Suppression of the photoparoxysmal response in photosensitive epilepsy with cenobamate (YKP3089)

Abstract

Objective: To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy.

Methods: In this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 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. Pharmacokinetics and safety were assessed.

Results: Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 μg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence.

Conclusions: This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy.

Clinicaltrialsgov identifier: NCT00616148.

Classification of evidence: This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.

Figure 1. Patient disposition

Seven patients enrolled in the study and received treatment. One patient withdrew consent after a 100-mg dose of cenobamate before intermittent photic stimulation (IPS) assessment. Five patients re-enrolled and progressed to a higher dose. ITT = intent to treat.

Figure 2. One-hour SPR (mean ± SD) on day −1 and changes in SPR on days 1 and 2 vs day −1

One-hour standardized photosensitivity range (SPR) (mean ± SD) on day −1 (placebo) and mean ± SD changes in SPR on days 1 and 2 (after cenobamate [CNB]) vs day −1 for the most sensitive eye condition. *n = 3.

Figure 3. Plasma concentration over time (mean ± SD) for 3 ascending doses of cenobamate