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.

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ONO-5788 is a novel low molecular weight orally administered molecule with potent and selective agonistic effects at the human SST2 receptor subtype. ONO-5788 could offer the advantages of a more convenient route of administration for patients with acromegaly and other indications and also a preferential safety profile compared to injections. Methods : This First in Human study includes a double-blind, randomized, placebo-controlled, single ascending dose (SAD) part (including an assessment of food effect) in healthy adult male and female volunteers, 18-55 years of age. 34 males and 14 females were enrolled. Subjects were randomised to ONO-5788 or placebo (6:2 ratio) in each cohort with escalating doses of ONO-5788 (0.4, 1.6, 5, 20, 50 or 120mg) assessed. The first 2 dose levels were dosed as an oral liquid solution, the 4 remaining dose levels were dosed as oral API in capsule. Findings : Preliminary blinded data suggested no significant safety issues during administration of single doses of ONO-5788. A low incidence of mild to moderate gastrointestinal adverse events was observed at the higher doses (loose stools n=4; abdominal cramping n=3; abdominal discomfort, abdominal tenderness, discolouration of stools, pale stools, dyspepsia, nausea, all n=2). There were no safety findings for safety labs, ECGs or vital signs and no SAEs were reported. A transient increase in serum glucose was noted at 6 hours post-dose (3 hours post-meal) which followed a dose-response pattern when comparing mean glucose values across all 6 cohorts; all subjects were asymptomatic and no intervention was required. Pharmacokinetics of ONO-5788 and its active metabolite (ONO-ST1-641) were well characterized at the doses tested. Parent drug concentrations were notably higher than the active metabolite (approximately 40-fold greater). A 300-fold dose range was explored (0.4mg to 120mg) but, using arithmetic mean Cmax, AUClast and AUCinf values, ONO-5788 exposure was approximately 59-90 times higher at the highest dose compared to the lowest and ONO-ST1-641 exposure was 139-193 times higher at the highest dose. There were less than dose-proportional increases in exposure observed with both ONO-5788 and ONO-ST1-641 at doses above 20mg. Lower exposure was observed with food at the 20mg dose. The mean half-life of ONO-5788 ranged between 6.4-22 hours and for ONO-ST1-641 between 62-110 hours. Conclusion : ONO-5788 was found to be well tolerated in this SAD study at all doses tested. The pharmacokinetic profiles of ONO-5788 and its active metabolite were well characterised with a half-life suggesting the potential for once-daily dosing. Safety, tolerability, pharmacokinetics and pharmacodynamics will continue to be assessed in healthy volunteers with multiple dosing, dosing of a cohort of elderly subjects and a proof-of-principle study to further characterize ONO-5788 prior to studies in patients.