Current and future pharmacotherapy options for drug-resistant epilepsy

References

• de Boer HM, Mula M, Sander JW. The global burden and stigma of epilepsy. Epilepsy Behav. 2008;12:540–546.
   PubMed Web of Science ®Google Scholar
• Klein P, Tyrlikova I. No prevention or cure of epilepsy as yet. Neuropharmacology. 2020;168:107762.
   PubMed Web of Science ®Google Scholar
• Perucca E, Brodie MJ, Kwan P, et al. 30 years of second-generation antiseizure medications: impact and future perspectives. Lancet Neurol. 2020;19:544–556.
   PubMed Web of Science ®Google Scholar
• Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78:1548–1554.
   PubMed Web of Science ®Google Scholar
• Chen Z, Brodie MJ, Liew D, et al. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol. 2018;75:279–286.
   PubMed Web of Science ®Google Scholar
• Rugg-Gunn F, Miserocchi A, McEvoy A. Epilepsy surgery. Pract Neurol. 2020;20:4–14.
   PubMedGoogle Scholar
• Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345:311–318.
   PubMed Web of Science ®Google Scholar
• Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: assessing the public health burden. Epilepsia. 2014;55:1479–1485.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Spruill T, Thurman D, et al. Recognizing and preventing epilepsy-related mortality: a call for action. Neurology. 2016;86:779–786.
   PubMed Web of Science ®Google Scholar
• 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;51:1069–1077.
   PubMed Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Koepp MJ, et al. report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): I. Drugs in preclinical and early clinical development. Epilepsia 2022.
   Google Scholar
• Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): II. Drugs in more advanced clinical development. Epilepsia 2022.
   Google Scholar
• Li Y, Zeng Y, Mu J, et al. The efficacy and safety of adjunctive perampanel for the treatment of refractory focal-onset seizures in patients with epilepsy: a meta-analysis. Epilepsia Open. 2022;7:271–279.
   PubMedGoogle Scholar
• Mahajan SS, Prakash A, Sarma P, et al. Efficacy, tolerability and safety of perampanel in population with pharmacoresistant focal seizures: a systematic review and meta-analysis. Epilepsy Res. 2022;182:106895.
   PubMed Web of Science ®Google Scholar
• Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist. Epilepsia. 2015;56:12–27.
   PubMed Web of Science ®Google Scholar
• Ettinger AB, LoPresti A, Yang H, et al. Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel. Epilepsia. 2015;56:1252–1263.
   PubMed Web of Science ®Google Scholar
• Andres E, Kerling F, Hamer H, et al. Behavioural changes in patients with intellectual disability treated with perampanel. Acta Neurol Scand. 2017;136:645–653.
   PubMed Web of Science ®Google Scholar
• Bresnahan R, Panebianco M, Marson AG. Brivaracetam add-on therapy for drug-resistant epilepsy. Cochrane Database Syst Rev. 2019;3:CD011501.
   PubMedGoogle Scholar
• Strzelczyk A, Kay L, Bauer S, et al. Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus. Epilepsia. 2018;59:1549–1556.
   PubMed Web of Science ®Google Scholar
• Ben-Menachem E, Mameniskiene R, Quarato PP, et al. Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies. Neurology. 2016;87:314–323.
   PubMed Web of Science ®Google Scholar
• Yates SL, Fakhoury T, Liang W, et al. An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epilepsy Behav. 2015;52:165–168.
   PubMed Web of Science ®Google Scholar
• Hirsch M, Hintz M, Specht A, et al. Tolerability, efficacy and retention rate of Brivaracetam in patients previously treated with Levetiracetam: a monocenter retrospective outcome analysis. Seizure. 2018;61:98–103.
   PubMed Web of Science ®Google Scholar
• Wiegand G, May TW, Ostertag P, et al. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol. 2013;17:631–638.
   PubMed Web of Science ®Google Scholar
• Citraro R, Leo A, Constanti A, et al. mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis. Pharmacol Res. 2016;107:333–343.
   PubMed Web of Science ®Google Scholar
• Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 2013;74:679–687.
   PubMed Web of Science ®Google Scholar
• Krueger DA, Wilfong AA, Mays M, et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology. 2016;87:2408–2415.
   PubMed Web of Science ®Google Scholar
• French JA, Lawson JA, Yapici Z, 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;388:2153–2163.
   PubMed Web of Science ®Google Scholar
• Curatolo P, Franz DN, Lawson JA, et al. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Health. 2018;2:495–504.
   PubMedGoogle Scholar
• Bakas T, van Nieuwenhuijzen PS, Devenish SO, et al. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res. 2017;119:358–370.
   PubMed Web of Science ®Google Scholar
• Ibeas Bih C, Chen T, Nunn AV, et al. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12:699–730.
   PubMed Web of Science ®Google Scholar
• Billakota S, Devinsky O, Marsh E. Cannabinoid therapy in epilepsy. Curr Opin Neurol. 2019;32:220–226.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270–278.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–2020.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018;90:e1204–e1211.
   PubMed Web of Science ®Google Scholar
• Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–1096.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Patel AD, Cross JH, et al. Effect of cannabidiol on drop seizures in the lennox-gastaut syndrome. N Engl J Med. 2018;378:1888–1897.
