Abstract
Abstract 4827
A novel orally administered small-molecule thrombopoietin receptor (c-Mpl) agonist, ONO-7746, was investigated in a double-blind, placebo-controlled single dose escalation study for its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy subjects.
A total of 48 subjects were enrolled into 6 cohorts of 8 subjects each. For each cohort, subjects were randomly assigned to receive ONO-7746 or placebo in a 3:1 ratio. After a single dose of study drug on Day 1 of each cohort, all subjects in a cohort were assessed on Day 21 for their overall safety, tolerability and changes in platelet count prior to proceeding to the next higher dose. The doses of ONO-7746 applied for each successive cohort were adjusted per Dose-Escalation and Stopping Rules, i.e. the successive dose was only a 1.5-fold increase from the previous dose if either of the following were observed: Two subjects had a platelet count increase greater than 400 × 109/L, or had a platelet count doubling from Baseline. Further dose escalation was terminated if 50% of the subjects in a cohort (4 subjects) demonstrated a platelet count increase > 400 × 109/L or doubling from Baseline. This study completed a total of 6 cohorts including 5, 10, 20, 50, 100, and 150 mg. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation.
Dose escalation was only increased 1.5-fold after the 100-mg cohort because of increases in platelet count, and dose escalation was ultimately terminated after the 150-mg cohort because 50% of subjects had a platelet count increase to > 400 × 109/L or doubling from Baseline. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 9 and 11, decreased from Days 11 or 13, and returned to baseline levels by Day 28. Maximum platelet count, change from Baseline values increased with ascending ONO-7746 dose level. The largest percent change from Baseline in platelet count (117.0%) was observed in the 150-mg cohort, compared with 14.7% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. The PK profile of ONO-7746 showed that the plasma concentrations reached Cmax at a median Tmax of 3.0 to 4.0 hours. The mean T1/2 ranged from 22 to 27 hours. The PK of ONO-7746 was linear in the dose range of 5 to 100 mg. In the dose range of 100 to 150 mg, Cmax and AUCinf increased greater than dose proportionally. One subject in the 150-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L that was considered mild in severity. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, vital sign measurements, 12-lead ECG and telemetry results.
The above observations indicate that ONO-7746 could increase platelet count even with a single dose. ONO-7746 is a potent once-daily oral c-Mpl agonist with demonstrated thrombopoietic activity in human subjects, safe and well tolerated at all the tested dose levels (5, 10, 20, 50, 100 and 150 mg).
Observed Platelet Count by Study Day
Hunt:ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:ONO Pharma USA: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.
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