Cenobamate & Fenfluramine: What's Changing for Uncontrolled Seizures? - Prof. Vicente Villanueva, Hospital Universitari i Politècnic La Fe, Valencia, Spain
Can newer epilepsy treatments help more people achieve seizure control - and does it matter when they're introduced? Epileptologist Vicente Villanueva shares with us findings from two studies investigating cenobamate and fenfluramine. He explains why earlier treatment may improve outcomes, how medication combinations and side effects affect quality of life, and what the research reveals about cognition, behaviour and sleep. Watch/listen/read here 👇!
Episode Highlights
Why introducing cenobamate earlier may improve seizure control
What Vicente's fenfluramine study reveals about seizure reduction, side effects and quality of life.
How medication combinations can influence treatment effectiveness and tolerability.
The future of epilepsy treatments that could change the course of the disease, rather than simply control seizures.
About Vicente
Dr. Vicente Villanueva, MD, PhD, is a neurologist, epileptologist and Head of the Refractory Epilepsy Unit and Epilepsy Surgery Programme at Hospital La Fe in Valencia, Spain. Since 2005, he has also worked in the hospital’s Multidisciplinary Epilepsy Unit, where he is Head of the Refractory Epilepsy Unit and Epilepsy Surgery Programme. He serves as a representative of the European Reference Network Epi-CARE, is a member of the International League Against Epilepsy (ILAE) Intellectual Disability Task Force, and sits on the Board of the European Consortium of Epilepsy Trials.
Full profile: Vicente Villanueva
Topics mentioned
cenobamate
fenfluramine
drug-resistance
efficacy
side effets
cognition
behaviour
sleep
polypharmacy
genetics
dravet
lennox gastaut syndrome
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Trailer
00:00 Vicente Villanueva
“Why to wait so many years if we have an effective medication that have better outcomes at the very beginning? So, that's the concept of this of this study and the conclusion. So, it's a medication [that’s] highly effective, working better in the earlier stages (as it happened with all the drugs), but at that at the end of the day was so effective; let's start earlier with this medication in order to have patients seizure-free, right. Or to have all of them or much of them with a better control.”
Intro
00:29 Torie Robinson
Why do some anti-seizure medications work better when they're introduced earlier - and how much difference can newer treatments make for people with drug-resistant epilepsy? Well, today we are joined by neurologist and epileptologist Dr. Vicente Villanueva, who’s Head of the Refractory Epilepsy Units at the University Hospital La Fe, and Ascires Hospital in Valencia, Spain. He’s going to share with us two studies: one about cenobamate and one about fenfluramine - what these tell us about seizure control, their side effects, impacts on quality of life, and why the future of epilepsy treatment might actually be about changing how the disease progresses, or stopping it from progressing completely?
Meet Vicente
01:09 Vicente Villanueva (00:05.178)
I'm a neurologist, I was training neurology more than 25 years ago. I'm working in epilepsy over the last 25 years.
How epilepsy treatments have changed
01:20 Torie Robinson (00:26.114)
So, given your experience, you've seen anti-seizure medications in terms of new ones being developed and availability really change over - not even just the past 10 years, but your whole career - tell us what that has been like and what have the effects been?
01:34 Vicente Villanueva (00:44.016)
You know, it's been a great change, I think. The changes has been done in two situations. First of all, I think we have medication that are producing less side effects than the medication that we have before, with less interaction and this is making the life of our patient better because they feel not as sedated or somnolent or dizzy, and this is quite good. And there are no interaction with other medication for whatever the reason that they were taking at some point. And the second is that we have more effective medication in 2 situations: first in some particular disease like Lennox Gastaut or Dravet where w new medication has been appeared. And also, in in the typical drug-resistant focal epilepsy; with the new with the new medication that are coming, I think the percentage of patients that are under control are much better. So, I will say that we have more tools to deal with epilepsy nowadays than those that I have when I started more than 25 years ago.
Why does drug-resistant epilepsy remain so difficult to treat?
02:41 Torie Robinson (01:53.71)
So, you say or imply we have more seizure control, but I think that's in some groups of people, isn't it? Cause we still have about a third of people (which is nuts), who don't have seizure control. And so why is that?
02:56 Vicente Villanueva (02:08.988)
The problem is that… first of all. epilepsy is a very complex condition; there are many epilepsies, so sometimes to get a treatment is not working.. it's working for some patients but not for others. This is did make things more complicated. And moreover, unfortunately, this 30% that is being traditionally seen as drug-resistant has been reduced but it's quite difficult in those patients so complicated with so high number of seizures to let them [be] seizure free. But probably because they’ve tried treatment strategies that we have are quite similar, all of them…
03:36 Torie Robinson (02:48.653)
Mmm.
