Marstacimab-Hncq

1 INDICATIONS AND USAGE HYMPAVZI is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients 12 years of age and older with: • hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, or • hemophilia B (congenital factor IX deficiency) 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 adult and pediatric patients 12 years of age and older with: • hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors, or • hemophilia B (congenital factor IX deficiency) without factor IX inhibitors. ( 1 )

2 DOSAGE AND ADMINISTRATION • See Full Prescribing Information for important dosing and administration instructions. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 ) • The recommended dosage of HYMPAVZI is: o Loading dose: 300 mg (two 150 mg injections) by subcutaneous injection o Maintenance dose: One week after the loading dose, initiate maintenance dosing of 150 mg every week by subcutaneous injection on the same day each week, at any time of day. ( 2.1 ) • Dose adjustment to 300 mg subcutaneous injection weekly can be considered. ( 2.1 ) • Factor VIII and factor IX products can be administered for the treatment of breakthrough bleeds in patients receiving HYMPAVZI. Do not use additional doses of HYMPAVZI to treat breakthrough bleeds. ( 2.4 ) • Temporarily discontinue HYMPAVZI before major surgery. ( 2.5 ) 2.1 Recommended Dosage For subcutaneous use only. The recommended dosage of HYMPAVZI for adult and pediatric patients 12 years of age and older is as follows: Loading Dose 300 mg (two 150 mg subcutaneous injections) If more than one injection is required to deliver a complete dose, administer each injection at a different injection site. Maintenance Dose One week after the loading dose, initiate maintenance dosing of 150 mg every week by subcutaneous injection on the same day each week, at any time of day. Dose Adjustment During Treatment Consider a dose adjustment to 300 mg subcutaneous injection weekly in patients weighing greater than or equal to 50 kg when control of bleeding events is judged to be inadequate by the healthcare provider. Safety and efficacy of HYMPAVZI at doses above 300 mg weekly have not been established. If more than one injection is required to deliver a complete dose, administer each injection at a different injection site. Missed Doses For patients on a maintenance dose of 150 mg: If a dose is missed, administer as soon as possible before the day of the next scheduled dose, and then resume usual 150 mg subcutaneous weekly dosing schedule (same schedule as prior to the missed dose or new schedule based on date of administration of missed dose). If more than 13 days have passed since the last dose was administered, administer a loading dose of 300 mg by subcutaneous injection followed by a resumption of 150 mg by subcutaneous injection once weekly thereafter. For patients on a maintenance dose of 300 mg: If one or more doses are missed, administer a dose as soon as possible, and then resume 300 mg subcutaneous weekly dosing schedule (same schedule as prior to the missed dose or new schedule based on date of administration of missed dose). 2.2 Preparation and Administration • HYMPAVZI is intended for use under the guidance of a healthcare provider. After proper training in subcutaneous injection technique, a patient may self-inject or the patient’s caregiver may administer HYMPAVZI, if a healthcare provider determines that it is appropriate. • Refer to the Instructions for Use for complete preparation and administration instructions. • Prior to subcutaneous administration, HYMPAVZI may be removed from the refrigerator and allowed to warm at room temperature [up to 86°F (30°C)] in the carton for 15 to 30 minutes protected from direct sunlight. Do not warm by using a heat source such as hot water or a microwave. After removal of HYMPAVZI from the refrigerator, use within 7 days or discard [see How Supplied/Storage and Handling (16) ] . • Administer HYMPAVZI by subcutaneous injection, once weekly, at any time of the day in the abdomen or front of thigh. Other injection sites are acceptable if required. Administration of HYMPAVZI in the back of upper arm (prefilled syringe only) or buttocks (prefilled pen only) should be performed by a caregiver or healthcare professional only. HYMPAVZI should not be administered into bony areas or areas where the skin is bruised, red, tender or hard, or areas where there are scars or stretch marks. HYMPAVZI should not be injected into a vein. Rotate the injection site with each new injection. • During treatment with HYMPAVZI, other medicinal products for subcutaneous administration should, preferably, be injected at different anatomical sites. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HYMPAVZI is a clear and colorless to light yellow solution. Do not use if the solution is cloudy, dark yellow, or contains flakes or particles. 2.3 Changing to HYMPAVZI Changing from prophylactic factor replacement therapy to HYMPAVZI: Prior to initiation of HYMPAVZI, discontinue treatment with clotting factor concentrates (factor VIII or factor IX concentrates). HYMPAVZI can be initiated at any time after discontinuing clotting factor concentrates. No data are available in patients changing from non-factor-based hemophilia medicinal products to HYMPAVZI. 2.4 Guidance on Use with Breakthrough Bleed Treatments Factor VIII and factor IX products can be administered for the treatment of breakthrough bleeds in patients receiving HYMPAVZI. Do not use additional doses of HYMPAVZI to treat breakthrough bleeds. Healthcare providers should discuss with all patients and/or caregivers the dose and schedule of clotting factor concentrates to use, if required, while receiving HYMPAVZI prophylaxis, including using the lowest possible effective dose of clotting factor concentrate [see Warnings and Precautions (5.1) ] . Please refer to the Full Prescribing Information for the clotting factor concentrate being used. 2.5 Temporary Interruption for Surgery and Other Interventions Management in the Perioperative Setting HYMPAVZI has not been evaluated in the setting of major surgery. Patients have had minor surgical procedures without discontinuing HYMPAVZI prophylaxis in clinical studies. For major surgery, discontinue HYMPAVZI and initiate management per local standard of care with clotting factor concentrate and measures to manage the risk of venous thrombosis which can be elevated in the perioperative period. Consult the product information for the clotting factor concentrate for dosage guidelines in patients with hemophilia undergoing major surgery. Resumption of HYMPAVZI therapy should consider the overall clinical status of the patient, including the presence of post-surgical thromboembolic risk factors, use of other hemostatic products and other concomitant medications [see Dosage and Administration (2.1) ] . Management in Patients with Acute Severe Illness There is limited experience with the use of HYMPAVZI in patients with acute severe illness. Reasons to consider temporary dose interruption of HYMPAVZI include occurrence of acute severe illness (e.g., serious infection, sepsis, trauma) in which there may be increased activation of coagulation and which the healthcare provider considers could increase the risks associated with HYMPAVZI administration. Treatment of acute severe illness should be managed per local standard of care, and continued treatment with HYMPAVZI in this situation should be weighed against the potential risks involved. Resume HYMPAVZI therapy once patient has clinically recovered [see Dosage and Administration (2.1) ] . 2.6 Pregnancy Testing Verify that females of reproductive potential are not pregnant prior to initiating HYMPAVZI [see Warnings and Precautions (5.3) , Use in Specific Populations (8.1 , 8.3) ].

