Pozelimab

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 )

Injection: 400 mg/2 mL (200 mg/mL) as a clear to slightly opalescent, colorless to pale yellow solution in a single-dose vial. Injection: 400 mg/2 mL (200 mg/mL) in a single-dose vial. ( 3 )

VEOPOZ is contraindicated in: Patients with unresolved Neisseria meningitidis infection [see Warnings and Precautions (5.1) ] . VEOPOZ is contraindicated in patients with unresolved Neisseria meningitidis infection. ( 4 )

Other Bacterial Infections : Interrupt treatment with VEOPOZ in patients who are undergoing treatment for a serious encapsulated bacterial infection until the infection is resolved. ( 5.2 ) Systemic Hypersensitivity Reactions : Interrupt infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. ( 5.3 ) Immune Complex Formation : Transition between other complement inhibitors has resulted in decreased drug concentrations and possible hypersensitivity reactions. Consider this potential if switching complement inhibitors to VEOPOZ. ( 5.4 )

5.1 Serious Meningococcal Infections Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The use of VEOPOZ increases a patient's susceptibility to serious and life-threatening meningococcal infections (septicemia and/or meningitis) caused by any serogroup, including nongroupable strains. Complete or update meningococcal vaccination (for serogroups A, C, W, and Y [MenACWY] and serogroup B [MenB]) at least 2 weeks prior to administering the first dose of VEOPOZ, according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of VEOPOZ therapy. If urgent VEOPOZ therapy is indicated in a patient who is not up-to-date with both MenACWY and MenB vaccines 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. Because of inhibition of complement activity by VEOPOZ, as well as risk of infection caused by nongroupable strains of N. meningitidis , vaccination does not eliminate the risk of meningococcal infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients and caregivers of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Interrupt treatment with VEOPOZ in patients who are undergoing treatment for serious meningococcal infection until the infection is resolved [see Contraindications (4) ] .

5.2 Other Bacterial Infections VEOPOZ blocks terminal complement activation; therefore, patients may have increased susceptibility to encapsulated bacterial infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae , and to a lesser extent, Neisseria gonorrhoeae . Patients treated with VEOPOZ may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP guidelines. Patients receiving VEOPOZ are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination. Interrupt treatment with VEOPOZ in patients who are undergoing treatment for a serious encapsulated bacterial infection until the infection is resolved. Counsel patients about gonorrhea prevention and advise regular testing for patients at risk.

5.3 Systemic Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported with administration of complement inhibitors. Interrupt VEOPOZ and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.

5.4 Immune Complex Formation Immune complex formation has been reported during the transition of therapy between complement inhibitors, resulting in transient decrease in drug concentrations as well as symptoms suggestive of hypersensitivity reactions. However, this has not been studied in patients with CD55-deficient PLE switching from other complement inhibitors to pozelimab. The potential for immune complex formation should be considered if switching complement inhibitors.

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.

Intravenous Immunoglobulin : May decrease pozelimab concentrations; avoid concomitant use. If concomitant use cannot be avoided, monitor patients for worsening of clinical signs and symptoms of disease. ( 7.1 )

7.1 Intravenous Immunoglobulin VEOPOZ has not been studied in combination with intravenous immunoglobulin. Intravenous immunoglobulin may interfere with the endosomal neonatal Fc receptor (FcRn) recycling mechanism of monoclonal antibodies such as pozelimab thereby decreasing serum pozelimab concentrations. Avoid concomitant use of intravenous immunoglobulin with VEOPOZ. If concomitant use cannot be avoided, monitor patients for worsening of clinical signs and symptoms of CD55-deficient PLE [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary Although there are no data on VEOPOZ use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, monoclonal antibodies can be actively transported across the placenta . In an animal reproduction study in monkeys, pozelimab-bbfg did not adversely affect embryofetal or postnatal development when administered from pregnancy confirmation through parturition at doses that produced exposure up to 3.3 to 3.8 times the predicted clinical exposures (on an AUC basis; see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other outcome. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In an enhanced pre- and postnatal development study, pregnant female monkeys were subcutaneously administered pozelimab-bbfg at doses of 5 or 50 mg/kg once weekly from confirmation of pregnancy (gestation day 20) through parturition (approximately gestation day 160). No adverse effects were observed on maintenance of pregnancy, pregnancy outcome, or on the development of offspring through postnatal day 90 at doses up to 3.3-3.8 times the predicted clinical exposures.

8.2 Lactation Risk Summary There are no data on the presence of pozelimab-bbfg in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are transferred into human milk. The effects of local gastrointestinal exposure and the extent of systemic exposure in the breastfed infant to pozelimab are unknown. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for VEOPOZ and any potential adverse effects on the breastfed infant from VEOPOZ or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of VEOPOZ for the treatment of CD55-deficient PLE have been established in pediatric patients 1 year of age and older. Use of VEOPOZ for this indication is supported by a single-arm study in 10 patients with active CD55-deficient PLE [see Adverse Reactions (6.1) and Clinical Studies (14) ]. The safety and effectiveness of VEOPOZ have not been established in pediatric patients less than 1 year of age.

8.5 Geriatric Use CD55-deficient PLE is largely a disease of pediatric patients. VEOPOZ has not been studied in the geriatric population.

Pozelimab-bbfg is a human, monoclonal immunoglobulin G4 P (IgG4 P ) antibody directed against the terminal complement protein C5 that inhibits terminal complement activation by blocking cleavage of C5 into C5a (anaphylatoxin) and C5b, thereby blocking the formation of the membrane-attack complex (C5b-C9, a structure mediating cell lysis).