Fenfluramine in the Management of Children and Adults with DS: Insights from Long-term Data and Real-world Evidence (Part 2)

Welcome back for part two of our conversation with Doctor Scott Perry, as we discussed the clinical implications of brand new published clinical data and real world evidence regarding the use of fenfluramine in children and adults with Dravet syndrome.

So, Scott, we have some brand new data that looks follows patients for upwards of seven and a half years. And I'd like to get your perspective on this.

So our very long term open label extension starts at about three years into a patient's journey on fenfluramine. So clinical trial initial open label median three years and then follows them for another at least year. And again some patients up to seven years. One of the endpoints in that study was again this clinical global impression of improvement. And we also looked at subscales. Tell me what spoke to you about our findings.

Well, first of all, as you said the designs are unique right? Generally when we're doing clinical trials, we have a clinical trial. We have an open label extension, all done drugs available, and you don't have a lot of years worth of open label, long term kind of extension data. So the fact that this one goes out to seven years, that's pretty unique altogether.

And then also when we're thinking about Dravet syndrome, which a lot of people, you know, always think of as a pediatric disease, which is not the case because young people who have Dravet syndrome, become adults with Dravet syndrome.

Yes, I well know.

So to have 30% of the people in this open label extension would be adults is meaningful. Now, you asked specifically about the CGI, uh, improvement scales. And what you saw in this open label extension is that the majority reported either no change or improvement. And so when you hear no change, you're like, well, that actually does mean something because they came in to this extension already from an extension where they had improvement. So the fact that they maintained that improvement, meaning no change is meaningful long term and even better, I think it's about a third of the patients in the study had an improvement, right?

Had further improvement upon what they entered in.

So longer time. Better things, you know, happening.

So I think that's I think that is I mean, that's important and that's, that's good knowledge for people to have when you're when you're talking to a patient about an outcome or a treatment, you know, to know that not only is it sustained from a seizure reduction perspective, which is what the original goal generally is with an anti-seizure med, but that this global improvement continues to grow for many people that are on the drug long term. Um, I think I think those are two main findings that I took from that, that I think are really useful in clinical practice to think about and to communicate with people.

When you're talking about different treatments we have available. And that persistence, the percentage of patients that once they made it through that first several years, they didn't drop out.

Right, exactly. So that's that's another key point is when you look, I mean, I think the number of discontinuation from adverse effects was zero. And really you only had a few percentage points, as I recall, of total dropout and which might have been lack of efficacy, maybe more common for a small population of people with Dravet syndrome. But in general, the numbers that dropped out over this very long, up to seven year study is single digits. So that's, that's that speaks to something too, right?

So I mean, if the efficacy data and the global improvement data doesn't do it for you, then. Well, they continued on the medicine long So you've got to imagine that's helpful.

Can we talk a little about the subscales. Because I was impressed. You know it's one thing to talk about global but to specifically call out cognition motor function uh behavior. What did we see?

So where first of all, where I think that's most useful is that when I think of the global impression of change scale, while it is supposed to be global, I think it is often as a person who fills it out. From the physician standpoint, it is often heavily weighted towards seizure reduction. You know, when you've got a person come in with huge seizure reduction, you're very likely to rate a global improvement higher. Even though we're supposed to be taking everything into consideration. So when you have a subscale that looks at motor and cognition behavior, and you see again, similar to the global scale that the majority showed either no change or improvements on top of that, I think that speaks to those things beyond seizure control, because now we're focusing a little more on cognition, specifically behavior specifically motor function specifically.

And you know, these are these are things that we know from a natural history standpoint, generally decline in this condition or at least plateau over time. So the fact that we're seeing a good proportion, people say there's improvement again. That's another encouraging finding.

One of the things that I commonly encountered was both physicians and caregivers. Some are more hesitant in trying new medications because they're worried about long term safety. So this study gives us unique opportunities. So can you describe the safety findings in this long term open label extension?