6 ADVERSE REACTIONS 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 ≥3% of HYMPAVZI-treated patients were injection site reaction, headache, and pruritus. ( 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 adolescent and adult patients with severe hemophilia A or B without inhibitors (coagulation factor activity <1%) enrolled in the BASIS study [see Clinical Studies (14.1) ] . Patients (N = 116) received HYMPAVZI prophylaxis 300 mg loading dose followed by 150 mg every week starting at Day 8 administered subcutaneously. Among patients receiving HYMPAVZI, 97% were exposed for 6 months or longer and 75% were exposed for at least 1 year. A serious adverse reaction of peripheral swelling occurred in one patient. Table 1 summarizes the adverse reactions reported in ≥3% of patients who received HYMPAVZI prophylaxis. Table 1. Adverse Reactions Reported in ≥3% of Patients Treated with HYMPAVZI During BASIS trial 12-month active treatment phase Adverse Reaction Number of Patients n (%) (N = 116) Injection site reaction 11 (9) Headache 8 (7) Pruritus 4 (3) A serious adverse reaction of venous thrombosis occurred in 0.9% of patients (1/116) treated with HYMPAVZI in the open-label extension study [see Clinical Studies (14.1) ] .

12.3 Pharmacokinetics Estimated mean marstacimab‑hncq C min,ss , C max,ss , and C avg,ss for adults and adolescents weighing at least 35 kg following marstacimab‑hncq 150 mg subcutaneous once-weekly administration are shown in Table 2. Marstacimab‑hncq area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) increase in a greater than dose-proportional manner over the dose range of 100 mg to 450 mg (0.67 to 3 times the approved recommended dosage). Mean steady-state accumulation ratio for marstacimab‑hncq is approximately 4 to 5. Marstacimab‑hncq steady‑state concentrations are achieved by approximately 60 days (8 th or 9 th subcutaneous dose) when administered once weekly. Table 2. Steady-State Marstacimab‑hncq Plasma Concentrations Following Once-Weekly Subcutaneous Administration of 150 mg (with a Loading Dose of 300 mg Subcutaneous) • Data are presented as arithmetic mean (%CV). • C min,ss = minimum plasma concentration at steady state; C max,ss = maximum plasma concentration at steady state; C avg,ss = average plasma concentration at steady state. Parameter Adults Adolescents C min,ss (mcg/mL) 13.7 (90.4%) 27.3 (53.2%) C max,ss (mcg/mL) 17.9 (77.5%) 34.7 (48.5%) C avg,ss (mcg/mL) 16.5 (81.2%) 32.1 (49.5%) Absorption Bioavailability of marstacimab‑hncq following subcutaneous administration is approximately 71%. Median T max ranges from 23 to 59 hours following multiple subcutaneous administrations of marstacimab‑hncq to patients with hemophilia. No clinically significant differences were seen in marstacimab‑hncq bioavailability when administered subcutaneously in the arm, thigh or abdomen. Distribution Marstacimab‑hncq steady-state apparent volume of distribution is 8.6 L in patients with hemophilia. Elimination Marstacimab-hncq is cleared via linear and non-linear mechanisms. Marstacimab‑hncq exhibited non‑linear pharmacokinetics due to target-mediated drug disposition (TMDD) which occurs when it forms marstacimab‑hncq/TFPI complex. Once the target becomes saturated, linear pathway (i.e., catabolism) dominates. Based on population pharmacokinetic analysis, 90% of marstacimab is expected to be eliminated by the end of approximately 1 month after the last dose (median time for 50% of drug to be eliminated is approximately 7 to 10 days). Metabolism Marstacimab‑hncq is expected to be metabolized into small peptides and amino acids by catabolic pathways in the same manner as endogenous IgG. Specific Populations No clinically significant differences in pharmacokinetics of marstacimab‑hncq were observed based on race, hemophilia type (A and B), mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m 2 ), and mild hepatic impairment (total bilirubin >1× to ≤1.5× ULN). The effects of geriatric age (>65 years), moderate to severe renal (eGFR <59 mL/min/1.73 m 2 ) and moderate to severe hepatic (Child Pugh class B and C) impairment on marstacimab‑hncq pharmacokinetics are unknown. Body Weight Body weight was a significant covariate impacting the pharmacokinetics of marstacimab‑hncq. Marstacimab‑hncq exposures over the body weight range of 35 to 120 kg show a trend for increase in exposure with decrease in body weight. However, dose adjustment based on body weight is not required. Pediatric Patients Marstacimab‑hncq clearance (CL) was 29% lower in adolescents (12 to <18 years of age) compared to adults (18 years and older). No clinically significant difference in adolescent marstacimab‑hncq CL (L/hr/kg) compared to adults was observed after adjusting for body weight.