All right, hello everybody. Thank you for attending today's Ask the Expert webinar on real-world experience and tips for treatments with the latest anti-seizure medications. Please note that this webinar does offer continuing education credits after completing the evaluation. You'll be taken to the evaluation immediately after the webinar. You will also receive an email when the on-demand version is available. Before we get started, I would like to take a moment to acquaint you with a few features of this web event technology. At any time, you may adjust your audio using any computer volume settings that you may have. On the right-hand side of your screen, you will see the Q&A window. There's a large window which holds all your sent messages and a smaller text box at the bottom where you will type in your questions. To send a question, click the text box and type in your text. And when finished, click the Send button. All questions that you submit are only seen by today's presenters. Your questions will be responded to in the order in which they were received and will be addressed at the end of the presentation. I'd like to introduce today's moderator, Dr. David Ficker, AES Online Education Committee Chair. David, whenever you're ready. Thank you, Ashley, and thanks everyone for joining today. We're excited to present to you our first webinar of 2022, which is the first of a series of four webinars we'll be offering throughout the year. Today's topic, as mentioned, is Real-World Experience and Tips for Treatment with the Latest Anti-Seizure Medications. And we're pleased to have Dr. David Vossler and Dr. Kevin Chapman present on these new medications. We've seen a number of new anti-seizure medications introduced over the past several years with unique mechanisms of action or for use in very specific epilepsy syndromes. This webinar today will discuss the real-world experience with these medications and provide you with some practical tips on using them in your epilepsy patients. Our learning objectives are as follows. To describe data from clinical trials on the outcome of the newest approved anti-seizure medications, including cannabidiol, parampanil, sinobamate, steropentol, fenfluramine, and breviracetam. And we'll discuss the clinical experience of the newest anti-seizure medications and apply this experience to your clinical practice. I'm gonna go ahead and introduce both speakers at the beginning, and we'll then let Dr. Vossler present the first part. So Dr. David Vossler is Medical Director of the Epilepsy Center and Neurophysiology Labs at the UW Medicine Valley Medical Center in Renton, Washington, and is a Clinical Professor of Neurology at the University of Washington School of Medicine in Seattle, Washington. He is Chair of the Council on Clinical Activities of the AES and is also a Fellow of the AES, the American Clinical Neurophysiology Society, and the American Academy of Neurology. He is a Contributing Editor of Epilepsy Currents and is a member of the Epilepsy Study Consortium. He's served on numerous committees and boards of national medical organizations and on editorial boards of numerous journals. He's the Principal Investigator on over 65 clinical trials and has published over 80 original articles and 10 book chapters. Dr. Kevin Chapman is a Pediatric Epileptologist and Clinical Researcher, and a Professor in the Department of Pediatrics at the Phoenix Children's Hospital and University of Arizona. His clinical practice centers on the care of pediatric patients with drug-resistant epilepsy and with a focus on evaluations for epilepsy surgery. He has an interest in intracranial monitoring and advanced EEG and neuroimaging post-processing techniques. His primary focus of research is on status epilepticus and electrical status epilepticus of sleep, and currently serves on the American Epilepsy Society Board of Directors. And again, I want to personally thank each speaker for presenting today, and we'll turn it over to Dr. Vossler for the first part of the presentation. Thank you, David, for the kind introduction, and I'd like to just go ahead and get started. So we decided to divide the six anti-seizure medications that David mentioned up into those that are probably more commonly used in pediatrics, and so Kevin will talk about those, and myself, being an adult neurologist, I'll limit my discussions to Rivaracetam, Sinovimate, and Parampanel. So my disclosures are listed here. I have no corporate connections, and you've probably seen variations of this slide over the years, and I must say when I started my neurology residency at Boston University in 1984, we had literally a handful of anti-seizure medications, and some of you may know that the last seizure medication introduced when I was a resident was Velproate. It was relatively new at that time, not totally new, in 1978. We had a long hiatus before Felvamate, the first new anti-seizure medication in 15 years came along, and since then, obviously, the slide shows, the graph shows that basically it's been an explosive situation, which is good for our patients, but makes things very complicated for all of us. Because of this complexity, Dr. Barry Goodall, who's a professor of pharmacology at University of Wisconsin, and I, along with our members of the Treatments Committee of the American Epilepsy Society, published a resource for you, and you can see it on this slide. At the bottom of the slide is actually a photo of the AES website, so please visit that, go to the second menu over, the left-hand one says Annual Meeting, then you see Clinical Care. Go to Clinical Care, you can drop down to Treatments, and you can access this resource. Also up above is listed the actual web address. What you'll see is, it's about 30 pages long, and our first version of this was published in Epilepsy Currents in 2018, and we actually realized that we're gonna have to update this periodically, so we updated it last in September 2020, when a number of these new medications came out. This is an example of the entry for cannabidiol. It is one of the more particularly complex ones. You'll see that the columns are drug formulations and DEA scheduling, FDA-approved syndromes for which the drug is indicated, proposed mechanisms of action, then pharmacokinetics, absorption, distribution, metabolism, and excretion, recommended initial doses, if appropriate, depending on the drug, for adults