Welcome, everyone. I'm Yigal Nochomovitz, one of the biotech analysts at Citi. My pleasure to have with me, my colleague, Samantha Semenkow, recently rejoined Citi as a senior analyst. This is the Rare Neuro Panel, and it's my pleasure to have with me, two distinguished CEOs in the space, Carole Ben-Maimon, the CEO of Larimar, and Emil Kakkis, the CEO of Ultragenyx. Welcome, both of you. Thank you very much for taking the time. Maybe just to start out, if you could just give a very brief, you know, two or three-minute overview of some of the rare neurology programs that you're focused on. Then from there, we can move into some more thematic questions related to development of drugs for rare neurology. So, Emil, you want to start? You want me to start first? Okay. Sure. Well, good morning, everyone. So I'm Emil Kakkis, CEO of Ultragenyx, and we've been formed about 13 years ago and have been building a portfolio of, of products in the inborn errors, bone, endocrine, and neurology. In the neurology space, our most important program is the Angelman program, and antisense oligonucleotide for Angelman, and we'll probably talk more about that as we get through the questions today. The first opportunity to turn on expression of genes in the brain and potentially change the future for a disease with developmental delay and a number of other abnormalities related to the Angelman syndrome, genetic defects. In addition to that, we're working on several other neurogenetic disorders. We have a gene therapy for CDKL5 deficiency that is heading to the clinic soon. It's basically an enzyme replacement into the brain with a AAV gene therapy. In addition to that, in the non-clinical stage, we're working on a prodrug for creatine transporter deficiency and a prodrug for GNE myopathy, both neuromuscular disorders, and we have a gene therapy for Duchenne muscular dystrophy that is a bit further back, but coming. And it gives us a number of possibilities, both in the brain as well as muscle, part of neurogenetics. So that's where our big story. We'll probably talk more about Angelman today. I'm Carole Ben-Maimon, CEO of Larimar Therapeutics. We are a clinical biotechnology company. We have a platform that allows us to deliver cargo across cell membranes. Our lead program is, we call it CTI-1601. It's for Friedreich's ataxia, which is a disease that is autosomal recessive and occurs where children are born looking relatively healthy. They get clumsy in their around puberty, wheelchairs in their twenties and thirties, and they die in their thirties and forties. They die from heart disease, and it's caused by a missing protein called frataxin. Frataxin is actually active inside the mitochondria. The challenge is to bring the protein across the cell membrane and across the mitochondria, and that's what our technology allows us to do. We have completed our phase I program. We showed increases in frataxin, in buccal cells and skin biopsies in a dose-dependent manner. We are now conducting a phase II dose exploration study that is ongoing. We have completed the 25 mg dose, which also showed increases in frataxin, and this is actually a very low dose. We weren't surprised by that, but we did see significant increases in frataxin at day 14, and then at day 28, after going to every other day, we saw a decrease. So we are now initiating a 50-mg cohort in that study, as well as initiating our open label extension study, which will allow us to dose 25 milligrams daily for an ongoing period. Which is really exciting because we'll get to see real-world use of the drug, where the patients take it home with them, they use it at home, and we'll get long-term frataxin data out of that study. So we're very excited where we are in the clinic. We're looking at some other diseases. We have not disclosed those as of yet, as we expand out the pipeline. So let's talk a little bit high level in terms of some of the developments in the, in the rare neuro space. There have been a lot of interesting approvals. Obviously, you mentioned FA, and we saw the approval of SKYCLARYS for Reata, but there have been others, RELYVRIO, QALSODY, DAYBUE, SKYSONA. So there's been quite a few this year. So I just wanted to get a sense from you in terms of, you know, what are the implications and learnings from these approvals, and, you know, what's your read on the FDA's willingness to exercise regulatory flexibility in some of these rare or some not so rare neuro diseases? What are your thoughts there? Well, I would say my experience is that a change in leadership within the neuroscience divisions has had an impact. Billy Dunn has left, and also a guy named Eric Bastings that were both there. Teresa Buracchio is now the head of it, and she's been making those decisions that you're talking about, and I think she's done a terrific job at seeing through all the data and applying the appropriate scientific insight to make good decisions. And I think this, it bodes well for us. I think the neurology area has been difficult in the past because of the way it was regulated, and we've certainly seen improvement in our relationship over in the