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

Abstract

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). 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. 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. Single oral doses of JNJ-26489112 were well-tolerated and the pharmacodynamic effects appeared to be dose-related in patients with idiopathic, photosensitive epilepsy.