Garadacimab

ANDEMBRY is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older. ANDEMBRY is an activated Factor XII (FXIIa) inhibitor (monoclonal antibody) indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older. ( 1 )

Injection: a sterile, preservative-free, slightly opalescent to clear, brownish-yellow to yellow solution available in the following: 200 mg/1.2 mL of garadacimab solution in a single-dose prefilled autoinjector 200 mg/1.2 mL (167 mg/mL) of garadacimab solution in a single-dose prefilled syringe with needle safety device Injection: 200 mg/1.2 mL solution in single-dose prefilled autoinjector ( 3 ) 200 mg/1.2 mL (167 mg/mL) solution in single-dose prefilled syringe with needle safety device ( 3 )

None. None. ( 4 )

None. None. ( 5 )

Most common adverse reactions (incidence ≥ 7%) are nasopharyngitis and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-6958 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 ANDEMBRY reflects the exposure in a total of 164 adult and pediatric patients aged 12 years and older with hereditary angioedema (HAE) from a placebo-controlled study, VANGUARD [see Clinical Studies (14) ] , and an open-label clinical study. Among the 164 patients who received at least one dose of ANDEMBRY 200 mg subcutaneously, 153 (93%) patients were exposed for at least one year. The median duration of ANDEMBRY treatment was 2.6 years. The safety data below is based on the 6-month placebo-controlled study (VANGUARD), in which ANDEMBRY 400 mg was administered subcutaneously as a loading dose followed by 200 mg (N=39) every month in patients with HAE. Demographics of the patients in this study are summarized in Clinical Studies [see Clinical Studies (14) ]. The safety of ANDEMBRY was similar across all subgroups of patients, including analysis by age, sex and geographic region. Table 1 provides the most common adverse reactions with ANDEMBRY with incidence ≥7% and more common than placebo. Table 1 Adverse Reactions with ANDEMBRY with Incidence ≥7% and More Common than Placebo in Patients with HAE (VANGUARD) Adverse Reactions ANDEMBRY (N=39) Placebo (N=25) n (%) n (%) Nasopharyngitis Consists of nasopharyngitis, rhinitis, and upper respiratory infections 8 (21) 3 (12) Abdominal Pain Consists of abdominal pain and abdominal pain lower 3 (8) 0 Specific Adverse Reaction(s): Injection Site Reactions In VANGUARD and an open-label clinical study, which included 57 patients who rolled over from VANGUARD, 164 patients with HAE received ANDEMBRY 200 mg subcutaneously every month. Injection site reactions (e.g., injection site bruising, injection site erythema, injection site hematoma, injection site pruritus, injection site urticaria) were reported in 23 (14%) patients. Laboratory Abnormalities: Prolonged Coagulation Tests (aPTT and PT) In the VANGUARD trial, the incidence of prolonged activated partial thromboplastin time (aPTT), defined as >1.4×ULN, was 3 (8%) patients in the ANDEMBRY group compared to 0 patients in the placebo group. Additionally, the incidence of prolonged prothrombin time (PT) or international normalized ratio (INR), defined as >1.3× ULN, was 6 (15%) patients in the ANDEMBRY group compared to 1 (4%) patient in the placebo group. None of the increases in aPTT, PT and INR were associated with bleeding events [see Drug Interactions (7.1) ] .

Drug Interference with Laboratory Test: ANDEMBRY can prolong activated partial thromboplastin time (aPTT) due to an interaction of garadacimab-gxii with the aPTT assay. ( 7.1 )

7.1 Drug Interference with Laboratory Test Coagulation Tests ANDEMBRY can prolong activated partial thromboplastin time (aPTT) due to an interaction of garadacimab-gxii with the aPTT assay. The reagents used in the aPTT laboratory test initiate intrinsic coagulation through the activation of FXII in the contact system, therefore inhibition of plasma FXIIa by ANDEMBRY can prolong aPTT in this assay [see Adverse Reactions (6.1) ] .

8.1 Pregnancy Risk Summary There are no available data on ANDEMBRY 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 garadacimab-gxii are transported across the placenta during the third trimester of pregnancy; therefore, potential effects on a fetus are likely to be greater during the third trimester of pregnancy. In an embryo-fetal development study in pregnant rabbits, garadacimab-gxii produced no evidence of fetal harm at doses up to approximately 100 times the exposure achieved at the maximum recommended human dose (MRHD) of 200 mg once monthly. In a pre- and post-natal development study in rabbits, garadacimab-gxii had no effects on survival, growth, or development of F 1 offspring at doses resulting in approximately 76 times the exposure achieved at the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population(s) is 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. Data Animal Data In an embryo-fetal development study in pregnant rabbits dosed by the intravenous route every 3 days during the period of organogenesis from gestation days 6 to 18, garadacimab-gxii produced no evidence of fetal harm or maternal toxicity at doses resulting in approximately 100 times the exposure achieved at the MRHD (on an AUC basis with maternal intravenous doses up to 100 mg/kg/dose). In a pre- and post-natal development study in rabbits dosed by the intravenous or subcutaneous route once every 5 days from the end of implantation (Gestation Day 7) to postpartum day 38 (end of the lactation period), garadacimab-gxii had no effects on survival, growth, or development of F 1 offspring at doses resulting in approximately 76 times the exposure achieved at the MRHD (on an AUC basis with a maternal intravenous dose of 100 mg/kg/dose). There was no evidence of maternal toxicity. Garadacimab-gxii crossed the placenta in rabbits. With a maternal dose of 100 mg/kg garadacimab-gxii on gestation day 29, fetal plasma concentrations were 40.8% of maternal concentrations following subcutaneous administration and approximately equivalent following intravenous administration.

8.2 Lactation Risk Summary There are no data on the presence of garadacimab-gxii or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to garadacimab-gxii are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ANDEMBRY and any potential adverse effects on the breastfed infant from ANDEMBRY or the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of ANDEMBRY for prophylaxis to prevent attacks of HAE have been established in pediatric patients aged 12 years and older. Use of ANDEMBRY for this indication is supported by evidence from a total of 6 pediatric patients aged 12 years and older enrolled in VANGUARD who received treatment with ANDEMBRY 400 mg loading dose administered subcutaneously followed by a maintenance dosage of 200 mg subcutaneously every month (n=4) or placebo (n=2). Results of the subgroup analysis for pediatric patients aged 12 years and older were consistent with study results for adult patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ]. The safety and effectiveness of ANDEMBRY have not been established in pediatric patients younger than 12 years of age.

8.5 Geriatric Use Of the total number of ANDEMBRY-treated patients in the clinical study for prophylaxis to prevent attacks of HAE, 6 (9%) were 65 years of age and older [see Clinical Studies (14) ] . No overall differences in safety or effectiveness of ANDEMBRY have been observed between patients 65 years of age and older and younger adult patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] .

Garadacimab-gxii is an inhibitor of activated FXII that binds to the catalytic domain of activated Factor XII (FXIIa and βFXIIa) and inhibits its catalytic activity. FXII is the first factor activated in the contact activation pathway and initiates the inflammatory bradykinin-producing kallikrein-kinin system. The inhibition of FXIIa decreases the activation of prekallikrein to kallikrein and the generation of bradykinin, which is associated with inflammation and swelling in HAE attacks, thus reducing the cascade of events leading to an HAE attack.