EEC 2026 | Which emerging epilepsy therapies are likely to change clinical practice?

Azetukalner probably is the molecule that every epileptologist should actually get their eyes on. They’re probably going to talk a lot about that on AES 2026 at the American Epilest Congress that is going to be in Denver this year. So this is one of the most advanced candidates they just submitted for FDA approval so it’s probably going to reach markets between the end of 2027 and the first semester of 2028. The main issues probably is probably going to be the neuropsychiatric adverse events, but I believe those are going to be probably worked out. And as I said before, Professor Jacqueline French from NYU, she talked about the X-TOLE part two. I’m not going to repeat myself, but it showed very promising because we’ve seen a part of the patients that were still on the open label would have seizure freedom for over 24 months or over two years. This is a result that we did not have without the medications. We only had it in this highly pharmacoresistant focal epilepsies with cenobamate. So that’s amazing because probably those patients already tried cenobamate and also failed. So perhaps the combination of cenobamate and azetukalner is going to be the next thing in epilepsy, who knows? But because azetukalner is a very different mechanism of action by opening channel V7 subfamily, and actually opening this channel so that the neuron could hyperpolarize instead of blocking depolarization, it’s going to affect the field in the next year or so. So I believe this is the molecule that we have to watch very closely, because it’s going to come out, patients are going to ask about them, and we’re probably going to have a lot of patients that will have an indication to actually try azetukalner in the future. So I believe that’s very interesting and that’s very amazing because it’s a very different target than we have in other ASMNs right now. So we’re going to marry very, very nicely in a rational polytherapy, polypharmacy kind of way with the medication that we have on the market. So patients are going to benefit a lot from this medication. And of course, we’re going to have to watch out for neuropsychiatric issues, but we had very trained on that because of the whole levetiracetam for neuropsychiatric issues, and also perampanel. So I believe it’s going to be very soon and it’s going to come to us in a very nice way.

One other thing that we actually saw during the European Epilepsy Congress was that the combination with cenobamate now also works in primary generalized tonic-clonic bilateral tonic-clonic seizures. So the trial that came out, just came out, showed an efficacy of over 70%, I believe, comparing with 40% in placebo. We know that these patients, they have lower seizure frequency, so it’s very hard to match them with the focal pharmacoresistant patients, but still, having a positive Phase III result actually gives us hope so that we could treat patients with pharmacoresistant primary generalized epilepsies as well with cenobamate, especially the ones that have bilateral generalized flanculant seizures. So this is probably going to open the cenobamate to a more wide window that we can apply them, not as valproate or even levetiracetam, but probably it’s going to be a good option in the next few years.

Another thing that came out in the European Congress was the positive Phase III trial for CDKL5 deficiency that showed that fenfluramine also have an important response in this population. Of course, we already use fenfluramine for Lennox–Gastaut syndrome and Dravet syndrome. Here in Brazil, it was only approved by now for Dravet syndrome. They just arrived in September. But it’s nice to hear that patients that actually have several seizures a day had such a nice response. And this is very interesting with the idea that I told you before about Dravet syndrome. Usually we don’t see any placebo response in this population because the seizures are very severe. So as in Dravet syndrome, CDKL5 deficiency also have a high seizure burden and also they respond very little to placebo. As you can see in the trial, we had almost 50% median reduction, I believe it was 48% median reduction of seizures with fenfluramine, compared with 3% of placebo, so almost random, the placebo response.

And of course, the greatest hope for the field in the next few years, especially for Dravet syndrome, as I said before, I’m going to say it again, is targeting the SCN1A mutation. So increasing the production of the healthy allele in the patient, so increasing SCN1A function, either by messing with RNA or by inputting the healthy gene within the neuron itself. So zorevunersen does the first and ETX101 does the second. So, I believe these molecules are probably going to be approved in a faster way because they are novel mechanisms of action in the next three to five years, I believe. It will be sooner than later. And also, we are going to have the medication for SCN2A. That is the medication elsunersen. That actually reduces the production of this channel that’s mutated. So, this is very exciting news and we’re probably going to tackle a lot of the issues that we have been able to tackle. So especially the neurodevelopmental findings from zorevunersen, the open label study, are very exciting. So I look forward to see that data published and also the randomized trials, the double-blind randomized trials, because despite having strong controls showing that this population actually improved, we know it’s ground truth that these patients do not improve. They actually get worse or they stabilize, they do not get better over time. But even so, we still have to have these double blind studies because it actually leaves no place for doubt that medications are actually working to make brain networks healthier and actually to make the patient overall much better. So I believe those are the issues and those are the things to look forward in the next few years in the field of epilepsy. And I believe it’s a very exciting time to be an epileptologist because as most epileptologists are working mostly with epilepsy surgery and now get to see these principles applied without having to actually take out a part of someone’s brain out and see similar results and see that we can change etiology itself on a molecular level are actually the holy grail of epileptologists. And that’s why we actually changed the names from anti-epileptic drugs to anti-seizure medication to leave it no space that we must look forward to antiepileptogenic treatments. And that’s what we’re doing now. And it’s a very exciting time to see where the field will go in the next few years.

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