Neurocrine Biosciences, Inc. (NBIX) Earnings Call Transcript & Summary

Welcome to this year's Biotech Focus conference. It's our first virtual one, and I hope everyone on the webcast is safe and staying at least moderately, seeing these days. I know the weather is kind of a compounding issue out in the Northeast. So just my best wishes to everyone who's joined us. And I will say, before we go to a partner discussion, our compliance would have a heart attack if I don't direct everyone to williamblair.com for a full list of disclosures. And just to start off, it's my pleasure to welcome all of our epilepsy panel members today. I've known some of you for years now, and it's always a pleasure to see progress in the field around epilepsy and the related disorders. And it's my pleasure to welcome Jackie French from NYU Langone Health. She's also the Epilepsy Foundation member/queen/everything. And she also runs an incredibly informative pipeline focused conference, which myself and my team has attended for a number of years now. So I encourage everyone to look into that. And I believe it's virtual this year as well. And I'll just -- maybe just start now with Amit and Simon, just with brief introductions, before we dig too much into the details. And Kyle, welcome. Thank you for jumping on. So maybe Amit, do you want to...

Sure. I'll start. Great. Thanks, Tim, and thanks, Myles, for having us on this panel. I'm Amit Rakhit, I'm the President and Chief Medical Officer at Ovid Therapeutics based in New York.

Thanks, Amit. And I echo Amit's comments. Tim, thank you for having us all. Great to be with colleagues. Simon Pimstone, one of the founders and CEO of Xenon Pharmaceuticals, primarily epilepsy-focused small molecule company.

And Kyle, I guess, do you want to give a brief introduction?

Yes. Kyle Gano, I head up the business development group here at Neurocrine. As the panel members know, we've struck up a partnership with Xenon. Really excited about working with Simon and his team. And even this morning, looking forward to having a conversation around some of the interest that we collectively have in this therapeutic space.

And maybe Myles before Jackie, so he can...

Sure. Myles Minter, I'm a biotech analyst here at William Blair, I cover the neurosciences spaces and Neurocrine Biosciences there. Yes, thanks, everyone, for joining. Pass over to Jackie.

I'm Jackie French. I wear a couple of hats. I'm a Professor of Neurology in the Epilepsy Group at NYU Langone. And in addition, I am Chief Medical and Innovation Officer of the Epilepsy Foundation and Founder and Director of the Epilepsy Study Consortium, which is a nonprofit that -- whose entire goal is to speed new therapies in epilepsy to people who need them by improving the conduct of trials and research. So as mentioned, the Epilepsy Foundation has a pipeline meeting that's coming up at the end of the month on the 27th, 28th. And if you want to see everything that's in development in epilepsy, including everything that's represented here among my colleagues, then please join us.

Thank you very much, everyone, for joining us. And maybe, Jackie, ahead of your pipeline conference at the end of the month. Could you maybe talk briefly about what do you think is kind of the state of epilepsy? We've had a number of new therapies launching, just tell me kind of where is the unmet medical need? And what do you think of kind of the innovation that we've seen over the past year or so?

Yes. I probably told this to every person that's on the panel here at one time or another, what I feel that the unmet need is and there are still many despite all of the antiseizure medicines. And by the way, I just want to point out to everybody, if you want to use the right terminology, we now talk about antiseizure medicines, which is really important as opposed to antiepileptic drugs. And that is -- leads me right into one of the unmet needs because we want to basically emphasize -- and it was interesting, I was having a discussion with Billy Dunn at the FDA. It's one of the few conditions, epilepsy, where you could say that it is both a disease obviously, but also seizures are a symptom of a disease, and they can be a symptom of many different diseases, obviously. So when we say antiseizure medicine, we're saying that most of the drugs in the space right now are actually symptomatic therapies. They treat seizures. It's a very good thing, and they do it -- some of them very well. We still need disease-targeted therapies, and those are going to be coming very quickly to the marketplace actually and perhaps by -- in the hands of some of the people on the call. And I think that the community, the patients, the doctors are all hungry for that type of innovation. Above and beyond that, you have to sort of subdivide the world into those patients who have a therapy that will control their seizures, and that's about 2/3 of people and those who, at the moment, do not have a therapy that will control their seizures. The people who do have a therapy still have an enormous list of needs and just to be very specific, they need better tolerated therapies that address comorbidities like depression and irritability that often are compounded by the drugs that we currently give them. They need safety and they need attention to women's issues because we do treat a lot of women during their childbearing years, that they don't produce [indiscernible] or any issues with either contraception or pregnancy. So we still have a lot of needs in that domain. And then obviously, for those who don't have a therapy that currently treats them, we need drugs that are better for the treatment-resistant patient. All the other things that I said still go for this group, it would be fantastic if we had drugs that actually were targeted such that we wouldn't have to go through 12 different drugs to figure out which one was good for Mrs. Smith. And I think people are really excited about the possibility that, that might happen even if it was an antiseizure medicine, right? And maybe that's genetics or maybe that's some other biomarker again, disease-modifying therapies. And I'm going to end by saying it would be fantastic if we had a drug that was a little forgiving that people wouldn't have to like put their life on the line if they miss a single dose of therapy out of 10 years of taking it properly.

