Insights into the Natural History of Patients with Dravet Syndrome from the BUTTERFLY Study

Speaker 1:

My name is Joseph Sullivan. I'm a Professor of Neurology in Pediatrics at the University of California, San Francisco, where I work as a pediatric epileptologist. I see all types of children with various forms of epilepsy, but over the last 7 to 10 years or so, I've really focused on Dravet syndrome, and I've had the opportunity to participate in a number of clinical trials in that space.

The BUTTERFLY Study is a study that we started three years ago with really the idea and goal of establishing a natural history with which we could then compare in a potential interventional trial. And so this was an observational study that included 36 patients between the ages of 2 and 18. And they were simply followed over those two years at periodic intervals where they had detailed neuropsychological assessments that included the Bailey, the Vineland, other questionnaires.

We, as the clinicians, were still able to treat them with best in class standards of care. So as an observational study, medications were changed based on the need for increasing seizures and the patients were followed over time at these various time points. And so the recent publication is reporting at the final 24 month. We had previously reported up to 12 month data. And when you look at a lot of the figures in the paper, we're really looking at all of the various subdomains in the Vineland and the Bailey that look at various subdomains of development.

We have long suspected and known in clinical practice that these patients make very small gains over a two year period of time. And so what that results in is when you compare Dravet children to neurotypical peers, although they're making slow steady gains, they're doing so at a much slower rate than would be expected. And so therefore there's this widening gap between Dravet patients at each age compared to where we would like them to be. And so when you extrapolate that forward into the adolescent and teenage years, unfortunately the overwhelming majority of patients living with Dravet syndrome have severe intellectual disability.

The importance of these findings is it really allows us to understand the salient domains that are impacted in these patients and I think, looking forward, serves as a baseline for which we want to improve upon. So these trials, right in these developmental and epileptic encephalopathies, we know development does take time. And so if there's any intervention that's being planned that we hope would have disease modifying possibility, we want to know where are we starting from. And because development takes time, it would really be challenging to do a two year long trial to see how development is changing over this period of time.

The BUTTERFLY Study informed us that you don't necessarily need two years, that maybe in one year we're already seeing that widening gap. And if we have an intervention that's going to impact the natural history, we can use each of these subdomains, and they're measurable over time to be convinced that the intervention is having the desired impact.

So the implications of this research is it really did set that foundation for what we long had felt to be true, and now some of the same neurodevelopmental assessments are being done in the interventional trial. And at this meeting, we reported out the ongoing clinical improvement that we're seeing in these non-seizure outcomes, mainly with the Vineland, and we're able to use this propensity waiting score to basically normalize the participants that we have in the interventional trial with those that participated in the natural history. So they're not the same patients, but by adjusting and correcting for a lot of the background demographics, we actually can have a lot more confidence that the changes that we're seeing when zorevunersen is given at various doses is clearly separating from what we would expect by natural history and I think strengthening the confidence that this therapy is having disease modification.