Evinacumab, a recombinant human monoclonal antibody (IgG4 isotype), is an angiopoietin-like protein 3 (ANGPTL3) inhibitor indicated as an adjunct to other lipid-lowering therapies for the treatment of adults and pediatric patients 5 years and older with homozygous familial hypercholesterolemia (HoFH). In the multicenter, double-blind ELIPSE-HoFH study (63 adults and 2 pediatric patients), patients were randomized to either evinacumab 15 mg/kg/dose IV every 4 weeks (n = 43) or placebo (n = 22) for 24 weeks; patients were allowed to continue baseline lipid-lowering therapies. Patients were receiving the following lipid-lowering therapies at baseline: 94% on a statin (77% high-intensity statin), 75% on ezetimibe, 77% on a PCSK9 inhibitor, 22% on lomitapide, 34% on apheresis, 44% on triple therapy (ezetimibe, PCSK9 inhibitor, and statin), 11% on a 4-drug regimen (ezetimibe, lomitapide, PCSK9 inhibitor, and statin), and 63% were on at least 3 lipid-lowering therapies. At week 24, evinacumab patients experienced a mean LDL-C reduction of 47.1% compared to 1.9% increase in the placebo group. Within the evinacumab group, LDL-C reductions were similar across the predefined subgroups of age, gender, limited LDLR activity, concomitant apheresis, and concomitant lipid-lowering therapies. At week 24, 1 pediatric patient who received evinacumab (15 mg/kg/dose IV every 4 weeks) experienced an LDL-C reduction of 73% compared to an LDL-C increase of 60% in 1 pediatric patient who received placebo. In an open-label extension study, 13 pediatric patients (12 to 17 years of age) received evinacumab 15 mg/kg/dose IV every 4 weeks as an adjunct to other lipid-lowering therapies for a median for 33 weeks. Evinacumab therapy was associated with a 52% reduction in LDL-C in the 9 patients who completed 24 weeks of treatment and had a lipid assessment. In another multicenter, 3-part, single-arm, open-label trial, 14 pediatric patients aged 5 to 11 years received evinacumab 15 mg/kg/dose IV every 4 weeks as an adjunct to other lipid-lowering therapies. Evinacumab therapy was associated with a 48% reduction in LDL-C at 24 weeks of treatment. Due to the potential for fetal harm, consider pregnancy testing prior to initiation of therapy for females of reproductive potential and advise use of effective contraception during treatment and for at least 5 months after the last evinacumab dose.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect for cloudiness, discoloration, and particulate matter prior to administration. Solution is a clear to slightly opalescent, colorless to pale-yellow solution. Do not use if cloudy, discolored, or particulate matter is present.
-Administered via intravenous infusion only.
Intravenous Administration
Dilution
-Using aseptic technique, withdraw the required volume of the solution from the evinacumab vial(s) and add the withdrawn volume to an infusion bag containing a maximum volume of 250 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
-Mix the diluted solution by gentle inversion; do not shake.
-The final concentration should be between 0.5 mg/mL and 20 mg/mL.
-Storage: If the diluted solution is not immediately administered, store under refrigeration for up to 24 hours from the time of preparation; alternatively, the diluted solution may be kept at room temperature prior to use as long as it has completed infusing within this 6 hours of preparation. Do not freeze.
Intravenous Infusion
-If refrigerated, allow diluted solution to reach room temperature prior to administration.
-Administer over 60 minutes through an IV line containing a sterile, in-line or add-on, 0.2 to 5 micron filter.
-May be administered without regard to the timing of lipoprotein apheresis.
-The prepared solution should not be mixed or administered simultaneously with other medications.
-If the patient develops signs of adverse reactions, including infusion or hypersensitivity reactions, the infusion rate may be slowed, interrupted, or discontinued.
Naso-pharyngitis (16% with evinacumab vs. 13%), influenza-like illness (7% vs. 6%), rhinorrhea (5% vs. 0%), upper respiratory infection (less than 3%), and nasal congestion (less than 3%) were observed in clinical trials.
Dizziness (6% with evinacumab vs. 0% with placebo), asthenia (4% vs. 0%), and pain in extremity (4% vs. 0%) were reported with evinacumab in clinical trials. Fatigue was reported in 15% of pediatric patients 5 to 11 years treated with evinacumab in an open-label trial (n = 20).
