Welcome to the Longboard Pharmaceuticals' 2023 Investor and Analyst Event. I'm Kevin Lind, President and CEO of Longboard. It's very nice to see all of you here in person, and I want to extend a welcome to all of the people online as well. We're very excited about this event because it's our first official in-person investor and analyst day that we've hosted as a company, and we're looking forward to framing what we believe is an extraordinary opportunity for LP352, a best-in-class 5-HT2C superagonist, currently being evaluated in the PACIFIC Study, with top-line data expected in January, a major catalyst for the company and what we've been working on since our inception in 2020. I'm enthusiastic to kick off the event, but before we begin, I'd like to remind you that we will be making forward-looking statements. These forward-looking statements include substantial risks and uncertainties that could cause material changes. Please see our full risk factors described in the company's reports filed with the SEC. I want to start off by thanking our external speakers, Gabi Conecker, Executive Director of DEE-P Connections, and the Chair of the Epilepsy Leadership Council, and Dr. Dennis Dlugos, Professor of Neurology and Pediatrics at Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Director of the Section of Clinical Neurophysiology and the Epilepsy Clinical Neurophysiology Fellowship, VP of the Epilepsy Study Consortium, and leading investigator of the PACIFIC Study. We're incredibly appreciative of your attendance. We know how much you do for patients in the community, and taking time away from that means a lot to us. I also want to introduce our Longboard team members that are joining us in the room today, Dr. Randall Kaye, our CMO, Brandi Roberts, our CFO, Chad Orevillo, our Head of Operations, Steven Spector, Head of BD and General Counsel, and Megan Knight, Head of IR. Today, we begin with an introduction to Longboard, our mission, and how we plan to deliver long-term shareholder value. Gabi Conecker will share her story and her role in advocacy leadership, as well as discuss the unmet need in the refractory epilepsy space and some great initiatives she and DEE-P are working on. Then Dr. Dlugos will cover the importance of the Epilepsy Study Consortium, how physicians are evaluating and treating patients, and the need to improve the treatment paradigm. Our CMO, Randall Kaye, will then cover LP352 and highlight the unique attributes of the molecule and design and objectives of the PACIFIC Study. I will then provide an overview of the commercial opportunity for LP352. We'll then have a Q&A session and end with a few concluding remarks. To our virtual attendees, you can submit questions via the Q&A box on the webcast at any point during the presentations. For our in-person attendees, we'll be running microphones in the room and ask that you limit your questions to one or two per turn. A copy of today's presentation is available on the Investor Relations section of the Longboard website and under the Events Presentations tab for those of you who are participating virtually. Now, let's get started. It's such a privilege to be here today to provide an update on what's been a seven-year journey for me and almost a three-year journey for some of you. When I joined Arena Pharmaceuticals in 2016, we had a strong belief that differentiated pharmacology mattered, that molecules with greater selectivity, specificity, and target engagement could translate into commercially differentiated best-in-class products. By 2020, when we spun Longboard out of Arena, we had even greater conviction in that belief. I'm incredibly pleased with the progress we've made since the spin-out. We have multiple potential best-in-class programs, and we're on the cusp of generating value inflection data for LP352 and LP659. We're going to spend today talking about the promise of LP352 as we prepare for data in January 2024. However, I'd be remiss if I didn't also mention how excited we are for LP659, our centrally acting S1P receptor modulator, as it enters phase I SAD trials later this year. Our goal today is to have everyone walk away from this event with an understanding of the following key themes for LP352. First, a tremendous unmet need exists in the treatment of the DEE space, both for DEEs with recently approved novel therapeutics and the broader DEE patient population. Second, polytherapy will continue to be the standard of care for DEE patients, and we believe that a safer, efficacious 5-HT2C with a more acceptable burden profile will be highly desired by patients, healthcare providers, and caregivers. And third, LP352 is a potential blockbuster, best-in-class molecule that is the result of over 20 years of research with differentiated selectivity and specificity, which we believe enables us to provide significant benefits over the currently available therapies and expand the market to a broader patient population. To frame the conversation today, DEEs commonly begin in infancy or childhood and are associated with frequent seizures of multiple types, intellectual disability, and significant developmental delays. We tend to talk about seizures and the importance of reducing seizures, but the reach extends far beyond seizures, as Gabi will talk about shortly. As a result, the goal of treatment goes beyond just seizure reduction. Caregivers, families, and healthcare providers look at the combination of safety, efficacy, and burden or hassle factor associated with each medication as they try to determine the best polytherapy option for their patient or loved one. Currently, there are over 25 DEE syndromes. Traditional drug development has focused on the larger DEE syndromes. As a result, there are multiple approved therapies for Dravet, Lennox-Gastaut, CDD, and Tuberous Sclerosis. We think there's a better approach that is far more fair to the DEE community, that would result in an adequate safety and efficacy information package across the DEE spectrum. So with that, I'd like to introduce Gabi Conecker. I've heard Gabi talk about her journey as a mom, a patient advocate for people living with DEEs, and as a healthcare professional. I'm so excited for her to share her journey with you today, because it will help you understand why we are so passionate and committed to what we are doing at Longboard. Gabi? Thank you so much, Kevin. It's really a pleasure to be here with you all today, and I know it's weird I still wear a mask, but you'll see why in just a minute. So thank you for having me. It's really important for me to be here with you all talking about this today, because I live in a space where every day I hear from families who are struggling with DEEs and who are lost and scared, and their children are dying. Just this morning, I had to post a remembrance of a child, 19 months old, who passed away in Turkey because there were no cures, there are no treatments that are really adequately caring for or treating our children. So, I am, first of all, a mom to 10-year-old Elliot, who you'll meet in just a second. But I'm also the co-founder and executive director of three distinct organizations under our foundation, Decoding Developmental Epilepsies, which look at specifically my son's disorder, which is SCN8A DEE. And then I'll tell you a little bit more about our collaborative efforts as we keep talking. So meet my son, Elliot. As I mentioned, Elliot is 10 years old, and he is incredible. He is the strongest human I've ever met. These children endure more than you could probably ever imagine in their short lives. Elliot has been hospitalized over 25 times. In his early life, he was in the code room three times, and there were many times when we thought we were going to lose him. He works incredibly hard. You can see this picture of him on the left here. He is working on his head control. He is inching towards head control, which he has been working on for 10 years, and every little bit of progress counts, and I, I want to celebrate that every single day, and we all celebrate our children and these inchstones that they make throughout their lives. As you can see, he's in the middle picture, he's in a stander. He cannot stand on his own. He does not have, you know, trunk control, head control, but he is a really sweet kid, and we feel really lucky to be his parents and that we get to care for him. I want to show you especially what Elliot's early years looked like. Elliot was born on his due date. He was perfect, but labor was very, very challenging. I was in labor for many days, and we couldn't figure out what was going on. He came out, he was beautiful. He started having weird movements, movements right away, that we kept bringing up to the pediatrician and saying: "Something isn't right. He keeps doing these movements. It looks like he's scared, and he's falling all the time." And I knew nothing. You know, my background is I have a master's in public health. I worked in international health for 20-something years, but I'd never seen anything like this, and I was not prepared for anything like this. So very quickly, it became clear that Elliot was struggling with a lot of really challenging things. He never met a developmental milestone. He was having what turned out to be infantile spasms, which went undiagnosed for many months and was on the inappropriate treatments for many months. And we, as I mentioned, were hospitalized quite frequently. First it was seizures that were not controllable, and then we got on cocktails of two and three and four and five medications, which helped some, but also heavily, heavily sedated Elliot. To this day, he is still on four anti-seizure medications, and I'm not sure I really know who he is because he is, he's drugged very heavily at all times to try to keep the seizures at bay. That also morphed into really intense, respiratory challenges for Elliot. He is severely hypotonic, so his muscle tone is very, very low, and so he cannot cough. You know, I wear a mask because if I bring something home, it means that Elliot will probably be in the ICU, intubated for a number of weeks and hopefully would survive, but we don't know if he would. We still are very cautious. We've lived that way for 10 years, frankly, even before COVID. This picture here shows some of what we've gone through. Elliot still gets hospitalized. Elliot still struggles with respiratory, respiratory challenges. He still struggles with seizures, despite being on 4 anti-seizure medications, none of which are indicated for his disorder, by the way, right? Many of the ones that he is on are 20 years old, right, and really are very general drugs that are not really meant for the kind of genetic epilepsies that we're seeing today. We know that what's on the horizon is much more targeted treatment, much more... Genetic therapies that are going to hopefully be targeting the specific disorders instead of putting band-aids on the seizures, which is really, that's all these drugs do, are they're band-aids for the seizures, and we're not really getting to the root of the, of the challenges for our kids. So I want to just give you a picture into what daily life looks like. Getting here or getting away from home is no easy feat. I had to privately hire a nurse who could help my husband, who's at home alone. Elliot requires 24-hour care. He has to be watched at all times to make sure he's not having seizures. He has to be given flushes through his GJ tube. If you're not familiar with what that is, that is that, Elliot used to get food into his stomach