Clinical Pharmacology Update: Evkeeza From Regeneron Pharmaceuticals, Inc
Evkeeza has been approved as an adjunct to other low-density lipoprotein cholesterol-lowering therapies to treat patients 12 years and older with homozygous familial hypercholesterolemia.
The FDA has approved Evkeeza (evinacumab-dgnb; Regeneron Pharmaceuticals, Inc) as an adjunct to other low-density lipoprotein cholesterol (LDL-C)-lowering therapies to treat patients 12 years and older with homozygous familial hypercholesterolemia (HoFH).
The approval carries the limitations that the effectiveness and safety of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH), and that the effects of Evkeeza on cardiovascular morbidity and mortality have not been determined.1 HoFH affects about 1300 Americans. The condition is ultra rare, occurring when 2 copies of the familial hypercholesterolemia genes are inherited, 1 from each parent. When left untreated, patients with HoFH have LDL-C levels of higher than 400 mg/dL and an increased risk of cardiac events and premature atherosclerotic disease as early as the teenage years.2
PHARMACOLOGY AND PHARMACOKINETICS
Evkeeza is a recombinant human monoclonal antibody and an angiopoietin-like 3 (ANGPTL3) inhibitor. ANGPTL3, a member of the angiopoietin- like protein family, is expressed mainly in the liver and is involved in lipid metabolism regulation by inhibiting lipoprotein lipase and endothelial lipase. Inhibition of ANGPTL3 results in lowered levels of LDL-C, high-density lipoprotein cholesterol, and triglycerides.
Evkeeza reaches steady-state plasma concentrations after 4 doses. It displays nonlinear clearance and is not likely to undergo renal excretion. Age, body weight, gender, and race do not appear to affect the pharmacokinetics of Evkeeza.1
DOSAGE AND ADMINISTRATION
The recommended dose of Evkeeza is 15 mg/kg administered as an intravenous (IV) infusion every 4 weeks. The diluted solution should be given via IV infusion over 60 minutes through an IV line containing a sterile in-line or add-on 0.2-μm to 5-μm filter. Evkeeza should not be mixed with other medications or administered concomitantly via the same infusion line as other medications. The infusion rate may be discontinued, interrupted, or slowed if signs and symptoms of an adverse reaction occur, including hypersensitivity or infusion reactions. Evkeeza is supplied in single-dose vials containing 345 mg/2.3 mL and 1200 mg/8 mL.1
The efficacy of Evkeeza was evaluated in a double-blind, multicenter, placebo-controlled, randomized trial of 65 participants with HoFH. The mean baseline LDL-C of participants before randomization was 255 mg/dL, with 94% of participants taking statins, 77% taking a PCSK9 inhibitor antibody, 75% taking ezetimibe, 34% receiving lipoprotein apheresis, and 22% taking lomitapide. In addition to continuing their background lipid-lowering therapies, participants were randomized to receive either Evkeeza 15 mg/kg IV every 4 weeks or a placebo for 24 weeks. After the 24-week double-blind treatment period, 64 of 65 participants entered a 24-week open-label extension period in which all participants received treatment with Evkeeza 15 mg/kg IV every 4 weeks.
The trial met its primary efficacy end point, which was the percent change in LDL-C from baseline to week 24. The participants receiving Evkeeza had a 49% reduction on average in LDL-C compared to those receiving the placebo. The 24-week open-label extension period demonstrated a similar reduction in LDL-C in those who had initially received the placebo and investigators found that the reduction in LDL-C was maintained in those who received Evkeeza during the blinded period of the trial.1,2
CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS
Serious hypersensitivity reactions have occurred during treatment with Evkeeza and its use is contraindicated in patients with a history of serious hypersensitivity reactions to the medication or any of its components.
If a serious hypersensitivity reaction occurs, Evkeeza should be discontinued and the standard-of-care treatment should be initiated, including monitoring until signs and symptoms resolve. Evkeeza may cause fetal harm. Obtaining a pregnancy test prior to beginning treatment should be considered in patients of childbearing potential, and those patients should use contraception during treatment and for at least 5 months after the last dose.
The most common adverse reactions were dizziness, influenza-like illness, nasopharyngitis, nausea, and rhinorrhea.1
1. Evkeeza. Prescribing information. Regeneron Pharmaceuticals, Inc; 2021. Accessed March 26, 2021. https://www.regeneron.com/sites/default/files/Evkeeza_PI.pdf
2. FDA approves first-in-class Evkeeza (evinacumab-dgnb) for patients with ultra-rare inherited form of high cholesterol. News release. Regeneron Pharmaceuticals, Inc. February 11, 2021. Accessed March 26, 2021. https://investor.regeneron.com/news-releases/news-release-details/fda-approves-first-class-evkeezatm-evinacumabdgnb-patients