That's -- thank you for kind of laying that landscape. And before we dig also into the pipeline, I do want to just maybe touch upon the recently approved drugs, if you could give us kind of a short kind of maybe your short experience/thoughts around them. I know some of them are pediatric, and I know you focus on adults. But I'm sure you still have plenty of opinions about -- So maybe we talk about CBD, FINTEPLA, Cenobamate. If that sounds fine?

So CBD obviously wasn't approved this year, but it got an additional indication. And when you're talking about new therapies for this year, I would also put in the rescue therapies. Because there were some key approvals there this year as well. So I would say that of all the years that I have looked at in the field of epilepsy, this has been an extremely good year. And it's funny because having been in this field for 30 years, you've heard the death knell over and over again of nobody is going to develop new therapies for epilepsy. The field is dead, and it's just so not true. I'm here to say to everybody out there. It is absolutely not true. We have drugs this year that I'm actually on record, I wrote an article saying that Cenobamate was a game changer. And the reason that I called it a game changer is because whereas even in a brief add-on study of 3 months that we typically do with all the drugs that have come to this point in people who, I mentioned, don't have a therapy that's treating them right now. We can maybe get 3% of them, 4% of them seizure-free with a new therapy, even for 3 months, never mind long term. Whereas that number for Cenobamate is a whopping 18%. I mean it's like -- it just puts all the rest to shame. So it's definitely for those 18%, whoever they are, it's going to be an amazing intervention. And like even when we talk about resective surgery in our surgical conference, one of my colleagues says, but remember that Cenobamate for this group of people actually is better than surgery. So think about that. So it's going to be a new way of thinking for people that, yes, you can -- because I hear over and over again, my colleagues, particularly in surgical conferencing, saying "Oh, this person is tired of drugs. They've tried drugs. They want to try another drug, but they want to try this drug." Now having said that, of course, there is the adverse effect that we have to keep an eye on of possible hypersensitivity reactions and slow titration because of that. And then moving on to FINTEPLA. Again, we saw trials that showed really game-changing improvement, really game-changing improvement, with a substantial number of children getting 75% and 90% and occasionally, 100% reduction in one of these severe epileptic encephalopathies being drive A, that essentially, we've had no really effective therapies for -- therapies definitely that make people better and reduce seizures, but this looks game changing. Again, we have an adverse effect that we have to keep an eye on, which we have not seen in children yet, but there is a rem. Doctors have to look at a video to understand the adverse event before they can prescribe the drug, which is appropriate. But right now, we don't have a danger signal, we just have a danger, theoretical threat, so -- of heart valve thickening. So both of those, definitely, it's going to be fascinating over the next year to see how it plays out and to see what benefit. Again, I always say every study that's done is a proof-of-concept and then it gets into the real world, and we have to see what it does in the real world, but there's definite potential there for both of those drugs. And then as far as Epidiolex, expanding into tuberous sclerosis, it's a little hard to like sort of parse that for me because within the tuberous sclerosis population, there are Lennox-Gastaut patients. There are patients with let's say, focal epilepsy. Actually, I was on a call yesterday and somebody said, we need to talk about the syndrome of tuberous sclerosis. And I said tuberous sclerosis is not a syndrome. It's an etiology. And we have lots of different etiologies. We have traumatic brain injury. We have anoxic injury. We have infection, many different causes of epilepsy. So we have to see how this plays out.

