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Maxim Jacobs
17 November 2016

Edison KOL call

Pediatric Epilespy

The second in our KOL series, Edison sponsors an interview between Dr Wirrell, Director of Pediatric Epilespy at the Mayo Clinic. and Max Jacobs (call leader). The conversation featured a discussion on the clinical course of various pediatric epilepsies and the place that Epidiolex might have in the treatment paradigm. 

Call Leader: Great. Thank you, Dr. Wirrell, for joining us. Could you just maybe start by just telling us about your background and your practice?

Doctor: Yes. I’m a pediatric epileptologist. I’m the Director of Pediatric Epilepsy in the clinic where I work. My clinical practice is solely focused on pediatric epilepsy. I do approximately 85 percent of my time as clinical time. In that clinical time, virtually all patients have epilepsy. They’re predominantly children with epilepsy, sorry, and the majority of them have medically intractable epilepsy.

Call Leader: Great. Thanks a lot. I was wondering, since we’re talking about Epidiolex, you know they recently had positive data in Dravet and LGS. Maybe we can start by can you just describe Dravet and LGS, how many of those patients do you normally see, and then maybe the clinical course of the disease, so when is it diagnosed and how is it diagnosed, et cetera?

Doctor: Both of those are amongst the most challenging of epilepsy syndromes in children. Dravet typically presents in the first year of life. Typically the initial presentation is with a convulsive seizure which may be a hemiconvulsive seizure often triggered with fever, typically often prolonged. Then, over the course of the first five years of life, these children have recurrent bouts of often status epilepticus with convulsive seizures often triggered by hyperthermia or photic stimulation. They also develop myoclonic seizures. Many of them develop atypical absences, other focal seizures, tonic seizures.

The children, although they are developmentally normal initially, in most cases by their later preschool years it’s clear that they’re not acquiring their developmental milestones as you would expect. The children are left with a variable degree of intellectual disability. The seizures are very medically intractable. We have some potential options that we can try, but the likelihood of complete seizure freedom with medication is very, very low. Currently I follow about 25 to 30 children with Dravet Syndrome in our practice.

Lennox-Gastaut Syndrome, a bit more variable presentation. Some of the children can present with infantile spasms initially that then evolve into Lennox-Gastaut, or some children just start to have multiple types of generalized seizures. Again, most of the children with Lennox-Gastaut have an underlying cause, either a genetic cause or a developmental change in the brain or something that injured the brain early in life. These children have, again, recurrent seizures, many of them with abrupt falls which can lead to injury. With Lennox-Gastaut, again, multiple medicines can be tried but the likelihood of seizure freedom is virtually zero. Again, cognitive impairment is part of that syndrome. Currently I’m following probably about 50 children with Lennox-Gastaut.

Call Leader: Great. Thanks. In terms of the developmental path of these patients, does their stage of development kind of regress every time they have a seizure? Are there certain seizures that are worse than others, in terms of affecting their development?

Doctor: They don’t regress with every single seizure, but certainly the recurrent prolonged seizures in Dravet Syndrome, and then very frequent nonconvulsive seizures. Some of these patients have such frequent seizures that we call it a nonconvulsive status, that they just actually go from one seizure into another seizure into another seizure into another seizure. In some of those patients that can go on for a period of several days. That also has a negative toll on their development.

Call Leader: Wow. What do you do when that happens?

Doctor: If it’s a long seizure, most of our patients do have rescue protocols and they’re given a medication based on that protocol when they come in with single prolonged seizures. The nonconvulsive seizures, we again often will admit them to hospital and try different options to try and get rid of the seizures. That can be benzodiazepines. It can be Depakote. It can be Keppra. Sometimes we give them a blast of steroid and that works. It can be quite a challenge to get the seizures under control.

Call Leader: Can you describe what your experience is with Epidiolex just in terms of were you in the trials or your knowledge is based ...

Doctor: We did participate in the trials. I obviously can’t disclose any specific information from our patients, but just the general information that has already been published on their website. We did participate in the trials. I think that that was an important thing, because this is a therapy that families really are very interested in.

Call Leader: Do you have experience with other CBD-based products or cannabinoid-based products?

Doctor: I do.

Call Leader: Can you just describe those?

