Marstacimab 150mg/1ml solution for injection pre-filled disposable devices

Abstract Hemophilia A and B, caused by deficiencies of coagulation factors VIII or IX, result in impaired thrombin generation with consequent spontaneous or trauma-related bleeding, particularly hemarthroses. Although prophylactic factor replacement therapy remains the global standard of care for hemophilia, it has significant limitations, including intravenous administration, breakthrough bleeding, inhibitor development, and deteriorating arthropathy despite prophylaxis. Marstacimab, an IgG1 monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), represents a novel non-factor approach. Marstacimab restores thrombin generation via the extrinsic pathway, bypassing intrinsic pathway deficiencies and offering prophylactic benefit independent of inhibitor status. Clinical evaluation across Phase 1b/2 and Phase 3 (BASIS) trials and ongoing extension studies has demonstrated robust efficacy. In Phase 3, marstacimab reduced annualized bleed rates by 91.6% compared with episodic treatment and was non-inferior to factor prophylaxis. Bleed control was sustained though zero-bleed outcomes were not uniformly achieved. Pharmacokinetic data support once-weekly fixed dosing independent of body weight, simplifying administration and potentially improving adherence. Across all studies, marstacimab demonstrated a favorable safety profile. Injection site reactions were the most common adverse events, while anti-drug antibodies, including neutralizing types, were transient and without clinical impact. Marstacimab, the first FDA-approved anti-TFPI antibody for prophylaxis in hemophilia A and B without inhibitors, addresses key unmet needs, particularly for hemophilia B patients lacking subcutaneous (SC) prophylaxis options. Its novel mechanism, ease of administration, and sustained efficacy position it as a significant therapeutic advance. Marstacimab‘s exact role in the hemophilia treatment armamentarium is yet to be established with the availability of coming real-world experience data. The long-term studies remain essential to fully demonstrate its role, especially in populations with inhibitors and in the context of evolving non-factor therapies. This review summarises currently available clinical data and contextualises these in light of other treatments in hemophilia.

Abstract licence: CC BY-NC 3.0

Marstacimab, an investigational human monoclonal antibody targeting tissue factor pathway inhibitor, demonstrated safety and efficacy in preventing bleeding episodes in patients with haemophilia. This multicentre, open-label study investigated safety, tolerability, and efficacy of long-term weekly prophylactic marstacimab treatment in participants with severe haemophilia A and B, with or without inhibitors. Adult participants were enrolled from a previous phase Ib/II study or de novo and assigned to one of two subcutaneous (SC) marstacimab doses: once-weekly 300 mg or a 300-mg loading dose followed by once-weekly 150-mg doses, for up to 365 days. Study end-points included safety assessments and annualised bleeding rates (ABRs). Of 20 enrolled participants, 18 completed the study. Overall, 70% of participants had treatment-emergent adverse events, including injection site reactions, injection site haematoma, and haemarthrosis. No treatment-related serious adverse events or thrombotic events occurred. Across all dose cohorts, mean and median on-study ABRs ranged from 0 to 3.6 and 0 to 2.5 bleeding episodes/participant/year respectively, demonstrating comparable efficacy to that observed in the short-term parent study. No treatment-induced anti-drug antibodies were detected. Once-weekly SC marstacimab prophylaxis was well tolerated, with an acceptable safety profile, and maintained long-term efficacy up to 365 days. (Clinicaltrials.gov identifier, NCT03363321).

Abstract licence: CC BY-NC 4.0

A phase 1b/2, three-month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment-emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on-demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose-related manner, with steady-state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment-related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).

Abstract licence: CC BY-NC 4.0