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First-in-Human Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of ONO-7684, an Oral Small Molecule Factor XIa Inhibitor in Healthy Subjects

D. Beale1, J. Dennison2, K.-M. Chavele1, K. Yoneda1, P. Smith1, M. Bruce1

1Ono Pharma UK Ltd, London, United Kingdom, 2Hammersmith Medicines Research, London, United Kingdom

Abstract Number: PB0196

Meeting: ISTH 2020 Congress

Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors

Background: Activated blood coagulation factor XI (FXIa) is one of the serine proteases involved in the amplification of thrombin production. Inhibition of FXIa reduces thrombin generation and prevents occlusive thrombosis. ONO-7684 is a FXIa inhibitor and novel oral anticoagulant with reduced bleeding risk in preclinical models.

Aims: This study was a first in human investigation into the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ONO-7684.

Methods: ONO-7684 was assessed in a multi-part, double-blind, placebo-controlled study in healthy adult subjects (ClinicalTrials.gov: NCT03919890) approved by a medical ethics committee. After informed consent was obtained, ONO-7684 or placebo was administered in a 3:1 ratio; in part A subjects were healthy males (single ascending dose: 1-300mg in the fasted state; food effect assessment at 80mg), in part B subjects were healthy males (multiple ascending dose, 80, 150 and 250mg once-daily for 14 days in the fed state). In total, 54 subjects were exposed to ONO-7684 over the 2 parts of the study. The PK, PD, safety and tolerability were assessed throughout the study.

Results: ONO-7684 was well tolerated; there were no signs of bleeding and all adverse events were mild or moderate. ONO-7684 demonstrated dose proportional PK with a mean half-life supportive of once-daily administration (Table 1). Exposure slightly decreased and Tmax was delayed following food. Steady state was reached within 7 days and the accumulation ratio was approximately 2-fold for Cmax and 2.3-fold for AUC. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C) (Table 2). At 250 mg in part B, the maximum mean aPTT (ratio-to-baseline) and FXI:C (% inhibition) were 2.78-fold and 92%, respectively, with minimal change in PT/INR.

Conclusions: ONO-7684 showed favourable tolerability, PK and PD suitable for further clinical development as a novel antithrombotic agent.

Sponsored by: Ono Pharmaceutical Co. Ltd., Japan

Parameter Treatment
  80 mg (N=6) 150 mg (N=6) 250 mg (N=6)
  Day 1 Day 14 Day 1 Day 14 Day 1 Day 14
Cmax (ng/mL) 553 (471, 649) 1041 (764, 1418) 1055 (832, 1338) 2004 (1382, 2906) 1771 (1296, 2422) 3704 (2674, 5131)
Tmax (h) 2.50 (1.00, 4.00) 4.01 (2.00, 12.0) 4.00 (2.00, 6.00) 4.01 (3.00, 8.00) 4.00 (2.00, 4.03) 4.00 (2.00, 12.0)
t1/2 (h) – 27.5 (22.5, 33.5) – 21.5 (12.4, 37.4) – 21.9 (19.4, 24.8)
AUC24 (h*ng/mL) 8107 (7179, 9155) 18853 (13987, 25413) 16345 (12271, 21772) 36290 (23891, 55125) 27863 (21305, 36440) 67048 (45857, 98030)
Cmax, AUC24, t1/2 are presented as geometric mean (95% confidence interval) are presented; Tmax is described as median (range).

[Table 1: Pharmacokinetic parameters following multiple dosing with ONO-7684 (Part B)]

Parameter Treatment
  Placebo (N=6) 80 mg (N=6) 150 mg (N=6) 250 mg (N=6)
  Day 1 24h Day 14 24h Day 1 24h Day 14 24h Day 1 24h Day 14 24h Day 1 24h Day 14 24h
aPTT [ratio to baseline] 1.015 ± 0.0393 1.047 ± 0.0418 1.532 ± 0.1193 1.869 ± 0.1629 1.781 ± 0.1736 2.063 ± 0.2609 2.056 ± 0.0906 2.526 ± 0.1459
Maximum on treatment [ratio to baseline] 1.087 ± 0.0264 2.070 ± 0.1521 2.345 ± 0.2753 2.782 ± 0.1470
FXI:C [% inhibition] -4.5 ± 6.80 2.1 ± 5.43 32.7 ± 3.54 61.0 ± 11.14 51.7 ± 11.16 73.0 ± 9.58 66.6 ± 6.49 86.1 ± 5.26
Maximum on treatment [% inhibition] 17.5 ± 3.41 74.7 ± 7.71 84.9 ± 5.16 92.3 ± 2.46
Data are presented as mean ± SD; aPTT: activated partial thromboplastin time; FXI:C: factor XI clotting activity

[Table 2: Summary statistics for aPTT and FXI:C following multiple dosing with ONO-7684 (Part B)]

To cite this abstract in AMA style:

Beale D, Dennison J, Chavele K-, Yoneda K, Smith P, Bruce M. First-in-Human Study to Assess the Safety, Pharmacokinetics and Pharmacodynamics of ONO-7684, an Oral Small Molecule Factor XIa Inhibitor in Healthy Subjects [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/first-in-human-study-to-assess-the-safety-pharmacokinetics-and-pharmacodynamics-of-ono-7684-an-oral-small-molecule-factor-xia-inhibitor-in-healthy-subjects/. Accessed December 11, 2023.

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