Maybe first, Amit, given that landscape, how are you thinking about 935 developments? And obviously, you have a big ELEKTRA readout coming up, but you -- some very interesting early data. How do you kind of position your product among the landscape?

Sure. Sure. Thanks, Tim. And I think that's a great -- with Jackie's backdrop of what's going on with this space. I think you see with our OV935 compound, which is in partnership with Takeda, we're looking at this as a novel first-in-class and a different mechanism of action, the cholesterol 24-hydroxylase inhibitor as I mentioned, 3 key data readouts coming out this quarter with the ELEKTRA data focused on the Dravet syndrome and Lennox-Gastaut population. But we also have our ARCADE data, which is in CDKL5 deficiency disorder and Dup15q syndrome. And then the long-term extension information from ENDYMION, which goes out to almost now, 2 years of data. So when we look at this, I think the unmet need is still very high in all these disease areas syndromes. When you see that you have anywhere from 18% seizure freedom from certain therapies or 20%, that means there's another 80% of people out there who are not responding or is not having as much of an effect as you would like. If you look at folks that have been in our programs, most of them have cycled through anywhere from 1 to 5 different antiseizure medications over time and have just been not satisfied, because they have not either gotten to seizure frequency reduction or the quality of those seizures have not changed or the overall burden of illness has been still high, that they cycle through multiple medication. And in some instances, we see that families have even just decided to come off of everything because nothing has worked for them, and this is better off just to be on no therapy. And so we see this high unmet need still and we hope that looking at our information with OV935, the previous information that we've shared with our adult study data and initially our ARCADE data, it looked like there was definitely an effect on these patient populations that have failed to various treatments. And I think -- and another piece is that we are looking at having a potential biomarker that you can measure for treatment effect as well. So with our 24HC, which is the enzyme metabolite that the enzyme we're inhibiting the metabolite, you can measure into plasma. And that also, hopefully, will be another avenue for clinicians to assess treatment effects by having a measurable biomarker that they can address with dose. So we're looking forward to that data coming forward in -- later in this quarter.

And Simon, you have a very broad pipeline, and Kyle is obviously, now a bit -- you guys are collaborating with that pipeline. Can you talk about maybe what Xenon is doing in terms of targeting specific kind of molecular level target? It's very -- almost similar to CH24 with Amit, but...

Again I think this follows one of the themes that Jackie had brought up, which is really trying to treat the disease and not just the seizures. Although as Jackie points out, there's still clearly room and importance in doing that. But we just got very interested in thinking about epilepsy from a molecular perspective and trying to find very important targets. Targets that may be important sort of overriders in neural circuitry, but also sort of precision medicine approaches for specific disorders. And KCNQ is a good case in point, where this is actually probably a more common disease than was originally thought. We see births of around 1 in 15,000 to 17,000 versus about 1 in 12,000 live births with Dravet Syndrome. So not that much rarer than Dravet really, based on fairly recent epidemiological data out of the U.K. And so we're approaching this in a way to try and identify these important developmental epilepsies, identify drugs that are more selective for modulating the underlying molecular cause of the disease and trying through, obviously, regulatory strategies to ensure that we can start to dose as young as possible in the children, obviously, deeming -- if it's deemed to be safe. We just believe that as early intervention as possible in a very targeted disease is probably the best chance we have in seeing improvements over time in the developmental consequences, cognition, intellectual impairment that are obviously important as a query of these diseases. And by the way, in many patients, unrelated to seizure control, and Jackie can talk to that better than I. But there seems to be certainly not a perfect correlation between seizure control and developmental outcomes by any means. And so I think that's a really important area, still of very, very high unmet medical need. And so the belief that we've had an hypothesis that at least we've brought today here is we want to make sure we can treat as early as possible, provided, we believe we can do it safely. And we want to make sure we can do this as selectively as possible with a really precision approach. And I don't think we can do more than that, ultimately, unless you're trying to treat a child in utero, which is going to be very difficult to predict. So looking at our KCNQ developmental epilepsy trial, for example, we do have and have had agreement with the FDA to treat children in our first study of 496, which is a reformulated version of retigabine in kids as young as 1 month. And so I think as far as I'm aware, Jackie will correct me on this, I'm sure. But there are not many trials in pediatric epilepsies that start out, so young. It's in a traditional step down approach in pediatric epilepsy. So I think that also shows very exciting recognition by the agency of the need and certainly, I think, great support for the institutions and companies trying to answer some of these questions. And so we feel very grateful for that dialogue, but that's the kind of approach. And Kyle can speak also to the sodium channel strategy we've taken, with a different disease with Neurocrine in SCN8A and potentially SCN2A as another disorder where we are developing selective modulators of the sodium channels, given what we believe the important role they play in hyperexcitability in epilepsy. So I'll leave that to Kyle as well. But that's the -- I hope that answers your question, Tim.