directly through a port, but he cannot empty his stomach fully because, again, he's very hypotonic. His muscles don't work. His systems are all interrupted because of the background of this disorder. So he now has a tube that was surgically placed into his jejunum, and that's where he gets predigested food through every day. So he has to get food slowly. He's on a, a feeding tube, on a pump, getting milk 20 hours a day, 22 hours a day, rather. And throughout the day, we've got to be watching for seizures. We have to be doing flushes, which is what that is, venting. You've probably heard of that. We have to get the air out of his gut. He has a lot of trouble with managing secretions in his mouth, so we have to be suctioning and swabbing his mouth all the time, because if he accidentally aspirates that, that often will lead to a pneumonia. And you can just look at this list and see. He's got—you know, he's still wearing diapers at 10. He has a vision impairment. He can't see. We have extensive therapies that we need to take on. Going to the bathroom every day is an hour's worth of work, two hours worth of work to get that to go. We have to catheterize him. So this is nonstop. When you have a child who has a DEE, you are living minute to minute. You are waiting to see what comes next. You never know. It's very unpredictable, and the time that it takes, the effort that it takes to care for our children is immense. My husband, who was a university professor, had to quit his job to be a full-time caregiver because first of all, the nursing shortage is so intense that there's not really consistent care. And I believe the reason Elliot is still alive is because of the care that we have really given and we've sacrificed a lot for, but he's worth it. He is an incredible kid, and we really love being his parents. So you know, early on, you saw that we had those three logos. Elliot did not get diagnosed until he was about a year and a half old. And before that, we started a foundation. We started to put together a foundation for rare and undiagnosed neurological disorders, which as soon as we got Elliot's SCN8A diagnosis, morphed into what is now the International SCN8A Alliance, which is a global alliance of, you know, partners around the world working to find better treatments, cures, and quality of life for our children with SCN8A. But we learned early on that disorders that have 800 kids, 400 kids, 700 kids, 1,000 kids, we cannot get there one by one. There's so much more support and help that we need. And so we developed something called DEE-P Connections, which is the Developmental and Epileptic Encephalopathy Project. And our mission here is really to provide support and resources and empowerment to caregivers of those who are caring for loved ones with DEEs. The way we do this is that we begun early on by doing webinars for families on critical topics like rescue medications, SUDEP, sudden unexpected death in epilepsy, which takes a fair number of our children. The idea here is that LGS doesn't have to do this alone. Dravet doesn't have to do this alone. KCNQ, CACNA1A, Dup15q, right? You've heard all of these letters and numbers put together, right? Our challenge, or our challenges are very similar across the disorders. The etiology, of course, is important in terms of, you know, how we look at these disorders, but we also have to remember that these are shared experiences. This group of now more than 40 partners works together to provide resources and support to families through our webinars, through support that we offer. But we also recognized very early on that not just is it really important to care for families and caregivers, but we have got to be doing research across the DEEs because there's so much that we can be learning together, and there are a lot of similarities across these disorders. This, the etiology as I mentioned, is important, but we know that there's a lot that is similar across these disorders, and if we are working together, we can get to the finish line faster. So we started something called the Inchstone Project. I mentioned earlier Elliot was moving, inching towards head control. So the Inchstone Project is really looking to work with partners like Longboard and a number of other really committed, industry partners who really get it, that we have got to be more thoughtful about the clinical development route and how we're measuring progress, in our children. The kind of progress that Elliot has made in the last few months in terms of his head control, if that's something that could be captured in an instrument, would be a huge thing to celebrate and, and really acknowledge that there is change. And we're doing this work collaboratively with a team of clinical outcome assessment experts from around the world, and excuse me, very closely with other patient advocacy groups. The idea really is to follow very closely the FDA guidance, PFDD guidances on how to do clinical outcome assessment work and build tools that are psychometrically sound, sensitive to meaningful change, meaningful change that is important to families, right? We know that the FDA has said you have got to be very patient-centric in how you are running your trials and what outcomes you're looking at. We are looking to really learn what families want across the DEEs. We're doing a DEE-wide survey right now. As you might not know, but is true, there's a lot of similarities across these disorders, right? They're looking for the same things, the same kinds of outcomes for their children. Really, this is an equity issue, right? Making sure that every person, no matter their ability, the severity of their disease, can have those inchstones of achievements be counted. And frankly, so we don't leave anything that could potentially help on the cutting room floor. The drug development process is lengthy and expensive, and frankly, I've heard many stories about testing that has been done within clinical trials that shows a real improvement for our kids. They wake up, they are more engaged, they are cognitively more present, but seizure counts aren't good enough, so the drug disappears, and our children go back into their sedated comas of medication. So, you know, we've been doing a lot of advocacy around this, that really we need to be thinking about the inchstones, not just the milestones within these communities, because that's where the progress is, that's where the change is. We know at the end of the day, what we're working to do is improve the quality of life for these families. If you can imagine, this is Anne Berg's, one of our partners in the Inchstone project. You imagine you have this little mouse, and you bring it home, you're so excited to watch it grow, right? You put it on the scale, and every single day you're waiting to see. I can see it growing with my own two eyes, but there's never a change on that scale. We are using the wrong instruments to measure change, right? That's the part, that's the Inchstone project. I wanna just pause, I'm not gonna do any more slides here, to really emphasize that we need to be thinking about this differently. You saw those slides. There are approved treatments for LGS, Dravet, CDD, and Tuberous Sclerosis Complex. Those are the four that have gotten the most attention, but there are dozens and dozens and dozens of other disorders that are out there that have no indications. But we're using those drugs, okay? 'Cause there's no other options out there. Those drugs are being used because we've exhausted every other option. There's, I think, maybe one or two drugs left that we can try with Elliot that we know would be very detrimental to his in many ways, so we haven't tried them. But the newer drugs that are coming out, those are the only other options we have. There's nothing else on the table, and I think we need to start thinking about drug development differently. And I'm really excited about the way that Longboard is approaching this, because basket trials have got to be the way we're thinking about moving forward with the DEEs. I've talked to you a little bit about, you know, why there are so many similarities, and how there are just a possibility that we could be doing more for so many more people if we thought about it in this way. And that's why every time I go to events and I see Randall talk or, you know, I we crisscross a lot. Every time I'm like: Yes, thank you, DEEs. We've got to be thinking about that. If you've seen an LGS trial, you've seen a basket trial, you've seen a cross DEE trial. Those kids have very different etiologies coming into those trials, right? They have SCN8A, they have KCNQ2, they have CACNA1A. Their secondary diagnosis is LGS. So there's a proven track record for this kind of thing that's been seen before. And ultimately, I think that I wanna leave you with a few messages that, you know, my story is really not uncommon. You heard about the struggles of care in daily life for, with Elliot and for my family. It's immense. It's every second of every single day. But there are hundreds of thousands of families out there with children who do not have approved treatments. They deserve better. They deserve something now. And I hate seeing disorder... I mean, drugs that are in trials three years to get one approval. Then they go, and they start again. They're like, "Okay, now let's move to the next indication. Let's move to the next indication." We don't have time. These kids are dying, as evidenced this morning when I had to post about another 19-month-old that died. We've got to think creatively, we've got to move on this, and we have to do it together. That's why I came here today. I made all of the sacrifice and the planning to make this happen, because this is important. I thank you for listening, and I thank you for recognizing that the future has got to be us working together across the DEEs to find better treatments as fast as possible for our kids. Not just to monitor seizures, but can improve quality of life and wake our children up and give us opportunities to give them the experiences that they deserve. Thank you. Thank you so much, Gabi. Every time we speak, I feel like I learn something new about you, Elliot, and your family's journey, so thanks for spending the time. I'd now like to introduce Dr. Dennis Dlugos. We've had the privilege of working with Dr. Dlugos and with the Epilepsy Study Consortium from early on in Longboard's inception. As the principal investigator on the PACIFIC Study, Dr. Dlugos has provided great insight into our study designs and plans for an LP352. Dr. Dlugos? Good morning, everyone. Thanks for being here in person or online. Thank you to Gabi for that such an important introductory talk. As Gabi said, DEEs require creative thinking, and I think Longboard has done that, thinking creatively and rigorously to design the PACIFIC trial that hopefully will open up new avenues for DEE treatment. ... So just quickly about me, I direct the epilepsy program at Children's Hospital of Philadelphia, and I serve as one of the vice presidents of the Epilepsy Study Consortium. So what is the Epilepsy Study Consortium? Well, we're a group of academic investigators that work with study sponsors, study sites, regulatory agencies, and advocacy groups to try to optimize clinical trial methodology, to, as quickly as possible, get valid, effective therapies to patients. One of the many challenges in a clinical trial is site-to-site variability, and the study consortium provides a central review of study participants to try to minimize, reduce