03:36 Vicente Villanueva
…and even we have made things better, and as I say more patients are under control, or for example we don't go to surgery with so many patients because they have the seizure control. I have to say that we need new strategies, new mechanism of action or new ways to deal with epilepsy than those that we have at the moment. Probably, most of the options that we have (I will say nearly all of them) are just traditional anti-seizure medications to stop seizures [but we need to have a step] further in and go to other strategies. Genetic treatment, I don't know, many others probably.
The FREEDON study: Why earlier cenobamate treatment matters
04:17 Torie Robinson (03:35.65)
So, well, that brings us on then to your Freedon study. And I know that involves cenobamate for people who aren't familiar with that. It's a relatively newer antiseizure medication. And I believe that in that you found that people who started cenobamate after trying fewer previous antiseizure medications, they were more likely to become seizure free as a result and achieve a greater reduction in their seizures. What's that about? Why is that?
04:34 Vicente Villanueva (04:02.182)
I would say that it happens with any medication. If you treat early it's gonna be better than is you treat it late in terms of efficacy. But the idea is that as we saw so high efficacy with this medication (which has been better than the efficacy we have seen in the past with other medication) the conclusion is that as we have started treatment before, we avoid years of having seizures, right?
05:10 Torie Robinson (04:32.269)
Mm.
05:11 Vicente Villanueva (04:32.492)
And the response in early stages is better. So why to wait so many years if we have an effective medication that have better outcomes at the very beginning? So, that's the concept of this of this study and the conclusion. So, it's a medication [that’s] highly effective, working better in the earlier stages (as it happened with all the drugs), but at that at the end of the day was so effective; let's start earlier with this medication in order to have patients seizure-free, right. Or to have all of them or much of them with a better control.
Why do previous treatment failures predict poorer outcomes?
05:45 Torie Robinson (05:10.417)
In the people who started in the trial later on, 90% of them still didn't have their seizures controlled. What is the theory behind that? Is it because we think that they started later on in life and they had basically some brain damage as a result of refractory seizures or is it down to something else?
06:04 Vicente Villanueva (05:35.899)
The approach is that the later you start a new medication, the chance to have to be successful is low, lower, right? So, if a patient have tried only 2 medications, you have a higher chance to let them [be] seizure-free. But if you start a medication after the failure of 10 medications, the chance to be successful is lower. Based on the fact that as when subsequent medication fail, this is an… this is a the effect that the this that epilepsy is more complex and the possibility to be successful is lower. So, I think it's more an effect of the refractoriness of this patient than based on the fact that the there are some brain damage, right.
06:58 Torie Robinson (06:37.002)
Okay, so, and is that brain damage that has occurred post, has occurred as a result of seizures or TBI, or is that brain damage that could have been there as a result of epileptogenesis, for instance?
07:09 Vicente Villanueva (06:51.836)
Both. The cause of epilepsy can be a brain damage, as you mentioned, traumatic injury, or an stroke or a tumour or whatever. And also, when a patient is having seizures for years, particularly convulsive seizures, the possibility to have to have brain damage is higher. Right?
07:32 Torie Robinson (07:21.166)
Mmm.
07:32 Vicente Villanueva (07:22.054)
But, the in in my opinion, the main predictor factor (coming back to the… your prior question), that predicts the success or not success of a medication is the number of prior antiseizure medication that has failed. If the number is high, the chance is lower.
Fenfluramine for developmental and epileptic encephalopathies (DEEs)
07:50 Torie Robinson (07:43.212)
And so now let's go to your fenfluramine study. For those who aren't familiar with that, can you just give us a bit about it, how it's used for people with developmental epileptic encephalopathies? Tell us about the drug.
08:02 Vicente Villanueva (07:55.591)
This is an a group of patients that I'm very happy there are many new options nowadays in the last year and other are coming. So, I think that there are…. this those patients are rare disease but when you pull all together it's not a rare disease because there are many patients, right?
08:25 Torie Robinson (08:19.629)
Mm-hmm.
08:26 Vicente Villanueva
And I'm very happy with this concept of developmental and epileptic encephalopathy that can pull all these cases: Lennox Gastaut, Dravet, or many other cases. So, in this study we wanted to see what happened in those patients that have Lennox Gastaut or Dravet and also for other patients that were not under the indication of the medication but based on a compassionate use were tried on the medication, and we wanted to see the effect in all these populations and to have further data. And I think the conclusion is that it's working in most of those developmental epileptic encephalopathies. Of course, those cases are quite complicated and it's not successful in all of them, but outcomes in my humble opinion are quite interesting - in the whole group.
Balancing seizure control and side effects
09:12 Torie Robinson (09:07.658)
“Interesting” is an interesting word, isn't it? Because I guess outcomes, we could look at seizure control, but I understand in your study that there were significant side effects experienced by a significant percentage of people at different stages of the study.
