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. 

Joseph Sullivan, MD

Articles

Dravet Syndrome: Transition of Care Into Adulthood

Managing Expectations for Patients With Dravet Syndrome

Therapies in Development for Dravet Syndrome

Dravet Syndrome: Fenfluramine and the Impact on Consensus Guidelines