Good morning, everybody. It's very nice to see you all here live and in person. Welcome to the Marinus Pharmaceuticals 2024 Analyst and Investor Event. I also want to extend a very warm welcome to everybody that's joining us on the webcast. My name is Sonya Weigle, and I'm the Chief People and Investor Relations Officer at Marinus. Before we begin, I'd just like to remind everyone of some of the statements made today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. For a description of these risks and uncertainties, and risks relating to our business in general, see the filings we've made with the Securities and Exchange Commission, including Form 10-K, 10-Q, and 8-K. Our Marinus speakers include Dr. Scott Braunstein, Chairman of the Board and Chief Executive Officer. Steven Pfanstiel, Chief Financial Officer and Chief Operating Officer. Dr. Joe Hulihan, Chief Medical Officer. Christy Shafer, Chief Commercial Officer. Lisa Lejuwaan, Senior Vice President and Business Unit Lead for Rare Genetic Epilepsy. And Dr. Alex Aimetti, Chief Scientific Officer. We're also very pleased to be joined by two external experts who are leaders in the field of TSC. Dr. Mary Kay Koenig, Director of the Center for the Treatment of Pediatric Neurodegenerative Disease and Director of Research for the Division of Child and Adolescent Neurology at the University of Texas McGovern Medical School, will highlight the TSC treatment landscape and will present new long-term extension follow-up data from Marinus' Phase 2 clinical trial patients. Dr. Rajsekar Rajaraman, Director of the UCLA Tuberous Sclerosis Center of Excellence and the UCLA CDKL5 Center of Excellence, and Associate Professor of Pediatric Neurology at UCLA Mattel Children's Hospital, will provide an overview on the significant unmet need that exists for patients and families with TSC. Dr. Raj will highlight some key similarities and differences between TSC and CDD patient populations and will share insights on Marinus' Phase 3 TSC trial. We're so very grateful for Doctors Koenig and Dr. Raj for their participation and for all who are joining us here today, both in person and virtually. Today's program will begin with an introduction to Marinus, our mission, and how we're executing to deliver long-term shareholder value, followed by an overview of ganaxolone science and rationale for use in refractory epilepsies. Next, Dr. Koenig and Dr. Raj will discuss the unmet need and treatment landscape in TSC, wrapping up the first section of our presentation with the first of two Q&A sessions. Then we will review our TSC clinical development program, followed by our commercial launch presentations, preparations, and strategy for future expansion and ganaxolone development. We'll close out today's session with a financial overview, concluding remarks, and the final Q&A session. Virtual attendees can submit questions via the Q&A box on the webcast at any point during the presentations. We'll be running microphones for those of you who are here in person and ask that you limit your questions to one per session. A copy of today's presentation is available on the Investor Relations section of the Marinus website and on the Resources tab of our webcast for those of you who are watching virtually. I'll now turn the presentation over to our Chairman and CEO, Dr. Scott Braunstein. Good morning, everyone. Nice to see you all. Thanks so much for joining us this morning. Maybe you can turn the mic down a little bit. Appreciate it. I want to thank our physicians who flew in to join us this morning. We really do appreciate it. It means a tremendous amount to the organization. I'm going to jump right into it today because we have a lot to cover and I'm going to do my best to talk as little as I can today and let our experts and our team really do all the heavy lifting. I'm going to. I just wanted to start a little bit about who we are at Marinus and why we come to work every day. We feel. I guess I'm running my slides? We feel very honored to do what we can to improve the lives of patients. And I was asked yesterday on a panel, you know, what am I most proud of? And I'm most proud of the fact that we've been able to help the lives of over 200 patients and families who suffer from CDKL5 deficiency, and very proud that we are the first drug to be approved in this indication. And I would say that is really the focus of our business model: how can we help patients with refractory epilepsies and their families, really live better lives? We've had a successful launch in CDD. We are looking forward to an equally exciting time with a new indication in TSC, and that's how we're going to spend most of our time today. Certainly, we think that ganaxolone has a very novel mechanism of action. We really believe the drug can differentiate itself in patients who really require new medications, and probably most importantly, that we have a therapy that can play very nicely in tandem with other therapies. How do we actually get there? As you know, we were approved in 2022 for CDKL5, CDKL5 deficiency disorder. We built a commercial team with a purposeful plan to prepare ourselves for bigger and better indications, and we're on the precipice of those indications. We are on track for the timing of the TSC trial. Our last patient visit was the middle of September. We're cleaning and locking the database as we speak. We expect, and we'll do everything in our power, to have data before the election, because certainly we want you all watching the election results that night and not to be focused on our top-line data, but I think importantly, we, this is the beginning for us. We were really happy to announce this morning that the U.S. Patent Office has allowed a new patent that will, we believe, really strengthen our patent portfolio and give us protection to 2043, and it's already had an influence on our thinking about moving into other DEEs and LGS specifically, and Joe will talk about that in just a little bit, so how do we actually get there, well, we're going to follow the same game plan that we've done to date. That is, we're going to run smart, thorough, and important clinical trials. With a positive study in TSC, we will have two distinct global trials in two specific indications where patients suffer from both generalized and focal seizures. I think one of the things that's been difficult for the commercial