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Editor: Preeti Patel Updated: 10/28/2023 9:22:20 PM


Evinacumab (evinacumab-dgnb) received approval from the United States Food and Drug Administration (FDA) in 2021 as an adjunct to other cholesterol-lowering treatments for patients aged 5 years and older diagnosed with homozygous familial hypercholesterolemia (HoFH). HoFH is a genetic disorder affecting lipid metabolism characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) levels of ≥300 mg/dL despite standard oral therapies due to diminished or absent LDL-receptor function. Early HoFH detection and prompt LDL-C level management are crucial to preventing hypercholesterolemia-related complications.[1] Drug regimens in HoFH include a combination of lipid-lowering therapies such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. These medications upregulate LDL-receptor expression in an attempt to reduce LDL-C levels.

Evinacumab is the first and only FDA-approved angiopoietin-like protein 3 (ANGPTL3) inhibitor for lowering LDL-C and other lipoproteins independently of LDL-receptor activity in HoFH.[2][3] The American College of Cardiology (ACC) endorses using evinacumab to manage HoFH.[4]

The diagnosis of HoFH is clinical; genetic testing should be performed if readily available. Possessing two mutant alleles for LDLR, Apo[b], PCSK9, or LDLR adaptor protein gene locus 1 is considered a positive test for HoFH. Clinically, an LDL-C ≥400 mg/dL and one or both parents having clinically diagnosed FH, positive genetic testing for a known LDL-C–raising (LDLR, PCSK9, Apo[b]) gene defect, or autosomal-recessive FH indicates a patient has HoFH. An LDL-C >560 mg/dL or LDL-C >400 mg/dL with either aortic valve disease or xanthomas at 20 years of age or younger could also meet the HoFH diagnosis criteria.

Inhibiting ANGPTL3, in turn, allows lipoprotein lipase and endothelial lipase to be uninhibited and aids in the breakdown of LDL. A phase 2 clinical trial demonstrated that the maximum dosage of evinacumab could decrease LDL levels by greater than 50%.[5] Evinacumab should be combined with other lipid-lowering medications, such as statins or PCSK9 inhibitors when treating HoFH. Additionally, patients should be advised to begin or continue lifestyle modifications such as diet and exercise to further aid in lowering LDL levels.

Evinacumab is being investigated for managing refractory familial and nonfamilial hypercholesterolemia and severe hypertriglyceridemia.[6] Evinacumab is not indicated in patients with high cholesterol levels due to other secondary medical conditions or hereditary heterozygous familial hypercholesterolemia. The safety and effectiveness of evinacumab have not been established in these patients.

Mechanism of Action

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Mechanism of Action

Mechanism of Action

Angiopoietin-like 3 (ANGPTL3) plays a prominent role in regulating lipid metabolism by blocking lipoprotein lipase (LPL) and endothelial lipase (EL). In HoFH, an increase in LDL-C levels is due to diminished or absent LDLR function slowing and preventing LDL clearance. Evinacumab is a monoclonal antibody (mAb) that binds to ANGPTL3, thereby allowing LPL and EL to enhance the clearance of VLDL remnants via remnant receptors in the liver, resulting in the decrease of LDL-C levels in an LDLR-independent manner.[7] This novel therapeutic idea stemmed from patients with a loss of function mutation of ANGPTL3, who were noted to have decreased LDL cholesterol, triglycerides, and HDL levels. These patients also had reduced cardiovascular risk compared to those without the loss of function mutation.[8] 


Absorption: A steady-state concentration of evinacumab is achieved after four doses. For adults, population pharmacokinetic modeling reveals an average steady-state trough concentration of 266 mg/L with a standard deviation of 120 mg/L.

Distribution: The estimated steady-state volume of distribution, determined through population pharmacokinetic analysis, is approximately 4.7 L.

Metabolism: The metabolic pathway for evinacumab remains uncharacterized. Evinacumab is a human monoclonal IgG4 antibody; it is believed to undergo degradation into small peptides and amino acids similar to endogenous IgG through catabolic pathways.

