LIB Therapeutics' lerodalcibep, a third-generation PCSK9 inhibitor, has shown promise in treating homozygous familial hypercholesterolemia (HoFH). The Phase 3 LIBerate-HoFH study, recently published in Lancet Diabetes & Endocrinology, evaluated the efficacy and safety of monthly lerodalcibep compared to evolocumab in a diverse, genetically confirmed HoFH population. The study's findings suggest that lerodalcibep could be a valuable addition to the limited treatment options available for this rare and severe genetic disorder.
LIBerate-HoFH Study Details
The LIBerate-HoFH study was a randomized, cross-over trial involving 66 patients aged 10 years and older from various regions, including the USA, Europe, Middle East, Turkey, and India. All participants had genetically confirmed HoFH and were on stable, maximally tolerated statin and other oral lipid-lowering therapies. The trial consisted of two 24-week treatment periods with lerodalcibep and evolocumab, separated by a washout period. The primary efficacy endpoint was the percent change from baseline in LDL cholesterol (LDL-C) concentration at Week 12, Week 24, and the average of monthly visits over the 24 weeks.
Efficacy and Safety Results
The study revealed that the mean LDL-C reduction, averaged across all monthly visits, was -9.1% with lerodalcibep and -10.8% with evolocumab. At Week 12, LDL-C reduction was -12% with lerodalcibep and -11.5% with evolocumab. At Week 24, the reduction was -4.9% with lerodalcibep and -10.3% with evolocumab. While LDL-C responses varied among patients, the percent change from baseline was similar for both drugs (r=0.79).
Both drugs were well-tolerated, with no treatment-related serious adverse events. Injection site reactions were reported in one patient (2%) on lerodalcibep and 15 patients (24%) on evolocumab.
Expert Commentary
Professor Derick Raal, Lead Investigator for the LIBerate HoFH trial, noted, "The LDL-C responses were generally similar in patients treated with both lerodalcibep and evolocumab. Lerodalcibep, with a small 1.2 mL monthly dose and long ambient stability, will be a welcome addition to the armamentarium for the treatment of HoFH." He also highlighted the study's confirmation of previous findings showing a poorer response to PCSK9 inhibitors in HoFH subjects compared to earlier trials.
Implications for HoFH Treatment
HoFH is a rare genetic disorder affecting approximately 1 in 300,000 people worldwide. It is characterized by significantly elevated LDL-C levels, leading to premature atherosclerotic cardiovascular disease. Current treatment options are limited, and many patients do not achieve adequate LDL-C control with existing therapies.
Lerodalcibep offers a convenient, once-monthly subcutaneous injection that does not require refrigeration, potentially improving patient adherence. LIB Therapeutics submitted a Biologics License Application (BLA) to the FDA in December 2024 seeking approval of lerodalcibep for reducing LDL-C in patients with atherosclerotic cardiovascular disease (ASCVD), or very high or high risk of ASCVD, and primary hyperlipidemia, including heterozygous and homozygous familial hypercholesterolemia (HeFH / HoFH).
LIBERATE-OLE Trial Results
At the American Heart Association (AHA) 2024 Annual Scientific Sessions, results were presented from the ongoing open-label extension trial, LIBERATE-OLE. Involving 703 HeFH patients, lerodalcibep demonstrated impressive efficacy, with over 80% of FH patients achieving more than a 50% reduction in LDL-C and approximately 70% reaching recommended LDL-C targets for individuals with ASCVD or high ASCVD risk during the 72 weeks. The treatment was well-tolerated over 72 weeks, with only 2.3% of doses associated with mild or moderate injection site reactions (ISRs) and no new safety concerns reported.
