A phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia

Abstract

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 ondemand 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. (Clini caltr ials.gov identifier, NCT02974855). K E Y W O R D Sblood coagulation factors, drugs, investigational, haemorrhage, monoclonal antibodies, thrombin I N TRODUC T IONHaemophilia is an X-linked bleeding disorder caused by deficiencies in clotting factors VIII (FVIII) or IX (FIX). 1 For patients with severe haemophilia [factor activity levels <1% (<0.01 iu/ml) 2 ], intravenous prophylactic clotting factor replacement reduces bleeding and prevents or slows progression of joint disease. [3][4][5] frequent intravenous This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single dose of marstacimab in Chinese participants with severe haemophilia

“…Median (range) baseline TGA peak level (a key coagulation-related clinical biomarker) of 9.20 (4.9−45.3) nmol in Chinese participants with severe haemophilia was similar to that seen in non-Asian patients with haemophilia (n = 26). 7 The treatment-related trends in all PD endpoints were similar to those seen in healthy White participants 6 and non-Asian participants with severe haemophilia following administration of a single 300 mg dose of marstacimab. 7 No The small sample size, with one participant with haemophilia B and none with inhibitors, is a potential limitation; however, it was acceptable for the study objectives.…”

“…6 C max %CV was also comparable with that seen in non-Asian participants with severe haemophilia. 7 Treatment-related changes were observed for all PD endpoints. The pharmacologic effects of marstacimab lasted more than 7 days on PD markers, and maximum or near-maximum effects occurred most often within the first week.…”

“…seen in non-Asian (White, Black/African American) adult male participants with severe haemophilia that received a single 300 mg dose in the first week in the previous phase 1b/2 study, which used sparsely sampled PK data. 7 Overall, inter-individual variability for marstacimab exposure, based on the percent geometric coefficient of variation (%CV), was 35% for C max and 60% for AUC last . These values were comparable with those seen in healthy Japanese and White participants.…”

“…9 For Chinese participants with severe haemophilia, median (range) baseline total TFPI (i.e., total target) levels of 131.50 (110.0−143.0) ng/mL were similar to those seen in healthy non-Chinese participants (n = 41) 6 and non-Asian patients with haemophilia (n = 26). 7 A previous phase 1 study suggested marstacimab undergoes target-mediated drug disposition, 6 and a related model was developed. 10 No clinically relevant racial difference was observed for baseline total TFPI, the target of marstacimab.…”

Hemophilia a patients with inhibitors: Mechanistic insights and novel therapeutic implications

“…Moreover, other humanized mAbs, such as marstacimab, which specifically binds to the K1 domain of the TFPI, have shown the feasibility and efficacy of targeting TFPI therapies in hemophilia. A phase 1b/2 clinical study demonstrated clinically meaningful reductions in ABRs and treatment-related changes for all pharmacodynamics biomarkers across all marstacimab dose levels in participants with hemophilia ( 120 ). Together, therapeutic advances in hemophilia with targeting TFPI treatments are promising.…”