and for children, minimum and maximum doses, serum levels, if there are serum levels available, selected adverse reactions, we couldn't list them all, contraindications, warning, and precautions, and finally, drug-drug interactions. So, for details on what we're gonna talk about today, please refer to that. We'd love to have you use it, have your fellows, residents, colleagues use it, and keep it, maybe print it out. It's available as a PDF. Print it out and keep it on your desktop. I can tell you, even though I wrote this with Barry and reviewed by the Treatments Committee, I keep a copy on my desktop because it's bloody complicated, as the Brits might say. So, we're gonna talk about briviracetam initially. It is now approved for use down to one month of age. That's a newer indication. The indications gradually go down in age over the years. So, certainly, Kevin would use this in his pediatric practice, as would I in my adult practice. The injectable form's only for kids 16 of age, older, and adults, and it's only approved as adjunctive treatment for focal seizures. The class of drugs is what I call a racetam class. Obviously, the prototype drug for this was levotracetam, but actually, some of you may know that the real prototype drug for this whole class was puracetam, which was available in Europe, never in the United States, for decades. It was a generic drug, very low potency, average dose would be over 7,000 milligrams a day. And so, this briviracetam is a very high-potency drug Remember, potency talks about the number of milligrams it takes to get the job done. Don't confuse potency with efficacy. Efficacy is effectiveness, but high potency means you only need, in this case, 100 milligrams a day or 200 milligrams a day, as opposed to something like puracetam. Well, what's its mechanism of action? I think everybody knows that levotracetam binds the SV2A vesicle protein and inhibits protein cycling. And certainly, levotracetam has that mechanism. It also, levotracetam is also effective at the ampaglutamate receptor and the HVA calcium channel. The mechanism action of briv, however, is more selective. It only binds the SV2A protein vesicle, and it has 15 to 30 times greater affinity for that vesicle binding than does levotracetam. It's also more lipophilic and penetrates the brain faster than levotracetam does. What these mechanisms and lipophilicity exactly mean in clinical practice at this time is not entirely clear. The pharmacokinetics are really pretty straightforward. It's linear. Its half-life is shown there, about nine hours, so pretty short. Unlike levotracetam, which is simply renally excreted, this is first metabolized in the liver. There's an amide hydrolysis that goes on, followed by cytochrome P450 oxidation using CYP2C9 and 2C19. Unfortunately, unlike levotracetam, this drug, brivaracetam, does have drug-drug interactions because of the oxidative metabolism. And then most of the drug is... 95% of the drug is renally excreted. Less than 10% is excreted unchanged. The drug-drug interactions I talked about are listed here, that the serum level of briv is decreased by rifampin, about 50%, almost half. So, for patients on rifampin, which would be an uncommon thing in my experience, keep that in mind. Also, enzyme-inducing anti-seizure medications, which I tend to forget myself, do decrease levels a little bit. A lot of people would say probably 20 to 25%. Maybe isn't a significant effect, but it is there nevertheless. Briv increases carbamazepine epoxide metabolite levels twofold, and of course, that is the sort of toxic epoxide metabolite of carbamazepine. Thankfully, these days, people are on carbamazepine less than they used to be. Certainly, that was the mainstay of treatment when I was a resident and fellow. Briv does increase phenytoin levels about 20%, which, for that drug, may be very, actually, very important. There were three main studies. I won't go through all of the details, but these were dose-ranging studies. You can see the doses employed. Now, keep in mind, this is the total daily dose that's shown here. It is a drug that is divided and given BID, so when I say 200 milligrams a day, it's really 100 milligrams BID. Efficacy, I can just briefly say, was, in this case, compared to placebo. So, they looked at the median percent reduction and mathematically calculate. It's not simple subtraction, but mathematically remove the placebo effect, and basically, 17 to 25% median percent reduction in patients who were on 100 milligrams total per day and about 26% above placebo median percent reduction for patients who were on 200 milligrams total for the day. So, the 50% responder rates are shown there, actually, on the slide. I wanted to show the median percent reductions, which are actually the US FDA approval primary efficacy endpoint. What they found was there was no added benefit if you gave levotiracetam with brivoracetam, so there's no point in doing that, but I will say there were patients who had been prescribed levotiracetam and there were patients who had been previously on brivor, excuse me, previously on levotiracetam who came into the trial, were put on brivoracetam, and did have a response. So, it can be appropriate based on those data for a patient who's failed LEV to go on BRIV. Side effects are listed here, somnolence, fatigue, dizziness, ataxia. There were some cases of suicidal ideation and behavior and irritability and psychosis, other things listed here, but those were lower than what were seen, actually, with placebo. So, if you look at the second bullet point here, there was a lower rate of suicidal ideation with BRIV than there was with placebo. Irritability and anger, and this is my own personal experience, the first statement there. I think it is less than with LEV. I was told by some colleagues that they thought it was, and my experience is it is in some cases, but not in others. I have one gentleman, he's Russian. He lives here near me, and he could not tolerate LEV, but he really did like BRIV, and it's been a great drug for him. Others, not so much. The irritability and anger seen in the clinical trials, so getting away from my own personal experience, but more broadly, the clinical trials, was 3% for patients that were on drug and 1% for placebo. So, I think these are reassuring, and then, I have already mentioned this, that if you add BRIV to LEV in the clinical trials, there was no added benefit, but it's worth trying, potentially, in patients who have failed LEV. And I don't want to make comparator statements because there were no clinical trials head-to-head. One versus the other, but this is a cost issue, and full disclosure, the drug is a branded drug, and so, therefore, it certainly is costlier than generic levotiracetam, costlier for the insurance companies. Okay, moving on to the second drug, and trying to keep this within the confines of the time that has been allotted. Sinobamate was approved in 2019 and marketed in May of 2020 for the treatment of focal onset seizures in adults. It is a monocarbamate drug, and you'll see here, I don't know if I have a pointer, I'm gonna move my arrow, I don't know if you can see that. If you can, the top left portion of, oh, there's a pointer, okay, thank you. Can I grab that? Yeah, there we go. Great, a pointer appeared. That's the carbamate molecule right there, or group, if you will, it's a monocarbamate, unlike felbamate, which is a dicarbamate. Mechanism of action is shown there, predominantly preferential inhibition, a persistent sodium current, with some modulation at GABAergic inhibition. PK is very simple, linear kinetics, but this is a long half-life drug, and in many ways, that actually leads to some advantages, possibly some disadvantages if you needed to stop it early, or if a significant adverse effect came up. Keeping in mind, basic pharmacology, it's always surprising to me how many people maybe were never taught this, that whenever you are chronically dosing a drug, when you start dosing that drug, and you start at a specific dose, it always takes five half-lives, approximately, to reach a steady-state plasma level, and so when you discontinue a drug abruptly, or you reduce the dose, it's gonna take five half-lives as well to reach a steady-state plasma level. Given this long half-life of about 55 hours, it takes two weeks to establish steady-state plasma level when you change the dose of sinobamate, or start the drug, so one needs to really keep that in mind for every drug, every drug, not just sinobamate. So long half-life drugs, very long time to steady-state plasma level. So it's ADME, absorption is good, metabolism distribution and excretion are complicated. As you see, the drug is metabolized by glucuronidation followed by multiple cytochrome P450 isozymes. Sinobamate inhibits CYP2C19. This is going to increase the plasma level of phenytoin substantially, almost two-fold. It's going to increase phenobarbital about 35%, and it also will inhibit the metabolite of clobizam. So the clobizam metabolite, which is N-desmethylobizam, the metabolite's metabolism is going to be markedly slowed, and so the plasma level of the metabolite will increase substantially, leading, for sure, to sedation. So you really need to, if the patient's on phenytoin, clobizam, or especially phenytoin and clobizam, but to some extent phenobarbital, you've got to keep in mind, you're going to have to start reducing the doses of those drugs as you're going up slowly on the dose of sinobamate. It does have modest effects on carbamazepine, and about a 40% reduction of lamotrigine. Couple of other things to keep in mind down below. So there were three adjunctive studies done. You can see that there are adverse effects. The most important ones to keep in mind are potential shortening of the QT interval. There aren't many drugs that shorten the QT interval. There are a lot of drugs that lengthen the QT interval, but you want to keep that in mind. Rufinamide is the only other anti-seizure medicine other than sinobamate that shortens the QT interval. So use caution if you use rufinamide and sinobamate together. And the most important thing, and if you've used the drug, you already know this, you have to go through a 12-week titration with the medication. The manufacturer has starter kits that are the way to go, absolutely. I usually have one in my drawer. Well, I won't show that because it has a brand name on it, but the point is, use the starter kits. You have to start low and go slow. When the C021 study was done, 1,339 patients, we used this slow startup schedule, and there were no cases of DRESS, drug reaction with eosinophilia and systemic symptoms, formerly known as multi-organ hypersensitivity. So that's important. That is a key thing. Use the starter kits. They're very easy. So the seizure reductions were substantial. In the C013 study, placebo, a median percent reduction with placebo was 22%, but the median percent reduction with synovia made at 200 milligrams a day was 56%, so very substantial. Likewise, in the C017 study, 24% reduction with placebo and the median percent reduction with either 200 or 400 milligrams was 55%. What really is remarkable and has held up now two years later in clinical practice is unparalleled seizure freedom rates, ranging between 21% and 28%. Those are the numbers from the C013 and C017, the two pivotal trials. In an open-label study that we presented at the AES just this past December in Chicago, we found that the seizure-free rates – I'm going to get the latest data for you. So patients who were in this open-label extension study, without getting into the weeds too much, 33.9% of patients were seizure-free at 12 months, so very substantial. So more to come on that, but I think that this is a really remarkable drug, and that's been my experience over and over and over again. Of course, not everybody responds, but those that do, they will often surprise you. I have no way of predicting who's going to have the seizure-free response. Let's see here. So somnolence is something to keep in mind. Absolutely – oh, sorry. So somnolence, take the drug at bedtime. It's a once-daily drug because of its long half-life, but give it at bedtime. It will mitigate that effect. Another way to mitigate the effect is, as I said, you've got to start decreasing the Clobazam dose probably by at least half eventually, otherwise you will get very sleepy. I've occasionally forgotten that and been reminded by my patients, you have to do that. You also have to taper and reduce sodium channel blocking anti-seizure medications. It was apparent to me in the clinical trial that we had to do that because, as a sodium channel blocker, when you – sonobamide is, if you add it to other sodium channel blockers – glucosamide, CARB, OX, Lamotrigine – you will get dizziness, ataxia, blurred, double vision in many of those patients. So don't give up. If they're already on a sodium channel blocker and you add sonobamide to it, the patient will say, oh, that sonobamide is making me very dizzy or off balance. And the patient, of course, will want to decrease the sonobamide. No, if they're – you know, you're putting sonobamide on because they aren't doing well on their baseline meds, lower the pre-existing sodium channel blocking drugs. And I can virtually assure you that will solve most of your problems. So finally is parabenol, a very different kind of drug. All three of these drugs are very, very different mechanistically and structurally. This is a novel medication. It's approved for adjunctive treatment for primary generalized tonic-clonic seizures as well as for focal seizures. And it's for children age 12 and above and for adults. The mechanism of action is it's a non-competitive – not a competitive but a non-competitive – selective antagonist of glutamate AMPA receptors and inhibits synaptic-driven influx of sodium. This is, as opposed to sonobamide, which was a long-acting drug, this is an ultra-long-acting drug with a half-life, a median half-life of 105 hours in the plasma. So again, to steady state, well, multiply 5 half-lives or 5 times 105. So you're well over 500 hours before you reach steady state plasma level. We're talking three or more weeks to reach a steady state plasma level. So please start at a low dose. Give it enough time. I would give it three weeks before you increase the dose. And this is just a cartoon. This is taken from Mike Rogoski's paper a couple of – a few years ago now. It shows that parampanel binds down – you can see the lower left side, the linking region that link the AMPA receptor to the transmembrane segments of the AMPA receptor. It binds at a different site, as you can see there. And basically, the parampanel sort of plugs up from conformational change, then the receptor plugs the pore so that sodium cannot enter the cell. This is metabolized, like many drugs, by CYP3A4. The most common isozyme that metabolizes drugs is CYP3A4, and this is one of those. And as a result of that, there are drug-drug interactions. So the common enzyme inducers, carbamazepine, OXCARB at higher doses, and phenytoin do increase the metabolism of parampanel. So for those drugs, especially for phenytoin, you'll want to go to a higher dose for parampanel than you will for non-inducing drugs. A couple of other interactions there. I'll throw in a little bit of thing. We just put together a podcast, and you may or may not have seen it, AES did with myself and a couple of other pharmacologists about these new oral anti-COVID drugs to treat COVID. And Paxlivid contains ritonavir, which is a known CYP3A4 inhibitor. So this will increase the plasma level of parampanel and a host of other anti-seizure medications. I won't get into that anymore, but I want to just bring that up here. Effectiveness is very high. Let me just say that in the one primary generalized tonic-clonic seizure study that Jackie French was a senior author on, the median percent reduction in tonic-clonic seizures was 76% for 8 milligrams a day of parampanel, as opposed to 38%, so exactly half, for placebo. So substantial effect. In my opinion, this differentiates this drug, and everyone should really remember that parampanel is approved for generalized tonic-clonic seizures of generalized onset, and keep that in their armamentarium when they're thinking about a patient that's failed multiple drugs who has primary generalized epilepsy. Don't forget parampanel. The efficacy in the focal-onset studies, the partial-onset studies, was a little bit less. Some of the side effects are listed here. Dosing is, ideally, you want to target about 8 milligrams a day, total daily dose, but if they're on enzyme-inducing anti-seizure medications, you can go to 12, as I said, because of the CYP3A4 induction. The drug was approved 10 years ago. I can't believe it. It's been that long, actually, but marketing was held up a tiny bit because of scheduling. There was a big scheduling delay at the DEA, and it came out as a Class 3 drug. Basically, my takeaways are here. Ultra-long half-life, so increase every 3 weeks. Very effective against primary generalized tonic-clonic seizures. And it is effective against focal-impaired awareness seizures. Mechanism of action makes me think maybe there are certain subgroups that it might be better in, and so that's an option for more research in the future. With that, I'll conclude my section, and at this point, if the organizer can open the audience poll, we have a question for you, which is, which of the anti-seizure medications are indicated for the treatment of focal-onset seizures and for the treatment of generalized onset tonic-clonic convulsions? Is it A, briviracetam, B, cenobamate, C, parampanel, D, briviracetam and parampanel, or E, cenobamate and parampanel? We'll give people a minute or two here. David, while the poll is being completed, there's a couple of questions that came through in the chat that I'll pose to you. The first question, have there been any head-to-head comparative trials of levotriacetam and briviracetam? And if so, can you share with us any information? Yeah, not to my knowledge. That's what I can say, is not to my knowledge. I don't recall having seen one. If I did, I'm sorry, I missed it. I don't recall it. Okay. And then the second question specifically was about briviracetam, but I'll broaden it to the other anti-seizure medications you talked about, was whether it's possible or even clinically indicated to obtain serum levels for these newest anti-seizure medications. Yeah, you definitely can get parampanel in that level, and I'd love to hear others' experience. I personally have been unable to get briviracetam or sinobamate levels, but I'd like to do so. So if somebody wants to put into the chat if they know briv and sinobamate levels are available, I would like to know that. But parampanel, absolutely, I get those from time to time. Another question pertains to some of the long half-lives of some of these newer medications. Is there a role for any type of loading dose to enhance initial serum concentration of these medications when starting? Well, certainly not for sinobamate. The FDA was, you know, there was a lot of discussion during the clinical trials. The initial two trials was sinobamate, the C13 and C17 trials. There were three cases of DRESS out of about, I want to say, 900 patients. FDA asked the company, they said, we totally understand that this is an effective drug, but we need you to go back and do a third study to, pardon the alliteration here, address the question of DRESS syndrome in those patients. And so, no, do not load patients with sinobamate. As to loading with BREV, which is a short-acting drug, that makes some, definitely makes some theoretical sense. It is available as an injection, and so that could be done in an off-label way. And then, finally, for parampanel, I think really for tolerability purposes, you know, I guess if you were really in a difficult situation with more of an acute situation, I guess, you know, loading is always a possibility. But I think for tolerability, it's best to go slow with parampanel. On a related note, there was a question that came through about using any of these newer medications in status epilepticus, and obviously that would be off-label. That would be off-label. I would point to the people who are interested in answering that question to a publication that we published in the November-December issue of Epilepsy Currents, November-December 21 issue of Epilepsy Currents, Juan Ochoa and several of us from the Treatments Committee at the Epilepsy Society, American Epilepsy Society, published a comprehensive review of the literature of using certain drugs for the treatment of super-refractory status epilepticus. There's a little literature on using parampanel in that situation, but it's not—but these drugs have—other than that, let me think, well, and I published the comprehensive review on refractory status epilepticus about a year ago, and that's also in Epilepsy Currents, and there I talk about some very small studies of briviracetam, uncontrolled class four studies. So, the bottom line is—and Sonoba may just, again, because the risk address would not be, I don't think, a candidate, a good candidate to be even studied for that or used for that. So, yeah, I'd refer you back to our two comprehensive reviews, one on refractory status epilepticus and the new one on super-refractory status epilepticus, for information and the references on briviracetam and parampanel. A question related to that would be about an update on an IV formulation of parampanel, if you're aware of any work in development of that formulation. Yeah, I don't have the same kind of company ties that I did in the past, and so if something is going on there, I'm not aware of that. Okay. And then, finally, several of our listeners commented that LabCorp can do Sonobamate levels, and Mayo Labs have done Breviracetam levels, so just to update the audience. So, I appreciate the comments from our attendees. So, LabCorp can do Sonobamate? Yep. And Mayo does Brev? Okay, good to know. Good to know. All right. So, with that—I'm sorry. Sorry, David. Go ahead. I was going to say, for the poll, the answers kind of were a little bit spread, but mostly centered on parampanel alone, and that is the correct answer. So, with that, I'll conclude my portion. Thank you, David. Great. Thank you, David. We'll next turn this over to Dr. Kevin Chapman, who will talk about some of the newer antiseizure medicines that have indications in very unique patient populations, and so I'll turn it over to Kevin. Thank you, Kevin. Great. Thank you, David. So, I do have some consults for current biosciences. I'm going to start with cannabidiol. I think everybody kind of knows how much excitement came around when that was first discussed, and there have been actually some good trials and was actually ultimately approved in June of 2018, Epidiolex was, initially for treatment of Lennox-Gastaut syndrome and Dravet syndrome down to two years of age. It has since been expanded to include tuberous sclerosis, and the age has been dropped down to one year of age. It is a phytocannabinoid, and it actually comes as a liquid medication. It's only available as a liquid. The medicine itself, the cannabidiol, is actually dissolved in sesame oil, so if you have an allergy to sesame oil, it's important to know that it is strawberry-flavored in case you're interested in that. As far as a mechanism of action, it's actually quite unclear how this works. It does seem that it doesn't interact at the CB1 and CB2 receptors, so there must be some other mechanism for which it seems to work. As far as the pharmacokinetics of this, it has a half-life of about 17 hours. Interestingly, there's an increased absorption for patients when they're taking this with a high-fat meal, so it's probably important that when patients do take it, they take it consistently either with or without a meal, so they shouldn't have a lot of differences in absorption. It does go through extensive metabolism via the CYP3A4 and CYP2C19 and has an active metabolite. Because of those metabolisms, there are drug-drug interactions that you need to be aware of, so drugs that inhibit those medications can alter the kinetics. In addition, the medication clearly inhibits the breakdown of endoclobazam, and since many of our patients are on clobazam at the time when this medication is started, we have to be aware that it may cause issues with sedation and somnolence. Also for our patients that have tuberous sclerosis, many of those may be on Everolimus, and we need to be aware that there can be changes in the serum levels of that medication for those patients. As far as dosing, the dosing of the medication starts, the recommendation is to start at 5 milligrams per kilogram per day divided BID, with the target dose depending on the indication, anywhere from 10 up to 25 milligrams per kilogram per day divided BID. One other point that I would make about the medication is the medicine when placed through G-tubes can cause issues, and so we encourage families to definitely flush the G-tube well with water, because particularly the PVC G-tubes can be damaged through long use of an oil-based product. As far as the responder rate, there have been four pivotal trials for Lennox-Gastaut and Dravet syndrome show a reduction of about 40% for drop seizures in Lennox-Gastaut patients, and then also a similar number of about 45% for convulsive seizures and Dravet syndrome. When you actually look at the studies for seizure freedom rates, the seizure freedom rate for Lennox-Gastaut syndrome was about 1 to 4%, while for Dravet syndrome it was listed at 7%. As far as adverse effects, the primary adverse effects that I see is usually the somnolence issues, and oftentimes in patients who are also taking Clovisam, and so I think it's important that if patients are taking Clovisam that we warn patients about this potential side effect, and I usually encourage at least dropping the dose by about 25% if not more if they're on a very high-dose medication. The other big issue probably relates to the fact that the medication is dissolved in oil, so I do have patients who will have issues with stomach upset, bloating, diarrhea, constipation, sometimes as much probably from the oil as the medication itself. There is an increased risk of transaminitis for patients particularly taking the medication without product acid, and so because of that, it is recommended that you monitor with an AST and ALT, as well as a total bilirubin at baseline, and then check that again at 1, 3, and 6 months after taking the medication. Beyond that, if the medicine stays stable, I don't think to keep repeating the lab draws. This is, I find, a very popular choice among patients. I'm constantly getting asked about whether their child may be a candidate for Epidiolex or Cannabidiol. I do always stress to families that the local Cannabidiol product that they can get in their local pot shop is not the same as Epidiolex and what we prescribe. And so I think it's important that we let families know that there is a difference between those products and what they can get locally. All right. So now to shift gears. The next medication I'll talk about is a medication, Steripental. It was approved in August of 2018 and is marketed as Diacomet. It is an aromatic allelic alcohol and is indicated for patients with Dravet syndrome who are two years of age and older who are also taking Clobizam. So the recommendation is that if they're on Steripental, they need to also be taking Clobizam. The medication comes as tablets and fruit-flavored packets, and those come as either 250 milligram or 500 milligram sizes. There is no liquid form available for this medication. The mechanism of action, it has an effect on GABA-A receptors directly. And in addition, through the drug-drug interactions, also tends to raise Clobizam levels as well as the indesmethylclobizam metabolite, and that may be part of the effect that it has to help control seizures. Unlike many of the medications that we have, this medicine does have nonlinear kinetics and lower or higher doses are associated with longer half-lives. You can see here that the half-life ranges from four and a half hours up to 13 hours, and therefore the medication should be given at least BID, and in some patients will need three time-a-day dosing. Metabolism is fairly complicated. Once again, using the cytochrome P450 isoenzymes, it is metabolized by our commonly seen CYP2C19 and 3A4 isoenzymes. Because of that, there are the drug-drug interactions I mentioned already, the Clobizam and indesmethylclobizam levels can become quite high with this medication, and other enzyme-inducers may actually decrease the steripental levels. So if they're taking phenytoin, carbamazepine, something like that, it's important to kind of keep that in mind. Because of the increase in the Clobizam and indesmethylclobizam may have to adjust the dose of the Clobizam level, so oftentimes I'll once again kind of reduce that Clobizam dose maybe by 25% or even higher if they're on a big dose of medication. As far as dosing, the idea is to start about 10 to 15 milligrams per kilogram per day, divided twice a day, with a target dose up to 50 milligrams divided BID at TID. With this medication, I think it's always important to think about starting low and going slow, and patients are more likely to tolerate the medication if you take that into account. There were two adjunctive trials with Dervais syndrome that were the pivotal trials and had a 50% reduction in convulsive seizures in Dervais syndrome of about two-thirds of patients, so 67% to 71%. The thing that is quite remarkable with this medication is the number of patients who had no seizures while on this medication. So you'll see here that it's listed as being between 25% and 43%, which is much higher than other medications that we typically see, especially in these very refractory Dervais syndrome patients. Adverse effects, likely because of the fact that they're on Clobizam, they can have issues with somnolence, ataxia, and agitation. In addition, we can have issues with weight loss and decreased appetite. Some patients can develop neutropenia or thrombocytopenia, so it's recommended that you get a complete blood count at baseline, and then repeat that while they're on the medication every six months. The fruit-flavored packets contain phenylalanine, and so if you have patients who have PKU, you just need to be aware of this and try to limit their exposure to that. As I mentioned, I'll just probably once again say, you may have a dose of Clobizam that the patient is on if you're starting them on steropentol. The next medication that we'll talk about is Phenfluramine, or Phentepla. This medication was approved in June of 2019 for patients with Dervais syndrome who are two years of age or older. It is a secondary amino compound that is actually quite similar to amphetamine, and it has a bit of a story past. You may remember Phenphen as part of the diet medication, or Phenfluramine as part of the diet medication Phenphen, and it was actually removed from the market in 1997 due to issues with heart valve disease as well as pulmonary hypertension. And a lot of that really is what mandated a lot of the caution around patients who have heart disease and also requiring routine screening of echocardiograms. The medication comes as a cherry-flavored liquid, which has this very odd concentration of 2.2 milligrams per milliliter, so requires a little bit of extra math. The mechanism of action is through its effect on serotonin levels, as well as an agonist at serotonin receptors. There is also some limited data that suggests maybe that it could have an effect on Sigma-1 receptors, which are important for modulating calcium signaling, but it needs to be seen. The pharmacokinetics are relatively long. It's about 20 hours, but it does require BID dosing. The metabolism, as with all these medications, there are metabolized through the cytochrome P450 system, as you can see here. There is an active metabolite for fenfluramine, and then some of the more common ones that we see as far as drug interactions, the CYP2C9 and 3A4, probably play a more minor role in metabolism of fenfluramine. As far as drug-drug interactions, medications that induce the CYP enzymes can reduce fenfluramine levels. And then something that I think we don't always think about is being aware if our patients are on other serotonergic drugs. So serotonergic antagonists, such as ciproheptadine, can actually reduce the efficacy of fenfluramine. Need to be aware of that. In addition, serotonergic agonists can induce a serotonin syndrome, and so for those patients that are on an SSRI, a tricyclic antidepressant, we need to be cautious about those, and specifically they point out that patients who are on MAO inhibitors should not take fenfluramine within 14 days of receiving one of those medications. So I think we just have to be a little bit more cautious and aware of those. I know of patients that may be on trazodone, and that can be a problem for use with fenfluramine. The titration schedule, you can see at the bottom, the idea is that the dose in which you start and titrate varies on whether they're taking steropentol and clobizam when you start it or if they are not taking those medications. As you can see down there, you might start with 0.1 milligrams per kilogram twice a day with either, but as you go up, it's going to be a slower titration if they're on concomitant steropentol or clobizam. As far as efficacy, there have been two adjunctive trials of Dravet syndrome. The responder rate, which is a 50% reduction in convulsive seizures, ranged from a little above 50% up to 68%. The number of patients who did not have seizures was similar to other medications, which was about 2% to 8%. As far as adverse effects, not surprising. If you recall that it is similar to an amphetamine, it could affect your appetite and induce weight loss. Patients have complained of somnolence with the medication. The things that we were most concerned about would include valvular heart disease and pulmonary hypertension. Because of that, there is actually a formal REMS program in place, much like vigabatrin. You have to actually sign up to participate in that program and be able to prescribe the medication. It requires that there is a baseline echocardiogram. That echocardiogram is repeated every six months. The REMS program, anybody is eligible to sign up for it, you can go to the website, centeplorems.com. I can tell you that I actually signed up on this and it took about 10 minutes. The thing that's a little bit different than with the vigabatrin REMS program is that you do have to actually pass a test. I can tell you there may be questions about echocardiogram extensively on that test. That's just something to keep in mind. Much like with stirapental, with finfluramine, I think we also have to realize that these patients are often on polypharmacy and that they may be very susceptible to adverse effects, particularly with the sedation when starting these medications. We oftentimes want to tell families that the medications really are worth it, that sometimes they just have to see if they can continue to work through some of these side effects, and that if we keep in our minds that if we start slow with the dose of medication and increase it slowly, that can actually really reduce some of those side effects. The good news is, is all of these medications are compatible with a ketogenic diet. The stirapental, but the flavored powder, that stuff must be like pixie sticks or something because it has a ton of sugar in it, probably to make it taste good. Just be careful about that. One thing I think we have to be very aware of in today's climate is cost. These medications are quite expensive. They are all going to need a prior authorization. You can see the cost there, and our patients are not going to be able to afford these medications out of pocket. Shifting gears a little bit, David had mentioned a little bit of this already, but the AES has really tried to stay ahead of new treatments that are available for COVID and associated diseases. One that has come out is Paxlovid. Paxlovid is a combination oral antiviral agent for patients who have mild or moderate COVID who are at increased risk for severe disease. The biggest thing to realize with this medication are some of the significant drug interactions. It is an inhibitor of CYP3A4, and so may affect anti-seizure medication levels, such as with cannabidiol, stirapental, which I mentioned. Then we may need to avoid CYP3A4 inducers, which may reduce COVID treatment effectiveness. For example, Sinovamate can sometimes be an issue. AES has a nice website where they talk about this in more detail, and as David mentioned, he did just recently do an excellent webinar, which was quite informative. These are my references, and so now we will move forward with the poll question, if I can have that shown. Okay, so mine's a little bit longer. As a case-based study, you're seeing an eight-year-old with a history of Dravet syndrome who has failed treatment with valproic acid, clobizam, and rifinamide. The family is interested in considering a new therapy. He has one to three general tonic-clonic seizures per week, lasting three minutes. He's currently being treated with levotracetam and zanisamide. The family denies any other significant past medical history. Which of the following would not be an appropriate next therapy based on his current treatment regimen? So A would be cannabidiol, B would be steripentol, C would be fenfluramine, D would be ketogenic diet, and E is vagus nerve stimulation. All right, well, I think that looking at this, it looks like everybody kind of got the right answer. The idea was that you do need to be on clobizam in order to start steripentol, and so I would not recommend starting with steripentol if you can avoid it, and maybe go with one of the other treatments first. Nice job, Eric. Thank you, Kevin. Of course. Thank you, Kevin, for that great review. A handful of questions have come through, and we'll go through those. There were some questions about whether these medications are ketogenic diet-friendly, which I think you answered on your summary slide. But one question asked about discontinuation of the ketogenic diet. Does that have any effect on cannabidiol levels with discontinuation? I have to say, I have not come across that as being an issue so far, but I have relatively few patients where that's come up. So I don't want to say for sure that it is or isn't an issue, but it hasn't been in my limited experience. Another very nice question came through about transitioning patients who take artisanal CBD products and converting them over to the prescription cannabidiol. Are there any tips or tricks you can have? Have you done that? Do you have any dosage recommendations if someone's transitioning over, or practical recommendations? Yeah. I think, in my mind, most of the patients that are on artisanal CBD products are actually generally on very low doses because they look at it like, I can afford one bottle of medication, and I need to make it last the whole month, whether my child is 5 kilos or 50 kilos. So definitely, if they are on a very low dose, I just start with the traditional dosing for Epidiolex. I think if they were somehow a very small child on a very high dose, then I think you could consider transitioning to starting a little bit higher dose and then discontinuing the artisanal product at the same time. But my experience is that that can be challenging. Part of it is you don't actually know what they're getting in that bottle. I'm always surprised. I bring the bottle, and they say, you know, my child is on a pure CBD product, and on the bottle it says that it's 50-50 THC and CBD because they just trust the people at the shop who is giving the medication. Okay. Awesome. Not surprisingly, there are a handful of questions about use of some of these medications for epilepsy syndromes that they're not indicated for, and I'll summarize those. So a couple of questions came through about prescription cannabidiol in refractory focal epilepsies or refractory generalized epilepsies, and is there data? There is limited data on this, and I think this would definitely be an off-label discussion. My experience is I have started in different epilepsy syndromes outside of Lennox-Gastaut or Dravet syndrome for cannabidiol. I think it works about the same for some of those. A lot of the patients with tuberous sclerosis can have a variety of seizure types, and they did show that it was effective for those, so I think that you don't necessarily have to have one of those indications, and because families ask about it so much, I oftentimes take the approach of it isn't approved. We can definitely try it and follow lab work and make sure that the patients are tolerating it okay, and if it doesn't work, we can try something else. A related question came up about using steropentol in adult patients who have epileptic encephalopathies or Lennox-Gastaut syndrome. Yeah, I definitely think if an adult has proven Dravet syndrome, then I would definitely encourage consideration for one of those medications, either finfluramine or steropentol. Aside of that, for the other epileptic encephalopathies, my bigger issue is oftentimes just getting it approved, because a lot right now, because of its cost, a lot of insurance companies are not approving it for off-label use. A couple of questions have pertained about using these medications together. For example, cannabidiol and steropentol in patients who have, let's say, refractory Dravet syndrome, for example. I'd be interested in your comments about that. Well, I mean, I definitely have found that it can be useful in those situations. I think we have to be a little bit cautious about polypharmacy in our patients, and if they're on four or five medications, adding in another medication or two, I'm always a bit leery about that. But I tend to find that families like staying on Epidiolex, so I'll oftentimes take something else away while adding in one of the other medications that they have not tried. But we just have to be aware that some of these drug interactions get very complicated and are difficult to predict, and warning families about, especially some of the issues with sleepiness and appetite can really help ward off phone calls, upset families who, all of a sudden, I didn't know my child would be sleeping so much, and I think it's important. And then a couple of questions came up about cognition and learning using these agents in—meaning effects on cognition and learning in the pediatric patients who have these syndromes and are put on these AEDs. Any studies or data on that? And I have to admit, I'm not aware of studies on that. I do believe if you have fewer seizures, you probably have a better chance of meeting some of your developmental milestones, especially for some of our children with A syndrome who have patients who have frequent seizures and prolonged status and in and out of the hospital. Some of these medications can be life-saving, especially for those—I've had patients who are in and out of the hospital all the time because of status, and they can be put on one of these newer medications like Steripental or Finfluramine, and it can make a big difference, at least reducing hospitalization rates. Thanks. And a related question came up after your talks, Kevin, about serum levels, particularly cannabidiol levels, and if those can be obtained, and if so, any suggestions about where those may be able to be obtained? As I recall, Arup has a cannabidiol level that she can obtain. I typically don't. I'm a little bit more on a weight-based dose in my patients and kind of going more based on side effects than actual levels of the medications. I'm not aware of drug levels being available for Steripental or Finfluramine. Thank you. And with that, we are at the end of the hour, so we will wrap up. I want to ask those of you that have attended to please take a few minutes to follow the link to complete the evaluation. The Online Education Committee would like to use your feedback as a guide in planning future webinars. And then on a related note, our next webinar will be May 27th, and the topic will be Beyond Closed Loop Stimulation, New Research Avenues and Clinical Insights in Utilizing Ambulatory ECOG from RNS. So again, I want to thank our speakers for spending time today sharing with us data and information on the newest anti-seizure medications. Thank you, everyone.

anti-seizure medications

epilepsy treatment

brivaracetam

cenobamate

perampanel

pediatric epilepsy

cannabidiol

stiripentol

fenfluramine

ambulatory ECOG