A Double-Blind, Placebo-Controlled, and Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Ono-7746 in Healthy Subjects

ONO-7746 is a potent orally administered thrombopoietin receptor (c-Mpl) agonist and can elevate platelet counts after a single dose in healthy subjects. Therefore, it could be potentially used for the treatment of thrombocytopenia associated with a variety of etiologies.

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ONO-7746 after multiple dose administration in healthy subjects.

A total of 60 subjects were randomly assigned to 5 groups of 12 subjects each to receive active ONO-7746 (9 subjects) or placebo (3 subjects) once daily for 14 days at doses of 1, 2, 4, 6, and 10 mg per day. Dose selection was adjusted based on data from earlier cohorts according to the dose-escalation procedures, i.e. Dose escalation was only permitted if adequate safety and tolerability were demonstrated and the results did not meet the stopping rule criteria at the previous dose level as described in the single-dose study. Subjects returned on Day 42 for follow-up assessments. ONO-7746 was administered once daily under fasted conditions at the dose of 1 mg to 10 mg for 14 days. Subjects were admitted to the clinical study site on Day –1 and remained at the site until discharge on Day 32. 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.

Maximum platelet count and change from Baseline values increased with ascending ONO-7746 dose level. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 12 and 17, decreased from Days 22 to 32, and returned to baseline levels by Day 42. The largest mean percent change from Baseline in average platelet count (145.9%) was observed in the 10-mg cohort, compared with 17.4% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. In general, endogenous TPO values and CD34+ cell counts seemed not to be affected by the administration of ONO-7746. The PK profiles of ONO-7746 showed that Cmax and AUC24h increased with dose and T1/2 after the last dose was similar to that after a single dose. The plasma trough concentration of ONO-7746 reached steady state by Day 10. The PK of ONO-7746 was not affected by multiple-dose administration. Six subjects in the 10-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 10⁹/L. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, influence on other blood cell counts, physical examination findings, vital sign measurements, 12-lead ECG and telemetry results, or slit lamp examination results. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation.

ONO-7746 is safe and well-tolerated at all tested dose levels. The PK, PD, and safety profile demonstrated in this study supports further clinical studies in thrombocytopenic patients.

Observed Platelet Count by Study Day

View largeDownload slide

View largeDownload slide

Close modal

Hunt:ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:Ono Pharmaceutical Co., Ltd.: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.