Long-term Management of Children and Adults with DS or LGS

Speaker 1 (00:07):

Hello, and thank you for joining us on this first in a series of video podcasts where we speak with leading experts in epilepsy on the clinical implications of our newest data on fenfluramine. I am Heidi Henninger, an adult epileptologist working in medical affairs at UCB. Before that, I practiced epilepsy for over 22 years in Maine, and during that time, I advocated for patients to have access to every treatment option, be it surgical, to neuromodulation to the newest anti-seizure medications, and even clinical trials. Today I have the pleasure of talking with Dr. Kelly Knupp, although you need no introduction, I'm going to ask you to introduce yourself for the audience. 

Speaker 2 (01:00):

Thanks, Heidi. I'm glad to be here. I am Kelly Knupp. I'm a pediatric epileptologist at the University of Colorado in Children's Hospital, Colorado. I'm a professor of pediatrics and neurology at the lead of the epilepsy clinical program and also the lead of the Dravet program. 

Speaker 1 (01:18):

And I believe you were an author on both of the papers that we're going to discuss today the open label extensions in Lennox-Gastaut syndrome and Dravet syndrome. Yes. 

Speaker 2 (01:31):
Yes. I have been an author on many of the fenfluramine papers, including the open label extension papers for Lennox-Gastaut and Dravet syndrome. 

Speaker 1 (01:41):
Dr. Knupp, would you please provide a brief introduction to Lennox-Gastaut syndrome and Dravet syndrome? 

Speaker 2 (01:48):

Sure, Heidi. So, both of these are part of what we call DEE is developmental and epileptic encephalopathies, and they do have some overlap, but have characteristics that help us differentiate a little bit. So, Lennox-Gastaut syndrome is a relatively difficult to control epilepsy that usually presents or evolves in the first couple years of life, has some characteristic EEG findings that we see slow spike and wave, something called paroxysmal fast activity and can have lots of different seizure types. One of the most common seizure types that we see in these patients are tonic seizures, but we can see lots and lots of other seizure types with this. And unfortunately, this is also associated with intellectual disability. It is very heterogeneous in what causes Lennox-Gastaut syndrome. So, when you look at a list of etiologies, it's kind of like anything that can go wrong in childhood can cause Lennox-Gastaut syndrome from acquired injuries like traumatic brain injury to underlying genetic disorders and everything else in between. So very heterogeneous but severe epilepsy syndrome that can be really difficult to manage. And we see that these children live into adulthood. So, you see this in adult epilepsy practices as well. Some of the features may not be as clear by the time we get to adulthood. So slow spike and wave may not be as readily prominent. Paroxysmal fast activity may be a little harder to find, but we see the other characteristic features there. 
Speaker 1 (03:24):

And Dravet syndrome in contrast is a little more homogeneous…

Speaker 2 (03:29):

Is a little more homogeneous. So most people with Dravet syndrome, it is secondary to a pathogenic variant in SCN1A. But these children we see have seizures usually presenting in the first year of life with really prolonged seizures, often in the setting of temperature changes or fever. So, first vaccines, first illness, getting in and out of a bathtub, things like that that change temperature. Characteristically, these seizures are what we call hemiclonic, where it's one side of the body that's shaking. And then as they move into the second year of life, we start to see other seizure types emerge. And we actually see some age-dependent changes in seizures throughout the lifespan. These children often have intellectual disability. Sodium channel blockers tend to make seizures worse, which can be a little tricky if we don't have an early diagnosis because they present with focal seizures often. And so we think about using focal medications, which often are sodium channel blockers. There are some other pathogenic variants that can be associated with this, but the most common thing is SCN1A that leads to the etiology. These children also have lots of non-seizure associated symptoms. We see a progressive gait disorder, we see ataxia, intellectual disability. So, lots of overlap between these two syndromes. 

Speaker 1 (04:51):

But is there still a significant unmet need in the management of seizures in LGS and DS? 

