Challenges in treatment selection in LGS

Joseph E. Sullivan, MD: Tracy, in terms of having this list available, is that a blessing or a curse? You have all these drugs that are – they all have these 20% to 30%. You have outliers, but what do you think of this?

Tracy Dixon-Salazar, PhD: First of all, if you are treating and you don’t know that the underlying etiology is genetic, you can really do harm. That’s how Dravet’s patients end up on sodium channel blockers when they shouldn’t be on them, and there’s contraindications that other genetic EEDs and so really understanding that ideology are kind of the first thing. We often call it the darts board approach to treating LGS after that, because we’ve already taken levetiracetam. That’s what a lot of patients try, carbamazepine, tegretol is still tried. We are often tried on these before we even get the LGS diagnosis or whatever the combination. There are 6 different generations of doctors practicing medicine and I’d wager that how LGS is treated or how frontline therapy for epilepsy is treated kind of depends on what generation you were trained in. there are no guidelines and there really aren’t any. There’s a strong sense in the space that these new drugs, like cannabidiol and fenfluramine, are really being rigorously designed and addressing 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 kind of represent the unexplored maybe it’s going to have a bigger impact in the population, so there is a real sensation of new mechanisms, new treatments coming out. I’ll tell you what, we tried and failed 26 different treatments before we found something, and you enter this loop. Doctors are happy because they think oh we can at least do something and you are not happy as a patient. You want to be happy with them because there are a lot of neurological diseases that don’t have a cure and we have a lot of anti-epileptic treatments that we can try but have hopes raised and hopes dashed trying, it didn’t work, then try change. Seizures change over time as the brain develops, but they also change in response to medications. When you give medicine you never really know what’s going to happen and it’s brutal on the family. I am glad to see however that more effective and comparative works are coming out. There’s the Cory-funded study looking at surgery, any epilepsy surgery versus the next antiepileptic drug in LGS patients. It will be an interesting study. Dravet Syndrome just published an excellent article on consensus guidelines using a Delphi process around the world. We have consensus guidelines in the United States [United States] which are about ten years old, and then we have one across the pond in Europe which is a few years old for LGS, but they don’t really match. I think there is interest now in exploring which are more powerful. Certainly the data that’s coming out of the health claim data and our surveys in our community suggests that some of the drugs like clobazam, clobazam seems like a drug that these patients take and stay on for a long time, but we’ I still see a fair amount of phenobarbital use and phenytoin use. These are difficult drugs when introduced to young children. This is where we strongly encourage our families. You don’t need to have a pediatric epileptologist or an adult epileptologist as your full-time doctor who you see 4 times a year. They can be part of your home care team, but you have to see them every year because the data is so complicated and so specialized that you need that kind of information. You need someone who weighs in on your treatment and we should probably at some point talk about adult providers who don’t think we’re struggling with them realizing they have LGS patients and not caring that there is a syndromic name for this and understand why you would even need to know that. It gets into a whole different kind of ball game when you talk 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 new essays. If you go back and look at the trials, the concomitant medications that people take before taking their study drug, they tend to be pretty consistent from trial to trial. As you mentioned, Tracy, clobazam, valproic acid, Lamictal tend to be kind of the mainstays that people were on before they got into trials, which ironically sounds a bit like to what we see in Dravet syndrome. We see valproic acid and clobazam and of course not lamotrigine, but we see common medications despite the fact that many patients were on maybe 20 or so medications before entering the trial. There may be data in there that is worth looking at that is kind of hidden in that background data.

Joseph E. Sullivan, MD: It’s not necessarily self-promotion of this generation, but the trials that have been happening over the last 5-7 years listen to our advocacy groups to look at more patient-centric outcomes. We’re looking at quality of life measures, sleep, executive function measures, all those things you mentioned Tracy that are more than just seizures. We know crises matter. We know we need to reduce seizures, but what if, as you said Kelly, and if some of the side effects in quotes could improve some of these other comorbidities that are so prevalent in each of these groups of patients. I think in the Kelly fenfluramine study, which you ran, even though the seizure reduction wasn’t as great as in the Dravet trial, there are still a lot of patients whose executive function has improved. This can go a long way in the daily lives of these patients and their caregivers.

Tracy Dixon-Salazar, PhD: I like that too. We had a drug – most EDE patients have constipation problems with constipation. We were taking a drug that caused diarrhea. Diarrhea was one of the side effects and it felt like yes as it counteracted the constipation issue we were facing. Sometimes you can also get this for sleeping if you have a rambunctious that will never sleep, sometimes the increased drowsiness and increased sleep can be helpful in some cases.

Joseph E. Sullivan, MD: Just to pick up on something you said Tracy as well; we must also try to call our adult epileptic colleagues there. Maybe LGS might have an advantage here because there’s at least more awareness of LGS in adult populations than in Dravet, but there’s still not a lot of knowledge and that’s not is not meant to be a review. It’s just kind of an observation that new drugs, oh they require that pre-clearance and for fenfluramine I have to echo. Maybe adopting some of the new drugs being approved when we can basically even though there’s no comparative effect in this trial, if we can just look at the effectiveness of these different agents and the fact that the majority of patients had been there before, done this and failed 26 or the big 5 so this should be hopefully enlightening and worth trying in patients.

Tracy Dixon-Salazar, PhD: I think phenytoin and phenobarbital were powerful drugs in their day and we often see older people still taking them. I know there is a temptation to go back to these powerful drugs. They are easier to obtain. They are cheaper. You have your experience with them for the older generation, but when you think about it, again, even on really strong agents like that, kids are eating, drinking, sleeping, pooping, peeing, taking their meds? Even if he is a severely intellectually disabled adult, does he do this? With these new drugs you can improve a lot of these things in these patients by trying the next treatment and that’s what we see in our community is that they want to try the next thing. They don’t want to continue on something that’s potentially oh it’s been around for a long time, and that might help and we’ll just leave you on it because what’s really going on in our community, nobody really knows, we’re adding another drug . We have no idea if it works or not because day to day input variance changes all the time in LGS and then in the long run you can really see a change. The community wants to try these new treatments. The community is ready to seek the echo. The community is ready to participate in clinical trials and literally use our children’s brains to do more for science than science is really doing for us right now and it is our responsibility to educate families about what is out there. and to give them every opportunity to access this treatment. I really respect what you doctors have to go through just to get access to these treatments for our families. Without a savvy doctor who’s willing to write a letter and work with us and work with our insurance company, which I’m sure is what you all went to medical school to do, without that we understand that we will never have access to the treatment, so it is on you in many ways.

Transcript edited for clarity

Martin E. Berry