A multicenter Phase II randomized, placebo-controlled single-blind trial with the SV2A ligand seletracetam in photosensitive epilepsy patients

Abstract

The objective of this study was to evaluate the effect of seletracetam (SEL), a potent modulator of synaptic vesicle glycoprotein 2A (SV2A), in patients with photoparoxysmal EEG response (PPR) to intermittent photic stimulation (IPS) as proof-of-principle of efficacy in patients with epilepsy. In this multicenter, single-blind Phase II study, adults with photosensitive epilepsy, with/without concomitant antiseizure medication therapy, underwent IPS under 3 eye conditions (at eye closure, eyes closed and eyes open) after a single oral dose of placebo (day − 1) or SEL (day 1; 0.5, 1, 2, 4, 10, or 20 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥ 1 time points for all eye conditions. Partial suppression was a ≥ 3-point reduction over ≥ 3 testing times vs the same time points on day − 1 in ≥ 1 eye condition. In addition, pharmacokinetics and safety were assessed. Of 27 evaluable patients, 9 reentered to receive a 2nd dosing 1–6 months later, providing a total of 36 individual exposures. At all doses administered − even the lowest −, several subjects reached a complete abolishment of PPR, with a rapid onset of effect. Overall, complete abolishment of PPR was obtained in 40–71 % of the patients; the effect increasing with the dose. In terms of effective doses to suppress PPR, SEL was at least 1,500 times more potent than levetiracetam and 10–20 times more potent than brivaracetam. Adverse events of SEL, including dizziness and somnolence, were mild to moderate. Pharmacokinetics of SEL demonstrated rapid absorption and a linear dose:plasma level relationship. This proof-of-principle study demonstrates that – based on our own experience − SEL is the most potent compound ever tested in the photosensitivity model.