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).
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.
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.
| • Data are presented as arithmetic mean (%CV). | ||
| • Cmin,ss = minimum plasma concentration at steady state; Cmax,ss = maximum plasma concentration at steady state; Cavg,ss = average plasma concentration at steady state. | ||
Parameter | Adults | Adolescents |
Cmin,ss (mcg/mL) | 13.7 (90.4%) | 27.3 (53.2%) |
Cmax,ss (mcg/mL) | 17.9 (77.5%) | 34.7 (48.5%) |
Cavg,ss (mcg/mL) | 16.5 (81.2%) | 32.1 (49.5%) |
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.
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.
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).
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.
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.
| • Data are presented as arithmetic mean (%CV). | ||
| • Cmin,ss = minimum plasma concentration at steady state; Cmax,ss = maximum plasma concentration at steady state; Cavg,ss = average plasma concentration at steady state. | ||
Parameter | Adults | Adolescents |
Cmin,ss (mcg/mL) | 13.7 (90.4%) | 27.3 (53.2%) |
Cmax,ss (mcg/mL) | 17.9 (77.5%) | 34.7 (48.5%) |
Cavg,ss (mcg/mL) | 16.5 (81.2%) | 32.1 (49.5%) |
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.
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.
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