Understanding the Therapeutic Potential and Promising Early-Stage Data on Azetukalner for Focal Onset Seizures

Focal onset seizures (FOS) remain one of the most common and challenging epilepsy subtypes to manage, particularly among patients who continue to experience seizures despite multiple antiseizure medications. Although the therapeutic armamentarium has expanded over the past two decades, most available options rely on overlapping mechanisms, and seizure freedom remains elusive for many individuals with drug resistant focal epilepsy. Xenon Pharmaceuticals’ azetukalner, formerly known as XEN1101, has shown some early promise as a potential treatment for FOS, with phase 2 data supporting the agent’s development to date.

At the recently concluded American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, the company presented several analyses regarding the medication, including the phase 2 X-TOLE trial (NCT03796962) and its open-label extension. In this study, 325 patients with FOS were randomized, with 275 entering the extension phase that lasted up to 7 additional years. Overall, findings revealed sustained and progressive reductions in seizure frequency, with median percent reductions approaching 91% by 48 months and notable seizure freedom signals even in a highly refractory population.

During the meeting, NeurologyLive^® caught up with Christopher Kenney, MD, FAAN, chief medical officer at Xenon, to discuss the rationale behind azetukalner, as well as the key efficacy and safety data presented. In addition to the data, Kenney previewed the phase 3 FOS program and parallel development in primary generalized tonic clonic seizures. Furthermore, he spoke on early preclinical thinking for a separate NaV1.1 potentiator program in Dravet syndrome with implications for sudden unexplained death in epilepsy (SUDEP).

NeurologyLive: To start, can you walk us through the mechanism of azetukalner and why Xenon believes this drug can be successful in a field with many existing antiseizure medications?

Christopher Kenney, MD, FAAN: Azetukalner is the name of the drug. Previously it was referred to as XEN1101, and for those who struggle with azetukalner, you can say AZK. We are really excited about this drug. First of all, there are a lot of antiseizure medications already available, so if you are coming along with a new one, you really have to bring something significant to the table. What we are bringing is a brand new mechanism.

If you think about a single neuron, for that neuron to fire there is an opening of sodium channels that drives neuronal firing. To turn off that neuronal firing, potassium channels open and help stabilize the neuron. What we are doing pharmacologically is coming along with a potassium channel opener, keeping it open longer and keeping the neuron in a more hyperpolarized state. That way, if there is neuronal firing, you prevent it from going into a state of repetitive firing.

The reason that is relevant is because we believe this drug can be helpful in any scenario where you have a hyperexcitable neuron. In epilepsy, there is a population of hyperexcitable neurons in an epileptogenic focus. So it provides utility in terms of preventing seizure initiation, and it should also help prevent seizure propagation or generalization. We think this mechanism gives the drug broad potential within epilepsy and potentially beyond neurology as well.

In addition to the mechanism, we are seeing really robust efficacy in both the short term and long term. In our phase 2b study, the separation between the high dose and placebo was the largest reduction in seizures ever seen in a focal onset seizure study. On top of that, this is a drug that is easy to use. It is dosed once a day. There is no titration. There are minimal drug drug interactions. We see rapid onset, with substantial seizure reduction within the first week of exposure.

Turning to the open label extension, can you walk clinicians through the 48 month interim results and the key long term takeaways from the X TOLE OLE?

Our plan is to update the open label extension every year at the American Epilepsy Society. To set the stage, in 2021 we rolled out the results of the phase 2b study, which we call X TOLE, and that is positioned as the first pivotal trial. That study has a seven year open label extension, and this year we are presenting a 48 month cut.

The population that entered the study was very impaired. Median seizure frequency was 13.5 seizures every 28 days. Half the patients were on three antiseizure medications, 40 percent were on two, and only 10 percent were on one. On average, patients had failed six antiseizure medications before entering the study. It is the most impaired focal onset seizure population ever assembled for a trial, so that context is important.

