Befovacimab, an anti‐tissue factor pathway inhibitor antibody: Early termination of the multiple‐dose, dose‐escalating Phase 2 study due to thrombosis

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.

Long‐term safety and efficacy of the anti‐tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results

“…Although emicizumab was generally well tolerated in clinical trials, 7,17–19 thrombotic microangiopathy and thrombosis occurred in participants receiving high cumulative doses of aPCC for breakthrough bleeding events while receiving emicizumab 17 . Other anti‐TFPI agents in development (e.g., concizumab and befovacimab) have been associated with thrombosis and the risk of coagulation 21,23,24 . Non‐fatal thromboembolic events occurred in three participants in phase III clinical trials of concizumab, which led to the temporary pausing of those trials 23,25 .…”

“…The use of other novel non‐factor therapies has been associated with thromboembolic events, requiring safety precautions for concomitant use with clotting factors and bypass agents. 1 , 21 , 22 , 23 , 24 Although emicizumab was generally well tolerated in clinical trials, 7 , 17 , 18 , 19 thrombotic microangiopathy and thrombosis occurred in participants receiving high cumulative doses of aPCC for breakthrough bleeding events while receiving emicizumab. 17 Other anti‐TFPI agents in development (e.g., concizumab and befovacimab) have been associated with thrombosis and the risk of coagulation.…”

“… 17 Other anti‐TFPI agents in development (e.g., concizumab and befovacimab) have been associated with thrombosis and the risk of coagulation. 21 , 23 , 24 Non‐fatal thromboembolic events occurred in three participants in phase III clinical trials of concizumab, which led to the temporary pausing of those trials. 23 , 25 A phase II dose‐escalation study of the investigational anti‐TFPI antibody, befovacimab, was terminated early because of thrombosis.…”

Nonfactor Therapies for Hemophilia

“…Notably, one anti-TFPI molecule, befovacimab (Bayer, Whippany, NJ) led to enough of a thrombosis concern that its development was discontinued. 11 Reviewing all the clinical trial data for these agents is beyond the scope of this review; however, a few key points will be made below. First, the only drug for which phase 3 clinical trial data is fully published is fitusiran in the recent publications of the ATLAS-INH (inhibitor patients) and ATLAS A/B (noninhibitor patients) trials.…”

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

“…Of these, befovacimab also targets the K1 domain of the TFPI ( 113 ). While favorable results were obtained from the preclinical in vivo studies and phase 1 clinical trials, the phase 2 study was terminated early due to three befovacimab-related thrombotic serious adverse events (SAEs) ( 114 ). Therefore, the therapeutic window of anti-TFPI treatment must be further investigated.…”