How predictive are photosensitive epilepsy models as proof of principle trials for epilepsy?

Yuen, Eunice; Sims, John R.

doi:10.1016/j.seizure.2014.03.011

Cited by 29 publications

(29 citation statements)

References 19 publications

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“…All 13 patients showed reductions of the SPR by at least three steps in at least one eye condition on day 2 (drug) compared with day 1 (placebo), firmly establishing the PoC for BGG492 in the epilepsy indication. 9,14 The onset of the suppressive effect appeared to be between 1 and 2 h in our study population, which is in line with the PK profile in healthy volunteers (Novartis data on file). In terms of duration of effect, the SPR response and suppression of PPR was maintained in the BGG492 50-and 100-mg dose groups.…”

Section: Discussionsupporting

confidence: 85%

“…Nonetheless, the efficacy and safety findings with BGG492 in this study in epilepsy patients with an epileptiform reaction to intermittent photic stimulation are important and demonstrate promise for AMPA receptor antagonists as a class in the indication of epilepsy. 9,14 This is the first time an AMPA receptor antagonist has been tested in this human model of reduction of SPR.…”

Section: Discussionmentioning

confidence: 99%

“…9 Dose levels in which 50-100% of patients had a positive response were considered as efficacious doses (ED 50-100 ). The doses investigated in the human PoC trials were either close to or encompassed the minimally efficacious dose (MED) for patients with epilepsy in general.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9] The proof-of-concept (PoC) study described here is the first to examine the efficacy of BGG492 in a human model of photosensitive epilepsy.…”

mentioning

confidence: 99%

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Dose‐dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship

et al. 2015

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SUMMARYObjective: Examine the efficacy of a competitive a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonist, selurampanel (BGG492), in the human photostimulation model. Methods:Patients with epilepsy and a generalized epileptiform electroencephalography response to intermittent photic stimulation (photoparoxysmal response or PPR; diagnosed ≥6 months prior to initial study dosing) were enrolled in a phase II, multicenter, single-blind, within-subject, placebo-controlled proof-of-concept (PoC) study. PPR was used as a biomarker to assess the efficacy and safety of BGG492 in three cohorts (cohorts I-III received BGG492 50, 100, and 15 mg, respectively). Primary endpoints were to evaluate the efficacy of single oral BGG492 doses in abolishment of PPR or a relevant reduction of the standardized photoparoxysmal response (SPR), and to evaluate time of onset and duration of response. Secondary endpoints were to evaluate maximal SPR reduction, determine the pharmacokinetic profile of BGG492, explore the pharmacokinetic/pharmacodynamic relationship, and evaluate the safety and tolerability of BGG492.Results: Ten patients were enrolled, with three participating twice, that is, in two cohorts (n = 13). Treatment with BGG492 resulted in abolition of PPR in seven of 13 patients in a dose-dependent manner: three, three, and one patient in cohorts I-III, respectively. All patients showed treatment-related reductions of SPR range of at least three steps in at least one eye condition (eye closure, eyes closed, or eyes open). Generally, onset of the suppressive effect appeared to be within 1-2 h post-BGG492 dose and continued in three patients at the 50-and 100-mg doses for 29-33 h. Most common adverse events across the BGG492-treated groups were headache and nasopharyngitis (three patients each), followed by dizziness, fatigue, and diarrhea (two patients each).Significance: The dose-dependent positive effect of BGG492 on the PPR and SPR in patients with photosensitive epilepsy in this proof-of-concept study supports further investigation of AMPA receptor antagonists in large-scale phase III trials.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9] The proof-of-concept (PoC) study described here is the first to examine the efficacy of BGG492 in a human model of photosensitive epilepsy.…”

mentioning

confidence: 99%

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Dose‐dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship

et al. 2015

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“…H3R antagonists are progressing well in clinical trials in the field of epilepsy. Recently, pitolisant showed promising outcomes in proof-of-concept trials in a human photosensitivity model of epilepsy (Figure 10, Table 4) [108,163]. Pitolisant completed several clinical phase 3 trials for a number of indications and has been found to promote wakefulness effectiveness in patients with excessive daytime sleepiness associated with epilepsy (phase 3) (http://clinicaltrials.gov) (Figure 10, Table 4).…”

Section: Epilepsymentioning

confidence: 99%

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

Sadek

Saad

Sadeq

et al. 2016

Behavioural Brain Research

136

129

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Antiepileptic Drug Development

Schmidt¹

2015

The Treatment of Epilepsy

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How predictive are photosensitive epilepsy models as proof of principle trials for epilepsy?

Abstract: Photosensitive POP trials are a useful tool to quantitatively predict efficacy in epilepsy, and can be useful as early and informative indicators in anti-epileptic drug discovery and development.

Cited by 29 publications

References 19 publications

Dose‐dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship

Dose‐dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship

Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases

Antiepileptic Drug Development

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