A third generation of the latest cholesterol-lowering medication — PCSK9-inhibitors — will soon be available for patients with homozygous familial hypercholesterolemia (HoFH), according to a January 24 article in The Lancet Diabetes & Endocrinology. Affecting approximately 30,000 individuals worldwide, HoFH is a rare but serious genetic disorder in which patients have markedly elevated levels (>10 mmol/L or 400mg/dL) of low-density lipoprotein (LDL- cholesterol), known colloquially as “bad cholesterol.”
If untreated, HoFH patients face fatty deposits in their skin and tendons, aortic valve disease, and premature atherosclerotic cardiovascular disease as early as in their first decade of life. Traditional treatment for HoFH entails statins and ezetimibe (Zetia), the former inhibits synthesis of cholesterol by the liver and the latter blocks the absorption of dietary cholesterol from the small intestine.
“Unfortunately, despite the use of statins and ezetimibe, the vast majority of patients with homozygous familial hypercholesterolemia still have markedly elevated LDL-cholesterol,” the authors write. “Therefore, these patients have the highest unmet medical need for additional LDL-cholesterol lowering therapies.”
Enter PCSK9 or proprotein convertase subtilisin/kexin type 9, a protein that binds to LDL receptors in the liver and prevents their recycling, thus reducing the liver’s ability to remove LDL-cholesterol from the blood. These protein inhibitors effectively lower LDL-cholesterol, are well tolerated, but require injections and are expensive. A decade ago, studies using monoclonal antibodies to inhibit this protein showed significant LDL-cholesterol reduction of approximately 30% in HoFH patients of mostly European ancestry. Subsequent trials in diverse populations of children and adults with HoFH using these monoclonal antibodies, or the short interfering RNA inclisiran (which inhibits liver PCSK9 synthesis) showed minimal overall reductions in LDL- cholesterol and a significant number (50% or more) of non-responders.
Lerodalcibep (LIB003) is a novel small recombinant fusion protein comprised of adnectin (derivative of an extracellular matrix protein, fibronectin, known for its “stickiness” and its roles in cell adhesion and migration) and the blood protein albumin. This engineered protein is meticulously crafted to bind and inhibit circulating PCSK9. Separate studies in heterozygous FH patients and in patients at high cardiovascular risk saw lerodalcibep reduce LDL- cholesterol by 65% and 63%, respectively. In this current study, called the LIBerate-HoFH phase 3 trial, the safety and efficacy of lerodalcibep is compared to the monoclonal antibody evolocumab in a diverse population of 66 HoFH patients, including patients from Türkiye and India as well as pediatric patients. All patients in this study underwent genotyping to confirm a genetic diagnosis of HoFH. They were then randomly assigned to receive monthly subcutaneous injections of either lerodalcibep 300 mg or evolocumab 420 mg for 24 weeks. Subsequently, an eight-week washout period was implemented prior to the crossover of treatments. Both PCSK9 inhibitors lowered LDL-cholesterol modestly, by approximately 10%, but 20% of the patients had a 30% or greater reduction in LDL-cholesterol, suggesting that lerodalcibep may be appropriate for some HoFH patients. Lerodalcibep is now seeking approval from the U.S. Food and Drug Administration and the European Medicines Agency.
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