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

Prospero, Nicholas A. Di; Gambale, Jay J.; Pandina, Gahan; Ford, Lisa; Girgis, Suzette; Moyer, John A.; Xi, Liwen; Nye, Jeffrey S.; Trenité, Dorothee Kasteleijn‐Nolst

doi:10.1016/j.eplepsyres.2014.01.018

Cited by 8 publications

(5 citation statements)

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“…Over time, drugs with different chemical structures and mechanisms of action have been tested in the PM. These include the histamine H3R antagonist pitolisant, 274 partial benzodiazepine agonists, 275 the AMPA/kainate receptor antagonist BGG492, 276 Kv7 potassium channel activation with ICA‐105665, 277 carisbamate, 278 the sulfamide JNJ‐26489112 279 and PF‐06372865, a selective GABA potentiator 280 . Cenobamate 281 is the most recently US Food and Drug Administration (FDA)approved ASM tested in photosensitive subjects.…”

Section: The Photosensitivity Modelmentioning

confidence: 99%

Visually sensitive seizures: An updated review by the Epilepsy Foundation

et al. 2022

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Light flashes, patterns, or color changes can provoke seizures in up to 1 in 4000 persons. Prevalence may be higher because of selection bias. The Epilepsy Foundation reviewed light-induced seizures in 2005. Since then, images on social media, virtual reality, three-dimensional (3D) movies, and the Internet have proliferated. Hundreds of studies have explored the mechanisms and presentations of photosensitive seizures, justifying an updated review. This literature summary derives from a nonsystematic literature review via PubMed using the terms "photosensitive" and "epilepsy." The photoparoxysmal response (PPR) is an electroencephalography (EEG) phenomenon, and photosensitive seizures (PS) are seizures provoked by visual stimulation. Photosensitivity is more common in the young and in specific forms of generalized epilepsy. PS can coexist with spontaneous seizures. PS are hereditable and linked to recently identified genes. Brain imaging usually is normal, but special studies imaging white matter tracts demonstrate abnormal connectivity. Occipital cortex and connected regions are hyperexcitable in subjects with light-provoked seizures. Mechanisms remain unclear. Video games, social media clips, occasional movies, and natural stimuli can provoke PS.

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Section: The Photosensitivity Modelmentioning

confidence: 99%

Visually sensitive seizures: An updated review by the Epilepsy Foundation

et al. 2022

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“…Furthermore, a reduction in PPR demonstrated in the photosensitivity model, along with measurement of plasma concentrations of compounds, can help establish the pharmacokinetic/pharmacodynamic relationship and identify optimal doses and duration of treatment effects for investigational AEDs. 2,7 In a meta-analysis, doses corresponding to 50% to 100% response in proof-of-concept photosensitivity trials were predictive, within 2-fold, of the minimally efficacious doses of the AED. 7 On the basis of the pharmacokinetic/pharmacodynamic findings from the current proof-of-principle study of cenobamate, a dose of 200 mg was included for further assessment in large phase 2 clinical trials in patients with focal seizures (ClinicalTrials.gov NCT01397968 and NCT01866111).…”

Section: Discussionmentioning

confidence: 99%

“…The photosensitivity model has been described extensively. 1–3,12,13 In this model, patients are exposed to IPS before and after placebo/AED intake at hourly intervals over a 3-day period. A standardized stimulation protocol is used to establish photosensitivity thresholds (in Hertz), which are translated into an SPR value in points.…”

Section: Methodsmentioning

confidence: 99%

“…In patients with photosensitive epilepsy, intermittent photic stimulation (IPS) typically results in a characteristic epileptiform response on EEG. 1,2 Photosensitivity or the IPS-induced photoparoxysmal response (PPR) on EEG is commonly associated with generalized epilepsies but can also occur in patients with focal epilepsy. 3,4 Standardized assessment of the PPR can be used as a proof-of-principle model for the assessment of investigational antiepileptic drugs (AEDs) in early clinical development.…”

mentioning

confidence: 99%

“…In the model, photosensitive patients are exposed to IPS, and a reduction in sensitivity to the number of standard visual stimulation frequencies after a single, acute dose of a potential AED is used as an endpoint. 7 The standardized photosensitivity range (SPR) is a reliable screening method for assessing AED efficacy and safety 2 and can inform dose selection for larger clinical trials. 7…”

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confidence: 99%

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

et al. 2019

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ObjectiveTo 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.MethodsIn 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.ResultsOf 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.ConclusionsThis proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy.ClinicalTrials.gov identifierNCT00616148.Classification of evidenceThis study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.

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