Potassium Channel Opener XEN1101 Offers Simplicity and Strong Efficacy in Seizure Control

XEN1101 (Xenon Pharmaceuticals), part of a class of chemicals called potassium-channel openers, is an investigational antiseizure medication in development for patients with focal epilepsy. This treatment is designed to avert seizures by boosting the flow of potassium out of nerves and stopping them from firing. Published in JAMA Neurology, new findings from the phase 2b X-TOLE trial (NCT03796962) assessing XEN1101 showed that treatment with the therapy was associated with seizure reduction in a robust dose-response manner.¹

X-TOLE is a phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial that assessed XEN1101 over an 8-week treatment period between January 30, 2019, and September 2, 2021. The trial also included a 6-week safety follow-up. Researchers enrolled adult patients who experienced 4 or more monthly focal onset seizures while receiving stable treatment at 97 sites in North America and Europe. On completion of this part of the study, patients were offered enrollment for an open-label extension (OLE). Those who did not participate in the OLE had follow-up safety visits at 1 and 6 weeks after the final dose. The primary efficacy end point was the median percent change from baseline in monthly focal onset seizure frequency.

Lead author Jacqueline French, MD, professor of neurology at NYU Grossman School of Medicine and chief medical officer of the Epilepsy Foundation, recently sat down in an interview with NeurologyLive® to discuss the main findings from the study and the future research of XEN1101. She talked about the percentage of treated participants with epilepsy who experienced seizure reduction, including those who achieved seizure freedom. French also spoke about how XEN1101 simplifies dosing and improves medication adherence for this patient population. In addition, she explained the significance of the long-term extension study and the potential for enduring benefits from using XEN1101.

NeurologyLive: What were the main findings from the study investigating XEN1101?

Jacqueline French, MD: When patients develop epilepsy, about two-thirds of the time it's easy to find a medication that will benefit them to get their seizures under control and one-third of the time we find that it is very difficult. Studies show that the antiseizure medicines that have failed patients are likely to fail with medicine number 3, number 4, number 5, and so on. This was a study of patients who had many different antiseizure medicines that failed them while still having quite a high seizure burden with at least 4 seizures a month. When we looked at the patients who enrolled, they were having more like 15 average seizures a month, which is quite a lot. We were trying to see whether we could find something that would benefit these patients, which are so difficult to treat.

Happily, what we found was that quite a number of them had a really nice response. We tested 3 different doses compared with sugar pill or placebo. The doses were a low dose of 10 mg, a moderately high dose of 20 mg and then a higher dose of 25 mg. The highest dose of the patients who were randomized to the placebo had about an 18% reduction in seizures, the placebo effect as we say. But the patients who were randomized to the high dose [active treatment] had a median of over 50% reduction. More importantly at that high dose, about 25% of them had more than 75% reduction in seizures, and about 8% of them stopped having seizures altogether. That is the real “brass ring,” getting people to stop having seizures.

What do these findings mean in particular for this hard-to-treat patient population?

There are a couple of things that we like to see in antiseizure medicines that we haven't seen recently. Things that make it easier for the patient and easier for the clinician about the treatment. Number one: with the number of the recent medications that have been approved, you need to very slowly ramp up the dose over time. This is very problematic for both the patients who take the medication with the seizures as well as their clinicians providing complicated instructions for them when they start. This investigational drug was started from the same dose the first day that they got it to the last day that they got it. It was very simple as patients would take this dose then go home and take that dose. That is a really nice aspect of the drug.

The second nice aspect of the drug is that it has quite a long half-life, meaning the amount of time it remains in the bloodstream over a day. Having that in an epilepsy population is very helpful because taking medication on a very regular schedule is important to keeping patients seizure free or at least having as few seizures as possible. If you are late on a dose or miss a dose, if the medicine doesn't stick around a whole long time in the bloodstream, then you might not have a whole lot of what we call medication forgiveness. You might be at risk for a seizure relatively quickly after you miss a dose. The longer that the medicine stays around in the bloodstream, the better off you are. The other advantage is the amount of times that you have to take it. There are some medications you have to take twice a day, some medications that you have to take even more than twice a day. In this case, people only had to take the medicine once a day or will only have to take the medicine once a day. That's an advantage as well.

When you get to the higher doses, as is true for almost all of our antiseizure medicine, people start to have difficulty tolerating the medication. It's not everyone, but some people will have adverse events as the medication dose increases. In this case, the same thing happened where more adverse effects were observed as the dose increased. The nice and reassuring aspect is that 96% of the people who were in the study decided to go into the open label extension study. This means that whatever happened to them during the study, they still wanted to take the medication and go on. Now, we have some results from that longterm extension study that suggests that the benefit that you see is going to be an enduring one. Patients remain seizure free into the longterm extension and that's been going on for some people for 3 years, or even longer. I personally have a patient who I enrolled in the study. This patient was having daily seizures and had multiple drugs that failed them as well as stimulation devices to epilepsy surgeries that failed, still was having all of these seizures. Now, this patient has been seizure free for 3 years.

Do you think that this treatment can be a game-changer in the landscape of care for epilepsy?

Yes, but also that's not going to be the outcome for everyone. In this incredibly difficult to treat population, to see a certain percentage of people go completely seizure free is reassuring. It is exciting every time we get a drug that gets a population seizure free, and eventually we hope it'll get everybody seizure free. This is the ultimate goal, and if we can't get them seizure free, at least we hope to get their seizure burden down to where they can have the best quality of life.

Is there anything else that you think should be investigated further with this therapy?

This is the first trial that compared the drug in a very rigorous way to a sugar pill. By the way, all of these are added on to the medication that patients are already taking. There will be another study because in order to get a drug approved, you need to do a second study and confirm the results of the first study. That study is already ongoing, and we are very much looking forward to the results of that one. In addition, this was a study of patients with focal epilepsy, which is the largest category of people with epilepsy, but there are other epilepsies. This is a drug that has the potential to be what we call broad spectrum, which means that it could control seizures and other types of epilepsy as well.

The first one that's being tested is patients with generalized epilepsy. Most of those patients have an underlying genetic reason for having seizures, not one single gene but just their whole genetic makeup makes their brain hyper excitable. Those patients are now being enrolled in another trial and we're hoping for very good results from that one. We now have a little window into what the benefit of the drug is, and we must expand that window to see who else we can help. Eventually, it would be interesting to see whether lower doses could control seizures in patients who don't have this very terrible treatment resistant epilepsy but have a milder form or even newly diagnosed.

The treatment might benefit people in the earlier phase of the disease or the earlier spectrum of the disease. In fact, one of the analyses that was done [from this trial] is going to be presented at the American Epilepsy Society Annual Meeting this year. When you look at this severe group, patients who were on the milder end and on the more severe end of it, it helped both. But the people who were on the milder end really did even better. They had an even better chance of their seizure stopping and or having a substantial reduction. Those were still patients who had quite a few drugs fail them and so that's a very good thing to see.

Transcript edited for clarity.

REFERENCES
1. French JA, Porter RJ, Perucca E, et al. Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial. JAMA Neurol. 2023;10.1001/jamaneurol.2023.3542. doi:10.1001/jamaneurol.2023.3542