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
In February of 2021, the FDA has approved Evkeeza (evinacumab-dgnb) injection, manufactured by Regeneron, as an add-on therapy to patients 12 years and older with homozygous familial hypercholesterolemia (HoFH). Homozygous familial hypercholesterolemia is a genetic condition that can cause severely high cholesterol. This condition is a rare, life-threatening health condition that is found in approximately 1 in every 250,000 individuals. It is due to patients having two mutations in a small group of genes that controls the way the body clears cholesterol. This results in extremely high levels of LDL cholesterol in the body. Patients with this condition can develop premature cardiovascular disease early in their lives. Many patients also don’t improve with other cholesterol-lowering drugs. These patients require aggressive treatment to avoid death before age 30.
Evkeeza works by binding to and blocking the angiopoietin-like protein 3, wcich helps break down fats faster. This would prevent a high amount of cholesterol circulating in the body. The effectiveness and safety of Evkeeza were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial. Patients taking Evkeeza found a much higher decrease in LDL cholesterol as opposed to the placebo. Some of the common side effects of Evkeeza are nasopharyngitis, influenzae-like illness, dizziness, rhinorrhea, and nausea. In the Evkeeza trials, they have also seen severe hypersensitivity reactions occur. Pregnant patients should also be advised that Evkeeza may cause harm to an unborn baby. Pregnancy testing should also be considered in patients starting treatment. Evkeeza also received orphan drug designation, which encourages drug development for rare diseases, therapy designation, and priority review designation for this indication.
References:
1. “FDA Approves First-in-Class Evkeeza™ (Evinacumab-Dgnb) for Patients with Ultra-Rare Inherited Form of High Cholesterol.” Regeneron Pharmaceuticals Inc., https://investor.regeneron.com/news-releases/news-release-details/fda-approves-first-class-evkeezatm-evinacumab-dgnb-patients.
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, FDA, https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol-0.