Data from the first of 3 phase 3 trials examing lerodalcibep provide insight into the effects of the once-monthly PCSK9 inhibitor in patients with heterozygous familial hypercholesterolemia.
Results of a phase 3 trial examining lerodalcibep, a monthly small binding protein PCSK9 inhibitor, suggest the agent could provide patients with heterozygous familial hypercholesterolemia (HeFH) an additional option for LDL-C reduction.
Presented at the European Society of Cardiology (ESC) Congress 2023, results indicate patients using the agent achieved mean placebo-adjusted reductions in LDL-C of 65% at 24 weeks, with 68% of patients achieving an LDL-C reduction of 50% or greater and the ESC guideline-recommended LDL-C targets. According to LIB Therapeutics, the study, which is named the LIBerate-HeFH trial, is one of 3, 52-week phase 3 trials examining lerodalcibep, with completion of the LIBerate-CVD and LIBerate-HR expected in early November 2023.1,2
“In this, the largest on active drug, and one of the longest, controlled trials in HeFH with an inhibitor of circulating PCSK9, lerodalcibep, demonstrated very effective and sustained reductions of LDL-C with just a monthly small 1.2 mL dose,” said principal investigator Derick Raal, MMed, PhD, distinguished professor and director of the Carbohydrate & Lipid Metabolism Research Unit in the Faculty of Health Sciences at the University of Witwatersrand.2
Impacting almost 1 in 300 people worldwide, HeFH poses a significant cardiovascular risk for more than 30 million people across the globe. With this in mind, development of therapies to improve LDL-C reductions in patients with HeFH stands to have a significant impact on cardiovascular risk.2
A randomized, double-blind, placebo-controlled phase 3 trial, LIBerate-HeFH enrolled 478 patients from 30 sites in 9 countries. This cohort hadmean age of 53 years, 51.7% were female, and the mean baseline LDL-C was 3.88 (Standard Deviation [SD], 1.66) mmol/L. Patients were randomized in a 2:1 ratio to monthly injections of lerodalcibep 300 mg or placebo therapy for 24 weeks. Per trial protocol, patients were seen in the clinic every 4 weeks for 20 weeks and then at 2-week intervals for Weeks 22 and 24.1
The primary outcomes of interest for the trial were the percentage change from baseline to week 24 in LDL-C and the mean of weeks 22 and 24. The trial also included multiple secondary endpoints, such as changes in apolipoprotein B, Lp(a), and achievement of ESC recommended LDL-C targets.1
In intention-to-treat analyses, use of lerodalcibep was associated with a mean absolute reduction in LDL-C from baseline of 2.08 (0.11) mmol/L [Least Squares [LS] mean Standard Error[SE]; 95% CI -2.30 to -1.87] with a percentage difference of –58.61 (3.25)% at Week 24. This apparent reduction grew in magnitude to 2.28 (0.10) mmol/L (95% CI -2.47 to -2.09) with a percentage difference of -65.0% (2.87) at the mean of Weeks 22 and 24 (P < 0.0001 for all).1
Analysis of secondary endpoints indicated lerodalcibep use was associated with placebo-adjusted reductions of 45.6% and 23.9% for apolipoprotein B and Lp(a), respectively at week 24 among patients who adhered to study protocol (P for all < .0001).1
“The results in patients with FH with the highest LDL-C and most difficult to achieve current treatment targets, are the most pleasing for me personally as patients with both HoFH and HeFH began my interest in lipid metabolism, where no effective drugs existed 50 years ago," said Evan Stein, MD, PhD, chief executive and chief scientific officer of LIB Therapeutics.
In their release announcing the ESC presentation, LIB therapeutics pointed out the aforementioned LIBerate-CVD and LIBerate-HR would examine use of lerodalcibep added to maximally tolerated oral lipid-lowering therapies to assess LDL-lowering in more than 1800 patients with cardiovascular disease, very high and high-risk for cardiovascular disease.2