Comprehensive Management of Dravet Syndrome - Episode 9
The impact of new drug approvals on the consensus guidelines for the treatment of Dravet syndrome.
Joseph Sullivan, MD: Getting back to our mechanisms, how do we think all this is coming together? We know it’s a serotonin drug, but do you think there are other mechanisms?
Elaine C. Wirrell, MD: I think it’s got to be other mechanisms, because I know that before I could access fenfluramine, before those clinical trials came, I tried other serotonergic agents, and I certainly did not see the impact that fenfluramine had, so there’s got to be something in addition to that. I know that it’s a positive modulator of sigma-1 receptors. Exactly how that works to help seizures I don’t know, but I think there’s got to be something other than serotonin there.
Joseph Sullivan, MD: Absolutely. We’re in the process of going back and doing a second version of our guidelines now that we have 2 new therapies with well-controlled phase 3 data. I should mention there was a second study looking at fenfluramine together with stiripentol, because there is that important drug-drug interaction that means the dose of fenfluramine does need to be a bit lower, at 0.4 mg/kg max, which is meant to approximate what the 0.7 mg is in the absence of stiripentol, and that trial also showed similar, 50% and 75%, responder rates. That led to its approval, so we now have that for the treatment of Dravet syndrome in ages 2 and up, and cannabidiol in treatment of Dravet for ages 1 and up now. With that, how is this going to shake up our guidelines, in terms of when we do sit down and put pen to paper, and how do you think each of these are going to fit into that algorithm, as you said?
Elaine C. Wirrell, MD: Certainly the 3 medications that were recently approved—the cannabidiol, fenfluramine and stiripentol—their responder rates, the benefit we get from those is much higher than we get from clobazam or valproate. If we have an effective medication, we want to use that in the first line, wouldn’t you say? I don’t want to wait until somebody has been through 2 or 3 other medications to use something I think has the biggest bang and the most effect. So, I think we’re going to start seeing people moving toward using those recently approved medications much earlier.
Joseph Sullivan, MD: Absolutely. And I think as we’ve seen with some of these natural history studies that have come out, that still have been pretty stable in terms of that developmental plateau that tends to happen around age 2 or 3, and then fast-forward, the number of patients who have moderate intellectual disability, or more. It begs the question of what if we can get this better control, not at age 9, which is the mean age for a lot of these studies, but what if we can get that better control at 18 months? And then what does that project out in terms of developmental trajectory? I guess I have cautious optimism because we still aren’t getting at the underlying cause. We’re still treating seizures better and doing it in a way that is overall well-tolerated, but that’s going to have impact.
Elaine C. Wirrell, MD: I think it probably will, because when you look at the Dutch study, which looked at the use of contraindicated medications that worsen seizures, the longer you were on a contraindicated medication, the poorer you did developmentally. From my clinical expertise and my experience, I think the kids who get better seizure control do better long term developmentally. So yes, you can’t fix the channelopathy with this, but if you can control those seizures better, I think they will do better in the long term.
Joseph Sullivan, MD: Agreed. Now, that assumes that these medications do provide a longer-lasting benefit. We now have the luxury of both of us having used cannabidiol and fenfluramine from the original trials, and now I have patients who have been on cannabidiol for 6, 7 years and fenfluramine for 4 years. What’s your experience been in terms of the durability of these 2 agents?
Elaine C. Wirrell, MD: I’m very excited about the durability, because oftentimes in drug-resistant epilepsies, as you know, you kind of go through the honeymoon phase and then you lose benefit, and I haven’t been seeing that. I think that for many of these children, while there are some where you lose the effect, many of them continue to have a pretty robust benefit from the medications long term.
Joseph Sullivan, MD: Exactly, that’s how I pitch it to a family as I’m going through, “It’s time now to try one of these newer medications.” I try to present the data in as transparent a way as I can, that this was the overall reduction compared to placebo with each of the drugs, this was the 50% responder rate. If there was a 75% responder rate, with the case of fenfluramine, present that. But ultimately, it’s a conversation with families, and it’s a decision that’s made. I think you and I and some of our other colleagues have said this before, that it’s not a matter of which medication, it’s a matter of when. I think unfortunately, because we still are striving for 90% reduction or 100% reduction, both of these new drugs are going to be used very likely in combination, and one family may be more comfortable starting with 1 first, and if that’s the 1 for them, great. But in all likelihood, if the data translate into the real world, which I think it has been, it’s very likely that both of these medications will be used in combination. Then I think it’ll be really interesting to see what types of responder rates we can see.
Elaine C. Wirrell, MD: I agree.
Joseph Sullivan, MD: Thank you for watching this NeurologyLive® Peers & Perspectives®. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming programs and other great content in your inbox. Thank you so much.
Transcript Edited for Clarity