Cenobamate: A Game Changer For Epilepsy? - Ricardo Morcos, Instituto de Neurociencias Synaptia, Spain
Neurologist Ricardo Morcos talks about the anti-seizure medication Cenobamate (brand names Xcopri (US) and Ontozry (EU)) and its potential benefits for people with refractory focal-onset seizures. This is part 1 of 2.
Please note that this is not an endorsement of any particular anti-seizure medication (Cenobamate or any of the others mentioned) and any questions or ideas from a patient or carer must be brought up with one’s neurologist/epileptologist.
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Ricardo Morcos
“We make sure that they have tried Cenobamate in many occasions. The question that always comes [up] in these meetings (that we have as doctors, epileptologists, neurologists, radiologists, social workers, everything, psychologists, everything we discuss patient, complex patients to evaluate if they are candidates for surgeries), and one recurring question is always “Has this patient tried Cenobamate?!”
00:26 Torie Robinson
Fellow homo sapiens! Welcome to, or welcome back to: Epilepsy Sparks Insights.
Who’s heard of the drug Cenobamate? If you haven’t yet, well, so get out your notepad to hear from neurologist Ricardo Mocos - who explains how Cenobamate may be that “magic pill” for heaps of people who currently/or so far have a refractory (uncontrollable) focal epilepsy.
Please do note that this is not an endorsement of any particular anti-seizure medication (Cenobamate or any of the others mentioned) and any questions or ideas from a patient or a carer must be brought up with one’s neurologist/epileptologist.
Please don’t forget to share your thoughts on this episode with us in the comments below, like the episode, and do subscribe so that we can educate and empower both more people affected by the epilepsies and indeed more clinicians with patients who have an epilepsy - to provide the best care possible.
01:17 Ricardo Morcos
Hello, I'm Ricardo. I'm an epilepsy fellow at Madrid in Vitas hospitals. I'm also a neurologist and I take care of children and adults with epilepsy.
01:28 Torie Robinson
Both? Both, that sounds quite challenging to do both children and adults?!
01:31 Ricardo Morcos
Yes, and as a fellow, I'm trying to learn the epilepsy across all ages from the early 1 or 2-year-old children to the old people. I think it's good when you're learning. Then of course, later in life, you sometimes have to pick sides, but I think it's interesting to have this whole perspective and I'm having it in my fellow[ship]. So, it's nice.
01:57 Torie Robinson
And so, you're currently a neurologist, but are you going to become an epileptologist then?
02:01 Ricardo Morcos
Yeah. It's a 2-year program and we learn about epilepsy and also EEG because we think that both things go all the way together. You have to learn a lot about EEG and a lot about patients and their lives.
02:16 Torie Robinson
We've spoken a bit about this before, but, so, there's a relatively new drug. Cenobamate is an anti-seizure medication that has not been around long, especially when we compare it to, I don't know, like...phenytoin or even, like, more, I don't know, sodium valproate or, you know, lamotrigine. It's a quite a new drug. Can you tell us a bit about that and what you think of this medication, please?
02:41 Ricardo Morcos
Cenobamate is one of our new tools. It was approved in the US in 2019 and in the European Union in 2021, so, it's one of our newer tools that we have to treat seizures. And I think there's a big excitement around this medication because of its efficacy in clinical trial. Many of us as epileptologists, as neurologists, we are considering this medication as a game-changer for many people, especially with a focal-onset seizure, yeah, that's the main use right now.
03:22 Torie Robinson
Right, and so you this if for people who have seizures that start in one part of their brain - they can become generalised seizures but they…it’s established that they just start in just one focal part of the brain?
03:33 Ricardo Morcos
Yeah, initially the indication was for focal epilepsies. Those type of epilepsies are usually the ones that are more complex and more difficult to treat. So, usually all the clinical trials start with this population of patients and then we expand the medication. So, right now we are doing studies to understand how well works Cenobamate for generalised onset epilepsy.
04:00 Torie Robinson
Okay.
