A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy

ABSTRACT

Introduction

Epilepsies are a group of heterogeneous brain disorder, and antiseizure medications (ASMs) are the mainstay of treatment. Despite the availability of more than 30 drugs, at least one third of individuals with epilepsy are drug-resistant. This emphasizes the need for novel compounds that combine efficacy with improved tolerability.

Areas covered

A literature review on the pharmacology, efficacy, tolerability, and safety of azetukalner (XEN1101), a second-generation opener of neuronal potassium channels currently in Phase 3 development as ASM.

Expert opinion

Results from the phase 2b clinical trial strongly support the ongoing clinical development of azetukalner as a new ASM. Its pharmacokinetic properties support convenient once-daily dosing, eliminating the need for titration at initiation or tapering at the conclusion of treatment. CYP3A4 is the main enzyme involved in its metabolism and drug-drug interactions can affect the drug exposure. Preliminary analysis of an ongoing open-label study reveals no reported pigmentary abnormalities. The upcoming Phase 3 clinical trials are expected to provide further insight into the efficacy, tolerability, and safety of azetukalner in treating focal-onset and primary generalized tonic-clonic seizures. Structurally distinct from currently marketed ASMs, azetukalner has the potential to be the only-in-class Kv7.2/7.3 opener on the market upon regulatory approval.

KEYWORDS:

• Antiseizure medications
• focal epilepsy
• generalized epilepsy
• seizures
• XEN1101
• azetukalner

Article highlights

• Azetukalner (XEN1101) is a new, second-generation, opener of potassium channels currently under development for the treatment of focal and generalized seizures

• Azetukalner is more potent and target-selective than retigabine/ezogabine

• Azetukalner does not give rise to tissue discoloration caused by dimer formation and may have an improved safety profile over retigabine/ezogabine

• Azetukalner is structurally unrelated to any currently marketed antiseizure medication

• Azetukalner has a pharmacokinetic profile suitable for once daily dosing without titration

• Findings of the phase 2b clinical trial strongly support the further clinical development of azetukalner

• Phase 3 clinical trials will provide additional insight into the efficacy, tolerability, and safety for the potential treatment of focal-onset and primary generalized tonic-clonic seizures

Funding

This paper was not funded.

Information resources

• International League Against Epilepsy (https://www.ilae.org)

• EpilepsyDiagnosis.org online diagnostic manual of the epilepsies (EpilepsyDiagnosis.org)

• International Bureau For Epilepsy (https://www.ibe-epilepsy.org)

Declaration of interest

SL has received speaker’s or consultancy fees from Angelini Pharma, Eisai, GW Pharmaceuticals, Medscape, and UCB Pharma and has served on advisory boards for Angelini Pharma, Arvelle Therapeutics, BIAL, Eisai, and GW Pharmaceuticals outside the submitted work. SL received research grant support from the Ministry of Health and the Ministry of University and Research outside the submitted work. ET received speaker’s honoraria from UCB Pharma, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, Sunovion Pharmaceuticals Inc., LivaNova and Novartis; consultancy funds from UCB Pharma, Biogen, Gerot-Lannach, Bial, Eisai, Takeda, Newbridge, GW Pharmaceuticals, Sunovion Pharmaceuticals Inc., and Novartis outside the submitted work; directorship funds from Neuroconsult GmbH. E. ET’s Institution received grants from Biogen, Red Bull, Merck, UCB Pharma, European Union, FWF Österreichischer Fond zur Wissenschaftsförderung, and Bundesministerium für Wissenschaft und Forschung. SM has served on advisory board for UCB Pharma and received consultancy fees from Eisai outside the submitted work. SM received research grant support from the Ministry of Health (MOH), from the nonprofit organization Foundation ‘Fondazione Cassa di Risparmio di Modena-FCRM.’ PS received fees and research grants from GW Pharmaceuticals, Zogenyx, Biomarin, and Kolfarma outside the submitted work. MS and FB have no conflicts of interest. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.