Pozelimab

1 INDICATIONS AND USAGE VEOPOZ is indicated for the treatment of adult and pediatric patients 1 year of age and older with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease. VEOPOZ is a complement inhibitor indicated for the treatment of adult and pediatric patients 1 year of age and older with CD55-deficient protein-losing enteropathy (PLE), also known as CHAPLE disease. ( 1 )

2 DOSAGE AND ADMINISTRATION See the full prescribing information for meningococcal vaccine and prophylaxis recommendations prior to the first dose of VEOPOZ. ( 2.1 ) Recommended Dosage: Day 1 (loading dose): Administer a single 30 mg/kg dose by intravenous infusion after dilution. ( 2.2 ) Day 8 and thereafter (maintenance dosage): Inject 10 mg/kg as a subcutaneous injection once weekly starting on Day 8. The maintenance dosage may be increased to 12 mg/kg once weekly if there is inadequate clinical response after at least 3 weekly doses (i.e., starting from Week 4). The maximum maintenance dosage is 800 mg once weekly. ( 2.2 ) See full prescribing information for instructions on preparation and administration. ( 2.2 , 2.3 , 2.4 ) 2.1 Recommended Vaccination and Prophylaxis for Meningococcal Infection Prior to First Dose of VEOPOZ Vaccinate patients for meningococcal infection (serogroups A, C, W, and Y [MenACWY] and serogroup B [MenB]) according to current ACIP recommendations for patients receiving a complement inhibitor at least 2 weeks prior to administering the first dose of VEOPOZ [see Warnings and Precautions (5.1) ] . If urgent VEOPOZ therapy is indicated in a patient who is not up-to-date with vaccines for both MenACWY and MenB according to ACIP recommendations, administer meningococcal vaccine(s) as soon as possible and provide the patient with antibacterial drug prophylaxis. The efficacy, duration, and drug regimens for antibacterial drug prophylaxis have not been studied in patients receiving complement inhibitors, including VEOPOZ. 2.2 Recommended Dosage and Administration The recommended dosage of VEOPOZ is as follows: Day 1 (Loading Dose) : Administer a single 30 mg/kg dose by intravenous infusion after dilution [see Dosage and Administration (2.3) ] . Day 8 and Thereafter (Maintenance Dosage) : Inject 10 mg/kg as a subcutaneous injection once weekly starting on Day 8 [see Dosage and Administration (2.4) ] . The maintenance dosage may be increased to 12 mg/kg once weekly if there is inadequate clinical response after at least 3 weekly doses (i.e., starting from Week 4). The maximum maintenance dosage is 800 mg once weekly. Doses greater than 400 mg require 2 injections. 2.3 Intravenous Infusion Loading Dose: Preparation and Administration Instructions VEOPOZ for intravenous use must be prepared and administered by a healthcare provider. Preparation Instructions for Intravenous Infusion Loading Dose Remove VEOPOZ vial(s) from refrigeration and allow the vial(s) to sit for at least 45 minutes at room temperature 20ºC to 25ºC (68ºF to 77ºF) before use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. VEOPOZ should be a clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial(s) if the solution is cloudy, discolored or contains particulate matter. Gently swirl the vial(s) in an upright position. Do not shake the vial(s) as this may result in foaming. Use a 21G stainless steel needle with Luer-Lok to withdraw the calculated volume of VEOPOZ from the vial(s). Discard any unused VEOPOZ remaining in the vial(s). Dilute VEOPOZ in an intravenous infusion bag of 25 mL to 250 mL of either 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 6.7 mg/mL to 20 mg/mL. Mix the diluted solution by gentle inversion. Do not shake. Administration Instructions for Intravenous Infusion Loading Dose Infuse through an intravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter. Infusion rate: infuse over a minimum of 1 hour; do not exceed maximum rate of 1000 mg/hour Do not co-administer other medications through the same intravenous line Observe the patient for 30 minutes following completion of the infusion [see Warnings and Precautions (5.3) ]. Storage of Diluted Intravenous Solution Administer the diluted VEOPOZ solution immediately after preparation. If not used immediately, store at room temperature up to 25°C (77°F) for no more than 8 hours from the time of preparation to the end of the infusion or refrigerate at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of infusion. If stored in the refrigerator, allow the diluted solution to come to room temperature prior to administration. Discard the unused VEOPOZ diluted solution after 8 hours if stored at room temperature or after 24 hours if refrigerated. Do not freeze the diluted solution. 2.4 Subcutaneous Maintenance Dose: Preparation and Administration Instructions VEOPOZ for subcutaneous use must be prepared and administered by a healthcare provider. Preparation Instructions for Subcutaneous Maintenance Dose Remove VEOPOZ vial(s) from refrigeration and allow the vial(s) to sit for at least 45 minutes at room temperature 20ºC to 25ºC (68ºF to 77ºF) before use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. VEOPOZ should be a clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial(s) if the solution is cloudy, discolored or contains particulate matter. Gently swirl the vial(s) in an upright position. Do not shake the vial(s) as this may result in foaming. Use a withdrawal needle (21G needle with Luer-Lok) to withdraw the calculated dose volume of VEOPOZ from the appropriate number of vial(s). Discard any unused VEOPOZ remaining in the vial(s). For patients receiving a dose greater than 400 mg, preparation of 2 separate injections will be required for subcutaneous administration of the total dose volume. Change the needle on the syringe to an injection needle fulfilling the following criteria: 25G to 27G and 1/2 or 5/8-inch stainless steel needle with Luer-Lok. Administration Instructions for Subcutaneous Maintenance Dose Inject VEOPOZ into the abdomen, thigh, or upper arm. Rotate sites. Do not inject VEOPOZ into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. When administering more than one injection, administer consecutively, each at different injection sites. Observe the patient for 30 minutes following completion of the first subcutaneous injection [see Warnings and Precautions (5.3) ] . Storage of Subcutaneous Injection Administer the subcutaneous injection within 4 hours of preparation. 2.5 Recommendations Regarding Missed Maintenance Subcutaneous Dose(s) If a subcutaneous maintenance dose of VEOPOZ is missed, administer as soon as possible within 3 days after the missed dose. Do not administer 2 doses on the same day to make up for a missed dose. If more than 3 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 4 days (96 hours).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Meningococcal Infections [see Warnings and Precautions (5.1) ] Other Bacterial Infections [see Warnings and Precautions (5.2) ] Systemic Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Immune Complex Formation [see Warnings and Precautions (5.4) ] Most common adverse reactions (in two or more patients) are: upper respiratory tract infection, fracture, urticaria, and alopecia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-855-583-6769 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. The safety of VEOPOZ was evaluated in 10 patients with CD55-deficient PLE (ranging from 3 to 19 years of age) in a single-arm study [see Clinical Studies (14) ] . The median duration of exposure was 104 weeks (range: 75 to 140 weeks). Adverse reactions reported in two or more patients are summarized in Table 1. Table 1: Adverse Reactions Reported in Two or More VEOPOZ-Treated Patients with CD55-deficient PLE in a Clinical Trial Adverse Reactions VEOPOZ N=10 n (%) Upper respiratory tract infection Composed of similar terms 3 (30) Fracture 3 (30) Urticaria 2 (20) Alopecia 2 (20) Additionally, injection site reactions (including dermatitis and erythema), metabolic acidosis, gingival bleeding, increased blood uric acid, increased liver enzymes, hematuria and proteinuria were reported in one patient each. Vital Signs: Four patients reported elevated systolic and/or diastolic blood pressure readings above the normal range for age at multiple study visits.