Speaker 2 (05:00):

In both of these patient populations, very rarely do we see seizure freedom. We hope for seizure freedom, but really our treatment goal for the most part is a compromise which is reduction of seizures and hopefully not a bad impact on comorbidities. So, we need to think about all of these things as we're making medication choices throughout their lifespan, but it is just very rare for these children to be seizure free. So, until that need is met, yes, there's a huge unmet need in both of these patient populations. 
Speaker 1 (05:30):

So randomized clinical trials, they give us initial efficacy data and help drugs get FDA approved. What is the role of open-label extension, especially going out a year or longer in informing our practice? 

Speaker 2 (05:48):

I think as a clinician, the open label extension data actually gives us a wealth of information because it's really kind of what does this drug look like in real world practice? I mean, it is still a very refractory patient population, a patient population that was willing to enroll in a randomized clinical trial. But it gives us an idea of, okay, now that everybody knows that you're on study drug, are you seeing benefit from it? Do those benefits outweigh the side effects that you're experiencing? I think often during the randomized clinical trial, we're blinded and so we don't know are these side effects related to drug? Are they something else? Everybody is really persistent in getting to the end so that they can get to the open label extension. So, they may actually tolerate some side effects that maybe the benefit of the reduction of seizures isn't worth it to them. Or maybe we're not seeing a huge reduction in seizures, but we're seeing an improvement in something else that we weren't measuring or we were measuring as a secondary outcome. And so I think looking at the persistence of patients to stay in the open-label extension is really helpful. 

Speaker 1 (06:57):

So, let's talk a little about the design of these two studies. There are some unique aspects in this, both open label studies compared to others that I've been involved in and a little about the different patient populations in the Lennox-Gastaut versus the Dravet open-label extension. 

Speaker 2 (07:20):
So let's first talk about the difference between the patient populations. So, the Lennox-Gastaut population had many more adults in it. 

Speaker 1 (07:29):

30%. 

Speaker 2 (07:30):

Yeah. Which is really nice to see because I think sometimes we end up excluding those adults with Lennox-Gastaut, and as you very well know, they need help also. And so I think that is a difference. In the Dravet study, we really stopped enrollment at age 18, although there was a small percentage, who were under 18 at the time they enrolled in the clinical trial. So by the time they got to the open-label extension or through the open-label extension, they were older than 18 and thus adults. On the other hand, both of these patient populations had poorly controlled seizures such that they were willing to enroll in a randomized clinical trial. And we saw, when you look at some of the other features, we see that most of the patients had failed five or six prior medications coming into the open-label extension. We had patients who were on three doses, they were on high dose, low dose or placebo, and we had to get all of those patients in a blinded fashion onto the same dose so that we could figure out what to do. And so, everybody was titrated to the low dose of 0.2 milligrams per kilo per day, and then held at that dose for a couple of weeks just to give everybody a chance to kind of stabilize. And that's a little unusual. Usually, the titration is a little bit faster. 

Speaker 1 (08:52):

More aggressive. 

Speaker 2 (08:52):

Yeah, and I think we look at the side effects during that time period, they were probably a little less than what we saw during the randomized clinical trial, which is important for us as clinicians when we're prescribing this in the real world to look at. 

Speaker 1 (09:07):

Okay. I think that's a great transition into talking about seizure reduction and what the data tells us. I'd like to talk about the efficacy data that we learn from the open label extension. So, let's review what the seizure reduction was and how we use that data to understand FINTEPLA’s efficacy. 

Speaker 2 (09:36):

30% reduction of seizures could be really significant. And the fact that patients stayed in the open-label extension and reported that tells us that that was meaningful to those families. So, I think that's the first thing to look at. The other thing that was kind of hidden in there and I think is super exciting is the seizure-free days. Not just seizure-free days, but consecutive seizure-free days went from 2 to 7. I mean, that's a week with no seizures of the seizures that we were counting. And that is really important to families to have that kind of experience and that kind of break from seizures. 

Speaker 1 (10:13):

Let's talk about actually, for those that might not be aware of the terminology, that primary outcome measure is seizures associated with the fall that include multiple seizure types, not just those drop tonic seizures that we think of. Could you remind our listening audience?