Nausea (5% with evinacumab vs. 2% with placebo), constipation (less than 3%), and abdominal pain (less than 3%) were reported with evinacumab in clinical trials.
In clinical trials, infusion-related reactions, including infusion site pruritus, fever, muscular weakness, nausea, and nasal congestion, were reported in 6 (7%) evinacumab patients compared to 2 (4%) placebo patients. Transient, mild to moderate hypotension and increases in heart rate have been reported during evinacumab infusion; resolved post-infusion without intervention. Anaphylactoid reactions may occur with evinacumab. In clinical trials, one evinacumab patient (1%) developed anaphylaxis. If a serious allergic reaction occurs, immediately discontinue evinacumab therapy and institute appropriate medical therapy.
Similar to other therapeutic proteins, there is a potential for immunogenicity with evinacumab therapy. In the clinical trial in pediatric patients 5 to 11 years, the incidence of antibody formation in evinacumab-treated patients was 5% (1 of 20). In the 1 patient that developed anti-evinacumab antibodies, there were no effects on efficacy or evinacumab concentrations. In clinical trials in adults and pediatric patients 12 years and older, no patients developed antibodies.
During clinical trials, infusion-related reactions were reported in 6 (7%) evinacumab patients compared to 2 (4%) placebo patients. Reported infusion-related reactions included infusion site pruritis, pyrexia, muscular weakness, nausea, and nasal congestion. One patient (1%) treated with evinacumab developed anaphylaxis in clinical trials. If a patient develops any signs of adverse reactions, such as an infusion-related or anaphylactic reaction, the rate of infusion may be slowed, interrupted, or discontinued.
Evinacumab may cause fetal harm when administered during pregnancy. Available data on the use of evinacumab in human pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Human IgG is known to cross the placental barrier; thus, evinacumab, a human IgG4 monoclonal antibody, has the potential to be transferred from the mother to the fetus. In an embryo-fetal development study, fetal malformations (domed head, dilation of the lateral and third ventricles of the brain, and flexed fore/hind paws) occurred when pregnant rabbits received subcutaneous evinacumab doses of 1, 5, 10 and 30 mg/kg every 3 days from gestation day 7 to day 19; maternal rabbit exposures were below the maximum recommended human dose (MRHD) of 15 mg/kg every 4 weeks. The other fetal malformations that occurred were consistent with maternal toxicity (including early deaths due to abortion and premature delivery at all doses, reduction in maternal body weight gains, and reduced maternal food consumption) and consisted of irregular and abnormal ossification in the skull, palate, and metacarpal, and enlarged anterior and/or posterior fontanelles. There were also increased incidences of post-implantation losses, resorptions (total, early, and late), and decreased fetal body weight consistent with maternal toxicity. At doses of 10 and 30 mg/kg subcutaneously every 3 days, evinacumab was found in the sera of fetuses at levels higher than in maternal serum. No adverse effects on embryofetal development were observed following subcutaneous evinacumab administration at doses of 5, 10, 30 and 100 mg/kg every 3 days to pregnant rats from gestation day 6 to day 18; maternal exposures were below the human MRHD exposure. Unexplained maternal deaths occurred at the 100 mg/kg dose. In pregnant rats, evinacumab was found to cross the placenta and be present at ratios (Cfetal/Cmaternal) of 0.42 to 0.65. In another study involving pregnant rats that received 30 and 100 mg/kg subcutaneously every 3 days starting 2 weeks before mating through gestation day 21 or lactation day 21, no maternal or developmental toxicity were observed. If a patient becomes pregnant while receiving evinacumab therapy, health care providers should report the exposure by calling 1-833-385-3392.
There are no data on the presence of evinacumab in human milk, effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to evinacumab are unknown. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated maternal condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.
Based on animal studies, evinacumab may cause fetal harm when administered to pregnant women. Consider pregnancy testing prior to initiating evinacumab therapy in females of reproductive potential. Contraception requirements for females include the use of effective contraception during drug treatment and for at least 5 months following the last dose of evinacumab.
For the treatment of homozygous familial hypercholesterolemia (HoFH) as an adjunct to other low-density lipoprotein-cholesterol (LDL-C) lowering therapies:
Intravenous dosage:
Adults: 15 mg/kg/dose IV every 4 weeks. Monitor LDL-C as clinically appropriate; the LDL-C lowering effect may be measured as early as 2 weeks after starting therapy.