Sure. I guess, Kyle, maybe that's a great time to hear from kind of Neurocrine's interest in the space and what kind of led you here?

Yes. I think maybe many of you don't know, but we've had a strong interest in some of the targets that have been in this space for several decades, and we haven't had much success ourselves. And I think for us and our collaboration with Xenon, we have a very significant appreciation for all the fantastic work the Xenon team has done to solve the very difficult problem on the sodium channels. That is finding selective molecules on the targets of interest, those that have been genetically validated and targeted for specific epilepsies and avoiding some of the untoward side effects of inhibiting other subtype sodium channels. So I think they've done an excellent job there in really are the leaders in the field as it relates to understanding the differences and nuances of inhibiting various sodium channel subtypes. And that's what really attracted us to the Xenon team. I think, Jackie, you touched on a number of recently approved medications. And while we certainly see value in those, I think that what we're mindful of is that, for the most part, those are repurpose compounds. They were found through more traditional phenotypic screening and you to take it through the clinic and see if you could see efficacy there. For Neurocrine and Xenon, I think where we land in a shared vision perspective, is using all the contemporary technology that should be applied to drug development, namely looking at things like target engagement target occupancy and understanding the translational medicine piece from preclinical to the clinic. We think that's going to give us a higher probability of success in the patient population as well as ensure that on the back end, once we show efficacy by understanding things like the target engagement and occupancy, we can be more sure of the safety and tolerability profile. And I think the combination of those elements make -- what we're trying to do is Xenon very interesting and attractive, and we look forward to bringing the medicine that we have in hand now into SCN8A patients later this year.

That's great. Thank you for that background. And Jackie, can you maybe touch upon the -- that importance and maybe that shift in towards selectivity and treating underlying disease, not going back to -- it's not an epileptic seizure, it's seizures are symptoms of something else.

Well, I'm going to say that, again, I'm now on paper as saying, we need both. And you can say, "Oh, well, unselective screening, not exciting." But when you get an 18% seizure-free rate from it, then it becomes exciting. It's really hard to know. I mean, if you are treating a symptom, right? Then a symptomatic screen makes sense. If you are treating the underlying disease, then some sort of screen for the underlying disease makes sense. And now I'm going to say great, but we don't have a validated one. So you got to be careful. And the example that I gave in my recent article was the difference between Padsevonil and Cenobamate, and some of you may be aware that Padsevonil was a drug that was specifically designed to attack treatment-resistant epilepsy. It used all of the knowledge, the underlying knowledge the mechanism of action was selected carefully. All of the new screening models that were supposed to represent specifically treatment-resistant epilepsy were used, favored over the standard models, whereas Cenobamate was just the same old, same old that we've always been doing. And guess what? When it got into the clinic, Padsevonil did not separate in a placebo-controlled add-on trial in focal epilepsy from placebo, whereas Cenobamate obviously did in a big way. So it's not always the right path. But we do have hope and faith that if we really understand what's driving seizures in certain diseases, than targeting that. And I think a good example of that might be the mTOR pathway, which we had a feeling was not only driving disease in tuberous sclerosis complex, but also driving seizures because of an overgrowth of cells that is suppressed by mTOR inhibition. And lo and behold, when you give that drug in tuberous sclerosis complex -- patients with tuberous sclerosis complex and seizures, the seizures go down. And there, the study was not originally designed to demonstrate that there is a disease-modifying effect, unfortunately, but there's a hint from the data that there may be and the next study in such a situation should try and capture is this disease-modifying or not. Are you seeing an effect that continues to increase over time as the drug is given and are there carryover effects when the drug is taken away. And the mTOR pathway disruption, we believe underlies other seizure diathesis as well. Another common pathway people are super excited about is inflammation and blood-brain barrier disruption. So if you really understand how those are driving the disease, you can attack them. I think that just saying, we have a compound, and we tried it in all these fancy models, and we know how it engages the target is not exactly enough.