Angelman program in this timeframe, and I think that, I'm encouraged. But it does show you how important one person can be and, and how the regulation works. And I think that they've made good decisions on those programs in difficult areas. In neurology, of all the areas, I respect how difficult it is to change your brain of a kid with a terrible disease, and I'm encouraged for what's gonna come forward if they continue the, the trend that they're showing us now. Yeah, I think we see very positive relationships with the agency. I've been working with the neuro division since longer than I want to admit, back to Paul Leber. And it has definitely been a transition and a recognition of the need to look at things more in a more novel way. I think Billy Dunn was amongst those who actually felt that way. I think clearly some of the Reata approval was probably under his. You know, he left the day after or the day before, but he obviously had an input. And I think Teresa is continuing. Teresa Buracchio, I totally agree, is continuing that flexibility. I think it's what's really important is building a data package. I think what we talk about flexibility, but I think what they are actually doing, and I think is really important, is looking at the whole data package and not focusing so much on the primary endpoint of a single study. And I think that's if they can maintain that attitude, that mechanism of action plays into this, biomarkers play into this, patient input, you know, and they can really start to look at the data package that's being submitted and developed. I think we'll see good things coming out, not only the neuro division, but some other divisions at the agency. You make a good point, you know, in taking that into account, when you're designing the trials, how do you approach those endpoint selections, both the primary as well as some of those, additional endpoints for that data package? And, you know, how do biomarkers fit into, that package? And how do you convince the FDA that those biomarkers are actually relevant, and, you know, tie that all up when you're actually designing the trials at the end of the day, you have that data package? Is that for me first? Okay, you want me to go first? Sure. So we're in a—we have the luxury of working in a disease space that we know the cause of the disease. So it's not like some of the other, more troubling diseases that we have to deal with in neuro or in other diseases, even muscular dystrophy and some of the others, where there's not necessarily. They're hypotheses, but there's not necessarily these very clear, direct links. In FA, the cause of this disease is deficiency in frataxin. Now, then the question comes, "Okay, you can increase frataxin, but can you increase it in the target tissues? Once you increase it, is it doing anything?" And so that's where I think the biomarkers really come into play, because if you can show you're increasing it, and now you can show you have an effect on something physiologic, we're looking at gene expression and lipid levels, which are completely off in these patients. The lipid profiles in these patients are very abnormal. So now you say you increase it, and you're normalizing something, or at least making it more normal, you really start to answer some of those questions. And that's why I say to me, it's really all about a data package. You're gonna have to have a clinical outcome, there's no question, you're gonna have to see something over a longer term that translates. But building that mechanism of action, fixing the problem, then looking at activity, starting to build all that package together, starts to really make it possible to convince not only regulators, but scientists, that the molecule is likely to be effective. So I think it's a combination of things, Samantha, that include clinical outcomes for sure, but also all of these other things that go into a development program. In the area of biomarkers, I think there's still a lot of room for approval, improvement. But the neurofilament story, which is part of the story with ALS, I think that's been building for a while, and neurofilament is really more of a downstream marker of injury, and the appreciation that less injury over time should result in less neurofilament release and the importance of that. I think it's an important step forward for the FDA to kind of include that mechanistic piece in the total picture. So I think that's what Samantha is saying. I think that piece is adding to what you see clinically. We need the FDA to do more on biomarkers, particularly in neurologic disorders. We've had a lot of discussions. Now, in Angelman, there are no good biomarkers, but in other programs, for example, some of the disorders that have been inborn errors related, there are a lot of good biomarkers, and the FDA has been more resistant. I've been leading a group to try to put more pressure upon them to use the good science and qualify those biomarkers because I think they're very relevant. For example, a disease like Sanfilippo syndrome, which I forgot to mention earlier, which is a late-stage program, but obviously good