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Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions

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Abstract

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox–Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes.

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References

  1. Richter T, Nestler-Parr S, Babela R, Khan ZM, Tesoro T, Molsen E, et al. Rare disease terminology and definitions-a systematic global review: report of the ISPOR Rare Disease Special Interest Group. Value Health. 2015;18(6):906–14. https://doi.org/10.1016/j.jval.2015.05.008.

    Article  PubMed  Google Scholar 

  2. Orphan Drug Act. 4th January 1983.

  3. EMA. 2000. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2000_141_cons-2009-07/reg_2000_141_cons-2009-07_en.pdf. Accessed 25 Oct 2019.

  4. FDA. https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/officeofscienceandhealthcoordination/ucm2018190.htm. Accessed 25 Oct 2019.

  5. NICE Citizens Council Report on Ultra Orphan Drugs. 2004.

  6. Luzzatto L, Hollak CEM, Cox TM, Schieppati A, Licht C, Kaariainen H, et al. Rare diseases and effective treatments: are we delivering? Lancet. 2015;385(9970):750–2. https://doi.org/10.1016/s0140-6736(15)60297-5.

    Article  PubMed  Google Scholar 

  7. Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, et al. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009;96(1):20–6. https://doi.org/10.1016/j.ymgme.2008.10.003.

    Article  CAS  PubMed  Google Scholar 

  8. Milne C-P, Ni W. The use of social media in orphan drug development. Clin Ther. 2017;39(11):2173–80. https://doi.org/10.1016/j.clinthera.2017.08.016.

    Article  PubMed  Google Scholar 

  9. Meekings KN, Williams CSM, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug Discov Today. 2012;17(13):660–4. https://doi.org/10.1016/j.drudis.2012.02.005.

    Article  PubMed  Google Scholar 

  10. Rosati A, Ilvento L, Lucenteforte E, Pugi A, Crescioli G, McGreevy KS, et al. Comparative efficacy of antiepileptic drugs in children and adolescents: a network meta-analysis. Epilepsia. 2018;59(2):297–314. https://doi.org/10.1111/epi.13981.

    Article  CAS  PubMed  Google Scholar 

  11. Nevitt SJ, Sudell M, Weston J, Tudur Smith C, Marson AG. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst Rev. 2017. https://doi.org/10.1002/14651858.cd011412.pub2.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Doring JH, Lampert A, Hoffmann GF, Ries M. Thirty years of orphan drug legislation and the development of drugs to treat rare seizure conditions: a cross sectional analysis. PLoS One. 2016. https://doi.org/10.1371/journal.pone.0161660.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ritter FJ, Leppik IE, Dreifuss FE, Rak I, Santilli N, Homzie R, et al. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox–Gastaut syndrome). N Engl J Med. 1993;328(1):29–33.

    Article  Google Scholar 

  14. Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. Lancet. 2000;356(9242):1638–42. https://doi.org/10.1016/s0140-6736(00)03157-3.

    Article  CAS  PubMed  Google Scholar 

  15. Depienne C, Trouillard O, Saint-Martin C, Gourfinkel-An I, Bouteiller D, Carpentier W, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet. 2009;46(3):183–91. https://doi.org/10.1136/jmg.2008.062323.

    Article  CAS  PubMed  Google Scholar 

  16. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017;376(21):2011–20. https://doi.org/10.1056/NEJMoa1611618.

    Article  CAS  PubMed  Google Scholar 

  17. Zogenix. https://zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-announces-positive-top-line-results-pivotal-phase-3. Accessed 25 Oct 2019.

  18. Zogenix https://zogenixinc.gcs-web.com/news-releases/news-release-details/zogenix-announces-positive-top-line-results-second-pivotal-phase. Accessed 25 Oct 2019.

  19. EMA. Orphan designation. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac0580b18a41. Accessed 25 Oct 2019.

  20. FDA. Designating an Orphan Product: Drugs and Biological Products. https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/default.htm. Accessed 25 Oct 2019.