And I think, Amit, you might be one of the -- only ones on the panel who also has some ASL kind of earlier stage programs. I know you just signed a deal for some gene therapy. Can you maybe put those in context? Those are obviously trying to get a little bit deeper down and incredibly interesting. But can you just give us kind of your view on the state of small molecules versus these other approaches?

Sure. I think it goes back to what both Simon and Jackie have mentioned about reaching -- and Kyle mentioned about reaching back into the etiology of the conditions that we are hoping to develop medicines for. So if you look at current small molecule therapies or the evolution of antiseizure medications in treatment practice have been focused on just seizures, alleviating the seizures initially. But then as we've become I would say, more sophisticated in the science and understanding different mechanisms of disease that we've been able to step back and go back in towards the key root of the pathophysiology of these conditions. And so there is a role to play for both small molecules. And now I think the emerging sciences of ASOs or other molecular type therapies, gene therapies that really target the underlying conditions. And I think that's where we focused -- at least at Ovid, some of our later-stage programs are small molecules, but our early research stages are focused much more on the molecular state, both on the neurodevelopmental side as well as the epilepsy side. And with partnerships that we have with, for example, that we have with the Columbia and University of Connecticut, looking at some of these early models and how we can bring those forth. They have their challenges, of course. I think you've seen other ASOs have emerged in other areas like, for example [indiscernible] and other areas. But I think it's an emerging space for us in the epilepsy field to look at what could be possible. If you look at GRIN2B, SCN8A, you just mentioned SCN1 associated with Dravet, those are all areas that have promised because you can start to identify not only just kind of the focus of this but also there's complexity there, too, because some of these genes target multiple other areas. And so looking at how you can be targeted towards the disease itself, without causing more adverse events on the other side, if -- when you're looking at the gene therapy level or molecular level. So I think it's an emerging science for us. We're actually very excited and looking at research bringing forward. But there's probably a balance, right? It's going to be individualized, as you all mentioned, some people, a small molecule will be perfect for them for their for managing whatever symptoms that they have or the manifestations of a condition, while others, a more targeted approach might be appropriate or it could be a combination. And I think that's something that appropriate combinations that will really to kind of transform some of the medical practice as we know it today.

Yes. That's super interesting. And maybe just getting back to the sodium channel-specific blockers, Simon. Like I'm just wondering what is the real importance of subunits sort of selectivity here. Is it a translation into chain to improve efficacy of our antiseizure medications? Or is it to balance out the safety profiles here? And then maybe for Kyle, interested why you're going the rare pediatric epilepsy pathway as opposed to creating a sodium channel blocker that might have a better risk-benefit profile than some of the drugs we have for focal epilepsy?

Should I kick off, Myles?

Yes, that will be great, Simon.

