New epilepsy pill halved seizures for many hard-to-treat patients

Adding a once-daily capsule called azetukalner cut focal seizures by a median of 53% at its higher dose in the phase 3 X-TOLE2 trial, against about 10% with a placebo. The 374 adults in the study had epilepsy that was still causing frequent seizures despite two or three other medicines. Results were published on 9 November 2026 in JAMA Neurology.

Xenon Pharmaceuticals, the Canadian company that makes azetukalner and paid for the study, has already asked the US Food and Drug Administration to approve it. The drug is not licensed anywhere yet. If it is approved, it would be the only epilepsy medicine on the market aimed at its target, a family of potassium channels in nerve cells, because the last drug of this kind is no longer sold.

The study authors, led by Jacqueline French of NYU Langone Health in New York, describe the result as one of the largest median reductions in seizures over placebo ever reported in drug-resistant epilepsy. That is a cross-trial comparison, which they also caution against, so treat it as context.

Who was in the X-TOLE2 trial?

These were people for whom epilepsy treatment had largely run out of road. On average they had lived with epilepsy for about 25 years. Before joining, they had tried and given up a median of five antiseizure medicines, and 89.8% were still taking two or three at study entry. Their median baseline was 12.75 focal seizures a month, so roughly three a week.

The trial ran at 138 hospitals and clinics across North America, South America, Europe and the Asia Pacific region between November 2022 and February 2026. Participants were randomly split into three equal groups: placebo, 15 mg of azetukalner or 25 mg, taken once a day with the evening meal. Nobody in the study knew which capsule they were getting, which keeps expectations from colouring the seizure counts. Our guide to placebo and blinding in clinical trials explains why this design matters for a condition where seizure diaries are self-reported.

Everyone kept taking their usual epilepsy medicines. Azetukalner was tested as an add-on, the way most new epilepsy drugs first reach patients. The double-blind phase lasted 12 weeks, and 322 people went on to an open-label extension where everyone gets the drug.

How many fewer seizures did people have?

The main measure was the median percentage change in monthly focal seizures compared with each person's own baseline. All three groups improved, which is normal in epilepsy trials, but the drug groups improved far more.

Both doses beat placebo on the main measure (P < .001 for each). The paper reports that the trial met six of eight efficacy end points in its pre-set testing order, including the main one and the first five secondary ones. Some of the rows above, such as the 75% and 100% reductions, were exploratory, so their P values are nominal and should be read as supporting evidence.

Speed was one of the more striking findings. Azetukalner is started at its full dose, with no slow build-up over weeks. In the first week alone, the 25 mg group had a median 45.2% fewer seizures than at baseline, against 19.3% on placebo, a statistically significant gap. The 15 mg group reached 33.3% in week one, which fell short of significance (P = .08). By week 12, the weekly reduction in the 25 mg group had grown to a median of 70.4%.

A later analysis looked at who had no seizures at all towards the end of the trial. In the final four weeks, 13.7% of people on 25 mg and 12.8% on 15 mg were seizure-free, compared with 4.0% on placebo. This was a post hoc analysis, meaning it was decided after the data came in.

What does a 53% drop look like for one person?

Medians describe the middle of a group, so individual results will vary widely. Still, a rough worked example helps.

Take someone having 12 focal seizures a month, close to the trial's median starting point. A 53% reduction would remove about 6.4 seizures (12 x 0.53), leaving roughly 5 or 6 a month. A 10% reduction, similar to the placebo group, would remove about 1.2, leaving close to 11. The difference between the two is about five fewer seizures a month, or more than one a week.

For the 54.8% of people on 25 mg who were "responders", seizures at least halved. For the rest, the benefit was smaller or absent. Our explainer on how to read clinical trial results covers why medians and responder rates tell different parts of the story.

How does azetukalner work?

Nerve cells in the brain have tiny gates called potassium channels. One family, known as Kv7 (specifically Kv7.2 and Kv7.3), acts as a brake. When these channels open, potassium flows out of the cell and calms it down, making it harder for the cell to fire in the rapid, synchronised bursts that cause a seizure.

Azetukalner is a Kv7 channel opener. According to the paper, it lets these channels open earlier and stay open longer, which strengthens the brain's own brake on runaway electrical activity. Most existing epilepsy drugs work on sodium channels, calcium channels, GABA signalling or the SV2A protein. A different mechanism matters for people already on two or three medicines, because adding a fourth drug that does much the same job as the others tends to help less.

