Veopoz Injection Prescribing Information

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:

2.3 Intravenous Infusion Loading Dose: Preparation and Administration Instructions

VEOPOZ for intravenous use must be prepared and administered by a healthcare provider.

2.4 Subcutaneous Maintenance Dose: Preparation and Administration Instructions

VEOPOZ for subcutaneous use must be prepared and administered by a healthcare provider.

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).

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.

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.

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.

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

8.2 Lactation

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.

12.1 Mechanism of Action

Pozelimab-bbfg is a human, monoclonal immunoglobulin G4P (IgG4P) 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).

12.2 Pharmacodynamics

The effect of pozelimab-bbfg on complement activity was measured by total complement hemolytic activity test (CH50). The magnitude and duration of reduction from baseline in CH50 by pozelimab-bbfg was dose dependent.

In healthy subjects receiving a single dose of VEOPOZ 30 mg/kg administered as an intravenous infusion over approximately one hour, the complete inhibition of CH50 was achieved at the end of infusion in all subjects, was maintained for 28 days, and returned to baseline 84 days post-dose. After a single dose of VEOPOZ administered as a 600 mg subcutaneous injection, the maximum reduction from baseline in CH50 was achieved 7 days post-dose in most subjects (range: 3 to 14 days), corresponding to Tmax, and returned to baseline 56 days post-dose.

In patients with CD55-deficient PLE receiving a single 30 mg/kg dose administered as an intravenous infusion over approximately one hour followed by a weight-tiered subcutaneous injection once weekly starting at Week 1, CH50 was completely inhibited by Week 1 for most subjects and by Week 12 for all patients.

In the same study of patients with CD55-deficient PLE, serum albumin concentrations increased as early as Week 1 and reached the normal range (≥3.5 g/dL) by Week 4 for most subjects and by Week 12 for all subjects. The serum albumin concentrations were maintained within the normal range for the duration of treatment. Endogenous serum IgG concentrations were also increased from baseline at Week 1 in all patients with CD55-deficient PLE and reached a stable concentration around Week 16 [see Clinical Studies (14)].

12.3 Pharmacokinetics

In healthy subjects, single intravenous infusions of VEOPOZ over approximately one hour resulted in dose proportional increases in mean Cmax, but greater than proportional increases in mean AUCinf (>16-fold) for total pozelimab concentrations in serum between 3 mg/kg and 30 mg/kg. The mean AUCinf 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 Cmax and 2.2-fold increase in mean AUCinf 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.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the study described below with the incidence of anti-drug antibodies in other studies, including those of VEOPOZ or of other pozelimab products.

Nine of the 10 patients 3 years of age and older with CD55-deficient PLE in the clinical study were evaluable for anti-pozelimab antibodies. None of these patients developed anti-pozelimab-bbfg antibodies during the 48-week treatment with pozelimab-bbfg. There is insufficient information to characterize the effect of anti-drug antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of pozelimab.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Serum Albumin Concentrations

The median time for serum albumin to reach at least 3.5 g/dL was 15.5 days (N=10; 95% CI: 8 to 28). All 10 patients achieved normalization by Week 12 and maintained serum albumin concentrations within the normal range through at least 72 weeks of treatment (Figure 1).

Figure 1: Serum Albumin Concentrations from 48 Weeks Pre-Treatment Through 72 Weeks on VEOPOZ in Ten Patients with CD55-Deficient PLE

Albumin Transfusions

Five of the 10 patients received a total of 60 transfusions in the 48 weeks prior to treatment. In the 48 weeks after starting treatment, one patient received one albumin transfusion.

Hospitalizations

Nine of the 10 patients were hospitalized for a total of 268 days in the 48 weeks prior to treatment. In the 48 weeks after starting treatment, two patients were hospitalized for a total of 7 days.

Additional Efficacy Results

Serum IgG concentrations reached normal values for age in all patients within the first 12 weeks of treatment; improvement was maintained through at least 72 weeks of treatment.

Store VEOPOZ vial refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. Discard unused portion.

Meningococcal Infection

• Advise patients of the risk of meningococcal, and other bacterial infections.
• Inform patients of the need to complete or update meningococcal vaccination for both MenACWY and MenB at least 2 weeks prior to receiving the first dose of VEOPOZ and to be revaccinated according to current ACIP recommendations for meningococcal vaccines while on VEOPOZ therapy.
• Inform patients that vaccination may not prevent meningococcal infection.
• Inform patients of the signs and symptoms of meningococcal infection and advise patients to seek immediate medical attention if any signs or symptoms of infection occur [see Warnings and Precautions (5.1)].

Other Bacterial Infections, Including Gonococcal Infection

• Inform patients of the increased risk of other bacterial infections, particularly those due to encapsulated bacteria.
• Inform patients of the need to receive vaccinations according to the ACIP recommendations.
• Advise patients to report any new signs and symptoms of infection.
• Counsel patients about gonorrhea prevention and advise patients at risk (e.g., sexually active) to seek regular testing [see Warnings and Precautions (5.2)].

Systemic Hypersensitivity Reactions

Advise patients to notify the healthcare provider and seek immediate medical attention if they experience any symptoms of systemic hypersensitivity reactions [see Warnings and Precautions (5.3)].