About EVKEEZA(evinacumab-dgnb) Injection1
Evinacumab-dgnb is an angiopoietin-like protein 3 (ANGPTL3) inhibitor monoclonal antibody (IgG4 isotype) produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. Evinacumab-dgnb has an approximate molecular weight of 146 kDa.
EVKEEZA (evinacumab-dgnb) injection is a sterile, preservative-free solution for intravenous use. The solution is clear to slightly opalescent, colorless to pale-yellow, and free from visible particles.
Each vial contains 345 mg/2.3 mL or 1,200 mg/8 mL. Each mL contains 150 mg of evinacumab-dgnb, and L-arginine hydrochloride (14.8 mg), L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.1 mg), L-proline (30 mg), polysorbate 80 (1 mg) and Water for Injection, USP. The pH is 6.
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hypersensitivity Reactions [see Warnings and Precautions]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Safety data are based on pooled results from two randomized, double-blind, placebo-controlled trials that included 81 patients treated with EVKEEZA. The mean age of EVKEEZA-treated patients was 48 years (range: 15 to 75 years), 52% were women, 5% were Hispanic, 82% were White, 7% Asian, 3% Black, and 9% Other. Forty-four (54%) EVKEEZA-treated patients had HoFH. Patients received EVKEEZA as add-on therapy to other lipid-lowering therapies, including maximally tolerated statin, ezetimibe, PCSK9 inhibitors, lomitapide, and apheresis.
Adverse reactions led to discontinuation of treatment in 2 (2%) patients treated with EVKEEZA, including 1 case of anaphylaxis, and 1 (2%) patient who received placebo. The most common adverse reactions (reported in greater than 3% of EVKEEZA-treated patients and more frequently than in placebo) are shown in Table 2.
Other adverse reactions occurring in less than 3% of patients treated with EVKEEZA and greater than placebo included constipation, upper respiratory tract infection, nasal congestion, and abdominal pain.
Transient, mild to moderate decreases in diastolic blood pressure and increases in heart rate occurred in clinical trials of EVKEEZA infusion but did not require intervention and resolved post-infusion.
Serious Hypersensitivity Reactions
Anaphylaxis was reported in 1 (1%) patient treated with EVKEEZA and 0% in patients who received placebo.
Infusion reactions were reported in 6 (7%) patients treated with EVKEEZA and in 2 (4%) patients who received placebo. The following infusion reactions occurred in EVKEEZA-treated patients: infusion site pruritus, pyrexia, muscular weakness, nausea, and nasal congestion.
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to EVKEEZA in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
No patients developed treatment-emergent antibodies to EVKEEZA.
Mechanism of Action
Evinacumab-dgnb is a recombinant human monoclonal antibody that binds to and inhibits ANGPTL3. ANGPTL3 is a member of the angiopoietin-like protein family that is expressed primarily in the liver and plays a role in the regulation of lipid metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). Evinacumab-dgnb inhibition of ANGPTL3 leads to reduction in LDL-C, HDL-C, and triglycerides (TG). Evinacumab-dgnb reduces LDL-C independent of the presence of LDL receptor (LDLR) by promoting very low-density lipoprotein (VLDL) processing and clearance upstream of LDL formation. Evinacumab-dgnb blockade of ANGPTL3 lowers TG and HDL-C by rescuing LPL and EL activities, respectively.
Administration of evinacumab-dgnb in HoFH patients resulted in reductions in LDL-C, total cholesterol (TC), HDL-C, apolipoprotein B and TG [see Clinical Studies].
The pharmacokinetic parameters described in this section are presented following administration of evinacumab-dgnb 15 mg/kg intravenously every 4 weeks, unless otherwise specified.
Steady-state is reached after 4 doses, and the accumulation ratio is 2. According to population pharmacokinetic modeling, the mean (standard deviation) steady-state trough concentration is 241 (96.5) mg/L, whereas the mean (standard deviation) Cmax at the end of infusion is 689 (157) mg/L. Due to non-linear clearance, a 4.3-fold increase in area under the concentration-time curve at steady-state (AUCtau.ss) for a 3-fold increase in evinacumab-dgnb dose up to 15 mg/kg IV every 4 weeks was predicted in patients with HoFH.
The total volume of distribution estimated via population pharmacokinetic analysis was approximately 4.8 L.
Evinacumab-dgnb elimination is mediated via parallel linear and non-linear pathways. At higher concentrations, evinacumab-dgnb elimination is primarily through a non-saturable proteolytic pathway, whereas at lower concentrations, the non-linear, saturable ANGPTL3 target-mediated elimination predominates. The elimination half-life is a function of serum evinacumab-dgnb concentrations and is not a constant.
