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

Area of Science:

• Cardiovascular Medicine
• Genetics
• Pharmacology

Background:

• Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by high LDL-C levels.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective in lowering LDL-C, but their efficacy in relation to LDLR gene variants in HeFH is not fully understood.
• Understanding the impact of LDLR genotype on PCSK9 inhibitor response is crucial for personalized treatment strategies.

Purpose of the Study:

• To evaluate the reduction in LDL-C achieved with PCSK9 inhibition in a large cohort of patients with HeFH, stratified by FH genotype.
• To determine if the LDL-C lowering effect of PCSK9 inhibitors is dependent on the residual functional activity of the LDLR gene.

Main Methods:

• A pooled subanalysis of a phase 3, open-label study of the PCSK9 inhibitor lerodalcibep in patients with HeFH.
• Participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks.
• LDL-C levels were assessed at weeks 48 and 72, with genetic testing performed to identify FH genotypes and assess LDLR variant function.

Main Results:

• Lerodalcibep treatment resulted in a mean LDL-C reduction of approximately 50.3% at both 48 and 72 weeks.
• Genetic testing revealed monogenic FH-causing variants in 61.5% of participants, with the LDLR pathogenic variant in 95.7% of those.
• LDL-C reduction with lerodalcibep was independent of the functional activity of the LDLR pathogenic variant.

Conclusions:

• Lerodalcibep significantly and consistently reduces LDL-C in patients with HeFH.
• The LDL-C lowering effect of lerodalcibep is independent of LDLR gene variant functional activity.
• These findings suggest that PCSK9 inhibition predominantly works by upregulating the unaffected wild-type LDLR in HeFH patients.