at least, site-to-site variability, that may help, as part of other efforts, reduce the placebo response rate. The key is consistency across study sites in a clinical trial. There's obviously a playbook, a protocol, inclusion, exclusion criteria, yet the sites have potential patients, participants, that they have cared for for years through a different lens. They may classify seizures differently, with different terminology, and all of that needs to be harmonized for the clinical trial to be as efficient and effective as possible. There's also the issue of seizure counting. Like it or not, seizure counting will probably remain as part of seizure trials. Some seizures are countable, others are not. It's important to recognize that. It's also important to be consistent. Perfect seizure counting is impossible, but consistent seizure counting is possible and is critical. So those are some of the things we think the study consortium brings to trials. So I'm going to quickly review this DEE term. It's a clumsy term. I want to deconstruct it. Why did the epilepsy community pick developmental and epileptic encephalopathies? There are reasons that have implications for clinical trials, and a lot of potential to help patients. This is epilepsy in one slide. A ridiculous oversimplification, but it highlights a couple of things. At the top, patients with epilepsy have seizures, by definition, which may be focal onset seizures, generalized onset seizures, or we can't tell what type of seizure it is, but they all have seizures. On the etiology column there, there are six causes of epilepsy. There they are. Notice, unknown is at the bottom. That remains maybe 40, 50% of causes, but that list is extremely helpful for clinicians and families trying to grapple with what is going on. Sometimes you don't exactly know, but you know there is a structural change in the brain. That's helpful. And then you see the other causes for epilepsy. On the other side, comorbidities, also known as associated conditions, all the other stuff, the developmental challenges, the sleep disorders, the behavioral challenges from top to bottom. Some patients with epilepsy have a syndrome like Lennox-Gastaut syndrome. An epilepsy syndrome is frankly an artificial construct, but some patients have a typical age of onset of their seizures, a typical seizure type, sometimes typical EEG patterns, sometimes a unified etiology, usually not, and often prognostic factors. Those come together in epilepsy syndromes. DEE is not an epilepsy syndrome. It is a broader term to try to help us better understand and treat patients with broader forms of epilepsy. So DEE, this is the start of trying to deconstruct this term, developmental and epileptic encephalopathy. It was not crafted with clinical trials in mind. It was crafted to remind us that epilepsy is more than seizures, that there is a developmental component and beyond that. But the DEE concept can be adapted for clinical trials. So allow me to deconstruct this term, and it may make more sense because you're going to hear it over and over again. So let's start with an EE, epileptic encephalopathy. This is rare, vanishingly rare. The point behind an epileptic encephalopathy is, see in bolder, epileptic activity. That means either seizures, typically frequent seizures, or an abnormal EEG, typically a very abnormal EEG, contributes to cognitive and behavioral symptoms above and beyond what would be expected from whatever the underlying cause is. Now, in the purest epileptic encephalopathy, there is no underlying cause. The patient has typical development, normal imaging, normal, typical genetics, and yet seizures and abnormal EEGs begin at a certain age and things, things get rough. The hope is that improving the epileptiform activity, that is, fewer seizures or a more normalized EEG, will help improve development. So this, this is not a DEE, but this is part of the term. So an example. So this is actually 17 seconds of a typically normal EEG. The patient is falling asleep here. All normal. This is the very next page... As the patient falls asleep, you see all that black ink in the, in the half of the screen, that is highly abnormal EEG activity. It has a name, SWAS, spike wave activation in sleep. So as you fall asleep, your EEG becomes chaotic. There are no seizures, but all night long, here's the next page, and the next page. This continues. That's an epileptic encephalopathy. That hurts the patient in terms of behavior and development. Treating that is a challenge, but when we can try to normalize the EEG, the patient can improve in terms of development and behavior. The other part of the term developmental encephalopathy, these are extremely common. Patients with developmental differences who don't typically have seizures, who don't have abnormal EEGs, or if they are abnormal, they're non-specific findings, and they have developmental differences. There are countless causes of developmental encephalopathy that don't come with seizures. And then put the two together, DEE, Developmental and Epileptic Encephalopathy. There are two components to any patient with a DEE. The developmental component means the cause, the etiology, which likely in and of itself brings behavioral and developmental consequences, and on top of that, there are seizures, often frequent, and on top of that, there are abnormal EEGs, often very abnormal, that also contribute to the developmental and behavioral challenges. So the question is, if we improve seizures with acceptable, tolerable side effects, ideally, as few side effects as possible, and as an extra bonus, if we, it can try to edge that EEG towards something more typical, does the patient's development or behavior improve? Inch by inch, mile by mile, we need progress on this front, and this is part of the reason why the DEE term is so important. Bottom line is, unless the treatments have acceptable side effects, they're not helpful. We don't need another seizure medicine that is highly sedating because that's, that's not going to move us forward. So an epilepsy syndrome that you heard about, Lennox-Gastaut syndrome, is, as Gabi said, a DEE. LGS is a DEE. The patients happen to have a characteristic EEG pattern that looks like this. You've probably heard the term slow spike and wave. Each of those seconds is a vertical line. There are two spike wave complexes between each vertical line. That's what we call slow spike and wave. We don't understand the pathophysiology of that. All the Lennox-Gastaut approvals, the patients had to have this EEG pattern. There are so many other DEEs, patients that don't have that pattern, and they are left out. They have no home in clinical trials at this point. So thinking about our treatment goals, as few seizures and as few side effects as possible, with a focus on, do the drugs work, efficacy, safety, tolerability, ease of use from a clinician point of view, decreased burden from a family point of view, that's the goal. So there are four DEEs with FDA-approved treatment. They are a tiny fraction of the DEE population, so we need a different approach. And this is where the PACIFIC Study was so helpful, novel, a forward-thinking in this approach. So these are the DEE criteria used in the PACIFIC Study. So notice at the top, the patients, for the purpose of this trial, they don't have Dravet syndrome or Lennox-Gastaut syndrome, because those are other arms in the PACIFIC trial. But the third arm of the PACIFIC trial are patients that have these features but don't meet criteria for Dravet or LGS. So the highlights are seizures start before age five years. There is developmental delay. Very importantly, and this gets into a little regulatory minutiae, but it's very important, the DEE patients have either focal and generalized seizures or multiple types of generalized seizures. You may ask, why is that? What about patients with multifocal epilepsy and DEE characteristics? Well, from a regulatory point of view, they are eligible for enrollment in focal epilepsy trials, and there are lots of drugs for focal epilepsy, but it's the patients with generalized or mixed epilepsy that are particularly left out. The EEG background is slow or disorganized, and then the second from the bottom bullet point, no history of idiopathic generalized seizures. That's maybe a little epilepsy minutiae, but there are patients with idiopathic generalized epilepsy, which is typically treatment responsive and with typical development that are treatment resistant. Maybe 20% of IGE are treatment resistant. They have unmet needs, but they are not DEEs, so we have to exclude those. So this was a very thoughtful, carefully crafted set of inclusion criteria that hopefully will be groundbreaking, not only for the development of this product, but for others as, as this broader DEE concept is embraced. And of course, patients in a clinical trial where seizures is an outcome, need to have some number of countable seizures. You see that at the bottom. The need for DEEs, top to bottom, is broad. The, the four DEEs with approved treatment, huge unmet needs. None of those treatments are transformative, not good enough, still too many side effects. You've heard the other DEEs are left out. The PACIFIC Study has taken this unique approach of broadening the DEE population within a clinical trial, and just a model of creative, timely, caregiver-informed, physician-informed thinking by Longboard. So I'll stop there, and we'll now hear more about PACIFIC and the product. Thank you. Thank you. Good morning. Welcome to the journey. I don't know if you realized that when you came in today, that you're joining us on a journey. It's kind of why we were so thoughtful in who we were gonna have sort of lead up into the speaking until I came up and gave the typical compound structure slides and pharmacokinetics of our product, because I think it helps to be grounded in what this journey is like. Gabi Conecker shared with us her journey as a mom, as a parent, as a caregiver, and a patient advocate, a passionate patient advocate, as you all heard, to give us a feel and a sense of what it's like. What a... We were joking last night, what a typical day in the life is in your, in your home, and I don't think there probably are any typical days. They all just start. And then hearing from Dr. Dlugos, who has also been on a multi-decade journey, as a academic research clinical physician who's dedicated his life to studying and understanding these conditions, and also being part of establishing new treatment paradigms, to develop new approaches and treatments, both on the diagnostic and the, and the management side. So I'm here to tell you a little bit about our Longboard journey that might seem like it started maybe a year and a half ago when we went public, or maybe a little bit before that, as Longboard got spun out from Arena. Actually, the journey started probably, Kevin, a little more like 20 years ago, with the basic science research that was conducted in the neuroscience area that serves as the fundamental approach that we've taken. I'm gonna share with you a little bit about our journey, and then Kevin will follow and talk about what we're seeing out in the landscape of the unmet medical need that dramatically exists out there. I guess for today, my part of the journey kind of begins here with the brain, perhaps. The brain region is involved in multiple types of seizures, something that we know. Dysfunction of different parts of circuitry can be involved in the cortex. We see that on the top-end portion