Based on a population pharmacokinetic analysis, the median time for serum evinacumab-dgnb concentrations to decrease below the lower limit of quantitation (78 ng/mL) is 19 weeks after the last steady-state dose of 15 mg/kg IV every 4 weeks.
The exact pathway through which evinacumab-dgnb is metabolized has not been characterized. As a human monoclonal IgG4 antibody, evinacumab-dgnb is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
Evinacumab-dgnb, a monoclonal antibody, is not likely to undergo renal excretion.
A population PK analysis conducted on data from 183 healthy subjects and 95 patients with HoFH suggests that the following factors have no clinically significant effect on the exposure of evinacumab-dgnb: age (12 to 75 years), gender, body weight (42 to 152 kg), and race (White, Asian, Black, and Other).
A 15-year-old patient with HoFH received evinacumab-dgnb at 15 mg/kg IV every 4 weeks. Steady-state trough and end-of-infusion concentrations were within the range observed in adult patients.
Patients with Renal Impairment
Observed trough serum evinacumab-dgnb concentrations at steady-state were comparable between patients with mild or moderate renal impairment and patients with normal renal function. No data are available in patients with severe renal impairment.
Patients with Hepatic Impairment
No data are available in patients with hepatic impairment.
Drug Interaction Studies
Drug interaction studies have not been conducted with evinacumab-dgnb. In a clinical trial, the concentrations of statins (atorvastatin, rosuvastatin, simvastatin) were not meaningfully altered in patients taking statins prior to and post administration of evinacumab-dgnb. Concentrations of evinacumab-dgnb were comparable in patients with HoFH taking or not taking background lipid-lowering therapy.
Study ELIPSE-HoFH (NCT03399786) was a multicenter, double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of EVKEEZA compared to placebo in 65 patients with HoFH. During the 24-week, double-blind treatment period, 43 patients were randomized to receive EVKEEZA 15 mg/kg IV every 4 weeks and 22 patients to receive placebo. After the double-blind treatment period, 64 of 65 patients entered a 24-week open-label extension period in which all patients received EVKEEZA 15 mg/kg IV every 4 weeks.
Patients were on a background of other lipid-lowering therapies, including maximally tolerated statins, ezetimibe, PCSK9 inhibitor antibodies, lomitapide, and lipoprotein apheresis. Enrolment was stratified by apheresis status and geographical region. The diagnosis of HoFH was determined by genetic testing or by the presence of the following clinical criteria: history of an untreated total cholesterol (TC) >500 mg/dL and either xanthoma before 10 years of age or evidence of TC >250 mg/dL in both parents. In this trial, 40% (26 of 65) patients had limited LDL receptor (LDLR) function, defined by either <15% receptor function by in vitro assays or by genetic variants likely to result in minimal to no LDLR function by mutation analysis.
The mean LDL-C at baseline was 255 mg/dL. In patients with limited LDLR function, the mean LDL-C at baseline was 307 mg/dL. At baseline, 94% of patients were on statins, 75% on ezetimibe, 77% on a PCSK9 inhibitor antibody, 22% on lomitapide, and 34% were receiving lipoprotein apheresis. The mean age at baseline was 42 years (range 12 to 75) with 12% ≥65 years old; 54% women, 3% Hispanic, 74% White, 15% Asian, 3% Black, and 8% Other or not reported.
The primary efficacy endpoint was percent change in LDL-C from baseline to Week 24. At Week 24, the least squares (LS) mean treatment difference between EVKEEZA and placebo in mean percent change in LDL-C from baseline was -49% (95% confidence interval: -65% to -33%; p<0.0001). After 24 weeks of open-label EVKEEZA treatment (Week 24 to Week 48), the observed LDL-C reduction from baseline was similar in patients who crossed over from placebo to EVKEEZA and was maintained in patients who remained on EVKEEZA for 48 weeks. For efficacy results see Table 1.
The LS mean LDL-C percent changes over time are presented in Figure 1.
At Week 24, the observed reduction in LDL-C with EVKEEZA was similar across predefined subgroups, including age, sex, limited LDLR activity, concomitant treatment with lipoprotein apheresis, and concomitant background lipid-lowering medications (statins, ezetimibe, PCSK9 inhibitor antibodies, and lomitapide).
Pediatric Patients with HoFH
In ELIPSE-HoFH, 1 pediatric patient received 15 mg/kg IV of EVKEEZA every 4 weeks, and 1 pediatric patient received placebo, as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe, PCSK9 inhibitor antibodies and lipoprotein apheresis). Both patients had null/null variants in the LDLR. At Week 24, the percent change in LDL-C with EVKEEZA was -73% and with placebo was +60%.