organization today is there are many doctors who don't see CDD patients. But we feel very differently about the TSC opportunity, that almost every neurologist, almost every epileptologist, sees a patient with TSC, and we really believe that that will be a critical part of expanding the story for ganaxolone and the value proposition of ZTALMY today. So not only is it a second indication, but it, it really adds to the body of evidence for the drug, and we will continue to add to that body of evidence. But you don't get there with just data. You have to execute commercially, and I think we've proven that we can do that. You'll hear a lot from Christy and Lisa today on how we're getting ready for our commercial launch, and we have to be ready to supply that drug as well. I'll talk a little bit about it later in my slides about our global expansion, which is really now just weeks away from us delivering our first shipments to our partners in Europe and in China, and we expect massive changes in the volumes that we have to produce, given those global launches and a new indication. We have a little step-by-step plan in how we're thinking about the future. Where are we today? We have to generate, we have to generate data, and we have to expand our current business. Certainly today, the discussion will be about expansion into TSC, and you'll hear a little bit about expansion, expansion into other DEEs, and that's relatively straightforward. I think what we bring to the table is some expertise on this business. We have now been in the orphan disease business for about three years. We are understanding that not every orphan disease is the same. There are certain requirements that families who have children suffering from CDKL5 need and are looking for, and there are families and patients who suffer from TSC, and those needs are very different, and you'll hear from Dr. Raj a little bit more about that, and certainly from Dr. Koenig today, as we think about how we really apply specific needs and goals for specific patient populations, and I think that's a critical part of what we will do differently to really execute in this marketplace. Certainly, patient access is a critical piece of the story. We could not be prouder of the fact that we have not had a patient who suffers from CDKL5 within label, who has not received our drug two years into launch. Within six months of launch, we had reimbursement in every state for Medicaid, which is a third of our business, it directly and almost two-thirds of our business indirectly, and we have over 80% commercial payers today, and that's a pretty powerful statement. And you're going to hear around our data sets and how our commercial team is thinking that we don't see that changing at all as we expand indications. And we certainly really appreciate working with payers who recognize there's a meaningful unmet need here. Patients do not have alternatives and are very willing to support novel therapies in this space.... And I think finally, what are we going to do as a company? We could really just spend our time with ZTALMY, but we will not stop there. We believe that there are other very intriguing opportunities in the rare orphan disease space. We've built a very robust business development team. We think there are other compounds that would be very complementary to our business. We're excited with successful data to really expand in that direction. We don't want to forget about the IV program. We still think there's a tremendous amount of value in the IV program. We'll meet with the FDA in the fourth quarter, but importantly, we've had multiple strategic discussions, and we feel particularly, we want to see the IV program get to the market, but we recognize that that program will be better off in the hands of a strategic partner. We're really hopeful by the first quarter or second quarter of 2025, we will be aligned with a strategic to really help us advance the IV program. I'm going to just wrap up on how we view the future on a global basis. We were approved in the U.S. for ZTALMY in really March of 2022, and we launched in the summer of 2022. In 2022, we were approved in Europe. Not a small feat for an NDA filing that was 500,000 pages. We're very proud of that, and we're very proud of the regulatory interactions we've had to date. We announced this year that ZTALMY has already been approved in China for CDKL5 deficiency. Our partner, Tenacia, did an amazing job to get that filing through the Chinese regulatory process in record time. So now we have to deliver, and we have to deliver on product globally. And that, too, is not a small feat. When we launched ZTALMY, we had an eighteen-month shelf life, and ZTALMY is a DEA product, which means it will sit in depots in Europe or in China for months before it's actually released. So we really had to solve a shelf-life issue. So we now have a two-year shelf life on the product. We're moving to a three-year shelf life on the product. We've continued to work very closely on a long-term manufacturing plan, and today, we feel we are ready to help supply the global markets for both the CDKL5 indication and the TSC indication. And in the time that we've been preparing, our partners have come back and told us they would like incrementally more product for both the European and the Chinese marketplaces. I'll remind you that we also have a strategic partnership in the MENA regions, where we will benefit directly from any sales within the MENA region, and an expanded access program, where we've now started to ship drug to patients in countries such as Canada. So this has been a bit of a process to get it right, but the last thing that we want to do is interfere with either our commercial business today, our clinical trial supply, and once we start shipping patient drug globally, we want to be able to provide drug to patients for the, the infinite future. And so we feel we're in that position now. We're making some critical investments in that manufacturing today to really think about ramping up our production five to tenfold. And Steve will talk a little bit about that later today, but we are ready to go, and I think there are critical economic benefits for these relationships as well. So that, I'm going to end there, and I'm going to turn it over to Alex Aimetti, our Chief Scientific Officer. Alex and I have now been working together for over