Abstracts

Rationale: ICA-105665 is a novel small molecule that opens neuronal KCNQ potassium channels and has demonstrated anti-seizure activity in multiple animal models. In a single ascending dose study, healthy volunteers tolerated doses up to 400 mg without evidence of dose limiting toxicity. This study was conducted to study the tolerance, safety and pharmacokinetics of ICA-105665 in healthy volunteers administered doses up to 200 mg BID for 7 days Methods: Male and female healthy volunteers, ages 18 to 45, were eligible to participate. Three cohorts of healthy volunteers were randomized 1:3 to receive placebo or ICA-105665, 50 mg, 100 mg, or 200 mg BID, in-clinic for 7 days. Subjects were followed in the clinic for an additional two days prior to discharge and returned for an outpatient follow-up on Day 16. Daily PK sampling occurred on Days 1-6 of dosing with intense sampling during the 48 hours following the final dose. Safety and PK data were reviewed before the subsequent cohort was enrolled at a higher dose. Results: All patients completed the 7 days of dosing without evidence of dose-limiting toxicity. Among the three cohorts, 18 patients reported 30 AEs; no SAEs were reported. No AE appeared to occur more commonly in the ICA-105665-treated subjects as compared to the placebo-treated subjects. The most commonly reported AEs among subjects that received any dose of ICA-105665 included headache (5 subjects) and somnolence, gastrointestinal disorders, and respiratory disorders (3 subjects each). Two AEs (sinusitis, headache) were considered moderate in severity; all other AEs were considered mild, and no subject discontinued because of an AE. No subject developed a dose-limiting toxicity, and no AE appeared to be related to dose. CNS-related AEs occurred at all dose levels and included dizziness (50 mg), formication (200 mg), headache (all doses) and somnolence (100 mg and 200 mg) All AEs resolved without sequelae. C_MAX and AUC_τ in the 50 mg, 100 mg, and 200 mg BID cohorts increased with increasing dose. Mean C_MAX values ranged from 1800 to 6600 ng/mL and mean AUC_τ ranged from 14,000 hr*ng/mL to 61,000 hr*ng/mL. Plasma half-life was 5.5 hrs, 6.4 hrs and 9.4 hrs respectively for the 50 mg, 100 mg, and 200 mg BID cohorts. Conclusions: Doses of 50 mg, 100 mg or 200 mg BID ICA-105665 were well tolerated in healthy volunteers. AEs were not dose-limiting, were rated as mild or moderate, and all resolved. ICA-105665 exhibited linear pharmacokinetics and the data support a twice-daily dosing regimen. Trough plasma concentrations of ICA-105665 at doses of 100 mg and 200 mg BID exceeded predicted efficacious plasma concentrations as derived from animal studies.