Fenfluramine in the Management of Children and Adults with DS: Insights from Long-term Data and Real-world Evidence

Welcome, and thank you for joining us on this second episode of Clinician's Corner, a series of conversations between myself and experts in caring for patients and families living with developmental and epileptic encephalopathies.

My name is Heidi Henninger an adult epileptologist with over 22 years’ experience practicing clinical epilepsy across my patient’s lifespan, striving to help them live up to their best potential. More recently, I brought my experience to UCB Medical Affairs to continue to raise the bar on what patients, caregivers, and families should expect from their epilepsy treatment.

In celebration of Dravet Syndrome Awareness Month, today’s conversation will examine our data on the use of fenfluramine in patients living with Dravet Syndrome, and I am so pleased to be speaking with Doctor Scott Perry, an internationally known expert in advancing the care of patients living with Dravet syndrome and other rare and complex epilepsies.

Scott, will you please introduce yourself for those who may be watching and haven't been lucky enough to meet you?

I'd be happy too. Heidi, thank you so much for inviting me to share this conversation with you today. I am Scott Perry. I am a pediatric epileptic and currently the head of Neurosciences and the director of the Genetic Epilepsy Clinic at Cook Children's Medical Center in Fort Worth, Texas. I'm fortunate for the last couple decades of my career to have spent a great deal of time taking care of children with developmental and epileptic encephalopathies, and specifically Dravet syndrome, where I spend a lot of my time.

Scott, I'd like to start our conversation with well, first, wishing you a happy Dravet Syndrome Awareness Month. Did you ever think 20 years ago, or even ten years ago, that we'd be using the adjective happy with Dravet syndrome awareness?

Uh, no. Uh, I'd say we're getting happier. Is what I'd say where we're at now. I mean, the last two decades of seeing great advances in this condition and some of the things we're seeing on the horizon and the changes in the kids and adults we've seen over time with this condition over those last two decades is just immense. Uh, and so, yeah, I think there is a lot to be happy for, and there's a lot to be hopeful for, for the future.

And while there is so much hope and research going on, let's talk about the state of the current care of patients and the impact of getting a diagnosis of Dravet syndrome on the caregiver journey, and a little about the burden of this, you know, lifelong multifaceted syndrome. Tell me a little about your experience.

Yeah. Well, I mean, you know, Dravet syndrome, as we said, is a developmental and epileptic encephalopathy. So, you've got a lot playing into this condition. First, when a child gets diagnosed with this condition is seizures. Seizures is they're frequent. They're prolonged.  

They often result in hospitalizations and emergency room visits. And you can imagine to a family who had an otherwise very healthy child before the onset of these seizures, that in and of itself is life changing. Now you've got a kid that needs to take medicine. You've got a kid that you're constantly worried about from a safety standpoint. But as a developmental and epileptic encephalopathy, it's important to remember it's not just about seizures. There are other problems. There are many other symptoms that come with these conditions. These children and adults ultimately have difficulty with sleep. They may have behavioral problems such as inattention or higher rates of autism. They can develop abnormal gait, so their ability to walk and ambulate can be complicated over time. They can have feeding problems. They can have autonomic dysfunction. So I mean the list goes on and on.

And that's just the impact of the child. And then there's the impact, you know, as you alluded to the family, siblings and, and, you know, other members of their community and caring for people with Dravet syndrome. So it's a significant condition that brings with it a great deal of burden. But I'll tell you, the parents and caregivers handle it incredibly well. Yeah. And have really, um, brought us to a lot of the things we're going to talk about today have really spurred the world to create these treatments to fix this condition.

I'm aware that you recently published a literature review on the mental health impacts to caregivers. Tell me more about that.

That topic. Um, yeah. It's a really special and unique topic that I don't think enough people really think about. You know, we spend our time, I know I spend my time usually seeing the patient and thinking about the patient first the seizures and then the other things that come with it. But it's really important to recognize, as I've said before, there are other people in the room, there's caregivers and there's siblings.

And, you know, what do we know about how they're handling Dravet syndrome? And the truth is, when we do this review, um, we know very little, if I'm being honest. You know, there's a lot of literature out there, but the amount of literature actually dedicated to looking at the impact on caregivers is pretty limited. What is out there tells us that there's much higher rates of anxiety. There's much higher rates of depression. Um, families and caregivers of people with Dravet syndrome suffer with, um, you know, stress and fatigue and poor sleep and all of those things, of course, further contribute to mental health conditions like anxiety and depression. And it's just not something that, um, you know, caregivers, caregivers are about taking care of their kid or their loved one, you know, and they don't take care of themselves probably enough.

So that's a lesson. I mean, that's a lesson right there. And it's a lesson. Can't do it alone. It's a lesson to people that care for them to ask.

Yeah. To ask about it. Are you taking care of yourself? And if you're not. Can I help you get some help for yourself? Because if you can't take care of yourself as a caregiver, then you can't take care of the person you're trying to provide care with as well. And so it's just a really important thing that I think has to be acknowledged that that we're not.

So that's a great point. Have you incorporated that into like your clinic routine is checking in with the parents, not just how Sally is doing?

Yeah, I mean, I've tried to, you know, you try to I obviously you only have so much time in any one meeting, but you try to think about all the points you need to hit, and that's definitely one of them you should hit is not only, again, how is the caregiver taking care of themselves, but what about the other siblings? Are the siblings you know, are the siblings to care for? Are they getting to do you know, their things? Are we, you know, maybe not getting to do the activities they wish we do because of all that's going on? You know, just trying to make sure everybody's taking care of the stuff. And if they're not that, you know, we're offering some opportunities to take care of that. I'd love to see us work more into a routine visit, you know, some screening of the family just to see if we can recognize the problems you're going on, maybe before they become major problems, crisis problems and try to avert that. I think that would be a really a have a big impact.

And in addition to that, just awareness of the burden. What can we do with our treatments? What impact can we have by reducing seizure burden or addressing some of the cognitive behavioral effects on the quality of life and the experience, the burden of the caregivers?

Well, I think I think that is one of the great things over the last, you know, decade or so that we do have new treatments that are really providing meaningful seizure reductions. So seizures has always been symptom number one, you know, that has been targeted. And the treatments we have are making significant decreases in those seizures. And a kid who has less seizures is certainly going to do better than the kid that has a lot of seizures.

Let's jump into fenfluramine. Fintepla is the first drug approved for Dravet syndrome that had profound seizure reduction in the randomized clinical trials and open label extension. What aspect of that seizure reduction data do you find most striking? Do you talk about with caregivers?

Yeah, well, we talk about that significant seizure reduction that was seen in those randomized controlled trials. When you look at that data, the highest dose group, the 0.7mg/kg group, had a reductions of over 60%,
62,64%. You had a responder rate of 70%. And then that continued in the open label extension with nearly 68% reduction reported.

So that's a lot of seizure reduction in a condition like Dravet syndrome, where the seizure frequency is a lot. I mean, that's a big burden. So that's a reduction that really provides, you know, meaningful impact. I think, uh, and really changed for me, uh, kind

100 of the landscape of treatment of Dravet syndrome when we got something that had that type of reduction.

And so consequently, where does Fintepla fall on your treatment algorithm? So early diagnosis, new patient.

When I'm thinking about treating a patient there's a lot of things I think about. One is obviously what kind of seizures are we dealing with. And in the very young age it's usually convulsive seizures which fenfluramine has great efficacy with. So I commonly think of it pretty early on. So with it's indication of two and up, I'm definitely thinking of it at age two. Um, to get it, especially if the kid is having frequent convulsive seizures.

I think, you know, the consensus guidelines put fenfluramine at the top, so it's something that should be considered early, because that meaningful seizure reduction early in life means better things long term I think.

Most parents are reluctant to choose between seizure control and quality of life. What I was struck by with fenfluramine and this initial data, was that they weren't having to choose. The majority of patients had clinically significant improvement in the tool we use in trials to judge clinical global impression of improvement. Is that your experience in clinical practice?

Yeah, it is in clinical trials. You do see use this global impression scale that people use. And the point of that scale is to try to understand the full picture, because we focus so much on seizure reduction, but we know that's not the entire picture of the quality of life, or how effective or the meaningfulness of what the medication does.

And so you did. You saw in those trials the open label extension that a majority of patients or their caregivers reported that they had improvements in the global impression or their global you know, severity of their disease. Um, and so I just think that just speaks to the benefit. And then from a clinical standpoint, I could say, yes, I would agree with that.

I think the biggest thing that I've told people is what happens with fenfluramine in this kind of reduction is all of a sudden seizures become not the major problem. So now the clinic visits are yes, there are some seizures, but there's so much reduced from where they were. Now let's talk about sleep and development and other things. And I think that just that speaks to that overall improvement, that it actually shifts the focus of clinical care to.

So it's not really a either or anymore. It's a yes and yeah.

Yes, yes we are. We're treating this and there's these other things we're going to treat. And you know, luckily, we got one thing knocked down a bit so we can even focus on the other things actually. I mean that's really important for so long you couldn't even think to focus on something else because you had so many seizures you had to deal with. So, uh, so yeah, I don't know, it's it's been, um, it's been a nice, uh, positive impact on overall care, I think.

So what do you say to families that are so excited about precision medicine that that they're reluctant to start anything? They're holding out for gene therapy? How do you talk to them?

Yeah. Well, first of all, I mean, you have to understand their excitement, right? I mean, we're talking about treatments that are really geared at the underlying reason for Dravet syndrome, the genetic problem. And so rightfully so. People are excited about the idea that we're going to correct it. But we also have to consider where we're at right now and today.

Right.

And so as a physician talking to a caregiver or a patient about therapy, if you're having seizures now and you are not in a place to have access to these therapies, these disease modifying therapies, which are still in clinical trial right now, then you need to take care of the seizures you're having now.

I mean, there's so many things I talk to about people about this. One thing people have to understand is that sudden, unexpected death in epilepsy is a real thing. And it is more common in people with Dravet than with other drug resistant epilepsies or other epilepsies in general. So any opportunity you have to reduce seizures is meaningful. Also, as we talk before just reducing the burden of this disease and, you know, missed work, missed days of school, making sure you're getting to your therapies, that's important.

Let's review some of the key safety findings from the fenfluramine randomized controlled trials and open label extension studies. Commonly reported adverse events in these studies included diarrhea, decreased appetite, and somnolence. Although there were no cases of valvular heart disease or pulmonary arterial hypertension during the randomized controlled trials or the open label extension, there have been post-marketing cases of both VHD and PAH reported.

Are you interested in learning more about Dravet Syndrome? Please join me for part two of our conversation with Doctor Scott Perry as we discuss newly published clinical data and real world evidence regarding the use of fenfluramine in children and adults with Dravet syndrome. We hope to see you then.