Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development

Epilepsia, Journal Year: 2024, Volume and Issue: 65(10), P. 2831 - 2857

Published: July 15, 2024

Abstract For >30 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided a forum for discussion of advances in development new therapies seizures epilepsy. The EILAT XVII conference took place Madrid, Spain, May 5–8, 2024. Participants included basic scientists clinical investigators from industry academia, other health care professionals, representatives lay organizations. We summarize this article information treatments preclinical early discussed at conference. These include AMT‐260, gene therapy designed to downregulate expression Glu2K subunits kainate receptors, treatment drug‐resistant associated with mesial temporal sclerosis; BHV‐7000, selective activator heteromeric Kv7.2/7.3 potassium channels, focal epilepsy; ETX101, recombinant adeno‐associated virus serotype 9 increase Na V 1.1 channel density inhibitory γ‐aminobutyric acidergic (GABAergic) neurons, SCN1A ‐positive Dravet syndrome; GAO‐3‐02, compound structurally related synaptamide, which exerts antiseizure activity least part through an action cannabinoid type 2 receptors; LRP‐661, structural analogue cannabidiol, Lennox–Gastaut syndrome, tuberous sclerosis complex; OV329, inactivator GABA aminotransferase, seizures; PRAX‐628, functionally potent sodium modulator preference hyperexcitable state RAP‐219, negative allosteric transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor regulatory protein γ‐8, rozanolixizumab, humanized anti‐neonatal Fc monoclonal antibody, LGI1 autoimmune encephalitis. Treatments more advanced are summarized Part II report.

Language: Английский

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A Highly Sensitive Triple Quad LC–MS/MS Method Development and Validation for the Determination of Bexicaserin (LP352) in Human Plasma and Urine Matrices

Biomedical Chromatography, Journal Year: 2025, Volume and Issue: 39(2)

Published: Jan. 17, 2025

ABSTRACT Bexicaserin is a highly selective agonist at the 5‐HT 2c receptor in clinical development for treatment of seizures associated with developmental and epileptic encephalopathies (DEEs). We report an LC–MS/MS method quantitative estimation bexicaserin human plasma urine. The sample preparation involves extraction internal standard ( 13 CD 2 ‐bexicaserin; IS) from 150 μL 50 urine using solid phase method. chromatographic separation IS was achieved on Poroshell EC‐C18 column 5 min gradient program. calibration curve ranged 0.1 to 100 ng/mL 1.0 1000 Intraday interday precision accuracy, linearity, matrix effect, recovery, carry‐over, dilution integrity, battery stability studies, incurred reanalysis were performed both intraday accuracy well within acceptable limits matrices. Stability studies showed that stable bench 24 h, autosampler over 54 five freeze–thaw cycles, long‐term storage −20°C −80°C > 368 days. validated methods successfully applied study.

Language: Английский

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From barbiturates to ganaxolone: The importance of chirality in drug development and in understanding the actions of old and new antiseizure medications

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108808 - 108808

Published: Feb. 1, 2025

Out of 37 antiseizure medications (ASMs) currently in the market, 17 are chiral molecules and an additional one (oxcarbazepine) is a prodrug compound licarbazepine. Of ASMs, six (ethosuximide, fenfluramine, methsuximide, mephobarbital, stiripentol vigabatrin) marketed as racemates, remainder licensed enantiomerically pure medicines. note, all ASMs introduced prior to 1990 were racemates. Stiripentol, fenfluramine vigabatrin only racemic approved by FDA >10 years after release regulatory guidelines on development Despite fact that pharmacokinetic pharmacodynamic differences between enantiomers have been recognized for decades, importance chirality understanding biological actions not widely appreciated, many recent publications refer these if they single molecular entity. In present article, we provide critical review developed 1920s, when mephobarbital was introduced, 2022, last ASM (ganaxolone) approved. We summarize available data stereoselective pharmacokinetics pharmacodynamics also discuss aspects related introduction medicines within current scenario Europe U.S., focusing stiripentol, examples different approaches. identified number knowledge gaps relevant use drugs epilepsy, including remarkable lack published information comparative pharmacokinetics, toxicity activity most ASMs. The clinical discussed, together with rationale follow-up compounds potentially improved efficacy, safety commercial viability.

Language: Английский

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Recent Advances in Pharmacologic Treatments of Drug-Resistant Epilepsy: Breakthrough in Sight

CNS Drugs, Journal Year: 2024, Volume and Issue: 38(12), P. 949 - 960

Published: Oct. 21, 2024

Language: Английский

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Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies

Pediatric Neurology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Off-label-Use von anfallssuppressiver und immunsuppressiver Medikation bei Epilepsien

