Can an Old Forgotten Diet Drug Treat a Rare Form of Childhood Epilepsy?

James Radke, PhD

Fenfluramine is back! The once maligned diet drug is making a comeback as a possible treatment for Dravet syndrome, a rare form of childhood epilepsy.
At the 12th European Congress on Epileptology (ECE) in Prague, Czech Republic, a poster was presented on the efficacy and safety data on ZX008 (low-dose fenfluramine) as an adjunctive therapy for seizures associated with Dravet syndrome. 
The ECE meeting also included several posters illustrating the incredible burden that Dravet syndrome can have on a family.
Recently, we talked with Joseph Sullivan, MD, director of the UCSF Pediatric Epilepsy Center in San Francisco, CA, about the posters and additional data being generated for the use of low-dose fenfluramine (ZX008) in patients with Dravet syndrome. The compound is being developed by Zogenix.

RDR: What is Dravet syndrome and how is it different from other pediatric forms of epilepsy?

Dr Sullivan: Dravet syndrome is a condition that presents in the first year of life in otherwise healthy neurologically normal children, and it typically presents with a prolonged seizure. It’s usually a convulsive seizure. There’s a whole body shaking, lasting 15 or 20 minutes, maybe even longer than 30 minutes.
So that in and of itself is already a bit of a red flag for something being different and is not just being a run-of-the-mill febrile seizure which are very, very common.
And then it usually a couple of weeks or a couple of months later,  a second prolonged seizure to occur. And then you can sort of extrapolate that forward where the child starts to continue to have seizures.
 We’ve been aided by the availability of genetic testing where 80 to 85% of children with Dravet syndrome will have an abnormal mutation in the SCN1A gene.

Do the seizures continue as the child ages?

Within a few years, other seizure types develop including myoclonic seizures that actually used to be called severe myoclonic epilepsy in infancy. And so those seizures develop and the children start to have, unfortunately, a developmental plateau and stagnation so that they start to fall behind their development compared to their age match peers.

What is the current management for it?

The current management remains anti-epileptic drugs that we know are more effective in this syndrome. There are also some drugs that are contraindicated. Some of the medications that will work at the sodium channel actually can exacerbate the condition. And then there are also special diets. The Ketogenic diet (high fat, high protein, low carbohydrate diet) can minimize seizures.
But the take-home point is that it’s unusual for these kids to have prolonged periods of seizure freedom, and so we really reset our expectations and try to minimize the number of those prolonged seizures that require hospitalization but reset the bar and really say that seizure freedom is not realistic.

What is ZX008?

The main mechanism of action for fenfluramine is through the serotonin pathway, and, in particular, it works at the it works at the 5HT1D, 2A and 2C receptors. How that exactly translates into seizure improvement is not really that well known. It may be something that’s independent of the serotonin pathway, but there’s a lot of recent research that does suggest that the anti-seizure mechanisms may be through the serotonergic pathway, but the details of that have not really been well elucidated.

Can you describe the latest clinical trial?

So the trial is a pretty standard double-blind placebo-controlled trial that actually has two different dosage arms, one of a 0.2 mg/kg/day and another 0.8 mg/kg/day. All the kids have to have a clinical diagnosis of Dravet syndrome that’s actually determined by an independent body called the Epilepsy Study Consortium. And then once they have been deemed to have Dravet syndrome, they also have to have a baseline of more than four convulsive seizures per 28 day period, and they have to have a normal cardiac echocardiogram because of the experience of fenfluramine back in the 90s that led to its removal from the market. So, if a patient has Dravet, has more than four convulsive seizures per month, and has a normal echocardiogram, they start in the screening phase where the families are simply counting seizures over six weeks to establish a clean baseline. And then if they have six seizures in those six weeks, they then get randomized in a 1:1:1 ratio of placebo, low dose or high dose, and then they’re followed over those 12 weeks and seen periodically for safety measures, including echocardiograms to make sure there are no changes in the cardiac valves. They keep an electronic seizure diary and the primary endpoint is reduction in convulsive seizures over that treatment period.

ECE Presentations

At the 12th  ECE  in Prague, Schoonjans and colleagues presented a poster of 9 young Dravet patients who had received low-dose fenfluramine. An earlier clinical trial enrolled older children. This new data focused on a younger cohort of patients. Additionally, several posters were presented looking at the burden of Dravet syndrome has on the family.  Dr Sullivan talked about these poster presentations in our interview

What data was presented at ECE in Prague?

One of the criticisms in the original cohort is that all the kids were older. So, in the new cohort, the kids are younger. The study of 9 patients found that the reduction in seizures ranged from  28% to100%  with some of the kids being seizure-free,  Most of the patients (7 of 9) had greater than 50% reduction seizure frequency.

Can you summarize the studies looking at the burden of Dravet syndrome has on patients and caregivers?

We’re looking at a lot of quality of life outcome measures, including measures of sleep and a lot of the families reported improvements in their sleep, presumably because they’re not as worried that their child is having as many seizures. And so that really translates into a huge caregiver burden in terms of what is involved in taking care of these patients.


Schoohjans A-S, Gunning B, Marchau F,  et al.   Fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients. Poster presented at the 12th European Congress on Epileptology; Prague Czech Republic; September 11-15, 2016. Abstract P593.
Jensen M, Liljenquist K, Gammaitoni A, et al. What areas of lives of caregivers of children with severe, refractory epilepsy are affected by caregiving? An expert panel report
Poster presented at the 12th European Congress on Epileptology; Prague Czech Republic; September 11-15, 2016. Abstract P214.
Irwin J, Pagano K, Rycroft C, Sabar U. Describing the humanistic burden of illness in Dravet syndrome - critical methodological questions remain. Poster presented at the 12th European Congress on Epileptology; Prague Czech Republic; September 11-15, 2016. Abstract P283.
Nabbout R, Auvin S, Chiron C, Irwin J, Mistry A, Williamson N. Towards a composite clinical endpoint: identifying a core set of patient and caregiver relevant outcome measures through qualitative research on the global impact of Dravet syndrome. Poster presented at the 12th European Congress on Epileptology; Prague Czech Republic; September 11-15, 2016. Abstract P293.
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