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Response to PCSK9 Inhibition Based on LDL Receptor Function in Familial Hypercholesterolemia: A Nonrandomized
Frederick J Raal1, Nyda Fourie2, Russell Scott3
1Carbohydrate and Lipid Metabolism Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor lerodalcibep effectively lowers low-density lipoprotein cholesterol (LDL-C) in patients with heterozygous familial hypercholesterolemia (HeFH). The LDL-C reduction is independent of the low-density lipoprotein receptor (LDLR) gene
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.
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, 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. Despite most participants receiving treatment with statins or ezetimibe, the mean (SD) baseline LDL-C was 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. 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. LDL-C reduction with lerodalcibep was independent of LDLR variant functional activity. More than 70% of participants achieved both a reduction in LDL-C of at least 50% and their ASCVD risk-based LDL-C goal.
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. 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.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04798430.
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