Evinacumab

1 INDICATIONS AND USAGE 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). ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of EVKEEZA is 15 mg/kg administered by intravenous (IV) infusion once monthly (every 4 weeks). ( 2.1 ) See the Full Prescribing Information for preparation instructions for the intravenous infusion. ( 2.2 ) Administer the 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. ( 2.3 ) Do not mix other medications with EVKEEZA or administer other medications concomitantly via the same infusion line. ( 2.3 ) The rate of infusion may be slowed, interrupted or discontinued if the patient develops any signs of adverse reactions, including infusion or hypersensitivity reactions. ( 2.3 ) 2.1 Recommended Dosage The recommended dosage of EVKEEZA is 15 mg/kg administered by intravenous (IV) infusion over 60 minutes once monthly (every 4 weeks). If a dosage of EVKEEZA is missed, administer as soon as possible. Thereafter, EVKEEZA should be scheduled monthly from the date of the last dosage. Assess LDL-C when clinically appropriate. The LDL-lowering effect of EVKEEZA may be measured as early as 2 weeks after initiation. 2.2 Preparation Instructions for Intravenous Infusion Calculate the dosage (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, discolored, or contains particulate matter. EVKEEZA is supplied as single-dose vials and does not contain a preservative. Prepare the diluted infusion using aseptic technique. Do not shake the vial. Withdraw the required volume from the vial(s) of EVKEEZA and transfer into an IV infusion bag of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Discard any unused portion left in the vials. Mix the diluted solution by gentle inversion; do not shake. Maximum diluent volume by patient weight is summarized in Table 1. Table 1: Maximum Diluent Volume by Patient Weight Patient Weight Maximum Diluent Volume 3 kg to less than 26 kg 5 mL/kg 26 kg to less than 45 kg 150 mL 45 kg and greater 250 mL 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 administered 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 preparation to the end of the infusion. Do not freeze the diluted solution. 2.3 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 through an IV line containing a sterile, in-line or add-on, 0.2-micron to 5-micron filter over 60 minutes. 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 (5.1) and Adverse Reactions (6.1) ]. EVKEEZA can be administered without regard to the timing of lipoprotein apheresis.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Common adverse reactions (≥5%) were nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, nausea, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-833-385-3392 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 [see Clinical Studies (14) ]. 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.

12.3 Pharmacokinetics 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 266 (120) mg/L in adult patients, whereas the mean (standard deviation) C max at the end of infusion is 718 (183) mg/L in adult patients. Due to non-linear clearance, a 4.3-fold increase in area under the concentration-time curve at steady-state (AUC tau.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. Distribution The steady-state volume of distribution estimated via population pharmacokinetic analysis was approximately 4.7 L in adult patients. Elimination 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 approximately 20 weeks after the last steady-state dose of 15 mg/kg IV every 4 weeks. Metabolism 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. Excretion Evinacumab-dgnb, a monoclonal antibody, is not likely to undergo renal excretion. Specific Populations A population PK analysis conducted on data from 183 healthy subjects and 139 patients with HoFH suggests that the following factors have no clinically significant effect on the exposure of evinacumab-dgnb: age (5 to 75 years), gender, body weight (20 to 152 kg), and race (White, Asian, Black or African American, American Indian or Alaska Native, and other races). Pediatric Patients Fourteen (14) patients aged 12 to less than 18 years 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. Twenty (20) patients aged 5 to less than 12 years with HoFH received evinacumab-dgnb at 15 mg/kg IV every 4 weeks. According to population pharmacokinetic modeling, the mean (standard deviation) steady-state trough concentration is 160 (57.6) mg/L in pediatric patients, whereas the mean (standard deviation) C max at the end of infusion is 419 (99.4) mg/L in pediatric patients. Steady-state trough and end-of-infusion concentrations were lower but within the range observed in adult patients. The predicted mean (standard deviation) steady-state trough and maximum concentrations were 135 (62) and 500(182) mg/L for patients aged 1 year to less than 2 years. The predicted mean (standard deviation) steady-state trough and maximum concentrations were 141(61) and 513(179) mg/L for patients aged 2 to less than 5 years. 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.