in purple. Could be in the striatum, it's in the sort of the middle, or in the thalamus area that's noted in yellow and, orange, respectively. And these can, depending on, where they're located and how they manifest, can be involved in non-motor seizures, like absence seizures, or very dramatic, using Dr. Dlugos' terminology, countable motor seizures, such as tonic-clonic seizures. But then there's this other little challenge and problem, is the brainstem, also can be, can be involved. Gabi described a case of SUDEP, or sudden, unexpected death associated with with epilepsy. If you start to hit that area in the brain that has responsibilities for cardiorespiratory function, it spreads to there, and you can have a very negative outcome. Some of the more simple outcomes are, induced seizures, such as febrile seizures, all can contribute there. So why do I start there? Because I kind of have to show you a brain first, before I start talking about why the brain matters when we start to think about 5-HT2C receptors. These receptors are expressed in seizure-related areas of the brain. We know, and this is depicted on the top right-hand side of the screen, the 5-HT2C receptor expression is restricted to the brain and spinal cord. They're highly expressed in the brainstem, and in inhibitory neurons, in the striatum, and thalamus. And this expression is also consistent in humans, in mice, and in other species. That becomes important when we start to think about preclinical models that might help us do some predictive assessments. There's other 5-HT2 receptors, 5-HT2B, bad. We'll just remember that way, and it'll be relevant in a slide or two. You note in the. It was very, very highly expressed in the heart and has been significantly associated with some very negative cardiovascular outcomes that we'll talk about with a precedent compound. 5-HT2A is expressed not so much and so strongly as 5-HT2C in the brain. The only problem with 5-HT2A is, well, I guess if you're kind of into magic mushrooms and so forth, it's a great receptor to have, because it causes hallucinations in its most potent form. But actually, in its very mild form, if you just are interacting with very subtly, you can cause issues such as insomnia. You could just ask Gabi what it's gonna be like if Elliot has any challenges with insomnia on any or every particular night. It can take away from that one short moment of time of respite. So we do believe the 5-HT2C receptor is important as it relates to seizures, and there's some background knowledge that's important to be aware of. And I'm just going to hit the first two because I think these are important. 5-HT2C modulation of the hippocampus pyramidal GABAergic neurons suppress hyperexcitability. Hyperexcitability, excessive neuronal activity, certainly is going to potentially lead to excessive amounts of potential seizures. The second point is rather interesting. So if you take a mouse and you knock out 5-HT2C receptor, it causes them to have spontaneous seizures, and a decreased threshold for pro-convulsive stimuli. So we know that the 5-HT2C receptor probably is an important aspect that maybe we should think about how can we control that a little bit. So we took a step back and looked at a precedent compound. Precedent compound is fenfluramine. This is a weight loss drug. Some brilliant scientists, as this drug was being pulled off the market, was just as aware of this data that we've talked about, about the role of 5-HT2C receptors in the management of epilepsy, and they took a step back, and they started a development program in Dravet. They did a pretty standard approach. They lowered the dose, and they experimented, and they got a great result. They found that not only in Dravet, but also in Lennox-Gastaut, there was a significant reduction in the degree of seizures. We're trying something a little bit different. We're starting at the beginning and saying: That's a really interesting precedent molecule. Can we replicate it? Because there's a couple of challenges. One very big one is, fenfluramine interacts with the 5-HT2B receptor. So there's a significant potential risk of cardiovascular adverse events, such a high risk that one of the toughest REMS is in place and requires frequent echocardiograms at baseline, and throughout the course of treating patients. So we've developed a brand-new molecule, and I'll talk to you a little bit about its function and interaction at a receptor level, but just looking at... So now I get to do my standard part of the talk. So now I get to look at the structure, which is kind of cool to me, but if you look at the structure of fenfluramine on the left, and LP352, this is not a tinkered molecule. This isn't a compound that you throw a hydroxy group on or a little methyl group. This is a fundamentally different molecule, and it was designed in order to have greater degree of selectivity and specificity. You see this on the top-hand portion of the slide, where we're looking at a great interactivity and binding, looking at EC50s and the Ki, or the dissociation constant. Great activity, 5-HT2C, and we didn't detect anything at A and B. So we think we have a great molecule that's based on precedent, but that's just a molecule. That's just something that we've made. Now we got to start to think of whether or not we actually have something that actually will have function as we enter into the therapeutic space. Just as a side note, something we actually haven't talked much about in some of the previous discussions that we've had is LP352 has a low potential for drug-drug interactions. DDIs are the fourth most important criteria that healthcare professionals think of when they're choosing an ACM. This is just a, sort of a heads up on some of the data that Kevin's going to talk about a little bit later. I stuck some market research into my medical talks. I hope that's cool. Given the nature of complex polypharmacy in this patient population with DEEs, avoiding drug-drug interactions is really, is really super important because many of the ASMs that are out and available are impacted or affected by CYP enzyme inhibition. Whether we're talking about CYP2D6 or CYP3A4, all commonly used medications. It's another burden on the clinicians. They have to think about drug-drug interactions, and it's a subsequent burden on the families and patients that are taking these medications where there is a DDI. We structured LP352 to minimize the dependency on CYP, on the CYP system for metabolism, and went a totally different route, rather to promote it as a substrate for the UDP, and I still to this day cannot pronounce the UGT thing, so we're just going to call them UGTs because it's easier. We did some confirmatory work, as LP352 as a victim, which looks at can you do anything? Can you combine it in any drug that is going to impact the plasma concentrations of 352? We've completed in vitro work, and this is just a heads up. We've done in vivo work, which is in healthy volunteers, in human, and we'll talk about this data at AES, which is in December. So just a heads up. I think it's a pretty cool thing to learn a little bit more on a novel approach to early discovery. So now we get to talk about how do we know about the potential of LP352? Did we do the right thing? Well, we start with preclinical validation. I'll talk about those models in a moment. Then clinical validation, very standard, SAD MAD studies. We've talked about this in the past, to make sure that we can determine what is the dosing that we should be employing that gets the plasma concentration to the right level, where you're balancing the pharmacokinetics with the safety profile of the compound. But then we also took another step, like, oh, that's cool, drug gets into plasma. We also wanted to know, well, what else happens when it gets into plasma? Does it get into—remember my first slide, does it get into the brain? Does it get into where it's supposed to be? And then when it does, do you see any kind of receptor interactivity? So I'm gonna go back to preclinical just for a minute, fly through the slide pretty quickly. We do know that LP352 inhibits seizure activity in multiple preclinical models. The ones that most people talk and get excited about is zebrafish. It's a great predictive model in Dravet, because it really does hone in on the 5-HT2C receptor and its ability to modulate the epileptiform-like activity that these zebrafish have. The data that I'm putting in front of you mimics the data that would be expected and that we've seen with another similar compound, which would be fenofibrate. We're seeing the same kind of pattern. That's great. We can go into more of the healthy volunteer studies as well. I'm gonna skip the standard SAD and MAD, and I'm gonna go right to what we thought was a pretty novel approach to understanding the drug in healthy volunteers. We know drug gets into plasma. We wanted to know, does it get into the CNS? Which we would expect it to, but does it do it in a clear, predictable fashion? And then once it gets there, what kind of receptor interactivity do we see? And what we looked at was simply qEEG findings. I'll skip to the chase on that one. What we did find is that we did see receptor interactivity. We saw it in a dose-dependent manner. Higher doses seems to express a little bit higher, with a higher degree of activity, and we also noted with continuous dosing, that finding didn't go away. In fact, it actually became more pronounced. So maybe this could be an interesting biomarker for us to think about in the future. But I'm going to take a tiny step back and talk about standard pharmacokinetics in plasma and CSF. On the right-hand side of the screen, it's 12 milligrams administered three times a day. On the left, it's 6 milligrams TID. This ring fences the doses that we're utilizing in a titration schema of our PACIFIC Study. So on the right, in that, bright purple color, is plasma. And on the bottom portion of that in maroon is CSF. We've depicted the Ki or the dissociation constant. This is the level that you want to get above, so typical in drug development. I kind of say, gosh, I'd like to be at or around the Ki throughout most of the dosing, dosing period. That's exactly what you see at, at 12 milligrams, whether you're at the trough end of dosing, both in plasma and probably more importantly, in CSF, you're seeing at or around the, the Ki, even at the, even at those lower points. Interestingly, on the left, even at 6 milligrams TID, the initial dose and dose titration, seeing great levels in terms of Ki's. So about probably 70%-80% of the way there, with a peak that gets you to where you want to be, that's consistent with the dosing regimen of our compound. But what's interesting is, unlike in antibiotics, where you want to be at and above the Ki all the time, in this therapeutic area, even the pattern that you're seeing on the left is perfectly acceptable because you're getting some degree of receptor interaction. You're dampening the potential response of a potential seizure. So I know some of this stuff you've heard a little bit before, and some of you are pretty interested in, Well, what's going on with PACIFIC? Give us the latest update, Randall. But first, let me go through the study design, although Dr. Dlugos did steal a little bit of the trial design. So, 50-patient study, enrollment is complete in terms of randomizing our last patient towards the end of August. We screen patients. They need to have a minimum of 4 or more countable, remotable seizures during that initial