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 prior Phase I studies, healthy volunteers tolerated ICA-105665 in single doses up to 400 mg and multiple doses up to 200 mg BID without dose-limiting side effects. In this study, ICA-105665 was tested in patients with epilepsy to assess the pharmacokinetics, safety and tolerability of ICA-105665 in the target patient population prior to initiation of efficacy trials. Methods: Male and female patients with simple or complex partial onset seizures were eligible for enrollment. All subjects enrolled were receiving a single anti-epileptic drug (AED). Patients on concomitant divalproex sodium (an enzyme-inhibiting AED) received 100 mg BID ICA-105665 and subjects taking concomitant lamotrigine or enzyme-inducing AEDs received 200 mg BID ICA-105665. Subjects were housed in a nearby hotel and reported to the clinic for evaluations through two days after the final dose. Subjects returned for follow-up evaluations on Day 16. Daily PK sampling occurred on Days 1-6 and intense sampling occurred during the 48 hours after the final dose. Results: One cohort of 6 subjects and one cohort of 8 subjects were enrolled. All patients completed the 7 days of dosing. At the doses tested, ICA-105665 was well tolerated with no reports of dose limiting adverse events (AEs) or serous adverse events (SAEs). Ten patients reported 17 AEs considered possibly related to study drug; all were CNS-related and rated as mild. All resolved either during or after the end of treatment period. Among the 14 patients in the study, the most common AEs were: increased energy (n=3), drowsiness (n=3), and hand tremor (n=2). Pharmacokinetic parameters of ICA-105665 in patients taking AEDs that do not induce CYP 450 enzymes were similar to pharmacokinetic parameters in healthy volunteers, including Cmax, and AUC. Patients taking divalproex sodium had plasma concentrations and pharmacokinetics similar to those of healthy volunteers. In the 5 subjects receiving CYP 450 enzyme-inducing AEDs (carbamazepine, phenytoin or phenobarbital), clearance of ICA-105665 at steady-state was increased compared to that of healthy volunteers. This resulted in reduced trough plasma concentrations and exposures, while the maximum plasma concentrations (CMAX) were similar to those from healthy volunteers at 200 mg BID. Plasma concentrations of concomitant AEDs did not appear to be affected by ICA-105665. Conclusions: As in healthy volunteers, ICA-105665 was well tolerated in patients with partial onset seizures. No dose-limiting toxicities were observed. Pharmacokinetics support BID dosing in future clinical trials. Plasma concentrations (steady-state and pre-dose) achieved in patients receiving non-enzyme inducing AEDs or the enzyme inhibitor divalproex sodium were similar to those in healthy volunteers and exceeded the predicted effective plasma concentrations based on animal studies. Doses may need to be increased to achieve comparable plasma concentrations in patients receiving enzyme-inducing AEDs.