GARADACIMAB- garadacimab_injection, solution

Garadacimab-gxii is an inhibitor of activated FXII that binds to the catalytic domain of activated Factor XII (FXIIa and betaFXIIa) 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. Garadacimab-gxii concentration-dependent inhibition of FXIIa-mediated kallikrein activity was observed in patients with HAE. Inhibition of FXIIa-mediated kallikrein activity was observed after the first dose. The pharmacokinetics of garadacimab-gxii are provided in Table 2 following subcutaneous administration of a single 200 mg dose to healthy volunteers and are presented as mean (SD), unless otherwise specified. Table 2 Garadacimab-gxii Pharmacokinetics Following Subcutaneous Administration The PK of garadacimab-gxii is similar between healthy volunteers and subjects with HAE Parameter Garadacimab-gxii Abbreviations: AUC = area under the plasma concentration-time curve; CI = confidence interval; C max trough,steady state max T max Exposure C max 18. 23) mcg/mL AUC 0-inf 11470 (4103) mcg∙h/mL C trough,Steady State HAE patients enrolled in the VANGUARD trial , Garadacimab-gxii exposure (based on AUC tau max 8. 93) mcg /mL Absorption Absolute Bioavailability 39 (34, 43)% T max 6 (2, 15) days Distribution Apparent Volume of Distribution 11. 17) Liters (L) Elimination Half-Life 17. 14) days Apparent Clearance 0. 008) L/h Metabolism Primary Pathway Expected to be metabolized into small peptides by catabolic pathways Specific Populations No clinically significant differences in the pharmacokinetics of garadacimab-gxii were observed based on age (age range: 12 to 73 years), gender, race, body weight (range: 43 to 153 kg), and mild to moderate renal impairment (eGFR 30 to <90 mL/min/1. 73 m 2 2 Pediatric Patients No clinically significant difference in garadacimab-gxii C max tau Drug Interactions No dedicated drug interaction studies have been conducted in humans. The observed incidence of anti-drug antibodies (ADA) 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 studies described below with the incidence of anti-drug antibodies in other studies, including those of garadacimab-gxii or other garadacimab products. In VANGUARD, 2. 6% (1/39) of patients who received garadacimab-gxii tested positive for anti- garadacimab-antibodies during the 6-month treatment period. The development of ADA against garadacimab-gxii did not affect pharmacokinetics (PK), safety, or clinical response.

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.

Recommended Dosage 2. 1 Subcutaneous use only. 2 Patients may self-administer. See full prescribing information for preparation and administration instructions. 2 The recommended dosage of ANDEMBRY is an initial loading dose of 400 mg (two injections of 200 mg) administered subcutaneously on the first day of treatment followed by a maintenance dosage of 200 mg administered subcutaneously every month. Missed Dose(s) If a dose of ANDEMBRY is missed, administer the dose as soon as possible. For subcutaneous use only. ANDEMBRY is intended for self-administration or administration by a caregiver. Prior to treatment initiation, train patients/caregivers on proper preparation and subcutaneous (SC) administration technique of ANDEMBRY [see Instructions for Use Prior to administration, remove ANDEMBRY from the refrigerator and allow to sit for 30 minutes at room temperature before use. Inspect ANDEMBRY visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ANDEMBRY is a slightly opalescent to clear, brownish-yellow to yellow solution. Administer ANDEMBRY subcutaneously into the thigh or abdomen ensuring to stay 1 inch (2 cm) away from the navel. The upper arm can also be used if a caregiver administers the subcutaneous injection. Discard the used ANDEMBRY into a sharps disposal container (closed puncture-resistant container). For detailed instructions on the preparation and administration of ANDEMBRY [see Instructions for Use].

Most common adverse reactions (incidence >= 7%) are nasopharyngitis and abdominal pain. 1 To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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) 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) 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 Placebo 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. , 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.

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 (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. 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 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. 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. 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) Clinical Studies (14) The safety and effectiveness of ANDEMBRY have not been established in pediatric patients younger than 12 years of age. 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) [see Adverse Reactions (6. 3) Clinical Studies (14).

