Evkeeza Drug Information
Generic name: EVINACUMAB
Angiopoietin-like 3 Inhibitor [EPC]
Uses of Evkeeza
is indicated as an adjunct to diet and exercise and other low-density lipoprotein-cholesterol (LDL-C) lowering therapies to reduce LDL-C in adults and pediatric patients, aged 1 year and older, with homozygous familial hypercholesterolemia (HoFH). EVKEEZA is an angiopoietin-like 3 (ANGPTL3) inhibitor indicated as an adjunct to diet and exercise and other low-density lipoprotein-cholesterol (LDL-C) lowering therapies to reduce LDL-C in adults and pediatric patients, aged 1 year and older, with homozygous familial hypercholesterolemia (HoFH).
Dosage & Administration of Evkeeza
| 5 mL/kg | |
| 150 mL | |
| 250 mL |
Side Effects of Evkeeza
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. Adverse Reactions in Adult and Pediatric Patients (aged 12 to 17 years) with HoFH 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 females; 5% were Hispanic; 82% were White, 7% Asian, 3% Black or African American, and 9% other races. 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, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, lomitapide, and apheresis.
Adverse reactions led to discontinuation of treatment in 1 (2%) patient who received placebo, and 2 (2%) patients treated with EVKEEZA, including 1 case of anaphylaxis. 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. Table 2: Adverse Reactions Occurring in >3% of Adult and Pediatric Patients Aged 12 to 17 Years Treated with EVKEEZA and Greater than Placebo in 24-Week, Pooled, Placebo-Controlled Trials Adverse Reactions Placebo (N = 54) % EVKEEZA (N = 81) % Nasopharyngitis 13 16 Influenza like illness 6 7 Dizziness 0 6 Rhinorrhea 0 5 Nausea 2 5 Pain in extremity 0 4 Asthenia 0 4 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 0% patients who received placebo and 1 (1%) patient treated with EVKEEZA. Infusion Reactions Infusion reactions were reported in 2 (4%) patients who received placebo and 6 (7%) patients treated with EVKEEZA. The following infusion reactions occurred in EVKEEZA-treated patients: infusion site pruritus, pyrexia, muscular weakness, nausea, and nasal congestion. Adverse Reactions in Pediatric Patients (aged 5 to 11 years) with HoFH Safety data are based on pooled results from a three-part, open-label trial in 20 pediatric patients with HoFH (aged 5 to 11 years) with a median treatment duration of 50 weeks. Part A was a trial of 6 patients who received a single intravenous dose of EVKEEZA 15 mg/kg to determine the dosage for the rest of the trial.
Part B was a single-arm, 24-week trial of EVKEEZA 15 mg/kg given intravenously every 4 weeks in 14 unique patients. Part C was a 48-week extension trial of EVKEEZA 15 mg/kg given intravenously every 4 weeks that consisted of 20 patients who entered directly from Parts A or B. The mean age was 9 years (range: 5 to 11 years); 60% females; 70% White, 10% Asian, 5% Black or African American, 5% American Indian or Alaska Native, and 10% other races. The safety profile of EVKEEZA observed in these patients was consistent with the safety profile observed in adults and pediatric patients aged 12 years and older, with the additional adverse reaction of fatigue.
Fatigue was reported in 3 (15%) patients.
Warnings & Cautions for Evkeeza
Serious Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have occurred with
EVKEEZA . 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.
Embryo-Fetal Toxicity
Based on the findings in animal reproduction studies, EVKEEZA may cause fetal harm when administered to pregnant patients. Administration of evinacumab-dgnb 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 dosage of EVKEEZA .
Pregnancy Safety for Evkeeza
Pregnancy Risk Summary Based on data from animal reproduction studies, EVKEEZA may cause fetal harm when administered to pregnant patients. Available human data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Evinacumab-dgnb is a human IgG4 monoclonal antibody, and human IgG is known to cross the placental barrier; therefore, evinacumab-dgnb has the potential to be transmitted from the mother to the developing fetus.
