The preclinical discovery and development of ezogabine for the treatment of epilepsy

Expert Opinion on Drug Discovery

Volumn 8, Issue 11, 2013, Pages 1429-1437

  Jankovic, Slobodan ^a   Ilickovic, Ivana ^a  

^a University of Kragujevac Medical Faculty   (Serbia)

Author keywords

Ezogabine; KCNQ potassium channels; Partial onset seizures; Pigment changes; Preclinical development; Retigabine; Urinary retention

Indexed keywords

CARBAMAZEPINE; DIAZEPAM; ETHOSUXIMIDE; ETIRACETAM; FLUPIRTINE; LAMOTRIGINE; PHENOBARBITAL; PLACEBO; POTASSIUM CHANNEL KCNQ; RETIGABINE; TOPIRAMATE; VALPROIC ACID;

ANTICONVULSANT ACTIVITY; ATAXIA; BINDING SITE; BLURRED VISION; BRAIN DISEASE; CARDIOTOXICITY; CONFUSION; CONVULSION; COORDINATION DISORDER; DIZZINESS; DOSE RESPONSE; DRUG DOSE INCREASE; DRUG DOSE TITRATION; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SAFETY; EPILEPSY; FATIGUE; HUMAN; HYPOKINESIA; LIP DISCOLORATION; LIVER TOXICITY; MAXIMUM TOLERATED DOSE; MOLECULAR BIOLOGY; MOTOR DYSFUNCTION; MUTAGENICITY; NAIL DISCOLORATION; NEPHROTOXICITY; NEUROTOXICITY; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PIGMENT DISORDER; PRIORITY JOURNAL; PSYCHOSIS; QT PROLONGATION; REVIEW; SKIN DISCOLORATION; SOMNOLENCE; TREATMENT OUTCOME; TREMOR; URINARY HESITANCY; URINE RETENTION;

ANIMALS; ANTICONVULSANTS; CARBAMATES; DRUG DISCOVERY; EPILEPSY; HUMANS; PHENYLENEDIAMINES; PRODUCT SURVEILLANCE, POSTMARKETING;

EID: 84886605873     PISSN: 17460441     EISSN: 1746045X     Source Type: Journal    
DOI: 10.1517/17460441.2013.837882     Document Type: Review

References (68)