biomarkers there. You could do clinical, but the clinical takes several years. The biomarkers give you answers in a much shorter period of time, so with a lot less variation and complexity. So I do think that the total picture matters, but the difficulty is, in neurology, if most of your treatment is doing is preventing decline, and decline takes a couple of years or three years to do, doing long randomized studies where the control group is gonna have to lose their life, is a very difficult thing to do, and this is true in some of the neurogenetics, sort of like Sanfilippo or a randomized control group, is basically their opportunity to be treated and die. It's impossible to do a study in that way. Natural history control studies have been very difficult to do. So if you have a clinical endpoint, you wanna have a natural history control for diseases that take two, three, four, five years to show progression, it's been very hard to do. It's all the situations where that has worked, which is like CLN2 or Pompe disease. In those situations, the decline rate within a year or two, right? It goes from nothing to horrible within a year or two. In that setting, the natural history controls have resulted in approvals, but anything taking two to five years in time, it's been very hard to get agreement on a natural history control. So we're gonna have to figure out this piece. How did you design with clinical endpoints that the control group is not being-- losing their lives over it? Which 'cause I just don't think no one believes that that's the right way, that we, as scientists and drug developers, should have a better way of figuring out if a drug works without having some kids get sacrificed in the process. I don't think all the agency yet fully appreciate that as one of the points of contention. So natural history control can be part of it, but I do think if you bring the biomarkers with some early clinical data, you should be able to enable more approvals, and I think that's an area for further improvement, particularly in some of the inborn errors, where the biomarkers are straight up the material accumulating because of the block. It's not so hard to imagine when you know exactly what the block is and what the biomarker comes from, to predict that this is gonna be better if you reduce this accumulating compound. So I think there's a lot of good things have happened, but I do think there's a lot of room for improvement on biomarkers, particularly in the neurology area. So if you can, if you can do a faster study, like you mentioned, I think you said Pompe, where the, you know, the decay on the natural history is fast enough to make it tractable, that's great. But what about other types of studies where you need to do a placebo for a rare neuro indication? How do you think about that? Would is that something I know it may be relevant potentially for your GTX-102 program, not necessarily just for Angelman's, but in general, I mean, how do you think about a placebo-controlled trial in these types of rare settings? I think the fundamental ethical question is: Is the control group gonna lose their opportunity to ever be treated and be permanently damaged by being in a trial? That's the fundamental question. In the Angelman syndrome, it is not a progressive disease. They are not losing function. They're not gonna be damaged by being in a trial for a six month or a year period, which would be looking at our data long enough to see the clinical effect. Now, the thing in Angelman that's very important is we're seeing improvement. We're not seeing just lack of decline. We're actually seeing improvement, which gives you more ability to see a change. So in Angelman syndrome, we have said we're supportive of doing a randomized controlled trial 'cause we can, and we can do it without harming kids, and we had that discussion with the FDA, and they were pleased. They were thinking maybe we were gonna try to go non-controlled, but I think in this situation, you should do a controlled trial 'cause you can. That means some patients are getting placebo intrathecal injections, but I don't think - I think that's the level of sacrifice I think we need to do, 'cause the benefit to those patients is they will cross over on the drug, which means they'll get access to to potential treatment way ahead of anyone else. So that's what they give up, but what they gain as well. In other disorders like Sanfilippo, it is not—it's unconscionable to put kids and have the control group, as currently apparently proposed, to have a kick-out of the placebo group if an individual reaches 15% brain damage, apparently is the 15 or 20% brain damage, then they can exit. What people don't realize, by the time they have that much damage, they've lost the window to actually save them. That means their brain is already on the decline stage, and treating them late will not save them. So what's really happened is they're. And the other truth about that program is you're trying to stabilize. So in order for the trial to win, the control group has to decline. That's the only way the trial works. It's not like if they decline, they