Evaluation of JNJ-26489112 in patients with photosensitive epilepsy: a placebo-controlled, exploratory study.

ABSTRACT

PURPOSE: To evaluate the activity of JNJ-26489112 in patients with photosensitive epilepsy and determine the doses that result in reduction or complete suppression of the intermittent photic stimulation (IPS) induced photoparoxysmal-EEG response (PPR). METHODS: In this multicenter, single-blind, within subject, placebo-controlled, sequential dose, exploratory study, 12 adult patients (3 men; 9 women) with idiopathic photosensitive epilepsy, with and without concomitant antiepileptic drug (AED) therapy, underwent standardized IPS under three eye conditions (open, during closure, and closed) for up to 12h after receiving a single oral dose of placebo on day 1, JNJ-26489112 on day 2, and a second dose of placebo on day 3. Based on review of the blinded EEG data, the standardized photosensitive range (SPR) (i.e., upper and lower frequencies of the IPS-induced PPR), was calculated for each eye condition at each time point. A positive response was defined as a reduction of the SPR in ≥3 out of 4 consecutive time points in ≥1 eye condition on either day 2 or 3 compared with baseline (day 1) while complete suppression was defined as disappearance of an IPS-induced PPR (i.e., SPR=0). For the first four patients (Cohort 1), JNJ-26489112 dose was 1000 mg, and the dose was escalated to a maximum of 3000 mg in subsequent cohorts. Blood and plasma samples were collected for pharmacokinetic evaluations along with measurements of concurrent AED concentrations. Safety was also assessed. RESULTS: The majority of patients showed a positive response on day 2 following JNJ-26489112 administration 3/4 patients (1000 mg dose), 3/4 patients (2000 mg dose), and 2/3 patients (3000 mg). There was an apparent dose-dependent effect observed in patients who exhibited complete suppression of the SPR 0/4 patients (1000 mg dose), 1/4 patient (2000 mg dose), and 2/3 patients (3000 mg dose). The median tmax of JNJ-26489112 (range 3.73-5.04 h) in plasma was similar across all 3 dose groups and plasma exposure of JNJ-26489112 increased proportionally with dose; approximate mean Cmax of 16, 28, and 42 µg/mL for the 1000-, 2000-, and 3000 mg cohorts, respectively. Concentrations of other AEDs did not appear to be affected by co-administration of JNJ-26489112. JNJ-26489112 was generally well-tolerated with the most frequent adverse events (>10%) reported being mild headache, dizziness, and nausea. CONCLUSION: Single oral doses of JNJ-26489112 were well-tolerated and the pharmacodynamic effects appeared to be dose-related in patients with idiopathic, photosensitive epilepsy.