Advances in Treatment for Epilepsy-New Anti-Seizure Medications

Video Transcription

It's my pleasure to speak for you today about new anti-seizure medications. We are, one could argue, moving from the abstruse world of genetics to the mundane world of  anti-seizure medications. But what I'm going to suggest to you is that the mechanisms of action of the three newest  anti-seizure medications that I will be discussing are anything but mundane. These are my disclosures.  And I would like to focus on predominantly the uniqueness of the mechanisms of action of these three new anti-seizure medications, and reflect briefly on how this affects the  spectra of efficacy of those medications. We'll talk a little bit about the associated adverse effects, and lastly, anticipated drug-drug interactions.  So we'll start with sinobamate, going in order of FDA approval. Sinobamate, as you know, was approved in the US in 2019 for the treatment of focal  or partial onset seizures in adult patients. Its putative mechanisms of action are twofold. It has an inhibitory, if you will, mechanism of action.  It's a positive allosteric modulator of the GABA A receptor. And in an anti-epilepsy medication, anti-seizure medication space that has a plethora of sodium  channel modulators, it too is a sodium channel modulator, albeit a sodium channel modulator with a twist.  The majority of our sodium channel modulators, as you know, affect or modulate sodium channels  by either binding to the fast and activated state of the sodium channel, or the slow and activated state of the sodium channel. Sinobamate, however, affects a different channel.  This is the persistent sodium current that is, as the name implies, persistently going into the cell. The faster the rate of that sodium current, the more excitable the cell is.  And by reducing that persistent current, we confer a different mechanism of action. So we've got two mechanisms of action, one of which is particularly unique.  This medication is not highly protein bound. It is hepatically metabolized, which is going to set us up for a handful of drug-drug interactions.  It's primarily glucuronidated, but there is then a secondary metabolism via the microsomal system.  So, for instance, if you co-administer it with an inducing anti-seizure medication, say Finitoin, then you will see reduced sinobamate plasma concentrations by a little less than  30%. It does have a nice, long 50 to 60-hour half-life, and it itself has effects on other medications.  It has a slight inducing effect on the microsomal system, specifically the 3A4 and 2B6 isozymes of the cytochrome P450 system.  But where we run into some of our challenges is with 2C19 inhibition. So that is going to, of course, affect three particular substances, phenobarbital, 2C19, Finitoin.  Once you saturate 2C9, we're going to be 2C19. And of course, the active metabolite of clobizam, indesmethylclobizam, is a 2C19 substrate.  So when we administer, when we start sinobamate in the setting of Finitoin, phenobarbital, or clobizam, it will behoove us to consider making compensatory reductions in these three  medications. Regarding efficacy, I've got on the right-hand side the results where we want seizures to go down. So the more the line goes down, the better the response.  And we're looking at the results of the second pivotal trial, whereby color-coded we have in non-color placebo, 100 milligrams, 200 milligrams, and 400 milligrams.  So by week eight, there was a statistically significant reduction in seizures in the 100 milligram sinobamate group.  We see a more robust response at 200 milligrams per day, and in the 400 milligram group, yet more robust response.  That quasi-dose response, or the appearance of a dose-response effect, is always nice to see. But let's raise the bar a little bit.  Let's not look just at median percent reduction in seizures. Let's look at seizure freedom. And that will be in the right-hand panel.  And with this, there were a handful of people over the course of 18 weeks that were seizure-free with placebo.  A few more patients at 100 milligrams per day, but we see a fairly robust freedom from seizure rate in the 400 milligram per day group.  And when we consider that the patients who populate these investigational drug trials are medically refractory patients who have failed multiple anti-seizure medications and  are on multiple concomitant medications, this is a quite robust number. In addition to this unique efficacy, we must consider adverse effects.  We also are using this medication, prescribing this medication in trials, administering this  medication, I guess I should better say, on a backdrop, a set backdrop of baseline medications.  So this forced titration is not a real-world situation, and we cannot make compensatory reductions in the concomitant medications.  So it is not uncommon with all of our anti-seizure medications that oftentimes the two most common  adverse effects in the trials are going to be some combination of somnolence and dizziness, and sinobamate is no exception.  Another dose-dependent adverse effect, typically not a significant issue, although if someone  has familial shortened QT interval syndrome, this could be a concern, is it does shorten the QT interval in a dose-dependent fashion.  Regarding idiosyncratic adverse effects, in the first 1,000 patients, give or take, who were first administered the medication, and this group of 1,000 includes both patients  and individuals who were in the safety trials and were started frequently at 50, 100, or at times even 200 milligrams per day as an initial dose.  There were three individuals who had a hypersensitivity reaction, specifically DRESS, drug reaction with eosinophilia and systemic symptoms.  One of those was a patient in the cardiac conduction trial who did die as the result of eosinophilic myocarditis.  