: Regarding the GWPCARE5 study you asked about, the abstract and the data report, the subsequent analysis of individuals that were affected by Lennox-Gastaut Syndrome—which is a severe form of epilepsy&mdash;and looks at the longer-term efficacy of the medication as well as tolerability after participating in a randomized double-blind placebo-controlled trial. And the notable findings in the study are that it was efficacious and well tolerated. 

One of the issues with efficacy that we always struggle with in epilepsy is the problem of transient efficacy. Sometimes when we find a seizure medication, it stops working, and that’s a problem because the seizures come back and the individual is no better off for having taken it. 

What I was heartened to see in this study is that the efficacy for the cannabidiol was sustained. If anything, it actually was a little better than the initial analysis early on. Obviously this didn’t have a placebo-controlled component in the open-label continuation. And with this analysis, however, the efficacy definitely did not drop below the results reported in the first randomized, double-blind placebo-controlled trial with the primary outcome of 12 weeks. And as they looked at it further, it seems like if anything, it only got better. This was in combination with the fact that the adverse-effect profile was not notably worse. This included in the study, the ability to use a dosage of up to 30 mg/kg per day by the investigator.  

Some study subjects were exposed to that; others were not. But even when the dosage was permitted to be at that level, the number of patients who completed the study was still quite high for an anticonvulsant drug trial. And the adverse-effect profile was very reasonable relative to other medications that are offered. 

The significance of this data is that they were collected over a longer period of time than the initial phase 3 study, which led to FDA approval. So it’s bringing new information about the long-term efficacy and tolerability of the medication. And I was really happy to see that the efficacy was maintained, and it seemed like it was very robust. Almost seemed like it got better over time. And the tolerability was similarly good. 

The adverse effects that we saw on the randomized placebo-controlled clinical trial were very similar to what we saw in the longer-term follow-up analysis, and it’s really nice not to have surprises come up as the medication is being used at higher doses. 

GWPCARE5 Trial Update: Lennox Gastaut Syndrome

: For the abstract presented by Dr Jonathan Halford, et al, regarding the long-term efficacy and tolerability in patients with Dravet syndrome over the 3-year interim analysis, it shows that the efficacy of cannabidiol in Dravet syndrome is maintained, and that’s really nice to see over a 3-year outcome because that’s a very long-term outcome study in Dravet syndrome, which is a very hard-to-treat form of epilepsy. 

It gives us that additional data. It also shows that the adverse-effect profile of the medication over that period of time was relatively comparable with the adverse-effect profile we saw in 12-week primary outcome study, which led to FDA approval. As a result, we didn’t get surprised by any rare or idiosyncratic reactions to the medication, which is really nice to see over a 3-year period. 

The significance of the study is that they followed the patients out for a longer period of time, and they also permitted a higher dose of cannabidiol at the highest-used dosing interval. They went up to a dosage of 30 mg/kg per day, which was not permitted in the study that led to FDA approval, and they followed them longer. The combination of those 2 factors really gives us more peace of mind and relief about the adverse-effect profile for cannabidiol.  

The incidence of dropout due to adverse effects was only about 9%, which is remarkably low for a seizure medication. Seizure medications are often part of life for a person who has epilepsy. They really want to do everything they can to avoid them, and they really don’t like to stay on them if there are adverse effects. The fact that 91% of individuals were willing to stay on them, when you take adverse effects into account, is pretty remarkable. 

GWPCARE5 Trial Update: Dravet Syndrome

: David Loring and his coauthors are presenting an abstract at the AAN [American Academy of Neurology] 2020 Annual Meeting, which discusses mood and quality of life in patients treated with brain-responsive neurostimulation. The main variable they took into account was whether the individuals were treated early versus late in their epilepsy course, with early and late defined as being within 10 years of epilepsy onset or after 20 years of epilepsy onset. And they compared those 2 groups and looked at the comorbidities within those populations. The notable finding is that individuals who had early treatment of their epilepsy using a brain-responsive neurostimulator device had a much lower incidence of psychiatric comorbidities, including depression. So that’s a really salient finding. It means that it’s important to treat epilepsy as early as possible and aggressively, including brain-responsive neurostimulation if that’s an appropriate therapy for the patient because it makes a difference whether they get it early in their course or late. 