period. They are then go into a randomization uptitration phase. In uptitration, they start at 6 mg TID. If they're tolerating it over the next 3-5 days, they can go up to 9, tolerating over the next 3-5 days, they can go up to 12. They can go up and down during that 15-day period. Remember, we're not pushing everyone to have to go up to 12. If they tolerate it, great. If they're not, we can bring them back down. At the end of the 15-day period, they're locked in at that dose, and they stay in the maintenance period for the next 2 months. After that, they go into a dose down titration, and then a follow-up 30 days later. A couple of things that I'll just mention that I think are important, some things that had changed or enhanced over the course of the study. We opened up the study to Australia late last year. That was to give us increased confidence of being able to deliver the study as planned on time. We also were able to lower the patient population group. The initial study was just 18 to 65, so that was basically an adult study. But as you know, as you heard from Mom earlier, treatment is probably better. It's not probably, it is going to be better. So we were able, in talking with the FDA and based on our available data, to work with them and lower the age group down to 12, also gives a little bit more confidence of being able to deliver the study on time. And then you'll note we also incorporated an open- label extension. It's important to family members who are making that commitment to be involved in research, that if they would like to continue on drug, to make it available, it's important to us, because it gives us long-term data. It gives long-term data from a safety standpoint, because we get to follow those patients out, in this case, for an additional year. But it also allows us, as we start to analyze the PACIFIC data, Kevin mentioned in January of this year, it gives us of next year, it gives us the opportunity to understand what happens with continuous treatment. Do we maintain that treatment effect throughout the course? Just a quick reminder on objectives. Primarily, it's to investigate safety, tolerability, and efficacy of our multiple doses in both adolescents and adults participants with, as you'll see, a broad variety of developmental and epileptic encephalopathies. And we have a variety of other secondary outcomes that are gonna be very important objectives. But it's actually identifying at the very, very bottom, the optimal dose or doses of LP352 to be putting into our planned phase III clinical trials. This is just a reminder, Dr. Dlugos talked a little bit about the diagnostic eligibility criteria, as we were thinking and planning and putting this together of those sort of three categories. We anticipated, you know, this is two years ago, as we're just doing our initial thinking, about 10 patients with Dravet, about 10 patients with LGS, and the remainder, the other 30, would be patients with other DEEs. We entered into the study, and patients came in. They were vetted through the Epilepsy Study Consortium. There were instances where patients carried a long diagnosis of LGS or LGS-like, but the Epilepsy Study Consortium looked at them a little bit more closely, it's like, actually, this might be consistent with another form of DEE, or I see they also carry that other genetic mutation that they were diagnosed with a year or two ago. They really should be categorized better in the other DEE category. A little backdrop to seizure reduction, which is an important primary endpoint, for these studies. This is a variety of different studies that are looking at percent seizure reduction over the course of the study. Typically, in these studies, you compare the placebo-based group to the investigational product, and you do it over the combination of the titration period plus the maintenance period. You combine those two together as your primary endpoint, and you get a sense of what we've seen when we start to study other diseases like LGS and Dravet and CDKL5 and Tuberous Sclerosis. You see that sort of top-end number in terms of% seizure reduction overall, which is very important when you're talking with a parent or a patient about this is the expected reduction. But I'm like a clinical development guy, so I wanna know, like, what's the placebo rates and what's occurring there? And you kind of get a sense of that in the gray. Placebo responses are in that sort of lower range. You see, you know, down to 7, in some instances as high as 17. So on the clinical development side, I'm looking at deltas, 'cause that's what I'm gonna put in front. That's how our studies in the future, and that's how we're gonna set up running the right study and conversations with the FDA. So I look at deltas around that kind of 20% range, 20% above and beyond placebo. It's clinically meaningful, and it's important, and it's, and it's important to patients and their families. So this is where we are in the PACIFIC Study. I'd like to give you an enrollment summary. We enrolled 52 patients overall that were randomized into the study. That's the breakdown, 42 in the U.S. and 10 in Australia. Very, very pleased that we were able to initiate an entire, I was gonna say country, but it's also kind of a continent, in a very brief period of time, and that they really did provide us with the confidence of being able to enroll this study on plan and as planned and on time. That's the backdrop to adult versus pediatric patients. So we'll define pediatrics in this case as 12-17, 12 out of the 52 pediatrics. So it was great that we were able to get a number of patients into that lower age range. There were also patients with lower body weight, so it'll help us as we think about dosing in our pivotal studies. In terms of diagnoses, for patients with Dravet, LGS, higher than we expected, and then a substantial number of patients with other DEEs of 19. What this sets up is an opportunity to do very interesting comparisons between the treatment effect, both from an efficacy as well as safety standpoint, between those, between those two groups. One would anticipate that there'll be a remarkable similarities between those two groups. And then importantly, the vast majority of eligible participants who completed the PACIFIC Study would be expected to enter into the open-label extension. 100% have entered, that have completed, have already entered, to date. I see Dr. Dlugos, smiling, and his eyebrows are up because he knows that's a good thing. It's a good thing because it will allow us to look at long-term safety and efficacy data. So where should you focus? So, top-line data in January, what should you be looking at? You really have to look at safety and tolerability first, because those are the essential components. We're expecting it to be in line with previous Longboard studies to date, well reflected by the therapeutic area and the expectations for the compound. The second thing to focus on is- Are we seeing clinically meaningful seizure reductions across the DE landscape? And is it consistent with the other approved treatments that I've just shown you before, that kind of ring-fenced area? Kevin will talk a little bit in a moment about some of the market research and the expectations of healthcare professionals of what they're looking for. Dosing, we'll have titration data across the three doses, that it will allow us to optimize the dosing in the phase III program. But remember, it wasn't a forced titration that everyone had to get up to 12, it was just based on tolerability. That's just an important factor, you know, for next year when we're sitting down, we're talking through the data. And then lastly, OLE participation is really important to us from a safety database standpoint. With the vast majority of patients entering into the open- label extension, it does enable for long-term safety data. As we're nearing the end of our phase II program, there's a few other things that we're involved in that relate to phase III readiness, supply chain, formulation, anticipations for the study, organizational ramp-ups, regulatory collaborations. Got to start talking early, can't wait till next year to start to think through and initiate those kinds of conversations. Phase III trial design is, the planning is already ongoing, and then will be modified and adjusted based on the PACIFIC Study readout. Next year we'll be, you know, we'll be continuing into the open label and maintaining that study to support long-term data, and then look towards a global phase III trial initiation. So that's the part of the journey that I have the pleasure of sharing with you, and our CEO and President, Kevin Lind, will talk about commercial implications. Thanks, Randall and the team for bringing in the PACIFIC Study largely on time and, as planned. Very excited to see the data later this year or early next year. So I get to talk about the part of the journey that is to come. And I'm incredibly excited about the potential for this molecule. In order to validate our understanding of the current unmet need for individuals living with DEEs, and to get preliminary feedback on the potential of LP352, we recently conducted some market research. And we performed a quantitative survey, which included 100 neurologists and epileptologists who see DE patients and had familiarity with both Epidiolex and Fintepla. We followed that up with DEE, a qualitative study with 20 healthcare providers to get a deeper insight into the responses we saw in the quant, sorry. Then we conducted a third study, which was a quant study with 30 parents of children living with DEEs that are not part of the four that have approved therapies. The goal was to really understand the challenges that these families face. I'm excited to talk about this data today. Let's start with the four approved, and we're just going to refer to them as the four approved, not because we're giving them special prominence, but just because that's where these novel medications have gone. We wanted to know more about these patients and what it looks like in the healthcare provider's practice. This chart shows answers to two questions. Starting with the blue bars, this is the percent of healthcare providers who report having at least one patient with the DEE. For example, 92% treat at least one patient with Lennox-Gastaut. Then the green bars are the number of patients with that DEE. As you can see, the most prevalent is LGS, which is consistent with the epidemiology data. In the case of TSC, you might look at that and say, "Hey, why does that not match the epidemiology?" That's because some of these patients have better seizure control, and they're not seeing these physicians. These four approved DEE indications represent an approximately $6 billion market. Fintepla is approved for two of these indications, Dravet and Lennox-Gastaut, and UCB believes that the peak sales are expected to be around EUR 800 million, despite the black box warning and REMS that Randall talked about previously. Epidiolex is approved in three of the indications, Dravet, Lennox-Gastaut, and TSC, and Jazz has said they expect sales to be greater than $1 billion in 2025. Those are large numbers, and we'll come back to them later. Despite the approvals of Fintepla and Epidiolex, and a handful of other new treatments, and despite patients being on approximately three anti-seizure medications, we see that healthcare providers report that patients with the approved four DEEs still have a heavy seizure burden in the range of 5-20 seizures per