Abstracts

Rationale: ICA 105665 is a novel small molecule that opens neuronal KCNQ potassium channels, has demonstrated anti-seizure activity in multiple animal models, and is being developed for the treatment of epilepsy. This first-time-in-humans study was conducted to determine the single-dose safety, tolerability and pharmacokinetics of ICA-105665. Methods: Study ICA-105665-01 was a single, ascending-dose study in human subjects initiated in August 2007 and completed in February 2008. Nine cohorts of 9 male subjects each were enrolled. Subjects were randomized (1:3) to receive one dose of placebo or ICA-105665 as an oral suspension in doses of 30, 50, 100, 150, 200, 250, 300, 350, and 400 mg. Safety and PK were evaluated for each cohort before the subsequent cohort was enrolled at a higher dose. Subjects returned to the clinic on Days 8 and 13 for outpatient follow-up assessments. Results: Oral ICA-105665 was rapidly absorbed, exhibited dose proportional increases in plasma concentration, and linear pharmacokinetics over the 30 to 400 mg range. ICA-105665 clearance did not appear to be affected by dose level. Mean peak plasma concentrations ranged from 1010 ng/mL (30 mg dose) to 5210 ng/mL (400 mg dose). Plasma half-life ranged from 5 to 9 hours. A total of 46 adverse events (AEs) were reported by 28 (35%) subjects; no SAEs or dose-limiting AEs were reported. Only 3 AEs were reported by more than 2% of subjects overall: headache (9%), upper respiratory infection (7%), and vessel puncture site pain (4%). The investigator considered most AEs to be unrelated to study drug; 15 AEs reported by 11 (14%) subjects were considered to be possibly related to the study drug. Three subjects reported moderate AEs; only one (headache) was considered possibly related to study drug and resolved. All other AEs were considered mild in severity. No trends in AE incidence or severity by active treatment dose were observed. There were no clinically significant alterations in ECGs, including QT intervals. Clinical laboratory, vital sign, and physical examination results were generally unremarkable, with no treatment-related trends observed. The maximum tolerated dose was not reached in this study. Conclusions: ICA-105665 was well tolerated in healthy, male subjects at single doses up to 400 mg with no dose-limiting AEs and no SAEs. ICA-105665 was rapidly absorbed and bioavailable following oral administration and exhibited linear pharmacokinetics (AUC and CL/F) over the 30 to 400 mg dose range. Peak plasma concentrations that exceeded the predicted efficacious levels (based on animal studies) were achieved for all doses. Further study of ICA-105665 is warranted.