   PubMed Web of Science ®Google Scholar
• Miller I, Scheffer IE, Gunning B, et al. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome: a randomized clinical trial. JAMA Neurol. 2020;77:613–621.
   PubMed Web of Science ®Google Scholar
• Laux LC, Bebin EM, Checketts D, et al. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: expanded access program results. Epilepsy Res. 2019;154:13–20.
   PubMed Web of Science ®Google Scholar
• Devinsky O, Nabbout R, Miller I, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia. 2019;60:294–302.
   PubMed Web of Science ®Google Scholar
• Privitera M, Bhathal H, Wong M, et al. Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: analysis from two randomized controlled trials. Epilepsia. 2021;62:1130–1140.
   PubMed Web of Science ®Google Scholar
• Madan Cohen J, Checketts D, Dunayevich E, et al. Time to onset of cannabidiol treatment effects in Dravet syndrome: analysis from two randomized controlled trials. Epilepsia. 2021;62:2218–2227.
   PubMed Web of Science ®Google Scholar
• Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia. 2016;57:1617–1624.
   PubMed Web of Science ®Google Scholar
• Thiele EA, Bebin EM, Bhathal H, et al. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex: a placebo-controlled randomized clinical trial. JAMA Neurol. 2021;78:285–292.
   PubMed Web of Science ®Google Scholar
• Thiele EA, Bebin EM, Filloux F, et al. Long-term cannabidiol treatment for seizures in patients with tuberous sclerosis complex: an open-label extension trial. Epilepsia. 2022;63:426–439.
   PubMed Web of Science ®Google Scholar
• Weinstock A, Bebin EM, Checketts D, et al. Long-term Efficacy and Safety of Cannabidiol (CBD) in patients with tuberous sclerosis complex (TSC): 4-year results from the expanded access program (EAP) (2405). Neurology. 2021;96:2405.
   Google Scholar
• Samanta D. A scoping review on cannabidiol therapy in tuberous sclerosis: current evidence and perspectives for future development. Epilepsy Behav. 2022;128:108577.
   PubMed Web of Science ®Google Scholar
• Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58:1586–1592.
   PubMed Web of Science ®Google Scholar
• Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–1251.
   PubMed Web of Science ®Google Scholar
• Bialer M, Perucca E. Does cannabidiol have antiseizure activity independent of its interactions with clobazam? An appraisal of the evidence from randomized controlled trials. Epilepsia. 2020;61:1082–1089.
   PubMed Web of Science ®Google Scholar
• Sharma R, Nakamura M, Neupane C, et al. Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate. Eur J Pharmacol. 2020;879:173117.
   PubMed Web of Science ®Google Scholar
• Guignet M, Campbell A, White HS. Cenobamate (XCOPRI): can preclinical and clinical evidence provide insight into its mechanism of action? Epilepsia. 2020;61:2329–2339.
   PubMed Web of Science ®Google Scholar
• Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology. 2020;94:e2311–e2322.
   PubMed Web of Science ®Google Scholar
• Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. Lancet Neurol. 2020;19:38–48.
   PubMed Web of Science ®Google Scholar
• Sperling MR, Klein P, Aboumatar S, et al. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study. Epilepsia. 2020;61:1099–1108.
   PubMed Web of Science ®Google Scholar
• Lattanzi S, Trinka E, Zaccara G, et al. Adjunctive cenobamate for focal-onset seizures in adults: a systematic review and meta-analysis. CNS Drugs. 2020;34:1105–1120.
   PubMed Web of Science ®Google Scholar
• Sander JW, Rosenfeld WE, Halford JJ, et al. Long-term individual retention with cenobamate in adults with focal seizures: pooled data from the clinical development program. Epilepsia. 2022;63:139–149.
   PubMed Web of Science ®Google Scholar
• Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337:581–588.
   PubMed Web of Science ®Google Scholar
• Gogou M, Cross JH. Fenfluramine as antiseizure medication for epilepsy. Dev Med Child Neurol. 2021;63:899–907.
   PubMed Web of Science ®Google Scholar
• Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394:2243–2254.
   PubMed Web of Science ®Google Scholar
• Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77:300–308.
   PubMed Web of Science ®Google Scholar
• Lagae L, Schoonjans AS, Gammaitoni AR, et al. A pilot, open-label study of the effectiveness and tolerability of low-dose ZX008 (fenfluramine HCl) in Lennox-Gastaut syndrome. Epilepsia. 2018;59:1881–1888.
   PubMed Web of Science ®Google Scholar
• Pong AW, Ross J, Tyrlikova I, et al. Epilepsy: expert opinion on emerging drugs in phase 2/3 clinical trials. Expert Opin Emerg Drugs. 2022;27:75–90.
   PubMed Web of Science ®Google Scholar
• Sperling MR, Klein P, Tsai J. Randomized, double-blind, placebo-controlled phase 2 study of ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures. Epilepsia. 2017;58:558–564.
   PubMed Web of Science ®Google Scholar
• Lamb YN. Ganaxolone: first Approval. Drugs. 2022;82:933–940.