Subcutaneous administration of evinacumab-dgnb to pregnant rabbits during the period of organogenesis resulted in fetal malformations (domed head, hydrocephalus, and flexed limbs) at doses below the maximum recommended human dose (MRHD). No adverse embryofetal effects were observed with subcutaneous administration of evinacumab-dgnb to pregnant rats during the period of organogenesis at doses below the MRHD. Measurable evinacumab-dgnb serum concentrations were observed in fetal rabbit and rat sera at birth, indicating that evinacumab-dgnb, like other IgG antibodies, crosses the placental barrier (see Data ). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
If a patient becomes pregnant while receiving EVKEEZA, healthcare providers should report EVKEEZA exposure by calling 1-833-385-3392. Data Animal Data In an embryo-fetal development study in pregnant rabbits, evinacumab-dgnb was administered subcutaneously at doses of 1, 5, 10 and 30 mg/kg every 3 days (Q3D) during the period of organogenesis from gestation day 7 to day 19. Evinacumab-dgnb was teratogenic in rabbits, causing domed head, dilation of the lateral and third ventricles of the brain, and flexed fore/hind paws at maternal evinacumab-dgnb exposures below human exposure at the MRHD of 15 mg/kg every 4 weeks, based on AUC. Other fetal malformations, consisting of irregular and abnormal ossification in the skull, palate, and metacarpal, and enlarged anterior and/or posterior fontanelles occurred and were consistent with significant 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). Increased incidences of post-implantation losses, resorptions (total, early, and late), and decreased fetal body weight were also consistent with maternal toxicity. Evinacumab-dgnb was present in the sera of fetuses born from mothers at 10 and 30 mg/kg/Q3D at levels higher than in maternal serum. In an embryo-fetal development study in pregnant rats, evinacumab-dgnb was administered subcutaneously at doses of 5, 10, 30 and 100 mg/kg/Q3D during the period of organogenesis from gestation day 6 to day 18. Maternal exposures to evinacumab-dgnb were below the human exposure measured at the MRHD. Evinacumab-dgnb resulted in unexplained maternal deaths at 100 mg/kg/Q3D. Evinacumab-dgnb crossed the placenta and was present at ratios (C Fetal /C Maternal ) ranging from 0.42 to 0.65. No adverse effects on embryofetal development were observed at any dose.
In a combined fertility, embryofetal, and pre- and postnatal development study, female rats were administered evinacumab-dgnb via subcutaneous injection at doses of 30 and 100 mg/kg/Q3D beginning 2 weeks prior to mating and continuing to gestation day 21 or lactation day 21. Mean maternal systemic exposures were below the human exposure at the MRHD throughout the study. No maternal or developmental toxicity was observed.
Pediatric Use of Evkeeza
Pediatric Use The safety and effectiveness of EVKEEZA as an adjunct to other LDL-C-lowering therapies for the treatment of HoFH have been established in pediatric patients aged 1 year and older. Use of EVKEEZA for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy, and safety data in pediatric patients aged 1 year and older . The safety profile of EVKEEZA in pediatric patients aged 1 to 11 years was similar to the safety profile in adults and pediatric patients aged 12 years and older, with the additional adverse reaction of fatigue in patients aged 5 to 11 years. The safety and effectiveness of EVKEEZA have not been established in pediatric patients younger than 1 year of age.
Contraindications for 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. History of serious hypersensitivity reactions to evinacumab-dgnb or to any of the excipients in EVKEEZA.
Clinical Studies of Evkeeza
Adult and Pediatric Patients Aged 12 Years and Older with HoFH Trial ELIPSE-HoFH (NCT03399786; Trial 1) was a multicenter, double-blind, randomized, placebo-controlled trial that evaluated the efficacy of EVKEEZA compared to placebo in 65 patients with HoFH (63 adult patients and 2 pediatric patients). During the 24-week, double-blind treatment period, patients were randomized to receive EVKEEZA 15 mg/kg given intravenously every 4 weeks (n=43) or placebo given intravenously every 4 weeks (n=22). 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 given intravenously 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. Enrollment 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. Baseline Disease and Demographic Characteristics 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% females; 3% Hispanic; 74% White, 15% Asian, 3% Black or African American, and 8% other races or race was not reported. Endpoint Results 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 the EVKEEZA and placebo groups 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 3. 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). Table 3: Lipid Parameters in Patients (63 Adults and 2 Pediatric Patients) with HoFH on Other Lipid-Lowering Therapies in Trial ELIPSE-HoFH (Trial 1) LDL-C ApoB Non-HDL-C TC TG Neither TG nor HDL-C were pre-specified in the hypothesis testing HDL-C One subject in the placebo group discontinued the trial before Week 24. The treatment difference and 95% confidence interval (CI) were estimated using a mixed model repeated measures analysis.
