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- Title
Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis.
- Authors
Mancuso, Maria Elisa; Ingham, Sheila J. M.; Kunze, Marc
- Abstract
Introduction: Befovacimab (formerly BAY 1093884) is a fully human monoclonal antibody able to bind to tissue factor pathway inhibitor (TFPI) and developed as a non‐replacement therapy for individuals with haemophilia A/B, with or without inhibitors. Aim: To assess the safety of multiple escalating doses of befovacimab in individuals with severe haemophilia A/B with or without inhibitors. Methods: In this non‐randomised, open‐label Phase 2 study (NCT03597022), adult males with <1% factor VIII or <2% factor IX and ≥4 bleeds in the previous six months were enrolled in three dose cohorts (100/225/400 mg). Participants received befovacimab subcutaneously once weekly. The primary endpoint was safety; secondary endpoints included annualised bleeding rate (ABR) and pharmacokinetics/pharmacodynamics (PK/PD) of befovacimab. Results: A total of 24 participants (n = 8 in each dose cohort) were treated for 2–47 weeks. Patients treated with 100 mg and 225 mg doses of befovacimab demonstrated improved bleeding control compared with pre‐study bleeding rates, with a dose‐dependent effect. Dosing was suspended and the study prematurely terminated following three drug‐related thrombotic serious adverse events (SAEs): two at the 225 mg dose and one at the 400 mg dose. These occurred in the absence of bleeding episodes or concomitant use of replacement/bypass therapies. No laboratory abnormalities were observed, and PK/PD data did not show correlation between SAE occurrence and levels of circulating befovacimab or free TFPI. Conclusion: Despite favourable initial results from preclinical and clinical studies, a positive safety profile of befovacimab was not confirmed. The lack of SAE‐related laboratory abnormalities or differentiating PK/PD characteristics in participants experiencing SAEs raises concerns about the predictability of thrombosis following befovacimab treatment and emphasises the need for further investigation into the therapeutic window of anti‐TFPI treatment.
- Subjects
BLOOD coagulation factor IX; BLOOD coagulation factor VIII; BLOOD coagulation factors; THROMBOSIS; IMMUNOGLOBULINS
- Publication
Haemophilia, 2022, Vol 28, Issue 5, p702
- ISSN
1351-8216
- Publication type
Article
- DOI
10.1111/hae.14595