Abstracts

Rationale: Seizures can occur as a reaction to flickering light in patients with photosensitive epilepsy. Photoparyoxysmal EEG responses (PPR) to intermittent photic stimulation (IPS) can be studied in the laboratory without eliciting clinical seizures, and sensitivity to IPS can be used as a quantitative indicator of antiepileptic drug (AED) activity. In these studies, the standard photosensitivity range (SPR) is defined by the lowest and highest threshold frequencies of IPS eliciting a PPR. Narrowing or abolishing the SPR indicates anti-seizure activity. ICA-105665 is a novel molecule that opens neuronal KCNQ potassium channels and has demonstrated anti-seizure activity in multiple animal models. In prior Phase I studies, healthy volunteers and patients with epilepsy tolerated ICA-105665 in single doses up to 400 mg and multiple doses up to 200 mg BID for 7 days without dose-limiting side effects. The pharmacodynamic effects of increasing oral doses of ICA-105665 on the SPR were investigated in a placebo-controlled study in patients with photosensitive epilepsy. To our knowledge, this is the first study of the effects of a KCNQ opener on the PPR. Methods: Male and female patients aged 18 to 60 years with a reproducible IPS-induced PPR on EEG were eligible for enrollment. The study was conducted as a single-blind, single dose, multiple cohort study. Four patients were enrolled in each of the first 3 cohorts. Patients could participate in more than one cohort. PPR responses to IPS were used to determine the SPR following placebo and ICA-105665. The SPR was quantified for 3 eye conditions (eyes closing, eyes closed, and eyes open) and the most sensitive condition used for assessment of efficacy over 3 days. A partial response was defined as a reduction in the SPR of at least 3 units at 3 separate time points following ICA-105665 compared to the same time points following placebo with no time points with > 3 units of increase. Complete suppression was defined by no PPR in all eye conditions at one or more time points. Results: Six individual patients participated in the first 3 cohorts (100 mg, 200 mg and 400 mg). Decreases in SPR occurred in 1 patient at 100 mg and 2 patients receiving 400 mg ICA-105665 (complete abolishment of SPR occurred in 1 patient at 400 mg). The SPR remained diminished for 24 hours after dosing in 1 patient. All AEs were mild in severity, and there were no serious AEs. No patient discontinued study participation because of an AE. There were no significant changes in vital signs or clinical laboratory studies. Conclusions: ICA-105665 reduced the SPR in some patients at single 100 and 400 mg doses. Based on the results in patients with photosensitive epilepsy, ICA-105665 should be assessed for anti-seizure activity in additional clinical studies of patients with other seizure types.