Doctor: We follow patients who are working through the state ... In Minnesota we have a state supply of cannabidiol where if the patient has one of the designated indications for cannabidiol they can obtain their cannabidiol through a state supply. We also have a number of families who obtain their various products from various mail services from Colorado or Oregon or online, various other sites that they go to. I think the actual amount in what they’re using is really, who knows? It’s completely unregulated.

Call Leader: Is the state supply in Minnesota, is that pretty standardized?

Doctor: That is pretty standardized. That is pretty standardized.

Call Leader: Do you base that dose on the Epidiolex dose?

Doctor: No. The state supply is a bit weird in that we certify patients but we don’t prescribe it and that the prescribing is by a pharmacist who works in one of the dispensaries. The dose that they’re using in Minnesota is very, very low. Probably too low, I think, to be effective.

Call Leader: What’s the cost of this?

Doctor: The cost through the state supply for most families is of the order of $500 a month.

Call Leader: That’s not covered by insurance usually?

Doctor: No. It’s not.

Call Leader: For the mail order from Colorado, I know the supply is not standardized and you don’t really know what you’re getting, but what’s generally the cost for those? Do you know?

Doctor: For I think the mail order many of the families that I’ve talked to are spending somewhere between $200 and $600 a month on their supply.

Call Leader: Great. Based on what you’ve seen from the Epidiolex data, where do you think it would go in the treatment paradigm for Dravet and LGS?

Doctor: I think for Dravet there’s been very few Class I studies that have been done. The only other one has been on stiripentol and there’s currently one that’s underway with fenfluramine. I think to me this is very exciting that this is a Class I study that is, it’s a randomized, placebo-controlled, and they documented efficacy. Now, the efficacy that they documented, again, it wasn’t stellar and it didn’t result in seizure freedom, but it did clearly document efficacy. Right now the first-line medications for Dravet that we use, including valproate, clobazam, topiramate, none of those have been shown to be efficacious in Class I studies. That’s all based on more Class III/IV evidence. I think that we can certainly look at using that early on. Probably maybe not first-line, but I think certainly early on. I think with the evidence now that it does reduce frequency of seizures, I think we can make a case to insurance that this is really one of the only proven treatments that we’ve shown in this.

For Lennox-Gastaut, we have a larger number of Class I studies. I see that, when we look at where we use it in the paradigm, probably we would start with things that we would typically use earlier on, things like topiramate, potentially valproic acid. I think certainly before we get to medications that were potentially more risky, like felbamate, in Lennox-Gastaut, I think most people would choose Epidiolex prior to felbamate. I see it maybe second- or third-line in patients with Lennox-Gastaut.

Call Leader: Is the toxicity relatively innocuous? How does it differ from the other drugs that you would use?

Doctor: As far as Epidiolex, and again we have to understand that there’s been a limited number of patients exposed, but we also know that this is not a brand new compound. This is a compound that has been used probably for centuries. It looks like it’s more nuisance kind of side effects, like a bit of a decreased appetite, some loose stools, and sleepiness. Overall, pretty well tolerated compared to if we look at something like felbamate, aplastic anemia, liver failure. If you had a child, which would you choose?

Call Leader: Good point. In terms of the efficacy of Epidiolex, do you think some of that positive data could just be part of a honeymoon effect of introducing a new drug in a patient?

Doctor: I think that’s certainly possible. A lot of the difficult epilepsy medications will work for a while and then will no longer work. I think that is going to be something that we will need to evaluate better once they release the data from the long-term open-label study and once that’s actually starting to be used in clinical practice.

Call Leader: Usually when you do see a honeymoon effect in whatever antiepilepsy drug, how long does that usually last? Is it six months?

Doctor: It’s usually a couple months, actually. Somewhere between two and six months, and then it starts to wane its effect.

Call Leader: When that effect wanes, do you switch them off drug or do you add another drug?

Doctor: Typically we would add. Then if that was effective we would wean what we felt was ineffective. Sometimes we go back and recycle these medications. One of the medicines that’s pretty notorious for causing a lot of honeymoon, and it can be pretty effective initially and then the effect wanes, is clobazam or ONFI. In that situation we often will wean the child off once the honeymoon is over. We replace it with something else. Then a year or two years later you could come back and retry that.

Call Leader: Why do you think that is?

Doctor: Why they’re having their honeymoon?

Call Leader: Yeah.

Doctor: I do not know. Presumably there’s something that’s happening genetically or structurally in the brain with the different channels that is causing that to happen, but I do not know.