So it was back to the drawing board and taking a page from what I suspect was the Lamotrigine  playbook, a safety trial was done where sinobamate was started in lower doses and slowly titrated  tested in over 1,300 patients or more. And there were no further cases of DRESS. So this is going to be our US FDA-approved titration, as we see in the middle, starting  at 12.5 milligrams per day for two weeks, increasing in biweekly intervals over 10 weeks to a typical target dose of 200 milligrams per day.  As far as formulations, this is available in tablets, 50, 100, 150, and 200 milligram tablets. There are 12.5 and 25 milligram tablets that are available in starter kits.  A caveat, I believe that Dr. Becker has a poster to this effect. It may be today. If not, it will be tomorrow.  But note that the patients who were in the trials in whom the target dose is appropriately 200 milligrams per day are a particularly medically refractory group.  But when treating patients who are perhaps less refractory, if there is a continuum of refractoriness, then perhaps we can stop at a lower dose and achieve the unique efficacy.  So in summary, the advantages of Sinobimate are its unique mechanism of action, its once-daily  dosing, and unique spectrum of efficacy, challenges, the slow titration, and potential pharmacokinetic  interactions such as demonstrated here where 2C19 inhibition will markedly increase levels of indesmethylclobizam, phenobarbital, or phenytoin unless they are appropriately reduced.  Switching gears, you've already heard mention of finfluramine, a drug that has a storied past in the U.S., was initially FDA-approved in 1973, used as an antidepressant, and then  as an appetite suppressant. And in the 90s, it was discovered that when paired with phentermine in the form of FinFin, it was a very potent and effective medication for weight loss.  But by 1997, it was also apparent that this combination carried an unacceptably high rate of cardiac valvulopathy and pulmonary hypertension. So this was pulled from the market.  To fast forward to 2020, it is now FDA-approved without the phentermine and in a lower dosage.  The dosage that was used for appetite suppression, the median dose in the individuals who had the cardiac and pulmonary issues was 60 milligrams per day.  So we're going to cap that dose at a little less than half that 60 milligram dosage. But it has been studied and FDA-approved now for the treatment of seizures associated with  Dravet syndrome as of 2020. And as of earlier this year, for the treatment of seizures associated with Lennox-Gastaut  syndrome, which has kind of a nice ring to it because there was a case report from the  early 80s, I believe 1983, a small case series of three patients by A. Cardi and Gastaut of three individuals who had self-induced photosensitive seizures  and finfluramine was effective in controlling those seizures. So now we go full circle and FDA approved for the seizures associated with that syndrome that bears Gastaut's name.  This mechanism of action is unique. We are well aware of the serotonergic effects. Finfluramine directly affects a serotonin transporter that then produces a cascade of  events that results ultimately in decreased uptake of serotonin and increased release of serotonin.  So it's a very potent serotonergic medication, which is it has its benefits and it has its potential downsides.  Regarding appetite reduction, one of its early uses, the serotonin subtypes that have been specifically linked to this appetite reduction effect are the 1B and 2C serotonin receptor  subtypes. There's a little bit of evidence for 2B, but frankly, not a lot. Its valvulopathy has been linked to 2B stimulation.  There may be some other factors, but stimulation of the 2B serotonin receptor subtype seems to be the most valvulopathic effect.  Its anti-seizure effects are predominantly linked to 2C, similarly with the appetite reduction, and 1D.  In addition to this serotonergic effect, it has an effect on the sigma-1 receptor. The sigma-1 receptor is receiving increasing attention in the world of developmental and  epileptic encephalopathies. This sigma-1 receptor is a ligand-modulated chaperone protein on the endoplasmic reticulum, so it plays a role in the folding of complex molecules.  And it is known that if you administer an epilepsy-prone mouse an inhibitor of this sigma-1 receptor or an antagonist, then it will have a pro-convulsant effect.  If you administer an agonist, a direct agonist, it will not have a clear anti-epileptic effect.  But if you administer this epilepsy-prone mouse a positive allosteric modulator, whether  it be fenfluramine or other positive allosteric modulator, it has a clear anti-epileptic effect. in that mouse.  So this sigma-1 receptor is of increasing interest and is clearly playing a role in the anti-epileptic effects of fenfluramine.  Fenfluramine not highly protein-bound, therefore it is readily dialyzable. It too is hepatically metabolized. It has a half-life of about 20 hours.  It is metabolized primarily to norefenfluramine, which is an active metabolite that has a longer half-life, upwards of 24 to 48 hours.  And that is subsequently metabolized to inactive compounds. Regarding effects on other medications or other medications' effects on it, I should  say, pharmacokinetically, stiropentol, which is known to be inhibitory at 1A2 and 2B6, we're kind of checking the boxes here when it comes to fenfluramine metabolism.  So not surprisingly, stiropentol is going to increase the half-life of fenfluramine. It's going to reduce the clearance.  We only have data for the situation of Clobizam plus stiropentol. So in the package insert for the US FDA, that is how this data is presented.  But we believe that this is predominantly a stiropentol effect. There is also a pharmacodynamic effect. We've got a medication, fenfluramine, which is an appetite suppressant.  