CINCINNATI– LIB Therapeutics Inc. (LIB), a privately-held, late-stage biopharmaceutical company advancing Lerodalcibep, a novel, third-generation PCSK9 inhibitor today announced the publication of Phase 3 LIBerate-HoFH study of Lerodalcibep in a globally diverse homozygous familial hypercholesterolemia (HoFH) population was published in Lancet Diabetes & Endocrinology (Raal, F.J. et al, 2025).
The LIBerate-HoFH study assessed the safety and efficacy of monthly lerodalcibep and evolocumab in a randomized, cross-over trial, with 24 weeks of treatment in each period separated by a washout period. This globally diverse trial included patients 10 years and older in USA, Europe, Middle East, Turkey and India with all subjects genetically confirmed for HoFH and on stable maximally tolerated statin and other oral lipid lowering therapy prior to randomization. The efficacy endpoints were the percent change from baseline in LDL cholesterol (LDL-C) concentration at Week 12, Week 24 and average of monthly visits over the 24 weeks.
Sixty-six patients were randomized with mean (range) age 28.7 (10-58) years, 30% were pediatric patients, 55% female, 32% Asian, and a mean baseline LDL-C of 410 mg/dL (10.59 mmol/L). Mean LDL-C reduction when averaged across all monthly visits was –9.1% with lerodalcibep and –10.8% with evolocumab. % LDL-C reduction at Week 12 was -12% with lerodalcibep and -11.5% with evolocumab, and at Week 24 (ITT analysis) was -4.9% with lerodalcibep and -10.3% with evolocumab.
LDL-C responses were highly variable between patients, but the percent change from baseline for LDL-C over 24 weeks was similar in individual patients for both drugs (r=0.79, see figure).
Importantly, genotyping and free PCSK9 suppression were not predictive of response.
Both drugs were well tolerated, with no treatment-related serious adverse events. Injection site reactions were reported in one (2%) of 65 patients on lerodalcibep and 15 (24%) of 62 patients on evolocumab.
“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,” said Professor Derick Raal, Lead Investigator for the LIBerate HoFH trial, Distinguished Professor and Director, Carbohydrate & Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand in South Africa. “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. 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. 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.”
Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic disorder and most severe form of Familial Hypercholesterolemia (FH), characterized by reduced hepatic clearance and resultant markedly elevated LDL-C leading to premature atherosclerotic cardiovascular disease as early as the first decade of life. HoFH can cause heart disease (including heart attacks and aortic valve disease) beginning in early childhood, if untreated. Treatment should begin at diagnosis, regardless of the person’s age. HoFH affects approximately 1 in 300,000 people worldwide.
LIB announced on December 23, 2024 the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) seeking approval of lerodalcibep to reduce LDL-C for the treatment of 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).