  21. Public summary opinon on orphan designation. Everolimus for the treatment of tuberous sclerosis. EMA http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/08/WC500095727.pdf. Accessed 25 Oct 2019.

  22. EMA. 2017. https://www.ema.europa.eu/en/documents/orphan-review/recommendation-maintenance-orphan-designation-time-marketing-authorisation-brineura-cerliponase-alfa_en.pdf. Accessed 25 Oct 2019.

  23. Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, et al. The best evidence for progressive myoclonic epilepsy: a pathway to precision therapy. Seizure. 2019;71:247–57. https://doi.org/10.1016/j.seizure.2019.08.012.

    Article  PubMed  Google Scholar 

  24. Chipaux M, Szurhaj W, Vercueil L, Milh M, Villeneuve N, Cances C, et al. Epilepsy diagnostic and treatment needs identified with a collaborative database involving tertiary centers in France. Epilepsia. 2016;57(5):757–69. https://doi.org/10.1111/epi.13368.

    Article  PubMed  Google Scholar 

  25. Alexandre V, Capovilla G, Fattore C, Franco V, Gambardella A, Guerrini R, et al. Characteristics of a large population of patients with refractory epilepsy attending tertiary referral centers in Italy. Epilepsia. 2010;51(5):921–5. https://doi.org/10.1111/j.1528-1167.2009.02512.x.

    Article  PubMed  Google Scholar 

  26. Oguni H, Otsuki T, Kobayashi K, Inoue Y, Watanabe E, Sugai K, et al. Clinical analysis of catastrophic epilepsy in infancy and early childhood: results of the Far-East Asia Catastrophic Epilepsy (FACE) study group. Brain Dev. 2013;35(8):786–92. https://doi.org/10.1016/j.braindev.2013.02.004.

    Article  PubMed  Google Scholar 

  27. Nabbout R, Auvin S, Chiron C, Irwin J, Mistry A, Bonner N, et al. Development and content validation of a preliminary core set of patient- and caregiver-relevant outcomes for inclusion in a potential composite endpoint for Dravet Syndrome. Epilepsy Behav. 2018;78:232–42. https://doi.org/10.1016/j.yebeh.2017.08.029.

    Article  PubMed  Google Scholar 

  28. Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A. Expert opinion on the management of Lennox–Gastaut syndrome: treatment algorithms and practical consideration. Front Neurol. 2017. https://doi.org/10.3389/fneur.2017.00505.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dunne J, Rodriguez WJ, Murphy D, Beasley BN, Burckart GJ, Filie JD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):E1242–9. https://doi.org/10.1542/peds.2010-3487.

    Article  PubMed  Google Scholar 

  30. Shinnar S, Pellock JM. The trials and tribulations of pediatric drug trials. Neurology. 2005;65(9):1348–9. https://doi.org/10.1212/01.wnl.0000183475.81594.29.

    Article  PubMed  Google Scholar 

  31. EMA. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/05/WC500090218.pdf. Accessed 25 Oct 2019.

  32. EMA http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070043.pdf. Accessed 25 Oct 2019.

  33. American Academy of Pediatrics http://www.aappublications.org/news/2016/04/06/FDAUpdate040616. Accessed 25 Oct 2019.

  34. Arzimanoglou A, D’Cruz O, Nordli D, Shinnar S, Holmes GL. A review of the new antiepileptic drugs for focal-onset seizures in pediatrics: role of extrapolation. Pediatr Drugs. 2018;20(3):249–64. https://doi.org/10.1007/s40272-018-0286-0.

    Article  Google Scholar 

  35. Pellock JM, Carman WJ, Thyagarajan V, Daniels T, Morris DL, D’Cruz ON. Efficacy of antiepileptic drugs in adults predicts efficacy in children: a systematic review. Neurology. 2012;79(14):1482–9. https://doi.org/10.1212/WNL.0b013e31826d5ec0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. FDA. Drugs for treatment of partial onset seizures: full extrapolation of efficacy from adults to pediatric patients 2 years of age and older guidance for industry. 2019. https://www.fda.gov/media/130449/download. Accessed 25 Oct 2019.