week, which is about 250-1,000 seizures per year. When we asked HCPs about LGS and Dravet, 62% answered a 5, 6, or 7 on a seven-point scale, that they remain frustrated with a lack of new treatment options. They also report that their patients with DEEs need more options with improved safety and efficacy, as we heard Dr. Dlugos talk about. Now that we understand more about these HCPs and their patients, we wanted to know more about how they think about introducing an ASM, an anti-seizure medication. Starting on the left, we gave the HCPs 100 points to allocate to factors that influence their prescribing decision. Of course, efficacy rises to the top, as that's the most important factor. Interestingly, about two-thirds is not efficacy. When you add safety with minimal DDIs, with other ASMs, with caregiver burden, you see that these three have a greater weighting than efficacy. This is re-reinforced with the qual, that we need to reduce seizures, keep these kids out of the hospital, reduce SUDEP, but also needs to be balanced with better life. Those important non-seizure outcomes and the reality of managing AEs for these families. And managing AEs and the bumps that come with a change of meds are real challenges, as we've heard earlier. I think Dennis, or Dr. Dlugos mentioned it earlier. If I see a patient, this is a different physician. If I see a patient with epilepsy and give them enough Valium, they'll be seizure free, but then they'll be sleeping all day. That's not quality of life. So we must find the cocktail that gives them the best seizure control with the least amount of side effects. With a better understanding of how HCPs make ASM prescribing decisions, we asked them specifically about Fintepla. Starting on the left, the gray bars are percent of HCPs who rated the most important criteria that HCPs consider when adding a med, and we asked a 6 or a 7 on that seven-point scale. The blue bars are the percent of HCPs who give Fintepla a 6 or 7 on that attribute. For example, 84% think that seizure control is extremely important, yet only 25% say that Fintepla is delivering excellent performance across that metric. You can see that across all of the most important criteria, Fintepla is underperforming. This quote sums it up nicely. What we continued here is, Fintepla is delivering efficacy that is not consistent with what they saw in the Dravet study. In addition to not delivering on efficacy expectations, Fintepla has limitations for a few other reasons. As you can see on the left, the ability to expand usage is hampered by concerns about the REMS program, CV safety, and a difficult prior auth process. This is particularly true of HCPs who primarily treat adults, as one adult epileptologist said on the quote on the right. Finally, it's limited by parent concerns about these same issues, with a quarter of parents declining to engage with Fintepla despite the HCP's recommendation. So we expect Fintepla to remain a niche product that will work very well for a small cohort of patients being treated by a limited number of KOLs. And that provides Longboard with an opportunity. As HCP caregivers, HCPs and caregivers are expected to continue to assess the safety, efficacy, and burden profile on a regular basis when patients go in for their echo, echocardiograms every six months. As we think about ways for LP352 to win, the first way is to capture the market with the approved four and win on a balance of safety, efficacy, and burden. We then asked HCPs about a blinded LP352 sampled product profile, which had the following characteristics. We actually asked them a couple of different characteristics, and we ran different scenarios by them. I'll run one because we can't spend all day on this. We assumed that LP352 gets indicated for the approved four DEE indications. We assumed a conservative seizure reduction based on Epidiolex-like seizure reduction in Lennox-Gastaut, which was 37%-44%, and Epidiolex's lowest demonstrated efficacy. The most common AEs as seen in our phase I, so headache, somnolence, dizziness, et cetera, and no cardiovascular warnings, REMS, echoes, as they're not currently required. Based on this profile, 74% of healthcare providers preferred LP352. This is due to perceptions of a superior safety profile and the sense that patients, parents will be more likely to give it a try. Based on that feedback, we believe LP352 has another way to win. Expand to caregivers and HCPs that are uncomfortable with the cardiovascular risk, the REMS, the echos, and the potential DDIs to treat patients with the approved four indications. With those two ways to win, LP352 has the potential to be as large or larger than Fintepla and Epidiolex, just by going after the approved four indications, Dravet, Lennox-Gastaut, TSC, and CDD. This may be our path forward in phase III, as the regulatory path and clinical trials are fairly straightforward and well understood. But then why do we spend all this time talking about the broad DE indication? Why do we spend so much time with folks like Abby and Dr. Dlugos? And it's because the unmet need is significant. So we asked those same physicians, what's their experience with other DEEs? It's striking. Almost all treat other DEEs. And interestingly, about half of the DE patients they see are other DEEs. The challenge is in terms of the patients that they see. About half of those 50% are made up of a small number of patients with individual genetic DEEs. But when you look at the seizure burden, the mean number of anti-seizure medications and unmet need, it looks very similar to the approved four. When we ask the caregivers, there's a fair bit of frustration which stems from their inability, without an approved for diagnosis, to access newer medications for their child. These parents are looking for equity. Because we believe the correct path is a broad DEE approach, we wanted to make sure those treating patients agree with us. So we asked those HCPs again, how would they think about a broad DEE indication? And you can see here that a substantial majority, 68%, prefer a broad DEE approach for LP352, with 80% anticipating that a broad indication would do exactly what we want to do, have a positive impact on treatment for patients with DEEs. And the parents believe that LP352 could give them hope for a better life. This is why we're passionate about exploring the opportunity for a broad DEE indication for LP352. This is why we are spending the time trying to come up with a new regulatory path forward. The unmet need is significant. So in summary, we believe LP352 can be a blockbuster drug just by replicating the developmental and regulatory pathway that has resulted in multiple approved drugs in the approved four. As a reminder, Fintepla is on its way to EUR 800 million based on Dravet and LGS. Epidiolex is on its way to $1 billion+ in Dravet, LGS, and TSC. But beyond the approved four is an opportunity to significantly expand that $6 billion market and give hope to people living with DEEs. So in summary, I hope we've demonstrated, first, the tremendous unmet need that remains in the approved four DEEs and the broader DEE population. Second, that HCPs and caregivers look beyond just efficacy to a balance of safety, efficacy, and limited burden. And third, that LP352 has multiple ways to win. I'd now like to open it to Q&A. As a reminder to our virtual attendees, you can submit questions via the Q&A box on the webcast at any point during the presentations. For in-person attendees, we'll be running microphones in the room and ask that you limit your questions to one or two per turn. Thanks, Kevin. We'll just take a minute while we get everybody set up here. All right, so just as a reminder, if you are online, you can submit your questions through the Q&A box on the online portal, and we will start with questions from analysts in the room. We do have line personnel with a microphone, so I ask that you wait for the microphone to get there and then just announce your name with your question, and we can get started. Hi. Thank you. Yatin Suneja from Guggenheim. Maybe a question for Dr. Dlugos. So the company talks about this efficacy bar, and they showed this beautiful chart where they are comparing all the efficacy data with currently available drugs. I'm just curious to hear from you: what would you like to see in this study from an efficacy standpoint? Is this the right bar that the company is showing us, where we are looking at phase III data, not the phase II? So just curious, what would you like to see? Yeah, thanks. Hey, thanks, Yatin. Dr. Dlugos, you wanna come to answer? Sure. I think of it as two different efficacy bars, and we'll focus on fenfluramine. Their fenfluramine LGS data was statistically significant, barely, and then their Dravet data was rather impressive for a trial. Either one would be a step forward. Obviously, closer to the Dravet result would be better for patients. The potential side, improved side effect profile, ease of use, reduced burden is the other axis. If they squeak by with a fenfluramine LGS result, that's still a win if it's well-tolerated and easier to use. Hopefully, it's better, much better, but we'll see. Two more questions, and then I'll pass it on. With regard to the, you know, other DEE, just curious, like, what type of, what type of an efficacy or a signal would you anticipate there? Because we understand for at least the four approved DEEs, there is a bar. But for these, for these non-DEEs, where nothing approved, there is no bar. So curious, what would you like to see? And then a question for the company: As you think about phase III, going into the phase III, would you go down to patients up to two years of age, or will it be two- ... 12, plus. Yeah, let me answer the first question first and then pass it over. We anticipate getting down to H2 by the phase III study. Dr. Dlugos. I would refer to something Gabi said, which is, let's not fool ourselves that Lennox-Gastaut is some homogeneous syndrome. It is a grab bag of etiology seizure types that at some point they had a certain EEG finding. So I think the broader DEE, while we don't know yet, 'cause it's novel, I think it's reasonable to look at those relative to the LGS results we have. Randall wanted to add something. Yeah, I think as you look at the data in January, there's a qualitative component to it when comparison DEEs. We have a large group of patients with LGS and a good size group with DEE other. I think a qualitative comparison to see if the efficacy appears to be similar qualitatively would be considered to be a pretty strong win. I'd focus more on that than necessarily what's the exact mean number, and is it matching, or are we seeing stat sig stuff? You know, it's a 52-patient study. Stat sig, you already know, is not gonna be a part of it. It's a qualitative look at this from a proof of concept study. Great. And then, go ahead. Joon Lee from Truist Securities. You know, Kevin, in your market research, about 26% of the physicians polled said that they would prefer Fintepla over LG... LP 562. What were the reasons for that? Yeah, I think the reasons are some physicians still prefer efficacy. And I think there's also a handful of physicians who are very comfortable with the profile of fenfluramine. And I think those... There are a number of patients who are very comfortable with fenfluramine out there today. It's not expected to get 100% market share. But we ran a much lower efficacy bar than what was seen with fenfluramine and Dravet. And so I think that that speaks to some of