Evaluating Lerodalcibep’s Role in Homozygous Familial Hypercholesterolemia Management
LIB Therapeutics Inc., a private late-stage biopharmaceutical company, has recently shared findings from the Phase 3 LIBerate-HoFH study, which examines Lerodalcibep, a third-generation PCSK9 inhibitor, for the treatment of homozygous familial hypercholesterolemia (HoFH). The study, published in Lancet Diabetes & Endocrinology, provides insights into the efficacy and safety of Lerodalcibep compared to Evolocumab, another PCSK9 inhibitor.
Overview of the LIBerate-HoFH Study
The trial followed a randomized, cross-over design in which 66 patients, aged 10 years and older from the USA, Europe, Middle East, Turkey, and India, were administered Lerodalcibep and Evolocumab over two 24-week periods, separated by a washout phase. Participants were already on the highest tolerable dose of statins and additional oral lipid-lowering therapies before enrollment.
The primary efficacy endpoints assessed LDL cholesterol (LDL-C) reduction at Week 12, Week 24, and as an average over the 24-week period.
Key Findings
The mean LDL-C at baseline was 410 mg/dL (10.59 mmol/L), indicating a severe lipid disorder.
The mean LDL-C reduction averaged across all visits was -9.1% for Lerodalcibep and -10.8% for Evolocumab.
At Week 12, LDL-C reduction was -12% with Lerodalcibep and -11.5% with Evolocumab.
At Week 24, LDL-C reduction was -4.9% with Lerodalcibep and -10.3% with Evolocumab.
LDL-C responses varied significantly among patients, but individual responses to both drugs showed strong correlation (r = 0.79).
Genotyping and free PCSK9 suppression were not predictive of LDL-C reduction.
Both drugs were well tolerated, with no serious adverse events linked to treatment.
Injection site reactions occurred in 2% of Lerodalcibep patients and 24% of Evolocumab patients.
Expert Insights
According to Professor Derick Raal, lead investigator of the study, the trial expands the understanding of PCSK9 inhibition in HoFH, particularly by confirming a generally modest LDL-C response among this patient population. While past studies showed PCSK9 inhibitors reducing LDL-C by 20-30%, more recent data—including those from India and pediatric HoFH patients—indicate a more modest effect. Notably, about 30% of patients exhibited a strong response to treatment, underscoring the unpredictability of response based on genetic profiling.
The Significance of HoFH Treatment
HoFH is a rare but severe genetic disorder characterized by severely elevated LDL-C levels, which lead to premature atherosclerotic cardiovascular disease (ASCVD), sometimes as early as childhood. The condition, affecting approximately 1 in 300,000 individuals worldwide, requires early and aggressive treatment to mitigate cardiovascular risks.
Regulatory Progress
On December 23, 2024, LIB Therapeutics submitted a Biologics License Application (BLA) to the FDA, seeking approval of Lerodalcibep for treating ASCVD, high-risk hyperlipidemia, and both heterozygous and homozygous familial hypercholesterolemia (HeFH/HoFH).
Commentary by SuppBase Columnist Alice Winters
The LIBerate-HoFH study offers an important update in the realm of lipid-lowering therapies, but its findings should be approached with measured expectations. While Lerodalcibep introduces a novel third-generation PCSK9 inhibition approach, the LDL-C reductions reported here are relatively modest—far lower than earlier expectations set by previous PCSK9 inhibitors. The study’s findings reinforce a key challenge in HoFH treatment: patient response is highly variable, and genotyping does not offer predictive value in determining who will benefit most.
From a clinical standpoint, the most striking takeaway is that while PCSK9 inhibitors remain an essential tool in lipid management, they are not a universal solution for HoFH patients. The presence of non-responders and the relatively mild reductions seen in this study suggest that combination therapy—including lipoprotein apheresis, statins, and other emerging therapeutics—will continue to be necessary for optimal disease management.
On a practical note, Lerodalcibep does present a few advantages over Evolocumab, particularly in terms of injection site reactions (only 2% vs. 24%) and the convenience of a smaller 1.2 mL monthly dose with room-temperature stability. These factors may improve patient adherence, an often-overlooked but crucial component of long-term therapy success.
However, the broader market implications are still uncertain. The FDA’s pending approval decision will be key, but assuming a green light, Lerodalcibep’s commercial success will hinge on whether clinicians view it as a meaningful advancement over existing options. Given the modest efficacy seen in the study, pricing, insurance coverage, and real-world effectiveness will heavily influence adoption rates.
Ultimately, while Lerodalcibep represents an incremental step forward, it does not appear to be a game-changer in HoFH treatment. The field still awaits a truly transformative breakthrough that can offer more robust LDL-C reductions across a broader patient population.