  37. Rheims S, Cucherat M, Arzimanoglou A, Ryvlin P. Greater response to placebo in children than in adults: a systematic review and meta-analysis in drug-resistant partial epilepsy. PLoS Med. 2008;5(8):1223–37. https://doi.org/10.1371/journal.pmed.0050166.

    Article  Google Scholar 

  38. Sandler A. Placebo effects in developmental disabilities: Implications for research and practice. Ment Retard Dev Disabil Res Rev. 2005;11(2):164–70. https://doi.org/10.1002/mrdd.20065.

    Article  PubMed  Google Scholar 

  39. Fernandes R, Ferreira JJ, Sampajo C. The placebo response in studies of acute migraine. J Pediatr. 2008;152(4):527–33. https://doi.org/10.1016/j.jpeds.2007.09.024.

    Article  PubMed  Google Scholar 

  40. Goldenholz DM, Moss R, Scott J, Auh S, Theodore WH. Confusing placebo effect with natural history in epilepsy: a big data approach. Ann Neurol. 2015;78(3):329–36. https://doi.org/10.1002/ana.24470.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Auvin S, Irwin J, Abi-Aad P, Battersvy A. The problem of rarity: estimation of prevalence in rare disease. Value Health. 2018;21(5):501–7.

    Article  Google Scholar 

  42. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, Boas WV, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676–85. https://doi.org/10.1111/j.1528-1167.2010.02522.x.

    Article  PubMed  Google Scholar 

  43. Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512–21. https://doi.org/10.1111/epi.13709.

    Article  PubMed  PubMed Central  Google Scholar 

  44. http://epilepsyconsortium.org/. Accessed 25 Oct 2019.

  45. Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med. 2018;378(20):1888–97. https://doi.org/10.1056/NEJMoa1714631.

    Article  CAS  PubMed  Google Scholar 

  46. French JA, Krauss GL, Wechsler RT, Wang XF, DiVentura B, Brandt C, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology. 2015;85(11):950–7. https://doi.org/10.1212/wnl.0000000000001930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. French J, Kwan P, Fakhoury T, Pitman V, DuBrava S, Knapp L, et al. Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial. Neurology. 2014;82(7):590–7. https://doi.org/10.1212/wnl.0000000000000119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. French JA, Temkin NR, Shneker BF, Hammer AE, Caldwell PT, Messenheimer JA. Lamotrigine XR conversion to monotherapy: first study using a historical control group. Neurotherapeutics. 2012;9(1):176–84. https://doi.org/10.1007/s13311-011-0088-3.

    Article  CAS  PubMed  Google Scholar 

  49. French JA, Wang S, Warnock B, Temkin N. Historical control monotherapy design in the treatment of epilepsy. Epilepsia. 2010;51(10):1936–43. https://doi.org/10.1111/j.1528-1167.2010.02650.x.

    Article  CAS  PubMed  Google Scholar 

  50. Wechsler RT, Li G, French J, O’Brien TJ, D’Cruz O, Williams P, et al. Conversion to lacosamide monotherapy in the treatment of focal epilepsy: Results from a historical-controlled, multicenter, double-blind study. Epilepsia. 2014;55(7):1088–98. https://doi.org/10.1111/epi.12681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kaminska A, Ickowicz A, Plouin P, Bru MF, Dellatolas G, Dulac O. Delineation of cryptogenic Lennox–Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res. 1999;36(1):15–29. https://doi.org/10.1016/s0920-1211(99)00021-2.

    Article  CAS  PubMed  Google Scholar 

  52. Oguni H, Tanaka T, Hayashi K, Funatsuka M, Sakauchi M, Shirakawa S, et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics. 2002;33(3):122–32. https://doi.org/10.1055/s-2002-33675.

    Article  CAS  PubMed  Google Scholar 

  53. Perez J, Chiron C, Musial C, Rey E, Blehaut H, d’Athis JP, et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia. 1999;40(11):1618–26. https://doi.org/10.1111/j.1528-1157.1999.tb02048.x.