Drug Interference with Laboratory Test: 7. 1 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.

NONCLINICAL TOXICOLOGY
Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of garadacimab-gxii. Fertility and reproductive performance were unaffected in sexually mature male and female rabbits that received garadacimab-gxii at intravenous doses up to 100 mg/kg once every three days (resulting in exposures in male and female rabbits up to approximately 100 and 80 times the MRHD on an AUC basis).
CLINICAL STUDIES
The efficacy of ANDEMBRY for prophylaxis to prevent hereditary angioedema (HAE) attacks was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study (VANGUARD [NCT04656418]) of 6 months duration. VANGUARD enrolled a total of 64 adult and pediatric patients 12 years of age and older with Type I or Type II HAE who experienced at least 2 investigator-confirmed HAE attacks over a 2-month period prior to treatment with ANDEMBRY or placebo. Patients were randomized in a 3:2 ratio (ANDEMBRY:placebo) to receive an initial loading dose of ANDEMBRY 400 mg administered subcutaneously followed by a maintenance dose of 200 mg every month, or matched placebo. Patients were required to discontinue other prophylactic HAE medications prior to entering the study. All patients were allowed to use on-demand medications for the treatment of HAE attacks during the study. The demographics and baseline characteristics of patients in VANGUARD are provided in Table 3. Table 3 Demographics and Baseline Characteristics of Patients in the VANGUARD Trial VANGUARD (N=64) Female, n (%) 38 (59) Race, n (%) Asian 6 (9) Black or African American 1 (2) Native Hawaiian or Pacific Islander 1 (2) White 55 (86) Other 1 (2) Hispanic or Latino, n (%) 3 (5) Mean age, years (SD) 41 (16) <= 17 years, n (%) 6 (9) > 17 years, n (%) 58 (91) C1-INH HAE Type 1, n (%) 56 (88) Prior HAE prophylaxis Within 3 months before screening 21 (33) Baseline HAE attack rate During 2-month period prior to treatment 1 to < 3 attacks 26 (41) >= 3 attacks 38 (59) The primary endpoint for VANGUARD was the monthly HAE attack rate at 6 months (number of investigator-confirmed HAE attacks per month). As shown in Table 4, the least squares mean for the monthly HAE attack rate was lower with ANDEMBRY compared to placebo. Table 4 Rate of Monthly HAE Attack at 6 Months in VANGUARD Rate of Monthly HAE Attack ANDEMBRY Placebo Abbreviations: CI=confidence interval; HAE=hereditary angioedema; LS=least squares Note: LS means were obtained from a Poisson model accounting for overdispersion with an offset term for time on treatment and fixed effects for treatment group and HAE attack rate over a 2-month period prior to treatment LS mean (95% CI) 0.22 (0.11, 0.47) 2.07 (1.49, 2.87) Percent reduction relative to placebo (95% CI) 89.2 (75.6, 95.2) P-value Obtained from a two-sided Wilcoxon rank sum test at alpha = 5% < 0.001 The monthly rate of HAE attacks requiring on-demand therapy and the monthly rate of moderate or severe HAE attacks were assessed as secondary endpoints in VANGUARD. There was a 91.2% reduction with ANDEMBRY relative to placebo in the monthly rate of HAE attacks requiring on-demand therapy and a 93.6% reduction with ANDEMBRY relative to placebo in the monthly rate of moderate or severe HAE attacks. Additional secondary endpoints assessed the proportion of patients with a >=50%, >=70%, >=90%, and 100% (attack-free) reduction in monthly HAE attack rate from the first dose through the end of the 6-month treatment period compared to the 2-month period prior to treatment. The proportion of patients with a >=50%, >=70%, >=90%, and 100% reduction was 95%, 92%, 74%, and 62% on ANDEMBRY versus 33%, 17%, 8%, and 0% on placebo, respectively.

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GARADACIMAB- garadacimab_injection, solution Product manual source documgent