Lerodalcibep Matches Evolocumab in LDL-C Reduction for HoFH

A Phase 3 study investigating lerodalcibep, a a novel, third-generation PCSK9 inhibitor, for homozygous familial hypercholesterolemia (HoFH), found the low-density lipoprotein cholesterol (LDL-C) response highly variable, but generally similar to evolocumab treatment.1

In December 2024, LIB Therapeutics Inc. announced the submission of a Biologics License Application (BLA) for lerodalcibep to the US Food and Drug Administration (FDA), seeking approval for the treatment of atherosclerotic cardiovascular disease (ASCVD) and primary hyperlipidemia, including HoFH and heterozygous familial hypercholesterolemia (HeFH).2

"This large study, the first with a more diverse global HoFH population, all genetically confirmed prior to entry and using a novel cross-over design of two PCSK9 inhibitors, adds to, and expands, our knowledge regarding the role of PCSK9 inhibition in HoFH patients who have the highest unmet medical need for additional LDL-C lowering therapies," Derick Raal, lead investigator for the LIBerate HoFH trial and director of carbohydrate and lipid metabolism research unit at the University of Witwatersrand, said in a statement.3

LIBerate-HoFH measured the safety and efficacy of monthly lerodalcibep and evolocumab in a randomized, cross-over design, with 24 weeks of treatment in each period, separated by washout. Patients aged ≥10 years across the US, Europe, Middle East, Turkey, and India with genetically-confirmed HoFH and maximally tolerated statin therapy, were randomized in the global trial.1

Overall, 66 patients were randomized into LIBerate-HoFH, with a mean age of 28.7 years and 55% female. Approximately 30% were pediatric patients, 32% were Asian, and all had a mean baseline LDL-C of 410 mg/dL (10.59 mmol/L). Efficacy endpoints included the percent change from baseline in LDL-C levels at Weeks 12, 24, and the average of monthly visits over that period.

Upon analysis, lerodalcibep achieved a mean LDL-C reduction of –9.1% across all monthly visits, compared with –10.8% for evolocumab. The percentage change in LDL-C reduction at Week 12 was –12% with lerodalcibep and –11.5% with evolocumab, followed by –4.9% and –10.3% at Week 24, respectively.

Results showed LDL-C response was highly variable across the population, although the percent change from baseline for LDL-C over 24 weeks was similar between treatment cohorts (r =.79). Neither genotyping nor free PCSK9 suppression was found predictive of treatment response.

Safety results confirmed the tolerability of the drug, without treatment-related serious adverse events. Injection site reactions were identified in 1 (2%) of 65 patients treated with lerodalcibep, compared with 15 (24%) of 62 patients treated with evolocumab.

Lerodalcibep clinical trial data has displayed sustained LDL-C reductions of ≥60% in patients with, or at very-high or high risk of, CVD and ≥50% in those with heterozygous familial hypercholesterolemia (FH) who have more severe LDL-C elevations. Lib Therapeutics indicated the drug could expand available treatment options for millions globally with CVD, including the 30 million individuals with FH. Approximately 1 in 300,000 people worldwide are affected by HoFH, a rare genetic disorder and the most severe form of FH.4

“Although earlier trials showed a reduction in LDL-C of 20 to 30% with monoclonal antibodies to PCSK9, this trial confirmed the findings of more recent trials in HoFH subjects from India and in pediatric HoFH patients showing a much poorer response,” Raal added.3 “Importantly, while more than 30% of patients showed a good response, the study demonstrated the inability to predict response based on genotyping, despite more than 90% free PCSK9 suppression with both drugs, reinforcing the rationale and guidelines for a clinical trial of PCSK9 inhibition in all patients with HoFH and continuing its use in responders.”

References

1. Raal FJ, Mehta V, Kayikcioglu M, et al. Lerodalcibep and evolocumab for the treatment of homozygous familial hypercholesterolaemia with PCSK9 inhibition (LIBerate-HoFH): a phase 3, randomised, open-label, crossover, non-inferiority trial. Lancet Diabetes Endocrinol. Published online January 23, 2025. doi:10.1016/S2213-8587(24)00313-9
2. Iapoce C. Lib Therapeutics submits bla for Lerodalcibep targeting reductions in LDL-C. HCP Live. December 19, 2024. Accessed January 29, 2025. https://www.hcplive.com/view/lib-therapeutics-submits-bla-for-lerodalcibep-targeting-reduction-in-ldl-c.
3. Lib Therapeutics announces publication of phase 3 study of Lerodalcibep in homozygous familial hypercholesterolemia (HoFH) in Lancet Diabetes & Endocrinology. Business Wire. January 27, 2025. Accessed January 29, 2025. https://www.businesswire.com/news/home/20250127840137/en/LIB-Therapeutics-Announces-Publication-of-Phase-3-Study-of-Lerodalcibep-in-Homozygous-Familial-Hypercholesterolemia-HoFH-in-Lancet-Diabetes-Endocrinology.
4. Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet. 2022;399(10326):719-728. doi:10.1016/S0140-6736(21)02001-8