Excretion: Evinacumab, a monoclonal antibody, is unlikely to be renally excreted. The elimination half-life of evinacumab is linked to its serum concentration, with an approximate duration of 20 weeks for the serum concentration to decrease below the lower detection limit.


Dosage Forms

Evinacumab should be administered in patients with HoFH via intravenous infusion therapy. For proper storage, evinacumab injection should be refrigerated between 36°F to 46°F (2°C to 8°C). The vial should be kept in its original carton to protect it from light exposure. Avoid freezing and shaking the vial.


Two standard single-dose vial preparations exist: 345 mg/2.3 mL (150mg/1mL) and 1200 mg/8mL (150mg/1mL). The dosage should be calculated using the patient's weight and will determine which prepared volume will be utilized. Withdraw the necessary quantity and transfer it into an intravenous infusion bag of up to 250 mL capacity, including 0.9% sodium chloride USP or 5% dextrose injection. Gently invert to mix the diluted solution; do not shake.

Adult Dosage

The recommended dosage is 15 mg/kg of body weight, administered once every 4 weeks by intravenous (IV) infusion over 60 minutes.[6]

Specific Patient Populations

Hepatic impairment: No clinical data is currently available for hepatic impairment.

Renal Impairment: Although the definitive pathway of metabolism of evinacumab is unknown, it is not thought to undergo renal clearance. Through preliminary studies, patients with mild-to-moderate renal impairment demonstrated similar steady-state concentrations as those with normal renal function. Dose adjustment is unnecessary for mild-to-moderate renal impairment. Data is lacking for patients with severe renal impairment.

Pregnancy considerations: Special consideration must be taken in pregnant patients, as some animal models demonstrated the potential for fetal toxicity causing malformations in organogenesis. Human data is not available to evaluate the risk to the embryo and fetus; patients should be aware of potential risks. Patients who start the medication should be counseled on contraceptive methods due to potential teratogenic risks. All patients at risk of becoming pregnant should be followed closely and counseled on the risk of pregnancy while receiving treatment with evinacumab.

Breastfeeding considerations: There is no known risk for breastfeeding in these patients. Due to the high molecular weight of 146,000 Da, the presence of evinacumab in breast milk is expected to be minimal. Furthermore, it is anticipated that the protein may undergo degradation in the infant's gastrointestinal tract, resulting in limited absorption. Without further information, cautious use of evinacumab is advised during breastfeeding, particularly when nursing a neonate or preterm infant.[9]

Pediatric and geriatric patients: There is no dosage adjustment for pediatric or geriatric patients, and the same ratio can be used to calculate the ideal dosage in pediatric and geriatric patients who meet the guidelines to initiate an evinacumab treatment regimen. Patients 65 years and older should be carefully evaluated before being prescribed evinacumab.

Adverse Effects

Adverse Effects

Some common adverse effects described by patients taking evinacumab are hypersensitivity reactions, nasopharyngitis, nausea, influenza-like illness, dizziness, extremity pain, and rhinorrhea.[10] Injection site reactions to evinacumab include erythema, pain, bruising, swelling, induration, rash, and pruritus.[11]

A severe anaphylactic reaction was the most severe adverse effect noted in clinical trials.[12] There appears to be no evidence of evinacumab altering hepatic or renal function, as indicated by stable plasma concentrations of aspartate transaminase (AST), alanine transaminase (ALT), and creatine kinase (CK) throughout the treatment periods.[11] Another potential complication of all monoclonal antibody treatments is the possibility of the development of immunogenicity. However, no patients in the clinical trials developed any emergent treatment antibodies to the evinacumab therapy.

Drug-Drug Interactions

No significant drug interactions of evinacumab have been identified. In a clinical trial, simvastatin, atorvastatin, and rosuvastatin concentrations were not significantly altered when administered with evinacumab. Further drug interaction studies should be conducted.



Evinacumab is contraindicated in patients with severe hypersensitivity reactions such as anaphylaxis.[13] Patients with a history of allergic reactions to any excipients in evinacumab should not be prescribed the medication.

