Marstacimab

HYMPAVZI is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 6 years of age and older with:

• hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors, or
• hemophilia B (congenital factor IX deficiency) with or without factor IX inhibitors. HYMPAVZI is a tissue factor pathway inhibitor (TFPI) antagonist indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients 6 years of age and older with:
• hemophilia A (congenital factor VIII deficiency) with or without factor VIII inhibitors, or
• hemophilia B (congenital factor IX deficiency) with or without factor IX inhibitors. ( 1 )

HYMPAVZI (marstacimab‑hncq) is a clear and colorless to light yellow solution available as: Prefilled Syringe

• Injection: 150 mg/mL in a single-dose prefilled syringe
• Injection: 75 mg/0.5 mL in a single-dose prefilled syringe Prefilled Pen
• Injection: 150 mg/mL in a single-dose prefilled pen
• Injection: 75 mg/0.5 mL in a single-dose prefilled pen
• Injection: 150 mg/mL and 75 mg/0.5 mL in a single-dose prefilled syringe ( 3 )
• Injection: 150 mg/mL and 75 mg/0.5 mL in a single-dose prefilled pen ( 3 )

None. None. ( 4 )

• Thromboembolic Events: Thromboembolic events may occur. Interrupt HYMPAVZI prophylaxis if symptoms occur. ( 5.1 )
• Hypersensitivity: Hypersensitivity reactions may occur. In the event of a severe allergic reaction, discontinue HYMPAVZI. ( 5.2 )
• Embryofetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 )
• Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment 1.2: HYMPAVZI can cause sporadic or transient increases in fibrin D-dimer and prothrombin fragment 1.2 above physiological values. ( 5.4 )

5.1 Thromboembolic Events HYMPAVZI is a tissue factor pathway inhibitor (TFPI) antagonist, and may increase the risk of thromboembolic complications. Venous and arterial thromboembolic events were reported in 0.8% of patients (2/259) treated with HYMPAVZI in the open-label extension study [see Adverse Reactions (6.1) ] . Patients with independent risk factors for thromboembolic events may be at increased risk of thromboembolic events with use of HYMPAVZI. HYMPAVZI has not been studied in patients with a history of previous thromboembolic events [see Clinical Studies (14.1) ] . Consider the benefit and risk of using HYMPAVZI in patients with known risk factors for thromboembolism. Interrupt HYMPAVZI prophylaxis if diagnostic findings consistent with thromboembolism occur and manage as clinically indicated. If factor VIII or factor IX products or bypassing agents are indicated in a patient receiving HYMPAVZI prophylaxis, the minimum effective dose according to the product label is recommended [see Dosage and Administration (2.5) ] .

5.2 Hypersensitivity HYMPAVZI may cause hypersensitivity reactions (including but not limited to urticaria and pruritus). If HYMPAVZI-treated patients develop a severe hypersensitivity reaction, advise patients to discontinue HYMPAVZI and seek immediate emergency treatment.

5.3 Embryofetal Toxicity Based on its mechanism of action, HYMPAVZI may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with HYMPAVZI and for 2 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

5.4 Increased Laboratory Values of Fibrin D-dimer and Prothrombin Fragment

1.2 Consistent with its mechanism of action and hemostatic effect, HYMPAVZI causes an increase in fibrin D‑dimer and prothrombin fragment 1.2 [see Clinical Pharmacology (12.1 , 12.2) ] . Sporadic or transient increases in levels of these biomarkers above physiological values were reported with no associated safety concerns [see Clinical Pharmacology (12.2) ] . Increased levels of fibrin D-dimer were seen in 10 (8.1%) pediatric patients age 6 to less than 18 years and 6 (4.4%) adults. Increased levels of prothrombin fragment 1.2 were seen in 13 (10.5%) pediatric patients age 6 to less than 18 years and 6 (4.4%) adults. For patients taking HYMPAVZI, these coagulation biomarkers may not be reliable predictive markers for clinical decision-making with suspicion of thrombosis such as deep vein thrombosis (DVT) and pulmonary embolism (PE).

