Dravet Syndrome and Lennox-Gastaut Syndrome: Perspectives from the Patient Journey - Episode 17
Tracy Dixon-Salazar, PhD, leads a discussion on challenges of treating LGS and real-world implications from clinical trial data on newer medications.
Joseph E. Sullivan, MD: Tracy, in terms of having this list available, is it a blessing or a curse? You have all these medications that are – they all have this 20% to 30%. You have some outliers, but what is your take on that?
Tracy Dixon-Salazar, PhD: First of all if you’re treating and you don’t know the underlying etiology is genetic then you can really do some harm. This is how Dravet patients end up on sodium channel blockers when they shouldn’t be on them, and there is contraindications that other genetic DEEs and so really understanding that ideology is sort of the first thing. We often call it the dart board approach to treating LGS after that because we've already been on levetiracetam. That's what a lot of patients get tried on, carbamazepine, tegretol is still tried. We often get tried on those before we even get the LGS diagnosis or whatever the combination is. There's 6 different generations of doctors practicing medicine and I would bet that the way that LGS is treated or the way first line therapy for epilepsy is treated kind of depends on the generation where you were trained if there are no guidelines and there really aren't. There is a strong feeling in the space that these newer medicines so cannabidiol and fenfluramine are really designed with rigor and approach new mechanisms. If you look back at the older drugs, the older generation of people with LGS have tried all the old drugs but these 2 new ones sort of represent the unexplored, maybe this is going to have a bigger impact in the population so there is a real feeling of new mechanisms, new treatments coming out. I'll tell you what, we've tried and failed 26 different treatments before we found something, and you get into that loop. Doctors are happy because they're like oh we can at least do something and you're not happy as a patient. You want to be happy with them because there are a lot of neurological diseases that have no treatment and we do have a lot of anti-seizure treatments we can try but that hopes raised and hopes annihilated of try, it didn't work, try and then the change. The seizures are changing over time because the brain is developing but they're also changing in response to the medicines. When you give a medicine you never really know what's going to happen and it's brutal on the family. I'm happy to see though that more comparative effective work is coming out. There's the Cory funded study looking at surgery, any epilepsy surgery versus the next seizure medicine in LGS patients. That will be an interesting study. Dravet syndrome just had a great paper that came out that did look at consensus guidelines using a Delphi process across the globe. We have some consensus guidelines in the US [United States] that are a decade old and then we have one from across the pond in Europe which is a few years old for LGS but they don't really match. I do think that there is an interest now in exploring which are the most powerful. Certainly, the data that's coming out from health claims data and from our surveys in our community is suggesting that some of the drugs like clobazam, clobazam seems to be a drug that these patients go on and they stay on for a long time but we're still seeing a fair amount of phenobarbital use and phenytoin use. Those are difficult drugs when you start them in young children. This is where we strongly encourage our families. You don't have to have a pediatric epileptologist, or an adult epileptologist be your full time doctor that you see 4 times a year. They can be part of your home care team, but you need to be consulting them yearly because the data is just so complicated and so specialized that you need that sort of information. You need somebody weighing in on your treatment and we should probably at some point talk about adult providers who don't feel we struggle with them realizing they have LGS patients and not caring that there's a syndromic name for it and understanding why you would even need to know that. It gets into sort of a whole different ball game when you're talking about LGS in the adult sphere.
Kelly Knupp, MD: Joe, one of the other areas where we can get some guidance is kind of hidden in some of our newer trials. If you go back and look at the trials, at the concomitant medicines that people are on before they went on their study drug, they tend to be pretty consistent across the trials. As you mentioned Tracy, clobazam, valproic acid, Lamictal tend to be sort of the mainstays that people are on before they went into the trials which is ironically somewhat like what we see in Dravet syndrome. We see valproic acid and clobazam and of course not lamotrigine, but we see some common medications despite the fact that many of the patients may have been on 20 something drugs before they went into the trial. There may be some data in there that's worth looking at that's kind of hidden in that background data.
Joseph E. Sullivan, MD: This is not necessarily to be self-promoting of this generation but the trials that have been happening in the last 5 to 7 years are listening to our advocacy groups to look at some more patient centered outcomes. We're looking at quality of life measures, sleep, measures of executive function, all those things that you mentioned Tracy that are more than just seizures. We know seizures are important. We know we need to reduce seizures but what if as you said Kelly, what if some of the quote unquote side effects could improve upon some of these other comorbidities that are so pervasive in each of these patient groups. I think in the fenfluramine study Kelly, that you led, even though the seizure reduction was not as great as it was in the Dravet trial there still are a lot of patients that had improvements in their executive function. That can go a really long way in terms of the day to day sort of grind that these patients and their caregivers are living.
Tracy Dixon-Salazar, PhD: I love that too. We had a medicine – most patients with DEEs have constipation issues with constipation. We were on a medicine that caused diarrhea. Diarrhea was one of the adverse effects and it was like yes because it counterbalanced the constipation problem that we were dealing with. Sometimes you can get that for sleep as well if you have a rambunctious that will just never sleep, sometimes the increased drowsiness and increased sleeping can be helpful in some cases.
Joseph E. Sullivan, MD: Just to circle back on one thing too that you said Tracy; we need to also try to put up a call there for our adult epilepsy colleagues. Maybe the LGS maybe has an edge here because there's at least more awareness of LGS in adult populations than there is in Dravet but still there's not a whole lot of knowledge and this is not meant to be a criticism. It's just kind of an observation that the new medicines, oh they require this prior-authorization and for fenfluramine I must get the echo. Maybe adopt some of the newer approved medications whereas we can basically even if there's not a comparative effect in this trial, if we can just look at the efficacy of these different agents and the fact that the majority of patients had already been there, done that and failed 26 or the big 5 then that should be hopefully illuminating that is going to be worth trying in patients.
Tracy Dixon-Salazar, PhD: I think phenytoin and phenobarbital were powerful drugs in their day and age and a lot of times we see older adults that are still on those. I know there's a temptation to go back to these powerhouse drugs. They're easier to get. They're cheaper. You've got your experience with them for the older generation, but when you think about it, again even on really strong agents like that are kids eating, drinking, sleeping, pooping, peeing, taking their medications? Even if they're an adult who is severely intellectually disabled are they doing any of that? With these newer medications you can improve a lot of those things in these patients by trying that next treatment and that's what we're seeing in our community is that they want to try that next thing. They don't want to go on something that is potentially oh it's been around for a long time, and it might help and we'll just leave you on it because what really happens in our community, no one really knows, we add another medicine. We have no idea if it's working or not because the day-to-day seizure variance is just changing all the time in LGS and then in the long term you can really see a change. The community wants to try these new treatments. The community is willing to go get the echo. The community is willing to be in the clinical trials and literally use the brains of our children to do more for science than science is really doing for us right now and it's our responsibility to be educating families about what's out there and giving them every opportunity to access that treatment. I do really respect what you guys as physicians must go through just to get access to these treatments for our families. Without a savvy physician that's willing to write a letter and work with us and work with our insurance company, which is I'm sure what you guys all went to medical school to do, without us getting that we are never going to get access to the treatment, so it falls to you guys in so many ways.
Transcript Edited for Clarity