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

作者：Raal FJ, Fourie N, Scott R, Blom DJ, Basson MMV, Kayikcioglu M, Roth M, Vest J, Kallend D, Stein EA · 发表于：JAMA cardiology · 年份：2026 · DOI：10.1001/jamacardio.2026.0879

IMPORTANCE: In individuals with heterozygous familial hypercholesterolemia (HeFH), it is uncertain whether and to what extent the reduction in low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy is dependent on the residual functional activity of the LDLR gene carrying the pathogenic variant. OBJECTIVE: To evaluate the reduction in LDL-C achieved with PCSK9 inhibition according to FH genotype in a large cohort of patients with HeFH. 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. 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. Data were analyzed from March 2025 to February 2026. INTERVENTION: All participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks. MAIN OUTCOME AND MEASURES: The co-primary efficacy end points were LDL-C reduction at weeks 48 and 72. Secondary and exploratory end points included LDL-C response according to FH genotype and the achievement of currently recommended LDL-C goals. RESULTS: Among 703 included participants (mean [range] age, 53.8 [18-80] years; 372 male [52.9%]), 86 (12.2%) were Black, South Asian...