1. Anand IS, Shah JS, Patel SK, Patel CN. Retigabine: a novel anticonvulsant drug. Indian J Pharmacol 2005;37: 340-1
2. Gunthorpe MJ, Large CH, Sankar R. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia 2012;53: 412-24. Excellent summation of knowledge about mechanism of action.
3. Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18: 25-9
4. Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998;18: 53-5
5. Wang HS, Pan Z, Shi W, et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 1998;282(5395): 1890-3
6. Zhou P, Yu H, Gu M, et al. Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels. Proc Natl Acad Sci USA 2013;110: 8726-31
7. Kaiboriboon K, Bakaki PM, Lhatoo SD, Koroukian S. Incidence and prevalence of treated epilepsy among poor health and low-income Americans. Neurology 2013;80: 1942-9
8. Lhatoo SD, Sander JW. Cause-specific mortality in epilepsy. Epilepsia 2005;46(Suppl 11): 36-9
9. La Vecchia C, Negri E. A review of epidemiological data on epilepsy, phenobarbital, and risk of liver cancer. Eur J Cancer Prev 2013;published online 12 March 2013; doi: 10.1097/CEJ.0b013e32836014c8
10. Nordentoft M. Prevention of suicide and attempted suicide in Denmark. Epidemiological studies of suicide and intervention studies in selected risk groups. Dan Med Bull 2007;54: 306-69
11. Téllez-Zenteno JF, Nguyen R, Hernádez-Ronquillo L. Injuries, accidents and mortality in epilepsy: a review of its prevalence risk factors and prevention. Rev Invest Clin 2010;62: 466-79
12. Pohlmann-Eden B, Weaver DF. The puzzle(s) of pharmacoresistant epilepsy. Epilepsia 2013;54(Suppl 2): 1-4
13. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51: 1069-77
14. Maehara T, Inaji M, Matsuura M. Surgical effects of focus resection for patients with intractable epilepsy. Neurol Med Chir (Tokyo) 2013;53: 281-6
15. Privitera M. Current challenges in the management of epilepsy. Am J Manag Care 2011;17(Suppl 7):S195-203
16. French JA, Gazzola DM. Antiepileptic drug treatment: new drugs and new strategies. Continuum (Minneap Minn) 2013;19(3 Epilepsy): 643-55
17. Gerlach AC, Krajewski JL. Antiepileptic drug discovery and development: what have we learned and where are we going? Pharmaceuticals 2010;3: 2884-99. Excellent review of development of antiepileptic drugs.
18. Barrese V, Miceli F, Soldovieri MV, et al. Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine. Clin Pharmacol 2010;2: 225-36
19. Wang X, Zhou H, Zheng J, et al. Identification and characterization of four process-related impurities in retigabine. J Pharm Biomed Anal 2012;71: 148-51
20. Lakshmi B, Saraswathi K, Reddy TV. Rp-hplc method development and validation for the analyisis of ezogabine in pharmaceutical dosage forms. Int J A Ps BMS 2012;1: 7-14
21. Ermer J. Validation in pharmaceutical analysis. Part I: an integrated approach. J Pharm Biomed Anal 2001;24: 755-67
22. Tatulian L, Delmas P, Abogadie FC, Brown DA. Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci 2001;21(15): 5535-45 .. Key study explaining mechanism of action of ezogabine.
23. Dupuis DS, Schrøder RL, Jespersen T, et al. Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352. Eur J Pharmacol 2002;437: 129-37
24. Wuttke TV, Seebohm G, Bail S, et al. The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol 2005;67: 1009-17. Key study explaining binding site for ezogabine.
25. Li P, Chen Z, Xu H, et al. The gating charge pathway of an epilepsy-associated potassium channel accommodates chemical ligands. Cell Res 2013;published online 25 June 2013; doi: 10.1038/cr.2013.82. Key study explaining binding site for ezogabine.
26. Rundfeldt C, Netzer R. Modulatory binding site in potassium channels for screening and finding new active ingredients. US6472165; 2002
27. Asta Medica Aktiengesellschaft. Pharmaceutically active 1,2,4-triaminobenzene derivatives, processes for their preparation and pharmaceutical compositions containing them. US5384330; 1995
28. Asta Medica Aktiengesellschaft. 1,2,4-triaminobenzene derivatives and processes for their preparation. EP0554543A2; 1993 .. Key patent for ezogabine.
29. Fitzgerald RN, Millar A, Fell Toczko J. Process for the preparation of retigabine. W02012098075A1; 2012
30. Szelenyi I, Brune K, Hermann R, Locher M. Combinations of Retigabine and Sodium Channel Inhibitors or Sodium Channel-Influencing Active Compounds for Treating Pains. US7799832; 2010
31. Asta Medica Aktiengesellschaft. Modifications of 2-amino-4-(4- fluorobenzylamino)-1- ethoxycarbonylaminobenzene, and process for their preparation. US5638151; 2003
32. Biljana Nadjsombati. Modified release formulation and methods of use. US20100323016; 2010
33. Rostock A, Tober C, Rundfeldt C, et al. D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res 1996;23: 211-23
34. Dailey JW, Cheong JH, Ko KH, et al. Anticonvulsant properties of D-20443 in genetically epilepsy-prone rats: prediction of clinical response. Neurosci Lett 1995;195: 77-80. Key pre-clinical efficacy trial.
35. Marescaux C, Micheletti G, Vergnes M, et al. A model of chronic spontaneous petit mal-like seizures in the rat: comparison with pentylenetetrazol-induced seizures. Epilepsia 1984;25: 326-31. Key pre-clinical efficacy trial.
36. Marescaux C, Vergnes M, Depaulis A. Genetic absence epilepsy in rats from Strasbourg - a review. J Neural Transm Suppl 1992;35: 37-69
37. Large CH, Sokal DM, Nehlig A, et al. The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: implications for clinical use. Epilepsia 2012;53: 425-36 .. Excellent review of pre-clinical studies with ezogabine.
38. de Sarro G, di Paola ED, Conte G, et al. Influence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice. Naunyn Schmiedebergs Arch Pharmacol 2001;363: 330-6 .. Key animal study showing adjunctive effect of ezogabine.
