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 prevalent, autosomal dominant genetic disorder resulting from mutations in one or more genes responsible for the breakdown of LDL-C (low-density lipoprotein cholesterol, “bad cholesterol”). More often than not, individuals will only inherit one of the defective genes, making them “heterozygous.” However, in unique cases, both parents may pass on a gene mutation to their offspring, making them “homozygous.” Clinical presentation of familial hypercholesterolemia is represented by markedly elevated LDL-C levels and a predisposition to early onset atherosclerotic cardiovascular disease (ASCVD). There are two primary methods whereby a patient is diagnosed to have familial hypercholesterolemia:
A DNA-based mutation in the LDLR, PCSK9 or APOB gene, each of which play a factor in LDL-C levels
Clinical presentation with characteristics indicative of familial hypercholesterolemia, primarily elevated LDL-C levels.
Delving more into the epidemiology of familial hypercholesterolemia, currently more than 1,600 mutations in the LDLR gene exist and are responsible for about 85% to 90% of familial hypercholesterolemia cases. Usually, LDLR, located primarily on liver cells, play a crucial role in eliminating LDL cholesterol from the bloodstream. However, when there are genetic mutations present on these receptors, this elimination process is disrupted, leading to excessive LDL-C levels in the blood as well as an extended LDL-C half life. For reference, LDL cholesterol usually has a half life of 1.5 days, however when an individual has FH, the half life extends to about 3 to 4 days in heterozygous FH and up to 6 days in homozygous FH. The five different classes of mutations in LDLR are shown below:
Common treatment agents for familial hypercholesterolemia include a high-dose statin, add-on therapy with Ezetimibe (a PCSK9 inhibitor) or in some cases, monoclonal antibodies such as alirocumab or evolocumab. This discussion post will explore the role of alirocumab (Praluent) in the treatment of familial hypercholesterolemia and discuss the results of the ODYSSEY LONG TERM Trial.
Alirocumab, also known as Praluent, is a human monoclonal antibody that attacks PCSK9. PCSK9 interacts with LDLR on the surface of hepatocytes and leads to degradation of LDLR within the liver, therefore causing an elevation of LDL-C levels in the blood. Praluent, by blocking the interaction between PCSK9 and LDLR, enhances the availability of LDLRs for LDL-C elimination, subsequently causing a reduction in LDL-C levels. The ODYSSEY LONG TERM Trial was a randomized, double-blind, multinational controlled trial consisting of 2341 patients who were at high risk for cardiovascular events, all of whom had LDL-C levels above 70 mg/dL. These patients were also already on statins at the maximally tolerated dose, either as monotherapy or in combination with other cholesterol-lowering agents. Participants in this trial were randomly assigned in a 2:1 ratio to receive either Praluent 150 mg subcutaneously every 2 weeks or matching placebo for a duration of 78 weeks. The primary efficacy endpoint was the percentage change in calculated LDL-C levels from baseline to week 24.
Study population:
Adult patients at least 18 years of age with heterozygous FH or with diagnosed coronary heart disease or a coronary heart disease risk equivalent.
LDL-C of at least 70 mg/dL at the time of screening.
Already receiving maximally tolerated statin, with or without other cholesterol-lowering agents.
Methods:
Patients were randomized in a 2:1 ratio to receive either Praluent 150 mg every 2 weeks or matching placebo.
Both treatments were administered as a 1 mL subcutaneous injection, which was administered through a pre-filled syringe.
Patients returned to the study site at weeks 0, 4, 8, 12, 16, 24, 36, 52, 64 and 78 and again 8 weeks after the completion of the trial (week 86) for a safety assessment.
Results:
The primary efficacy endpoint in this trial was the percentage change in LDL-C levels from baseline to week 24 of the trial. The secondary endpoint was the percentage change in LDL-C levels during the administration of the study medication along with additional lipoprotein parameters at weeks 12 and 24.
Out of the 2341 patients recruited in the trial, 1553 of them were assigned to the treatment group (Praluent) vs. 788 were assigned to placebo.
The mean rate of adherence was about 98% for the Praluent group versus 97.6% in the placebo group.
The mean percentage change in calculated LDL-C levels from baseline to week 24 was -61.0% in the Praluent group versus a minimal increase of 0.8% in the placebo group, resulting in a difference of -61.9% (P<0.001)
At week 24, the average absolute LDL-C level was about 48 mg/dL in the Praluent group versus 119 mg/dL in the placebo group.
By week 24, about 79% of the patients in the Praluent group had met their goal LDL-C level of less than 70 mg/dL, whereas only 8.0% had met this goal in the placebo group.
A consistent reduction in LDL-C levels from baseline was observed from week 4 to week 78 in the Praluent group.
Discussion:
The ODYSSEY LONG TERM Trial demonstrated a significant reduction in LDL-C levels with Praluent compared to placebo. When used as add-on therapy in patients already receiving a maximally tolerated statin dose, with or without other cholesterol-lowering agents, Praluent reduced LDL cholesterol levels by about an extra 62% in high-risk patients. This result was consistently observed over the 78 week treatment period. This high efficacy was also observed across different subgroups of patients, including those with heterozygous versus homozygous familial hypercholesterolemia. The most common adverse effects that were seen with the use of Praluent were injection site reactions, ophthalmologic disorders and myalgia.
Resources:
Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. doi:10.1056/NEJMoa1501031
Rosenson R, Durrington P. Familial hypercholesterolemia in adults: Overview. UpToDate. December 10, 2023. Accessed April 15, 2024. https://www-uptodate-com.jerome.stjohns.edu/contents/familial-hypercholesterolemia-in-adults-overview?search=what+is+familial+hypercholesterolemia&source=search_result&selectedTitle=1~114&usage_type=default&display_rank=1#H4212208012.
Rosenson R, Durrington P. Familial hypercholesterolemia in adults: Treatment. UpToDate. December 7, 2023. Accessed April 15, 2024. https://www-uptodate-com.jerome.stjohns.edu/contents/familial-hypercholesterolemia-in-adults-treatment?search=familial+hypercholesterolemia&source=search_result&selectedTitle=2~114&usage_type=default&display_rank=2#H632142877.
Pejic RN. Familial hypercholesterolemia. Ochsner J. 2014;14(4):669-672.
Alirocumab (Lexi-Drugs). Lexicomp. Accessed April 15, 2024. https://online-lexi-com.jerome.stjohns.edu/lco/action/doc/retrieve/docid/patch_f/5750788?cesid=4oyE3LPjb96&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dpraluent%26t%3Dname%26acs%3Dfalse%26acq%3Dpraluent#use.