Joseph E. Sullivan: Going back Kelly, so we have all these medicines, and then Mary Anne even just mentioned first-line, second-line, third-line, I think we have to remind ourselves that, what it was prior to 2017. We didn't have any FDA approved medications for the treatment of seizures associated with Dravet Syndrome. Yet, you rattled off, Kelly: valproate, clobazam, levetiracetam, so maybe we have a whole different spectrum of folks that are hopefully watching this. And so, why were those medications even thought to be indicated for a patient with Dravet?

Kelly Knupp, MD: Well, I think one of the things that has kind of gone unmentioned is, there are some medications, like lamotrigine, carbamazepine oxcarbazepine, the sodium channel blockers, that makes seizures worse. There's a whole list of medicines that we just cross off the list at the beginning. I know that if Ingrid Schaeffer is watching, she would comment that maybe lamotrigine is something for some patients that may not be contraindicated, so I have to give that shout-out to her. But I think for the vast majority of us, we avoid those medications. It means we are largely using broad spectrum medications, and I think looking at even the clinical trials that were done previously and current, the newer clinical trials, it does seem that many of our patients are in the mainstays of valproic acid and clobazam. It seems that somehow our patient population is gravitating to those medications, and it must be because they're a little more efficacious than the others, even though they haven't been studied in this situation. In my patient population, we were fortunate to have access to stiripentol before it became FDA approved, and that was a game changer for many of our patients, it kept them out of the ICU. And in fact, one of my patients was recently admitted for something unrelated to their Dravet Syndrome, and the residents commented that our current group of residents haven't seen a Dravet patient admitted to the hospital. It doesn't happen much anymore, whereas we used to always meet these patients in the ICU.

Joseph E. Sullivan, MD: Exactly. But now, you touched upon this broad spectrum of medications, and I think that that's what kind of got me. One of the things that got me interested in epilepsy is: how can it be that there are all these different seizure types? We try to characterize them by looking at the videos and the EEG and then maybe there's a group of medicines that may work a little bit better for this seizure type, and we'll get into this when we talk about Lennox-Gastaut. But the key is: these patients have many different seizure types, and in some ways we can look at some of these papers, and we'll get into some of the studies, where we try to identify all the different seizure types and try to see if there's one type that maybe responds a little bit better. Maybe there is some directionality in some of these studies, but in the end, in my experience, if they're going to respond, a lot of the concerning seizure types do respond regardless. And I've heard others say that these medications that have labeling and approval for Dravet Syndrome or Lennox-Gastaut Syndrome are not necessarily syndrome specific, but rather it's this sort of pseudo-specificity, right? And it's working for multiple seizure types and maybe in the big picture, they're just broad-spectrum medications. I still think it's important for us to understand and make these clinical observations in terms of counting seizures and different seizure types because there are different seizure types that carry with them more morbidity and more negative impact on quality of life. All seizures are not the same. I think unless we can get into those details, we're not going to be able to refine our treatment approaches. So let's get into this. Now, I think, I'll just give my own little color here. I feel like we're often talking about Dravet Syndrome and Lennox-Gastaut Syndrome together, and they share a lot of similarities, in terms of what I mentioned in the introduction. But they're just so different. I think a lot of what may be, this is my opinion, with Epidiolex, all of a sudden this trial of a cannabinoid that was creating a lot of fervor here in the US, it put Dravet Syndrome and Lennox-Gastaut Syndrome, in mainstream. We didn't see Dravet Syndrome on CNN, or we didn't see different pieces on the media about Lennox-Gastaut syndrome. I feel like this really did catapult us to where we are now, with all of these different sponsors that are trying to look and see if their compound, which is great for us on the screen as clinicians who take care of these patients, and as parents, we're always looking to try and get our patients as close as we can to seizure freedom. So with that really long intro, maybe we should start, actually, Kelly, with cannabidiol and you mentioned where you are. You also were on the forefront of the cannabis and epilepsy movement in Colorado. Maybe share some of the anecdotes that you had with that early experience and we'll get into the FDA-approved cannabidiol and what that has shown in the Dravet Syndrome patient population.

Kelly Knupp, MD: I think it's really important that as we talk about this that we clarify when we're saying cannabidiol: we're actually talking about pharmaceutical-grade cannabidiol as opposed to the oral cannabis extracts. Where I live in Colorado, we were not part of the initial trials because of some legal reasons surrounding the access to even a study drug of cannabidiol in our pharmacies. Our patient population was largely interested in using the oral cannabis extracts. There were a handful of patients that were reporting huge benefits with these medications, but, by and large, many of our patients didn't actually experience as much improvement as was initially reported and I think it's important to keep in mind that many of these were anecdotal cases. Some of the challenges that our families were reporting, though, is having consistency of drug. The product that they were receiving from month to month would vary, would smell different, would taste different, would have different reported concentrations in it and that was really a struggle for many of our families, particularly if they had had a good month the month before and then got a new product and couldn't sustain that. I think the studies of cannabidiol did demonstrate benefit in this patient population and I think that's really important to know that at higher doses, patients did better than they did at lower doses, and there were patients who did see an improvement in overall seizures. I was trying to remember, Joe maybe you remember better, if their outcome was seizures associated with that drop or if it was convulsive motor seizures.

Joseph E. Sullivan, MD: Yeah, for Dravet it was all convulsive motor seizures. And then for the Lennox-Gastaut, it was seizures that resulted in a drop.

Kelly Knupp, MD: There was demonstrated benefit and I certainly do have patients now who have benefit on cannabidiol. I think one of the things that my patients and I have talked a lot about is that the oral cannabis extracts are not necessarily cannabidiol, and so if you've tried an oral cannabis extract, it may not be the same as cannabidiol, and so it's important to give that another try.

Transcript Edited for Clarity