [SD] absolute change, -72.6 [50.5] mg/dL and -71.8 [48.0] mg/dL) at weeks 48 and 72, respectively.

与lerodalcibep相关的低密度脂蛋白胆固醇（LDL-C）平均（标准差）降低幅度分别为第48周的50.3%（28.9%）和第72周的50.3%（28.7%）（平均[标准差]绝对变化分别为-72.6 [50.5] mg/dL和-71.8 [48.0] mg/dL）。

Of 740 participants (92.5%) who underwent genetic testing, monogenic FH-causing variants were found in 455 participants (61.5%), including 432 participants (95.7%) with the LDLR pathogenic variant.

在740名（92.5%）接受基因检测的参与者中，发现455名（61.5%）携带单基因家族性高胆固醇血症（FH）致病变异，其中包括432名（95.7%）携带LDLR致病变异的参与者。

LDL-C reduction with lerodalcibep was independent of LDLR variant functional activity.

Lerodalcibep引起的低密度脂蛋白胆固醇（LDL-C）降低与低密度脂蛋白受体（LDLR）变异的功能活性无关。

More than 70% of participants achieved both a reduction in LDL-C of at least 50% and their ASCVD risk-based LDL-C goal.

超过70%的参与者实现了至少50%的低密度脂蛋白胆固醇（LDL-C）降低，并达到了基于动脉粥样硬化性心血管疾病（ASCVD）风险的LDL-C目标。

conclusions_and_relevance

These findings suggest that lerodalcibep was associated with significantly and consistently reduced LDL-C in patients with HeFH, with response found to be independent of LDLR function of the pathogenic variant.

这些发现表明，lerodalcibep与家族性高胆固醇血症（HeFH）患者的低密度脂蛋白胆固醇（LDL-C）显著且一致降低相关，且发现响应与致病变异的低密度脂蛋白受体（LDLR）功能无关。

These findings support that LDL-C reductions in patients with HeFH with PCSK9 inhibition are predominantly mediated by upregulation of the unaffected wild-type LDLR.

这些发现支持，在家族性高胆固醇血症（HeFH）患者中，通过PCSK9抑制导致的低密度脂蛋白胆固醇（LDL-C）降低主要是通过上调未受影响的野生型低密度脂蛋白受体（LDLR）来介导的。

trial_registration

ClinicalTrials.gov Identifier: NCT04798430.

临床试验注册号：NCT04798430。