Pipeline of Progress: Epilepsy Medications on the Horizon
This webinar is the first in our Pipeline of Progress series, created especially for people living with epilepsy and the loved ones who support them.
This interactive webinar will help you understand what new treatments are on the horizon and what researchers are working on right now.
Our speaker, Dr. Fountain, is a highly respected epileptologist and a leader in clinical trials. He’ll walk you through epilepsy medications in Phase 3 trials, exciting ideas scientists are exploring, and a few promising treatments that may be getting closer to approval. We also have a moderated Q&A, where viewers asked questions in a safe and welcoming space.
The Pipeline of Progress series is generously supported by independent educational grants from Lundbeck, Stoke Therapeutics, and Xenon Pharmaceuticals and produced by CURE Epilepsy. CURE Epilepsy is solely responsible for the selection of the presenters and moderators. The opinions and recommendations expressed are those of the presenters and do not necessarily reflect the opinions, recommendations, or endorsements of CURE Epilepsy.
Q&A Transcript
Can neurologists tell whether you need potassium channel or sodium channel medications? And if so, how?
The only way to tell is if you have a specific genetic condition, which we know that you have abnormal sodium or potassium channels. For people with, for instance, SCN2A or SCN8A, those genetic conditions, we know they have abnormal sodium channels. Not only that, we know if they’re up-regulated or down-regulated. Some drugs might be more or less appropriate depending on whether it’s up-regulated or down-regulated, meaning you have overactivity or underactivity. Through genetic testing is the only way you can tell that. For people with what you might call garden variety epilepsy, so refractory focal seizures, or if you don’t know the cause, then we don’t know anything about sodium channels or potassium channels that would make one or another better, that is modulating one or another better.
I guess the fundamental question is, is one drug targeting potassium channels better than another drug that targets sodium channels? In general, unless we know a specific mechanism, then we don’t know which is better. Not only that, we don’t know which one is better among the drugs that exist today. We don’t have any randomized controlled trials. I listed 34, we didn’t talk about them all of course, 34 drugs approved for epilepsy and I think 10 or 12 in development. So not only do we not have comparisons among that, we don’t have comparisons among any of those in a randomized controlled trial, with just a few exceptions, and we don’t have controls among any of the most commonly used drugs. We don’t know for those.
Are children included in trials like this?
Yeah, there’s two answers to that. For conditions that are common in adults, the standard approach is to do trials in adults first to see that it’s safe and effective before exposing children, and the concept is children can’t quite consent for themselves. They can ascent if they’re old enough and can understand, but you’re putting them in a research study in which they might not know the consequences. So we start with adults and see it’s safe and effective, then move to children. That would be true for things like focal epilepsy.
But are there any common focal epilepsies that exist that are different in adults and children? The answer is no. A few years ago, as a result of some efforts from the community, actually, the FDA now allows extrapolation from adults to children. Once a drug is developed in adults for what I’m calling garden variety epilepsies, so meaning refractory focal seizures, the drug doesn’t have to have placebo-controlled studies in children. Instead, they can take that effectiveness research and just extrapolate and think it’s going to be good in children down to age one now. It requires other research to show it’s safe in children and to know the dosing and how it’s metabolized in children, but those aren’t typically placebo-controlled studies. For refractory focal seizures, it’s done in adults and typically doesn’t have to be done in children for efficacy studies, although others do.
Now, on the other hand, if something doesn’t exist in adults or starts in early childhood, then those studies are done in children. For genetic conditions that begin in childhood, the research is done in children. Often, adults are included, but it’s a bit uncommon for adults to be in a position to be in those clinical trials. They can, but often they’re so far advanced down the pathway that it doesn’t make as much sense or is much more complicated than enrolling children who are at the beginning of the whole process. For example, in the DEEs, commonly that would be in children.
How are medications determined to be safe or not during pregnancy?
That’s a tough one. We don’t have a way to prospectively give people the medicine. Typically, we’d say, “We’re going to give half of you placebo and half of you drug. We’re going to see who has problems and did more people on drug than placebo have the problem.” But we can’t do that for pregnant women because we’d be exposing it to them, so instead we have pregnancy registries, which we ask people with epilepsy who are taking these drugs, once they’re pregnant or becoming pregnant, ask them to register in the registry and then follow them prospectively over time. That’s kind of the best we can do. Pregnancy registries then look backwards to see if it caused problems. That sort of two or three kind of problems you might think of is, did they have a problem during pregnancy? Did the baby have a problem right after it was born? Birth defect, for instance, is what we tend to focus on. We can count that and understand it. There’s some drugs that cause that and some that don’t seem to.
And then third that’s harder to figure out is, did it cause a problem later in development? We’re just now having research emerge from that. So that’s how we figure it out. Not surprisingly, that means we have to have a lot of women register in the registries to determine this, and that means we only know it for the most common drugs. For example, for lamotrigine, we have a lot of information. It’s been around a long time. A lot of young women take it, so a lot of information. It seems like there’s no greater rate of birth defects, for instance. For valproate, which is Depakote, also been around a long time, a lot of young women used to take it, we know that it has an increased risk of birth defect. We discourage women from taking it when there’s an alternative, although they might need to take it.