must decline in order for the treatment to be approved. So what you're really doing is saying this control group is all condemned to death, and that's just not okay. So that's fundamental with this. We're very much, we have done many randomized placebo-controlled trials where the control group is not gonna be harmed by doing this. They may be delayed, they may have some inconvenience, but they're not gonna be harmed. I think we, as a society, have to come up with better ways to assess science than doing an experiment that harms people. Yeah, we have a little bit of a different situation. First of all, SKYCLARYS, Omaveloxolone, has been approved, and as a new drug that actually changes the progression rate, you take a slowly progressive disease and now slow it down even more, and now you're gonna have to do an even longer trial to show whether or not you have an impact on top of it. And the question, if you exclude patients from taking OMAV, is that ethical, right? Because there's one drug out there, there's nothing else for these people. With FA also, it is a slowly progressive disease, and if you can measure something in two or three years, it isn't reversible, but you could still potentially intervene and prevent further decline. Also, many of these patients are adults and not children, although the earlier you treat, the more likely you are to have an effect. But we haven't really had the conversations yet with FDA as to what will constitute an endpoint in our development program 'cause we're still so early. But I totally agree with you. There's gotta be some ethics that play into this that we just can't ignore. And it's not. It's in a lot of diseases. Most of these diseases are not reversible. So whatever decline the placebo group has, they're gonna have to live with for the rest of their lives, and that has to be taken into account. And I think the FDA is much more open to hearing those arguments. I also think the patient community has become much more sophisticated at how to lobby FDA, not only as individual diseases, which I think has been the problem in the past, but sort of banding together in groups. I think just DMD alone has had a huge effect on other communities and their openness to hearing things, but I think patient advocacy groups also play a huge role. And we've talked a lot about U.S., but the problem is just as big in Europe, as it is in the U.S., and needs to be really taken into account as well, because in Europe, biomarkers are really even more challenging, than they are in the U.S. And these populations obviously exist in places not only, in the U.S., but around the world. I think in Europe it's really been evolving, too. Yeah. The MHRA was a very strong and rational voice within EMA, and now they're not part of EMA. So- Yeah I think you're seeing a little more of replication of U.S. views in the rest of EMA. Yep. That's a loss. In the Mepsevii program, for example, we got EMA scientific advice that allowed a biomarker primary endpoint- Mm-hmm Just because of the rare disease, and FDA had rejected that. But I think that's changed now. That might not have happened these days. So EMA as an organization has changed a lot. MHRA was really the premier organization that had a highly experienced crew, people that were very knowledgeable. And I think the EMA has changed because of the loss of the MHRA as part of that group. Yeah. I think also we see differences even between different countries, even within EMA. Mm-hmm. Obviously, the scientific voice is consensus, but we, if you really talk directly to the individual regulatory authorities, there are differences. And I think, you know, I've seen for over the decades, as I'm sure you have, a lot of times it waxes and wanes. What FDA is doing when they're progressive, Europe becomes less progressive, and vice versa. It's really kind of a seesaw of effects. Agreed. How do you think about patient identification for your studies? Like, Carole, I feel like you're in a maybe more fortunate situation with Friedreich's ataxia, a very strong patient community, strong patient advocacy. So how do you think about it from that perspective, in the context of Omaveloxolone recently being approved, all the way down with really rare neuro diseases where patient identification is more challenging, and how do you, you know, design your trials and find the patients across that spectrum? Yeah, I think FA is a different animal than a lot of rare diseases for a whole host of reasons. The advocacy group is clearly one of them, but the disease is very easily diagnosed. I mean, it takes a couple of years sometimes because people think they're just weird kids. But eventually, when they get to the neurologist, there are pathognomonic physical signs and it gets diagnosed. And then there's a blood test, which is also easy, and it's a we know the cause. I think in other rare diseases, it is a much bigger challenge, especially underdiagnosed. And the other problem we have in FA is it's very territorial. There are populations in the United States, in Europe, and in Australia. It does not exist in Asia, in most of South America, a