Pharmacokinetics, pharmacodynamics and safety of BAY 2433334, a novel activated factor XI inhibitor, in healthy volunteers: A randomized phase 1 multiple‐dose study

Abstract

Aim To evaluate BAY 2433334, an oral activated factor XI (FXIa) inhibitor, in volunteers. Methods Phase 1 study of healthy men at a German centre. Part A: randomized, single‐blind, multiple dose‐escalation study of BAY 2433334 (25/50/100 mg once daily [OD]) vs. placebo. Part B: similar design to Part A; evaluated BAY 2433334 25 mg twice daily. Part C: nonrandomized, open‐label study; evaluated potential interactions between BAY 2433334 (25/75 mg OD) and midazolam (7.5 mg), a CYP3A4 index substrate. Primary variables: treatment‐emergent adverse events (TEAEs; Parts A and B); area under the plasma concentration–time curve (AUC) and maximum plasma concentration of midazolam and α‐hydroxymidazolam (Part C). Study period: 18 days plus follow‐up visit. Results Parts A and B: 36 participants randomized to BAY 2433334; 12 to placebo. Part C: 48 participants assigned to BAY 2433334 plus midazolam. BAY 2433334 was well tolerated in all study parts. AUC and maximum plasma concentration of BAY 2433334 in plasma appeared dose proportional over 25–100 mg OD, with low‐to‐moderate variability in pharmacokinetic parameters. Multiple dosing caused minor‐to‐moderate accumulation and a mean terminal half‐life (15.8–17.8 h) supporting once‐daily dosing. Dose‐dependent FXIa activity inhibition and activated partial thromboplastin time prolongation were observed. BAY 2433334 appeared to have a minor effect on AUC for midazolam (ratio [90% confidence interval]: 1.1736 [1.0963–1.2564]) and α‐hydroxymidazolam (0.9864 [0.9169–1.0612]) only for BAY 2433334 75 mg OD on day 10. Conclusion Multiple dosing of BAY 2433334 in healthy volunteers was well tolerated, with a predictable pharmacokinetic/pharmacodynamic profile and no clinically relevant CYP3A4 induction or inhibition.

Factor XI Inhibitors for Prevention and Treatment of Venous Thromboembolism: A Review on the Rationale and Update on Current Evidence

“…Asundexian is a small molecule direct inhibitor of FXIa with oral bioavailability and a terminal half-life of approximately 17 h. Asundexian is renally eliminated to less than 15% and has no clinically relevant interaction with cytochrome P450 (CYP) 3A4 ( 94 ). The safety of 2 different dose regimens (20 and 50 mg once daily) was studied in a randomized, double-blind, phase II study in 753 patients with atrial fibrillation and moderate-to-high risk for stroke and bleeding ( 95 ).…”

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa

“…The onset of action of asundexian, milvexian, 26 osocimab, 24 and abelacimab 27 is rapid, whereas it takes longer time periods for IONIS FXI‐R x to lower FXI concentrations to therapeutic levels with a correspondingly long duration of the anticoagulant effect 19 . Osocimab (mean elimination half‐life, 30–44 days 24 ) and abelacimab (elimination half‐life, 25–30 days 27 ) have been shown to have a long duration of effect, whereas milvexian has a half‐life that may be suitable for once‐ or twice‐daily dosing, 26 and phase I data suggest asundexian is a suitable candidate for once‐daily oral anticoagulation 28,29 ; this is being further evaluated in phase II.…”

Factor XI Inhibition for the Prevention of Venous Thromboembolism: An Update on Current Evidence and Future perspectives

“…They have a short half-life and a renal clearance similar to DOACs. 37 , 38 In contrast, ASOs (such as Factor XI LICA, IONIS FXI-LRx/ISIS 416858) and monoclonal antibodies (such as Xisomab 3G3/AB023, Osocimab/BAY1213790 or Abelacimab/MAA868) have longer half-lives for up to 30 days, which enables a decreased frequency of administration and thus may increase the patient adherence and compliance. 39–41 Antibodies and ASOs approaches to target FXI differ in their onset of action; upon administration, monoclonal antibodies lower FXI function after hours, while the effect of ASOs only becomes apparent after several weeks.…”

“… BAY 2433334 dose-dependently inhibited FXIa activity and increased activated partial thromboplastin time. / Healthy adult caucasian men Aged 18–45 yo Kubitza et al 2022 38 Asundexian (BAY2433334) 96 Parts A and B: n= 36 active; n=12 to placebo. Part C: n= 48 active plus midazolam Safety (physical examination, vital signs, 12-lead electrocardiogram (ECG) and clinical laboratory evaluation) Tolerability Pharmacokinetic parameters Pharmacodynamic parameters Interaction with Midazolam Multiple dosing of BAY 2433334 in healthy volunteers was well tolerated, with a predictable pharmacokinetic/pharmacodynamic profile and no clinically relevant CYP3A4 induction or inhibition.…”