    Article  CAS  PubMed  Google Scholar 

  54. Kassaie B, Chiron C, Augier S, Cucherat M, Rey E, Gueyffier F, et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia. 2008;49(2):343–8. https://doi.org/10.1111/j.1528-1167.2007.01423x.

    Article  Google Scholar 

  55. McTague A, Howell KB, Cross JH, Kurian MA, Scheffer IE. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol. 2016;15(3):304–16. https://doi.org/10.1016/s1474-4422(15)00250-1.

    Article  PubMed  Google Scholar 

  56. Baraban SC, Dinday MT, Hortopan GA. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun. 2013. https://doi.org/10.1038/ncomms3410.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sourbron J, Schneider H, Kecskes A, Liu YS, Buening EM, Lagae L, et al. Serotonergic modulation as effective treatment for Dravet syndrome in a zebrafish mutant model. ACS Chem Neurosci. 2016;7(5):588–98. https://doi.org/10.1021/acschemneuro.5b00342.

    Article  CAS  PubMed  Google Scholar 

  58. Zhang YF, Kecskes A, Copmans D, Langlois M, Crawford AD, Ceulemans B, et al. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: inhibition of epileptic seizures by the serotonin agonist fenfluramine. PLoS One. 2015. https://doi.org/10.1371/journal.pone.0125898.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Heilker R, Traub S, Reinhardt P, Scholer HR, Sterneckert J. iPS cell derived neuronal cells for drug discovery. Trends Pharmacol Sci. 2014;35(10):510–9. https://doi.org/10.1016/j.tips.2014.07.003.

    Article  CAS  PubMed  Google Scholar 

  60. Chong PF, Nakamura R, Saitsu H, Matsumoto N, Kira R. Ineffective quinidine therapy in early onset epileptic encephalopathy with KCNT1 mutation. Ann Neurol. 2016;79(3):502–3. https://doi.org/10.1002/ana.24598.

    Article  CAS  PubMed  Google Scholar 

  61. Mikati MA, Jiang YH, Carboni M, Shashi V, Petrovski S, Spillmann R, et al. Quinidine in the treatment of KCNT1-positive epilepsies. Ann Neurol. 2015;78(6):995–9. https://doi.org/10.1002/ana.24520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rensing N, Han LR, Wong M. Intermittent dosing of rapamycin maintains antiepileptogenic effects in a mouse model of tuberous sclerosis complex. Epilepsia. 2015;56(7):1088–97. https://doi.org/10.1111/epi.13031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63(4):444–53. https://doi.org/10.1002/ana.21331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nobbout R, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056):2153–63. https://doi.org/10.1016/s0140-6736(16)31419-2.

    Article  CAS  PubMed  Google Scholar 

  65. Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E, Minlebaev M, et al. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat Commun. 2014. https://doi.org/10.1038/ncomms5563.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Zhang B, Zou J, Rensing NR, Yang MH, Wong M. Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol Dis. 2015;80:70–9. https://doi.org/10.1016/j.nbd.2015.04.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. TSC alliance. https://www.tsalliance.org/researchers/preclinical-consortium/. Accessed 25 Oct 2019.

  68. Auvin S, Pineda E, Shin D, Gressens P, Mazarati A. Novel animal models of pediatric epilepsy. Neurotherapeutics. 2012;9(2):245–61. https://doi.org/10.1007/s13311-012-0119-8.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Auvin S, Cilio MR, Vezzani A. Current understanding and neurobiology of epileptic encephalopathies. Neurobiol Dis. 2016;92:72–89. https://doi.org/10.1016/j.nbd.2016.03.007.

    Article  CAS  PubMed  Google Scholar 

  70. Plotkin MD, Snyder EY, Hebert SC, Delpire E. Expression of the Na-K-2Cl cotransporter is developmentally regulated in postnatal rat brains: a possible mechanism underlying GABA’s excitatory role in immature brain. J Neurobiol. 1997;33(6):781–95.

    Article  CAS  Google Scholar 

  71. Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, et al. The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397(6716):251–5. https://doi.org/10.1038/16697.

