title: Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy.
abstract: OBJECTIVE
  To assess the effects of ICA-105665, an agonist of neuronal Kv7 potassium channels, on epileptiform EEG discharges, evoked by intermittent photic stimulation (IPS), the so-called photoparoxysmal responses (PPRs) in patients with epilepsy.
  
  
  METHODS
  Male and female patients aged 18-60 years with reproducible PPRs were eligible for enrollment. The study was conducted as a single-blind, single-dose, multiple-cohort study. Four patients were enrolled in each of the first three cohorts. Six patients were enrolled in the fourth cohort and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS frequencies (steps) were used to determine the standard photosensitivity range (SPR) following placebo on day 1 and ICA-105665 on day 2. The SPR was quantified for three eye conditions (eyes closing, eyes closed, and eyes open), and the most sensitive condition was used for assessment of efficacy. A partial response was defined as a reduction in the SPR of at least three units at three separate time points following ICA-105665 compared to the same time points following placebo with no time points with more than three units of increase. Complete suppression was defined by no PPRs in any eye condition at one or more time points.
  
  
  RESULTS
  Six individual patients participated in the first three cohorts (100, 200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred in one patient at 100 mg, two patients receiving 400 mg ICA-105665 (complete abolishment of SPR occurred in one patient at 400 mg), and in four of six patients receiving 500 mg. The most common adverse events (AEs) were those related to the nervous system, and dizziness appeared to be the first emerging AE. The single patient in the 600 mg cohort developed a brief generalized seizure within 1 h of dosing, leading to the discontinuation of additional patients at this dose, per the predefined protocol stopping rules.
  
  
  CONCLUSIONS
  ICA-105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects.
authors.affiliation: Department of Medical Genetics, Utrecht University, Utrecht, The Netherlands. dkasteleijn@planet.nl
authors.forename: Dorotheé G A
authors.initials: DG
authors.lastname: Kasteleijn-Nolst Trenité
authors.forename: Victor
authors.initials: V
authors.lastname: Biton
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: French
authors.forename: Bassel
authors.initials: B
authors.lastname: Abou-Khalil
authors.forename: William E
authors.initials: WE
authors.lastname: Rosenfeld
authors.forename: Bree
authors.initials: B
authors.lastname: Diventura
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Moore
authors.forename: Seth V
authors.initials: SV
authors.lastname: Hetherington
authors.forename: Greg C
authors.initials: GC
authors.lastname: Rigdon
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004827:Epilepsy / Q000188:drug therapy* / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects*; D005260:Female; D006801:Humans; D051656:KCNQ Potassium Channels / Q000819:agonists* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010775:Photic Stimulation; D016037:Single-Blind Method; D013997:Time Factors; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D051656:KCNQ Potassium Channels
keywords: Epilepsy; ICA-105665; Ion channel; Kv7 potassium channel; Photoparoxysmal response; Photosensitivity; Proof of concept model