ONO‐7684 a novel oral FXIa inhibitor: Safety, tolerability, pharmacokinetics and pharmacodynamics in a first‐in‐human study

Abstract

The objectives of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of ONO-7684, a novel activated factor XI (FXIa) inhibitor, in healthy subjects.Methods: This was a first-in-human (FIH), randomised, placebo-controlled, doubleblind, single and multiple dose study in healthy subjects under fed and fasted conditions. This study consisted of two parts: single ascending dose (Part A; 1, 5, 20, 80, 150 or 300 mg ONO-7684 or placebo) and multiple ascending doses (Part B; 80, 150 or 250 mg ONO-7684 or placebo daily for 14 days). In both parts, subjects were randomised in a 3:1 ratio to receive ONO-7684 or placebo.Results: ONO-7684 was well tolerated at all dose levels tested following both single and repeated doses, with a low overall incidence of treatment-emergent adverse events. There was no evidence to suggest a bleeding risk. Dose proportionality in exposure was observed for the range of 1-300 mg ONO-7684 in Part A. In Part A, the half-life of ONO-7684 administered in the fasted state ranged from 16.0 to 19.8 hours. In Part B, the half-life of ONO-7684 administered in the fed state ranged from 22.1 to 27.9 hours, supporting once daily oral dosing. ONO-7684 strongly inhibited factor XI coagulation activity (FXI:C) and increased activated partial thromboplastin time (aPTT), with a mean maximum on treatment percentage inhibition versus baseline of 92% and a mean maximum on treatment ratio-to-baseline of 2.78, respectively, at 250 mg ONO-7684 daily. Conclusions:The data generated in this FIH study demonstrate the promising potential of oral FXIa inhibition and ONO-7684 for indications requiring anticoagulation.

First-In-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of SHR2285, a Small-Molecule Factor XIa Inhibitor in Healthy Subjects

“…The PD parameters of SHR2285 in this clinical study were also similar to those for previously reported oral small-molecule FXIa inhibitors (Perera et al, 2018;Beale et al, 2021;Thomas et al, 2021). In this study, SHR2285 administration prolonged APTT, which was similar to the results of preclinical animal model studies.…”

“…The PK profile of SHR2285 was comparable with other small molecular FXIa inhibitors such as ONO-7684, BMS-962212, and BAY 243334 ( Perera et al, 2018 ; Beale et al, 2021 ; Thomas et al, 2021 ). The rapid plasma distribution of SHR2285 supports further investigations of this drug for acute anticoagulant therapy because drugs with a rapid increase in exposure may be more suitable for such subjects.…”

“…In FXI-deficient animal models or patients, there is no evidence of obvious bleeding by targeting FXIa, which supports FXIa as a potential therapeutic target for anticoagulant therapy ( Mackman et al, 2020 ). Several candidate drugs targeting FXIa have entered the early stage of clinical development, including small-molecule FXI inhibitors (JNJ 70033093 [BMS-986177], BAY 2433334, ONO-7684, BMS-962212, and EP-7041) ( Hayward et al, 2017 ; Perera et al, 2018 ; X.; Wang et al, 2020 ; Beale et al, 2021 ; Thomas et al, 2021 ), FXI antibodies (abelacimab [MAA868], osocimab [BAY1213790], and xisomab [AB203]) ( Koch et al, 2019 ; Lorentz et al, 2019 ; Thomas et al, 2019 ; Weitz et al, 2020 ), and a FXI-antisense oligonucleotide ( Buller et al, 2015 ). However, no FXIa-targeted drugs have been approved for clinical use.…”

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

“…In addition, due to the COVID-19 pan -demic, enrollment in the ANT-004 study was stopped early and thus the fully planned data set of PK, PD, and immunogenicity data for monthly subcutaneous administration of abelacimab could not be collectedParenteral administration of abelacimab demonstrated a fa-vorable safety profile with no clinically relevant bleeding events Antisens oligonucleotides or ASO / Healthy subjects aged 18–65 yo Liu et al 2011 57 ISIS-FXIRx Single dose SC 50 mg/kg n=8 100 mg/kg n=8 200 mg/kg n=16 300 mg/kg n=8 8x SC injections n=12 Safety (adverse event (AE) clinical and laboratory tests safety, tolerability, pharmacokinetics and pharmacodynamics No study drug related bleeding events were reported. No clinical or biological significant modification occured One serious AE (allergic reaction) occured Small molecule NCT03919890 Part A enrolled men only, Part B enrolled men or women of non-childbearing potential aged 18–55 yo Beale et al 2021 58 ONO-7684 72 Part A n= 36 active n= 12 Part B n=24 Safety (adverse event (AE) reporting using the Medical Dictionary for Regulatory Activities (version 22.0), clinical laboratory tests (biochemistry, haematology and urinalysis), vital signs, electrocardiograms (ECGs), physical examination and cardiac telemetry) Tolerability Pharmacokinetic parameters Pharmacodynamic parameters No signal on safety total of eight (16.7%) out of 48 fasted subjects and one (12.5%) out of eight fed subjects reported treatment-emergent adverse events (TEAEs) in Part A, and three (12.5%) of 24 subjects reported TEAEs in Part B ( Table 2 ). There were no severe or serious TEAEs and no TEAEs that led to treatment discontinuation or interruption.…”

Sulfonated non‐saccharide molecules and human factor XIa: Enzyme inhibition and computational studies

“…Orthosteric small molecule inhibitors of FXIa have also been developed (Al-Horani, 2020a, 2020bAl-Horani & Afosah, 2018;Beale et al, 2021;Dilger et al, 2022;Kubitza et al, 2022;Wong et al, 2022). In fact, the reporting of X-ray crystal structures of FXI(a) has contributed to structure-and ligand-based drug design (Fradera et al, 2012;Jin et al, 2005).…”