Safety, Tolerability, and Pharmacokinetic Profile of the Novel Translocator Protein 18 kDa Antagonist ONO-2952 in Healthy Volunteers.

PURPOSE

To investigate safety, tolerability, and pharmacokinetic properties of single and multiple doses of novel translocator protein 18 kDa antagonist ONO-2952 in healthy subjects.

METHODS

Double-blind, placebo-controlled single (SAD) and multiple (MAD) dose escalation studies were conducted. Healthy men and women aged 18 to 55 years inclusive and without history of psychiatric disorders were eligible. Forty-eight volunteers received single doses of ONO-2952 (3, 10, 30, 100, 200, or 400 mg) or placebo under fasted conditions (SAD study), and 36 received ONO-2952 (30, 60, or 100 mg/d) or placebo for 21 consecutive days under fed conditions (MAD study). ONO-2952 10 and 200 mg were administered under fasted and fed conditions in the SAD study to investigate the effect of food on the absorption of ONO-2952. Safety assessments included adverse events, vital signs, 12-lead ECGs, and clinical laboratory evaluations. Plasma and urine pharmacokinetic profiles of ONO-2952 were determined.

FINDINGS

Across both studies, mean age ranged from 29.8 to 39.8 years, most participants were white, and the proportion of female volunteers was 52%. No treatment or dose-related trends in adverse events were observed. The most frequent adverse events were headache and presyncope (n = 2 each [SAD study]) and constipation and headache (n = 3 each [MAD study]). All headache and constipation episodes were possibly related to the study drug. Plasma ONO-2952 concentrations peaked 2.5 to 3.5 hours (SAD study) and 3.0 to 4.0 hours (MAD study) postdose. ONO-2952 systemic exposure increased less than dose proportionally under fasted conditions. Fed conditions significantly increased exposure compared with fasted conditions: geometric mean ratios of Cmax (90% CIs) were 229% (176-299 [10 mg]) and 778% (623-971 [200 mg]), and AUClast were 159% (131-192 [10 mg]) and 382% (288-506 [200 mg]). In the MAD study, the systemic exposure of ONO-2952 increased in a slightly greater than dose-proportional manner. Geometric mean accumulation ratios (95% CI) of AUC24 were 2.50 (2.09-2.98 [30 mg]), 2.23 (1.85-2.68 [60 mg]), and 2.73 (2.10-3.55 [100 mg]); and Cmax were 1.65 (1.43-1.90 [30 mg]), 1.56 (1.31-1.85 [60 mg]), and 1.85 (1.38-2.49 [100 mg]).

IMPLICATIONS

ONO-2952 was safe and well tolerated in these early clinical studies investigating safety, tolerability, and pharmacokinetic properties of single and multiple doses. ONO-2952 systemic exposure increased in a less than dose-proportional manner under fasted conditions and in a slightly greater than dose-proportional manner under fed conditions. These results support the progression of ONO-2952 to further studies in humans. SAD study: ClinicalTials.gov identifier: NCT01364441. MAD study: ClinicalTrials.gov identifier: NCT01489345.