New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development

Abstract

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABA A receptors and includes Staccato ® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABA A receptor α and β subunits is being investigated, with Lennox-Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.

Established and emerging GABAA receptor pharmacotherapy for epilepsy

“…The prospect of maximizing therapeutic effects associated with GABA A receptor modulation whilst minimizing drug dependence and sedation has led to the development of several subtype-selective compounds with promising pre-clinical characteristics, some of which are undergoing clinical development. ENX 101 is a α2, α3 and α5 subtype selective positive allosteric modulator that was well-tolerated by subjects in a Phase 1 study and is now undergoing Phase 2 testing for refractory focal epilepsy ( Castellano et al, 2020 ; Jankovic et al, 2021 ; Perucca et al, 2023b ). KRM-II-81 is an imidazodiazepine that is also highly selective for α2 and α3 subunit containing GABA A receptors.…”

“…GABA exerts much of its inhibitory influence through GABA A receptors which comprise a diverse group of ligand-gated ion channels that serve as common targets for antiseizure medications ( Perucca et al, 2023a ; Perucca et al, 2023b ; Bryson et al, 2023 ). Indeed, some of the earliest developed antiseizure medications such as potassium bromide and phenobarbital act primarily through positive allosteric modulation of the GABA A receptor and, more recently, there has been great interest in the development of novel compounds that precisely modulate inhibitory pathways through specific GABA A receptor subtypes ( Engin et al, 2018 ; Owen et al, 2019 ; Jankovic et al, 2021 ; Cerne et al, 2022 ; Witkin et al, 2022 ).…”

Phytotherapeutic options for the treatment of epilepsy: pharmacology, targets, and mechanism of action

“…However, during the seizure, the voltage-gated potassium channels (Kv) fail to efflux enough K + ions out of the cell to maintain a normal level of ions inside the cell, which causes an imbalance of the action potential and again leads to the disturbance of excitatory and inhibitory cycle of the neurons and finally develops seizure (Gao et al, 2022). In addition, a few more channels and enzymes are involved in the initiation and propagation of seizure (Rho and Boison, 2022;Perucca et al, 2023a;Perucca et al, 2023b).…”

Modern Principles in the Treatment of Epilepsy

“…Приведены результаты исследований, выполненных в период последних 5 лет, сравнивающих эффективность комбинаций противоэпилептических препаратов и их лекарственные взаимодействия [15], а также риски проявления неблагоприятных побочных явлений. В ходе анализа литературы сформулированы современные направления исследований, описана разработка группы инновационных методов лечения заболевания с применением генной терапии, нейростероидов и новых лекарственных препаратов [5].…”

“…Положительное влияние таких препаратов обусловлено улучшением процесса работы нейронов посредством выделения в качестве нейромедиатора гамма-аминомасляной кислоты и улучшение тока ионов натрия в потенциал-зависимых каналах нейронов. По данным доклинических исследований нейростероид ETX-155 эффективен в различных моделях эпилептических приступов у грызунов (максимально переносимая доза-135 мг) [5]. Предварительный анализ данных трех пациентов с фоточувствительной эпилепсией показал неубедительные результаты, по мне-нию группы исследователей, вызванные более низкой концентрацией вещества в плазме в отличие от предварительно ожидаемой.…”