five years, and happy to turn the mic over to him to talk a little bit more about ganaxolone. Excellent. Thank you, Scott. We're certainly excited about what we're building here at Marinus, and, you know, really confident that we can execute on our mission to improve the lives of patients while simultaneously growing the business. One of the main reasons why we have this confidence is really kind of centered around the science of ganaxolone, which we truly believe is unique and differentiated compared to what currently exists on the market today for rare epilepsies. Why is that? I think first and foremost, it's important to understand that ganaxolone is a part of a unique, new class of compounds called neuroactive steroids, which exhibits a GABAergic mechanism of action that's distinct from other anti-seizure medications on the market today. Now, neuroactive steroids, they get their name because they're derived from steroid precursors and have that classical four-ring structure, but they do not act on classical hormone, steroid receptors. Instead, neuroactive steroids alter neuronal excitability by modulating GABA A receptors. Now, ganaxolone specifically targets sites on GABA A receptors that are distinct from other GABAergic molecules, and this is a key differentiating feature in that it acts on both synaptic and extrasynaptic GABA A receptors, where compounds such as benzodiazepines only act on synaptic receptors. Now, why do we think that this matters, and first, it's critical to understand the normal neuronal synapse shown here, that has a distribution of synaptic, GABA A receptors shown in blue and extrasynaptic GABA A receptors shown in green. There's a growing body of non-clinical evidence that suggests that during chronic and uncontrolled or prolonged seizures, there's a trafficking or internalization of synaptic GABA-A receptors, making them unavailable for drug targeting. And it's biological processes like this that make us believe that there is this waning of efficacy that's oftentimes seen with other GABAergic compounds that act exclusively at the synaptic GABA-A receptor. So again, by acting at both types of receptors, ganaxolone aims to maximize the inhibitory tone, differentiating it from other anti-seizure medications. So as such, we feel like ganaxolone's unique mechanism of action, coupled with the following clinically important characteristics, position it well for use and development in refractory epilepsy, such as DEEs. First, ganaxolone has demonstrated potent anti-seizure effects across diverse non-clinical seizure models, suggesting its potential for broad-spectrum anti-seizure activity. This is highly relevant within the DEE patient population, which oftentimes exhibits multiple seizure types, and it would certainly be desirable if there was one agent that could be effective across a broad range of seizure types that these patients are experiencing. Ganaxolone's clinical efficacy in generalized seizures has been established in our CDKL5 trial that I'll speak about here shortly, and we aim to demonstrate ganaxolone's efficacy in focal seizures, which is commonly experienced by patients with TSC. So two potentially positive studies in patients with very different seizure types would further validate its broad-spectrum anti-seizure efficacy from a clinical perspective. Next, patients with refractory epilepsy often are on multiple anti-seizure medications to manage both the frequent and the multiple seizure types. Ganaxolone does not appear to have any clinically relevant drug-drug interactions, which does enable it to be used with polypharmacy in these patient populations. Ganaxolone is metabolized by CYP3A4, and when administered in the presence of another CYP3A4 substrate, such as midazolam, it doesn't appear to have any impact on the activity or levels of that drug. Similarly, when administered in the presence of strong CYP3A4 inhibitors or inducers, there were no clinically significant changes to ganaxolone levels. Lastly, ganaxolone has been dosed in over 2,200 children and adults and has been shown to be generally well-tolerated, with somnolence-related adverse events being the most commonly reported adverse event, aligning with the GABAergic mechanism of action. In addition, there are no requirements for additional clinical monitoring, such as cardiac or drug level monitoring, which is oftentimes associated with other anti-seizure medications and really does present a burden to both the family and the provider. So all in all, we believe that these drug attributes of broad-spectrum anti-seizure activity, lack of clinically relevant drug-drug interactions, coupled with a generally well-tolerated safety profile that does not require additional clinical monitoring, really positions ganaxolone as an optimal choice for use and development in refractory epilepsies. So here's an example that I referenced earlier of ganaxolone's effects in CDKL5 deficiency disorder, which is a severe genetic epilepsy often diagnosed within the first year of life. In this study, patients were experiencing approximately 50 seizures per month in the baseline, despite trying 7 prior and 2 concomitant anti-seizure medications. Patients that were treated with ganaxolone demonstrated a 27% placebo-adjusted treatment effect, which was highly statistically significant and led to the approval of the drug back in 2022. Moving to the right, these data demonstrate the sustained reduction in generalized major motor seizure frequency in the open-label portion, where 50 patients experienced a median 48% reduction in seizure frequency at two years. Now, published literature would suggest that there's a significant waning of efficacy over three to six months with other anti-seizure medications in CDKL5, so we believe that these data are differentiated compared to other anti-seizure medications, potentially due to the mechanism that I spoke about earlier. And although this is just one clinical example of ganaxolone's durability, we'll also share some additional data today related to some early signals of a sustained responses in patients with TSC. Which does bring me to my last slide related to TSC, and here I will just very briefly describe our clinical development program in TSC, which is another rare disease where many patients have refractory epilepsy, again, primarily focal seizures. Our physician thought leaders who