Familial Hypercholesterolemia & Evkeeza
Familial hypercholesterolemia is a disease that is commonly inherited and characterized by a dysfunction in cholesterol metabolism. The disease results in higher-than-normal levels of low-density lipoprotein (LDL), which many people may know as the “bad cholesterol”. This happens due to an impaired function of LDL receptors due to a genetic defect. There are typically five ways in which the LDL receptor is dysfunctional: the LDL receptor is not synthesized, the LDL receptor is not expressed on the cell surface because of improper transport, the LDL receptor does not bind to LDL, the LDL receptor does not properly cluster in clathrin-coated pits for endocytosis, or the LDL receptor is not recycled back to the cell surface. All of these lead the way to higher-than-normal levels of LDL. With familial hypercholesterolemia, there is a lifetime exposure to LDL that can cause complications from an early age. This disease state is not rare, but it is oftentimes missed, and an early diagnosis and treatment can prevent the complications such as the development of premature atherosclerotic cardiovascular disease.
Manifestations of familial hypercholesterolemia usually begin in adulthood, but the clinical effects can be seen earlier in life which is why diagnosis early on is very important. Being able to identify and treat the disease early is key to preventing complications and death. Many barriers exist in the diagnosis of familial hypercholesterolemia including mistaking other coronary artery disease risk factors for familial hypercholesterolemia factors, which can leave the disease undiagnosed for several generations. Cascade screening is a method in which providers screen for familial hypercholesterolemia in first- and second-degree relatives of patients that are diagnosed, but this method can still miss some individuals. The diagnosis of familial hypercholesterolemia is based on lipid levels, family history, physical findings, and genetic analysis. The physical findings can include tendon xanthomas, tuberous xanthomas, arcus corneae, or xanthelasma. It is important to note that these physical findings may not be present in those who have familial hypercholesterolemia and that they help aid in the differential diagnosis. There are three well-defined tools that are currently used to diagnose familial hypercholesterolemia: The US Make Early Diagnoses Prevent Early Deaths Program Diagnostic Criteria (MEDPED), The Dutch Lipid Clinic Network Diagnostic Criteria, and The Simon Broome Register Diagnostic Criteria.
The treatment of familial hypercholesterolemia should optimally start early, but as it is underdiagnosed it is often treated later in life. Long-term drug treatment can reduce or even eliminate the lifetime risk of coronary heart disease. In addition to lifestyle modifications, statins are the initial drug choice for all adults with familial hypercholesterolemia and children eight years or older with heterozygous familial hypercholesterolemia. Statins increase the expression of LDL receptors by reducing HMG-CoA reductase. It is important to note that the low potency statins are usually not enough to treat this disease and moderate to high potency statins should be used. Combination therapy will most likely need to be employed in many patients. There are now novel drugs on the market to treat familial hypercholesterolemia including a recently approved monoclonal antibody, evinacumab-dgnb, under the brand name Evkeeza. The indication is for an injectable add-on therapy for patients 12 years of age and older with homozygous familial hypercholesterolemia. The FDA designated Evkeeza as an orphan drug meaning that it is considered a breakthrough therapy design for rare diseases.
References:
1. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015;33(2):169-179. doi:10.1016/j.ccl.2015.01.001
2. Center for Drug Evaluation and Research. FDA approves add-on therapy for patients with genetic form of severely. U.S. Food and Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol-0. Accessed January 18, 2022.
3. Surma S, Romańczyk M, Filipiak KJ. Evinacumab - The new kid on the block. Is it important for cardiovascular prevention?. Int J Cardiol Cardiovasc Risk Prev. 2021;11:200107. Published 2021 Sep 22. doi:10.1016/j.ijcrp.2021.200107
Familial hypercholesterolemia is a hereditary condition caused by genetic mutations that result in significantly increased levels of cholesterol in the blood. Clinically, it is defined by elevated serum levels of low-density lipoprotein (LDL) cholesterol. Genetically, it is categorized into two types: (1) autosomal dominant (AD), and (2) codominant inheritance conveyed with a rate of 90% or higher. Familial hypercholesterolemia involves three primary genetic mutations: defects in the LDL receptor (the most prevalent), apolipoprotein B (ApoB), and proprotein convertase subtilisin/Kexin type 9 (PCSK9). These mutations hinder the function of LDL receptors, reducing the uptake of LDL cholesterol and leading to elevated LDL cholesterol levels. The severity and onset of cardiovascular disease depend on whether the patient has a homozygous or heterozygous mutation. Children who inherit defective genes from both heterozygous parents typically have very few functioning LDL receptors, resulting in extremely high LDL cholesterol levels and early-onset cardiovascular disease.