    Article  CAS  PubMed  Google Scholar 

  72. Ben-Ari Y. Excitatory actions of gaba during development: the nature of the nurture. Nat Rev Neurosci. 2002;3(9):728–39. https://doi.org/10.1038/nrn920.

    Article  CAS  PubMed  Google Scholar 

  73. Farrant M, Kaila K. The cellular, molecular and ionic basis of GABA(A) receptor signalling. Prog Brain Res. 2007;160:59–87. https://doi.org/10.1016/S0079-6123(06)60005-8.

    Article  CAS  PubMed  Google Scholar 

  74. Galanopoulou AS. Dissociated gender-specific effects of recurrent seizures on GABA signaling in CA1 pyramidal neurons: role of GABA(A) receptors. J Neurosci. 2008;28(7):1557–67. https://doi.org/10.1523/JNEUROSCI.5180-07.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Galanopoulou AS. GABA(A) receptors in normal development and seizures: friends or foes? Curr Neuropharmacol. 2008;6(1):1–20. https://doi.org/10.2174/157015908783769653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pressler RM, Boylan GB, Marlow N, Blennow M, Chiron C, Cross JH, et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol. 2015;14(5):469–77. https://doi.org/10.1016/s1474-4422(14)70303-5.

    Article  CAS  PubMed  Google Scholar 

  77. Bumetanide US study. https://www.clinicaltrials.gov/ct2/show/NCT00830531?cond=bumetanide&draw=1&rank=6. Accessed 25 Oct 2019.

  78. Mullier B, Wolff C, Sands ZA, Ghisdal P, Muglia P, Kaminski RM, et al. GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors. Neuropharmacology. 2017;123:322–31. https://doi.org/10.1016/j.neuropharm.2017.05.017.

    Article  CAS  PubMed  Google Scholar 

  79. Schlumberger E, Chavez F, Palacios L, Rey E, Pajot N, Dulac O. Lamotrigine in treatment of 120 children with epilepsy. Epilepsia. 1994;35(2):359–67. https://doi.org/10.1111/j.1528-1157.1994.tb02445.x.

    Article  CAS  PubMed  Google Scholar 

  80. Chiron C, Dulac O, Beaumont D, Palacios L, Pajot N, Mumford J. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol. 1991;6:S52–9.

    Article  Google Scholar 

  81. Chiron C, Kassai B, Dulac O, Pons G, Nabbout R. A revisited strategy for antiepileptic drug development in children designing an initial exploratory step. CNS Drugs. 2013;27(3):185–95. https://doi.org/10.1007/s40263-012-0035-9.

    Article  CAS  PubMed  Google Scholar 

  82. Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39(5):508–12. https://doi.org/10.1111/j.1528-1157.1998.tb01413.x.

    Article  CAS  PubMed  Google Scholar 

  83. Fehr S, Wilson M, Downs J, Williams S, Murgia A, Sartori S, et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet. 2013;21(3):266–73. https://doi.org/10.1038/ejhg.2012.156.

    Article  CAS  PubMed  Google Scholar 

  84. Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gerard M, et al. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia. 2008;49(6):1027–37. https://doi.org/10.1111/j.1528-1167.2007.01520.x.

    Article  CAS  PubMed  Google Scholar 

  85. Klein KM, Yendle SC, Harvey AS, Antony JH, Wallace G, Bienvenu T, et al. A distinctive seizure type in patients with CDKL5 mutations: hyepmotor-tonic-sapsms sequence. Neurology. 2011;76(16):1436–8.

    Article  CAS  Google Scholar 

  86. Melani F, Mei D, Pisano T, Savasta S, Franzoni E, Ferrari AR, et al. CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life. Dev Med Child Neurol. 2011;53(4):354–60. https://doi.org/10.1111/j.1469-8749.2010.03889.x.

    Article  PubMed  Google Scholar 

  87. Muller A, Helbig I, Jansen C, Bast T, Guerrini R, Jahn J, et al. Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy. Eur J Paediatr Neurol. 2016;20(1):147–51. https://doi.org/10.1016/j.ejpn.2015.09.001.