12.3 Pharmacokinetics In healthy subjects, single intravenous infusions of VEOPOZ over approximately one hour resulted in dose proportional increases in mean C max , but greater than proportional increases in mean AUC inf (>16-fold) for total pozelimab concentrations in serum between 3 mg/kg and 30 mg/kg. The mean AUC inf increased by 3.5-fold between 10 mg/kg and 30 mg/kg. In healthy subjects, single subcutaneous injections of VEOPOZ resulted in approximately 1.5-fold increase in mean C max and 2.2-fold increase in mean AUC inf between 300 mg and 600 mg. In patients with CD55-deficient PLE, a single dose of VEOPOZ 30 mg/kg administered as an intravenous infusion over approximately one hour resulted in median (range) total pozelimab trough concentration of 180 (52.8, 268) mg/L at Week 1. The predicted mean (SD) trough concentrations of total pozelimab at steady state are 330 (94.2) mg/L and 385 (112) mg/L for VEOPOZ 10 mg/kg or 12 mg/kg (up to a maximum 800 mg) once weekly via subcutaneous injection(s), respectively, following the intravenous loading dose. Absorption In healthy subjects, following subcutaneous injection of 600 mg, the bioavailability of pozelimab-bbfg is estimated as 51%. The median (range) time to reach peak concentration was 7 (3 to 7) days following a single subcutaneous injection of 300 mg or 600 mg in healthy subjects. Distribution In healthy adult subjects with a mean body weight of 70 kg, the mean (SD) volume of distribution following a single intravenous dose of 30 mg/kg was 3.3 (0.4) L. The mean (SD) apparent volume of distribution following a single subcutaneous injection of 300 mg and 600 mg was 6.0 (0.9) L and 8.6 (2.7) L, respectively. Elimination Pozelimab-bbfg is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Pozelimab-bbfg elimination is mediated via linear and non-linear pathways. At higher concentrations, pozelimab-bbfg elimination is primarily through the linear non-saturable proteolytic pathway, whereas at lower concentrations, the non-linear, saturable C5 target-mediated elimination predominates. In healthy adult subjects, the median (range) terminal half-life of total pozelimab in serum was 13.5 (10.0, 17.2) days following a single 30 mg/kg dose administered as an intravenous infusion. The median (range) terminal half-life was 14.1 (8.6, 17.3) days following a single 600 mg subcutaneous injection. In patients with CD55-deficient PLE, steady-state total pozelimab concentrations were reached at approximately 20 weeks following subcutaneous injection once weekly. Specific Populations Body Weight Body weight was a significant covariate on the pharmacokinetics of pozelimab-bbfg. Renal and Hepatic Impairment Pozelimab-bbfg, a monoclonal antibody, is not likely to undergo renal or hepatic excretion. Drug Interaction Studies Drug interaction studies have not been conducted. Intravenous Immunoglobulin (IVIg) may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as pozelimab-bbfg, which may decrease serum pozelimab concentrations [see Drug Interactions (7.1) ] .