Speaker 2 (10:33):

Yeah, no, I think you raised a really good point and something that I try to point out to people. We used to call these drop seizures, which isn't really part of our terminology when we talk about seizures as part of the lay terminology. And oftentimes when we talk about drop seizures, people think about atonic seizures, but these were seizures associated with the fall. So, this is any seizure type that will make you fall or if you were standing that you would've fallen. So generalized tonic-clonic seizures, tonic seizures, atonic seizures are in there and focal to bilateral and focal to tonic-clonic. Yep, exactly. So it really is a group of seizures that isn't really part of how, from an academic epilepsy perspective, we think about seizures, but is a really good way to kind of group these seizures in a way that is meaningful to both families and to providers and to regulatory agencies. 

Speaker 1 (11:34):

So, I find sometimes that explaining a median percent reduction, so like 30% reduction in seizures to families can be hard. So, thank you for talking about seizure free days. What about responder rates, that 50% responder rate? How do you interpret that for families? 

Speaker 2 (12:00):

Yeah. I think numbers are sometimes hard for families unless we can make it individualized for them, but 50% means half of the people saw at least a 30% reduction. So at least 50% of people saw a 30% reduction of seizures. 

Speaker 1 (12:19):

And then vice versa, 33% of patients had at least a 50% or more reduction in seizures. So, a third. Excellent. Let's talk a little about the efficacy in Dravet syndrome and what we saw there. 

Speaker 2 (12:36):

So, we did see greater efficacy in Dravet syndrome, but I think it's really important to keep in mind that Lennox-Gastaut syndrome is a very heterogeneous population. So, lots of different reasons why people have Lennox-Gastaut syndrome from acquired injury to genetic causes. So, a lot of reasons and presenting at lots of different ages with lots of different seizure types, whereas Dravet syndrome for the most part is largely related to a pathogenic variant in SCN1A. And so, we did see more improvement in seizures in that patient population, but it was also a very homogenous population. And so I would've expected that if I took all of my patients with epilepsy and put all of them on the same medication, I would expect across the board, some people are going to respond well, and some people aren't going to respond well. Whereas if I take a patient population and we have a medication that we know is effective in that patient population, I would expect to see a better responder rate there. 

Speaker 1 (13:38):

And so the close to 70% reduction from baseline is…. 

Speaker 2 (13:47):

That is huge. We also saw an increase in seizure-free days in this patient population and a not insignificant number of patients who were seizure-free or nearly seizure-free, which is really exciting for that patient population. 

Speaker 1 (14:00):

I am also interested going back to LGS for a moment. I know that we looked at efficacy in specific seizure types and generalized tonic-clonic seizures in particular. 

Speaker 2 (14:16):

Yeah, I think this is kind of exciting and important for us to think about. Families will often ask me, I take this medicine for this type of seizure and this medicine for this type of seizure, which isn't really how we use our medications. I wish we could, but it doesn't really work that way. But we really worry about our patients who are having generalized tonic-clonic seizures, particularly if they're having them at night, because we know that increases their risk of SUDEP - sudden unexplained death in epilepsy patients. And so to see that there was a reduction in generalized tonic-clonic seizures in particular with this medication was really exciting to see because that is a seizure type that we worry about. We saw other seizure types that had improvement as well. And I also think we need to keep in mind that there are seizure types that are really challenging to measure in a clinical trial, and we probably don't have great measures of those. So myoclonic seizures, absence seizures, we know that patients had those, but it's just challenging to have a family count how many myoclonic seizures one has. I mean, if they turn to wash their hands, they may have missed two. And so we don't get an accurate count of that. 

Speaker 1 (15:29):

That's why we focus on the countable motor seizures. 

Speaker 2 (15:32):

The countable motor seizures. Exactly. Or seizures associated with a fall because you don't miss a fall when that happens when you turn your back. But generalized tonic-clonic seizures is something that I know I worry about I'm sure you worried about in your patients. And so to see that preferential reduction in that close to 50% yeah, is really exciting to see. And I think particularly for our patients where that, I think that fenfluramine helps with all seizure types, but particularly for our patients who are having more generalized tonic-clonic seizures that would push this up in the options for me. In talking to that family.

