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

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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.

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Refer to the Instructions for Use for complete preparation and administration instructions.

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Prior to subcutaneous administration, HYMPAVZI may be removed from the refrigerator and allowed to warm at room temperature 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)].

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Administer HYMPAVZI by subcutaneous injection, once weekly, at any time of the day in the abdomen or thigh. Other injection sites are acceptable if required. Administration of HYMPAVZI in the 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.

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During treatment with HYMPAVZI, other medicinal products for subcutaneous administration should, preferably, be injected at different anatomical sites.

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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)].

5.1 Thromboembolic Events

HYMPAVZI is a tissue factor pathway inhibitor (TFPI) antagonist, and may increase the risk of thromboembolic complications.

HYMPAVZI has not been studied in patients with a history of previous thromboembolic events [see Clinical Studies (14.1)]. Interrupt HYMPAVZI prophylaxis if diagnostic findings consistent with thromboembolism occur and manage as clinically indicated.

If factor VIII or factor IX products are indicated in a patient receiving HYMPAVZI prophylaxis, the minimum effective dose of factor VIII or factor IX according to the product label is recommended [see Dosage and Administration (2.4)].

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)].

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.

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 without inhibitors have been established in pediatric patients aged 12 years and older [see Clinical Studies (14.1)]. Use of HYMPAVZI for this indication is supported by evidence from an open‑label, multi‑center phase 3 study in 19 adolescents and 97 adults with hemophilia without inhibitors.

The safety and effectiveness of HYMPAVZI have not been established in pediatric patients younger than 12 years old.

8.5 Geriatric Use

One patient 65 years of age and older was enrolled in the clinical studies for hemophilia A or B without inhibitors [see Clinical Studies (14.1)]. Clinical studies of HYMPAVZI did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

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).

12.2 Pharmacodynamics

Marstacimab‑hncq causes an increase in total TFPI (comprised of free TFPI and TFPI bound to marstacimab) and downstream biomarkers of thrombin generation such as prothrombin fragments 1+2, peak thrombin, and D‑Dimer in patients with hemophilia. These changes were observed and persisted over a 7-day period following a single subcutaneous dose and were reversible after treatment discontinuation.

12.3 Pharmacokinetics

Estimated mean marstacimab‑hncq Cmin,ss, Cmax,ss, and Cavg,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 (Cmax) 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 (8th or 9th subcutaneous dose) when administered once weekly.

Absorption
Bioavailability of marstacimab‑hncq following subcutaneous administration is approximately 71%. Median Tmax 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 m2), 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 m2) 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.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and the specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of ADA in other studies, including those of marstacimab‑hncq or of other marstacimab products.

During the 12-month active treatment phase in the BASIS study, 23 of the 116 (19.8%) ADA‑evaluable marstacimab‑hncq‑treated patients developed ADAs. Among the 23 patients who tested positive for ADA, 6 patients (26%) developed neutralizing antibodies (NAbs) against marstacimab‑hncq. Subjects who received marstacimab‑hncq and developed anti-marstacimab-hncq antibodies had reduced marstacimab-hncq steady‑state concentrations, geometric mean decrease in the range of 24% to 50%, compared to those who did not develop anti‑marstacimab‑hncq antibodies through the course of the treatment period.

There was no identified clinically significant effect of ADAs, including NAbs, on safety or efficacy of marstacimab‑hncq over the treatment duration of 12 months.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to assess marstacimab‑hncq for the potential for carcinogenicity or mutagenicity. Marstacimab‑hncq did not affect fertility when administered as a repeat dose to male rats at doses up to 1000 mg/kg/dose and an exposure margin of 212-times the exposure at a clinical dose of 300 mg subcutaneous weekly. No effects were observed in male or female reproductive organs in the repeat‑dose toxicity studies of up to 6 months in duration in rats and 3 months in duration in cynomolgus monkeys at doses of 1000 mg/kg/dose and 500 mg/kg/dose and exposure margins at least 201- and 219-times, respectively, the AUC exposure at a clinical dose of 300 mg subcutaneous weekly.