Children and Adolescents 5 to 17 years: 15 mg/kg/dose IV every 4 weeks. Monitor LDL-C as clinically appropriate; the LDL-C lowering effect may be measured as early as 2 weeks after starting therapy.
Maximum Dosage Limits:
-Adults
15 mg/kg/dose IV every 4 weeks.
-Geriatric
15 mg/kg/dose IV every 4 weeks.
-Adolescents
15 mg/kg/dose IV every 4 weeks.
-Children
5 to 12 years: 15 mg/kg/dose IV every 4 weeks.
1 to 4 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No data are available on evinacumab use in patients with hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed in mild or moderate renal impairment. No data are available in patients with severe renal impairment.
*non-FDA-approved indication
There are no drug interactions associated with Evinacumab products.
Evinacumab, a recombinant human monoclonal antibody (IgG4 isotype), is an angiopoietin-like protein 3 (ANGPTL3) inhibitor. ANGPTL3, part of the angiopoietin-like protein family, is primarily expressed on the liver and has a role in the regulation of lipid metabolism through inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL). ANGPTL3 inhibition leads to reductions in LDL-C, HDL-C, and triglycerides (TG). Evinacumab reduces LDL-C through the promotion of very low-density lipoprotein (VLDL) processing and clearance upstream from LDL formation; this process is independent of the LDL receptor (LDLR). In addition, ANGPTL3 inhibition rescues LPL and EL activities resulting in TG and HDL-C reductions, respectively.
Evinacumab is administered intravenously. Based on a population pharmacokinetic analysis, steady-state is reached after 4 doses (15 mg/kg/dose IV every 4 weeks) and evinacumab has an accumulation ratio of 2. Evinacumab has an estimated total Vd of 4.7 L. Evinacumab elimination occurs via both parallel linear and non-linear pathways. At higher concentrations, the primary route of elimination is through a non-saturable proteolytic pathway. However, at lower concentrations, elimination primarily occurs via the non-linear, saturable ANGPTL3 target-mediated pathway. Thus, elimination half-life is based upon evinacumab concentrations and is not constant. Although the exact route of metabolism is not known, it is expected that evinacumab, similar to endogenous IgG, is degraded into small peptides and amino acids via catabolic pathways. Evinacumab is not expected to undergo renal excretion.
Affected cytochrome P450 (CYP) isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Intravenous Route
After IV administration of evinacumab 15 mg/kg/dose every 4 weeks, the mean steady-state trough concentration is 266 +/- 120 mg/L and the mean Cmax at the end of the infusion is 718 +/- 183 mg/L. Based on non-linear clearance, a 3-fold increase in evinacumab dose up to 15 mg/kg/dose IV every 4 weeks is expected to result in a 4.3-fold increase in steady-state AUC. The median time for serum evinacumab concentrations to decrease below the lower limit of quantification (78 mg/mL) is 19 weeks after the last steady-state dose of 15 mg/kg/dose IV every 4 weeks.
-Special Populations
Hepatic Impairment
No data are available on evinacumab therapy in patients with hepatic impairment.
Renal Impairment
Steady-state evinacumab serum trough concentrations were similar between patients with normal renal function and patients with mild or moderate renal impairment. No data are available in patients with severe renal impairment.
Pediatrics
Children and Adolescents 12 to 17 years
Three patients aged 12 to 17 years who received evinacumab 15 mg/kg/dose IV every 4 weeks had steady-state trough and end-of-infusion concentrations (Cmax) that were within the range observed in adult patients.
Children 5 to 11 years
Steady-state trough and end-of-infusion concentrations were lower, but within the range observed in adult patients, in pediatric patients 5 to 11 years. In a pediatric study, 20 patients aged 5 to 11 years received evinacumab 15 mg/kg/dose IV every 4 weeks. According to population pharmacokinetic modeling, the mean steady-state trough concentration is 174 +/- 74.1 mg/L, whereas the mean Cmax at the end of infusion is 444 +/- 111 mg/L.
Geriatric
Age (up to 75 years) was not shown to have an effect on the pharmacokinetics of evinacumab.
Gender Differences
Gender was not shown to have an effect on the pharmacokinetics of evinacumab.
Ethnic Differences
Race (White, Asian, Black, and Other) was not shown to have an effect on the pharmacokinetics of evinacumab.
Obesity
Weight was not shown to have an effect on the pharmacokinetics of evinacumab.