Seletracetam

We recently reported that seletracetam (SEL), a highly potent derivative of levetiracetam (LEV), reduces or abolishes the photoparoxysmal electroencephalographic response (PPR) to intermittent photic stimulation (IPS) in patients with epilepsy. Most of the 27 patients in this study were on comedication with different antiseizure medications (ASMs). Here, we reanalyzed the raw data of this clinical trial to determine which, if any, of the ASMs reduced (or increased) the effect of SEL on PPR in individual patients. This was possible because a group of six patients were not taking any ASM, and groups of similar size received different comedications. The effect size of SEL on the standard photosensitivity range (SPR) was calculated by the area under the effect curve from 0 to 8 h (AUEC [0–8]) as SPR change from predose. All patients experienced PPRs in response to IPS during placebo treatment, indicating that the PPR was resistant to treatment with their steady‐state ASMs. Oral single‐dose treatment with SEL reduced/abolished PPR in most (32/36) exposures, but significant effects of ASM comedication were found. Patients comedicated with LEV + lamotrigine or LEV + valproate exhibited significantly lower AUEC (0–8)s than patients without comedication, whereas no significant effects of lamotrigine or valproate alone were found. Despite the significant reduction of AUEC (0–8) in patients on comedication with LEV, SEL still reduced or abolished PPR in the majority (7/9) of exposures.

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.