Marstacimab

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 with and without inhibitors 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.

There were no clinically relevant differences in pharmacodynamic effects between haemophilia participants with and without inhibitors following weekly subcutaneous administration of marstacimab.

The pharmacokinetics of marstacimab were determined via non-compartmental analysis in healthy participants and haemophilia A and B patients with and without inhibitors as well as using a population pharmacokinetic analysis on a database composed of 287 participants (224 haemophilia patients with and without inhibitors and 63 healthy participants) who received once weekly subcutaneous (30 mg to 450 mg) or intravenous (150 mg and 440 mg) doses of marstacimab.

Marstacimab exhibited non-linear pharmacokinetics with systemic exposure to marstacimab, as measured by AUC and C_max, 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.

No clinically meaningful differences were seen in marstacimab exposures between haemophilia participants with and without inhibitors.

Mean steady-state accumulation ratio for marstacimab was approximately 4 to 5, 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 8^th or 9^th subcutaneous dose when administered once weekly. For marstacimab 150 mg subcutaneous once weekly, population estimates of mean C_max,ss, C_min,ss, and C_avg,ss for adults and adolescents are shown in the following table.

Steady-state marstacimab plasma concentrations in haemophilia A and B patients with and without inhibitors following once-weekly subcutaneous administration of 150 mg marstacimab (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

Absorption

Following multiple subcutaneous administrations of marstacimab to haemophilia patients, median T_max ranged from 23 to 59 hours. Bioavailability of marstacimab following subcutaneous administration was estimated to be about 71% by population pharmacokinetic modelling. No clinically relevant differences were seen in marstacimab bioavailability between arm, thigh and abdomen.

Distribution

Marstacimab steady-state volume of distribution in haemophilia patients was 6.0 L based on a population pharmacokinetic analysis. This limited extravascular distribution suggests that marstacimab is restricted to the intravascular space.

Biotransformation

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.

Elimination

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 0.017 L/hr. 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 11 days).

Special populations

Body weight, age group, race, and haemophilia type

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 exposures (geometric mean steady state AUC, C_max and C_min) were 2.6 to 3.2-fold higher in adolescents compared to adult haemophilia patients; 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 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 after adjusting for body weight. Marstacimab weight-adjusted linear clearance was 26% higher in Asian participants as compared to non-Asian participants. 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 impairment

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=198; eGFR ≥90 mL/min/1.73 m²) or mild renal impairment (N=25; 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.

Hepatic 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=204; total bilirubin and AST ≤ ULN) or mild hepatic impairment (N=20; 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.

Impairment of fertility

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.

Drug-drug interaction

Coadministration of marstacimab (50 mg/kg) with rFVIIa in haemostatically normal rats was tolerated at a dose of 0.8 mg/kg rFVIIa but at a higher dose of rFVIIa (3 mg/kg) was associated with an increased incidence and/or severity of acute thrombi/emboli in the lung and injection site. Coadministration of marstacimab (30 mg/kg) with aPCC (10-100 U/kg/day) in haemostatically normal rats resulted in higher mean thrombin-antithrombin complexes and mean platelet volume than were observed with aPCC alone.