04:0Ricardo Morcos
So, probably, and also, it's approved in America and in Europe for adults (for people older than 18 years old). But we are also studying it in children because it's also probably very efficace.
04:18 Torie Robinson
And what is that success rate when…(by success, at the moment, I'm talking about stopping and preventing seizures) in the people who take it?
04:28 Ricardo Morcos
So, every time we discuss this efficacy, we have to see 3 different types of studies: one is the clinical trials (which are the ones that regulatory agencies look [at]) and those are usually 3-month follow up patients in a very controlled setting, then comes 1-year follow up, those are called open-label extension studies where you can change things, change the other medications and the patient and the doctor knows, they both know, that they are getting the medication (because [in] the first [study], the clinical trials are double-blinded usually (you don't know if you are getting the medication or the placebo)).
05:12 Torie Robinson
Right.
05:12 Ricardo Morcos
And then you have the real-world data (that we call it) (it is the series that the different hospitals publish about their own experiences with real patients that we call in real life with uncontrolled settings - I mean, people with their problems with their other medications…
05:29 Torie Robinson
So, it’s just regular people, like…
05:31 Ricardo Morcos
Yeah
05:32 Ricardo Morcos
…going to the hospital and they are being followed-up in registries). So, every type of study has pros and cons. But if we see in Cenobamate, all of them show more or less the same results - that's a very good thing! And the result from the clinical trial shows that the respondent rate (that's what we call when patient reduce at least 50% of the seizures)...
06:01 Torie Robinson
Okay…
06:01 Ricardo Morcos
… at the higher dose, was around 60%! 6 out of 10 people with this very drug resistant epilepsy responded at least with 50% reduction of the seizures! So, those results were never seen with any other drugs before Cenobamate.
06:25 Torie Robinson
Gosh, so with other drugs (just to compare it with some of the other anti-seizure medications), you know, how does 50 to 60% compare?
06:34 Ricardo Morcos
In this population, usually other drugs show [a] maximum half of the efficacy! And if we see… maybe the number is easier to understand… If we see the seizure…
06:47 Torie Robinson
Right…
Ricardo Morcos
seizure-freedom rate, seizure freedom rate at the dose between 200 and 400 differs (of course, the higher the dose, the higher the chances you have to be seizure free). But it's around (in the clinical trial), was around 20%. The seizure-freedom rate of Cenobamate is 20%! And we know (from the statistics) that when we have a drug resistant patient after 3, 4, 5…
07:14 Torie Robinson
Yeah…
07:14 Ricardo Morcos
…medications, the success rate is less than…
07:17 Torie Robinson
Tiny.
07:17 Ricardo Morcos
Yeah. 1%, 2%, 3%! Usually that's why we indicate the evaluation for epilepsy surgery in patients with focal epilepsy. And so, we've seen 20% (with a higher dose, in the clinical trial) of seizure freedom. That’s, that is a game changer that can save people from surgery even! If we are evaluating a patient for surgery, this is a long way, sometimes takes time to evaluate and to do the surgery. And in the meantime, what we are doing, in many epilepsy surgery centres and units, is trying to Cenobamate in the meantime, just to see if this patient reduces the seizure or is even seizure-free and we can save the surgery. And this can happen!
08:09 Torie Robinson
That's cool! So, you're basically… you've got somebody in… who’s working towards potential surgery (so, going through all the different, you know, things that they must do, so, like, certain EEGs, whether it be regular, intracranial, whatever), and, at the same time, pushing them on this new drug just to see…. So, they don't fall off the list for surgery should they need it. But maybe this drug will work.
08:29 Ricardo Morcos
We make sure that they have tried Cenobamate in many occasions. The question that always comes [up] in these meetings (that we have as doctors, epileptologists, neurologists, radiologists, social workers, everything, psychologists, everything we discuss patient, complex patients to evaluate if they are candidates for surgeries), and one recurring question is always “Has this patient tried Cenobamate?”! So, we should….
08:56 Torie Robinson
Really?