39. Tober C, Rostock A, Rundfeldt C, Bartsch R. D-23129: a potent anticonvulsant in the amygdala kindling model of complex partial seizures. Eur J Pharmacol 1996;303: 163-9
40. Mazarati A, Wu J, Shin D, et al. Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study. Epilepsia 2008;49: 1777-86
41. Smith MD, Adams AC, Saunders GW, et al. Phenytoin- and carbamazepine-resistant spontaneous bursting in rat entorhinal cortex is blocked by retigabine in vitro. Epilepsy Res 2007;74: 97-106
42. Straub H, Köhling R, Höhling J, et al. Effects of retigabine on rhythmic synchronous activity of human neocortical slices. Epilepsy Res 2001;44: 155-65
43. Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the Ninth Eilat Conference (EILAT IX). Epilepsy Res 2009;83: 1-43
44. McCallum LA, Pierce SL, England SK, et al. The contribution of Kv7 channels to pregnant mouse and human myometrial contractility. J Cell Mol Med 2011;15: 577-86
45. Löscher W, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices. Epilepsy Res 1991;9: 1-10
46. Summary Basis of Decision. Potiga-, Health Canada. 2012. Available from: http://www.hc-sc. gc.ca [Last accessed 13 July 2013]
47. Trobalt- (retigabine). Summary of Product Characteristics. Glaxo Group Ltd, at European Medicines Agency. Available from: http://www.ema.europa. eu/docs/en [Last accessed 13 July 2013]
48. Luszczki JJ, Wu JZ, Raszewski G, Czuczwar SJ. Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model. Naunyn Schmiedebergs Arch Pharmacol 2009;379: 163-79
49. Deeks ED. Retigabine (ezogabine): in partial-onset seizures in adults with epilepsy. CNS Drugs 2011;25: 887-900
50. French JA, Abou-Khalil BW, Leroy RF, et al. RESTORE 1/Study 301 Investigators. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology 2011;76: 1555-63 .. Key clinical trial for registration of ezogabine.
51. Brodie MJ, Lerche H, Gil-Nagel A, et al. RESTORE 2 Study Group. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology 2010;75: 1817-24 .. Key clinical trial for registration of ezogabine.
52. Porter RJ, Partiot A, Sachdeo R, et al. 205 Study Group. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology 2007;68: 1197-204 .. Key clinical trial for registration of ezogabine.
53. Porter RJ, Burdette DE, Gil-Nagel A, et al. Retigabine as adjunctive therapy in adults with partial-onset seizures: integrated analysis of three pivotal controlled trials. Epilepsy Res 2012;101: 103-12
54. Gil-Nagel A, Brodie MJ, Leroy R, et al. Safety and efficacy of ezogabine (retigabine) in adults with refractory partial-onset seizures: interim results from two ongoing open-label studies. Epilepsy Res 2012;102: 117-21
55. Harris JA, Murphy JA. Retigabine (ezogabine) as add-on therapy for partial-onset seizures: an update for clinicians. Ther Adv Chronic Dis 2011;2: 371-6
56. Yamada M, Welty TE. Ezogabine: an evaluation of its efficacy and safety as adjunctive therapy for partial-onset seizures in adults. Ann Pharmacother 2012;46: 1358-67
57. Ciliberto MA, Weisenberg JL, Wong M. Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy. Drug Healthc Patient Saf 2012;4: 81-6
58. Martyn-St James M, Glanville J, McCool R, et al. The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: a systematic review and indirect comparison. Seizure 2012;21: 665-78
59. Orhan G, Wuttke TV, Nies AT, et al. Retigabine/Ezogabine, a KCNQ/K(V) 7 channel opener: pharmacological and clinical data. Expert Opin Pharmacother 2012;13: 1807-16
60. Retigabine (Trobalt): indication restricted to last-line use, and new monitoring requirements after reports of pigment changes in ocular tissue, skin, lips or nails. 2013;6(12):A2
61. GlaxoSmithKline. Open-label, multiple dose study to evaluate the pharmacokinetics, safety, and tolerability of ezogabine/retigabine as adjunctive treatment in subjects aged from 12 years to less than 18 years with partial onset seizures or Lennox-Gastaut syndrome. ClinicalTrials.gov Web site. Bethesda, MD: National Library of Medicine. 2011. NLM identifier: NCT01494584 Available from: http://clinicaltrials.gov/ct2/show/NCT01494584?term=NCT01494584 [Last accessed 22 July 2013]
62. GlaxoSmithKline. RTG113388, a long-term, open-label safety extension study of retigabine/ezogabine in pediatric subjects with partial onset seizures (12 years old) and subjects with Lennox-Gastaut syndrome (12 years old). ClinicalTrials.gov Web site. Bethesda, MD: National Library of Medicine. 2012. NLM identifier: NCT01668654 Available from: http://clinicaltrials.gov/ct2/show/ NCT01668654?term=01668654&rank=1 [Last accessed 22 July 2013]
63. Chhim RF, Shelton CM, Christensen ML. Recent new drug approvals, part 2: drugs undergoing active clinical studies in children. J Pediatr Pharmacol Ther 2013;18: 14-38
64. GlaxoSmithKline. An Open Label, Randomised, Repeat Dose Study to Assess the Pharmacokinetic Performance of FiveEzogabine/Retigabine Modified Release (MR) Formulations at Steady State Compared to the Immediate Release (IR) Formulation. ClinicalTrials. gov Web site. Bethesda, MD: National Library of Medicine. 2012. NLM identifier: NCT01332513 Available from: http:// clinicaltrials.gov/ct2/show/NCT01332513?term=ezogabine&rank=7 [Last accessed 22 July 2013]
65. GlaxoSmithKline. Risk of Urinary Retention with Ezogabine. ClinicalTrials. gov Web site. Bethesda, MD: National Library of Medicine. 2012. NLM identifier: NCT01462656 Available from: http://clinicaltrials.gov/ct2/show/ NCT01462656?term=ezogabine&rank=21 [Last time accessed 22 July 2013]
66. López-Muñoz F, Alamo C. Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today. Curr Pharm Des 2009;15: 1563-86
67. López-Muñoz F, Alamo C, García-García P. The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. J Anxiety Disord 2011;25: 554-62
68. Pattnaik BR, Hughes BA. Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium. Am J Physiol Cell Physiol 2012;302:C821-33