    Article  CAS  PubMed  Google Scholar 

  88. Trinka E, Brigo F. Antiepileptogenesis in humans: disappointing clinical evidence and ways to move forward. Curr Opin Neurol. 2014;27(2):227–35. https://doi.org/10.1097/wco.0000000000000067.

    Article  CAS  PubMed  Google Scholar 

  89. Lux AL, Osborne JP. A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: Consensus statement of the west Delphi group. Epilepsia. 2004;45(11):1416–28. https://doi.org/10.1111/j.0013-9580.2004.02404.x.

    Article  PubMed  Google Scholar 

  90. Glauser TA, Cnaan A, Shinnar S, Hirtz DG, Dlugos D, Masur D, et al. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med. 2010;362(9):790–9. https://doi.org/10.1056/NEJMoa0902014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. French JA, Gil-Nagel A, Malerba S, Kramer L, Kumar D, Bagiella E. Time to prerandomization monthly seizure count in perampanel trials: a novel epilepsy endpoint. Neurology. 2015;84(20):2014–20. https://doi.org/10.1212/WNL.0000000000001585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Auvin S, French J, Dlugos D, Knupp K, Perucca E, Arzimanoglou A, et al. Novel study design to assess the efficacy and tolerability of antiseizure medications for focal-onset seizures in infants and young children: a consensus document from the regulatory task force and the pediatric commission of the International League against Epilepsy (ILAE), in collaboration with the Pediatric Epilepsy Research Consortium (PERC). Epilepsia Open. 2019. https://doi.org/10.1002/epi4.12356.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Auvin S, Williams B, McMurray R, Kumar D, Perdomo C, Malhotra M. Novel seizure outcomes in patients with Lennox–Gastaut syndrome: post hoc analysis of seizure-free days in rufinamide study 303. Epilepsia Open. 2019;4(2):275–80. https://doi.org/10.1002/epi4.12314.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Motte J, Trevathan E, Arvidsson JFV, Barrera MN, Mullens EL, Manasco P, et al. Lamotrigin for generalized seizures associated with the Lennox–Gastaut syndrome. N Engl J Med. 1997;337(25):1807–12. https://doi.org/10.1056/nejm199712183372504.

    Article  CAS  PubMed  Google Scholar 

  95. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G, et al. A double-blind, randomized trial of topiramate in Lennox–Gastaut syndrome. Neurology. 1999;52(9):1882–7. https://doi.org/10.1212/wnl.52.9.1882.

    Article  CAS  PubMed  Google Scholar 

  96. Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA, Investigators OVS. Randomized, phase III study results of clobazam in Lennox–Gastaut syndrome. Neurology. 2011;77(15):1473–81. https://doi.org/10.1212/WNL.0b013e318232de76.

    Article  CAS  PubMed  Google Scholar 

  97. Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology. 2008;70(21):1950–8. https://doi.org/10.1212/01.wnl.0000303813.95800.0d.

    Article  CAS  PubMed  Google Scholar 

  98. Thiele EA, Marsh ED, French JA. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial (vol 391, pg 1085, 2018). Lancet. 2018;391(10125):1022.

    Article  Google Scholar 

  99. de Calbiac H, Dabacan A, Marsan E, Tostivint H, Devienne G, Ishida S, et al. Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish. Ann Clin Transl Neurol. 2018;5(5):510–23. https://doi.org/10.1002/acn3.542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ogden KK, Chen W, Swanger SA, McDaniel MJ, Fan LZ, Hu C, et al. Molecular mechanism of disease-associated mutations in the Pre-M1 helix of NMDA receptors and potential rescue pharmacology. PLoS Genet. 2017. https://doi.org/10.1371/journal.pgen.1006536.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Marwick K, Skehel P, Hardingham G, Wyllie D. Effect of a GRIN2A de novo mutation associated with epilepsy and intellectual disability on NMDA receptor currents and Mg(2+) block in cultured primary cortical neurons. Lancet (London, England). 2015;385(Suppl 1):S65-S. https://doi.org/10.1016/s0140-6736(15)60380-4.