Well, I think the biggest thing to understand from it is that there weren't any new findings really. So the adverse effects that were reported in the randomized controlled trials and the open label extension prior were very similar to what you saw here. There were no discontinuation during the study because of adverse events. So that's very important. It's very important to know there were no cases of pulmonary arterial hypertension or valvular heart disease, which is something that we have to monitor when we're treating people with that. So I think that's reassuring because a lot of if you're going to see adverse effects generally with fenfluramine, it's going to be early on in the treatment. Um, and so to see that long term that that holds up that you didn't see anything new appear is encouraging and informative to treatment.

I'd like to touch on and follow up on the VHD and, uh, pulmonary artery hypertension, because we just released the results of our five years worth of CV safety registry, which is data collected from that REMS program.

So we now have 4695 patients who have been enrolled in REMS and received Fintepla. And what we found is a rate of valvular heart disease of 0.15%, and pulmonary hypertension is 0.06%.

Yeah. I think that's, um. I mean, from a clinical perspective, right?

This is a conversation that we.

Yeah. How do you. Yes. How do you talk to caregivers.

When you're talking to a caregiver about this obviously you're saying, hey, there is a REMS program. We've got to get cardiac echos in the US. We're going to do them every six months while you're on treatment. And so obviously there's going to be questions that follow that rightfully so.

Yeah.

Um, and this kind of data is really reassuring. I mean, what I, what I, you know, let my patients know, the families know is that, first of all, the point of the REMS program and most importantly, the point of the echoes is to monitor this, because echoes can find these changes that could progress to something symptomatic, can find it before they become symptomatic.

Yeah, that's the point of doing the echo. And if we see it, then we can act on that. If it means taking off the medication, if that's what we have to do. We can do that. And but that's the point. That's the point of that safety.

But now behind that to the numbers you just mentioned here, we're talking about people that have been treated with the drug. And the percentage of people that actually had any findings is incredibly small.

So along those lines of practical managing, of side effects, what common things when you're starting a patient, what do you see as the most common side effects that you may have some advice for us in treating the medication?

Well, probably. I guess the most common thing I might see, or at least warn people about, is the potential for some appetite suppression. So it's really most of the time, at least in my experience, appetite suppression. And generally that's going to appear in the first couple of weeks. My general impression of what happens is it resolves within a few weeks. But I just warn my one of my parents and caregivers about it so that they're aware of that.

Um, there's been, you know, potentially some cases where you might get a little bit of sleepiness. I mean, sleepiness is pretty common with any anti-seizure medication. So it can happen. But that's also tends to be transient sometimes. Uh, maybe more so in the setting of, uh, stiripentol, where we know there's some interaction between those two medicines and sometimes maybe a little bit slower titration is necessary. It you know, it each each person maybe practices that a little bit differently. But in general that's my information. I give them that, that we need to watch for.

Clinical trials are important in gathering initial efficacy, safety data, some longer term safety data. But I'm really excited that we have recently published, uh, Real world evidence. Looking at what happens when patients outside of clinical trials are started on fenfluramine. What percent Stay on the medication and what the downstream effects of that are. Could you tell us a little about the study design and this Komodo claims data and what we looked at.

Yeah. So well, first of all, real world evidence is important, right. Because open label extensions, no matter how long you make an open label extension, is still protocol driven. So there's still some rules around, you know, what you're on when you're getting seen, how you're being treated, whatever. And we know that's not what happens, right? People in clinical trials get seen a lot more often than they do if they're out in the real world being cared for.

So real world evidence gives us a better feeling of what really happens in a real medicine, right? And so in this particular study, we use the Komodo Health Claims database. And this is a database that tracks de-identified, real world data on over 325 million individuals in the United States. And you get information like demographic information, diagnostic information, treatment, prescription history, and you can use that to understand health care resource utilization. You can understand anti-seizure medication claims and what prescriptions are being given, and whether those prescriptions or those medicines are continuing or being discontinued. So really get a feel for how is a medicine being used and what impact maybe does it have on on the utilization of the health care system for that patient?

Okay.

So for this particular study, we're looking at people with Dravet syndrome started on fenfluramine, and we looked at a period of six months before they received the prescription and looked at about six months post that prescription to look at different things like, again, health care resource utilization, because that is an indirect marker probably of its tolerability and also its efficacy.

Sure.

Because if you're on it longer, we'll assume, you know, you could assume that they're tolerating it better. And then from an efficacy standpoint, if the resource utilization changes, you can get a feeling for it to make a positive impact or a negative impact. So that's what the study was about.

Okay. So what did we find in terms of persistence. So if you started fenfluramine how many patients actually completed six months.

Uh, so about 84% of individuals continue to fill prescriptions for at least six months in the group. That was fenfluramine with other meds. And then we also actually had a group that we looked at that was fenfluramine that was not also using stiripentol or cannabidiol. And that also had a similar persistence rate. So that would, you know, I would suggest the medicine was well tolerated and probably effective in this real world setting.

What does that look like in terms of hospitalizations, ambulance calls, E.R. visits?

Yeah. So this is what I think is most interesting about these kind of studies, because, you know, when you use these medicines in clinical practice from day to day, you get a feel that it's made kind of some impact. But when you can look at these claims and see things change, then that really supports that feeling that you have. And so for this particular study, the resource utilization decreased in things such as seizure related emergency room visits, neurology office visits, the need for unique rescue anti-seizure medications. So rescue medication filling rescue medications decrease, which would suggest you must have needed less rescue medicines. I would think less and less seizure related outpatient visits and less seizure related inpatient visits. That's, I think, supports that. It's made a positive, uh, there's positive impact with this treatment, I think.

You told me once something about that, what it means to have less hospitalizations.

Yeah. We talked before. Right. That in my couple decades worth of doing Dravet syndrome, one difference in the last decade is at when I see kids with Dravet syndrome now, I see them in clinic where I used to see them in the hospital. And I think that really speaks to the changes we've seen with these type of therapies that are really changing the landscape of seizure reduction and overall outcome.

So to summarize our conversation today, we've looked at randomized controlled trials, open label extensions, very long term open label extensions and real world data. What's the take home message. Let's bring it home.

Uh, there's a lot of take home messages.

One is as far as the treatment of Dravet syndrome goes. We've got some really meaningful seizure reductions in fenfluramine. It is a well tolerated drug that is well tolerated long term, and that we see not only persistence of seizure reduction, but we see continued improvements in a global impression or global improvement, which suggests, uh, more global non seizure outcomes are improving over time too. And that it's something we should think about early on, because the earlier we think about making these meaningful changes in seizure frequency for this kind of condition, I think the better the long term outcomes that people will be.

As I said before, what I'm seeing these days in my practice is very different from what I saw a decade ago, and I think a lot of that is related to early diagnosis and appropriate and effective treatment early on.

So what would you say to providers who are still not using fenfluramine?

Yeah, I mean, I understand when new medicines come out, especially when new medicines that have, for instance, a REMS program like fenfluramine that it can seem like there's a barrier, something pretty tough to jump over, right? But the truth is, that the impact we see from this reduction, um, of seizures and these other improvements that we talked about are certainly worth jumping over that barrier, first of all, and I will tell you, the barrier is not that high. Um, it's not the you know, the program is not that complex to complete.

And we've seen before, like a number needed to treat is pretty low in the number needed to treat with this drug is pretty low to get these kind of outcomes. So you see that. So I think people should try it if they haven't tried it, see what happens, Experience it, and I think they'll see it's very beneficial to the patients.

Is there any other data that you'd like to see to further explore the impact of fenfluramine?

Yeah, I think the real world data we have is pretty interesting. And I think you're going to see more real world data. So I think the longer time that the longer, longer we have real world outcome data, just like with the open label extension, I think the longer we can see what's happening in the real world, the more beneficial that will be to people understanding where this treatment and other treatments fit in the treatment paradigm for Dravet syndrome.

Well, stay tuned because a longer study is in the works.

Thank you for joining me today, Scott.

Yeah, thanks.

I really enjoyed it.

It was a Pleasure.