Yes. No, thank you. It's an important question, of course. I think probably the really interesting lesson that explains this or exemplifies as well is the fact that these pan selective sodium blocking -- sodium channel blocking drugs are essentially contraindicated in Dravet syndrome. This is a disease, which is in 80% of kids caused by loss of function mutations in the NAV1.1 sodium channel. And so the concept of adding a sodium channel blocking drug in these children, which further worsens the phenotype because of added GABAergic inhibitory block imposed by its inhibitory effect on the NAV1.1 channel, it has been known -- and Jackie can speak to this for a while, and these drugs are avoided typically in these children. And so as we think about targets in the sodium channel suites and the family, there is absolutely no need in an antiepileptic drug or an antiseizure medicine to have NAV1.1 inhibition. There's no need to have the 1.5 cardiac isoform inhibited. There's probably no need to have the 1.4 muscle expressed isoform inhibited. And so if that's the case, the whole concept really of a more selective strategy at least targeting the sodium channels. And that's not to say it's going to cure every patient's seizures or epilepsy, is to really allow a greater degree of target engagement, due to the fact that you have less inhibition of unwarranted or unwanted channels. And so here, we have drugs now that can have really maximal effect in knocking down 1.6 and 1.2, particularly, which are highly expressed in the pyramidal cells and in the excitatory neurons. And we know from genetic studies in animals and in humans that these particular targets have a very important role to play. If you have gained a function effect in these genes, you have hyperexcitability setting in at a young age and so we've taken that approach with really the answer to your question being, we're hoping to get drugs that we can dose at higher exposures at target tissue, with less exposure on the other tissues or other targets. And we'll see, to Jackie's point, we don't know, ultimately, if this is a better strategy or not. But I will say, I think about epilepsy a lot like -- and I still see patients -- and my background is in cardiac disease, I treated a lot of patients with hypertension and diabetes. And I think of these diseases quite similarly. Hypertension, you measure blood pressure. It's your -- but your consequence is cardiac left ventricular hypertrophy, renal disease, microvascular disease. And we optimize treatment with polypharmacy. And we optimize effects long-term with lower doses of drugs of different mechanisms. And so I'm not yet suggesting there's a drug that's one size fits all. That's not the case. But I think if we start to have in our arsenal an array of products that are probably better tolerated at desired doses, I think we can complement some of these drugs in a polypharmacy strategy, hopefully, introduce them earlier in the disease and get better long-term outcomes. Just as we've seen in hypertension, just as we see in diabetes and many other chronic illnesses. Jackie can speak to this better than I in epilepsy. But that's the way we think about it. So a little bit of both, Myles. Safety and efficacy, but this isn't going to be the bullet that solves all of epilepsy. Kyle?

Yes, Simon. It was a very good description there, what we're trying to achieve. I think just to build on that, I think I'm probably the only one in the room here that doesn't have an MD. So I apologize if things don't come out as they should. But for me, being a chemist, I really like the concept of kind of doing things from a rational standpoint and thinking back 20 years ago when we realized we were using medicines that were racemics or mixtures of compounds, and only one of the components was doing the work and the others just came along for the ride and potentially adding to the tolerability or safety issues. I think pulling that through our collaboration for Xenon, what we want to do is make sure we're inhibiting the relevant subtype sodium channels that we think that are important for efficacy and avoid the rest. And I think, Simon, touched on it there is that's the hypothesis. Of course, we've got to see how it plays out in the clinic, ultimately. But the goal here is to get selective NAV1.6 inhibitors and NAV1.2, 1.6 inhibitors into the clinic. So a selective 1.6 and then a dual inhibitor would be something that we would like to bring forward into the clinic and test in patients. In terms of where we landed in terms of SCN8A versus other focal seizures, I think that's a great question. And for Neurocrine, we have a long history of trying to maximize value programs by studying different types of indications for a given mechanism or compound. We understand that new chemical entities are rare, and it's important to study them across a broad spectrum of disease states in a manner that appreciates this rarity. It's one thing to say, I've got 2 compounds here. Let's move one forward in this rare indication, and one forward in this larger disease state. It just doesn't happen that way. You have one compound, and you've got to figure out where you have the best opportunities to exceed. And it's this concept of a pipeline was in a program that has always been in the back of our minds. I think things are a little bit different here with Xenon, however, because I think when you start talking about rare pediatric diseases, epilepsy, seizure disorders, there's an unmet need in every patient counts in a clinical program. And we feel ever more important that we need to start our efforts here on SCN8A. For 352 or 901, the Xenon compound that we're moving forward with the biology is really sound in AGA. We've got really nice animal models of disease and very potent effects in those animal models with our lead compound. So our goal really from the inception of our discussions with Xenon was to pursue a program that leverages this biology, this validated technology on this disease state. And I think from here, we'll let the science and data guide us. We're going to learn a lot from this initial study in SCN8A patients. Obviously, there are other areas that we want to study, focal onset seizures would be a logical next step. And that's something that we'll look at pursuing as well. Right now, it's all about SCN8A and building on the momentum that Xenon team has provided. Once we signed the collaboration, we're just trying to continue that and get it into patients as quickly as possible and see if we can offer a medicine that's better than their high dose alternatives that they're using right now.