    Article  Google Scholar 

  102. Pierson TM, Yuan H, Marsh ED, Fuentes-Fajardo K, Adams DR, Markello T, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1(3):190–8. https://doi.org/10.1002/acn3.39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Milligan CJ, Li M, Gazina EV, Heron SE, Nair U, Trager C, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014;75(4):581–90. https://doi.org/10.1002/ana.24128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Numis A, Nair U, Datta A, Sands T, Oldham M, Patel A, et al. Lack of response to quinidine in KCNT1-related neonatal epilepsy. Epilepsia. 2018.

  105. Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76(3):457–61. https://doi.org/10.1002/ana.24229.

    Article  CAS  PubMed  Google Scholar 

  106. Mullen SA, Carney PW, Roten A, Ching M, Lightfoot PA, Churilov L, et al. Precision therapy for epilepsy due to KCNT1 mutations: a randomized trial of oral quinidine. Neurology. 2018;90(1):E67–72. https://doi.org/10.1212/wnl.0000000000004769.

    Article  CAS  PubMed  Google Scholar 

  107. Stas JI, Bocksteins E, Jensen CS, Schmitt N, Snyders DJ. The anticonvulsant retigabine suppresses neuronal K(V)2-mediated currents. Sci Rep. 2016. https://doi.org/10.1038/srep35080.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Kalappa BI, Soh H, Duignan KM, Furuya T, Edwards S, Tzingounis AV, et al. Potent KCNQ2/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus. J Neurosci. 2015;35(23):8829–42. https://doi.org/10.1523/jneurosci.5176-14.2015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ihara Y, Tomonoh Y, Deshimaru M, Zhang B, Uchida T, Ishii A, et al. Retigabine, a K(v)7.2/K(v)7.3-channel opener, attenuates drug-induced seizures in knock-in mice harboring Kcnq2 mutations. PLoS One. 2016. https://doi.org/10.1371/journal.pone.0150095.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Pisano T, Numis AL, Heavin SB, Weckhuysen S, Angriman M, Suls A, et al. Early and effective treatment of KCNQ2 encephalopathy. Epilepsia. 2015;56(5):685–91. https://doi.org/10.1111/epi.12984.

    Article  CAS  PubMed  Google Scholar 

  111. Sands TT, Balestri M, Bellini G, Mulkey SB, Danhaive O, Bakken EH, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia. 2016;57(12):2019–30. https://doi.org/10.1111/epi.13596.

    Article  CAS  PubMed  Google Scholar 

  112. Anderson LL, Thompson CH, Hawkins NA, Nath RD, Petersohn AA, Rajamani S, et al. Antiepileptic activity of preferential inhibitors of persistent sodium current. Epilepsia. 2014;55(8):1274–83. https://doi.org/10.1111/epi.12657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Thompson CH, Hawkins NA, Kearney JA, George AL. CaMKII modulates sodium current in neurons from epileptic Scn2a mutant mice. Proc Natl Acad Sci USA. 2017;114(7):1696–701. https://doi.org/10.1073/pnas.1615774114.

    Article  CAS  PubMed  Google Scholar 

  114. Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain. 2017;140:1316–36. https://doi.org/10.1093/brain/awx054.

    Article  PubMed  Google Scholar 

  115. Atkin TA, Maher CM, Gerlach AC, Gay BC, Antonio BM, Santos SC, et al. A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy. Epilepsia. 2018;59(4):802–13. https://doi.org/10.1111/epi.14037.

    Article  CAS  PubMed  Google Scholar 

  116. Baker EM, Thompson CH, Hawkins NA, Wagnon JL, Wengert ER, Patel MK, et al. The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy. Epilepsia. 2018;59(6):1166–76. https://doi.org/10.1111/epi.14196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Boerma RS, Braun KP, van den Broek MPH, van Berkestijn FMC, Swinkels ME, Hagebeuk EO, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: a molecular neuropharmacological approach (vol 13, pg 192, 2016). Neurotherapeutics. 2016;13(1):238. https://doi.org/10.1007/s13311-015-0386-2.

