AAN 2024 | Update from the X-TOLE open label extension study of XEN1101 in focal epilepsy

The X-TOLE study was the Phase II study with this new potassium channel opener. Some people may be familiar with the previous potassium channel opener that was available, called retigabine or ezogabine. That drug went through Phase I, Phase II, and Phase III, was approved by the FDA, but unfortunately was taken off the market after it was determined that it caused blue discoloration of the fingernails and the sclera, and it was unclear whether that would cause long term problems for people. But it was really a proof of concept that potassium channel opening was an important mechanism and that it was capable of improving the lives of people with treatment-resistant epilepsy. So, fortunately, this is another compound that has the same mechanism. It also worked, but it has some benefits compared to the previous compound. In addition to not producing the dimerization that caused the blue discoloration, it has a very long half-life, it needs no titration (so it can be started at the therapeutic dose), and it needs to only be taken once a day, whereas retigabine needed to be taken three times a day. A drug in the epilepsy space that only needs to be taken once per day is definitely advantageous. We don’t really know about any major drug interactions at the moment, and we don’t know of any major safety issues. There was another safety issue with retigabine involving people having bladder issues, and so far there have been a few people who have had some minor bladder issues with this drug, but nothing where they even needed to discontinue therapy. They could continue therapy with it. So far, we don’t know of any serious safety concerns. Of course, it’s early days, but cautiously optimistic on that.

In the randomized, placebo-controlled Phase II trial, we saw very nice efficacy, which was dose-related, with the highest efficacy being at 25mg. All of the individuals who were in the randomized, placebo-controlled trial had an opportunity to go into the open-label extension, and now the open-label extension has been ongoing for some patients over three years; quite a substantial period of time. Over 50% of the people that were in the original study continue on the drug. Usually there’s an attrition year on year, so still having over 50% of them is a testament to the fact that they are receiving benefit from the drug. The people who are continuing on the drug now – more than 50% of the original group – are seeing a median of somewhere between 75% and 90% reduction in their seizures. In the long-term extension, they’re certainly not losing benefit and there’s sustained benefit over time. They’re getting substantial benefit and they’re tolerating the drug to the extent that they want to stay on it for a long-term exposure. So far, the signs are very good. There is one Phase III study that’s ongoing and another Phase III study in another type of epilepsy; generalized epilepsy. Hopefully soon we’ll have those enrolled and get more data and know even more. But people are certainly talking about this drug, as a drug that can make people seizure-free, and that will provide a game-changing improvement in the lives of people with treatment-resistant epilepsy.