little bit in Brazil, but only a few patients. And then there's a smattering, there's a population in Canada. So we're, you know, when Omaveloxolone got approved, we're really limited at where else. You know, it's not like you can just go to another territory and do a, do a study that's powered. There just aren't enough patients, which is the other thing that we're, we're sort of thinking about and wrestling with, but I think you probably have a lot more experience with some of these other diseases than I do. Yeah. Well, there's a lot of variation between types of disease. I mean, Angelman has a very strong patient advocacy activity and has some distinctive neurologic features, but it can take a while for some of them to get diagnosed. But I don't think patient ID has been a problem for us in that program. I think the bigger problem comes in things like Sanfilippo syndrome, for example, where the first couple of years are the critical period. You really need to treat before two years, but the diagnosis may not come until they're between two and six, and so a lot of the kids will be diagnosed after, and so early diagnosis becomes really critical. In other disorders, like we've worked on the past, like Glut1, for example, a seizure developmental delay, looks like so many other things. If doctors aren't doing panels for genetic typing, then it's not happening. And we found that a lot of insurance companies weren't supporting genetic panels for kids with seizure developmental delay. And really, you can't distinguish. I was a clinician, you can't tell precisely in all these diseases which one it is. It could be a variation of a common one, or it could be an ultra-rare one. You don't know. What we've been doing is supporting free diagnostic testing as part of our patient diagnosis program, which we run out of medical affairs, and we just as we're looking for patients and trying to help doctors get diagnosed, we provide access to free testing to help them find their patients. And we don't just support for our diagnoses; we support just a panel that allows them to cover the differential diagnosis. That costs some money, but in the end, it helps us find patients earlier. And I think that eventually insurance should be covering a neurogenetic panel. If you have a kid who, one, has developmental delay and some other neurogenetic findings, they should be getting screened genetically for the problem, and because it could be very distinct and important things, the time frame may be short for taking action. And with the MPS disorders, there is a big push now for more newborn screening. MPS I is on the RUSP now, and there are methods for doing that. So I think the lysosomal diseases should be closer now to getting panel screening and newborn screening. I think it's a thing that will have to happen because if you're not really symptomatic before age two or you don't have distinctive symptoms, you may not come to saying, "I need a diagnosis," right? It may not be distinctly evident yet, and therefore, you'll miss the window. I think in this situation, newborn screening is gonna be essential for the ultimate, best outcome for those kids. With some movement in newborn screening for some MPS, it's really possible to do essentially all of them. So we hope that that's gonna happen. The EveryLife Foundation has been working on getting RUSP alignment legislation across the country so that every state aligns with the RUSP. If we get every state doing the minimal screening based on the RUSP panel, which is the Secretary's Committee for Newborn Screening, if every state aligns with the federal government, then all we need is change what the federal government committee says, then all the states will align. Instead of doing what we're doing right now, which is every state has, like, a different plan, which is craziness. So the EveryLife's plan was to get all the states to align with the RUSP and then make the RUSP the single national focus on newborn screening, at least for the minimum, so that everyone at least is screening a certain set of diseases, particularly ones where treatment early is critical and where diagnosis is often delayed past that critical window. I think that's a big issue also is because the reach has to be out past the academic centers, right? Because these kids are not being followed. So, you know, again, FA sort of has advantages. They don't get diagnosed until six, seven, eight years old, unless, of course, they have a sibling. And then they aren't really in wheelchairs, even if the earliest diagnosis until 11 years past that. So there's plenty of time to intervene. I think the real challenge for us as we look at different opportunities and different pipeline opportunities is how do you get to a kid within the first six months? Most of these kids are seeing primary care docs, and then they get referred, and, like you're saying, by the time they get diagnosed, there's not really much you can do. And so these diseases that really move quickly early in life are much more challenging, I think, from the standpoint of patient identification. Maybe we can spend a little more time