    Article  PubMed  Google Scholar 

  118. Abs E, Goorden SMI, Schreiber J, Overwater IE, Hoogeveen-Westerveld M, Bruinsma CF, et al. TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice. Ann Neurol. 2013;74(4):569–79. https://doi.org/10.1002/ana.23943.

    Article  CAS  PubMed  Google Scholar 

  119. Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of Tuberous Sclerosis Complex. Hum Mol Genet. 2011;20(3):445–54. https://doi.org/10.1093/hmg/ddq491.

    Article  CAS  PubMed  Google Scholar 

  120. Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74(5):679–87. https://doi.org/10.1002/ana.23960.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Work conducted by JHC is supported by the NIHR GOSH BRC. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Author notes

  1. Rafal M. Kaminski

    Present address: Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland

Authors and Affiliations

  1. PROTECT, INSERM U1141, Université de Paris, Paris, France

    Stéphane Auvin & Catherine Chiron

  2. Service de Neurologie Pédiatrique, AP-HP, Hôpital Universitaire Robert-Debré, 48, Boulevard Sérurier, 75935, Paris Cedex 19, France

    Stéphane Auvin

  3. UCB Pharma, Braine-l’Alleud, Belgium

    Andreja Avbersek, Rafal M. Kaminski & Pierandrea Muglia

  4. The Kork Epilepsy Center, Kehl-Kork, Germany

    Thomas Bast

  5. Medical Faculty of the University of Freiburg, Freiburg, Germany

    Thomas Bast

  6. Service de Neurologie Pédiatrique, AP-HP, Hôpital Necker-Enfanst Malades, Paris, France

    Catherine Chiron

  7. Neuroscience Department, Children’s Hospital Anna Meyer-University of Florence, Florence, Italy

    Renzo Guerrini

  8. Department Development and Regeneration, Section Paediatric Neurology, University Hospitals, University of Leuven, Leuven, Belgium

    Lieven Lagae

  9. UCL NIHR BRC Great Ormond Street Institute of Child Health, London, UK

    J. Helen Cross

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Funding

UCB Pharma has supported the meeting of the experts in June 2017.

Conflict of interest

Stéphane Auvin has served as consultant or received honoraria for lectures from Advicenne Pharma, Biocodex, Eisai, GW Pharma, Novartis, Nutricia, Shire, UCB Pharma, Ultragenyx, Zogenix. He has been investigator for clinical trials for Advicenne Pharma, Eisai, UCB Pharma and Zogenix. Andreja Avbersek and Pierandrea Muglia are full time employees of UCB Pharma. Rafal Kaminski was an employee of UCB Pharma during the time this analysis was completed. Thomas Bast has participated as a clinical investigator or DMC member for Eisai, Marinus, Novartis, Nutricia and UCB Pharma. He has been a member of advisory boards and/or speaker for BIAL, Biocodex, Eisai, Desitin Arzneimittel GmbH, GW Pharmaceuticals, Shire, UCB Pharma and Zogenix. Catherine Chiron has been member of advisory boards and/or speaker for BIAL, Biocodex, UCB Pharma and Zogenix. J. Helen Cross has participated as a clinical investigator for GW Pharma, Marinus Pharmaceuticals, Vitaflo and Zogenyx. She has been a member of advisory boards and speaker for Eisai, GW Pharma, Nutricia and Zogenix. All renumeration has been made to her department. Lieven Lagae is a member of an advisory board and invited speaker for Epihunter, Livanova, UCB Pharma, Shire and Zogenix. Renzo Guerrini received honoraria from Biocodex, Eisai Inc., UCB Pharma, ValueBox, ViroPharma, Zogenyx and research support from the Italian Ministry of Health, the European Community Sixth and Seventh Framework Thematic Priority Health, the Italian Ministry of Education, University and Research, the Tuscany Region, the Telethon Foundation, the Mariani Foundation, and The Italian Association for Epilepsy.

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Auvin, S., Avbersek, A., Bast, T. et al. Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions. Drugs 79, 1917–1935 (2019). https://doi.org/10.1007/s40265-019-01223-9

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