https://orcid.org/0000-0002-1279-8123
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ABSTRACT
Introduction
Developmental epileptic encephalopathies (DEEs) pose significant challenges due to their refractory nature and limited treatment options. Despite advancements in genetic understanding, effective therapies targeting underlying pathophysiology are lacking. Serotoninergic dysfunction has been implicated in epilepsy, sparking interest in serotonin as a therapeutic target.
Area covered
This article explores the potential of bexicaserin, a selective 5-HT2C receptor agonist, as an adjunctive antiseizure medication in DEEs. Bexicaserin is thought to modulate GABAergic neurotransmission, suppressing central hyperexcitability. Preclinical studies demonstrate its efficacy across various seizure models. Clinical trials, including the Pacific Study, reveal promising results in reducing motor seizures. However, challenges such as adverse effects and treatment discontinuation underscore the need for further investigation.
Expert opinion
The efficacy of 5-HT2C serotoninergic agonists, validated in preclinical and clinical studies, highlights serotonin’s role in DEEs. Bexicaserin offers new therapeutic possibilities, potentially synergizing with existing antiseizure medications. Polypharmacotherapy, targeting distinct pathways, may enhance therapeutic outcomes. Monitoring pharmacological interactions and addressing central nervous system comorbidities are crucial for optimizing treatment strategies. Further research is needed to elucidate bexicaserin’s mechanisms and potential antiepileptogenic effects.
Article highlights
Bexicaserin, a selective 5-HT2C receptor agonist, exhibits promise as an adjunctive treatment for developmental epileptic encephalopathies, targeting central hyperexcitability.
Preclinical studies demonstrate bexicaserin’s efficacy in reducing seizure activity across various animal models of epilepsy.
Phase 1b/2a clinical trial, named the Pacific Study, reveals bexicaserin’s effectiveness in reducing motor seizures, particularly in patients with Dravet syndrome and Lennox-Gastaut syndrome.
Pharmacokinetic assessments reveal bexicaserin’s rapid absorption, dose-dependent exposure with peak plasma concentration reached within 90 min with no food effect, and metabolism via glucuronidation.
By targeting serotoninergic systems, bexicaserin may pave the way for comprehensive therapeutic interventions beyond epilepsy management, also addressing epilepsy-associated comorbidities in DEEs.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Longboard Pharmaceuticals provided a scientific accuracy review at the request of the journal editor. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.