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Thromboembolic Events [see Warnings and Precautions (5.1) ]
• Hypersensitivity [see Warnings and Precautions (5.2) ] Adverse reactions reported in ≥2% of HYMPAVZI-treated patients were injection site reaction, headache, pyrexia, arthralgia, diarrhea, pruritus, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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 HYMPAVZI was evaluated in adults and pediatric patients 6 years of age and older with severe hemophilia A (FVIII <1%) or moderately severe to severe hemophilia B (FIX ≤2%) with and without inhibitors enrolled in the BASIS and BASIS KIDS studies. A total of 259 patients received the recommended HYMPAVZI prophylaxis loading dose followed by a weekly maintenance dose starting at Day 8 administered subcutaneously [see Clinical Studies (14.1 , 14.2 , 14.3 )] . One-hundred-thirty-five (52%) were adults (18 years of age and older), 56 (22%) were adolescents (12 to less than 18 years of age), and 68 (26%) were children (6 to less than 12 years of age). Among patients receiving HYMPAVZI, 90% were exposed for 6 months or longer and 82% were exposed for at least 1 year. The median duration of exposure across the studies was 364 days (min, max: 14, 406 days). Table 1 summarizes the adverse reactions reported in ≥2% of patients in all age groups who received HYMPAVZI prophylaxis. Table 1. Adverse Reactions Reported in ≥2% of Patients Treated with HYMPAVZI During BASIS and BASIS KIDS studies 12-month active treatment phase By Age Group Adverse Reaction Number of Patients 6 to less than 18 Years n (%) (N = 124) Number of Patients 18 Years and Older n (%) (N = 135) Number of Patients (All Age Groups) n (%) (N = 259) Injection site reaction Injection site reaction is a grouped term which includes the following terms: injection site pruritus, injection site swelling, injection site erythema, injection site bruising, injection site induration, injection site pain, injection site edema, injection site hematoma, injection site hemorrhage, injection site warmth, and injection site urticaria. 19 (15) 11 (8) 30 (12) Headache Headache is a grouped term which includes migraine. 9 (7) 10 (7) 19 (7) Pyrexia 12 (10) 3 (2) 15 (6) Arthralgia 4 (3) 5 (4) 9 (3) Diarrhea 5 (4) 2 (2) 7 (3) Pruritus 1 (1) 5 (4) 6 (2) Rash 2 (2) 3 (2) 5 (2)

Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) No clinically significant differences in standard measures of coagulation including activated partial thromboplastin time (aPTT) and prothrombin time (PT) were observed following marstacimab‑hncq therapy.

8.1 Pregnancy Risk Summary Based on its mechanism of action, HYMPAVZI may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on HYMPAVZI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Female animal reproduction studies have not been conducted with HYMPAVZI. Although there are no data on marstacimab‑hncq, monoclonal antibodies can be actively transported across the placenta, and marstacimab‑hncq may cause fetal harm. The background risk of major birth defects and miscarriage for the indicated populations 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.

8.2 Lactation Risk Summary There are no data on the presence of marstacimab‑hncq in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to marstacimab‑hncq are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HYMPAVZI and any potential adverse effects on the breastfed infant from HYMPAVZI or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential HYMPAVZI may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1 )] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating HYMPAVZI treatment. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with HYMPAVZI and for 2 months after the last dose.

8.4 Pediatric Use The safety and effectiveness of HYMPAVZI to prevent or reduce the frequency of bleeding episodes in hemophilia A or B with and without inhibitors have been established in pediatric patients 6 years of age and older [see Clinical Studies (14.1 , 14.2 , 14.3 )] . Use of HYMPAVZI in pediatric patients for this indication is supported by evidence from two open‑label, multi‑center studies (BASIS and BASIS KIDS). These two studies treated 56 adolescents (12 to less than 18 years of age). BASIS KIDS treated 68 children (6 to less than 12 years of age). Efficacy and adverse reaction profile were comparable between pediatric patients and adults [see Adverse Reactions (6.1) and Clinical Studies (14.1 , 14.2 , 14.3) ] . Differences observed in steady‑state pharmacokinetic (PK) exposures between pediatric patients and adults were mostly accounted for by body weight [see Clinical Pharmacology (12.3) ] . The safety and effectiveness of HYMPAVZI have not been established in pediatric patients younger than 6 years of age.

8.5 Geriatric Use Two patients 65 years of age and older were enrolled in the clinical studies for hemophilia A or B with or without inhibitors [see Clinical Studies (14.1 , 14.2) ] . Clinical studies of HYMPAVZI did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently from younger subjects.

Marstacimab‑hncq is a human monoclonal IgG1 antibody directed against the Kunitz domain 2 (K2) of TFPI to neutralize TFPI activity and enhance coagulation. TFPI is the primary inhibitor of the extrinsic coagulation cascade and negatively regulates thrombin generation within the extrinsic pathway of coagulation by inactivating the protease functions of FXa/FVIIa/TF complex. TFPI binds to and inhibits the factor Xa active site via its second Kunitz inhibitor domain (K2).