And it is not uncommon that we will consider giving ciproheptadine to stimulate appetite. This is probably not a good idea if a patient is on fenfluramine, because ciproheptadine  and other serotonin antagonists will decrease fenfluramine efficacy. And lastly, not unexpectedly, drugs that increase serotonin, SSRIs, MOA inhibitors, do, when  co-administered with fenfluramine, have increased risk of serotonin syndrome efficacy. On the left, we're looking at convulsive seizures with Dravet syndrome.  In the green, we have high dose, 0.7 milligrams per day. In the blue, we have low dose, 0.2 milligrams per kilogram per day.  Responder rates, 68% for high dose, 38% for low dose versus 12% for placebo. And a nice number of patients who were convulsion free.  In the right panel, we see the results for the treatment of Lennox-Gastaut syndrome. If we ignore the titration period and just focus on the maintenance period, responder  rates are good at both low and high dose. And as we raise the bar and look towards super responders or more robust responders, high dose is more effective than low dose.  Adverse effects with Dravet syndrome. The most common adverse effects were decreased appetite and lethargy.  And with Lennox-Gastaut syndrome, again, not unexpectedly decreased appetite, also somnolence fatigue, and a few patients with gastrointestinal issues.  Regarding the cardiac valvulopathy, the valvulopathy that was seen with FinFin was very similar to that pathologically that has been identified with carcinoid syndrome.  So we have good evidence that this valvulopathy is via a serotonergic mechanism. We also have theoretical reasons to believe that this is also the reason for the pulmonary  artery hypertension. In the Dravet open label extension where patients had serial assessments with echocardiogram,  there was no valvular heart disease or pulmonary artery hypertension. Formulations, there's a powder for oral solution in two capsule sizes.  The titration you see here, total daily dosage of 0.2 milligram per kilogram per day, maximum  dose 26 milligrams per day, we go up to 0.4 and then to 0.7 over the course of two weeks.  It is reasonable to titrate more slowly if we have any concerns, but inadvisable to accelerate the titration.  There is a RIMS program that you need to be certified if you're going to in the U.S. prescribe this, and there's a similar program in Europe.  And a patient must be registered so it can be monitored that they are getting their every six month echocardiograms.  In the waning moments, I will lastly talk about Canaxalone, approved this year in the U.S. for the treatment of seizures associated with cyclin-dependent kinase-like 5-deficiency  disorder or CDKL5 deficiency disorder in patients down to the age of two years. Canaxalone has been around for a while, and there have been some interesting trials.  And it is nice to see it hit the market with this specific indication. It is a synthetic analog of allopregnenolone, which, as we know, has two interesting mechanisms of action.  It has the straightforward activation of synaptic GABA-A receptors. This produces a rapid phasic inhibition, but additionally, it activates those extra synaptic  delta subunit containing GABA-A receptors, and this produces a persistent, more tonic inhibition.  Very quickly, for those such as myself who are not of the pediatric epileptology perspective, CDKL5 gene is located on the X chromosome. This is a rare disorder, CDD, we'll call it.  The prevalence is approximately four to one, female to male. Individuals who are affected present with early life seizures and severe psychomotor developmental abnormalities.  Seizures begin at a median age of six weeks. Ninety percent of these individuals have seizures by three months.  About a quarter of them will present with infantile spasms with or without hypsarrhythmia on the EEG.  An epileptic encephalopathy ensues, and ultimately, the epilepsy settles into a picture of multifocal seizures and myoclonic seizures.  Developmentally, there is severe global developmental delay and intellectual disability, and there are characteristic movement disorders, hypotonia, and hand stereotopies.  This drug is also hepatically metabolized. It has a plasma half-life of 34 hours, but it is a very lipophilic medication, so it  has a redistribution half-life when it's initially administered of about seven to 11 hours, which may, in part, explain its TID dosing regimen.  Strong inducers will reduce canaxalone plasma concentrations. Fortunately, although 2C19 does play a role in metabolism, 2C19 inhibition does not result  in clinically relevant changes. Here is the pivotal trial in the CDKL5 patients, and we see 24% of patients were responders  cutting their seizures at least in half versus 10% of placebo patients. Most common side effect, somnolence. It is available as an oral suspension.  You see the titration dichotomized between low-weight individuals and individuals above 28 kilograms, so to those of you who, like I, tend not to think of the world in milligram  per kilogram, 150 milligrams TID in my patients greater than 28 kilograms for a week, 300 TID for a week, 450 up to a target dose of 600 milligrams TID.  In summary, clearly a unique mechanism of action. It is the only anti-seizure medication approved for the seizures associated with CDD.  The primary challenge is obtaining canaxalone in patients who do not have CDD. So in summary, we have a number of advances that have occurred and, as you have seen at  this meeting, continue to occur in our anti-seizure medication armamentarium. And we are seeing a burgeoning number of unique mechanisms of action, and with those unique  mechanisms of action, unique spectra of efficacy. And I will end with a note, a quote from Dr. Penry, be a master of the molecule.  And if we can be a master of the molecule, we will do right by our patients.

