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

For adults, adolescents and pediatric patients 6 to less than 12 years of age, 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 fragment 1+2, peak thrombin, and D‑dimer in patients with hemophilia with and without inhibitors. These changes were observed and persisted over a 7-day period following a single subcutaneous dose and were reversible after treatment discontinuation. Sporadic or transient increases in D-dimer and prothrombin fragment 1+2 above physiological values were reported in the study with no associated safety concerns.

There were no clinically relevant differences in pharmacodynamic effects between hemophilia participants with and without inhibitors or between age groups, following weekly subcutaneous administration of marstacimab‑hncq.

Drug Interaction

In Vitro Studies
In vitro studies in plasma from patients with hemophilia A and B with inhibitors demonstrated that marstacimab‑hncq in combination with rFVIIa resulted in no additive effect on thrombin generation compared to marstacimab‑hncq treatment alone. Thrombin generation increased when marstacimab‑hncq was used in combination with aPCC compared to marstacimab‑hncq treatment alone without exceeding peak thrombin levels achieved in non-hemophilic plasma treated with marstacimab‑hncq alone and in some cases were within the range reported for non-hemophilic normal plasma.

12.3 Pharmacokinetics

Estimated mean marstacimab-hncq Cmin,ss, Cmax,ss, and Cavg,ss for adults and adolescents weighing at least 25 kg following marstacimab-hncq 150 mg subcutaneous once‑weekly administration (with a loading dose of 300 mg subcutaneous), and for pediatric patients 6 to less than 12 years of age weighing at least 19 kg following marstacimab‑hncq 75 mg subcutaneous once‑weekly administration (with a loading dose of 150 mg subcutaneous) are shown in Table 2.

In adults and adolescents, the marstacimab‑hncq area under the plasma concentration-time curve (AUC) and the 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).

In adult and adolescent patients, the 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. Similar results were observed in pediatric patients 6 to less than 12 years of age.

Absorption
Bioavailability of marstacimab-hncq following subcutaneous administration is approximately 71% for adults, adolescents and pediatric patients 6 to less than 12 years of age. 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
For adults, adolescents and pediatric patients 6 to less than 12 years of age, marstacimab-hncq steady‑state apparent volume of distribution is 6.0 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 using adult and adolescent data, 90% of marstacimab‑hncq 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 11 days). Similar results were observed in pediatric patients 6 to less than 12 years of age.

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 in any of the age groups based on race, hemophilia type (A and B), inhibitor status and mild hepatic impairment (total bilirubin >1× to ≤1.5× ULN). In adults and adolescents, no clinically significant differences in pharmacokinetics of marstacimab‑hncq were observed based on mild renal impairment (eGFR of 60 to 89 mL/min/1.73 m2). 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 in adults and adolescents over the body weight range of 25 kg to 120 kg, and exposures in pediatric patients 6 to less than 12 years of age over the body weight range of 19 kg to 59 kg, show a trend for increase in exposure with decrease in body weight. However, dose adjustment based on body weight is not required for any of the age groups.

Pediatric Patients
Patients 12 to less than 18 years of age: Marstacimab‑hncq exposures (geometric mean steady‑state AUC, Cmax and Cmin) were 2.6- to 3.2‑fold higher in adolescents compared to adult patients with hemophilia; however, body weight accounts for most of these differences in exposures. These differences in PK did not translate to a clinically relevant difference in levels of the downstream pharmacodynamic marker peak thrombin between adults and adolescents.

Patients 6 to less than 12 years of age: Marstacimab‑hncq exposures (geometric mean steady‑state AUC, Cmax and Cmin) in patients with hemophilia 6 to less than 12 years of age are approximately 1.2- to 1.5‑fold higher than those in adult patients with hemophilia and approximately 1.7- to 2.8‑fold lower than those in adolescent patients with hemophilia; however, body weight accounts for most of these differences in exposure. Similar to adults and adolescents, these differences in PK do not translate to a clinically relevant difference in levels of the downstream pharmacodynamic markers between the age groups.

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.

Following weekly subcutaneous marstacimab‑hncq dosing in patients with hemophilia 12 years of age and older with and without inhibitors for approximately a year in the BASIS study, 33 of the 167 (19.8%) ADA‑evaluable patients treated with marstacimab‑hncq developed ADAs. Among the 33 patients who developed ADAs, 8 patients (24.2%) developed neutralizing anti-drug antibodies (NAbs). Subjects who received marstacimab‑hncq and developed ADAs had reduced marstacimab‑hncq steady‑state concentrations, geometric mean decrease was in the range of 19% to 47%, compared to those who did not develop ADAs through the course of the treatment period.

Following weekly subcutaneous marstacimab‑hncq dosing in patients with hemophilia 6 to less than 18 years of age with and without inhibitors for approximately a year in the BASIS KIDS study, 14 of the 91 (15.4%) ADA‑evaluable patients treated with marstacimab‑hncq developed ADAs. Out of the 14 ADA‑positive patients, 4 patients were 12 to less than 18 years of age (4/24; 16.7%), 10 patients were 6 to less than 12 years of age (10/67; 14.9%). Among the 14 patients who developed ADAs, 5 patients (35.7%) developed NAbs, 1 patient was 12 to less than 18 years of age (1/3; 25.0%) and 4 patients were in 6 to less than 12 years of age (4/10; 40.0%). In subjects 12 to less than 18 years of age who received marstacimab-hncq and developed ADAs had reduced marstacimab‑hncq steady‑state concentrations, geometric mean decrease was in the range of 28% to 64%, compared to those who did not develop ADAs through the course of the treatment period. In subjects 6 to less than 12 years of age who received marstacimab-hncq and developed ADAs had increased marstacimab‑hncq steady‑state concentrations, geometric mean increase was in the range of 45% to 113%; however, exposure was comparable between ADA-positive and ADA-negative subjects after accounting for body weight.

Although lower mean marstacimab‑hncq concentrations were reported in patients aged 12 years and above who were ADA‑positive compared to those who were ADA‑negative 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. Overall, the safety profile of marstacimab‑hncq was similar between patients with ADAs (including NAbs) and those without.