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Previous studies revealed that phenylhistamines and histaprodifens possess higher potency and affinity at guinea pig histamine H 1 -receptor (gpH 1 R) than at human histamine H 1 -receptor (hH 1 R). However, we recently identified an imidazolylpropyl-with higher potency and efficacy at hH 1 R compared with gpH 1 R. The aim of this study was to reveal the molecular basis for the species differences of synthetic ligands. We studied 11 novel phenylhistamines and phenoprodifens. H 1 R species isoforms were expressed in Sf9 insect cells, and [3 H]mepyramine competition binding and GTPase assays were performed. We identified bulky phenylhistamines with higher potency and affinity at hH 1 R compared with gpH 1 R. Molecular dynamics simulations of ligand-H 1 R interactions revealed four potential binding modes for phenylhistamines possessing an additional histamine moiety; the terminal histamine moiety showed a high flexibility in the binding pocket. There are striking similarities in ligand properties in bulky phenylhistamines and UR-AK57. Comparison of bulky phenylhistamine binding mode with binding mode of UR-AK57 suggests that only one of these four binding modes should be established. The higher potency is explained by more effective van der Waals interaction of the compounds with Asn 2.61 (hH 1 R) relative to Ser 2.61 (gpH 1 R). In addition, two stable binding modes for phenoprodifens with different orientations in the binding-pocket were identified. Depending on phenoprodifen orientation, the highly conserved Trp 6.48 , part of the toggle switch involved in receptor activation, was found in an inactive or active conformation, respectively. We identified the first phenylhistamines with higher potency at hH 1 R than at gpH 1 R and obtained insight into the binding mode of bulky phenylhistamines and imidazolylpropylguanidines.

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.

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