Warning and Precautions

Embryofetal toxicity: Evinacumab also poses a potential harm for embryofetal toxicity. Patients on evinacumab should use contraceptive methods throughout the therapeutic interval and for 5 months following the last dose of evinacumab therapy.

Hypersensitivity reactions: Evinacumab has been linked to severe hypersensitivity reactions, including anaphylaxis. If significant hypersensitivity signs or symptoms emerge, stop the evinacumab infusion, administer standard-of-care treatment, and monitor until resolution.[14]


Throughout evinacumab therapy, lipid panels should be routinely drawn to measure triglyceride, LDL-C, and total cholesterol levels. The LDL-C levels may be checked as early as 2 weeks after initiating therapy with evinacumab to see if quantitative values have fallen. Patients should be evaluated regularly by their prescribing practitioner to monitor their lab values and ensure no adverse effects have occurred since the last infusion. If a scheduled evinacumab administration is missed, patients should receive the IV infusion as early as possible. Following the previous dosage, new regular monthly infusions should be scheduled to ensure effective treatment. Routine administration and follow-up appointments with the practitioner are vital to providing safe and effective evinacumab treatment. As severe hypersensitivity reactions have occurred with evinacumab, if signs or symptoms of severe allergic reactions occur, discontinue evinacumab infusion. Treat the hypersensitivity reaction per standard-of-care protocols and observe the patient until signs and symptoms resolve.[4]


There is no significant toxicity associated with evinacumab therapy apart from embryofetal toxicity.[15] There is no antidote to evinacumab. There are no known contraindications in patients with either renal or hepatic impairment. Further studies should be performed to more accurately assess any long-term complications or adverse effects that may arise from evinacumab therapy.[16][17] If patients experience adverse reactions to the evinacumab, they should consult their prescribing or primary care practitioner as quickly as possible.

Enhancing Healthcare Team Outcomes

HoFH is a hereditary condition that negatively affects lipid metabolism. HoFH leads to high cholesterol levels, in particular, high LDL-C levels. High cholesterol levels predispose to early cardiovascular disease, which may lead to increased atherosclerosis. Increased atherosclerosis can lead to the development of either stroke or myocardial infarction.

Evinacumab is a novel monoclonal antibody medication used to treat HoFH. This medication may effectively treat patients with refractory outcomes to more conventional pharmacologic and lifestyle modifications. Evinacumab has been shown to lower LDL-C levels effectively in patients with HoFH. Evinacumab may be best used with other lipid-lowering medications and dietary and lifestyle modifications to achieve optimum results.[18]

Evinacumab does require prior authorization before administration, with specific guidelines needing to be met, which may vary per insurance company. Another critical factor to consider before the administration of evinacumab is the cost.[19] Due to the novelty of the medication, the expense of evinacumab may be quite high, with the annual wholesale cost as high as $450,000. Citing the substantial price of $450,000 per person per year for evinacumab, the National Lipid Association emphasizes the urgency for cost-effective approaches by proposing a novel technique: customizing doses using weight bands, a departure from the conventional mg/kg method and dose individualization as per the LDL-C response. This method can accomplish a 34% reduction in cost without compromising efficacy and offers a promising strategy to reduce the financial burden.[20] 

Managing HoFH usually requires the expertise of cardiologists and endocrinologists. However, primary care practitioners are essential to the optimal care of patients with HoFH patients as they routinely check laboratory values, including lipid panels. Pharmacists also play an indispensable role in managing HoFH; multiple lipid-lowering therapies must be rigorously trialed before initiating evinacumab therapy.

Other healthcare team members integral to evinacumab therapy are nurses, many of whom will start the intravenous lines and initiate the transfusion therapy. Many will be responsible for preparing the infusion and ensuring proper dosage and administration.

Patients should feel comfortable with their treatment plan and receive informed consent of all the risks and benefits before initiating treatment. In the event of anaphylaxis, emergency department practitioners should rapidly stabilize the patient. An interprofessional team approach with open communication between primary care practitioners, specialists, nurses, and pharmacists can optimize the patient outcomes of evinacumab therapy.



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