For a lot of drugs in between, we don’t know. For these brand new drugs, which I think maybe is the nature of the question, we exclude pregnant women from clinical trials. We say, “You can’t be in the trial if you’re pregnant. Not only that, if you get pregnant during the trial, you have to leave the trial,” and that’s because we don’t know if it’s safe for the baby. But then of course, we also don’t know if it’s going to affect pregnancy. So you have to wait quite a while after approval to figure that out.
Does it matter where in the brain the seizures comes from in terms of the efficacy of these drugs, especially for focal seizure medications?
It really does make sense that you might think that. That’s a perfectly reasonable question. The most commonplace seizures come from in the brain is the temporal lobe. The temporal lobes behind the temples are particularly ticklish. They tend to have the electrical storm. About half of all epilepsy or maybe more is from the temporal lobes among focal epilepsy. The next most common site is the frontal lobe, and that’s about another 25%. Then the whole rest of the brain is the rest of them. We know a lot about temporal lobe epilepsy, less about the others. But if you take those cells out and put them in a dish, so to speak, and look at their physiology, what happens when they have a seizure? We, overall, don’t know any difference between a neuron having a seizure in the temporal lobe and frontal lobe. They’re undoubtedly different, but we don’t know enough about them to help us understand if one drug is better than another. In the future, we might very well, but at the moment I’d say we don’t.
Is there a specific genetic test series you would recommend these days for people with refractory focal epilepsy?
Yeah, I’d recommend… In the whole field, there’s standard recommendations as a standard of care that, if you have refractory seizures, whether they’re focal or generalized, genetic testing, and there’s sort of three kinds of genetic testing. To cut to the chase, the important part is that most people would have what’s generally called whole-exome or whole genome-sequencing. The idea there is that, from a sample of blood, you could sequence someone’s entire DNA, all their whole DNA, and then compare it to another group of people who don’t have epilepsy and look at the differences. You’d say, “Ah, this group of people without epilepsy doesn’t have these particular genetic changes, and you do, as a person with epilepsy, have it.” And if it’s in a gene that we know causes epilepsy and if it’s a variant in that gene that we know is in a whole family of people that causes epilepsy, we say, “Aha, that’s the cause.”
If you are identical to that group of other people that don’t have epilepsy, we say, “Well, we didn’t find anything.”The dilemma is that, very often, we find someone who has a genetic change that’s different from these other people, but we don’t know if it’s causing their problem or not. And the more genes you look at, the more you’re going to find that in a way. The short answer is I’d recommend whole exome or whole genome, which are kind of similar sorts of things. Whole genome’s the biggest test you can do to look for causes of epilepsy.
There’s another test that’s actually much easier to get, easier to interpret. That’s an epilepsy panel. It’s a genetic test that just looks at the specific genes. That would be the most popular probably, maybe even still, but was definitely, just a few years ago, most popular. And then after that, there are other genetic tests you can get. So if those are negative… For people who have more than epilepsy, so if they also have, let’s say, some developmental problems or particularly things you can see, changes in their face or in their arm to their legs, that kind of thing, then there’s another genetic test that looks at how the chromosomes or genetic materials rearranged, chromosomal microarray it’s called, or CMA sometimes.
But I think the answer to the nature of the question is, in my view, well, I guess in the whole field’s view, you should have genetic testing if you persist in having seizures because you might first find out something you can treat one way or another. If you’re an adult with focal epilepsy, we’re probably not going to find something we can dramatically treat, but it might help guide us in the future. The second is because it might alter the kind of treatments you do. For example, surgery might not be a good idea if you have focal seizures and have genetic cause sometimes. I think genetic testing is definitely the way to go.
Do drugs, particularly Depakote, impact male physiology?
Yeah, we typically focus on female physiology on how drugs affect menstrual periods or fertility or pregnancy, but there’s also evidence that they affect men as well. They typically don’t affect fertility in a substantial way, so we don’t have a lot of research about that. They may change the patterns that men have. As a practical aspect, it’s infrequent for drugs to affect male fertility in a substantial way, but it’s possible.
Is there anything in the pipeline for partial motor focal epilepsy caused by scar tissue as a result of traumatic brain injury?
That is a question kind of dear to me. CURE sponsored a study I was an investigator in, along with the principal investigator Pavel Klein, looking for markers that might help us understand who would develop post-traumatic epilepsy. It’s a vitally important thing. It’s very common. When we think about epilepsy, we tend to think about everybody that epilepsy and seizures are main problem. So if you have post-traumatic epilepsy and you have a bunch of other problems, you have a big head injury, you kind of get… The epilepsy almost gets neglected, but that’s a big group of people who we really should help. The answer is no. I’m not aware of anything far along the pipeline. I will say that there is a group I know about that’s developed… There are two groups that are developing drugs that we hope will help prevent post-traumatic epilepsy, something I’m involved with that seems to dramatically help brain injury after trauma, but nothing near the phases that we’re talking about and nothing I’m aware of in clinical trials.