In an open-label extension study, 13 pediatric patients with HoFH (12 to 17 years of age) received 15 mg/kg IV of EVKEEZA every 4 weeks as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe, PCSK9 inhibitor antibodies and lipoprotein apheresis) for a median treatment duration of 33 weeks. The mean percent change from baseline in LDL-C at Week 24 was -52% in 9 patients who completed treatment and had a lipid assessment at Week 24. Overall, the effect of evinacumab-dgnb on lipid parameters in pediatric patients with HoFH was generally similar to that seen in adults with HoFH.
EVKEEZA is contraindicated in patients with a history of serious hypersensitivity reaction to evinacumab-dgnb or to any of the excipients in EVKEEZA. Serious hypersensitivity reactions, including anaphylaxis, have occurred [see Warnings and Precautions].
- The recommended dose of EVKEEZA is 15 mg/kg administered by intravenous (IV) infusion over 60 minutes once monthly (every 4 weeks).
- If a dose of EVKEEZA is missed, administer as soon as possible. Thereafter, EVKEEZA should be scheduled monthly from the date of the last dose.
- Assess LDL-C when clinically appropriate. The LDL-lowering effect of EVKEEZA may be measured as early as 2 weeks after initiation.
Preparation Instructions for Intravenous Infusion
- Calculate the dose (mg), total volume (mL) of EVKEEZA required, and the number of vials required based on the patient’s current body weight.
- Visually inspect the solution for cloudiness, discoloration, and particulate matter prior to administration. EVKEEZA is a clear to slightly opalescent, colorless to pale-yellow solution. Do not administer if the solution is cloudy or discolored or contains particulate matter.
- EVKEEZA vials are single-dose containers and do not contain a preservative. Observe aseptic technique when preparing EVKEEZA.
- Do not shake the vial. Withdraw the required volume from the vial(s) of EVKEEZA and transfer into an IV infusion bag containing a maximum volume of 250 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix the diluted solution by gentle inversion; do not shake.
- The final concentration of the diluted solution should be between 0.5 mg/mL and 20 mg/mL depending on the patient’s current body weight.
- Administer the diluted solution immediately after preparation and discard any unused portion left in the vial.
- If not used immediately, store the diluted solution refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for no more than 24 hours from the time of preparation OR at room temperature up to 25 °C (77 °F) for no more than 6 hours from the time of infusion preparation to the end of the infusion. Do not freeze the diluted solution.
Administration Instructions for Intravenous Infusion
- If refrigerated, allow the diluted solution to come to room temperature prior to administration.
- Administer EVKEEZA diluted solution via IV infusion over 60 minutes through an IV line containing a sterile, in-line or add-on, 0.2-micron to 5-micron filter.
- Do not mix other medications with EVKEEZA or administer other medications concomitantly via the same infusion line.
- The rate of infusion may be slowed, interrupted or discontinued if the patient develops any signs of adverse reactions, including infusion or hypersensitivity reactions [see Warnings and Precautions and Adverse Reactions].
- EVKEEZA can be administered without regard to the timing of lipoprotein apheresis.
EVKEEZA (evinacumab-dgnb) injection is a clear to slightly opalescent, colorless to pale yellow solution. It is supplied as one single-dose vial per carton.
- 345 mg/2.3 mL (150 mg/mL) NDC 61755-013-01
- 1,200 mg/8 mL (150 mg/mL) NDC 61755-010-01
Store in a refrigerator at 2 °C to 8 °C (36 °F to 46 °F). Store the vial in the original carton to protect from light. Do not freeze. Do not shake.
EVKEEZA does not contain a preservative. If not used immediately, store the diluted solution refrigerated at 2 °C to 8 °C (36 °F to 46 °F) for no more than 24 hours from the time of preparation OR at room temperature up to 25 °C (77 °F) for no more than 6 hours from the time of infusion preparation to the end of the infusion [see Dosage and Administration].
Serious Hypersensitivity Reactions
Serious hypersensitivity reactions have occurred with EVKEEZA. In clinical trials, 1 (1%) EVKEEZA-treated patient experienced anaphylaxis versus 0 (0%) patients who received placebo. If signs or symptoms of serious hypersensitivity reactions occur, discontinue EVKEEZA infusion, treat according to the standard-of-care, and monitor until signs and symptoms resolve. EVKEEZA is contraindicated in patients with a history of serious hypersensitivity reaction to evinacumab-dgnb [see Contraindications].
Based on the findings in animal reproduction studies, EVKEEZA may cause fetal harm when administered to pregnant patients. Administration of evinacumab to rabbits during organogenesis caused increases in fetal malformations at doses below the human exposure. Advise patients who may become pregnant of the risk to a fetus. Consider obtaining a pregnancy test prior to initiating treatment with EVKEEZA. Advise patients who may become pregnant to use effective contraception during treatment with EVKEEZA and for at least 5 months following the last dose of EVKEEZA.