Call Leader: I was just wondering, when you in your dealing with the different sales forces who come by to your office and leave samples, et cetera, which companies do you think have the strongest pediatric neurology sales teams?

Doctor: I think that ... Jeez. Which has the strongest?

Call Leader: Or at least your favorite?

Doctor: They’re not my favorites. Mallinckrodt has a ... They’re always at us for it. The make the ACTH. They have a pretty ... I don’t want to use the term in-your-face, but it’s a little bit like that. They’re frequently contacting you. I think Upsher-Smith does a nice job with potential for midazolam. They contact you, but they’re not so in-your-face. Lundbeck had been pretty involved with ONFI. I think maybe a little bit less recently. Those are probably the big ones.

Call Leader: Great. That’s very helpful. Just back to Epidiolex, for the course of Dravet and LGS, what sort of seizure-free rate do you normally see for first-line therapy in Dravet and LGS patients?

Doctor: You don’t get them seizure-free.

Call Leader: You never get seizure-free?

Doctor: You don’t get seizure-free.

Call Leader: Do you get patients at least who go down like 70 percent?

Doctor: Yeah, some of them. 70 percent would be a really good response. 50 percent. We typically will say, “Jeez, I think that’s a pretty good drug,” if it’s dropped 50 percent. It also depends on the seizure type. For Dravet, if they’re having some absence seizures that’s less or myoclonics that’s less of a big deal. If they’re having the recurrent prolonged convulsive seizures, that’s what we really want to focus on.

Call Leader: Do you just keep adding additional drugs until you get to seizure-free or closer to seizure-free or some of these prolonged seizures being absent? How does that work?

Doctor: If we add drugs, we typically like to take away drugs. I really don’t like ... My ideal is to have a patient on one. For most of my kids with Lennox-Gastaut or Dravet Syndrome I typically have them on probably three. I don’t like to go above three. I think if you add a drug you need to think about, “Jeez. What’s not working?” and take one away as well. Then I think it’s really making sure that the families have reasonable expectations. That’s something that we address pretty much at diagnosis, that if you have Lennox-Gastaut or you have Dravet Syndrome, the likelihood of us being able to get your child seizure-free is pretty low. We really have to balance what are the side effects of medication and what are the risks and harm from seizures themselves.

Typically we get to a place that we say, “You know, seizure control is not 100 percent, but it’s pretty good and the quality of life is pretty good and my child is on now a regimen of medications that they’re tolerating well. They’re not causing significant sleepiness, appetite issues, behavioral issues, and so that’s a good place to be.” That’s typically how we treat that.

Call Leader: Great. That’s very helpful. When you do add another drug, I figure the biggest effect is probably with the first drug and then you get smaller effects with the add-ons. What sort of response rate do you see with those?

Doctor: It depends which drug you use. In Dravet, we’re typically starting with clobazam or valproate. Then, if one of those isn’t working, we’re typically adding in the other. Even with after those two medications, I have very few people with Dravet Syndrome who get adequate seizure control with that combination. Most of them, we’re adding in another agent which could be, right now it’s Topamax, it’s stiripentol, or it’s ketogenic diet is typically what we’re going with.

Call Leader: How effective is ketogenic diet?

Doctor: For these kids with Dravet Syndrome or Lennox-Gastaut it can be certainly in reducing seizures. Again, seizure freedom is generally pretty unlikely. I would say less than five percent. In reduction of seizures, probably half of these children can have a greater than 50 percent reduction in seizures with ketogenic diet. Then, the other thing with ketogenic diet is you can often get the kids on lower amounts of medication, so they actually brighten up if they’re not using so many medications at such high doses.

Call Leader: There’s a theory out there that Epidiolex works mainly by increasing the effects of some other antiepileptic drugs in their system. Do you share that view?

Doctor: No. I don’t. I think Epidiolex has ... Because that was the same theory that came out with stiripentol, that stiripentol in Dravet works by increasing clobazam. I think it’s bunk. I think a lot of these kids have been on much higher doses of clobazam. Typically yes it does increase clobazam, but what we see is then the children develop side effects that are clobazam-related. We reduce that and we actually get similar levels of clobazam yet seizures are better. I think that it has an independent action.

Call Leader: Do you think that, however it works, do you think that can translate into other refractory epilepsies in general?

