Novel antiseizure medications in the development pipeline: promising candidates and recent failures

Baraban SC, Dinday MT, Hortopan GA (2013) Drug screening and transcriptomic analysis in Scn1a zebrafish mutants identifies potential lead compound for Dravet syndrome. Nat Comm 4:2410

Article  Google Scholar 

Bialer M, White HS (2010) Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 9:68–82

Article  CAS  PubMed  Google Scholar 

Butlen-Ducuing F, Pétavy F, Guizzaro L, Zienowicz M, Haas M, Alteri E, Salmonson T, Corruble E (2016) Regulatory watch: challenges in drug development for central nervous system disorders: a European medicines agency perspective. Nat Rev Drug Discov 15:813–814

Article  CAS  PubMed  Google Scholar 

Devinsky O, Vezzani A, O’Brien TJ, Jette N, Scheffer IE, De Curtis M, Perucca P (2018) Epilepsy. Nat Rev Dis Primers 4:18024

Article  PubMed  Google Scholar 

Devinsky O, King L, Bluvstein J, Friedman D (2021) Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder. Ann Clin Transl Neurol 8:639–644

Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, Mathews GC, Benke TA, Delpire E, Jensen FE, Staley KJ (2005) NKCC1 transporter facilitates seizures in the developing brain. Nat Med 11:1205–1213

Article  CAS  PubMed  Google Scholar 

French JA, Porter RJ, Perucca E, Brodie MJ, Rogawski MA, Pimstone S, Aycardi E, Harden C, Qian J, Rosenblut CL, Kenney C, Beatch GN (2023) Efficacy and safety of XEN1101, a novel potassium channel opener, in adults with focal epilepsy: a phase 2b randomized clinical trial. JAMA Neurol 80:1145–1154

Article  PubMed  PubMed Central  Google Scholar 

Fuentes J, Parellada M, Georgoula C, Oliveira G, Marret S, Crutel V, Albarran C, Lambert E, Pénélaud PF, Ravel D, Ari BY (2023) Bumetanide oral solution for the treatment of children and adolescents with autism spectrum disorder: results from two randomized phase III studies. Autism Res 16:2021–2034

Article  PubMed  Google Scholar 

Gurrell R, Iredale P, Evrard A, Duveau V, Ruggiero C, Roucard C (2022) Pronounced antiseizure activity of the subtype-selective GABA(A) positive allosteric modulator darigabat in a mouse model of drug-resistant focal epilepsy. CNS Neurosci Ther 28:1875–1882

Article  CAS  PubMed  PubMed Central  Google Scholar 

Han Z, Chen C, Christiansen A, Ji S, Lin Q, Anumonwo C, Liu C, Leiser SCM, Aznarez I, Liau G, Isom LL (2020) Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Sci Transl Med 12:eaaz6100

Article  PubMed  Google Scholar 

Iori V, Iyer AM, Ravizza T, Beltrame L, Paracchini L, Marchini S, Cerovic M, Hill C, Ferrari M, Zucchetti M, Molteni M, Rossetti C, Brambilla R, Steve WH, D’Incalci M, Aronica E, Vezzani A (2017) Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis 99:12–23

Article  CAS  PubMed  Google Scholar 

Kesselheim AS, Hwang TJ, Franklin JM (2015) Two decades of new drug development for central nervous system disorders. Nat Rev Drug Discov 14:815–816

Article  CAS  PubMed  Google Scholar 

Klein P, Dingledine R, Aronica E, Bernard C, Blümcke I, Boison D, Brodie MJ, Brooks-Kayal AR, Engel J Jr., Forcelli PA, Hirsch LJ, Kaminski RM, Klitgaard H, Kobow K, Lowenstein DH, Pearl PL, Pitkänen A, Puhakka N, Rogawski MA, Schmidt D, Sillanpää M, Sloviter RS, Steinhauser C, Vezzani A, Walker MC, Löscher W (2018) Commonalities in epileptogenic processes from different acute brain insults: do they translate? Epilepsia 59:37–66

Article  CAS  PubMed  Google Scholar 

Klein P, Kaminski RM, Koepp M, Löscher W (2024) New epilepsy therapies in development. Nat Rev Drug Discov 23:682-708

Koepp M, Trinka E, Löscher W, Klein P (2024) Prevention of epileptogenesis—are we there yet? Curr Opin Neurol in press

Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Jansen F, Feucht M, Krsek P, Nabbout R, Jansen AC, Wojdan K, Sijko K, GÅ’owacka-Walas J, Borkowska J, Sadowski K, Domanska-Pakiela D, Moavero R, Hertzberg C, Hulshof H, Scholl T, Benova B, Aronica E, de Ridder J, Lagae L, Jozwiak S (2021) Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP trial. Ann Neurol 89:304–314