Is there anything that is particularly helpful for somebody with nocturnal seizures or any different treatment paradigms that would be helpful?
In general, no. But if we kind of drill down on some specifics, nocturnal seizures are often due to frontal lobe epilepsy. Frontal lobe epilepsy, depending on its cause, might be amenable to surgery, for instance, but yet is often neglected. Nocturnal seizures can be particularly bad because, if you have a seizure at night while you’re asleep, it might increase your risk of SUDEPs, a unexplained death in epilepsy. SUDEP is uncommon, but a horrible thing when it does happen, and so there’s kind of a greater motivation to think about seizures at night, even if we don’t have something exactly directed at that to treat it. So we’d think about frontal lobe epilepsy in terms of doing more diagnostic things and more workup, and at least, in my case, being a bit more aggressive about the workup, trying to find it in case it is amenable to surgery. Along there would be certainly genetic testing because there are certainly some genetic causes of frontal lobe epilepsy, and that might influence that surgical workup, for instance.
This is a great time, not exactly talking about drugs, but devices to detect seizures that might help detect seizures at night that would help prevent SUDEP. We don’t know that’s the case, but it’s logical that would be the case. So we hope that we, right now, have devices that can detect seizures, particularly at night. I would definitely advocate for that. It’s not quite the same as treating them, but at least they’d be identified so someone could come and intervene and you’d know you’re having them. So that’s a whole nother issue. Regardless of how bad they are, if you don’t know you’re having them, then we can’t go tell your doctor to change your treatment.
I don’t think that was the nature of the question. I think the nature of the question probably was… There’s something about frontal lobe seizures you could pinpoint with a specific drug. There are drugs in development for specific causes of frontal lobe seizures, so something that was called autosomal dominant nocturnal frontal lobe epilepsy, so genetic cause, that is kind of a prototype or an example of a specific receptor, the acetylcholine receptor. There’s some drugs that have been thought about that might work specifically in that receptor. That goes back to figuring out what’s causing it. And if you figure out what causes something treatable, then you might have a specific treatment for it. That might be the nature of the question you’re asking about this particular type of epilepsy. But as a location, we don’t have a treatment.
Would you say that this generation, this new generation, of treatments will have a better side effect profile than past medications?
We certainly hope so. Among those generations, the first generation not just had annoying side effects, they had toxic end organ bad things that could happen to people. The second generation of drugs did a little better, but you still kind of felt miserable. The third generation, some of them have very few side effects and are very well tolerated. So I think the expectation is that the drugs under investigation now will have to at least do that well, probably do better than that. And the theory is that by being selective, they’ll have fewer side effects.
There’s an idea they’d also be more effective, and the great thing is that, you can probably tell I’m a bit of a skeptic. “In God, we trust to always bring data,” is what I might say, but the data we have so far shows the seizure reduction is substantially more than we’ve seen in the past, and the tolerability is very good. It looks like they’ll be more effective and more tolerable, but I’d say we’re not really going to know that until they’re sort of out in the wild, until we can give them to people and see how they feel in a regular home environment.
Post-event questions, answered by Dr. Fountain via email.
Is RAP 219 similar MOA to Fycompa?
They both work on the “excitatory” pathway of nerve transmission that uses glutamate as the transmitter substance. Fycompa (Perampanel) works on a variety of subtypes of glutamate receptors in the AMPA class. RAP219 works specifically on the TARP subtype of AMPA receptors which has difference components from other AMPA type of glutamate receptors. It is hoped that targeting the TARP subtype of receptor will be more effective with fewer side effects, although RAP219 is still early in development.
The current guidelines suggest that once an individual fails two meds, the chance of another med working is very low (I believe it’s under 5%). Does the addition of these new meds change those odds at all?
It is not known exactly what the effect of the new medications will be in reducing the proportion of people with medication-resistant epilepsy. The medications in development being discussed here are still in the research phase and have not been approved by the FDA yet, and are not available at the pharmacy. They still have to complete clinical trials, be reviewed by the FDA, and then be distributed to pharmacies. If these drugs actually reduce seizures more than the current drugs then they could eventually reduce the proportion of people with medication-resistant epilepsy. It seems unlikely they will reduce seizure frequency in everyone, though.
Why is there less focus on generalized tonic-clonic seizures? Are generalized harder to control or rarer?
The discussion today focused on focal seizures because they are more common. However, most of the drugs discussed are also being explored for generalized tonic-clonic seizures. I am not aware of any completed randomized controlled trials for generalized tonic-clonic seizures for any of the drugs we discussed. It generally takes longer to complete these studies so they may be on the horizon.
Are epilepsy medications also conducive to individuals experiencing irregular seizures?
Most people with epilepsy have seizures are irregular intervals. Antiseizure medications are intended to reduce the frequency of seizures in everyone with epilepsy who has the appropriate type of seizure. Even those with rare seizures may benefit from taking antiseizure medications.
How is the current U.S. federal administration affecting epilepsy research?
There have been many budget cuts to federally funded programs for epilepsy research. However, the current environment has not yet significantly altered the pathway for the antiseizure medications that have made it to the human clinical trial stage.
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