are here today, who I'll introduce here shortly, will provide a much more thorough overview of the condition. But I just want to again conclude my section by introducing our clinical development program here in TSC, which started with an open-label Phase 2 study, and in that study, we learned a lot of critical information that we applied to Phase 3. Specifically, we noticed that higher rates of somnolence were reported, which corresponded to lower efficacy in the Phase 2 study. We firmly believed that if we were able to improve the tolerability and allow patients to effectively titrate up to effective therapeutic doses, that it would lead to incrementally improved efficacy. As a result, we revised the titration schedule of ganaxolone in the Phase 3 study, of which, as Scott mentioned, recruitment is complete and the last patient has completed their final double-blind treatment phase visit. And to date, these blinded data suggest that the revised titration schedule may have had the desired impact of very low rates of discontinuation, as well as high patient retention in the open-label extension. We'll certainly dive into these topics in much more detail in Joe's section in a little bit, but with that, I'd like to introduce our thought leaders here for today. First, with Dr. Mary Kay Koenig. Dr. Koenig is a neurologist and a professor and Associate Vice Chair for Clinical Research at the University of Texas McGovern Medical School. She is also a co-director at the Tuberous Sclerosis Center and Director of Research for the Division of Child and Adolescent Neurology at McGovern Medical School. She's been working with TSC patients for close to 20 years and was previously the chair of the Department of Defense Panel on TSC Research. She was also a member of the expert panel to develop consensus recommendations for the treatment of TSC, and currently sits on the TSC Alliance Advisory Board. Second, Dr. Rajaraman is an associate professor in pediatric neurology at the UCLA Mattel Children's Hospital. He is also a director of the UCLA Tuberous Sclerosis Center of Excellence and director at the UCLA CDKL5 Center of Excellence. Dr. Raj has presented research at multiple major medical meetings, including American Academy of Neurology, Child Neurology Society, and the American Epilepsy Society meetings. He's an active member of AAN and AES. So thank you, Dr. Koenig and Dr. Raj, and with that, I'll turn it over to Dr. Koenig. Thank you. Thank you, Alex, and thanks, Scott, for having me here. So I always look forward to an opportunity to talk to people about tuberous sclerosis. It's one of my favorite topics. As Alex mentioned, I've been in this field for about 20 years. I actually came into it kicking and screaming. I was brought in by a geneticist, Dr. Hope Northrup, who was instrumental in identifying the TSC2 gene. So we have had a TSC Center of Excellence since 2007, and our center is one of the largest in the country. We actively follow about 600 patients with tuberous sclerosis. Excuse me. We see about 300 patient visits per year. In our center, we follow both children and adults with tuberous sclerosis complex. We have currently three neurologists. Up until this year, it was just me. I finally managed to bring in two more. We have two geneticists, we have a nephrologist, we have a pulmonologist, we have a cardiologist, both pediatric and adult, and we've been very active in research in this field for many years. So I'm gonna start by telling you just a little bit about tuberous sclerosis. So it is a genetic disorder. It's autosomal dominant, so it does tend to run in families. It does occur sporadically as well, but by being an adult and pediatric center, we're able to follow patients throughout their lifetime, as well as following families with this condition. It is the leading cause of genetic epilepsy and autism. About half of the patients have autism, and about half of them are intellectually impaired. It also causes abnormal skin pigmentations and tumor formation in multiple organs. It affects about one in 6,000 individuals, which is about 1.5 million people worldwide, and about 50,000 people here in the United States. It affects people of all races and ethnicities equally. So it can be caused by one of two mutations, either in the TSC1 or TSC2 genes. We finally worked out about 15, 20 years ago, why there are two genes that cause the same disease, and it's because the gene products actually interact with each other and form a complex. And so effectively, they, they form one protein product that acts the same way. Common symptoms we'll go through, but epilepsy is one of the major manifestations of tuberous sclerosis. About 90% of patients with tuberous sclerosis will have epilepsy. The majority of these present in childhood, and about two-thirds of them are refractory to all therapy. The severity of your epilepsy does correspond with the degree of intellectual impairment, and the earlier seizures onset and the less well controlled they are, the more severe, the neurologic outcomes can be. I think I already said this. Okay, so what are some of the more common manifestations that we see? Hypomelanotic macules are one of the key findings. You see white spots on patients. This is often one of the things that pediatricians will recognize and trigger referrals to a geneticist or neurologist. Facial angiofibromas, these are very classic findings that are seen on the face. They usually don't appear until your prepubescent age range. It looks a lot like acne, and it can persist. Ungual fibromas, these are some of the skin findings that are very classic. They're these little bumps that occur in the fingers and toes, right around the nail beds. You also see retinal hamartomas. These are tumors that can occur in the eyes. They often are present. They don't typically affect vision, but they're very noticeable. And then cardiac rhabdomyomas. This one has become very important lately because these are often picked up on the 20-week ultrasound that is done in all women, currently, when they're receiving good prenatal care, and it's one of the ways we identify the majority of children with tuberous sclerosis. So almost all of them, we would say probably close to 90%, are now identified prenatally in the United States. We almost always know when a baby is being born with tuberous sclerosis, and they do receive a genetic consult