Doctor: I think so. I think there’s certainly a lot of enthusiasm in the media. I think you always have to take that with a little grain of salt, because the media tells you about the amazing cases and they don’t tell you about the other cases that it didn’t work for. There’s certainly a lot of enthusiasm in other types of epilepsies. There’s currently a trial that is looking at tuberous sclerosis-related epilepsy. Then I think we have a whole host of patients who have other types of intractable generalized or other types of intractable focal epilepsies who likely would also benefit from CBD. That’s just not been looked at. I think that there certainly is a large population that could potentially benefit from this.

Call Leader: Would you require specific data in a specific type of epilepsy before you used it in that group, or once it’s approved will you just use it off-label and see what happens?

Doctor: We use off-label all the time. Ideally I would like data from a randomized placebo-controlled trial. The reality is that that often doesn’t happen. We often will use other medications off-label. The challenge really is, is getting the insurance to cover. If something comes out and it’s only for Lennox-Gastaut and we try and use it for something else, that can be quite a challenge to actually get the insurance companies to pay for it. One of the big issues that we run into, for example, is for clobazam, for ONFI. The trials were in Lennox-Gastaut, so when it was released it was released for Lennox-Gastaut. It clearly has a much broader benefit, but insurance has their head in a bit of a very limited tunnel vision. They say, “No. Not Lennox-Gastaut, not going to cover it.” That’s our biggest challenge.

Call Leader: Are you able to successfully appeal that decision?

Doctor: Sometimes.

Call Leader: What do you have to do to get that successful appeal?

Doctor: Typically we have to say, “Look. They’ve tried all of these other medications. This is the diagnosis they have.” We have to provide, sometimes there have been other bits of literature showing that it can be beneficial. Again, it’s pretty challenging sometimes. Some insurance companies, no matter how far you go to try and document that you’ve tried all of the other good options, they still say no at the end.

Call Leader: Which ones are especially difficult?

Doctor: I can’t give you specific ones. I can tell you that in my experience probably about 60 percent of the time we can convince them with a reasonable amount of effort. Then, 20 percent of the time, absolutely no way no how.

Call Leader: Is it a matter of just pricing? Are there certain branded drugs that they’re less strict about because of the price or does it not matter? Is it just a branded versus generic and label sort of thing?

Doctor: I think that clobazam’s a little expensive but it certainly doesn’t break the bank. That’s one that we’ve had a real challenge at times getting coverage for. I’m not sure it’s just the super expensive ones.

Call Leader: Do you have a sense of at what price would Epidiolex be a no-go generally based on your experience with payors?

Doctor: I don’t, actually. That’s probably a good question for payors. I think that probably it would need to ... The newer medicines that are available for LGS, things like Banzel or ONFI, probably they wouldn’t want to come in too much higher than those. Otherwise, they’re going to be at the latter part of the market for that.

Call Leader: What do you think about vagul nerve therapy?

Doctor: I think that certainly it can be considered. I think in some kids you can have a reduction in seizures. I think overall in our hands, and we tend to use it later down the line, we get at best a third to half of patients having a greater than 50 percent reduction. The concern with vagus nerve therapy, first of all, it’s a surgery. It’s not a big-deal surgery, but it does require placement of a wire that goes around the vagus nerve. If that device is ineffective you cannot remove that wire because of concern of injury to the vagus nerve. That wire stays with the patient through life and potentially has concerns if you’re wanting to get another MRI or things like that. I think that vagus nerve, you’re putting something in somebody, you’re not sure it’s going to work. It’s not as simple as, “Jeez, you can just stop taking this medication if it doesn’t work.” You’ve got that in you for life.

Call Leader: That sounds not terribly attractive. In terms of just other types of surgeries, how do you decide when to offer or when to suggest surgery?

Doctor: First of all, for Dravet Syndrome I don’t think there’s any evidence that, other than maybe VNS, I don’t think there’s any evidence that other surgeries, callosotomies or temporal lobectomies or anything, are effective. For Lennox-Gastaut the majority of kids are not going to be a surgical candidate for resective surgery, where they actually try and remove a certain area of the brain. Small numbers can be, but the majority will not. Callosotomy can be potentially beneficial for kids with Lennox-Gastaut if they’re having recurrent drop seizures. Typically we consider that if they’ve been on through reasonable trials of what we would say would be the usual effective medicines, so valproate, topiramate, lamotrigine, Banzel, ONFI, potentially felbamate, and then ideally ketogenic diet. If we still have patients who are still really struggling with drop seizures with that we often will have a discussion about callosotomy.

