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 November 30, 2021.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - 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/