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.

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

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