Article  CAS  PubMed  Google Scholar 

Leclercq K, Matagne A, Provins L, Klitgaard H, Kaminski RM (2020) Pharmacological profile of the antiepileptic drug candidate padsevonil—characterization in rodent seizure and epilepsy models. J Pharmacol Exp Ther 372:11–20

Article  CAS  PubMed  Google Scholar 

Lemonnier E, Degrez C, Phelep M, Tyzio R, Josse F, Grandgeorge M, Hadjikhani N, Ben-Ari Y (2012) A randomized controlled trial of bumetanide in the treatment of autism in children. Transl Psychiatry 2:e202

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lemonnier E, Villeneuve N, Sonie S, Serret S, Rosier A, Roue M, Brosset P, Viellard M, Bernoux D, Rondeau S, Thummler S, Ravel D, Ari BY (2017) Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders. Transl Psychiatry 7:e1056

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lersch R, Jannadi R, Grosse L, Wagner M, Schneider MF, von Ãlpnagel SC, Heinen F, Potschka H, Borggraefe I (2022) Targeted molecular strategies for genetic neurodevelopmental disorders: emerging lessons from dravet syndrome. Neuroscientist 29:732–750

Article  PubMed  PubMed Central  Google Scholar 

Löscher W, Klitgaard H, Twyman RE, Schmidt D (2013) New avenues for antiepileptic drug discovery and development. Nat Rev Drug Discov 12:757–776

Article  PubMed  Google Scholar 

Löscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H (2016) Synaptic vesicle glycoprotein 2A Ligands in the treatment of epilepsy and beyond. CNS Drugs 30:1055–1077

Article  PubMed  PubMed Central  Google Scholar 

Löscher W, Potschka H, Sisodiya SM, Vezzani A (2020) Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev 72:606–638

Article  PubMed  PubMed Central  Google Scholar 

Löscher W, Sills GJ, White HS (2021) The ups and downs of alkyl-carbamates in epilepsy therapy: how does cenobamate differ? Epilepsia 62:596–614

Article  PubMed  Google Scholar 

Löscher W (2021) Single-target versus multi-target drugs versus combinations of drugs with multiple targets: preclinical and clinical evidence for the treatment or prevention of epilepsy. Front Pharmacol 12:730257

Article  PubMed  PubMed Central  Google Scholar 

Löscher W, Kaila K (2022) CNS pharmacology of NKCC1 inhibitors. Neuropharmacology 205:108910

Article  PubMed  Google Scholar 

Löscher W, White HS (2023) Animal models of drug-resistant epilepsy as tools for deciphering the cellular and molecular mechanisms of pharmacoresistance and discovering more effective treatments. Cells 12:1233

Article  PubMed  PubMed Central  Google Scholar 

Löscher W (2023) Is the antiparasitic drug ivermectin a suitable candidate for the treatment of epilepsy? Epilepsia 64:553–566

Article  PubMed  Google Scholar 

Muglia P, Hannestad J, Brandt C, DeBruyn S, Germani M, Lacroix B, Majoie M, Otoul C, Sciberras D, Steinhoff BJ, Van Laere K, Van Paesschen W, Webster E, Kaminski RM, Werhahn KJ, Toledo M (2020) Padsevonil randomized phase IIa trial in treatment-resistant focal epilepsy: a translational approach. Brain Commun 2:fcaa183

Article  PubMed  PubMed Central  Google Scholar 

Olsen RW (2018) GABA(A) receptor: positive and negative allosteric modulators. Neuropharmacology 136:10–22

Article  CAS  PubMed  PubMed Central  Google Scholar 

Pressler RM, Boylan GB, Marlow N, Blennow M, Chiron C, Cross JH, De Vries LS, Hallberg B, Hellstrom-Westas L, Jullien V, Livingstone V, Mangum B, Murphy B, Murray D, Pons G, Rennie J, Swarte R, Toet MC, Vanhatalo S, Zohar S (2015) 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 14:469–477

Article  CAS  PubMed  Google Scholar 

Rademacher M, Toledo M, Van Paesschen W, Liow KK, Milanov IG, Esch ML, Wang N, MacPherson M, Byrnes WJ, Minh TDC, Webster E, Werhahn KJ (2022) Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: results from two double-blind, randomized, placebo-controlled trials. Epilepsia Open 7:758–770

Article  PubMed  PubMed Central 

留言 (0)

沒有登入
gif