EEC 2026 | Phase II/III POWER1: efficacy, safety and lessons learned for vormatrigine in epilepsy

So the POWER1 trial is a trial that actually got us very excited because it’s a functionally new type of sodium channel blocker. So vormatrigine is a small molecule that targets the functionally either inactivated or open sodium channel that actually has sustained depolarization during rapid and repetitive firing, which is exactly the mechanism that we want to stop seizures, right? And it actually gave us some really good data from the Maximal Electroshock model that actually targets focal and generalized epilepsy in animals and showed that it may be more active even though in lower doses just in comparison to the other medication such as cenobamatee and so forth. So the POWER1 trial was the first randomized control trial with placebo. The patients would start with 20 milligrams during six weeks of either placebo or vormatrigine. Then they would switch to 30 milligrams through vormatrigine. The patient that were on the medication and the patient with placebo would continue on placebo. So it was during the whole trial, eight weeks of screening and 12 weeks of treatment. So the trial actually was a little, we were a little sad that the primary endpoint was negative. So the first hope that we had that it would actually change our paradigm of sodium channel blockers that would block only seizures and not block other functions of the brain was actually negative. So this was very close. I believe P was 0.28. And what I actually saw was that probably the lower dosage of 20 milligrams was not effective enough because a secondary analysis showed that when patients switched to 30 milligrams, the trial actually, the drug actually had a very greater response rate for around 45 to 50% median reduction in monthly seizures. So despite the primary endpoint being negative, the secondary endpoint of the proportion of patients that actually got over 50% of seizures reduction during the trial was positive, especially because it counted, especially the last stand of the trial, which patients were having 30 milligrams a day. So, one thing I didn’t say before is that this is a once-a-day medication, so it doesn’t require titration, it already is the full dosage. What we actually learned from the trial is that despite the molecule having functionally having less interference with normal functions, it actually showed that patients would have dizziness in a greater proportion in patients who had been receiving vormatrigine. Around 40% of patients actually had dizziness comparing with 13% of patients in placebo. And also patients were described in being more drowsy, which was around 18% versus 6% in placebo. So the trial was primarily inactive, but there is a path forward, so the medication is not dead yet. I believe functionally active sodium channel blockers will be the future that block the persistent sodium current. Vormatrigine does this very similarly to cenobamate and actually targets the persistent sodium channel. So with the results from cenobamate being so good, we would expect that one medication that actually targeting that same pathway would actually have a good result.

So what we learned from this trial, and especially from sub-analysis that was presented in the European Epilepsy Congress, is that there were a few issues, especially patients who were already receiving two or more sodium channel blockers that unfortunately the trial did permit to enter the trial, actually had a much lower response rate than patients that were actually receiving only one or zero sodium channel blockers. That actually made sense. We already noticed that patients that already have a mechanism, a similar mechanism in action, when we add another anti-seizure medication that targets the same mechanism of action, they have higher rates of adverse events and they have lower rates of seizure control. So we kind of already knew this, but it was good to see that patients who are not receiving those medications actually did better. Another thing that the secondary analysis did show was that patients that were from high recruiting centers that probably have more diverse patients and were more involved in their treatment actually did a lot better. So the response rate was around 45% median reduction compared to placebo in those trials, especially the 30 milligram dosage, which was actually very close to 50% reduction, which is very good in a highly refractory population. So the path forward here, I think the central message here about vormatrigine and POWER1 is that it’s only the first step. So there was a lot of issues that were learned during the trial, and especially how to manage the medication, which is very potent compared to other sodium channel blockers that we have. So patients would have, this is my experience, patients would have incredible response in the first weeks, but we would have to lower their medications that the trial did allow, especially the sodium channel blockers, very quickly, so they would adapt to the medication. And once they adapted, they would stay on. For my center here, I think we have around 88% of patients that actually transitioned from the POWER1 to the open label extension that are actually still on the open label. And most of them actually did have a good response. So the path forward probably is they’re going to do a few adjustments in the inclusive criteria of POWER2 and POWER3, especially, I believe, the blocking of patients that actually were having more than one sodium channel blocker. And probably they’re going to focus more in the centers that actually had a high volume of patients in POWER1. I believe those are going to be the central changes, but there’s still a path forward. I believe that Praxis is the company that’s actually doing the POWER1, 2, and 3 trials are going to restart the trial soon. I believe before the end of the year, POWER2 will be restarted and we’ll finally have answers. And also another thing that I forgot to say is that probably the lower dosage, that’s the 20 milligrams is going to be forgotten. So we’re going to move for 30 or 40 milligrams and so forth. So I believe that’s a path forward and it’s a very exciting new mechanism of action that from my experience here in my center are probably going to have a very nice role in controlling focal seizures but we still have we still open a discussion that if it’s going to be positive in the future we hope it will but the trials will say.

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