on specific programs for each of your companies in the last 15 minutes. So, Emil, just on Angelman's and GTX-102, if we can just drill down a little bit more there. If you could sort of put the efficacy data in context for what you've shown so far. You've reported data across a wide variety of scales, Bayley, CGI, Vineland, I think also ORCA. Where would you like to direct investors' attention in terms of which scales are most relevant for determining efficacy? And what would you consider to be clinically meaningful on these different scales? Well, first of all, Angelman syndrome is a complex multi-domain disease. It has many different domains of dysfunction, and our view is that efficacy should be looked across those domains. Our preference and the primary endpoint that captures either a multi-domain responder index-type endpoint, where we're looking across five domains, or the version the FDA has accepted so far is a CGI score, which is a little bit of a multi-domain assessment, is another approach which was accepted for the Ovid Angelman trial, but also as part of the Rett approval, was one of their co-primaries. So the CGI multi-domain would be the best way to capture multiple domains. We're more proponent of the multi-domain responder index. We've written a paper on it. It means you would look at, let's say, five domains and pick a score like Bayley, you know, it could be an Angelman severity scale, Vineland, or special behavior scale, et cetera. There's several scales, and each scale then is scored based on whether they have a, an important difference or not. And that approach is very powerful. It allows for heterogeneity in the population, and you can have responses in some patients in these two domains or three domains and some in the other domains. It allows you to capture the efficacy, I think, in a very powerful way, and we think that's the best strategy. But the FDA hasn't quite accepted it. We've had meetings and even had a big group meeting with agency about it. I think they're intrigued by it because it sort of allows all comers into the trial. You don't have to select based on what the primary is. You can just accept everyone, and that's a feature of the multi-domain responder next, treat the people the way they are, rather than picking the ones that match the endpoint you're picking. So the underpinnings of Angelman assessment, though, is to look at the domains that are important to parents. One of them is communication, both receptive and expressive. These kids often don't hear their name or understand their name, don't learn their own name. They don't understand instructions, right? Everything is done by showing them because they just have no language or auditory communication. That's important. Expressive communication, being able to express your wants, not just saying words, but saying words or pointing, creating other gestures that communicate. We take that for granted, but these kids can't do that, right? So those are all important. So communication is certainly important domain. Behavior, a lot of the kids have very aberrant behavior that can be very disruptive, some more than others. Some kids scratch and pull hair of other kids. They're not trying to hurt them, they're trying to communicate, but they don't know how, and that is their reaction. Reduction of that is very important for parents because if they're not just, you know, scaring other kids, then they can go to someone's house, for example, and not have a problem. So aberrant behavior is another type of a domain of issue. Beyond that, I think things like sleep are really important. These kids have trouble sleeping. It's probably disrupts their whole day when they haven't slept, but they have trouble. Some kids have terrible problems with sleep, some less so. But sleep is an important one. We have the Angelman Severity Assessment. It's a developed scale for sleep problems in Angelman syndrome. Fine motor, the kids don't use a pincer grasp. They grab with a fist. They can't do fine control. For example, they can't feed themselves with a fork by spearing the food and putting it in their mouth, right? They just claw at it. They don't know how to do it. But we've seen the ability to start using a fork, grabbing with the right grasp, and poking the food and eating it, and feeding yourself. So that's really important type of function. Gross motor for Angelman, they have an ataxia that is very distinctive. This is why they have a very wide-based gait, and they have their arms out wide. It used to be said they sort of walk as if they're a marionette, that someone is moving their arms and legs. Very distinctive walk, and they fall down a lot for that reason. Their proprioception, how they put their foot on the ground is not well. So if there's any bumps or an unevenness, they'll trip and fall. Walking on something like grass or uneven surface, very difficult for an Angelman syndrome, so the kids fall down all the time. It means you're helping them up all the time, and they're getting hurt because of it. So being able to run or work, play in the grass, for example, and not fall down constantly, those