title: Dose-dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship.
abstract: OBJECTIVE
  Examine the efficacy of a competitive α-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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Child Neurology Division, Department of Pediatrics, Università "Sapienza" Roma, Rome, Italy.
authors.forename: Dorotheé
authors.initials: D
authors.lastname: Kasteleijn-Nolst Trenité
authors.affiliation: Department of General Epileptology, Bethel Epilepsy Centre, Bielefeld, Germany.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0001-8666-1640
authors.initials: C
authors.lastname: Brandt
authors.affiliation: Saxonian Epilepsy Center Radeberg, Radeberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayer
authors.affiliation: Department of Neurology, Epilepsy Center Hessen - Marburg, Philipps-University, Marburg, Germany.|Epilepsy Center Franfurt Rhein-Main, Department of Neurology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Rosenow
authors.affiliation: Neurology & Psychiatry Clinic, Wittnau, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmidt
authors.affiliation: Epilepsiezentrum Kork, Kehl-Kork, Germany.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Steinhoff
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Gardin
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Georges
authors.initials: G
authors.lastname: Imbert
authors.affiliation: Biogen Idec Inc., Cambridge, MA, U.S.A.
authors.forename: Donald
authors.initials: D
authors.lastname: Johns
authors.affiliation: Novartis Development, Basel, Switzerland.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Sagkriotis
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kucher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D020195:Epilepsy, Reflex / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010775:Photic Stimulation / Q000009:adverse effects*; D052999:Quinazolinones / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D052999:Quinazolinones; C000591013:selurampanel
keywords: Antiepileptic drugs; BGG492; Kainate; Photoparoxysmal; Selurampanel; α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid