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

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13‐16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from preclinical or early (phase I) clinical studies were presented. The compounds reviewed include adenosine and adenosine kinase inhibitors, BIS‐001 (huperzine A), 2‐deoxy‐d‐glucose, FV‐082, FV‐137, JNJ‐40411813, JNJ‐55511118 and analogs, ketone‐enhanced antiepileptic drugs, oxynytones, OV329, TAK‐935 (OV935), XEN901, and XEN1101. Many innovative approaches to drug development were presented. For example, some compounds are being combined with traditional antiepileptic drugs based on evidence of synergism in seizure models, some act as inhibitors of enzymes involved in modulation of neuronal activity, and some interact in novel ways with excitatory receptors or ion channels. Some of the compounds in development target the etiology of specific epilepsy syndromes (including orphan conditions) through precision medicine, and some offer hope of producing disease‐modifying effects rather than symptomatic seizure suppression. Overall, the results summarized in the report indicate that important advances are being made in the effort to develop compounds with potentially improved efficacy and safety profiles compared with existing agents.

[1]  M. Koepp,et al.  Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in more advanced clinical development , 2018, Epilepsia.

[2]  S. Dewey,et al.  Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction. , 2018, Journal of the American Chemical Society.

[3]  H. Lavreysen,et al.  Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2–positive allosteric modulator JNJ‐46356479 and levetiracetam in the mouse 6‐Hz (44‐mA) model , 2018, Epilepsia.

[4]  C. D. Makinson,et al.  Selective targeting of Scn8a prevents seizure development in a mouse model of mesial temporal lobe epilepsy , 2018, Scientific Reports.

[5]  Jodi L. Smith,et al.  Targeted Blockade of TARP-γ8-Associated AMPA Receptors: Anticonvulsant Activity with the Selective Antagonist LY3130481 (CERC-611). , 2017, CNS & neurological disorders drug targets.

[6]  H. Lavreysen,et al.  Efficacy of mGlu2‐positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures , 2017, Epilepsia.

[7]  M. Zilberter,et al.  Chronic inhibition of brain glycolysis initiates epileptogenesis , 2017, Journal of neuroscience research.

[8]  T. Tomson,et al.  Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) , 2017, Epilepsia.

[9]  M. Richardson,et al.  Lamotrigine and levetiracetam exert a similar modulation of TMS‐evoked EEG potentials , 2016, Epilepsia.

[10]  O. Dulac,et al.  From genotype to phenotype in Dravet disease , 2017, Seizure.

[11]  Xuening Li,et al.  Evaluation of the in vitro and in vivo metabolic pathway and cytochrome P450 inhibition/induction profile of Huperzine A. , 2016, Biochemical and biophysical research communications.

[12]  Stacey B. B. Dutton,et al.  Huperzine A Provides Robust and Sustained Protection against Induced Seizures in Scn1a Mutant Mice , 2016, Front. Pharmacol..

[13]  Y. Vandermeeren,et al.  Effect of a single dose of retigabine in cortical excitability parameters: A cross-over, double-blind placebo-controlled TMS study , 2016, Epilepsy Research.

[14]  K. Jacobson,et al.  South (S)- and North (N)-Methanocarba-7-Deazaadenosine Analogues as Inhibitors of Human Adenosine Kinase. , 2016, Journal of medicinal chemistry.

[15]  A. L. Goldin,et al.  SCN8A encephalopathy: Research progress and prospects , 2016, Epilepsia.

[16]  W. Drevets,et al.  Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression , 2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[17]  T. Lovenberg,et al.  Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8 , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[18]  D. Bredt,et al.  Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8. , 2016, Journal of medicinal chemistry.

[19]  E. Kossoff,et al.  Use of dietary therapies amongst patients with GLUT1 deficiency syndrome , 2016, Seizure.

[20]  D. Henshall,et al.  Epigenetics and Epilepsy. , 2015, Cold Spring Harbor perspectives in medicine.

[21]  T. Tomson,et al.  Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII) , 2015, Epilepsy Research.

[22]  A. Megens,et al.  Preclinical evaluation of the antipsychotic potential of the mGlu2-positive allosteric modulator JNJ-40411813 , 2015, Pharmacology research & perspectives.

[23]  Xiaojia Li,et al.  Efficacy of and Patient Compliance with a Ketogenic Diet in Adults with Intractable Epilepsy: A Meta-Analysis , 2015, Journal of clinical neurology.

[24]  X. Langlois,et al.  Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor , 2014, Pharmacology research & perspectives.

[25]  Jacy L. Wagnon,et al.  Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy , 2014, Human molecular genetics.

[26]  A. Pitkänen,et al.  Posttraumatic epilepsy — Disease or comorbidity? , 2014, Epilepsy & Behavior.