In the open label extension, 275 patients rolled over from the phase 2b study. Across all comers, 20.7% achieved seizure freedom for a year or more. If you look specifically at patients who have been in the study for years, 38% achieved at least one year of seizure freedom. Notably, 10% of those patients have now been seizure free for 48 months or longer.

If you look at the literature, the chance of someone who has failed three antiseizure medications becoming seizure free is typically in the low single digits. So these data are quite striking.

What is different this year is that we looked at the data from a more prescriber focused angle. We asked, if a patient achieved seizure freedom for six months and then had a breakthrough seizure, should you give up on the drug or continue? Among patients who had at least six months of seizure freedom, about 43 percent met that criteria. If they later had a breakthrough seizure, 69 percent went on to achieve another six months or more of seizure freedom, and 57 percent achieved another year or more.

The takeaway is that a breakthrough seizure does not necessarily mean the drug has failed. That is important practical information for clinicians.

And beyond the percentages, each of those data points represents a patient. The most rewarding part of my job is hearing stories at meetings like AES about patients who are seizure free for the first time in their lives and can go to college, get married, or live independently.

What should clinicians know about the long term safety profile of azetukalner?

The double blind phase 2b study is helpful because you can directly compare drug to placebo. Open label studies do not have that comparison, so there are limitations. That said, what we are seeing in the four year open label extension is very consistent with the double blind data, and we are not seeing surprises.

The most common adverse event remains dizziness. The second most common is headache. The third is COVID infection, and the fourth is somnolence. Three of those four were also seen in the phase 2b study. The COVID signal is likely related to longer exposure during the pandemic rather than the drug itself.

Overall, the safety profile has been stable and predictable over time.

Looking ahead, can you outline what is next for azetukalner in terms of phase 3 development and additional seizure indications?

Based on the phase 2b data, we moved directly into phase 3 for focal onset seizures. We have two phase 3 studies, X TOLE2 and X TOLE3. X TOLE2 is the key study for the United States, and we expect results at the beginning of next year. If those data are consistent with phase 2, we plan to submit a new drug application.

In parallel, we are also developing azetukalner for primary generalized tonic clonic seizures. Most companies do this sequentially, but based on the mechanism, we felt confident pursuing these programs in parallel. Those studies take longer, so that will be further down the road.

We are also developing the drug in psychiatry. Azetukalner is in phase 3 development for major depressive disorder, with two ongoing studies, and a bipolar depression study has recently started. Because depression and anxiety are so common in refractory epilepsy, we are prospectively collecting mood data at every visit in every epilepsy study to understand whether that signal translates to this population.

At AES 2025, Xenon also highlighted early stage pipeline work in Dravet syndrome, including implications for SUDEP. Can you briefly explain that program and its potential relevance?

Dravet syndrome is caused by haploinsufficiency of SCN1A, meaning one NaV1.1 sodium channel functions normally and the other does not. Our approach is to pharmacologically take advantage of the functioning wild type NaV1.1 channels by introducing a NaV1.1 potentiator, analogous to what we are doing with Kv7 channels.

These patients are extremely impaired, with severe seizures, developmental delays, motor challenges, and cognitive impairment. While there are exciting genetic and antisense approaches in development, we are working on an oral therapy that could complement those strategies.

Our program is not yet in the clinic, but we hope to enter clinical development next year. In preclinical Dravet mouse models, we have seen reductions in seizure frequency, improvements in motor function, and notably, an elimination of SUDEP in treated animals. You never know how preclinical findings will translate clinically, but we are encouraged and moving forward.

More broadly, it is important for the field that patients eventually have multiple therapeutic options, including genetic, antisense, and oral therapies.

Transcript was edited for clarity. Click here for more AES 2025 coverage.

REFERENCE
1. French JA, Porter RJ, Perucca E, et al. Long-Term Safety and Efficacy of Azetukalner, a Novel, Potent KV7 Potassium Channel Opener, in Adults With Focal Epilepsy: ≥48-Month Interim Analysis of the Ongoing 7-Year X-TOLE Open-Label Extension. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. ABSTRACT 3.356