Azetukalner (XEN1101)

Roughly one third of adults with epilepsy continue to have seizures despite available antiseizure medications. In a 30-year longitudinal cohort of participants with newly diagnosed epilepsy, 1,144 participants (63.7%) had been seizure free for the previous year or longer at the end of the study period, and the authors concluded that overall outcomes in newly diagnosed epilepsy have not improved despite the availability of many new medications with differing mechanisms of action. The yield of each successive medication falls steeply. Expressed as model-predicted probabilities, the first regimen gave a probability of seizure freedom of 50.5%, the second added 11.6%, the third added 4.1%, and from the fourth regimen onward each additional medication added approximately 1% or less. An earlier cohort in the same clinical setting reported that 222 of 470 previously untreated participants (47%) became seizure free on their first medication and 67 (14%) on a second or third, and that among participants with no response to the first medication only 11% subsequently became seizure free when the first failure was due to lack of efficacy, compared with 41% when it was due to intolerable side effects. A 2025 update reported that 64% of participants were seizure free, a proportion identical to that reported in the smaller 2000 study from the same setting.

Tolerability and interaction burden compound this efficacy ceiling. In up to a quarter of people, tolerability issues may lead to treatment discontinuation and harm adherence, and polypharmacotherapy further increases the risk of drug interactions and adverse events. Carbamazepine, phenobarbital, phenytoin, and primidone induce cytochrome P450 enzymes while valproic acid inhibits them, changing the serum concentrations of other antiseizure medications and of anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobial drugs, antineoplastic drugs, and immunosuppressants. Enzyme-inducing medications also affect sex hormone metabolism, vitamin D homeostasis, bone metabolism, and cholesterol synthesis, and reduce the effectiveness of hormonal contraceptives. Valproate, phenobarbital, and topiramate increase the risk of major congenital malformations, and in the United Kingdom valproate must not be prescribed to any woman or girl able to have children unless the conditions of the Pregnancy Prevention Programme are followed, because around 1 in 9 babies (11%) exposed in pregnancy will have a birth defect.

The only previously marketed potassium channel opener, ezogabine, also known as retigabine, is no longer available. Its United States label carried a warning that the product can cause retinal abnormalities with funduscopic features similar to those seen in retinal pigment dystrophies, restricted use to adults who had responded inadequately to several alternative treatments, and required baseline and six-monthly visual monitoring by an ophthalmic professional. Approximately 10% of participants in long-term clinical trials developed skin discoloration, generally after two or more years of treatment and at doses of 900 mg or greater, and retinal pigmentary abnormalities occurred in about one third of participants examined after approximately four years of treatment. The product was withdrawn from the United States market in 2017 after use declined, and the European Commission withdrew the marketing authorisation for Trobalt on 19 July 2018 at the request of the marketing authorisation holder, for commercial reasons.