14.1 Hemophilia A without FVIII Inhibitors or Hemophilia B without FIX Inhibitors

The efficacy of HYMPAVZI was established in 116 adult and pediatric patients (aged 12 years and older and ≥35 kg) with severe hemophilia A without FVIII inhibitors or severe hemophilia B without FIX inhibitors enrolled in the BASIS study (NCT03938792), an open-label, multi-center, two-phase study. Severe hemophilia is defined as factor activity less than 1%. Patients with a history of coronary artery disease, venous or arterial thrombosis or ischemic disease were excluded from the study.

Following screening, patients entered a 6-month observation phase and were enrolled to two cohorts based on the factor replacement treatment they were receiving prior to study entry: on‑demand or routine prophylaxis. Patients who completed the observation phase were to receive 12 months of HYMPAVZI. Of the 116 patients who received HYMPAVZI, 33 patients were in the on‑demand treatment cohort and 83 were in the prophylactic treatment with FVIII or FIX cohort during the observation phase. Patients who completed the 12‑month BASIS study were eligible to enroll in an open-label extension study (NCT05145127).

Patients received an initial 300 mg loading dose of HYMPAVZI followed by maintenance doses of 150 mg of HYMPAVZI once weekly for 12 months. Dose escalation to 300 mg of HYMPAVZI once weekly was permitted after 6 months of treatment in patients weighing ≥50 kg and experiencing ≥2 breakthrough bleeds. Fourteen (12%) underwent dose escalation.

The mean annualized bleeding rates (ABRs) for treated bleeds were 38 and 7.85 in the observational phase for the on-demand and prophylaxis cohorts, respectively. All patients in the on-demand cohort had one or more target joints at study entry and 36% had 3 or more target joints at study entry. In the routine prophylaxis cohort, 57% of the patients had one or more target joints at study entry and 16% had 3 or more target joints at study entry.

The efficacy of HYMPAVZI for each cohort was based upon the ABR of treated bleeds during treatment with HYMPAVZI compared to ABR during the observational phase. Other objectives of the study included evaluation of HYMPAVZI prophylaxis on the incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds.

Among the 116 patients treated with HYMPAVZI in the BASIS study, the mean age was 32 years (range 13 to 66); 19 patients were 12 to <18 years of age and all were male. Fifty-six (56) patients were White, 58 patients were Asian, 1 patient was Black or African American and 1 patient had race information unreported; 12 patients identified as Hispanic or Latino and 104 patients identified as not Hispanic or Latino. The patient population included 91 with hemophilia A and 25 with hemophilia B.

Patients with On-Demand Factor-Based Therapy in Observational Phase
Table 3 shows the efficacy results of HYMPAVZI prophylaxis compared with on-demand factor-based therapy. HYMPAVZI prophylaxis demonstrated superiority over on-demand factor-based therapy in incidences of treated bleeds, spontaneous bleeds, joint bleeds, total bleeds and target joint bleeds.

Patients with Routine Prophylactic Factor-Based Therapy
Table 4 shows the efficacy results of HYMPAVZI prophylaxis compared with routine prophylactic factor‑based therapy. HYMPAVZI prophylaxis demonstrated non-inferiority to routine prophylactic factor‑based therapy as measured by ABR of treated bleeds as well as incidences of spontaneous bleeds, joint bleeds, target joint bleeds and total bleeds.

16.1 How Supplied

HYMPAVZI (marstacimab‑hncq) injection is a sterile, preservative-free, clear and colorless to light yellow solution available as a 150 mg/mL single-dose prefilled syringe or pen for subcutaneous administration.

Prefilled Syringe
Each carton (NDC 0069-1510-01) contains one single-dose prefilled syringe (Type I glass) with a plunger stopper (chlorobutyl elastomer) and a stainless steel 27 gauge, ½ inch staked needle with a rigid needle shield (thermoplastic elastomer).

Prefilled Pen
Each carton (NDC 0069-2151-01) contains one single-dose prefilled pen with needle guard. The syringe inside the pen is made from Type I glass with a plunger stopper (chlorobutyl elastomer) and a stainless steel 27 gauge, ½ inch staked needle with a rigid needle shield (thermoplastic elastomer).

HYMPAVZI is not made with natural rubber latex.

16.2 Recommended Storage and Handling

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Store refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light.

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If needed, HYMPAVZI may be stored one time at room temperature [up to 86°F (30°C)] in its original carton to protect from light for up to 7 days. Once stored at room temperature, do not return to the refrigerator and discard after 7 days.

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Do not freeze.

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Do not shake.