before they're even born because of this finding of cardiac rhabdomyomas. So typically, the baby is born, we recognize they have tuberous sclerosis, the genetic testing is sent right away, and they begin following with a neurologist at birth. So recognition of seizures, early onset of treatment, and intervention is key to helping these children reach their best developmental outcome. And with prenatal ultrasounds, early detection of cardiac rhabdomyomas. This has become a much better reality here for most people with tuberous sclerosis. So what else do we see? LAM, lymphangioleiomyomatosis is a common factor seen in women. It is a cystic condition of the lungs, where you get tumors and cysts forming throughout the lungs. It looks a lot like COPD, where there's the cystic transformation. It can require lung transplantation. And then renal cysts can occur, where there's cystic replacement, or you can get renal tumors called angiomyolipomas in the kidneys. These typically occur in older patients. All of these things can be reasons for referral in patients that have not yet been diagnosed. I'm a neurologist, so I care much more about the brain, so I did put up some pictures for you guys. There are three findings that we see in the brain. One of them is something called cortical tubers. I don't know if I have a pointer or not, but over here on the edge, you see these white areas, where there's abnormal areas of brain formation. I always tell people these are like birthmarks on the brain. They're usually present at the time that someone is born. They're areas where the brain does not form correctly. Oh, there, I have arrows. You can also see various types of malformations. This was actually a patient that we saw. This was her postnatal MRI scan. You can see that half of her brain did not form correctly. She ended up having surgery to disconnect that half of her brain from the other half of her brain when she was about two months old because she was born seizing and didn't stop seizing, no matter what we did. Subependymal nodules, you can see them there. Clearly, I have arrows. These line the lateral ventricles, or the fluid spaces within the brain. They're present in about 90% to 95% of patients with tuberous sclerosis. They don't really do anything or cause any problems, but they're another indicator that someone has tuberous sclerosis. And lastly, the most concerning finding that we see in the brain is something called a subependymal giant cell astrocytoma. This is actually a brain tumor. It is benign, so it doesn't metastasize, but it does cause a significant amount of morbidity in about 20% of patients with tuberous sclerosis. In the last 20 years since I've been doing this, our therapies for tuberous sclerosis have continued to advance astronomically. When I first started doing this, the therapy for this tumor was to go in and surgically remove it, and then wait for it to come back and go in and surgically remove it again, and then wait for it to come back and go in and surgically remove it again. Do this as many times as you needed to through the course of a patient's lifetime. If you can't tell, that tumor is located as much in the midline of someone's brain as you can possibly get, and every time you go in and surgically remove it, you have to pass through lots of normal brain tissue to get to it. Now, we have medicine that we just provide to patients, and it makes them shrink and go away. So one thing that people who treat tuberous sclerosis know is that the therapies are advancing really fast. We're always on the lookout for the newest therapy, the newest way to help these patients, and our treatment modalities have improved dramatically in the last 20 years. So TSC is most commonly diagnosed. Well, it used to be most commonly diagnosed in early childhood after seizures. It's now most commonly diagnosed after the detection of cardiac rhabdomyomas on MRI scans. Nobody's ever proven that or written it up, so we still say that it's diagnosed after the onset of seizures, but really, it's almost always diagnosed prenatally now. Most infants with TSC have their first seizure within the first year of life. And refractory epilepsy, again, is strongly correlated with poor developmental and cognitive outcomes. So the earlier you can recognize the seizures and get them under control, the better it is. So we typically see babies within the first few weeks of life, if not in the NICU. We spend a considerable amount of time educating the parents about what seizures look like. We provide them with videos of different types of seizures. We expect them to call us and/or bring the children back to the emergency room as soon as seizures onset so that we can initiate therapy. We do EEGs every six weeks to start looking for an indication that seizures could be occurring, and seizure control is one of the most critical things in infants with tuberous sclerosis. So other than for infantile spasms, which is a special type of seizures you see usually in infancy, the management of seizures in TSC is just like it is for other types of epilepsy. There's not really a lot of special ways that you treat it. You just treat it like you treat other epilepsy. There's not really anything to say one medicine works better than another, except for everolimus and Epidiolex. These are the only two drugs that have ever been specifically tested to look at epilepsy and tuberous sclerosis, and those have been studied. Those do have specific indications for tuberous sclerosis. Most neurologists will use them, and we will use them in children. They're not first line, either of them, for most people. They both have very significant interactions with other medications, and they both have a very significant side effect profile that you have to consider pretty strongly when you're looking at them, and they're not magic. They don't stop the seizures in everybody. They work great for some people, they work for a period of time for some people. Usually, we consider surgery the same way you do for other refractory epilepsies, especially after someone has failed their third medication. Despite everything we do, two-thirds of all of our epilepsy patients with tuberous sclerosis still remain refractory. Something else that is a big focus in tuberous sclerosis right now is what we call TAND, or tuberous sclerosis associated neurocognitive disorders. This has