Introduction
Evkeeza (evinacumab-dgnb) is a novel monoclonal antibody developed by Regeneron Pharmaceuticals for the treatment of homozygous familial hypercholesterolemia (HoFH). Approved by the FDA in February 2021, it represents a significant advancement in the management of this rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease.
Mechanism of Action
Evkeeza is a fully human monoclonal antibody that binds to and inhibits angiopoietin-like 3 (ANGPTL3). ANGPTL3 is a protein that regulates lipid metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). By inhibiting ANGPTL3, Evkeeza reduces:
- VLDL production and secretion from the liver
- Lipolysis of VLDL and chylomicrons
- Hepatic uptake of LDL and HDL particles
This mechanism results in significant reductions in LDL-C, HDL-C, and triglyceride levels, independent of LDL receptor function, making it particularly effective for HoFH patients who often have defective LDL receptor pathways.
Indications
Evkeeza is indicated as an adjunct to other LDL-lowering therapies in adult and pediatric patients aged 12 years and older with homozygous familial hypercholesterolemia.
Dosage and Administration
Standard dosing: 15 mg/kg administered intravenously every 4 weeks Administration:- Administer as an IV infusion over 60 minutes
- Initiate at a slower infusion rate (1 mL/min for first 30 minutes)
- May increase to 2 mL/min for remaining infusion if tolerated
- Pre-medication with antihistamines, antipyretics, and/or corticosteroids may be considered
- Do not mix with other medications or solutions
- Renal impairment: No dosage adjustment required
- Hepatic impairment: Use with caution; limited data available
- Pediatric: Safety and efficacy established in patients ≥12 years
- Geriatric: Limited data available
Pharmacokinetics
Absorption: Administered intravenously, resulting in complete bioavailability Distribution: Steady-state volume of distribution approximately 5.4 L Metabolism: Expected to be metabolized via proteolytic enzymes into small peptides and amino acids Elimination: Half-life approximately 17-20 days Clearance: Linear pharmacokinetics with clearance approximately 0.17 L/dayContraindications
- History of serious hypersensitivity reaction to evinacumab-dgnb or any excipients
- Severe hepatic impairment (Child-Pugh Class C)
Warnings and Precautions
Hypersensitivity reactions: Serious reactions including anaphylaxis have been reported. Monitor patients during and after infusion. Embryo-fetal toxicity: Based on animal data, may cause fetal harm. Advise females of reproductive potential of potential risk. Hepatic effects: Monitor liver enzymes; discontinue if signs of liver injury occur Lipid effects: May significantly reduce HDL-C levels; clinical significance unknownDrug Interactions
- No formal drug interaction studies conducted
- Theoretical potential for interactions with other monoclonal antibodies due to FcRn pathway saturation
- No expected interactions with cytochrome P450 substrates
Adverse Effects
Most common adverse reactions (≥5%):- Nasopharyngitis (16%)
- Influenza-like illness (12%)
- Dizziness (8%)
- Nausea (7%)
- Back pain (6%)
- Fatigue (6%)
- Increased AST/ALT (5%)
- Hypersensitivity reactions (2%)
- Hepatic enzyme elevations
Monitoring Parameters
Baseline:- Lipid profile (LDL-C, HDL-C, triglycerides)
- Liver function tests (AST, ALT)
- Pregnancy test in females of reproductive potential
- Lipid profile at regular intervals (typically every 3-6 months)
- Liver enzymes every 3 months for first year, then periodically
- Monitor for infusion reactions during and after administration
- Blood pressure and vital signs during infusion
- Cardiovascular event monitoring
- Ophthalmologic examinations (theoretical concern for retinal changes)
Patient Education
- Explain the nature of HoFH and importance of continued lipid management
- Inform about potential infusion reactions and their symptoms
- Emphasize need for regular monitoring and follow-up appointments
- Discuss importance of continuing other lipid-lowering therapies
- Advise females of reproductive potential about potential fetal risks and need for contraception
- Instruct to report any signs of hypersensitivity reactions or liver problems
- Explain that HDL-C reduction may occur but clinical significance is unknown
References
1. FDA Prescribing Information: Evkeeza (evinacumab-dgnb). February 2021. 2. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for Homozygous Familial Hypercholesterolemia. N Engl J Med. 2020;383(8):711-720. 3. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 Inhibition in Homozygous Familial Hypercholesterolemia. N Engl J Med. 2017;377(3):296-297. 4. Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in Patients with Refractory Hypercholesterolemia. N Engl J Med. 2020;383(24):2307-2319. 5. ClinicalTrials.gov: ELIPSE HoFH Study (NCT03399786) 6. European Medicines Agency Assessment Report: Evkeeza. 2021.