Fenfluramine Efficacy for Dravet Syndrome & LGS


Anup Patel, MD: There are other treatments now available, and I’d love us to start talking about some of those other treatments. Specifically, Elaine, I want you to comment on the publications that are coming and some of the data in the trials as they relate to fenfluramine, those Zogenix products.

Elaine C. Wirrell, MD: Fenfluramine is actually a very interesting product. It was used many years ago in combination with phentermine as a weight loss agent and that was pulled off the market because of concerns of cardiac valvulopathy and pulmonary hypertension. So there was obviously some concern going in about safety and this medication. In Belgium, it has been continuously available by royal decree, and that’s another interesting story that we don’t have time to go into. But it has been shown to be efficacious in patients with Dravet syndrome.

We have just completed a couple of randomized placebo control trials. Many centers in the United States participated. There were also centers around the globe. And for kids with Dravet syndrome, fenfluramine appears to be very efficacious. Looking at the outcomes, to get into the trial you had to be having at least 1 convulsive seizure per week with the higher dose, a 0.8 mg per kg per day to a maximum of 30 mg a day of fenfluramine, and they chose those doses to be sure that they would minimize the risk of cardiac toxicity. But they had a 70% responder rate. And furthermore, when they looked at patients who became nearly seizure-free, or seizure-free, so they went from having at least 1 seizure a week, to over the 3-plus-month trial, having 0 to 1 seizures in that time, a quarter of patients. So that was really remarkable.

There’s also been some preliminary data that are unpublished suggesting that there may be an improvement in executive function as well. So not only do we improve seizures, but potentially we can make that child more alert and hopefully maybe improve development. I think that’s still very preliminary and we can’t say that. I think the other important thing is when they looked at adverse effects they have not seen any child who has developed cardiac toxicity from that.

Anup Patel, MD: What adverse effects did you see when you were conducting these studies?

Elaine C. Wirrell, MD: A little bit of sedation and some appetite issues were the main effects that were seen.

Anup Patel, MD: This treatment is now being studied in Lennox-Gastaut syndrome [LGS]. Elizabeth, if you could comment a little bit on some of the data, or some of the trial information as it relates to fenfluramine and Lennox-Gastaut syndrome.

Elizabeth A. Thiele MD, PhD: I think there’s a lot of excitement about the LGS trials as well, because the Dravet trials, the efficacy looked quite good. Both trials had very good efficacy, and when you look at placebo-corrected, there is still 65% and 55% mean reduction in seizures.

There is no reason, at least that I’m aware of, to think that the mechanism of action of fenfluramine would be specific to Dravet. So I am hoping that the efficacy in the LGS trial is as good. Again, we’ve also been involved in the Dravet trials, and I do agree with Elaine. I think this appears to be a very well tolerated medication. So similar to the trials looking at cannabidiol between Dravet and LGS, the LGS trials are also looking at seizures that could lead you to fall. And so we’ll see when the data come out.

Anup Patel, MD: You mentioned the mechanism of action of fenfluramine. What do we know?

Elizabeth A. Thiele MD, PhD: It modulates serotonin and beyond that, I don’t think serotonin was ever a big player in the world of epilepsy. Jean Aicardi might have been ahead of all of us by about 30 or 40 years thinking about it. But I think it’s now generated a lot of interest about what kind of role could serotonin and serotonin modulation play in epilepsy.

Anup Patel, MD: Do you think there’s more to that story than with other types of medications as it relates to serotonin?

Elizabeth A. Thiele MD, PhD: That’s a really good question. Once we started seeing this, I think a lot of us have been sitting here, huh, what about those kids we’ve had on SSRIs [selective serotonin reuptake inhibitors] for anxiety and other things, and could it have played some role in seizures? I haven’t looked at that and as far as I know, I don’t know if there are data available on that.

Jesus Eric Pina-Garza, MD: I’ll give you an antidote again. I have had several families with epilepsy refractory to treatment optimized with comorbidities that I share with them. I have seen in the past someone in your situation that we treat the anxiety or the depression, and epilepsy became controlled with a serotonin drug. So I wonder if this may benefit epilepsy, and clearly, there’s some evidence now that is connective. But I think there’s more connection than we know, and the thing beyond that is that in behavioral neurology, the future is here. We’re doing a lot of pharmacogenomics and target to specific therapies. So the modification of the serotonin varies a lot, depends on your receptors and other things. So I think there’s a lot of things to come in epilepsy too. And I’m looking forward to seeing it.

Elizabeth A. Thiele MD, PhD: I was just going to say, I agree with your anecdote, and I think many of us have seen the same thing. But I think for many of patients, I know that anxiety and stress are definitely triggers for their seizures. So I think it’s kind of, you know—

Jesus Eric Pina-Garza, MD: More than one thing.

Elizabeth A. Thiele MD, PhD: Yes.

Anup Patel, MD: Or cyclical. I mean it doesn’t have to be mutually exclusive. I think that when we look at treatments, we obviously want to try to use as few medications to treat as many of the issues that ongoing, and I think that this is a great example.

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