become a focus in the last five years. We've always known that people with tuberous sclerosis have other neurocognitive differences than other neurotypical people. We talked about the fact that half of them can have intellectual disability, half of them can have autism, but TAND really is a term that encompasses a lot more than just that. They can also have sleep disturbances, they can have learning disabilities, they can have an increase in psychiatric complications. We see more depression, more schizophrenia, more of all of these different types of behavioral problems. So this term TAND has come about to encompass all of these different findings associated with Tuberous Sclerosis and all the different neuropsychiatric findings. All of these things are also related to epilepsy in one way or another, and are often seen in an increased frequency in people who are having seizures. So the voice of the patient, this is a report that was done by the Tuberous Sclerosis Alliance back in two thousand and seventeen. And it's really interesting. So the TS Alliance is the patient advocacy group for TS, and it's a great group. And what they did was they put a bunch of patients together and their caregivers, and they tried to find out what was important to them. So if you were gonna design a therapy for your patients, what do you want to treat? Not what does the pharmaceutical company want, or the doctors, what do they think is important? No, they wanted to know what the patients thought was important, and so epilepsy and TAND were the two things that were found to be most disruptive to daily living, and they were least likely to be controlled by the existing treatment modalities, and that's really important. Those were the things that the families and the patients most wanted controlled, so 82% of caregivers reported that their children or their ward, 'cause some of these are adults, suffered from epilepsy. 72% of those reported that they had to make moderate to large changes in their lifestyles just because of their ward's epilepsy. I think that's a really significant thing for us to think about, just having to change our entire life because someone we take care of or live with has epilepsy. Most people indicated that their definition of seizure control was different than that of a physician or their physician. I'm a neurologist. The first thing we learn in neurology school is seizure control means no seizures. That is what you do. You have an epilepsy patient come in, you stop their seizures. That is the only acceptable outcome. That's not true for most of these patients. If you have a TSC patient and they're having hundreds of seizures a day, or even 20 seizures a day, reducing it to two or three times a day, that's welcome to them. They're very happy with that, and a lot of them will be perfectly content with that. Their definition of seizure control is very different from what the FDA thinks is seizure control or what the doctor thinks is seizure control. They just want to be better than they are now. If their seizures go from falling to the ground and shaking to just having a head drop or just having an arm shake, that's better, and for them, that might be what they consider seizure control. The caregivers of the patients emphasize that although the complete elimination of seizures is ideal, something that's much more realistic to them and still valuable is a reduction in seizures. I think we need to keep that in mind in this patient population. We're not looking to necessarily eliminate seizures, we just need to make them better. I have this story here about Courtney, and this is something that she wrote. And she was talking about a child that she had, and remember, this is a genetic autosomal dominant disorder. So she said when she was 20, she had her first child, a girl with beautiful blonde hair, blue eyes. She named her Mary Sue, and like Courtney, she was diagnosed with tuberous sclerosis. She'd started learning, picking up things. She was doing all the things that a 15-month-old baby should do until her seizures started. And this is a very common story that we hear in tuberous sclerosis. Everything's going great, and then the seizures start. She's been on many medications. She lists them all here: Keppra, phenobarbital, Topamax, Trileptal, Onfi, clonazepam, and Diastat. She's 2 now. She has seizures every day, even with three medications that she takes twice a day, and the seizures are only getting worse. In January, we met with the neurologist to talk about what Courtney says, "Plucking out the active tumors that were firing off the seizures." It would be a long process, EEG that lasted three to five days, and then an internal EEG that would be about 10 to 15 days. This is the process of epilepsy surgery. It is a very invasive, very prolonged process. So they go for the EEG, and they told us that they were on the right side, and now they're telling us they're all over, and they can't even do this surgery anymore. So we're stuck giving medicine that won't work and a little girl fighting through seizures every day. Again, this is a super common story that we hear. This is a baby having multiple seizures, losing her developmental milestones. She's tried multiple medications, nothing's working, and what options do they have? Once you've run through all the medicines, you know what we do? We start over. We say, "All right, well, she failed phenobarbital a year ago. Let's try that again. Maybe it'll work this time."