This free webinar outlines therapies in development for epilepsy and seizures, including promising therapies for patients with treatment-resistant epilepsy and children with severe epilepsy. The webinar also focuses on drugs that may not only reduce seizures, but improve treatment of the underlying disease.
The webinar is presented by Dr. Jacqueline French, a professor of Neurology in the Comprehensive Epilepsy Center at NYU Langone School of Medicine and Founder/Director of the Epilepsy Study Consortium. Dr. French’s presentation was followed by an interactive Q&A session.
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Audience Q&A with Dr. Jacqueline French
You mentioned schedule 1 and schedule 2. Can you explain these different stages a little bit further?
There are drugs that are considered to be controlled substances, which means that people can become dependent or get addicted to them. The more likelihood that there is that people will get addicted to them, the higher the level of control that the government puts on the distribution of those drugs. We all think of drugs like heroin and morphine. Heroin, in fact, is the most controlled of drugs because it is so addictive and also because it has no medicinal use. The drugs that are in the schedule 1 are considered to be highly addictive and have no medicinal use whatsoever. People are surprised to know cocaine, for example, is not schedule 1 because there is a use of cocaine for some eye diseases, so it’s actually scheduled 2.
It’s extremely difficult to even do research on schedule 1 compounds because they are so highly regulated by the government and very difficult, obviously, you can’t prescribe them because they have no medicinal use. Once a drug is known to have a medicinal use and it becomes schedule 2, then it is much more easier to move that product around to have it in pharmacies without like 10,000 locks on every door where this substance is being held and it just makes things much, much easier. Then you go down the line. For example, many of our epilepsy drugs are on the schedule of potentially addictive drugs.
You’d be surprised, drugs that perhaps people who take them would say, “I can’t imagine anybody would use these if they didn’t have to.” There is some evidence that in fact people do try and get them for recreational use and not for medicinal use and that includes drugs such as Pregabalin or Lyrica drugs such as a Vimpat or Lacosamide. Yes, those are restricted to some degree, but they’re only scheduled 4, so they’re lightly restricted. As you go up to schedule 3, schedule 2 and schedule 1, you get more and more and more restriction.
A drug such as Epidiolex and Fenfluramine and drugs that are being developed for Dravet Syndrome for instance, will they be available to others with similar seizures, but may not have the Dravet or that clinical diagnosis?
In the United States specifically, the FDA doesn’t put restrictions on doctors to say, “You can only prescribe a drug for what it has been FDA approved for and is on the FDA label.” The studies that are done and the diseases that are studied in the trials, will lead to a label that says, “This has been shown to be safe and effective in condition A, B, or C.” I could prescribed that drug for condition, D, E and F, but there are a couple of issues that I would have to have in mind as a physician.
Number one is that, there is a certain amount of liability because I am going what’s called off-label. My patient that I’m treating might say, “I came to some harm from what you did and really you weren’t doing the proper thing because the FDA didn’t say it was approved for this particular indication.” You were taking on some risk when you prescribed off-label, although many, many, many people do it. It’s done all the time.
The second thing is that, your insurance company might say, “Hey, this is a reasonably expensive drug and nobody has said that for your condition it’s effective, so why are we going to pay for it?” One or two things can happen. It may be that your doctor can then appeal to the insurance company and provide extra information and the insurance company can eventually agree to pay for it or they may just completely not agree under any circumstances. We have had that issue arise with one of our other drugs that is only approved for what we call an orphan condition and that is a Clobazam or Onfi. It’s a reasonably expensive drug and it’s only approved for Lennox-Gastaut Syndrome and sometimes I can get it for my patients and sometimes the insurance company will just completely stonewall and say, “No, you can’t have it.”
Do you know what the mechanism of action in the Cenobamate trial that you referenced earlier is?
Cenobamate, we do not specifically know the mechanism of action. However, it is in the class of drugs called carbamate. There was one other drug that was approved for epilepsy that’s in that class and that is Felbamate. We do not know its mechanism. We know that it is somewhat related. It’s a second cousin or a third cousin of Felbamate. Felbamate was a very effective drug for many people with epilepsy, but as a many of the audience may know, it is used very rarely now because it caused serious liver problems and a plastic anemia which has not been seen with this drug. If it was as efficacious as Felbamate, that would be a good thing and perhaps in some conditions it’s more and the rest remains to be seen.
Do we know whether there are targeted treatments for those epilepsies in development?
The first answer is yes. On the slide that I showed, there were a couple of genetic conditions that there are targeted treatments. Excuse me. Glut-1 deficiency is a great example where these are children who have a genetic defect that prevents their brains from turning glucose into energy. They have an energy defect in the brain and over time, that leads to seizures as well as an increase in cognitive dysfunction. There is a targeted therapy of a drug that can be used by the brain to produce energy that’s not glucose and therefore could reverse the specific problem in these children. That is one example of a treatment that is specifically targeting one genetic condition.
