Marstacimab is a human monoclonal IgG1 antibody directed against the Kunitz domain 2 (K2) of tissue factor pathway inhibitor (TFPI), the primary inhibitor of the extrinsic coagulation cascade. TFPI initially binds to and inhibits the factor Xa active site via its second Kunitz inhibitor domain (K2). The action of marstacimab to neutralise the inhibitory activity of TFPI may serve to enhance the extrinsic pathway and bypass deficiencies in the intrinsic pathway of coagulation by increasing free factor Xa available to increase thrombin generation and promote haemostasis.
Consistent with its anti-TFPI mechanism, marstacimab administration to haemophilia patients causes an increase in total TFPI and downstream biomarkers of thrombin generation such as prothrombin fragments 1+2, peak thrombin, and D-Dimer. These changes were reversible after treatment discontinuation. Sporadic or transient increases in D-Dimer and prothrombin fragments 1+2 above physiological values were reported in the Phase 3 study with no associated safety concerns.
The pharmacokinetics of marstacimab were determined via non-compartmental analysis in healthy participants and haemophilia A and B patients as well as using a population pharmacokinetic analysis on a database composed of 213 participants (150 haemophilia patients and 63 healthy participants) who received once weekly subcutaneous (30 mg to 450 mg) or intravenous (150 and 440 mg) doses of marstacimab.
Marstacimab exhibited non-linear pharmacokinetics with systemic exposure to marstacimab, as measured by AUC and Cmax, increasing in a greater than dose-proportional manner. This non-linear pharmacokinetic behaviour is caused by target-mediated drug disposition (TMDD) and concentration dependent non-linear elimination of marstacimab which occurs when marstacimab binds to endothelial TFPI.
Mean steady-state accumulation ratio for marstacimab was approximately 3 to 4, relative to the first dose exposure following weekly subcutaneous dosing of 150 mg and 300 mg. Steady-state concentrations of marstacimab are expected to be achieved by approximately 60 days, i.e. by the 8th or 9th subcutaneous dose when administered once weekly. For marstacimab 150 mg subcutaneous once weekly, population estimates of mean Cmax,ss, Cmin,ss, and Cavg,ss for adults and adolescents are shown in the following table.
Steady-state marstacimab plasma concentrations following once-weekly subcutaneous administration of 150 mg (with a loading dose of 300 mg subcutaneous):
Parameter | Adults | Adolescents |
---|---|---|
Cmin,ss (ng/mL) | 13 700 (90.4%) | 27 300 (53.2%) |
Cmax,ss (ng/mL) | 17 900 (77.5%) | 34 700 (48.5%) |
Cavg,ss (ng/mL) | 16 500 (81.2%) | 32 100 (49.5%) |
Following multiple subcutaneous administrations of marstacimab to haemophilia patients, median Tmax ranged from 23 to 59 hours. Bioavailability of marstacimab following subcutaneous administration was estimated to be about 71% by population pharmacokinetic modeling. No relevant differences were seen in marstacimab bioavailability between arm, thigh and abdomen.
Marstacimab steady-state volume of distribution in haemophilia patients was 8.6 L based on a population pharmacokinetic analysis. This limited extravascular distribution suggests that marstacimab is restricted to the intravascular space.
Metabolism studies were not conducted with marstacimab. Similar to other therapeutic proteins with molecular weights above the glomerular filtration cut-off, marstacimab is expected to undergo proteolytic catabolism and receptor-mediated clearance. In addition, based on the TMDD, marstacimab is expected to be also cleared by target-mediated clearance as formation of marstacimab/TFPI complex.
Excretion studies were not conducted with marstacimab. Based on the molecular weight, marstacimab is expected to undergo catabolic degradation and is not expected to be renally cleared. Marstacimab is cleared via linear and non-linear mechanisms. Following multiple subcutaneous doses and based on a population PK analysis, marstacimab linear clearance was approximately 0.019 L/hr. Mean effective steady-state half-life of marstacimab was estimated to be approximately 16 to 18 days for both adults and adolescents and across dose groups.
Although weight was an important covariate to describe the pharmacokinetics of marstacimab, no alteration in dosing is required based on weight in patients weighing ≥35 kg. Marstacimab clearance (CL) was 29% lower in adolescents (12 to <18 years of age) compared to adults (18 years and older). After adjusting for weight, CL (L/hr/kg) in adolescents was estimated to be approximately 3% lower compared to that in adults, indicating that weight accounts for most of the differences in CL. This difference in PK did not translate to a clinically relevant difference in levels of the downstream pharmacodynamic marker peak thrombin between the 2 groups.
The impact of haemophilia type on the pharmacokinetics of marstacimab was not found to be clinically relevant in the patient population.
Race (Asian vs. non-Asian) was not identified as a covariate influencing marstacimab pharmacokinetics. Marstacimab weight-adjusted clearance was 32% higher in Asian patients as compared to non-Asian patients. This difference is not considered clinically relevant. There are insufficient data to evaluate potential differences in the exposure of marstacimab in other races or ethnicity.
Clinical studies of marstacimab did not include a sufficient number of patients aged 65 years and older to determine whether there are differences in exposure compared with younger patients.
Renal clearance is not considered important for elimination of mAbs due to their large size and inefficient filtration through the glomerulus. Clinical studies have not been conducted to evaluate the effect of renal impairment on the PK of marstacimab.
All patients with haemophilia A and B in the population pharmacokinetic analysis had normal renal function (N=129; eGFR ≥90 mL/min/1.73 m²) or mild renal impairment (N=21; eGFR of 60 to 89 mL/min/1.73 m²). Mild renal impairment did not affect the pharmacokinetics of marstacimab. There are no data available on the use of marstacimab in patients with moderate or severe renal impairment.
Marstacimab is a monoclonal antibody and is cleared via catabolism rather than renal excretion and a change in dose is not expected to be required for patients with renal impairment.
Clinical studies have not been conducted to evaluate the effect of hepatic impairment on the PK of marstacimab, as it is generally not considered clinically relevant for mAbs.
All patients with haemophilia A and B in the clinical studies had normal hepatic function (N=135; total bilirubin and AST ≤ ULN) or mild hepatic impairment (N=15; total bilirubin >1× to ≤1.5× ULN). Mild hepatic impairment did not affect the pharmacokinetics of marstacimab. No data are available on the use of marstacimab in patients with moderate or severe hepatic impairment.
Marstacimab is a monoclonal antibody and is cleared via catabolism rather than hepatic metabolism and a change in dose is not expected to be required for patients with hepatic impairment.
Nonclinical data reveal no special hazard for humans based on repeat-dose toxicity, including safety pharmacology endpoints, and local tolerance. Reversible mixed cell infiltration, haemorrhage, and necrosis were observed at the injection sites in rats following subcutaneous injection. No studies have been conducted to assess the potential for carcinogenicity, mutagenicity, or effects on embryo-foetal development.
Marstacimab did not affect fertility or early embryonic development when administered as a repeat dose to male rats at doses up to 1 000 mg/kg/dose and an exposure margin of 212× the AUC exposure at a clinical dose of 300 mg subcutaneous weekly.
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