Homozygous familial hypercholesterolemia (HoFH) is a rare and life-threatening condition affecting approximately 1 in 250,000 individuals. Patients with HoFH possess two mutations in a specific set of genes responsible for cholesterol metabolism, leading to extremely high levels of low-density lipoprotein cholesterol (LDL-C) commonly known as bad cholesterol. These levels can range from 500 to 1,000 mg/ dL, which is more than four times the normal range. Patients with HoFH are at risk for developing early-onset cardiovascular diseases, such as heart attacks and heart disease, often during their teenage years or early 20s. Additionally, in HoFH, the potentially fatal disorders of angina pectoris, myocardial infarction, aortic supra-valvular and valvular stenosis in HoFH could occur even in childhood. Many patients do not respond to conventional cholesterol-lowering medications, and without intensive treatment, the condition can be fatal before the age of 30.
The diagnosis of homozygous familial hypercholesterolemia (HoFH) is primarily clinical, with genetic testing recommended if available. A positive diagnosis for HoFH involves the presence of two mutant alleles in the LDLR, ApoB, PCSK9, or LDLR adaptor protein 1 genes. Clinically, an LDL-C level of 400 mg/dL or higher, coupled with one or both parents having diagnosed familial hypercholesterolemia, positive genetic test results for an LDL-C raising gene defect (LDLR, PCSK9, ApoB), or autosomal-recessive FH indicates HoFH. Additionally, an LDL-C level exceeding 560 mg/dL, or an LDL-C level over 400 mg/dL accompanied by aortic valve disease or xanthomas by age 20, also meets the diagnostic criteria for HoFH.
Evkeeza (evinacumab-dgnb) received approval from the FDA in 2021 as an adjunct to other cholesterol-lowering treatments for patients aged 5 years and older diagnosed with (HoFH). Evkeeza is the first and only FDA-approved inhibitor of angiopoietin-like protein 3 (ANGPTL3) specifically for lowering LDL-C and other lipoproteins in individuals with (HoFH), functioning independently of LDL-receptor activity. By inhibiting ANGPTL3, Evkeeza allows lipoprotein lipase and endothelial lipase to function without restriction, aiding in the breakdown of LDL. A phase 2 clinical trial showed that the maximum dosage of Evkeeza could reduce the LDL levels by over 50%. For effective treatment of HoFH, Evkeeza should be used in combination with other lipid-lowering medications, such as statins or PCSK9 inhibitors.
As discussed earlier, the mechanism of action of Evkeeza works by targeting and inhibiting angiopoietin-like protein 3 (ANGPTL3), a key regulator of lipid metabolism. Angiopoietin-like 3 (ANGPTL3) is crucial in lipid metabolism regulation by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). In HoFH, elevated LDL-C levels result from reduced or absent LDL receptor (LDLR) function, which impedes LDL clearance. Evkeeza, a monoclonal antibody, binds to ANGPTL3, allowing LPL and EL to promote the clearance of very low-density lipoprotein (VLDL) remnants through remnant receptors in the liver, hence reducing LDL-C levels independently of LDLR activity. Some common side effects of Evkeeza include nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. Although HoFH is a devastating condition, the discovery and development of treatments like Evkeeza offer hope for the future. This progress exemplifies the potential of ongoing research and innovation in providing effective therapies even for the most challenging diseases.
References:
Patel, N., Parmar, M., & Patel, P. (2023, October 28). Evinacumab. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK597342/
Vaezi, Z., & Amini, A. (2022, September 26). Familial hypercholesterolemia. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK556009/
Center for Drug Evaluation and Research. (n.d.). FDA approves add-on therapy for patients with genetic form of severely. U.S. Food and Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol-0