08:56 Ricardo Morcos
Yeah, everywhere! Yeah, that is we call it a game-changer because like all the newer medication that we have - we have advanced a lot in the last 10 or 15 years in terms of security; these new drugs are more secure and have less side-effects but in terms of efficacy they were not not good for this 30% of the patients with drug resistant epilepsy; they are stil…l they have been always a third of the patients and now we can act on those patients with drugs.
09:33 Torie Robinson
And so what are the potential negatives of this drug then? Because, you know, it's often weighing up the pros and cons of these drugs, and like, you know, sometimes, if you… if you become seizure free “Great…”, but is it “great” if the side effects are rubbish? So, tell us about that.
09:47 Ricardo Morcos
Cenobamate has something that has a dual mechanism of action. So, it acts on GABAergic neurons (those are the inhibitory neurons and they increase the levels of GABA and then they block the sodium channel (because the sodium channel helps the neuron to depolarise and be excited, I mean, it's an excitatory transmission)). And so, usually, as we use the Cenobamate in this population that is very drug resistant (I think this will change in the future; we will use it more, but right now we are using it in difficult to treat patients, usually, Cenobamate has this mechanism of action), it can interact with other drugs that act on the same level…
10:35 Torie Robinson
Okay….
10:35 Ricardo Morcos
…on those receptors. So, for GABAergic drugs, usually we see somnolence, ok. And for sodium channel blockers; the most common side effects are dizziness, ataxia, or double vision. Those are the most common side effects. The good thing is - and this is a big challenge for us as doctors - is that when you use Cenobamate, as it's so effective, you should reduce concomitant medication to prevent/to help to alleviate side effects. Because it's usually...
11:15 Torie Robinson
Sorry, what's “concomitant medication”? What's that?
11:18 Ricardo Morcos
It’s the other anti-seizure medications that you are on before taking Cenobamate.
11:23 Torie Robinson
Okay.
11:24 Ricardo Morcos
Usually, because those are usually people who are drugs resistant, yeah, well, sometimes they were partially effective…
11:32 Torie Robinson
Mmm.
11:32 Ricardo Morcos
So, it's good because Cenobamate gives you this opportunity to discuss with the patients “Okay, let's review your medication because now we have to make room for a new medication that it will probably (at least, statistically) be more effective than all of those.”. But, sometimes you can decrease the dose of the other anti-seizure medications. Sometimes you can just take it off. And so, I think it is complicated and this is one of the things that has limited its use, because you have to be confident and reduce other medication once the side-effects start. And if you don't have any side effect, you usually can reduce other medication because of [the] efficacy [and] say “Okay, we are now in a situation where we have reduced the seizures, let's take out this medication!”. If you have side-effects (from the other medications]; you do it quite quickly So there are some recommendations: I suggest all the clinicians that they should read To from the biggest centres in the world one is the “Spanish consensus” and another one from America that tells you how to manage these anti…older anti-seizure medications to prevent side effects. Of course, sometimes we cannot prevent it all, but we can reduce and solve them. And at the same time, being able to enjoy, let's say the benefits of having an effective anti-seizure medication. But this is not easy to do; it takes time and sometimes during that journey, you have to see your doctor a little bit more frequently. And this is something we have to consider every time we use Cenobamate. We have a slow titration scheme every 2 weeks (similar to Lamotrigine) and during those weeks we are adjusting the other anti-seizure medication to prevent side effects.
13:22 Torie Robinson
And commonly, people will be on, say, antidepressants and stuff as well. It's not… it's often not just an anti-seizure medication. So, does that need to be considered too?
13:42 Ricardo Morcos
No, there's no interaction mainly with the main and common antidepressant or any other common medications. It's usually… interactions are in terms of the site of action…
14:59 Torie Robinson
Yep.
13:59 Ricardo Morcos.
…We call it dynamic interaction and also the kinetic of the drug can change; the level of the drugs can change. So, if you are on Clobazam, for instance (that is a very common drug); as Clobazam acts on GABA, GABA receptor, you should decrease the dose. We all know that, and so we usually reduce the dose of Clobazam because it works really well with Cenobamate, but it has to be Clobazam at a very low dose (maybe 5-10 milligrams, depending on the patient). But we usually reduce it because it will help Cenobamate, but if you keep it very… in a very high level/in a very high dose, you will have a lot of somnolence/or drowsiness.
