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

Autor: Mahlangu JN; University of the Witwatersrand, Johannesburg, South Africa.; National Health Laboratory Service, Johannesburg, South Africa.; Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa., Lamas JL; Hospital Dr. Sótero del Río, Puente Alto, Santiago, Chile., Morales JC; Hospital Dr. Sótero del Río, Puente Alto, Santiago, Chile., Malan DR; Phoenix Pharma, Mount Croix, Port Elizabeth, South Africa., Šalek SZ; University Hospital Centre Zagreb, Zagreb, Croatia., Wang M; University of Colorado Hemophilia and Thrombosis Center, Aurora, Colorado, USA., Boggio LN; Rush Hemophilia and Thrombophilia Center, Chicago, Illinois, USA., Hegemann I; Haemophilia Comprehensive Care Center, University Hospital, Zurich, Switzerland., Mital A; Medical University of Gdańsk, Gdańsk, Poland., Cardinal M, Zhu T; Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA., Sun P; Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA., Arkin S; Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2023 Jan; Vol. 200 (2), pp. 229-239. Date of Electronic Publication: 2022 Aug 23.
DOI: 10.1111/bjh.18420
Abstrakt: 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).
(© 2022 British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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