Call Leader: How many drugs usually have they already tried by the time they get to the surgery conversation.

Doctor: Most of them have tried seven or eight, anyways. Most of them have tried ketogenic diet.

Call Leader: Is that just in your general patient population? Is seven or eight generally the amount that people have tried if they’ve had Dravet for several years?

Doctor: That’s often, depending on how quickly the Dravet was diagnosed. Many patients have been tried on what are now known to be ineffective medications before the diagnosis of Dravet was made. Typically five or so medications for Dravet. As far as surgery, though, some of the ... It depends on the center. There are a limited number of places that actually are using VNS a fair bit earlier. I don’t think that’s in the patient’s best interest. I don’t know if it’s revenue generation or what, but there is a concern there.

Call Leader: You’ve mentioned that sometimes people are given the wrong drug when they have Dravet. Are a lot of the Dravet patients or LGS patients, are they sometimes misdiagnosed early on?

Doctor: Yeah. I think less so for the LGS because I think that there’s still, the LGS is still the garbage bag of all bad epilepsy that starts early in life. If you’ve got a bad epilepsy that starts early in life, you must be Lennox-Gastaut. I still think it’s a bit of a garbage bag for that. A lot of Dravet patients are not recognized as having Dravet Syndrome. They’re kind of thrown into this Lennox-Gastaut garbage bag, or whatever. “Jeez, they have intractable focal epilepsy,” or something like that. I think it’s getting better. I think there’s more recognition from the general child neurologists about what Dravet Syndrome is, but I still think that there’s a way to go.

Call Leader: Do you have any estimate for what percentage of your Dravet patients were actually originally misdiagnosed, a roundabout number?

Doctor: A large number. Actually we published data when we looked at efficacy of stiripentol a few years ago. That was multi-center data from the US. It took on average 4.8 years for a diagnosis of Dravet Syndrome to be made after the patient started developing seizures.

Call Leader: Wow.

Doctor: That’s too late. That’s too long to wait.

Call Leader: Yes. I would think so. What happens to the death rate? How high is the death rate for some of these patients? Is the death rate generally because of status epilepticus or is it due to falls or accidents?

Doctor: It really depends. Dravet Syndrome, there’s been some reasonable papers. It looks like probably 10 to 15 percent of kids with Dravet Syndrome don’t hit their adult years. Sometimes that can be status epilepticus. Not infrequently it can be sudden unexplained death in epilepsy or it can be accidental death. For kids with Lennox-Gastaut, certainly SUDEp is a risk for those as well, as is status epilepticus, but many of those children have very, very profound brain abnormalities and very severe developmental delay just on the basis of the underlying etiology for their Lennox-Gastaut. Many of those children will succumb to recurring pneumonias or just general medical problems that affect the very neurologically-impaired child, so they may not be seizure-related.

Call Leader: What are your thoughts on fenfluramine from Zogenix? Are you familiar with that at all?

Doctor: Mm hmm (affirmative). I think that actually is a very exciting potential agent. I think the initial data look really exciting. I think that we really do need to see some Class I studies done, and that is currently ongoing. I think that the data that they have, they actually show that there are patients who achieve seizure freedom for a number of years, which is almost unheard of in Dravet Syndrome.

Call Leader: Do you think that there’s potential for fenfluramine to be used, if the data holds up of course, ahead of Epidiolex, or would it just, because of the safety issues, just always be probably after?

Doctor: Probably if it looks as good as it does in their small studies, probably ahead would be my view. The data that GW put out on Epidiolex from their randomized-control trial, the stuff they put online, yes they improved but seizure freedom typically wasn’t achieved. That’s where I think fenfluramine has the benefit.

Call Leader: You think that parents would be okay with the potential side effects?

Doctor: Yeah. Again, I think that needs to be looked at. Again, if the data hold out, the cardiac issues seem to be when it was used in very high dose in combination, when it was used as fen-phen for obesity. In the more moderate doses that they used in Belgium, they did not see ... It was a small n absolutely from their sample, but that did not seem to be an issue. Cardiac issues did not seem to be problematic.

Call Leader: Great. That was very helpful. Thank you, Dr. Wirrell. Those are all my questions. Again, thank you for your time.

Doctor: All right. Thank you.

Call Leader: Have a great day.

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