... So, I have been fortunate to be involved in the Marinus study since 2020. I was part of the original Phase 2 study, and I pulled my numbers before I came, just so that I would make sure I remembered. I enrolled five subjects in the original Phase 2 study. And interestingly, all of my five subjects were able to roll over into the open-label extension. What you see here, there were 23 subjects that enrolled. There was a good reduction in seizure frequency, and 30% had a 50% response rate. Nine patients, 39%, qualified for and entered the long-term extension phase, and I may be a little biased because, again, five of those were mine. The median age was 22 years, the median baseline seizure frequency was 28, and seven patients completed the 2-year follow-up. That included all five of mine. The median reduction within two years was 56%. So for the patients that this works for, this works! It works really well, and it worked better than it did in the first year, in the first part of the study. It kept working. This goes back to what Alex was saying earlier about the potential for long-term benefit, as opposed to a lot of drugs, where you see this honeymoon effect. You start it, and it works for 2 to 3 months, and then it stops working. This seemed to really work, and during months 22 to 24, the median seizure reduction was 87%, and the safety findings were very good. So overall, I've treated 11 patients with this. 10 of them have shown improvement in their seizures. Two of them have become seizure free on this therapy, and I've only had 1 that stopped it because it didn't work. You know, like I said, I'm one person at one center. We have a lot of refractory patients, but I'm really excited to see this Phase 3 data when it comes out. We've had an amazing experience with this therapy. You know, I know there was a lot of concerns in the Phase 2 with a lot of the sleepiness and tolerability and things like that. Sure, my patients got sleepy on the Phase 2, but we spent a lot of time working with them, you know, on titration. Go up, go down, let's try it again. If it's working, it's stopping your seizures. Your seizures are really bad. Let's try coming back down the dose a little bit and stay on it, and then let's go back up on the dose a little bit. And so we managed to get our patients through it. And again, like Alex mentioned, for Phase 3, they changed the titration schedule, and we haven't had nearly as many of the tolerability issues. So when you get the patients on it, you get them on it at the right dose, it does seem to be working, and I have been super impressed with this therapy in this patient population. This kind of reduction in seizures, again, you're not resolving the seizures, but you are making them significantly better. This kind of reduction can really change someone's life. Hi, everyone. Thank you to Marinus. It's a pleasure to speak to everyone today, and it's a pleasure to speak with Dr. Koenig. My name is Raj Rajaraman. I'm a pediatric epileptologist at UCLA. I've been at UCLA for about 12 years, and I initially started the CDKL5 Center of Excellence in 2018, 2019. All started because of families that had extremely difficult to control epilepsy and hard seizures, and I wanted to do something for those families, and my interest was in rare genetic epilepsies. Then I've been seeing tuberous sclerosis patients for about a decade. And then an opportunity became available where I could take over the Tuberous Sclerosis Center of Excellence in 2019, 2020. And we've had a UCLA Center for TSC since 1990 s, and we have about 100 patients, pediatric and adult. UCLA covers both, and we continue management of those families. So, I'm board-certified in pediatric neurology, neurophysiology, and epilepsy, and my interest is in rare genetic epilepsies. Approximately 75% of my patients are early-onset epilepsies, developmental epileptic encephalopathies, and about 50% of my patients have tuberous sclerosis, about less than 5% have CDD, and that's kind of due to the incidence of the disease. TSC is a lot more common, and I see a lot more TSC patients. These communities mean a lot to me. You can see that the TSC Step Forward to Cure Walk in 2024, we have a walk every year in Los Angeles. It's at a racetrack. It's raising funds for the Tuberous Sclerosis Alliance, which is a patient advocacy group, which is in its fiftieth year. The CDKL5 Family LA Meetup was at Disneyland. That's to support the International Foundation for CDKL5 Research. Again, a patient advocacy group that's been around for about a decade, and there was a meetup in Los Angeles. I'm very close to both communities. I care very much for them. And my interest in rare genetic epilepsies and doing clinical trials have kind of luckily brought both of these kind of communities together for me. I'll compare tuberous sclerosis and CDD, being that I have a lot of experience in both populations. I was part of the Phase 3 Marigold Study, which got the FDA-approved, FDA approval for ZTALMY. I was part of the Phase 2 and Phase 3 study for TSC, and I see all these patients in a clinical setting as well. So CDKL5 deficiency disorder is about one in 40,000, and tuberous sclerosis complex is in one in 6,000. Like Dr. Koenig showed, the skin findings and the MRI changes, it's a lot more easier to diagnose tuberous sclerosis complex. It's taught in medical schools. There's a lot of different multisystem findings, so a pediatric neurologist or pediatrician can pick up these findings and kind of do the MRIs. The MRIs are very clear. You could do the MRI and say, "Hey, this is tuberous sclerosis." While with CDKL5 deficiency disorder, the majority of patients will have a normal MRI, so you would have to do genetic testing. Some providers are not comfortable doing genetic testing. You really have to go down that pathway in order to identify those kiddos, so I think TSC, the frequency and the incidence is definitely higher, but also the ability to capture and diagnose these kids are a lot easier. In terms of inheritance, CDKL5 deficiency disorder is X-linked. It's mainly in girls. The reason why is that girls have two X chromosomes, and they get some of the protein from the good X chromosome, while if a boy has a X and a Y, the X chromosome is definitely affected. They don't have another X chromosome to help out, so the boys could be more severe. They don't make it past in utero, so the majority of CDD kids are X-linked in females. TSC is autosomal dominant. Seizures in CDKL5 is usually more common, I would say more than 90%, and these kids seize earlier on, so within the first couple of months of life. With tuberous sclerosis, again, it's about 80%-90%, but about two-thirds will have a seizure in the first year of life, and a third will have a seizure later on. And about two-thirds are refractory in TSC, while the vast majority of CDD kids are refractory and have a more severe daily epilepsy. Infantile spasms is a catastrophic epilepsy seizure type that is seen in both syndromes, and epilepsy surgery is common in tuberous sclerosis. So Dr. Koenig showed the MRI with the birthmarks, the tubers. Those can be resected and can be a treatment option for tuberous sclerosis. While CDKL5 is a more generalized epilepsy, the MRIs are normal, so it's pretty difficult to do