Understood. And maybe, Amit, could you talk a bit about the potential for biomarkers? I know that, that's kind of to be determined. And there's -- but it seems elegant if the clinical results obviously support. But can you just maybe speak a little bit about 935 and a potential for a biomarker?

Sure. So the 935 compound, OV935 is basically an enzyme inhibitor, it inhibits an enzyme cholesterol 24-hydroxylase, which is the enzyme that converts cholesterol in the brain to a more soluble form or excretion out of the blood-brain barrier to 24-hydroxy cholesterol. So only about 0.4% of your cholesterol ever is metabolized in the brain because it's such a core part of tissue structure and brands. But the 24HC is what we believe modulates at the NMDA receptor to have its effect on epilepsy or seizures as we're looking at. And it looks like there's also some sort of anti-inflammatory effect, which we've shown in the data that was presented last year, potentially in -- with effects on glial cells and astrocytes for inflammation. But that 24HC, once it does its kind of role in the -- within the CNS, once it travels out into the plasma, it's measurable. So we are able to measure the 24HC. And our previous data with the adult data and data that we shared previously, have shown that there is a strong correlation between the level of enzyme and inhibition that we see with the levels of 24HC that's measured in the blood. And so that really shows us that when we looked at our early-stage, kind of Phase I studies, you need about 70% to 80% inhibition to have some of that treatment effects happening. And you could even push that enzyme inhibition all the way up to the high 90s-percent, before starting to see some of the -- any adverse events that would be limiting. And so that is a strongly correlated, almost a linear correlation so that there is a high potential that using 24HC in the blood, you could individualize therapy for a person and have a sense of where their enzyme inhibition is to get to treatment effect. This is barely -- there's not that many biomarkers that are available in using antiseizure medications. So that's something that we're very encouraged by because that could really help move down towards a more individualized approach once you have kind of a starting dose and individualized therapy to treatment effect. And that's more information to come. We've incorporated the 24HC levels in all of our studies. So that we will be able to look at different diseases, anywhere from Dravet to Lennox-Gastaut to CDKL5 and have that information available so that this potential for a biomarker is very high in our -- the development path.

That's incredibly exciting. And maybe, Jackie, we only have about 3 more minutes here. I apologize but I just love to hear from you about what you're excited from in the pipeline. Obviously, everyone here has an exciting compound. But I would love to just hear some of your kind of high-level pipeline.

I was going to say that's like making a mother choose between her children. You can't do that.

That's only around [indiscernible]

So I am excited about the possibility in the future of disease targeted and disease-modifying therapies. It's going to be really exciting to see how the genetic therapies, the ASOs and the other gene therapies for monogenetic disorders turn out. I mean, I have to say, again, I'm just flabbergasted by how much progress we've made and how much we have the potential to make in the near future with the programs that are ongoing now, and I hear about exciting programs every day. The wonderful thing about epilepsy is that it comes in so many -- I think other panelists have mentioned this before -- so many shapes and sizes and causes and consequences. And it's not going to be a single magic bullet. It's going to be many different shots on goal. And we've already seen that that are going to give the solutions. But little by little, we're going to see more and more and more people come under control with the therapies that are available. And the thing that has fueled me through my entire career of epilepsy is that for many people, you take away their symptom of seizures and you take away their medical condition, and they can go back to a life of perfect health and perfect quality. And that is not an opportunity you get in a lot of diseases. So -- and for the children, and I think Simon touched on this, with epileptic encephalopathy, in some cases, we're finding out now that even an antiseizure drug given at the correct time during the development of the disease, can actually rescue that child from a life of not only seizures, but a life of developmental delay and comorbidities. So I just encourage everybody to keep going.

Thank you very much, everyone, for participating in the panel. It's definitely an exciting time for epilepsy and in seizure disorders. And the progress that I've just seen in a handful of years is impressive. So thank you, everyone, for participating.

Thanks, Tim.

Thank you, everyone.

Thanks, everyone.

Good seeing you.