are all gross motor-type improvements that I think would be important. So these are all these different things, and some kids have more of one problem than the other. We're talking about kids who have the same deletion genetic type, right? So their fundamental genetic defect is the same, nearly the same, but how it manifests depends on all the other genetics of the brain. The brain expresses 10x more genes than anywhere else in the body, right? That's how much more complicated the brain is. So there's so many other genetic loci that will affect expression, that all genetic diseases have that much heterogeneity. And we have to be able to design endpoints that manage the heterogeneity and allow you to capture efficacy, heterogeneity in manifestations, the heterogeneity in progression, heterogeneity in responsiveness, and irreversibility and reversibility. So is what makes it challenging. But fortunately, for Angelman, we see kids getting better. And in neurology, if you can see things getting better, it's a whole different game than just preventing decline. Well, how much more work do you have to do to help get the FDA over the hump in terms of accepting this multi-domain responder index? What other arguments do you need to make, or is it just a matter of showing them more data, or? I think we haven't really debated yet, Andrea, with our division. We've been talking to the FDA at a higher level. We have to show them the data we have. Right. We haven't brought them enough data yet. Okay. Last year, we spent time, and this year, titrating, optimizing. We're now expanding a cohort at a, what we think is a nominal, dose for loading, and that's going on right now. We'll certainly have the data we already have from extension patients that we can use to help support an approach. But our point would be to have a larger body of patients, ultimately 30 or 40 patients, who've been treated in a more consistent way. That would give us the kind of data set that would allow us to look at the endpoint a number of ways and show them why a multi-domain responder index actually is giving you an accurate and meaningful, analysis of the data. But remember, the multi-domain responder is all the underpinning endpoints are still in the study, so you don't lose them. It's just a way of analyzing them that allows you to capture the totality of data in a mathematically accurate way. But the other endpoints are there for evaluation, too. So I think we have made progress on understanding the multi-domain nature. They know it's complicated. They've asked us to see the clinical outcome group, which we will this year, and start that process. But for the first approval of Angelman, of this type of treatment, I think, you know, we're comfortable with trying to blaze a trail. We've done it in other rare diseases that have never had any trials before, and it takes developing the data. I think we have a lot of good data to give us, I think, many options, actually, on endpoints. Carol, so you mentioned in your intro that the 25-mg cohort efficacy and safety data that, that you saw. I'm wondering, you know, how does that data influence your expectations for the 50-mg cohort, which I, which I believe you're gonna start in the near term? And what do you need to see in that cohort to convince you that that should be your go-forward dose? Yeah, so we're very optimistic, and we have data from our MAD study on the 50 mg for seven days that clearly shows a significant increase in frataxin, more dramatic than what we saw in the 25, even for 14 days, but also... And so I think we're very hopeful about the 50 mg. Obviously... It's experimentation, so things can happen. But we're very optimistic about the 50 mg. When it comes to exactly where do we need to go, we've actually done an analysis where we looked at the age of onset for various patients, their change in FARS by year, and it's actually FARS, not mFARS, because it's older data, and then the frataxin levels. And there's a clear correlation and a continuum. Patients who have onset of disease earlier have lower frataxin levels and a much faster rate of progression. I think, quite honestly, any measurable increase in frataxin is worth pursuing because it may not halt the disease, but it will slow disease, and it's already a slowly progressive disease, and that gives more time for more innovation and more experimentation and more dose escalation. I think at least we don't wanna throw the baby out with the bathwater. It would be great to get to heterozygous levels of 50%, but getting to 30 or 40% will probably still likely impact the disease progression and shouldn't be dismissed as, as useless. It could be very useful. And then, in combination with some of the other therapies that are now in development and coming out, you may actually really be able to impact the quality of life of these people for the long term. So we're very hopeful. I think we're actually, quite honestly, as excited, though, about the open-label extension, because, like I said, we're gonna have patients who are, for the first time, taking the drug home with them. We think it signals that