What the study means is that early intervention is critically important. Epilepsy is a severe disease, and it has lots of comorbidities that we’re trying to treat, and we like to have the ability to treat both the seizure comorbidity as well as some of the psychiatric comorbidities. And this data set tells us that by treating it early, we can actually affect mood.  

Dr Joseph Sullivan and his coauthors are presenting an abstract at the AAN [American Academy of Neurology 2020 Annual] Meeting regarding the long-term safety and efficacy of ZX008, which is fenfluramine, for Dravet syndrome. And they’re reporting their interim results of an ongoing open-label extension study, and that lengthens our follow-up for the patients that were reported in the phase 3 study, which led to or might lead to FDA approval. Their primary findings were that the medication was efficacious and well tolerated. The efficacy was quite startling. It showed a reduction of over 75% in seizure frequency in 37% of study subjects. Effect size is appreciable, and I think it’s much higher than other seizure medications that have been at this point in their approval process.  

The other part of the long-term outcome that I was heartened to see was the results of the ongoing cardiac surveillance because this medication was associated with valvulopathy when used in conjunction with phentermine in the past. We had concerns about valvulopathy. The echocardiography for these study subjects, which received a dose starting at 0.2 and was titrated up to a maximum daily dose of 26 mg per day, showed that there was no valvulopathy. All had echocardiography done on a routine basis, and the chance of missing subtle valve changes is very, very low. It was a concern that we had going into the investigational process of a new anticonvulsant medication, and it has really shown nothing of concern. 

The primary significance of the data is that the medication is very effective, and for the population being treated that have intractable epilepsy, these are really impressive numbers in terms of the effect size. Not only is the effect size large, but the adverse-effect profile is very favorable. It also failed to document any evidence of valve changes in the 2-year follow-up. That doesn’t mean there won’t be, but it does give us great confidence interval that that incidence is low. 

AAN 2020 Data: Neurostimulation and Adjunctive ZX008

: The abstract being presented by Dr Pavel Klein and his coauthors regarding the use of cenobamate in patients with uncontrolled focal seizures was exciting because it showed sustained efficacy for very robust randomized clinical trial data that were originally presented. It also shows a modest adverse effect profile. The value or the number in the abstract that sticks out the most to me is the percentage of patients who continued with treatment past 24 months, and that number for the cenobamate study was 69.6%. That tells me that patients are getting enough value—in terms of seizure control&mdash;out of the medication that they’re willing to stay on it because whatever adverse effects they might have are modest enough that it’s worth taking the medication. 

Other factors that are important of the cenobamate study are that it was performed in adults and it used different doses of 100 mg, 200 mg, and 400 mg daily. We have some sense of what the tolerability range of dosing is and the fact that all those doses were reasonably well tolerated and efficacious. The efficacy did seem like it got more robust with time, with the seizure reduction being 65% at the 6-month time point and going up to 76% over the 2- to 2½-year time frame. And that was made all the more remarkable by the fact that just over a fifth of the patients were actually seizure-free. 

I was also excited to see a few forms of rescue medication. The 1 I was most excited about was the nasal diazepam, because it will be very comparable in terms of dosing to rectal diazepam, which a lot of my patients who are pediatric, graduate from. So if you have a younger child who has the diazepam rectal formulation for the abortive treatment of seizures, once they’re old enough that rectal treatment is a little socially problematic or too privacy invasive, they can be switched to the nasal formulation, which doesn’t have those problems, which is great. 