09:28 Vicente Villanueva (09:24.656)
Yeah, this population, unfortunately, is highly medicated. It's those are taking a lot of drugs and it's very complicated to escape side effects. So, this is something that happened. And one objective in most of this study is to see if the number of medic… comedication is reduced at the end of the day…
09:51 Torie Robinson (09:47.938)
Yeah.
09:51 Vicente Villanueva
…and it was slightly reduced. So, I think that side effects are… unfortunately, were frequent with in this population with any drug but if we can find something that was successful and successful sometimes is not seizure free but it's to have less seizure or free of most disabling seizures you can discontinue other medication.
Cognition, behaviour and quality of life
10:14 Torie Robinson (10:12.462)
Mm. What do you think about the impacts on cognition and mood for the people who are... and also were these people children or were they adults or both?
10:22 Vicente Villanueva (10:19.844)
All of them. Yeah, I think this is something that should be better studied in the future. But we have seen with the evaluation that we did (that was mainly based on carers and a physician opinion) an improvement in cognition, in behaviour, in sleep, and so on. We still need to measure much better because we don't do it very well in clinic. But I'm optimistic that this medication and also other medications that are in the market and will be coming will improve this part in this.
Managing cenobamate side effects
11:00 Torie Robinson (10:58.744)
Fabulous. And just going back to cenobamate quickly, I hear a lot of horrible comments about cenobamate online from patient groups. Nasty, right? You're nodding! And what would be your reaction to that? We understand that there are awful reactions from some people, but in the whole grand scheme of things, what are we looking at?
11:22 Vicente Villanueva (11:19.964)
You know, I think this medication in focal seizure has been the most effective that we have in our hands in the last years, and it is true that can be associated to side effects, but the strategy is to know how to deal with them. If you know how to deal with them, I think that most patients will benefit. I wouldn't say everyone because it's not possible and it happened with any medication, but in my humble opinion, what I try to do is if I have a good tool to deal with epilepsy, I try to use it as much better as I can in order to be successful. So, I think that those comments are based on side effects that can happen, this is true, and I think that we as physicians what we need to do is to try to manage them as good or as best as possible.
Finding the right combination of treatments
12:13 Torie Robinson (12:13.878)
And does that sometimes involve… I mean, we don't want to do polypharmacy, but sometimes that can involve a combination of medications or some influence to a diet or to lifestyle or environment?
12:29 Vicente Villanueva (12:28.11)
Everything, but mainly are the co-medication. This medication is used in patients that has tried 2 antiseizure medication before and most of them are polymedicated. So, this combination of this drug with other drugs can provoke side effects. Also, lifestyle, as you mentioned is very important so everything is important but to find the right combination is key here.
12:56 Torie Robinson (12:59.808)
Does it feels like pick and mix, sometimes? Like, how do you know, like “We’ll try this, we'll try this.”, haha?
13:01 Torie Robinson
Haha!
13:01 Vicente Villanueva (13:04.722)
Haha! You know, still, medicine is a little bit an art, right, haha? So yeah, it's true. I know we know we know very well the drugs. This is science (I was joking!).
13:16 Torie Robinson
Haha!
13:16 Vicente Villanueva
But at the end of the day, you need to know how to combine the medication. And this is something that you learn with years of experience. It is not it is not learnt when you read a paper or when you are aware of medication. You need to have to be experienced with the medication, to be aware of side effects, to know your patients about what happened with them when you are using a particular combination and if you pull all this together, I think you can be successful. This is still very important in medicine.
The future: Treatments that change the course of epilepsy
14:45 Torie Robinson (14:00.704)
If you can predict it, what does the next 5, 10, 15, 20 years hold? When if we're trying to improve the quality of life of all these different types of people affected by these epilepsies...
13:58 Vicente Villanueva (16:33.122)
Yeah, I think the new strategies will be to be dealing with or to the drugs or the medication or the treatment that will be [a] disease modifier. That means that it's not only medication to have seizures under control, but to have a medication that could be started in the patient as soon as possible and change the course of the disease. This is probably easier to understand in genetic disease than when you can replace the gene or to replace the damaged protein or whatever. But also, I think that could happen in a structural epilepsies with some strategies. So, I think the future of the treatment will go with medication that change the course of the disease. I think that will be the hopefully the future.
Closing thoughts & thanks
14:53 Torie Robinson
Thank you so much to Vicente! So, newer treatments are giving us more options for controlling seizures - but when we use them, how we combine them and how they affect quality of life can be just as important. And we have reason to be excited about the potential future(!) - where maybe we could change the course of an epilepsy and maybe that could prevent some of its longer-term effects. If you found this episode useful, please like, subscribe and share - and we'll see you next time on Epilepsy Sparks Insights.