   PubMedGoogle Scholar
• Knight EMP, Amin S, Bahi-Buisson N, et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2022;21:417–427.
   PubMed Web of Science ®Google Scholar
• Garriga-Canut M, Schoenike B, Qazi R, et al. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat Neurosci. 2006;9:1382–1387.
   PubMed Web of Science ®Google Scholar
• Stafstrom CE, Ockuly JC, Murphree L, et al. Anticonvulsant and antiepileptic actions of 2-deoxy-D-glucose in epilepsy models. Ann Neurol. 2009;65:435–447.
   PubMed Web of Science ®Google Scholar
• Lian XY, Khan FA, Stringer JL. Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats. J Neurosci. 2007;27:12007–12011.
   PubMed Web of Science ®Google Scholar
• Loscher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res. 2016;126:157–184.
   PubMed Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: a summary of the fifteenth Eilat conference on new antiepileptic drugs and devices (EILAT XV). I. Drugs in preclinical and early clinical development. Epilepsia 2020; 61:2340–2364.
   Google Scholar
• Huang BX, Hu X, Kwon HS, et al. Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding. Commun Biol. 2020;3:109.
   PubMed Web of Science ®Google Scholar
• Kim HY, Spector AA. N-Docosahexaenoylethanolamine: a neurotrophic and neuroprotective metabolite of docosahexaenoic acid. Mol Aspects Med. 2018;64:34–44.
   PubMed Web of Science ®Google Scholar
• Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361:31–39.
   PubMed Web of Science ®Google Scholar
• Fares RP, Belmeguenai A, Sanchez PE, et al. Standardized environmental enrichment supports enhanced brain plasticity in healthy rats and prevents cognitive impairment in epileptic rats. PLoS One. 2013;8:e53888.
   PubMed Web of Science ®Google Scholar
• Bar-Klein G, Swissa E, Kamintsky L, et al. sec-Butyl-propylacetamide (SPD) and two of its stereoisomers rapidly terminate paraoxon-induced status epilepticus in rats. Epilepsia. 2014;55:1953–1958.
   PubMed Web of Science ®Google Scholar
• Shekh-Ahmad T, Hen N, McDonough JH, et al. Valnoctamide and sec-butyl-propylacetamide (SPD) for acute seizures and status epilepticus. Epilepsia. 2013;54(Suppl 6):99–102.
   PubMedGoogle Scholar
• Feja M, Meller S, Deking LS, et al. OV329, a novel highly potent gamma-aminobutyric acid aminotransferase inactivator, induces pronounced anticonvulsant effects in the pentylenetetrazole seizure threshold test and in amygdala-kindled rats. Epilepsia. 2021;62:3091–3104.
   PubMed Web of Science ®Google Scholar
• Meisler MH, Helman G, Hammer MF, et al. SCN8A encephalopathy: research progress and prospects. Epilepsia. 2016;57:1027–1035.
   PubMed Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: a summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development. Epilepsia 2018; 59:1811–1841.
   Google Scholar
• Bialer M, Perucca E. Lorcaserin for Dravet syndrome: a potential advance over fenfluramine? CNS Drugs. 2022;36:113–122.
   PubMed Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: a summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development. Epilepsia 2020; 61:2365–2385.
   Google Scholar
• JA F. Phase 2b Efficacy and safety of XEN1101, a novel potassium channel modulator, in adults with focal epilepsy (X-TOLE). In: American Epilepsy society meeting. Chicago IL: USA; 2021. p. 2021.
   Google Scholar
• Zaccara G, Schmidt D. Do traditional anti-seizure drugs have a future? A review of potential anti-seizure drugs in clinical development. Pharmacol Res. 2016;104:38–48.
   PubMed Web of Science ®Google Scholar
• Wood M, Daniels V, Provins L, et al. Pharmacological profile of the novel antiepileptic drug candidate padsevonil: interactions with synaptic vesicle 2 proteins and the GABAA receptor. J Pharmacol Exp Ther. 2020;372:1–10.
   PubMed Web of Science ®Google Scholar
• Muglia P, Hannestad J, Brandt C, et al. Padsevonil randomized Phase IIa trial in treatment-resistant focal epilepsy: a translational approach. Brain Commun. 2020;2:fcaa183.
   PubMedGoogle Scholar
• Lu C, Zheng J, Cao Y, et al. Carisbamate add-on therapy for drug-resistant focal epilepsy. Cochrane Database Syst Rev. 2021;12:CD012121.
   PubMedGoogle Scholar
• Elger CE, Hong SB, Brandt C, et al. BGG492 as an adjunctive treatment in patients with partial-onset seizures: a 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study with an open-label extension. Epilepsia. 2017;58:1217–1226.
   PubMed Web of Science ®Google Scholar
• Lavreysen H, Ahnaou A, Drinkenburg W, et al. Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor. Pharmacol Res Perspect. 2015;3(1):e00096.
   PubMedGoogle Scholar
• Metcalf CS, Klein BD, Smith MD, et al. Efficacy of mGlu2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures. Epilepsia. 2017;58:484–493.
   PubMed Web of Science ®Google Scholar