AAN 2020 Clinical Trial Data: Uncontrolled Focal Seizures 

: One of the presentations that was going to occur at the AAN [American Academy of Neurology] Annual Meeting that we were really excited about was the long-term data from the open-label extension of the GW [Pharmaceuticals, plc] CBD [cannabidiol], or Epidiolex, trial in Lennox-Gastaut syndrome [LGS]. What we found in the long-term open-label extension is that the majority of patients who participated in the randomized controlled portion did enter the open-label extension. We were really pleased to see that the tolerability, overall, was pretty good, although there were adverse effects. Most adverse effects were mild and were very similar to the adverse effects we had seen in the randomized controlled trials.  

We were also very happy to see that throughout the open-label extension period efficacy was maintained, and many people had a significant reduction in seizures. At every time point, when we looked, over 6% of kids were completely seizure-free. Given the highly refractory nature of the patients who enrolled in this trial, I was really impressed by those results. 

We all know that patients with Lennox-Gastaut syndrome, almost by definition, develop highly refractory epilepsy. Even though we’ve had several products available that we know can help in Lennox-Gastaut syndrome, including several that have been FDA approved for the treatment of seizures in LGS, there continues to be a significant unmet need for safe and well-tolerated therapies for these patients.  

There has been a lot of enthusiasm about CBD based on the randomized controlled trials, but those were brief, several-week trials. They were 14-week trials, including titration. To see that the efficacy is maintained over a much longer period of time and that the tolerability was really pretty good means to me and a lot of other people that it looks like GW CBD is going to be a very important addition to the options we have for the treatment of these patients. 

What’s also been very reassuring is that if you look across all the open-label extension trials that GW Pharmaceuticals has—the LGS open-label extension, the Dravet syndrome open-label extension, as well as the TS [tuberous sclerosis] study, we’re seeing very consistent profiles with regard to tolerability as well as maintenance of efficacy.  

I think it means that although this is not a medication that’s going to be a big win for every patient, clearly, many patients are going to benefit from this. 

Another presentation that was going to be presented on at AAN was the open-label extension from the GW CBD Dravet syndrome trials. Very similar to what was seen in the LGS open-label extension, the majority of patients who were in the randomized controlled trials did enter the open-label extension. Over 95% of patients from the randomized controlled trial did enter the open-label extension, and what we saw, again, which was similar to the LGS trial, is there was maintained efficacy during that time. The tolerability also continues to have a very favorable profile compared with many of our other anticonvulsant medications.  

There were, which was not really surprising, a high number of adverse events. Most of them were mild, many of them resolved, and most of them did not lead to discontinuation from the trial. Again, this suggests that GW CBD is going to be a very important treatment option for patients with seizures associated with Dravet syndrome. 

Cannabidiol for Lennox-Gastaut Syndrome and Dravet Syndrome

: One of the presentations I was most excited about at AAN [American Academy of Neurology] was the open-label extension from the GW [Pharmaceuticals, plc] trial in tuberous sclerosis complex [TSC]. Taking care of patients with tuberous sclerosis has been a focus of the majority of my career. We know that two-thirds of patients with tuberous sclerosis develop highly refractory epilepsy. This is much higher than what is seen in the general epilepsy population. 

What we saw in the randomized controlled portion of the trial is that similar to LGS [Lennox-Gastaut syndrome] and Dravet syndrome, CBD [cannabidiol] appears to be effective for many people with refractory seizures in TSC. What we learned from the open-label extension, similar to the LGS and Dravet trials, is that the efficacy is maintained and the tolerability is good. 

The difference between the TSC trial and the LGS and Dravet trials is that the doses of CBD were higher. As opposed to 10 and 20 mg/kg per day, it was 25 and 50 mg/kg per day.  

We also learned from the randomized controlled portion that efficacy is there. It’s not really linear. The efficacy at 50 mg/kg is pretty similar to what we saw in the other trials, but the higher concentration, or a higher dose, is also pretty well tolerated.  

As expected, there were more adverse events. Particularly, there were more cases of diarrhea and more fatigue. It’s important to know that if patients do need to titrate up to those higher doses, it can still be safe, well tolerated, and effective. 

Another abstract at AAN that involved the GW CBD trials was an abstract about a tuberous sclerosis CBD trial. That was a really interesting abstract looking at how soon efficacy was seen in those patients. When we start a patient on a medication, it’s important to know if it will take weeks to titrate up to a certain level before we see efficacy. Or can it be seen earlier?  