a resective surgery to stop their seizures. Because the seizures are more severe in CDD and the development is more affected, a lot of the milestones are also affected. So in TSC, the majority of kids are able to walk independently, in CDD, it's only about 25%, the rest need assistance or wheelchair-bound. Cortical visual impairment is very common in CDD, so the eyes, the optic tract, all that works well, but the signal from the eyes to the brain is affected. So it makes it more difficult for them to participate in speech therapy, physical therapy, because their vision is impaired and there is difficulty, as you imagine, to participate in therapies. While tuberous sclerosis complex, for the majority, their vision is okay, and they're able to participate in these therapies. In terms of also the development and being affected by comorbidities, TSC is pretty rare to have a G tube, while about a quarter of our CDD kids are fed via a G tube. I put this slide up just to show the kind of landscape of anti-seizure medications, and it's been over about 100 years in which we've been using anti-seizure meds, starting a little bit after 1910 with phenobarbital. And with over 30 medications, at least on the market, you can see that there's very few that are evidence-based or have FDA approval for certain indications. So ZTALMY was FDA approved for CDD, cannabidiol and everolimus is FDA approved for TSC, and vigabatrin has some evidence also for tuberous sclerosis. But the vast majority of medications are we are using based on our prior approach, our clinical practice, some evidence, some conversations. But I think when it comes to providers having confidence in a medication, once you have the approval, confidence from caregivers, when you have the evidence showing that this drug has been effective for that patient population, that can definitely give more confidence and strength to prescribing it. So you know, the thirty medications that I showed previously, a lot of them have some limitations. And the good thing about ZTALMY that I've noticed is that a lot of these limitations aren't an issue with ZTALMY. So drug-drug interactions, very minimal of ZTALMY, non-CNS tolerability issues, not an issue again. We I usually don't do routine labs with ZTALMY. No, out of those 30 medications, the majority of them have not been kind of evidence-based studied in tuberous sclerosis. We are doing a Phase 3 study to show that this medication could be effective. We're not really concerned, and, Dr. Hulihan will go over about mTOR inhibitors and the interactions with ganaxolone. But as far as I know, there isn't much of an interaction, and I would say the Phase 3 study that we're doing now is looking at pediatric and adults. So a lot of drugs that we're using, we use in adult population, and then we apply to pediatrics, but the safety and confidence we are at least able to show in the trial. In the Phase 2 study, I had several patients enrolled, and I did see some sedation in my patients, but not-- I didn't discontinue any of those patients, but it was apparent. And there's a couple things that kind of play into that. I would say in tuberous sclerosis, there's a wide spectrum in how these patients present. So some patients are neurotypical. It's very difficult to know that these patients have tuberous sclerosis per se, and they could verbalize to you to say, "Hey, you know, I'm definitely more tired. I'm more sedated." They are having difficulties in school. It's the-- They can present easier, and families can pick it up sometimes. With CDD, because of the severity of the disease, it might be a little bit harder to say: "Okay, this patient's sedated. Is it related to the medication?" While in TSC, some of these patients, it's a lot more obvious, and an interesting point is that. So on the bottom, we have patient with somnolence-related adverse events, and you would see that 17 people had somnolence, and then six did not. The group that did not have somnolence had a higher seizure reduction. To me, as from a clinical standpoint, that makes sense because during sleep or during sleep transitions, your brain is more hypersynchronous, and you are at risk to have more seizures. During sleep, during transitions of sleep, your seizures can increase. If you're awake, alert, and you're not sleeping as much, your seizures can also drop down, but you can also see a larger seizure reduction. So the patients who did not have somnolence or sedation had a 28% seizure reduction, which is pretty noticeable. So if the titration has improved with the Phase 3 study and the sedation somnolence is also reduced, a possibility that the seizure reduction will also increase. In the Phase 2, discontinuation rate was low, about 4, and 74% reported somnolence-related adverse events, and because of the increased rate of sedation in the Phase 2, there was a change in the titration schedule, and I think the titration schedule for the Phase 3 is more in line with what I do clinically. In the Phase 2, it was stepwise, about 25% increase every week, while in the Phase 3, they started lower, and they maintained a lower percentage increase, and then they increased it more in later during the tail end of the titration. And that's how I do in kind of clinical practice. You start low, and you titrate up slowly, and you don't necessarily have to do a stepwise increase. So you can do... And it doesn't have to be equal increase every time. So in the Phase 3, they started lower than about 10%, then went to 20%, so it was already much slower than compared to the Phase 2. And then that's real-life experience. If you start a medication, you start as low as you can because you want the family to be comfortable with the medication. You don't want to see adverse events early on, and as this time goes on, you can increase a little more quicker because the patient is more adjusted to the medication. Like I was saying, the Phase 3, that titration schedule, I had no patients complain of sedation or had any issues. The discontinuation rate due to adverse events in the Phase 2 was 17%. Phase 3 blind is less than 3%, and the total discontinuation rate in the Phase 2 is 26%, and the Phase 3 is about 6.2%. So overall, I think that's, in all the various clinical trials I've been involved with, that's a very low discontinuation rate. So I'm definitely pleased to see that. Okay. I'm just moderating. