Joseph Sullivan, MD

 I see some of my patients with Dravet syndrome up to the age of 22, 23. But we know that there are many adults living with Dravet syndrome, and they are frustrated that many of these clinical trials they’re not eligible for. But I wonder if we could take a minute to speak to issues that are important when our young adults transition to adult epilepsy providers, and how we can help them and help our colleagues through that transition.

 It’s a tough time, as you know, for families. They’re suddenly having to move on to a new medical team. They’ve been with us often for 15, 20 years, and so they know us well. It’s often a time of anxiety for them, but I do think it’s really important because many of our children’s hospitals have an upper age limit beyond which you cannot admit [a patient], and if you’re in a medical crisis and suddenly that’s when you’re meeting your adult team, that’s not a good time. And then, many of those young adults will actually develop other adult medical conditions that we as child neurologists are not very comfortable dealing with. I do think the need to transition is really important. It’s a process, so it’s something that I sit down and talk with families about and make sure they understand how Dravet syndrome evolves, how seizures evolve. As you go from childhood through to young adulthood, seizures are often briefer. You often don’t see the myoclonics or the absences anymore, but some of the other comorbidities can worsen. Sometimes behavior problems, anxiety issues, gait problems, or even Parkinsonian features can emerge, so [they need to] know what to watch for there.

I think the legal and financial side is also really important to have a discussion about, and that’s typically our social workers who will get involved with the families. Have a discussion about ensuring guardianship is in place by the time that the person turns 18, so that parents can continue to be the decision makers for their child. We need to make sure that if insurance is going to change, if you are on state Medicaid and suddenly when you turn 19 that’s going to change, they understand that, and they continue to get good medical insurance. Then what we can do for our adult colleagues is to provide them a much more succinct document of summarizing that particular patient. For many of these patients, if you look at paper charts, they used to be stacked up to here, and there would be several stacks. And I think the EMR [electronic medical record] has not made things easier; there’s often more papers involved. I think from our standpoint, we know this patient well; a quick 2-to-3-page summary that we can provide to our adult colleague to say, “Here are the medications the patient is on. Here are the ones they’ve tried in the past.” We don’t want to repeat a medication if it didn’t work, or if it caused an [adverse] effect. Dietary therapies, what investigations have been done, what comorbidities does this person have. Within 2 to 3 pages, they get a really nice summary of who that patient is. 

I think [we can] also just be there for any questions your adult colleague has. Where I work, I’m fortunate that I can sometimes go to the first visit with the adult neurologist, and that’s super helpful, but I know that in many cases that’s not possible because those visits take place in different centers. Whatever we can do to ensure that our adult colleagues are able to know that patient well, and that we’re there if there are any questions about therapies they may want to use [is important].

Absolutely. I couldn’t agree more about this individualized document that can capture things that aren’t necessarily apparent in the medical record, a lot of the psychosocial background, and the journey we’ve been on with these families. We know, because as you said, they’ve been with us for 15 years, and those are still important features to the care of a patient and the family. I know you and I and others are trying to come up with a document as well that gives guidelines and tips for the adult neurologist and epileptologist to understand what issues are important to the young adult with Dravet syndrome and also to understand where they’ve come from. We should be mindful of someone who had their first seizure 20 years ago, and likely was not treated in an optimal way just because we didn’t have great options; multiple episodes of status [epilepticus]. There’s certainly a lot of trauma that needs to be processed by the family and is good for the adult providers to know. 

The fact that we’re having this conversation and that people are hopefully watching, I think is amazing, to see how far we’ve come. It’s a testament to organizations like the Dravet Syndrome Foundation, interest from industry, and trying to help these rarer pediatric epilepsies. It’s been certainly a journey for my career here.

 I think it’s been super exciting to see all of these advances and what’s on the horizon, the potential to even cure this with genetic therapies, so that’s super exciting. I think though, we’re not quite there yet, and we still have patients who are having lots of seizures. I think also looking beyond the seizures, the comorbidities can also be super impactful on quality of life for those patients as well as their families and siblings. We don’t want to lose sight of that, and its support for the family.

Well, thank you. As always, it’s great chatting with you. Hopefully, we’ll be together in person soon.

Joseph Sullivan, MD: Thank you for watching this 

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Videos

Joseph Sullivan, MD, and Elaine C. Wirrell, discuss the transition of care into adulthood of patients with Dravet syndrome. 

Dravet Syndrome: Transition of Care Into Adulthood 

The families who are coming to you and asking about these therapies, how do you manage expectations?

I think I share their enthusiasm, because it’s hard not to. This sounds very exciting. They’ve done some very careful animal studies that have looked at this. The Encoded [Therapeutics, Inc therapy] also has that regulatory sequence that allows the gene to target the GABAergic interneurons, where the problem is in Dravet syndrome. So I certainly share their enthusiasm. I think they need to understand that although it may seem to work well in mice, mice are not humans, and we need to do careful studies. And our Dravet families have been through quite a number of clinical trials recently, and I think they fully understand, and they support the need for clinical studies. They want to be sure that a therapy is safe. They have a lot of excitement about it, but they also want to be sure that therapy is safe, and so they encourage us to do that. Families are very keen to be involved in these clinical trials overall. Then I think connecting them as well with organizations like the Dravet Syndrome Foundation [is important]. They can meet other families to discuss, “How are you thinking about this?” They put pages online that summarize these trials. I think that’s very helpful as well. I think discussing with the families the potential benefit, the potential risks, and then updating them as we hear more [is the way to manage expectations].

Absolutely. I think it brings it full circle, in terms of the importance of making this diagnosis as early as possible so we can make families aware of these potential clinical trial opportunities. Because especially with these potentially disease-modifying therapies, I think our collective feeling is that the sooner you intervene the better, so that’s going to put the pressure on us as a clinician community to make this diagnosis as early as possible, to educate families about what is the likely outcome with our current medications. I feel so grateful that families put their trust in me in recommending these trials. I get that hard question, “If it was your son or daughter, what would you do?” I think we’re so indebted to the patient community for trusting their kids in these trials to try to improve not only their lives but the lives of future patients with Dravet syndrome.

I agree. Part of it is the importance of careful education for the families, because if you’ve got a 12-month-old with Dravet, they’re probably developmentally still looking pretty normal. For them to understand what that disease holds, we can certainly provide some of that information, but I think connecting with the Dravet Syndrome Foundation is also really empowering for them to understand the natural history of this disease and to make informed choices for their child.

Key opinion leaders discuss managing patient expectations regarding clinical trials for Dravet syndrome treatment.  

Managing Expectations for Patients With Dravet Syndrome  

We’re still looking at seizures, and we’re maybe seeing some of these behavior and executive improvements with fenfluramine. But we really need something beyond seizure control, right? We’ve got to try to get at that underlying SCN1A haploinsufficiency. And it’s exciting. I’m sure you’re as excited as I am to be involved with some of these other clinical trials that have either started or will be starting soon that are trying to get at some underlying disease-modifying approaches. It almost seems like science fiction to me, in the sense that 5 years ago I probably put my foot in my mouth and said to some families, “I just don’t see gene therapy in my lifetime.” I was having a hard time wrapping my head around what, at least I thought, was the conventional approach of gene editing. 

That’s why we have these super-bright PhD people who have an interest in this area.

I think that’s been very exciting to see develop.

Exactly, and it’s exciting to think that it could extend to other pediatric epilepsy genetic diagnoses, not just Dravet syndrome. But right now, there’s a lot of focus on Dravet syndrome, and that’s obviously why we’re here. Maybe you could explain, for me and for our audience, this technique that’s the antisense oligonucleotide that’s in phase 1/2 clinical trial.

Sure. What that is, it targets mRNA. In Dravet syndrome what happens is the pathogenic variant leads to degradation, nonsense mediated decay of this mRNA, so it can’t function to then make protein. What this antisense oligonucleotide does is it kind of forms this bridge and it prevents the degradation from happening, and so it restores normal NaV1.1 protein. It resolves that haploinsufficiency you see in Dravet syndrome and restores normal levels of protein. So with that, there’s a lot of excitement that that then targets the underlying pathogenesis. The hope is that it will not only improve seizures but also reduce the risk of SUDEP [sudden unexpected death in epilepsy], and it looks, at least in animal studies, that that might occur, and may also improve many of the other comorbidities, sort of attenuate the developmental concerns that we see, improve gait issues, behavior. So it’s very exciting.

 Absolutely. I get some questions from families who say, “Well, does my child’s mutation qualify?” This is not going in and fixing the variant your child may have, but rather is taking advantage of that working nonmutated copy, to basically tell it to do more, or to use the products of its labor in a more effective way that ultimately translates into, as you said, increased expression of that NaV1.1 channel. And in those animal models, it has done exactly that. When they look at the expression not only of the messenger RNA, but of the percentage increase in the sodium channel, it approximates that of an individual, or of a mouse in this case, who has two working copies of the SCN1A gene. Then there’s another, also equally brilliant, approach to use an adeno-associated virus, AAV technology, which conventionally has sometimes been used to insert the actual gene into the genome so that it does “fix” them. But the SCN1A gene is too large to be packaged in that virus. 

So Encoded Therapeutics, [Inc] has devised this approach where a genetic promoter essentially binds to the working, nonmutated allele, the working SCN1A copy, and effectively tells it to produce more of this messenger RNA, which can then be translated into hopefully a working sodium channel, the NaV1.1 protein. It’s the same sort of end result, but a different way of getting there. Both of these approaches are either in early clinical trial or are going into clinical trial very soon, and so it is exciting to think about not only FDA-approved medications to treat seizures, but something that could get at the root cause. I think there’s a lot of interest, certainly from us as clinicians and our colleagues, but even more interest on the part of the patient community, because this is what they’ve been asking for, for so long.

A discussion of new developments for the treatment of Dravet syndrome beyond seizure control including gene editing and therapy.  

Therapies in Development for Dravet Syndrome 

 Getting back to our mechanisms, how do we think all this is coming together? We know it’s a serotonin drug, but do you think there are other mechanisms?

 I think it’s got to be other mechanisms, because I know that before I could access fenfluramine, before those clinical trials came, I tried other serotonergic agents, and I certainly did not see the impact that fenfluramine had, so there’s got to be something in addition to that. I know that it’s a positive modulator of sigma-1 receptors. Exactly how that works to help seizures I don’t know, but I think there’s got to be something other than serotonin there.

Absolutely. We’re in the process of going back and doing a second version of our guidelines now that we have 2 new therapies with well-controlled phase 3 data. I should mention there was a second study looking at fenfluramine together with stiripentol, because there is that important drug-drug interaction that means the dose of fenfluramine does need to be a bit lower, at 0.4 mg/kg max, which is meant to approximate what the 0.7 mg is in the absence of stiripentol, and that trial also showed similar, 50% and 75%, responder rates. That led to its approval, so we now have that for the treatment of Dravet syndrome in ages 2 and up, and cannabidiol in treatment of Dravet for ages 1 and up now. With that, how is this going to shake up our guidelines, in terms of when we do sit down and put pen to paper, and how do you think each of these are going to fit into that algorithm, as you said?

Certainly the 3 medications that were recently approved—the cannabidiol, fenfluramine and stiripentol—their responder rates, the benefit we get from those is much higher than we get from clobazam or valproate. If we have an effective medication, we want to use that in the first line, wouldn’t you say? I don’t want to wait until somebody has been through 2 or 3 other medications to use something I think has the biggest bang and the most effect. So, I think we’re going to start seeing people moving toward using those recently approved medications much earlier.

Absolutely. And I think as we’ve seen with some of these natural history studies that have come out, that still have been pretty stable in terms of that developmental plateau that tends to happen around age 2 or 3, and then fast-forward, the number of patients who have moderate intellectual disability, or more. It begs the question of what if we can get this better control, not at age 9, which is the mean age for a lot of these studies, but what if we can get that better control at 18 months? And then what does that project out in terms of developmental trajectory? I guess I have cautious optimism because we still aren’t getting at the underlying cause. We’re still treating seizures better and doing it in a way that is overall well-tolerated, but that’s going to have impact.

I think it probably will, because when you look at the Dutch study, which looked at the use of contraindicated medications that worsen seizures, the longer you were on a contraindicated medication, the poorer you did developmentally. From my clinical expertise and my experience, I think the kids who get better seizure control do better long term developmentally. So yes, you can’t fix the channelopathy with this, but if you can control those seizures better, I think they will do better in the long term.

Agreed. Now, that assumes that these medications do provide a longer-lasting benefit. We now have the luxury of both of us having used cannabidiol and fenfluramine from the original trials, and now I have patients who have been on cannabidiol for 6, 7 years and fenfluramine for 4 years. What’s your experience been in terms of the durability of these 2 agents?

 I’m very excited about the durability, because oftentimes in drug-resistant epilepsies, as you know, you kind of go through the honeymoon phase and then you lose benefit, and I haven’t been seeing that. I think that for many of these children, while there are some where you lose the effect, many of them continue to have a pretty robust benefit from the medications long term.

 Exactly, that’s how I pitch it to a family as I’m going through, “It’s time now to try one of these newer medications.” I try to present the data in as transparent a way as I can, that this was the overall reduction compared to placebo with each of the drugs, this was the 50% responder rate. If there was a 75% responder rate, with the case of fenfluramine, present that. But ultimately, it’s a conversation with families, and it’s a decision that’s made. I think you and I and some of our other colleagues have said this before, that it’s not a matter of which medication, it’s a matter of when. I think unfortunately, because we still are striving for 90% reduction or 100% reduction, both of these new drugs are going to be used very likely in combination, and one family may be more comfortable starting with 1 first, and if that’s the 1 for them, great. But in all likelihood, if the data translate into the real world, which I think it has been, it’s very likely that both of these medications will be used in combination. Then I think it’ll be really interesting to see what types of responder rates we can see.

The impact of new drug approvals on the consensus guidelines for the treatment of Dravet syndrome. 

Dravet Syndrome: Fenfluramine and the Impact on Consensus Guidelines 

Before we wrap up, let’s talk about 1 more thing. Are these types of therapies going to be appropriate for older children or even adults? We don’t have any data. The preclinical model is all in mice. But any thoughts about if it’s ever going to be too late to intervene for some of these patients? Trevor, if these treatments get approved, would you recommend it for your 25-year-old patient if they were shown to be safe and effective?

It’s an issue that requires a conversation. Obviously, if you’re having that conversation with parents of a 1-year-old, it’s a very different conversation from 1 with parents of a 25-year-old. If there’s a treatment that’s effective, even if it can mitigate some of the progression, it’s worth doing. Every parent will want to know that, even if it’s late in the game. If it may make some positive difference, I want it for my child. Under those circumstances, I would absolutely recommend it.

 Elaine or Elizabeth, what are your thoughts?

 The other potential issue is that we know SUDEP [sudden unexpected death in epilepsy] doesn’t go away. SUDEP is a risk that continues through adulthood. If this really significantly reduces seizures and gets rid of that SUDEP risk or markedly reduces it, that’s very exciting as well. As Trevor says, it needs to be a conversation. But I certainly would not exclude adults from this treatment.

 I completely agree. Sure, there’s great excitement that if we can identify Dravet early—after that first seizure with a gene panel, and treat early with a genetic therapy—could that be life transforming and changing? Hopefully it can be. But even if I had a 25-year-old or a 40-year-old who I knew had Dravet, if it was an effective therapy—and as Elaine said, would reduce or eliminate the SUDEP risk—I’d absolutely want it to be available for that patient as well.

There’s this theme that it’s never too late, right? The brain always has the ability to learn, adapt, and develop. If you look at some of the clinical trials we’ve talked about, the mean age in a lot of these trials is 9 or 10 years. Hundreds if not thousands of seizures have passed in these poor children’s lives, yet we were able to see improvements in behavior and executive function by giving symptomatic seizure relief. Imagine if we can give symptomatic seizure relief plus get at the underlying etiology. We all agree that earlier is going to be better but that at the same time, it’s never too late.

To close, for all our neurologists watching, I wonder if we could go around and each give 1 tip or helpful piece of advice for them if they’re treating patients with Dravet syndrome. Elaine, I’ll start with you.

 One thing we hadn’t talked much about was having a really good rescue plan. We know that this group of patients is very susceptible to prolonged seizures and breakthrough seizures, so it’s important to have a clear rescue plan at home and medication. Typically, in young persons with Dravet syndrome who tend to have a high risk of going into status epilepticus, we say that if you see a convulsive seizure, don’t wait the 5 minutes. Just give the rescue medication. But you should also have a plan for what should happen if that rescue medication doesn’t work. It gets tougher because there’s a lot more individuality between what works for status epilepticus or prolonged seizures after the rescue medication has failed. It’s important to develop that as the neurologist who knows that patient best.

 These are just pragmatic suggestions. For a number of patients, the triggers are the major issue. Having a preventive plan for the triggers is also really important, especially for hypothermia. Be able to address it when they begin to see it. That gives parents some element of control over the risk for status epilepticus. Obviously, some kids have different triggers. It’s important to be able to talk with families about what triggers their child has and to help obviate that as much as possible. Each individual trigger and trial can be an episode of status epilepticus, and if you can stop just 1 or 2, you’ve made a difference. Having the parents involved in that process is so important.

 One would be to recognize it; especially child neurology. You’re right. Everyone knows Dravet syndrome. There’s been a lot of excitement, particularly for recent trials and FDA approval, but I still see kids who could have been diagnosed earlier. More available access of genetic testing, which should definitely become standard of care for epilepsies in childhood with these more specific treatments, is very important.

If I had to give 1 piece of advice in addition to what Elaine and Trevor said, it would be to recognize the impact on the family. That’s where epilepsy centers can be helpful, because epilepsy centers I know about have a better infrastructure for providing support for families and siblings and resources to refer people to than many child neurologists who are treating everything we’re able to. The impact on the siblings and parents is incredibly profound. I feel very passionate that we should not only treat seizures but also take care of patients and families.

 You took the words right out of my mouth. With a lot of my child neurology colleagues, epilepsy seizures is half of what they do. Sometimes there may be this reticence, like “I got this.” Many times you do. But as we’ve hopefully shown, there’s so much value in making a precise diagnosis, making it as early as possible, and using the available literature for some new therapies to help optimize the treatment. Equally important, we close with these clinical trials. The way these trials are going to be successful, and the way we’re going to get them in the hands and brains of the patients who need them, is for them to be aware of the trials and these comprehensive epilepsy centers where we all take care of more than a handful of these patients. That’s going to allow these patients and their families the best opportunity for improvement in their overall quality of life as we work toward a cure.

Thank you, all. This has been a lively discussion. I look forward to doing this in person soon. To our observers and attendees, thank you for watching this 

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The panelists discuss the possibility of treating Dravet syndrome in older children and adults and the effects if the therapies were effective.  

Therapies for Children and Adults with Dravet Syndrome 

We’re going to move on to our last topic, which is exciting things on the horizon. Elizabeth, you mentioned that it’s wicked cool that we have 3 FDA-approved drugs for the treatment of seizures. Some are showing improvements in executive function and quality of life. But we still need something that gets at the underlying cause and is potentially disease modifying. I’m wondering if you can start us out with what things are on the horizon. We can have an open discussion of how we feel about these and where they may fit into this patient population.

There’s an enormous amount of excitement and interest, in both the patient community and the academic community, about the role of genetic therapies. I find that the patients with Dravet syndrome are very sophisticated compared with many of my other patients. Patients are coming in and asking about these therapies. In some cases, they’re explaining to me how the therapies work.

I was at a meeting several years ago about the future of pediatric trials and treatment. It was an interesting meeting because there were the patient advocacy groups, government agencies, pharmaceutical companies, and a group of academic epileptologists. It was clear from the patient communities that they want a cure. It’s really exciting we have these FDA-approved medications that show pretty good efficacy in treating seizures in Dravet syndrome, but families consider the seizures a symptom of having Dravet. They view genetic therapy as more of a possible cure. I get that. I’m also wicked excited about seeing whether they’re effective therapies. Will the efficacy be maintained? Are we able to disease modify in a profound way by early identification and treatment of the whole disorder rather than the symptoms of the disorder?

Absolutely. As you said, seizures are just 1 symptom of the syndrome. I’ve often said that even when someone is having very frequent seizures, if you add up the number of minutes or hours in their week or month, the majority of the time, they’re not seizing. But those are the times when they have to be watched 24-7 or are impulsive or hyperactive. Not until we get at that underlying cause can begin to address some of those things.

I’m with you, Elizabeth. When patients would ask me about gene therapy a few years ago, I really felt like, “I don’t see it.” I was trying to understand based on what I learned in medical school. How are you going to get this gene into the right neurons? Then, all of a sudden, we go to some of these talks and you’re like, “Wow, I wasn’t taught that in medical school.” Maybe we can talk a little about the 2 that are truly on the horizon. There’s 1 in a phase 1/2 clinical trial with Stoke Therapeutics, using this antisense oligonucleotide. Elaine, do you want to talk a little about your knowledge of that? We can all provide some color as best as we understand it.

 Yes. It’s exciting because it’s targeting the underlying pathophysiological mechanism. It really targets the channelopathy. The hope is that you will improve not only seizures but also these other comorbidities. It’s an antisense oligonucleotide that actually prevents the nonsense-mediated decay of the mRNA strand and restores the haploinsufficiency of Nav1.1, the protein. Work in animal models has shown that it can almost essentially prevent SUDEP [sudden unexpected death in epilepsy], which is very exciting. That’s in clinical trials. We’ll see what the impact is on not only seizures but development and other comorbidities, including things like SUDEP. That’s a therapy that’s probably going to need to be given every several months. I don’t think we know the frequency of that, but it’s very exciting.

To speak of that, to get it into the brain, it’s not a pill. It’s a lumbar puncture. It’s given into that space so it can go into the spinal fluid and circulate around in the brain. In the phase of the clinical trials it’s in, this is different from any other pediatric epilepsy treatment we’ve had before, where there are some safety data in adults. We don’t have the luxury of signing up healthy adults to undergo a lumbar puncture. This first trial is somewhat of a safety trial because we need to understand what doses, just like any other drug we talk about. Of course, we hope we get some signal based on the efficacy. Stay tuned for that. There will hopefully be some exciting data in the coming years.

There’s another approach that I’ll speak to and ask others if they want to chime in. Encoded Therapeutics is also working on a genetic therapy that uses an AAV, or an adeno-associated virus. As it turns out, the SCN1A gene is too big to fit inside 1 of these viruses in the classical sense, where you can give the virus and it gets inserted into the patient’s—in this case—neurons. They’ve developed a very slick approach where a promoter is inserted into the virus and it binds to the working copy—the nonmutated copy—of the SCN1A gene. It binds upstream, telling that gene to make more of the messenger RNA transcripts. The result is hopefully the same: More of the transcript gets translated into the protein, and then you restore the function of those inhibitory interneurons.

The difference with this therapy is that it has to be given directly into the ventricular system for it to be more widely distributed through the central nervous system. But on the positive side, it would be a single dose. The dose is correct. It would be a single procedure. That promoter would bind to that wild-type allele and tell it to keep making that messenger RNA. Those trials are planning to start up within the next 6 to 12 months, so that’s another exciting approach that we hope will get all the syndromes and other symptoms and issues that these patients have.

The panel discusses future gene therapies in development for Dravet syndrome. 

Looking to the Future of Dravet Syndrome Therapies  

It highlights the importance, again, of the specific syndrome diagnosis because it really was our patient community that was reaching out for these cannabinoids, I should say and that gave almost preliminary data to say, this is worth exploring and think a very similar story followed with fenfluramine. It was observations in a small cohort of patients who, at the time, weren’t even known to have Dravet syndrome. But just looking back at some of the commonalities in terms of this pattern or photosensitivity and pattern sensitivity to sort of stumble upon, “Wow, this may have a specific role in Dravet syndrome.” I remember it was at one of the first international epilepsy meetings that I was fortunate to go to in Rome, [Italy], and it was when the initial data was presented about the small Belgian code. I think it was in 2016, and I was like, “Well, that’s great but, how can I get it?” Because at that point in time it was only royal decree in Belgium that you could get it. Short of picking up and moving to Belgium, it was great news, but thankfully, things moved forward, and the compound went into the same rigorous phase 3 clinical trials. There was a lot of I think concern around, is this going to be very, very effective, but is it going to be plagued by some of the cardiac valvular observations that happened when it was used as part of a weight-loss regimen back in the 90s. 

I’ll just quickly summarize what we saw in those trials. Again, phase 3 double-blind placebo-controlled trial, looking at a couple of different doses—the 0.7 milligrams per kilogram dose and a lower dose of 0.2 milligrams per kilogram. Again, those doses were largely chosen based on the small 10, 12 patients that were treated by the original Belgian physicians and then a placebo arm. Thankfully, at the end of that placebo-controlled phase when everything was unblinded, the 50% responder rate was 70%. So 70% of patients experienced a 50% reduction in seizures or more, and you can imagine so 70%. Well, what about those that they did even more than 50% reduction? For the first time, I think in a long time, we were able to see a 75% so-called responder rate with almost half of the patients achieving that. If you sort of think about how that, and then the placebo was significantly lower and then lastly, again, you’re kind of getting greedy. Well, 75%, what about 100%? How many are seizure-free? Well, seizure freedom, I think is still such a high bar because this may seem like a silly statement, but once you have one seizure, you can therefore not be seizure-free again. At least in that time period that you’re studying. So we looked at what we term near seizure freedom—having either no seizures or a single seizure during that 14-week trial, and if you lump together the low dose and the high dose 25% of patients actually achieved that outcome. Now, I feel we’re setting the stage for what is possible. Getting back to 3 months of seizure freedom and only 10% of patients, now we’re pushing that up a little bit to 25% was just so refreshing to see and experience as an investigator in the trial to have some of these patients come in and be like, “What do you mean you haven’t had. Really? Can I look at your diary again? You haven’t had a seizure?” It was really, really exciting. I’m wondering when you saw these kids coming in beyond seizures, did you see other things in them where we finally get to see them not getting rescue meds and having these frequent seizures that they’d been having?

I think so much about quality of life and Dravet is related to seizures and breakthrough seizures and prolonged seizures. I think that’s a very negative impact on quality of life both for the kids and the families. I saw these kids actually being able to be kids and being able to get to school more often and participate in family activities more often. Families were getting better sleep. They certainly appeared better rested. So I think certainly improvement and alertness in the kids with less seizures. I think we have seen that even more as we’ve been able to. Then, if you’re in a placebo-controlled trial you can’t touch the other medications, but if a medication works and then we can get you off some of those medications that you were on that were giving you more side effects, but maybe weren’t working as well then we really start to see these kids become more alert and quality of life improves. So absolutely that’s a big impact.

As you mentioned, when you’re in one of these clinical trials, you’re stuck on not making any changes and we put these kids and their parents and caregivers through all these other assessments to try and make sure that the drug is safe and we want to understand if it’s well-tolerated and so they had echocardiograms because of the prior history. We did all these developmental sorts of questionnaires, mainly again, to ensure that it was safe because if someone is put to sleep and on the couch or their behavior falls apart, but their seizures improve, that could be a negative outcome for these families. Thankfully, the safety profile was very favorable. There still has not been any cases of valvulopathy seen in any patient. There was decreased appetite, which we went into this expecting because it was part of a weight-loss drug. But, thankfully, the majority of the time that is self-limiting and, in my experience, it comes back, and the kids continued to gain weight as we would expect them to. And this development of being more alert, I mean this safety measure that was put in there, the brief survey really showed that not only did it not decrease their behavior, or worsen their behavior and executive function, but in those patients that actually responded, a subset of them had clinically meaningful and clinically significant improvements in their brief. So again, this was like the first time that we started to see, “Maybe if we can get,” and I think the family said this, “if we can just…I know Johnny is in there. If we can stop. If we can reduce the seizures, it’ll allow him to thrive.” And I think we’re starting to see some of that.

Joseph Sullivan, MD, provides an overview of the recent approval of fenfluramine oral solution for the treatment of Dravet syndrome. 

Recent Approval of Fenfluramine Oral Solution 

For the viewers, you’ll notice that we haven’t really talked about some of the newer medicines. I don’t really want to say that we’re being stuck back in our last consensus guideline, but I think it highlights how far we’ve come because when we were finalizing those guidelines, we knew that these other treatments were entering into clinical trials, but we didn’t yet know. We were very, very optimistic that they were going to show efficacy and play an important role in our treatment paradigm, but we didn’t have the data at that time, and so we didn’t want to wait. We wanted to get out what we could at the time but now we have 2 more compounds that I think are very deserving of discussion. So the first that was approved was cannabidiol. I know you’re an investigator on some of the trials and so I’m wondering if you could walk us through that story. It’s such a cool story! And just explain some of the data about efficacy and tolerability.

I think that there was clarity, a lot of interest, a little bit of hype, actually, in the media about what impact medical marijuana could have on Dravet [syndrome]. We know a lot of our families were using sort of more artisanal products or nonpharma grade products, and were reporting benefits from that, but a careful clinical trial had not been done. I think when you’re looking at, “does this really work or not,” we as physicians really want to see the randomized placebo-controlled clinical trial. Unfortunately, we had a pharma company who actually made pharma-grade cannabidiol. It was pure cannabidiol without THC, which I think is really important because I think many of us are a little uncomfortable treating a child with THC, which potentially has more neurocognitive impacts. That clinical trial was done, and it did show that for many patients with Dravet syndrome, add-on cannabidiol was efficacious at reducing seizure burden. Again, complete seizure freedom was pretty rare, but it did reduce seizure burden and it did so with actually very few side effects. The side effects often were fairly mild. They often were self-limited. They would go away with time and many patients had a significant benefit in seizure burden.

It was. I couldn’t agree more in terms of all the hype, and I believed it. I had no reason to not believe my families that were coming in and sourcing their cannabidiol on their own, and they were not ending up in the hospital, but we really did need this phase 3 data, which was the studies were very well done and multiple studies that reproduce the results that we know that it’s real. I think the fact that it seems to be so well-tolerated [is important]. All of these medicines have their own side effects, but when we look at the ones that we’ve already been discussing, valproic acid and clobazam again, the majority do tolerate them. But you look at cannabidiol and it just did seem to be very well tolerated. I’m not sure if that’s been your experience as well.

It has. I think you have to be a little cautious using it with clobazam. You need to reduce clobazam dose a bit in order to avoid excessive sedation. Some loose stools is typically what we commonly see, but again, for many kids that’s a limited side effect. It goes away on its own.

Absolutely. It’s exciting. I remember as a pediatric epileptologist, we finally had a new drug that came to market with an indication for pediatrics as opposed to having it be done in adults with partial-onset seizures and have it trickled down to these other syndromes. I think equally fascinating is much like many of the medications that we use just in epilepsy in general, we think we understand the mechanism of action, but interestingly with cannabidiol, there are some theories about it working at this G protein and then these other track receptors and things. It’s called TRPV1 [transient receptor potential cation channel subfamily V member 1] channel. Again, this is getting beyond my basic science knowledge. We suspect that these drugs that work against multiple seizure types, and across syndromes that doesn’t only work for Dravet syndrome. It probably does have many mechanisms that we just don’t understand but as long as we understand the safety profile, I’m OK with that. I’m OK with saying, I don’t know why it works, but it works, and it seems to be safe, so let’s go with it.

I agree. I suspect that a lot of the way we think certain medications work, there’s probably further mechanisms that we don’t understand, and we don’t know yet.

Elaine C. Wirrell, MD, provides an overview of cannabidiol oral solution for treatment of seizures associated with Dravet syndrome. 

Dravet Syndrome: Cannabidiol Oral Solution 

I’m wondering, how do you approach that? You have a patient who comes to you on 4 medications, do you try to rock the boat a little bit?

 Definitely, especially if their seizures are not well controlled. We don’t often now see kids on contraindicated medications, but you still need to look at that. So if they’re on a sodium channel agent or they’re on lamotrigine, those are medications that I tend to try and get rid of because we know that those actually can exacerbate seizures. For the other medications, each child is individual. You may have one child where valproic acid was super effective, and then another child where it really did squat. What I often will do is I’ll say, “Look, your child’s on 4 medicines—rate them. Which one do you think the child is responding to the best?” Get them to rank them 1 to 4. Then [ask], “Which one do you think is causing the most side effects?” By doing that, I think it’s helpful because you get the family’s perspective on what they feel has worked best for their child and I think that’s much more helpful info than you can get from looking through reams and reams of medical records. Then you can make a decision on which one you want to try and get rid of.

Absolutely. I find if you just mention one, you’ll often get a reaction— “No, don't take that one away.” “That one was life-changing for us.” As opposed to others, they’ll just be like, “Yeah, and in retrospect, I don’t think that did squat.” Then I know that if the families really can’t tell, which again most of them can, then what I personally do is I try to look at the potential side effect profile and eliminate the one that may. Again, maybe they’re tolerating it, but a lot of these kids have been on these medicines for many years and so it’s hard to know what “Johnny” looks like without sodium valproate, for example. We keep bringing up sodium valproate, valproic acid, you and I, and some of our colleagues, work together on consensus guidelines to try and put some months of order supported by the data if it existed in terms of how we should approach the treatment of these patients. I recall having our few calls and at that time meeting in person to discuss this project. I think we were surprised that a lot of what we were doing was really not rooted in much data. Valproic is a very broad-spectrum anti-seizure medication. As you’d already mentioned, [with] all these different seizure types that unfortunately occur in this patient population, it seems to make sense to pick a broad-spectrum medicine. We came to the conclusion that valproic acid and clobazam were sort of the first-line syndrome specific treatments. I quantify it in that way because these patients don’t come in saying, “I have Dravet syndrome.” They come in with their prolonged seizure. Maybe they’re diagnosed with febrile seizures. Maybe they’re diagnosed with epilepsy and put on levetiracetam, and then the genetic testing is done and it’s, “Oh, you have a truncating mutation, the SMC1A gene and you have Dravet syndrome.” In my opinion, at least. It doesn’t mean they need to be immediately switched to valproic acid or clobazam as soon as you have this Dravet diagnosis if they’re doing well on levetiracetam. Are you going a few months seizure-free? Are you not having episodes of status? Then that’s OK. You can keep them on levetiracetam but unfortunately, we know from the natural history that it’s highly likely that seizures are going to pick up again in the setting of levetiracetam, and then we would reach for something like valproic acid or clobazam. Then along that same exercise, as we learned from our search, there’s often these often suboptimal [treatments]. Could you go through the second-line treatments that we sort of came to the conclusion in that consensus?

 Sure. Just a comment on the first-line treatment. The responder rates for both of those medications was between 25% and 50%, so they were certainly not cureless for most kids. Second-line, we had a ketogenic diet that was reasonable, and I think many people still use that pretty early on in treatment. I’ve certainly had good success with that in kids with Dravet syndrome. Topiramate also; there’s limited data to suggest that that might be efficacious. Then stiripentol, although it wasn’t available in the U.S. yet. It is now for a prescription, but it wasn’t then. Many of us were using it anyways, and we’re finding that it was beneficial second-line for Dravet syndrome. Particularly with reducing status epilepticus.

Absolutely. I know we have some colleagues to whom we really need to pitch the ketogenic diet in a nonjudgmental way. Don’t get me wrong. We know it’s difficult. It changes how someone eats and already, you may have a child who is a picky eater and is difficult to care for, so limiting their diet even more just may sound like a crazy idea, but certainly, it is much easier today in 2021 than it was 10 years ago with all the availability of these low carbohydrate products that are still healthy and well-balanced for their overall growth and development. Certainly, families need to give them the benefit of the doubt. I think if they do it and it works, they will say, “Why didn’t I do this sooner?”

We have phenomenal dieticians who can be very creative and make this easier as well for the child and family.

I should mention, this should not be done on your own. It really should be done with guidance and expertise of an epilepsy dietician that can really help you with this.

Joseph Sullivan, MD, and Elaine C. Wirrell, MD, discuss the management of seizures for Dravet syndrome with different approved therapies.  

Dravet Syndrome: Management of Treatment  

Now we have our patient that’s either a new diagnosis of Dravet [syndrome] or has an established diagnosis but comes to us for a second opinion and just want to know what else can we try. We’re going to get into how far we’ve come in 2021, but what are your reasonable expectations in terms of having a conversation with a family that you’re meeting for the first time? What do you say is our treatment goal?

Well, I think we’ve actually had a lot of excitement in this field. In the last few years, we’ve seen three new FDA [Food and Drug Administration]-approved medications for Dravet syndrome, which have higher efficacy than our other previous first-line medications that we use. So that’s very exciting to me and very exciting for the Dravet community for families. I still think that most of the time it’s not completely realistic to expect a 100% seizure freedom. I would love to think that ultimately, we are going be able to get there, but I do counsel my families that Dravet syndrome is a drug-resistant epilepsy and there will more than likely be breakthrough seizures. The goal is really to try and reduce that seizure burden, so particularly the prolonged seizures, the ones that are taking the kids into the ER, into the ICUs; we want to get rid of those. The convulsive seizures as well. We really want to reduce the seizure frequency because those are the ones that place those patients at highest risk of sudden unexpected death in epilepsy. Those are the ones we really want to focus on, and then some of the kids will also have pretty frequent absence seizures and almost go into an obtundation status or nonconvulsive status, and I think that also has a significant impact on development, so we need to be paying attention to those as well.

Absolutely. I think just framing it with some optimism that, “Look, I’m having this conversation with you now, but it is a very different conversation than I would have had with you had we met 5 years ago.”

 Still tempering great things, but we still have a long way to go, and I know there was that paper that came out of the European survey that looked at over 500 kids with Dravet, and it was only 10% to 15% that had experienced no seizures in the prior 3 months. Now, that is before some of these new treatments that we’re going to talk about here shortly, but I think that puts it into context. If a child was doing well for 2 to 3 months, you can be grateful for that, but at the same time don’t be devastated. It’s hard for me, as [I am] not a caregiver of someone with Dravet. Of course, they’re going to feel devastated because they finally feel they get this period, but to at least acknowledge that 3 months is actually good and we’re still going to try to do better. Certainly, we need to be very mindful of side effects. With our other non-Dravet patients, I’m very mindful of piling on more than 3 medications and I think that actually, we’ve learned a lot with Dravet too, that 2 to 3 medicines is probably a sweet spot. Again, I say that with caution, as I do have some [patients] for [whom more medication] does seem to be working for them, and they tolerate it, but be mindful of if you’re talking about adding a 3rd medication to medication 1 and 2, you’re acknowledging that 1 and 2 are not as effective as you’d like them to be.

Exactly. I think that’s obviously anxiety-provoking for families. I think for other clinicians, they’re like, “Why would you want to take something away? They’re still having seizures.” It’s a leap of faith. When I’m writing out the decrease I have to admit, I get a little bit squeamish, but I think unless we try to do that, that’s where we can avoid having our kids and young adults on so many medications. Then you’d be really getting into the quandary of what’s doing what…and then what do you appeal back?

Experts discuss the goals of treatment of patients with Dravet syndrome regarding seizure freedom and seizure burden. 