Another reason to look at this is, since the trial did include higher doses, was to see, once we saw how soon efficacy occurred, if those patients would also possibly respond at a lower dose, as we saw in the LGS and the Dravet syndrome trials. Efficacy was seen pretty early. Typically, efficacy was seen within the first 2 weeks of the trial. During the titration, people were working up to their dose, so that was also good. We also learned from that data analysis that the adverse events were seen relatively early, and many resolved within the course of treatment. Again, this tells us that if we do start patients on GW CBD, we can let the families know that they won’t have to wait months to see efficacy from this drug, which matters. If you’re watching your child have seizures or if you’re having seizures daily, it’s good to know it won’t take months, hopefully, for a medication to work. It may be a matter of weeks. Also, if we are going to have tolerability issues, we will see them early on. We’re learning how to troubleshoot those to make sure our patients tolerate this medication well. 

Cannabidiol Treatment for Tuberous Sclerosis Complex

: An abstract that I was going to present at the AAN [American Academy of Neurology] Annual Meeting that I was really excited about was an open-label investigator-initiated trial of fenfluramine in Sunflower syndrome. Sunflower syndrome is a pretty rare epilepsy that, over the past 6 years, we’ve been spending a lot of time trying to better understand and characterize. Sunflower syndrome is kind of characterized by a child looking toward the sun, being drawn toward the sun, and then waving her hands in front of the sun, often several hundred times per day. Some of the children do this only when outdoors in sunlight, but many of them do it indoors as well. And it’s not only characterized by many seizures during the day, but it can really impact their safety, when walking in the street, and their ability to learn, since some of the children do this throughout the day in a classroom. 

This is a very highly refractory epilepsy. We have seen over 50 kids with this. We also tried to characterize it through an online survey. Most of our anticonvulsant medications are not effective here. Drs Jean Aicardi and Henri Gastaut, in the early 1980s, had written a letter to the editor of New England Journal of Medicine describing 3 children with self-induced photo-stimulated epilepsy. The first was clearly a kid that would meet the definition of what we now call Sunflower syndrome, and all 3 benefited from fenfluramine. Zogenix gave us the ability to start 10 children with Sunflower syndrome on fenfluramine. At the meeting, I was going to get to give the results of the trial. 

Of the 10, 1 did not complete the study. She developed a rash, which we do not think was drug-related since rash has really not been an adverse effect of fenfluramine. However, she decided not to continue. Of the other 9 who did complete the trial, 1 of them did not respond. The other 8 children did respond. These are children who had been on other prior anticonvulsant medications without efficacy. In these children, we saw a median of 84% reduction in their seizures. Pretty impressive.  

The other thing we did as part of that trial was neuropsychological testing before and after. I was kind of surprised but excited to see that during that time, the children had a mean 18-point increase in their IQ [intelligence quotient], which is pretty impressive. We also looked at EEGs [electroencephalograms] before and after and saw that fenfluramine had a significant impact on EEGs. We saw a decrease in the frequency of epileptiform discharges. Often, these children also have a photoconvulsive or photoparoxysmal response with strobe during an EEG, and we saw a reduction in that. This suggests that, at least in these children, fenfluramine may be effective in this rare epilepsy where nothing else typically is. We were pretty wicked excited about that. 

I’m very excited about the data we have in Sunflower syndrome. When we did this internet-based REDCap survey, we found that many of these children had been on all the broad-spectrum anticonvulsant drugs without benefit. Many had been on CBD [cannabidiol] without benefit. Diet can be effective for some. I’ve found that these children really suffer with this epilepsy. Even though most of them are cognitively fine, this is very impactful. Many are bullied, so some are home schooled. Most of them have poor self-concepts, self-esteem, because of the bullying, because of these episodes, and the parents are very concerned.  