There is a drug called Ganaxolone that is being tried specifically in children with CDKL-5, which is another specific genetic defect. It doesn’t reverse the specific issue in CDKL-5, but there are reasons to believe it might be effective in CDKL-5. There are a number of drugs that are specifically targeting genetic defects. I think that what you may also be asking is, are we trying to reverse the genetic defect that caused the epilepsy to begin with, as was the case with the tuberous sclerosis and Everolimus? There are some attempts at that. They’re a little bit further away probably from the clinic, but, for example, there’s a drug called Endololin being tested in children with genetic code problems where there’s a certain part of the gene that’s supposed to create a protein that is very important for the development or the running of the brain. When that gene is being read, it comes upon a mutation and that whole mechanisms stops. It’s called the stop codon and that protein can’t be created.
This drug actually allows the information in the gene to be read even when that mutation is in the middle of it and that protein to be created. That would be really amazing if that works and it might actually be able to prevent the disease if it was given early enough to a child who had that genetic defect. These are the almost science fiction things that are turning into reality in clinical trials.
When you said the period of follow up is eight weeks or 12 weeks, are they on drug during those eight to 12 weeks or do they stop taking drugs and see what happens in the next eight to 12 weeks?
The way trials work is, usually, they start with what’s called the baseline period, which is just a period where we can figure out what the frequency, the typical frequency of seizures is. Let’s say an individual has four seizures a month or five seizures a month or 10 seizures a month, whatever that number is, it’s determined during an eight-week baseline. Then at the end of that baseline, they get randomized and they continue on there. During the baseline and during the study, they’re continuing to take whatever medication their physician has given them, a combination of medications that is the best control that they can get.
At that point they’re randomized to either adding the new drug or adding a sugar pill. Then for eight to 12 weeks they carry on and they see whether the seizure frequency that was determined during the baseline, is actually going to go down or go up or whatever happens. That goes on for eight to 12 weeks. Then at the end of that the randomized portion of the trial is over and they go into what’s called the open-label extension. During that time, everybody can be on the medication. The doctor knows the dosage, they know that the medication is being administered, they can manipulate it, they can change the background medications or whatever is considered to be optimal for that individual. During the double-blind they may or may not be taking the study medication, but once they get to the open-label extension, everybody is given the study medication on top of the medication that they’re already taking.
Are these drugs safe to take while a woman is pregnant?
Pregnancy, we always advise that drugs that are in clinical trials, women should not go into clinical trials if they are planning pregnancy and in fact we have significant safeguards in place. People have to sign a consent that says that during the trial, they will use appropriate birth control, so that they will not get pregnant and we make sure that they or receiving a birth control that’s likely to be effective, so that they will not get pregnant because this is not the time when you want to be experimenting to see whether this medication will adversely affect the fetus. Because, first, you want to make sure that the drug actually works, is safe and effective. Once the drug is safe and effective and is approved and is then available to the public, then over time some women will take it and will become pregnant. Only then, can we really know entirely whether the drug is safe during pregnancy.
We have many pregnancy registries that accumulate data on the drugs once they are in the clinic, but it is unfortunately a very slow process. It may take decades before there are enough women in the registries that we have really good information about whether the drug is safe in pregnancy or not. Even some of the drugs that have been around for a really long time and Lacosamide is one good example, we don’t have enough information really to say for an absolute assuredness that it is safe in pregnancy. We do have information as immediately when the drug is approved, as to whether it’s caused birth defects in animals. The label that’s put on the drug by the FDA, will say either the drug has been shown to be safe in animals, but we don’t know about humans or the drug has been shown not to be safe in animals, but we don’t know about humans or the drug has been shown to be harmful in animals and harmful in humans, so that it gives them an A, B, C or D rating.
The higher the letter, the worse it is. A class D drug would be one where it’s been shown and this is, Valproic Acid or Depakote is in this class that is both harmful in animals and also has been shown to be harmful in people during pregnancy. The A designation is almost never given where we say, “Oh we absolutely know it’s as safe as houses and anybody can take it and it’s perfectly fine. Most seizure medications are either B or C.
Where do we get more information on clinical trials?
The Epilepsy Foundation actually has a lot of information on epilepsy.com. If people want to know whether there is a trial that they could sign up for then that is an excellent place to look, there is a section of epilepsy.com where the trials that are underway describe a little bit of information about what we know about the drug and what the trial would be like if you were to enroll in it. That’s one good thing that’s on epilepsy.com and there’s also a part of epilepsy.com where there is a pipeline. You can see all of the drugs that are currently in development and what stage of development they’re in, whether they’re in early development or they’re close to the clinic.