Sibeprenlimab

VOYXACT is indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk for disease progression. This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether VOYXACT slows kidney function decline over the long-term in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. VOYXACT is an A Proliferation Inducing Ligand (APRIL) blocker, indicated to reduce proteinuria in adults with primary immunoglobulin A nephropathy (IgAN) at risk for disease progression. ( 1 ) This indication is approved under accelerated approval based on reduction of proteinuria. It has not been established whether VOYXACT slows kidney function decline over the long-term in patients with IgAN. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory clinical trial. ( 1 )

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

VOYXACT is contraindicated in patients with serious hypersensitivity to sibeprenlimab-szsi or any of the excipients of VOYXACT. Serious hypersensitivity to sibeprenlimab-szsi or any excipients in VOYXACT. ( 4 )

Immunosuppression and Increased Risk of Infections: Before initiating VOYXACT, assess for active infections. During treatment, monitor for signs and symptoms of infection. ( 5.1 ) Immunosuppression and Immunization Risks: Live vaccines not recommended within 30 days prior to initiation of VOYXACT or during treatment. ( 5.2 )

5.1 Immunosuppression and Increased Risk of Infections VOYXACT suppresses the immune system by reducing antibody production, which may increase the risk of infections. Patients with chronic or recurring infections may have an increased risk of serious infection. In clinical trials, infections occurred in 49% of patients treated with VOYXACT compared with 45% of patients treated with placebo. Before initiating VOYXACT, assess patients for active infections. During treatment, monitor patients for signs and symptoms of infection. If a serious infection develops, consider interrupting VOYXACT until the infection is controlled. There are limited clinical study data with concomitant use of VOYXACT and systemic immuno-suppressants. Consider the potential for increased immunosuppression when coadministering VOYXACT and immuno-suppressants or when initiating VOYXACT before or after immuno-suppressive therapy.

5.2 Immunosuppression and Immunization Risks Because of its mechanism of action, VOYXACT may interfere with the immune responses to vaccines and increase the risk of infection from live vaccines. Live vaccines are not recommended within 30 days prior to initiation of VOYXACT or during treatment with VOYXACT as safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving VOYXACT or on the efficacy of immunizations administered while receiving VOYXACT.

The following clinically significant adverse reactions are described elsewhere in the labeling: Immunosuppression and Increased Risk of Infections [see Warnings and Precautions (5.1) ] Immunosuppression and Immunization Risks [see Warnings and Precautions (5.2) ] Most common adverse reactions are upper respiratory tract infection and injection site erythema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 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 VOYXACT was evaluated in a randomized, double-blind, placebo-controlled, clinical study in patients with IgAN (VISIONARY). The median duration of exposure was 44 weeks in the 259 patients treated with VOYXACT and 48 weeks in the 251 patients administered placebo. The most common adverse reactions (reported in ≥10% of patients treated with VOYXACT and at a higher incidence than placebo) in patients treated with VOYXACT and placebo, respectively, were infections (49% versus 45%) and injection site reactions (24% versus 23%). The most common infection was upper respiratory infection (15% versus 14%), and the most common injection site reaction was injection site erythema (13% versus 12%). Most adverse reactions were reported as mild or moderate in severity and resolved without treatment interruption or discontinuation.

8.1 Pregnancy Risk Summary There are no available data on VOYXACT use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Monoclonal antibodies, such as sibeprenlimab-szsi, can be actively transported across the placenta as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy (see Clinical Considerations ) . In an enhanced prenatal and postnatal development (ePPND) toxicity study, administration of sibeprenlimab-szsi subcutaneously to pregnant monkeys did not result in any adverse effects on embryofetal or postnatal development at exposures approximately 10-times the clinical exposure at the maximum recommended human dose (MRHD) based on area under the curve (AUC) ( see Data ). The background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. 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. Pregnant women exposed to VOYXACT, or their healthcare providers, should report VOYXACT exposure by calling 1-833-869-9228 or visiting www.VOYXACT.com. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk IgA nephropathy is associated with adverse maternal outcomes, including increased rates of cesarean section, pregnancy-induced hypertension, pre-eclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including stillbirth and low birth weight. Fetal/Neonatal Adverse Reactions Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Therefore, VOYXACT may be present in infants exposed in utero . Consider the potential clinical impact of VOYXACT exposure in infants who were exposed to VOYXACT in utero . Data Animal Data In an ePPND toxicity study, subcutaneous administration of sibeprenlimab-szsi once every two weeks to pregnant cynomolgus monkeys from gestation Day 20 through delivery (includes the period of organogenesis) did not result in any adverse effect on embryofetal or postnatal development at the single tested dose of 101 mg/kg, which provided an approximately 10-fold margin to the clinical exposure at the MRHD based on AUC.

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

8.4 Pediatric Use Safety and effectiveness of VOYXACT in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of VOYXACT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients. No clinically meaningful differences in the pharmacokinetics of VOYXACT were observed in patients aged 65 and over compared to younger adult patients [see Clinical Pharmacology (12.3) ].

VOYXACT binds to APRIL with a dissociation constant (K D ) of 0.95 pM, which blocks signaling at the B cell maturation antigen (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) receptors. Inhibition of APRIL results in reduced levels of serum galactose-deficient immunoglobulin A1 (Gd-IgA1), which is implicated in the pathogenesis of IgAN.