14:46 Torie Robinson
Going… sort of continuing with the sort of side effects, what about mood? Depression, anxiety, other mood disorders are very common in people with epilepsy. And sometimes as a result of taking medications, whether that's direct or indirect, whether it affects your cognitive function (that can cause you depression or whatever. What are the impacts of the drug when it comes to cognition and mental health?
15:10 Ricardo Morcos
It has an..I mean it has an indirect effect. Like Lamotrigine or Valproate - we know that they have a positive effect on mood, for instance, or depression. Cenobamate doesn't have this particular mechanism of action or effect, but I think that it helps you. I mean, it helps you to reduce medication that you already have that can have a negative effect. So, at the end, it helps you to reduce the burden of the medication of the patient. And if you have a very effective medication that reduces seizures, then this will improve, probably, quality of life and other aspects of your life. So, I have to say, particularly this medication:, it doesn't have a positive effect on mood or cognition in general. But what we see when we evaluate in the long term, of the reduction of the seizures, we see improvement in those areas. So, at the end, you know, at the end it has an impact, but it's not, by itself, let's say, like all the drugs have. Of course, it's a new medication and we will see long term, like 20 years… I mean, the first clinical trial has been 10 years ago, so we have information, but of course, once we use the medication in the whole population, then we see all the things, but it's more or less neutral. The only things, the precaution that we have to have in our mind is that if we increase those very quickly, we can have allergies.
16:50 Torie Robinson
Oh! But only if you do it quickly?!
16:52 Ricardo Morcos
Exactly. Yeah, we reduce the risk like Lamotrigine of this allergy is called DRESS Syndrome (it's basically a skin rash…
17:00 Torie Robinson
Yeah.
17:00 Ricardo Morcos
plus other things like fevers) and so then the titration period is long. You increase those every 2 weeks and you have a titration initiation pack: the medication comes in a box with all the pills that you take 2 weeks, these those 2 weeks, these those and you increase those from 12 .5 milligram up to usually 200 milligram, very slow every 2 weeks. And in doing that, we have learned that you prevent these skin rashes…
17:36 Torie Robinson
Oh!
17:36 Ricardo Morcos
…and the side effects. And it gives you time, also, to talk about with your patient, with patient about side effects because you are going really slow, so, you can discuss “Oh, have you noticed somnolence or drowsiness, or double vision?”. Okay, and then you are adjusting, all the time, the other anti-seizure medications.
17:57 Torie Robinson
Thank you very much to Ricardo for sharing with us - in part 1 of 2 - such valuable insight into Cenobamate! Tune in to part 2 with Ricardo next week to hear more about trying Cenobamate out - from the perspectives of both a clinician and a person with an epilepsy. If you’re interested in learning more, make sure that you check out the paper “Spanish consensus on the management of concomitant antiseizure medications when using cenobamate in adults with drug-resistant focal seizures” - the link to which you can find in the text below.
Check out more about Ricardo and his work on the website torierobinson.com (where you can also access the podcast, video, and transcription of this episode), and if you haven’t already, don’t forget to like, comment, and subscribe to the channel, share this episode with your friends/colleagues/family members(!) and see you next week!
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Ricardo Morcos is a neurologist and his passion is the study of the complexity of the brain and human life. His training has been nourished by various medical perspectives - he has had the opportunity to study in Argentina, Germany, UK (Queen Square), and Spain (Barcelona and Madrid). Each of these sites have provided him with a unique perspective on understanding people and the complex processes of health and illness.
His main focus, currently, is on the management of epilepsy, both in adults and children, and addressing its clinical, molecular, pharmacological, and psychosocial aspects. He has a special interest in genetics and is an active part of several clinical research projects in complex epilepsies.
Ricardo believes that medicine is a constantly evolving field and it is his commitment to continue learning and applying advanced knowledge to provide the best possible care to his patients.
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