these physicians really do care a little bit more about efficacy than the overall burden. But we've had this conversation before. If you are at a tertiary care center where you know the cardiologist, where you have a phenomenal patient access program to get things reimbursed, fenfluramine is probably pretty easy to use. It's not as easy for the parents, you still have to get, as Gabi said, you still have to get your kid into the cardiologist's office every six months. But that's not really a healthcare provider problem. It's kind of a, "Hey, you guys deal with it. Another consideration that I thought was interesting is the mechanism of action. You know, why would they care what the mechanism is as long as you show, you know, the efficacy of seizure reduction? And, you know, I just added to that, you know, there are sodium channel blockers, GABA-targeting drugs, and, you know, serotonin. Is that a consideration when you add on three drugs, that you don't want two of the same class or something like that? Or how do you think about this? Dr. Dlugos. I think from a side effect point of view, if you add drugs with similar mechanisms of action, it's unclear. You might get better efficacy, but you probably will get additive side effects. I think there's data on that. I appreciate your question about the mechanism of action, 'cause I think probably like a lot of fields, neurologists like to think they're smarter than they are. So goal mechanism of action, it's precise, so I like that. And we do, but it boils down to efficacy, tolerability, and burden. I think that is a fair point. It does influence some docs, you know, but in the end, it's gonna be driven by the, you know, the efficacy, tolerability, safety. Hey, Gavin Clark Gartner from Evercore ISI. Thanks for putting on this really great event. So one question for the Longboard team and one for Dr. Dlugos, which I'll come back to. For your PK slide in healthy volunteers, you showed the exposure relative to the Ki. What is the reason we should be looking at that as opposed to the EC50? And kind of similarly, do we even have this exposure relationship that we can compare to for Fintepla? So you wanna go for it? Sure. Great important question that gives me the opportunity to clarify a little bit. The most important aspect of that study was actually the predictability of the dosing of LP352. The fact that it goes in the plasma, in a dose-proportional way, gets into the CSF and then the receptor intractability. The reason for choosing the Ki is my clinical pharmacologist tells me that that is the one that is not dose-dependent. It's a more accurate reflection of the pharmacology in human than going just by EC50, that can be manipulated a little bit by a theoretical dose. That's his sort of view of it. At the end of the day, what's gonna matter most is when we look at the, is the, at... When we look at the pharmacokinetics in our specific study and see how that matches up with the efficacy. All this does, it gives us a setup for what's the right ring fence doses to be putting into our clinical trial, but at the end of the day, it comes down to the clinical data. But I'm glad you asked that question. Yeah, I'm glad you asked it, because, again, it would be wonderful if you could look at that slide for every neuromolecule and say: This is an effective drug, and this is not. That's not how it works, unfortunately. ... Yeah, no, that's super helpful. And then one for Dr. Dlugos. Looking at your patients today who are on Epidiolex, it, broadly speaking, I know it's a tough question to answer, but broadly speaking, how many would you say are sub-optimally or inadequately managed today, where you may look to add on another option? 80%, and that's probably a conservative estimate. You know, great hope for Epidiolex. Natural, easy to use, effective. I think we all wish it worked better than it did and was better tolerated than it is, so high percentage. Thanks. Yeah. From a family perspective, that's absolutely true. And I think it's worked in ways different than people thought it would. People had great hopes that Epidiolex was gonna be, you know, do great things for seizures, and we find for families, not so much the seizures, it's the alertness, it's the cognitive piece that comes out, which is highly valuable, but it's gonna require probably additional, you know, treatment beyond that, you know. Good morning, Laura Chico, Wedbush Securities. Thank you very much for the presentation. In the split on the enrollment, you mentioned there were 40 adults and 12 pediatrics. I'm just curious how you're thinking about response by age. Should we anticipate distinctions there? Randall, you want to answer that? I'm gonna try. It's a great, it's an interesting... I think it would be really hard to necessarily look for different responses in the different age groups. And the reason for that is it's a very, very small group relative to the larger group. And as anticipated, there'll be variability on different weights at that lower end, like for 12- and 13-year-olds. So I think it'll be important data to look at, that helps inform our phase III study, so that we, as we go down to 12 and 10 and 6, and all the way down to 2, that we're thinking through the right dosing regimen. But as far as differential in their direct efficacy parameters, I probably will be looking at PK a little bit more closely than just what's the% seizure reduction. And tolerability is gonna be an important aspect as well. Okay. I know that doesn't directly answer your question, but is it close enough? Yeah, that'll, that'll do for now. Maybe one follow-up then, just on, you mentioned the phase III. What is the base case scenario right now for phase III? Would this be a planning for a basket study? And I guess, how do you proceed, for next steps? Sure. We're a nimble biotech company. We can keep multiple thoughts in our head at once. We don't have to have just one phase III trial design. If we have to go down the path of following what everybody else did, that's pretty straightforward. It wouldn't take us very long to design that study, write up the protocol, and be ready to go. We think that that translates into a very large potential market for LP352. But we do believe that there is an opportunity today to lay the groundwork, to have those conversations that we're having. We are spending time across the industry trying to build bonds and bridges because this paradigm has to change. You cannot just go and say, half of these kids will end up with no novel therapeutics for the foreseeable future because of an artifact of how certain trials were designed in the past. As both these two amazing speakers have said, Lennox-Gastaut is a basket. We're not calling it a basket, we call it an indication. Why is Lennox-Gastaut an indication and DEE not? So to answer your question, we're planning on two paths forward. We're working through both of them. The interesting thing is, we've done the analysis. The cost is about the same. The timeline is about the same. The upside potential, the ability to change the way these patients are treated, is really the only difference. And so as Randall said, we're spending time with regulators and other folks to try and really see, but we have to wait and get those answers. We will continue to inform our path forward and come back to everyone, but there is an absolute blockbuster opportunity in both options, and that's what excites me. But the most important thing, to finalize the point, the most important thing is to get this molecule to the patients that need it. So we will do what's right to make sure that this molecule makes it to the market if it deserves to be on the market. Thank you. I think we have a question over here, too, if we wanna take turns on our side. Mm-hmm. Hi, Sumant Kulkarni from Canaccord Genuity. Thanks for the event and for taking my question. So as our understanding of DEEs evolve and what you just said now, what would be the single kind of clinching argument that you could put forth to the FDA to convince the agency that a basket approach might be necessary? Would it be something that is more endpoint related, or it could be something that might be a common biomarker across DEEs, for example? Dr. Dlugos, you want to start, and then I can jump in. Sure. So, I think the FDA cares about labeling, and I think, ... the way that DEE is defined in this trial, it would avoid, clearly, a pitfall that I think the FDA is concerned about. A child with epilepsy and a learning difference. Oh, that's a DEE. There's a developmental component, there's an epilepsy component. But that, the future label, to fast forward, based on these DEE inclusion criteria, would avoid, I think, FDA concerns that DEE is too broad. It means too many things. So it may be an odd place to start the answer, but I would jump to the future label, and that set of inclusion criteria is labelable, I think, in a reasonable way that would bring meaning to clinicians and pass muster with the FDA. Yeah, just to, just to add a little bit. If you want the single most one thing, which is a totally unfair question, but the single most, thing is always precedent with the FDA. That's just how they, that's just how they operate. There is precedent of doing broad-based basket study-like approaches that will result in a broad label. Avanir is a, is a pretty good example with, with Nuedexta in pseudobulbar affect, as precedent, and I think we'll start to see some new precedents made in, in probably mitochondrial disease. And this is not that novel approach. This has been done in oncology for, for about a decade and a half so far. So I, I think that precedent will help. But what they will look for is commonality in treatment effect, both safety and efficacy. Not exactly the same, but things that are similar. I think that's what they'll go by, is a precedent compounds that can lead to conclusions that say: Yeah, I think if you get safety and efficacy information across the landscape, that would be pretty compelling, rather than the unfair approach right now, which is just studying this condition one by one and leaving families like Abby's family to just wait and wait and wait. It's a much fairer approach, and it's data-based. The other point, again, Lennox-Gastaut is a basket. It is. Then the final point, you asked about biomarkers. Great question. I think we would all love to get there. Unfortunately, today, the easiest way to get drugs approved is to count seizures. We would all love to get to those inchstones, not milestones, as part of the approval process. But I think, as Gabi said, the metrics aren't there yet. We probably need to start treating patients earlier, sooner. We would love to see biomarkers become an important part of this field. But my sense is, as of today, it still is going to be seizure reduction as the easiest way to get any molecule approved. Just also quickly add in that I think that FDA is listening. They're listening very hard, and caregivers are speaking up, patient advocates are speaking up, that this has got to happen, and it's got to happen soon, that families are desperate for treatments early as possible. Time is brain, you may have heard, and that is absolutely critical for our kids. So, you know, Inchstone Project is working on engaging the FDA to have these exact conversations, and meetings like the LGS meeting, it came up. You know, this is, this is the conversation moving forward. So I think they're gonna be hearing it more and more from the patient-centric, you know, from the patient-centered