Familial Hypercholesterolemia & Evkeeza

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:

1. Patel, N., Parmar, M., & Patel, P. (2023, October 28). Evinacumab. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK597342/ 

2. Vaezi, Z., & Amini, A. (2022, September 26). Familial hypercholesterolemia. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK556009/ 

3. 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 

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: 

1. A DNA-based mutation in the LDLR, PCSK9 or APOB gene, each of which play a factor in LDL-C levels 

2. 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. 

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.