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 AND EVINACUMAB
Familial Hypercholesterolemia (FH) is a genetic disorder that is characterized by high cholesterol levels (Low-density liproprotein, also known as LDL-C) from birth. There are four main mutations in patients diagnosed with FH. These are mutations of the LDL receptor, apolipoprotein B (Apo B), proprotein convertase subtilin/kexin 9 (PCSK9), and low-density lipoprotein receptor adaptor protein (LDLRAP). Heterozygous FH is more common, however the homozygous FH is the more dangerous version of the disease. Heterozygous FH is found in 1 in 250 people and is recessive without symptoms. However people with heterozygous FH has 50% chance of having a child with homozygous familial hypercholesterolemia. Homozygous familial hypercholesterolemia can lead to Cardiovascular disease if left untreated. There is a risk of early onset of CHD, especially since diagnosing for FH usually in adulthood. Diagnosing occurs in children with consistent levels of LDL >160 mg/dl and adults with LDL >190 mg/dl. Patients with parents who have heterozygous FH should be tested regularly in order to avoid CHD. Other symptoms that can occur is atherosclerosis, which are arteries covered in plaque, CAD, cerebrovascular disease, and aortic aneurysm. Lifestyle modifications include stop smoking, exercise, and lose weight if obese. If a patient was diagnosed with hypertension and diabetes mellitus, they should treat those diseases as well to decrease ASCVD risk.
Commonly used lipid lowering therapies include statins, ezetimibe, bile acid sequestrates, niacin, and PCSK9 inhibitors. First- line treatment includes high intensity statin such as atorvastatin 40-80 mg/day and rosuvastatin 20-40 mg/day. A new drug emerged to treat Homozygous familial hypercholesterolemia. Evinacumab (Evkeeza) is a humanized monoclonal antibody and angiopoietin-like 3 (ANGPTL3) inhibitor approved for adjuvant treatment in patients 12 years old and older. By inhibiting angiopoietin, Evinacumab results in an increase of lipid metabolism, a decrease in LDL-C, HDL-C, and triglycerides (TG). This is the first ANGPTL3 inhibitor approved in the United States. It is given 15 mg/kg every 4 weeks in an iv infusion over 60 minutes. It should be used in combination with other LDL-C lowering medications. Side effects includes nasopharyngitis, abdominal pain, flu-like symptoms, infusion related reaction, and dizziness. Watch out for hypersensitivity reaction, which includes rash, hives, itching, and burning. If patient has a hypersensitivity reaction, discontinue medication and monitor. In studies done on animals, evinacumab caused fetal malformations, therefore pregnant woman should avoid taking this medication. WOmen should take a pregnancy test before beginning the treatment and avoid pregnancy for at least 5 months after alst dose. In addition, humanized monoclonal antibodies are expensive, therefore patients should be warned about payments before beginning treatment.
Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015 May;33(2):169-79. doi: 10.1016/j.ccl.2015.01.001. PMID: 25939291; PMCID: PMC4472364.
Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK, Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan KC, Gipe DA, Khilla N, Pordy R, Weinreich DM, Yancopoulos GD, Zhang Y, Gaudet D; ELIPSE HoFH Investigators. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020 Aug 20;383(8):711-720. doi: 10.1056/NEJMoa2004215. PMID: 32813947.
Singh S, Bittner V. Familial hypercholesterolemia--epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015;17(2):482. doi: 10.1007/s11883-014-0482-5. PMID: 25612857.
As of March 2023, officials with the FDA have extended the approval for evinacumab-dgnb (Evkeeza; Regeneron Pharmaceuticals, Inc) as an adjunct to other lipid-lowering drugs for children 5 to 11 years of age with homozygous familial hypercholesterolemia (HoFH). Evinacumab-dgnb was previously approved in February 2021 as an adjunct to other treatments that reduce low-density lipoprotein cholesterol (LDL-C) in patients aged 12 years and older with HoFH.
Evinacumab-dgnb is the first FDA-approved treatment that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3), a protein that plays a key role in lipid metabolism, and it is the first treatment indicated for children as young as 5 years of age to treat dangerously high levels of LDL-C.
Evinacumab-dgnb was evaluated in a 3-part, single-arm, open-label trial in which the drug was added to other lipid-lowering therapies in patients 5 to 11 years of age with HoFH. Part A (n=6) was a phase 1b trial that evaluated the pharmacokinetics, safety, and tolerability of the drug. Part B (n=14) analyzed the efficacy of evinacumab-dgnb over a 24-week treatment period with patients at an average of 9 years of age. Of these patients, 86% were on statins, 93% were on ezetimibe, 50% were on LDL apheresis, and 14% were on lomitapide. Patients were administered evinacumab-dgnb 15 mg/kg every 4 weeks intravenously with their lipid-lowering treatment regimen.
The trial’s primary endpoint was change in LDL-C at week 24 and secondary endpoints included the effect of evinacumab-dgnb on other lipid parameters—such as apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein[a], and total cholesterol—as well as efficacy by mutation status, safety and tolerability, immunogenicity, and PK.
Even with having received treatment with other lipid-lowering drugs, patients enrolled in the phase 3 trial had an average LDL-C level of 264 mg/dL, which is more than twice the target (<110 mg/dL) for pediatric patients with HoFH. After treatment with evinacumab-dgnb, these patients experienced a drop in LDL-C by 48% at week 24 on average, which achieved the primary endpoint. There were also significant declines in other key secondary endpoints, including levels of apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol, and total cholesterol.
“Since it was first approved, Evkeeza has become the standard of care for homozygous familial hypercholesterolemia in those aged 12 years or older. We’re gratified that now children as young as 5 years old have the potential to benefit from this treatment,” said George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, in a press release. “As a first-in-class medicine for this relentless disease, Evkeeza exemplifies the promise of genetics-based research to transform treatment paradigms. Evkeeza’s journey from target discovery to treatment innovation was only made possible due to our long-term investment in genetics research and monoclonal antibody technologies, and this remains a central tenet of our science-first approach to this day.”
References:
1. EVKEEZA® (evinacumab-dgnb) injection, for intravenous use . (2023, March). U.S. Food and Drug Administration. Retrieved from accessdata.fda.gov/drugsatfda_docs/label/2023/761181s001lbl.pdf
2. FDA approves first-in-class Evkeeza® (evinacumab-dgnb) for young children with ultra-rare form of high cholesterol. Regeneron. News release. March 22, 2023. https://investor.regeneron.com/news-releases/news-release-details/fda-approves-first-class-evkeezar-evinacumab-dgnb-young-children
3. FDA approves first-in-class Evkeeva (evinacumab-dgnj) for patients with ultra-rare inherited form of high cholesterol [news release]. Tarrytown, NY; February 11, 2021: Regeneron. https://investor.regeneron.com/node/24876/pdf
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.