point of view, that this is what needs to happen. Yeah. Thank you. I'm Patrick Trucchio at H.C. Wainwright. First question is for Dr. Dlugos. In the prepared remarks, you talked about the importance of having consistent seizure counting. So I'm wondering if you could talk a little bit more about seizure counting, how this has maybe changed over time, how you ensure consistency site to site, and then maybe for the Longboard team, how the seizures are being counted, particularly as you look at this across different subtypes of DEEs. So honestly, I don't know that seizure counting at the first level has changed much over time. I think it's very clear for when a trial is starting that this message is now clearly heard by sponsors, and I'll defer to Longboard, but I believe they heard it, that when a patient's enrolled, you're enrolling a family, really, and you know, there's a lot of things that have to be covered in those baseline screening visits. But this notion of, all right, let's talk through a typical day and how day after day, from baseline to the end, are you going to count seizures? And let's talk about ways to do that more consistently. So it's a, it's a low-tech conversation with the family, recognizing that perfection is not the goal, but consistency is. You know, the entry point is a diary, and, you know, I'm sure you're aware, paper versus electronic, pros and cons to both. Sponsors can deal with both, families can deal with both, but it's, it's a, it's a low-tech conversation that validates this is hard. We don't want perfection, but let's talk about, based on your family, consistency. Yeah. So maybe I can make a comment more on the, on the sponsor side, because we take a lot of guidance from Dr. Dlugos and the Epilepsy Consortium. So when a patient family member refers to a seizure and they describe it, we utilize the Epilepsy Consortium to put a name on it, and a very consistent name. So during the screening period, when patients are recording in their electronic diary with a paper backup, and they're recording everything, the consortium does a review of all of that and sometimes recategorizes them, and then sometimes just reinforces, "Yeah, that's the, that's the right name." Consistency is important, and while I would love to hope that if Gabi or her husband were recording seizures in a diary, that it would be exactly the same, it wouldn't be. So we use one caregiver that does all the recording, so there's consistency there. We use an electronic diary. Electronic diaries are not great for everyone. And so they have a paper diary, and then we help them, the CRO helps them of entering that data into the system accurately. And then there's this one little other technique that we use, which is called bug and nag. Which is if a patient misses a day of recording, they are bugged and nagged later that next day, and that bug and nag continues throughout the entire course of the study. It's not fun, but it is a way of getting inconsistent data. Just a follow-up then on the PACIFIC trial and the enrollment. Just in terms of the considerations as far as tolerability that enables adjustment to the dosing, what are you trying, or what would you be looking to avoid and as you look to uptitrate, or if you're kind of forced to downtitrate as you know, as enrollment continues? So when we, as a sponsor, are talking with the investigator sites and the patients during the titration period, we'll say we want them to be on a dose that they titrate. Sometimes it can be a challenge for a patient to communicate an adverse event. It would be hard for Elliot to communicate, "Mom, I'm having a headache." But we will rely upon the mom saying he or she's not like themselves, or they're refusing food, which would be a good way of saying they're probably having some GI tolerance if they're orally fed and when food is put in front of their mouth. So we will look at these kind of vast concept of tolerability. All we want to do is get patients on a dose in the PACIFIC Study that they can tolerate or learn from how we're doing the dose escalation, to see if there are other strategies to get patients on a dose that they tolerate. The rule of thumb in as a clinician, Dr. Dlugos, correct me if I'm wrong, start low and go slow. They're not great concepts in a clinical trial, when everything is about, Can you go a little faster here? So we have to sort of balance that out a little bit. So we hope to learn a lot from the titration period of what is the best way of starting low. Are we starting low enough? Are we going slow enough? Can we go a little bit faster? Can we start a little bit higher? It's a simple question that would probably take me another hour to really go through it, but let's look at the data in January, and we can continue that. Can I add one thing, though? Yeah. I think the other thing we are looking for is what's the maximum dose? This is going to be the first 5-HT2C that is dose optimized for these patients. And so we will have, as I think we talked about earlier, some younger patients with lower BMI. We're gonna have some adult patients with higher BMI. I'm not sure we are going to see a dose-response curve here based on those characteristics. We might. It might be beautiful. We might see no dose-response curve because you might have a handful of patients sitting at 6 milligrams who are lower BMI, and you have a handful at 12, or you might have some at 9. That's the point of this study, really, to figure out what is the dose we want to move forward with. Because if you look at how cannabidiol is used, and Dr. Dlugos can add, you start low, and you titrate up to tolerability. It's not about forcing every patient to the highest dose. Is that fair? Yes. Yeah. Thank you very much. All right, so maybe we'll take, we'll take Gavin. Go ahead. It's just a follow-up. Thanks for taking my question again. Just a follow-up, actually, on Yatin's first question that he asked. Like, so it's probably for Dr. Dlugos or maybe Ms. Conecker, kind of a combination. So it's easy to look at the slide 53, you guys pulled at the efficacy and say, "Okay, in trials, Fintepla is a strong drug in Dravet, weaker in LGS. Epidiolex works across the board, maybe weaker, like we said before." Is that your experience in the real world, or is there a lot more variability? Maybe it's not this cut and dry. I think, in clinical practice, I think fenfluramine is underperforming in Dravet compared to the clinical trial results. It's not, it's not widely used in LGS because it, it is a, it's a tough sell based on efficacy and the burden. So I, I don't have a lot of experience with, with LGS because it just can't get out of the, can't get out of the starting gate. And Epidiolex, like I said before, on, on every level, efficacy, tolerability, ease of use, has underperformed. That, that's sort of my clinician lens. Yeah. I think the bottom line is that we need better. We need more, we need better, and it's, nothing is really doing what we really need it to do for our kids and our families. And so, yeah, I think that ultimately, they are underperforming because the market share, right, in terms of, like, who is out there and who needs what, we need- ... more, and we need better, and we need cleaner, you know, that aren't, you know, sedating our kids and. But most of our kids are on cocktails of four and five drugs, too, so it's always hard to tell what's doing what, and what's doing what in combination with what. So we'd love to see, you know, maybe we eventually can get kids down onto one or two drugs, and then you really can start to tell a little bit more, too. Yeah. That's helpful. Great. Well, the questions in the room have been really good, and, and we do have some questions online, but they have been answered now with some questions that came in in the room. But I do have a few more that I just wanted to throw out, to the group. So this one's coming from, Charles Duncan from Cantor. So starting with for Randall, what has been the experience with the OLE, i.e., rollover rate, persistence, and also re-enrollment patterns blinded in terms of age range, in terms of specific enrollment with patients under 18 and over 18? And then also maybe for Dr. Dlugos, would you expect a greater effect size in under 18 and over 18? Charles, thank you for the seven-part question. I think at this stage, the most we can talk about is the vast majority of patients as of this moment, 100% have gone into the open- label extension. This is a fluid study. You know, we completed randomization of patients just getting into the study in August. So, my answer will change until we talk about data in January. So you're unfortunately gonna hold some of the other seven parts just a little bit longer till January. Okay. And as far as the response rate, I would not really expect a big difference in response rate between 12 and 17 and 18 and above. I think the... By that age, within these syndromes, including the broader DEs, the seizure types are largely established, and I wouldn't expect much of a difference. Okay, great. Thank you. And then I'll take one question from Kalpit Patel from B. Riley. I know we've talked about it a little bit, but could we expand a little bit on what the next steps are in terms of engaging with the regulatory authority to discuss plans for a broad basket study, which is perhaps the next study? Sure. In my experience working at a previous company, working on a basket broad-based approach, it is a series of discussions that has to be data-based. We have some data. We'll have more data, obviously, in January. But starting those conversations now, with our thinking, needs to be started and should be started and has started. You know, sharing details back and forth with the thinking process probably won't help all that much. We'll put that information out, as it becomes more concrete. You know, as Kevin said earlier, there's multiple ways that we think we can approach of quickly, safely, effectively getting this medication, to patients. There's a very standard by precedence approach that other companies have taken in Dravet and LGS and CDKL5. That's a reasonable approach. That is a go in. We just think that there's a better way of approaching it, and we think the FDA will be open to it because there are a lot of patients out there that won't have adequate safety and efficacy information, and might never do it. And so we think a way of approaching it is actually running the studies and learning and taking that data to decide, does it make sense? Can we actually treat these patients broadly? It's exactly what Dr. Dlugos and his colleagues are doing right now when they're facing a patient who's two or three or four. They're starting off with a variety of different medications, some of which have been tested for safety and efficacy, some of which is just based on great, wonderful decades of experience. We just think a data-based approach is something the FDA is gonna be, will be open to and embrace. Great. All right. Well, I think that's all the time we have for Q&A, so I'll turn it back over to Kevin for final remarks. Thank you all for attending, both in person and virtually. Thank you to Dr. Dlugos and to Gabi. It's always wonderful to spend time with you. I always feel like I learn so much. We're excited about the opportunities for Longboard. We're incredibly excited about the value, potential value-creating event with LP352 coming in January, and we look forward to sharing more on LP659 as we move into the clinic. So have a great day, and thanks for your time.