[27]  E. Funkhouser,et al.  Psychiatric and neurologic risk factors for incident cases of new‐onset epilepsy in older adults: Data from U.S. Medicare beneficiaries , 2014, Epilepsia.

[28]  P. Veggiotti,et al.  Dietary Treatments and New Therapeutic Perspective in GLUT1 Deficiency Syndrome , 2014, Current Treatment Options in Neurology.

[29]  E. Aronica,et al.  Glial adenosine kinase – A neuropathological marker of the epileptic brain , 2013, Neurochemistry International.

[30]  Gabriel M. Belfort,et al.  The Major Brain Cholesterol Metabolite 24(S)-Hydroxycholesterol Is a Potent Allosteric Modulator of N-Methyl-d-Aspartate Receptors , 2013, The Journal of Neuroscience.

[31]  Eleanor M. Pritchard,et al.  Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. , 2013, The Journal of clinical investigation.

[32]  D. Nordli.  Epileptic Encephalopathies in Infants and Children , 2012, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[33]  Fabrice Wendling,et al.  Mechanisms of physiological and epileptic HFO generation , 2012, Progress in Neurobiology.

[34]  Uwe Schulte,et al.  High-Resolution Proteomics Unravel Architecture and Molecular Diversity of Native AMPA Receptor Complexes , 2012, Neuron.

[35]  Raman Sankar,et al.  The mechanism of action of retigabine (ezogabine), a first‐in‐class K+ channel opener for the treatment of epilepsy , 2012, Epilepsia.

[36]  R. Nicoll,et al.  The Expanding Social Network of Ionotropic Glutamate Receptors: TARPs and Other Transmembrane Auxiliary Subunits , 2011, Neuron.

[37]  E. Kossoff,et al.  Ketogenic diets: Evidence for short- and long-term efficacy , 2009, Neurotherapeutics.

[38]  Kevin Bray,et al.  Targeting tumor metabolism with 2‐deoxyglucose in patients with castrate‐resistant prostate cancer and advanced malignancies , 2010, The Prostate.

[39]  M. Baulac,et al.  Visual Field Loss in Patients with Refractory Partial Epilepsy Treated with Vigabatrin , 2009, CNS drugs.

[40]  J. Luszczki,et al.  Pharmacodynamic and pharmacokinetic interactions between common antiepileptic drugs and acetone, the chief anticonvulsant ketone body elevated in the ketogenic diet in mice , 2009, Epilepsia.

[41]  C. Stafstrom,et al.  Anticonvulsant and antiepileptic actions of 2‐deoxy‐D‐glucose in epilepsy models , 2009, Annals of neurology.

[42]  A. Pitkänen,et al.  From traumatic brain injury to posttraumatic epilepsy: What animal models tell us about the process and treatment options , 2009, Epilepsia.

[43]  B. Abou-Khalil.  Levetiracetam in the treatment of epilepsy , 2008, Neuropsychiatric disease and treatment.

[44]  Shigeyoshi Itohara,et al.  Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. , 2008, The Journal of clinical investigation.

[45]  U. Heinemann,et al.  Acetylcholine‐induced seizure‐like activity and modified cholinergic gene expression in chronically epileptic rats , 2008, The European journal of neuroscience.

[46]  R. Simon,et al.  Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. , 2007, Brain : a journal of neurology.

[47]  Avtar Roopra,et al.  2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP–dependent metabolic regulation of chromatin structure , 2006, Nature Neuroscience.

[48]  Stephen C Cunnane,et al.  Breath acetone predicts plasma ketone bodies in children with epilepsy on a ketogenic diet. , 2006, Nutrition.

[49]  E. Simpson,et al.  Engineering embryonic stem cell derived glia for adenosine delivery , 2004, Neuroscience Letters.

[50]  C. Stafstrom.  Dietary Approaches to Epilepsy Treatment: Old and New Options on the Menu , 2004, Epilepsy currents.

[51]  D. Russell,et al.  Knockout of the Cholesterol 24-Hydroxylase Gene in Mice Reveals a Brain-specific Mechanism of Cholesterol Turnover* , 2003, Journal of Biological Chemistry.

[52]  A. Zangara.  The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease , 2003, Pharmacology Biochemistry and Behavior.

[53]  R. Nicoll,et al.  Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins , 2003, The Journal of cell biology.

[54]  J. Rho,et al.  Acetoacetate, Acetone, and Dibenzylamine (a Contaminant in l‐(+)‐β‐Hydroxybutyrate) Exhibit Direct Anticonvulsant Actions in Vivo , 2002, Epilepsia.

[55]  W. Burnham,et al.  Dietary Fat, Ketosis, and Seizure Resistance in Rats on the Ketogenic Diet , 2000, Epilepsia.

[56]  R. Dingledine,et al.  The glutamate receptor ion channels. , 1999, Pharmacological reviews.

[57]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[58]  S. Nakanishi,et al.  Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat , 1993, Neuroscience.