There is history here. An older Kv7 drug, ezogabine (called retigabine in Europe), was approved and later taken off the market. Long-term use was linked to skin discolouration and pigment changes in the retina, warnings that appear in its US prescribing information. The X-TOLE2 authors say azetukalner is chemically different, does not form the pigmented compounds blamed for those problems and has no relevant effect on GABA receptors. Investigators monitored skin and eyes closely in this trial and saw no concerning events, nor any through 48 months in the earlier X-TOLE extension study.

What side effects did people report?

Side effects were more common at 25 mg, and that is the main trade-off. At least one side effect was reported by 62.4% of people on placebo, 67.2% on 15 mg and 82.3% on 25 mg.

Dizziness stood out. It affected 3.2% on placebo, 9.6% on 15 mg and 31.5% on 25 mg. The 25 mg group also had more tremor (12.1%), headache (11.3%), fatigue (11.3%), confusion (10.5%), problems finding words (9.7%) and walking difficulty (9.7%). Most of these are familiar effects of drugs that quieten brain activity.

The more telling number is how many people stopped. Side effects led 3.2% of the placebo group, 4.8% of the 15 mg group and 14.5% of the 25 mg group to quit treatment permanently. In practice, the 15 mg dose looked close to placebo for tolerability, while 25 mg worked better but was harder to stay on.

A few rarer events are worth knowing about. Four people across all groups had urinary retention, one of whom needed a catheter. The paper notes that Kv7 channels also help control the bladder muscle. Two people taking azetukalner had psychotic episodes, one of them serious, and both resolved. Serious side effects overall affected 2.4% on placebo, 3.2% on 15 mg and 5.6% on 25 mg. No one died.

Separately, in September 2026 Xenon paused new enrolment in its trials of azetukalner for depression and bipolar depression after reviewing neuropsychiatric side effects in those studies. Patients already enrolled are continuing, and the company says the pause does not affect its ongoing epilepsy studies.

What are the limits of this trial?

Twelve weeks is short for a lifelong condition. The open-label extension will show whether the benefit lasts and whether more people become seizure-free over time. Data from the earlier phase 2b X-TOLE study offer a hint: 38.2% of people treated for at least 48 months went 12 months or more without a countable seizure. Open-label results carry no placebo comparison, though, so they are weaker evidence.

The trial also counted seizures from day one, because there was no dose build-up. That makes it hard to line up these numbers against other epilepsy drugs, whose trials usually start counting after a titration period. There was no head-to-head comparison with another medicine.

The population was 81.8% White, and 96.3% were under 65. The participants also had severe, long-standing epilepsy. Xenon plans a separate study, X-FIRST, to test azetukalner as a first add-on in people with less difficult epilepsy, starting in early 2027 according to its third-quarter update.

When could azetukalner be available?

Xenon announced on 17 September 2026 that it had submitted a New Drug Application to the FDA for focal seizures. The filing rests on X-TOLE2 and the earlier phase 2b X-TOLE study, and the company says the epilepsy programme has generated more than 1,500 patient-years of safety data. The company has not published an expected FDA decision date in the releases we reviewed. Our explainer on how new medicines get approved walks through what usually happens after a filing like this.

Outside the US, the picture is slower. A third phase 3 trial, X-TOLE3, is still recruiting and is intended to support applications in other countries, so filings with the European Medicines Agency or the UK's MHRA are not expected yet. Another phase 3 study, X-ACKT, is testing azetukalner for primary generalised tonic-clonic seizures in adults and teenagers aged 12 and over.

The World Health Organization estimates that around 50 million people worldwide have epilepsy and that up to 70% could live seizure-free with proper diagnosis and treatment. The people in X-TOLE2 belong to the remainder, whose seizures continue despite several drugs.

This site has also covered other recent neurology trials, including the oveporexton results in narcolepsy type 1 and remibrutinib in relapsing multiple sclerosis.

What should people with focal epilepsy do now?

Azetukalner can't be prescribed yet, so nothing changes today. If your seizures continue despite medicine, the most useful step is to ask your neurologist or epilepsy nurse whether you have been assessed at a specialist epilepsy centre. That review can open up options such as other licensed medicines, surgery assessment or device treatments.

Trials are another route. The X-TOLE3 and X-ACKT studies were still enrolling according to Xenon's November update, and the X-TOLE2 record on ClinicalTrials.gov links to related studies. Our guide on how to find and join a clinical trial explains how to search by condition and location.

Useful questions to take to your next appointment:

• Am I on the right combination of medicines for my seizure type?
• Would a referral to a specialist epilepsy centre help me?
• Is there a trial near me that I could be eligible for?

Xenon has said it will present more azetukalner data at the American Epilepsy Society meeting in Denver on 4 to 8 December 2026.

This article is for information only and is not medical advice. Never stop or change an epilepsy medicine without talking to your doctor, because stopping suddenly can trigger severe seizures.