Monthly PCSK9 inhibitor cuts cholesterol by half on top of statin, ezetimibe therapy
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Key takeaways:
- Lerodalcibep, an investigational PCSK9 inhibitor, decreased LDL cholesterol on top of existing oral agents compared with placebo.
- Patients also saw reductions in all atherogenic lipids and lipoproteins.
ATLANTA — An investigational monthly PCSK9 inhibitor cut LDL cholesterol by more than 50% at 1 year among adults with CVD or with very high risk, in addition to background statin and ezetimibe therapy, researchers reported.
The LIBerate-HR study also showed that lerodalcibep (LIB003, LIB Therapeutics) was associated with “robust” reductions in all atherogenic lipids and lipoproteins, with more than 90% of patients able to achieve new European Society of Cardiology cholesterol guideline targets at the end of the study, Eric Klug, MBBCh, associate professor at the University of Witwatersrand School of Clinical Medicine in Johannesburg, said during a late-breaking clinical science presentation at the American College of Cardiology Scientific Session.
“Lerodalcibep offers a novel, effective alternative to existing PCSK9 inhibitors,” Klug said. “There is substantial LDL reduction on top of existing oral agents, and the ability for more than 90% of patients to achieve the new ESC guidelines, with robust reductions in all atherogenic lipids and lipoproteins.”
Lerodalcibep is a third-generation PCSK9 inhibitor and a small binding protein designed to block PCSK9 binding to the LDL receptor, preventing LDL receptor degradation, increasing LDL receptor recycling, enhancing LDL clearance and lowering LDL levels, Klug said. The small size and high solubility of the drug allows a smaller injection volume that still achieves stable and prolonged LDL reductions between injections.
As Healio previously reported, lerodalcibep further reduced LDL compared with placebo in well-treated patients with heterozygous familial hypercholesterolemia in the phase 3 LIBerate-HeFH study, with a safety profile similar vs. placebo.
For the current study, Klug and colleagues analyzed data from 922 adults from 11 countries on stable statin plus ezetimibe therapy with established CVD and an LDL of 70 mg/dL or higher, or at high risk for CVD and an LDL of 100 mg/dL or higher. The mean age of participants was 64 years; 45% were women; 22.1% were Black, multiracial or South Asian. Mean baseline LDL was 116 mg/dL and 10% of participants had FH. Researchers randomly assigned participants to monthly lerodalcibep 300 mg (n = 615) or placebo (n = 307) for 52 weeks. The coprimary endpoints were percent change from baseline in LDL at week 52 and the mean of weeks 50 and 52. Secondary outcomes included achievement of LDL targets and other lipid and apolipoprotein changes, as well as a safety analysis.
In the intention-to-treat analysis, participants assigned to lerodalcibep achieved an average placebo-adjusted percentage reduction in LDL cholesterol of 56.19% at week 52 (P < .0001), with a 62.69% reduction seen when averaging weeks 50 and 52 (P < .0001).
More than 90% of patients in the lerodalcibep group achieved a reduction of 50% or more LDL reduction and attained the target LDL level for their risk group, compared with 16% of participants in the placebo group.
Additionally, Klug noted that apolipoprotein B fell by an average of 43% and lipoprotein(a) decreased by 33%.
“The tolerability and safety of lerodalcibep was similar to placebo, with a monthly, small 1.2 mL subcutaneous dose with long ambient stability, allowing for patient home use.” Klug said.
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Klug E, et al. Late-breaking clinical trials II. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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