Video Summary

The presentation explores three innovative anti-seizure medications, focusing on their unique mechanisms and efficacy. First is Sinobamate, approved in 2019, which acts as a positive allosteric modulator of the GABA A receptor and a sodium channel modulator. Challenges include drug-drug interactions and adverse effects like somnolence. The next drug, Fenfluramine, previously withdrawn due to cardiac risks, was approved in 2020 for Dravet and Lennox-Gastaut syndromes. It works through serotonergic pathways and the sigma-1 receptor, with appetite reduction as a common side effect. Finally, Cannabidiol, approved in 2023, targets seizures in CDKL5 deficiency disorder. It's a synthetic analog of allopregnanolone, affecting GABA-A receptors, with somnolence as a noted side effect. These medications offer new options by addressing unique pathways but come with respective challenges needing careful management.

Asset Subtitle

Presenter:

David Burdette, MD, is Epilepsy Section Chief at Spectrum Health in Grand Rapids, Michigan. He is an assistant professor at Michigan State University College of Human Medicine in Grand Rapids, Michigan. Dr Burdette earned his medical degree from Boston University in Boston, Massachusetts. He completed a residency in neurology at Boston University and fellowships in epilepsy and clinical neurophysiology at the University of Michigan Medical Center. He has led numerous seminars and grand rounds at regional and national meetings on current and new therapeutic options in the treatment of epilepsy. He is principal investigator for ongoing clinical trials of novel pharmaceutical and surgical treatments of medically intractable epilepsy. He has published on the pharmacologic and neuromodulatory treatments of refractory epilepsy and has authored textbook chapters on epilepsy, antiseizure medications, and advances in electroencephalography. His primary research interest is neuromodulation, particularly neurostimulation of thalamic nuclei.

Keywords

anti-seizure medications

Sinobamate

Fenfluramine

Cannabidiol

GABA A receptor

drug-drug interactions