We’ve actually had families that have moved, literally, to places where they think there would be less sunlight, thinking that they could help reduce their children’s seizure frequency. The fact that fenfluramine helped 8 of 9 children who took the medication gives hope to this community that there will be an effective treatment. 

Fenfluramine for Sunflower Syndrome

: Looking at the content from the AAN [American Academy of Neurology] Annual Meeting, while it was disappointing for all of us that we couldn’t be there in person, it’s wonderful that they’re making the abstracts and the platform presentations available. There’s a lot to learn, and there’s a lot of excitement about what’s going on currently in neurology. And not only in epilepsy—I think in almost every field of neurology, there have been really exciting advances.  

It’s a very exciting time in epilepsy, with the current medications—fenfluramine, CBD [cannabidiol]&mdash;as well as other medications in clinical development. And now, also, with the concepts with some of these rare genetic epilepsies, considerations that genetic approaches would be safe and effective are also very, very exciting. I think their future has been bright in the treatment of different neurological disorders, and the future is even brighter than before.  

It’s an exciting time to be able to talk to families about treatment options for their children or family members with epilepsy. We now have many, many options that are not only effective but safe and well tolerated, so it’s really encouraging that we can now help our patients more than we were able to even 10, 15 years ago. 

 Epilepsy Treatment Outlook

: We were going to present our long-term data of the open-label study for patients with Lennox-Gastaut syndrome at the annual American Academy of Neurology meeting, and unfortunately, we couldn’t do that in person. But it’s still very important information that we have to share, as it relates to the open-label study.  

We now have data up to 170 weeks for patients who were in the open-label trial. These are patients who have Lennox-Gastaut syndrome. They were participating in the randomized, double-blind, placebo-controlled trial and then went into the open-label study. We’ve been able to follow them, both from an efficacy and safety standpoint. As far as results go, we didn’t learn about any new adverse events or effects that were seen in these patients, and the efficacy—as it relates to both the primary and secondary end points of drop atonic seizures and all seizures&mdash;did not decrease. It was maintained at the same high level that was seen during the pivotal trials all the way up through 170 weeks. The important take-home messages for folks are that efficacy can remain for patients on Epidiolex, or cannabidiol, for Lennox-Gastaut syndrome, and the adverse effect profiles are very similar, without any new ones cropping up later in treatment. 

The important thing that the data tell us about safety and efficacy is efficacy is maintained throughout the course of being on cannabidiol and the adverse effect profile was also very similar to what was seen in the pivotal trials. Most patients will have some sort of adverse event, which is seen in all epilepsy medication trials. The more common ones, as they relate to this medicine, are the same, with diarrhea being number 1. That was seen in over 20% of the patients. As far as efficacy goes, specifically for primary end points, we were still able to attain a decrease in median seizures in the 40% to 60% range, which is very significant. 

Long-Term Data for Cannabidiol in Lennox-Gastaut Syndrome

: Another important study presented in abstract form was the long-term safety and efficacy data for patients on cannabidiol for Dravet syndrome. These are patients who have Dravet syndrome; participated in the pivotal, randomized, double-blind, placebo-controlled trials; and were able to go into the open extension. These patients were followed for a very long period, and now we have those data. Their mean dose was about 22 mg/kg per day, so it was similar to what the label has for the patients who are being given this medication in a commercial format. Once again, the adverse effect profile was very similar to what we saw during the pivotal trials, and nothing new emerged from those studies.  

In addition, the efficacy was maintained. The median seizure reductions from baseline were similar to what we saw in the pivotal trials. They were in the 45% range and higher for convulsive seizures. That was the primary end point for this study. What we’re able to show is long-term use of cannabidiol in this format is still efficacious for patients with Dravet syndrome, and no new adverse effects emerged after patients were treated over that period. Specifically, these data went up to 156 weeks. These were very long-term data supporting the use of this medication without any new adverse events developing. 

Additional important points, as far as safety and efficacy, are that this is a good study to look at long-term exposure to this medication in patients who are commonly treated with other antiseizure medicines that are commonly given to patients with Dravet syndrome. The 3 most common concurrent antiseizure medications in this study were clobazam, valproate, and stiripentol. That is something you’re going to see. The adverse effect profile was not more significant because these patients were on these concomitant medications, and efficacy and safety were still maintained throughout the duration of treatment with this medication. 

