Azetukalner (XEN1101)

The treatment position addressed by an adjunctive potassium channel opener is add-on therapy for adults whose focal onset seizures persist on existing antiseizure medications. Clinical practice guidance defines that position by the number of failed medications rather than by mechanism. The International League Against Epilepsy defines drug-resistant epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used medication schedules, whether as monotherapy or in combination, to achieve sustained seizure freedom, and NICE adopts that definition. Approximately 30% of people with focal epilepsy have seizures that are not controlled by antiseizure medications. NICE directs that a single medication be used whenever possible, that an add-on treatment be considered when monotherapy is unsuccessful, and that when trials of add-on treatment do not reduce seizures the regimen chosen should be the one providing the best balance between effectiveness and tolerability.

Mechanistic diversity supports adding a new mechanism rather than a further agent from a class already used, since combining medications with various mechanisms of action appears more efficacious than combining medications sharing the same or comparable mechanisms. Expert consensus on the most recently approved adjunctive agent argues against reserving new mechanisms for late-stage use, recommending introduction after the failure of two adequately dosed antiseizure medications rather than at later stages of treatment. Azetukalner was studied in exactly this position: participants in X-TOLE2 had a median of five prior antiseizure medications, 51.3% were taking three concomitant medications, and approximately 40% were taking concomitant cenobamate.

The care setting is specialist outpatient neurology care with access to a tertiary or comprehensive epilepsy centre. NICE requires that all people with suspected or confirmed epilepsy have access to a tertiary epilepsy service via their specialist, and sets a four-week referral target when seizures are drug resistant or treatment causes intolerable side effects. The National Association of Epilepsy Centers recommends that all epilepsy centres regularly assess medication adherence and side effects as part of routine outpatient care, and regularly screen for drug-resistant epilepsy. Once-daily oral dosing with food, without titration and without dose adjustment of concomitant antiseizure medications, would place administration in the same setting as other oral adjunctive antiseizure medications.