Speaker 1 (16:07):

Also, I wanted to call out because 30% of the patients in the open-label study in LGS were adults. We did some post-hoc analysis of efficacy in adults. Can we talk a little about that? 

Speaker 2 (16:25):

So I mean, I think there are some really interesting data here in our adult patients where we actually saw a greater reduction of seizures of our countable seizures and our generalized tonic-clonic seizures compared to the pediatric population. So, the pediatric population had about a 25% reduction, and the adult population had about a 40% reduction even with the dose cap. And this is also a patient population that's had seizures for a longer period of time. In other situations, we have some suggestion that the sooner we treat somebody's seizures, the more likely we are to see a response. Yet in this patient population that had had epilepsy for a longer period of time, we saw a greater reduction of seizures. This may also speak to some of the unmet need in our patient population. I think it's really important to, as we're seeing patients, whether they're pediatric or adult patients, that there is always more room for improvement. And we may actually get more improvements in our adult patients with this medication. 

Speaker 1 (17:30):

So, one of the challenges of treating patients with developmental and epileptic encephalopathy, specifically LGS and Dravet syndrome, is that these conditions are so much more than seizures. And I know so many caregivers are reluctant to start a new anti-seizure medication even if the seizures aren't well controlled because they don't want to sacrifice quality of life or cognitive status alertness. Given the importance of managing the comorbidities, the developmental challenges, let's talk about what some of those measurements were that we used. 

Speaker 2 (18:17):

So, CGI was used in both studies and also the clinical trial and really is a very simple question that we ask families. And the primary caregiver as well as clinicians of compared to baseline, before they started,  (18:37) are things very much better, much better, better, the same, a little worse, much worse, or very much worse. So very simple Likert scale of ‘how are you doing?’ And in both patient populations, the Dravet syndrome group and the LGS group, we saw improvement. Not surprising, in the Dravet syndrome population, we actually saw 80% of people reporting any improvement at all. And about 60% of people reporting much improved or very much improved. In the LGS population, we saw 60% of patients reporting improvement. Any improvement, any improvement, and about 35% reporting much improved or very much improved. But I think it's really important to keep in mind that these numbers don't just reflect the improvement in seizures. They could also reflect an improvement in sleep, being more alert, being more attentive. So, it was really everything including seizures, but not just limited to seizures that people were reporting. 

Speaker 1 (19:43):

As an investigator in the study. Can you put a little color on there?

Speaker 2 (19:45):

Absolutely! Yeah, yeah. Improvement in sleep, having consecutive seizure-free days. We had some families that had seizure-free days and did have reduction of seizures, but maybe they were a little more clustered in one day instead of spread out through the week.

Speaker 1: So, the numbers didn't tell the whole story.

Speaker 2: Right. Seizure numbers don't tell the whole story, and that goes both directions, but maybe seizures are better, but behavior is worse. And that's a family that maybe wouldn't have rated things quite as improved as if behavior and seizures had gotten better. I think it's really important that it is not just seizures. I can stop anybody's seizures by bringing them into the ICU and intubating them. That is not a good quality of life. And so our patients are not just seizure numbers, they are everything else that they need to do throughout the day. Was it easier to get them in school? Did they actually pay more attention in school?  (20:45) Were they able to interact with their siblings a little better, friends a little better? All of those things are really important. And we did see some of those things in the quality of life measure that was used. And so overall quality of life improved. And there were some specific areas that improved as well, including socialization, stigma, anxiety. So, a number of these measures we saw improvement in. Is that because seizures were reduced? Is it because of the medication? That's really hard to tease that out, but families will take whatever improvement they can get. And I think it's important when we're talking to families as we're using a medication, not to just assess their seizure frequency, but to assess all the other things that we may see improvement in. Because it may be that the family doesn't see as much improvement in seizures that they were hoping to see, but they see some improvement in one of the other symptoms associated with their LGS or their dravet Syndrome. And so for clinicians, it's really important that we're getting the big picture. 

Speaker 1 (21:51):

So, we talk about open-label extensions, the primary purpose being looking at long-term safety and efficacy. So, let's transition now to discuss the safety findings of the studies. 