Deleted Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Zusammenfassung Zur Behandlung der Epilepsien stehen zahlreiche anfallssuppressive Medikamente (ASM) zur Verfügung, die auf Basis klinischer Studien für bestimmte Indikationen und Altersgruppen zugelassen sind. Allerdings erfordert Vielzahl verschiedener Epilepsietypen Syndrome häufig einen Off-label-Einsatz von ASM, wenn Patienten unter aktuellen Therapie nicht anfallsfrei werden oder diese vertragen. Ähnliches gilt Verwendung verschiedenen immunsuppressiven Medikamenten Anfällen Epilepsien, infolge autoimmuner Enzephalitiden auftreten, mit dem Unterschied, dass hier bisher keinerlei zugelassene Substanzen existieren. Der Off-label-Use beschreibt Anwendung eines Medikaments außerhalb zugelassenen Indikationen, Dosierungen Altersgruppen. Insbesondere in Epilepsietherapie tritt dies auf, etwa bei Kindern Zulassungsalter, generalisierten entwicklungsbedingten epileptischen Enzephalopathien. Obwohl zusätzliche Behandlungsoptionen bietet, führt es zu einigen Herausforderungen klinischen Praxis. Es fehlen oft klinische Daten Sicherheit Wirksamkeit, was Unsicherheiten Bezug Dosierung Nebenwirkungen führen kann. Eine sorgfältige Aufklärung ihrer Angehörigen über Nutzen Risiken ist daher essenziell, ebenso wie eine umfassende Dokumentation Entscheidungsfindung. Da regelhaft den Kostenträgern übernommen wird, – insbesondere kostenintensiven neueren Patentschutz vorherige Klärung Kostenübernahme sinnvoll, um wirtschaftliche vermeiden.

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Targeting Kv7 Potassium Channels for Epilepsy

CNS Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 play a critical role in modulating susceptibility to seizures, mutations genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation has long been considered an attractive target search for novel antiseizure medications. Ezogabine (retigabine), first Kv7.2/3 activator introduced 2011 treatment focal was withdrawn from market 2017 due declining use after discovery its association with pigmentation changes retina, skin, mucosae. A formulation ezogabine pediatric (XEN496) recently investigated children KCNQ2-related developmental epileptic encephalopathy, but trial terminated prematurely reasons unrelated safety. Among openers clinical development, azetukalner shown dose-dependent efficacy against drug-resistant seizures good tolerability profile no evidence pigmentation-related adverse effects early studies, it is now under investigation phase III trials generalized tonic-clonic major depressive disorder. Another activator, BHV-7000, completed I studies healthy subjects, excellent at plasma drug concentrations exceed median effective preclinical model anticonvulsant activity, data patients are available date. other activators development as potential medications, pynegabine CB-003 have safety pharmacokinetic results not yet reported. Overall, interest targeting indications remains strong. Future breakthroughs area could come exploitation mechanistic differences action activators, molecules combine mechanisms action.

Language: Английский

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Physiologically Based Pharmacokinetic Modeling to Predict Drug–Drug Interactions of Soticlestat as a Victim of CYP Induction and Inhibition, and as a Perpetrator of CYP and P–Glycoprotein Inhibition

Clinical Pharmacology in Drug Development, Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Abstract Soticlestat (TAK‐935) is a cholesterol 24‐hydroxylase inhibitor. A physiologically‐based pharmacokinetic model has been developed to predict potential soticlestat drug–drug interactions (DDIs) using the Simcyp v20 Population‐based Simulator and verified with data from single‐/multiple‐rising‐dose clinical DDI studies. Simulated area under plasma concentration–time curve 0 infinity (AUC 0‐inf ) maximal drug concentration (C max based on were generally within 2‐fold of observed values for all doses. Model‐simulated versus AUC C geometric mean ratios (GMRs) with/without itraconazole (potent cytochrome P450 [CYP] 3A inhibitor), mefenamic acid UDP glucuronosyltransferase [UGT] 1A9 inhibitor) ≤1.10‐fold. As primarily metabolized by UGT enzymes incorporates rifampin's induction CYP3A only, underpredicted soticlestat's rifampin. However, user‐defined rifampin induction, predicted GMR was 1.5‐fold value, meeting acceptance criteria. Hence, appropriate evaluating DDIs inhibitors inducers not evaluated in studies; low/not clinically relevant (<50% impact exposure). Furthermore, no significant following coadministration sensitive CYP2C8, CYP2C9, CYP2C19, CYP3A4, P‐glycoprotein substrates.

Language: Английский

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The Epilepsy Drug Pipeline: Update on Near-to-Market Therapies

Seminars in Neurology, Journal Year: 2025, Volume and Issue: 45(02), P. 287 - 297

Published: April 1, 2025

Abstract Since the first antiseizure medication (ASM) was introduced in 1857, more than 30 medications have been approved by United States Food and Drug Administration (FDA) for treatment of epilepsy. However, limitations efficacy tolerability led to one-third patients suffering from uncontrolled seizures. Recent advances genetics, disease modeling, high-throughput target-based phenotype-based screening, study design, identification novel mechanisms action or routes delivery resulted 200 therapeutics currently under development epilepsy pipeline. This discusses near-to-market drugs advanced clinical development, with select earlier stages. Background regarding mechanisms, animal studies, pharmacokinetics, pharmacodynamics, efficacy, tolerability, safety data are provided each drug when available.

Language: Английский

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A comprehensive review of evolving treatment strategies for Dravet syndrome: Insights from randomized trials, meta-analyses, real-world evidence, and emerging therapeutic approaches

Epilepsy & Behavior, Journal Year: 2024, Volume and Issue: 162, P. 110171 - 110171

Published: Nov. 29, 2024

Language: Английский

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