the FDA actually saw the frataxin level increase. They would not be allowing us to go into an open-label extension trial, and have patients exposed to all the trials and tribulations and problems and risks associated with clinical trials if they didn't think there was a potential for benefit. and so we're actually very excited to see what happens over the long term in that open-label extension. It was a commitment we made to these patients, as you were just alluding to, that if they were gonna participate in our placebo-controlled trials, they would have access to drug, and it's taken us a while to get there, and so we're very excited to be in open-label extension as well and give these patients access. Yeah, I agree. I was very excited- Yeah To see you announce the open-label extension, particularly daily dosing- Yeah For an extended period of time. A long time. You know, can you talk about the data that we're gonna get from the open-label extension, when we'll see it, and how you expect that to inform- Yeah Future potential development? So we start enrolling in the Q1 of next year. It's an academic center study, so it takes a little longer to get all the bureaucracy done. And our first cut of the data will be the Q4 of next year. And it'll be frataxin, obviously, safety, and any other biomarker data that we might have as we start to move through the program with gene expression and lipid data. And then, obviously, it will have some insight into use, you know, compliance and things like that, which are really important with an injectable drug in this population. It's not insignificant that they have limited dexterity. Our patients are pretty progressed. More than 50% of them are in wheelchairs already. And so they do get upper limb dexterity problems, so we wanna make sure caregivers can administer it, and if not, patients can administer it themselves. So getting that experience is really critical to long-term success. Great. And you talked a bit about the potential for background OMAV in the open-label extension, but the question is, is 1601 safe with OMAV? Can you talk about some of your efforts to sort that out, and when will you speak with the FDA? Yeah. I mean, given the effect of OMAV on a lot of the cytochrome P450 system, and drug interactions, we wanna be really careful. And so we are doing drug-drug interaction studies of our own. That data should be coming in the H2 of this year, relatively soon. That data will get submitted to FDA. We are having conversations with FDA about how we might think about including patients. It's obviously gonna complicate things somewhat, but we wanna make sure that we understand our safety profile, and we also get over the hump with their safety, disabled and liver function increases and all that. So we wanna make sure that patients are stable, and that all has come to sort of a good place, and then we can start drug. We're thinking about it. We're talking to the FDA. We'll make sure they're on board, but those conversations are just going on. Looking forward to this evidence. Just, I'll try to squeeze in one more for Emil on Angelman. So you have an Analyst Day or R&D Day next month, where I believe you're gonna make some comments about Angelman's, but sort of broad comments. And then next year you're gonna have a more detailed unveiling of the expansion data. So could you just kind of describe that in a little bit more detail? And, you know, what's kind of the trigger in terms of what you wanna see from the totality of the evidence for Angelman's to really have the conviction to move into pivotal? Yeah. So in October, our Analyst Day will focus on the extension patients who have been titrating and been treated for a period of time now, as well as the few patients from the first group of patients that have been redosed. We'll focus on data, and then we'll cover some values from the endpoints, as well as the clinical influence of what's happening to them. And I think it should be a meaningful update on what's going on in the program. We're gonna push out the expansion data patients, mainly because we wouldn't have maybe 8-10 patients with data through six months of treatment by the end of the year. And so our feeling was it was just too small a set. We haven't seen data yet, but it's just not enough in. But because a lot of patients got enrolled in July, we have well more than 20 already enrolled. We should be able to provide then data on 20 early in the year, and that was what we pushed out. I think getting 20 or more patients worth of data will give you a kind of a handle on what's happening, and so that's... We'll push out the expansion then. But the data in October will include a significant amount of data from the current extension patients and the redosing patients, and I think provide a meaningful update on how the drug's doing and what we expect from the drug, and a little bit about how we expect a trial to be designed and the kind of things we will be measuring. Perfect. All right. Well, we're out of time. Thank you both very much. Thank you. A lot of fun. Thanks for having us. Thank you. Good luck with the conference.