Abbreviations: HoFH=homozygous familial hypercholesterolemia, ITT=intent-to-treat, LS mean=least squares mean, N=number of randomized patients, CI=confidence interval Baseline (mean), mg/dL (N=65) 255 171 278 322 124 44 LS Mean: EVKEEZA (N = 43) −47% −41% −50% −47% −55% −30% Mean percent change, based on safety population (EVKEEZA, n=44; placebo, n=21); HDL-C is presented for completeness but was not an efficacy endpoint that was statistically analyzed. LS Mean: Placebo (N = 22) +2% −5% +2% +1% −5% +1% LS Mean Difference from Placebo (95% CI) −49% (−65 to −33) −37% (−49 to −25) −52% (−65 to −39) −48% (−59 to −38) −50% (−66 to −35) - The LS mean LDL-C percent changes over time are presented in Figure 1. Abbreviations: LS mean=least squares mean, HoFH=homozygous familial hypercholesterolemia, DBTP=double-blind treatment period, SE=standard error Figure 1: Calculated LDL-C LS Mean Percent Change from Baseline Over Time Through Week 24 in Patients (63 Adults and 2 Pediatric Patients) with HoFH in Trial ELIPSE-HoFH (Trial 1) Pediatric Patients (aged 12 to 17 years) with HoFH In an open-label trial (Trial 2), 13 pediatric patients with HoFH (aged 12 to 17 years) received 15 mg/kg of EVKEEZA given intravenously 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 the 9 patients who completed treatment and had a lipid assessment at Week 24. Overall, the effect of EVKEEZA on lipid parameters in pediatric patients aged 12 to 17 years with HoFH was generally similar to that seen in adults with HoFH. Pediatric Patients (aged 5 to 11 years) with HoFH Trial R1500-CL-17100 (NCT04233918; Trial 3) was a multicenter, three-part, single-arm, open-label trial in pediatric patients aged 5 to 11 years with HoFH . Part B of this trial evaluated the efficacy of EVKEEZA 15 mg/kg given intravenously every 4 weeks as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe, lomitapide, and lipoprotein apheresis) for 24 weeks in 14 patients with HoFH. Baseline Disease and Demographic Characteristics In Part B, the mean LDL-C at baseline was 264 mg/dL. At baseline, 86% of patients were on statins, 93% on ezetimibe, 14% on lomitapide, and 50% were receiving lipoprotein apheresis.
The mean age at baseline was 9 years (range 5 to 11); 57% females; 0% Hispanic; 57% White, 14% Asian, 7% Black or African American, 7% American Indian or Alaska Native, and 14% other races. Mean body weight was 40 kg. Body mass index (BMI) was 20 kg/m 2. Endpoint Results The primary efficacy endpoint was percent change in calculated LDL-C from baseline to Week 24. At Week 24, the mean percent change in calculated LDL-C from baseline was −48% (95% confidence interval: −69% to −28%). For efficacy results see Table 4. HDL-C and TG reductions observed in this trial were similar to changes seen in Trial 1, see Table 3. At Week 24, the reduction in LDL-C with EVKEEZA was similar across baseline characteristics, including age, sex, limited LDLR activity, concomitant treatment with lipoprotein apheresis, and concomitant background lipid-lowering medications (statins, ezetimibe, and lomitapide). Table 4: Lipid Parameters in EVKEEZA-Treated Pediatric Patients (aged 5 to 11 years) with HoFH Who Received Concomitant Lipid-Lowering Therapies (Trial 3) LDL-C ApoB Non-HDL-C TC Abbreviations: HoFH=homozygous familial hypercholesterolemia, N=number of randomized patients, CI=confidence interval Baseline (mean) (N=14) 264 mg/dL 168 mg/dL 282 mg/dL 316 mg/dL Percent Change from Baseline at Week 24 (95% CI) -48 (-69 to -28) -41 (-59 to -24) -49 (-68 to -30) -49 (-65 to -33) Pediatric Patients (aged 1 to less than 5 years) with HoFH Clinical data were collected through an expanded access program that required each patient's treating physician to provide adequate documentation to demonstrate that the patient met the eligibility criteria for the program and to provide effectiveness information, including LDL-C values.
The efficacy of EVKEEZA was evaluated in 6 patients aged 1 to less than 5 years with HoFH. Four females and two males were enrolled in the program. At baseline, 83% of patients were on statins, 83% on ezetimibe, 17% on PCSK9 inhibitors, and 17% were receiving plasmapheresis. The mean LDL-C at baseline was 499 mg/dL (range 238 to 872 mg/dL), the mean age was 3.2 years (range 1.1 to 4.4 years), and the mean weight was 14.5 kg (range 8 to 17 kg). Patients received 15 mg/kg EVKEEZA every 4 weeks for up to 98 weeks.
Administration of EVKEEZA resulted in a reduction of LDL-C. Figure 1
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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