Rare Childhood Epilepsies: Dravet Syndrome and Lennox-Gastaut Syndrome - Episode 4
Elizabeth Thiele, MD, PhD, and Elaine C. Wirrell, MD, discuss the FDA approval of cannabidiol as an oral solution for the treatment of seizures, specifically for both Dravet and Lennox-Gastaut syndromes.
Elizabeth Thiele, MD, PhD: We’ll turn from that overview of these 2 syndromes, which are near and dear to our hearts, to recently approved medications. We’ll start with cannabidiol [CBD] because it was the first FDA-approved medication specifically for Dravet syndrome. That’s huge for the Dravet community, and it’s the first FDA-approved medication derived from cannabis. As you know, I’ve been involved in cannabidiol development. Prior to this I hadn’t spent a lot of time in trials and hadn’t spent much time if any thinking about cannabis. Although we’re trying to figure out the real mechanism of action of the medication for both of cannabidiol and fenfluramine, they’re different. They’re different from our existing medications, which causes me to be excited.
If you look at how we haven’t impacted the incidents or frequency of refractory epilepsy, even with all our new antiseizure medications, 1 thought is that they’re all either tested on the same models or have similar mechanisms of action. It’s very exciting that these are different. Right now, the best guess is that CBD doesn’t work through the endocannabinoid receptors. The evidence is pretty convincing. That’s important to know too because you think, “Here’s a vital cannabinoid. It must work through the endocannabinoid system.” But it doesn’t. This G protein, GPR55, modulates calcium, and TRPV1 modulates adenosine and several mechanisms of action. That’s exciting.
Elaine C. Wirrell, MD: And the anti-inflammatory component potentially too?
Elizabeth Thiele, MD, PhD: Absolutely. We’re just at the tip of the iceberg of our understanding of the role of inflammation in epilepsy. Initially, it was approved for 2 years old and up for Dravet syndrome and LSG [Lennox-Gastaut syndrome] in the United States. What was your feeling on the trials that were done? There were 2 in LGS and 2 in Dravet, and they were all positive. What did you think when you saw the results of the clinical trials?
Elaine C. Wirrell, MD: Looking at those clinical trials, I found that most of my patients who had LGS and Dravet met those entry criteria. The nice thing about those clinical trials is they didn’t cherry-pick, but they made it relevant to the disease. That meant those trial results are very relevant to the larger group of patients with these conditions in my practice. As you mentioned, for both conditions the trials were positive. If we look at the [Orrin] Devinsky trial for Dravet syndrome, that included children aged 2 to 18 years old having at least 1 convulsive seizure per week during their baseline period. They were randomized to either placebo or Epidiolex, the pharma-grade, at CBD 20 mg/kg per day.
Looking at how they did, seizure freedom was uncommon. Only 5% in the treated group were seizure-free in the trial period compared with none of the placebo. They did see a significant reduction in convulsive seizure frequency. The adjusted median difference was about 20% to 23%. With the Epidiolex, the pharma-grade CBD was very helpful. Looking at those adverse effects, it was a well-tolerated medication. Many of these kids have issues with decreased appetite, a bit of tummy upset, and a bit of sleepiness. Some developed diarrhea, but for most of those children the adverse effects resolved pretty quickly.
It was a well-tolerated medication. For Lennox-Gastaut, in the clinical trials, they looked at the placebo, the 10 mg/kg per day dosage, and the 20 mg/kg per day dosage, and there wasn’t a ton of difference between the 10 and 20 mg/kg. The 20 mg/kg was a bit better, but marginally. The adverse effects were better in the 10 mg/kg. Those trials showed that there was a benefit from the 10 and 20 mg/kg per day dosages. The adverse effects were well tolerated.
One thing that did come out of those trials is a slightly higher rate of transaminitis. Potentially none of those children developed liver failure, but particularly in children on valproic acid, about 9% or 10% of developed elevated transaminases for which you either reduce the dose or you hold steady and most resolved on their own. It’s well tolerated with reasonable efficacy.
Elizabeth Thiele, MD, PhD: I agree. The other thing was, there was this adverse effect of diarrhea or loose stools. Many of my patients’ parents thought that was a positive effect. A lot of these kids were chronically constipated and were on MiraLAX, on very tedious bowel regimens, and many were able to back off that. I probably had more people thinking that was a positive than a negative, although when going to the higher doses, we did see that more often.
In the expanded-access program they were involved with before the trials, we even dosed up to 50 mg/kg per day. Sesame seed oil, as well as CBD, is a mild laxative as well. Another thing from the Lennox-Gastaut trials that’s important—I was being asked all the time, “Is this good for focal seizures? Does this work in adults?”—is they gave us data that this can work for focal seizures, even before the tuberous sclerosis trial proved it. A lot of people with LGS have a focal etiology to their seizures. Between a fourth and a third of the patients enrolled in the LGS trials were adults over age 18 and up to age 55. We had data from the trials that this was a medication that was probably broad spectrum because it was effective for LGS, Dravet, and focal seizures and was efficacious across the age span.
Elaine C. Wirrell, MD: And tolerated well across the age span.
Elizabeth Thiele, MD, PhD: Wicked well tolerated. We use a lot of Felbatol. When you discuss risk-benefit ratio, it’s a different conversation to talk about CBD as opposed to some of our other medications.
This transcript has been edited for clarity.