Long-Term Data for Cannabidiol in Dravet Syndrome

: In this pivotal subanalysis we really wanted to look at the safety as it relates to children being exposed to brivaracetam during the pivotal trials. Not much literature existed as it relates to pediatric patients and their exposure to brivaracetam. This is one of the first key studies that shows that this medication was well tolerated by patients being given brivaracetam. The median dose was around 4 mg/kg per day, which does suggest that a good dose of this medication can be tolerated by patients, and the adverse effect profile was not alarming. The most common adverse events were very similar to what you see with other antiseizure medications, and that includes tiredness, fever, and decreased appetite. 

What we found was significant, as it relates to the brivaracetam data in children, is that this medication can be tolerated very well for patients with focal seizures that either become secondary generalized or don’t generalize. It gives us some of the first information that has been published as it relates to pediatric patients and their tolerability for brivaracetam. This medication is a safe option, and this study and abstract we just presented have proven that exact finding.  

Brivaracetam in Children With PGS or Mixed Seizure Types

: The perampanel FREEDOM trial is a very interesting study done in Asia. In this study, they wanted to look at perampanel as monotherapy in 2 doses: 4 mg per day and then 8 mg per day. Now, what’s important to know is this is a phase 3 study. It had a pretreatment at baseline, followed by a titration and maintenance phase. During the maintenance phase, they looked at anybody who had seizures. If they did, they were able to have their dose titrated up to the 8 mg per day. But they were actually able to look at safety and efficacy in both ranges. After the additional 30 weeks of treatment, and during the entire maintenance phase, they did see significant patients with seizure-freedom rates. 

The efficacy, or at least this freedom from seizures, in patients on 8 mg per day of perampanel was much higher than the 4 mg per day, and hovered around 70% or more. The other important findings from this study was that this medication was well tolerated. It had some adverse events, which were commonly seen in other antiseizure medication trials. Specifically, being tired was another common event. More importantly, they did not report significant behavioral changes, which has been seen and published in other studies looking at perampanel. The takeaway from this study is that either 4 mg or 8 mg of perampanel may be a good option as monotherapy for patients with partial-onset seizures with secondary generalization. 

The other important aspects of this abstract are that the median seizure reductions were not reported—and those are the normal end points that we usually report, as it relates to studies in the United States&mdash;nor did the authors comment on the responder rate, which is the percentage of patients who had at least a 50% or more reduction of their seizures. One can conclude that would be very high, given the fact that 64% of patients on 4 mg per day had no seizures during the maintenance phase of the study, and 75.3% of patients on 8 mg had no seizures during the duration of the study. That does suggest there is a significant seizure-freedom rate as it relates to both doses in the patients who were given this medication as monotherapy. That’s very important to note because those are very high seizure-freedom rates, which makes this medication a potential option for this population of patients with partial-onset seizures. 

FREEDOM Trial: Perampanel Monotherapy for Recurrent POS

: The only other important data I would like to have shared from this meeting were related to some of the other studies that looked at novel treatments in both pediatric and adult epilepsy. I think there remains a gap as far as the medications used to treat patients with epilepsy, because there are still patients who do have epilepsy. Unfortunately, we don’t have access to a lot of that information because not all of the abstracts are available at my time of review, but I hope that in the future we’re able to get that. 

The other aspects of the annual meeting for the American Academy of Neurology that we weren’t able to have access to was the content around quality measures and quality improvement. There was a significant portfolio of sessions related to these important topics, and I’m hopeful that at the 2021 meeting, this gap can be closed, and we can all convene back in person. The final thing I have to say about missing meetings is I also miss the aspects of the social interactions I have with my friends, colleagues, and other professionals in the field. I hope, once again, we’ll see each other in person sometime in the near future.

AAN 2020 Annual Meeting: Epilepsy Highlights