Speaker 2 (22:06):

In both of these open-label extensions, the LGS and the Dravet syndrome, we had side effects reported, which is expected. We always worry about risk associated with medications. Any medication that we use, including things that are over the counter, have significant risks associated with it. When we look at the LGS study, there were a handful of people who left the study because of side effects, but those were largely related to change in seizure in the Dravet, 5.3%, yes, a small percentage. 

Speaker 1 (22:48):

Small, due to side effects. Yeah. 

Speaker 2 (22:49):

When we look at the Dravet syndrome cohort in the open-label extension, again, it was a small percentage. A handful were related to appetite, which was something that was top of mind of everybody, but the others were related to change in seizure and behavior again. So going into this, I think the things that were concerning to both providers and caregivers alike, regulators, regulators, as the company, really, were cardiac risk concern about valvular heart disease and pulmonary arterial hypertension and appetite suppression. Many children with DEEs do not eat well. And so having a medication that previously had been used to suppress appetite was concerning to people. And we did see that. The appetite, I just want to clarify! We actually did not see any cardiac issues associated in the open-label extension. Post-marketing, we have seen some, and you probably have more information on that than me. 

Speaker 1 (23:54):

Sure, sure. So yeah, during the study, as you know, it was required to have very frequent monitoring with echoes, and we have a risk evaluation and mitigation strategy post-approval where patients are required to have baseline echoes and echoes every 6 months while taking fenfluramine, and then 3 to 6 months after discontinuation and through the monitoring of this REMS program, some post-marketing cases of VHD and PAH have been identified. But that early testing allows identification prior to the development of symptoms. 

Speaker 2 (24:38):

I think this is very reassuring to both providers and caregivers that we're monitoring this and that we're going to try and pick up anything earlier before it becomes symptomatic, which I think is good. 

Speaker 1 (24:51):

The appetite. Let's talk about that and then how you dealt with that. 

Speaker 2 (24:56):

Yeah, so I think this is something that we need to share with all families before we try to share all the risks with families before we start a medication. I think preparing them to expect a decrease in appetite is a very appropriate thing. It was only in the Dravet syndrome open-label extension that we saw a very small number. I think it was three children who withdrew because of that side effect. We did see a decrease in appetite though, and fairly commonly in both of the open-label extensions, but we actually saw that appetite got better towards the end and people regain some of the weight that they had lost. 

Speaker 1 (25:41):

I think 77% regained the weight over the course of the year. Do you think that low dropout for side effects had anything to do with that slower titration, I wonder?

Speaker 2 (25:55):

Yeah, I wonder if we titrate a little bit more slowly, then you have time to kind of settle into it. And families also have a time to be able to try and address decrease in appetite a little bit more from a behavioral perspective. Maybe they need to offer different foods, offer foods more frequently, and we're able to manage that. Behavior change is something that was reported in both groups. I will tell you, in our patient population when we were participating in the study, some of the families who reported behavioral change actually said, my child is more alert and is now able to create a behavior problem. And so, while it was reported, it wasn't always a bad thing, and that was also something that improved over time. And in the long run, some of those families actually were very happy that their children were more alert and a little more ornery and pushing back a little bit. So, I think it's always important to kind of think about these side effects. 

Speaker 1 (27:01):

So looking forward, what are the data gaps that clinicians and caregivers are still…questions that are still being asked to understand the role of fenfluramine use in Lennox-Gastaut and Dravet syndrome? 

Speaker 2 (27:20):
Yeah, I mean, I think we still need more real-world data. We have a good sense of how this impacts seizures, and we have a good sense about how this is impacting quality of life. But what about other things like emergency room visits, ambulance calls, access, need to use rescue medicines? These may be some things for us to think about. Can we tease out a little bit more the quality of life improvements that we see in the real world? 

Speaker 1 (27:52):

Well, you are setting us up perfectly for the Future video podcasts because this year is a really exciting year for real world evidence in the FINTEPLA story. So having turned over 5 years, we are accumulating the data to answer those questions. And I hope you'll join us on a future podcast or at least stay tuned and listen in for some of the answers to these questions. Thank you for your time today. Thank you. This was fun.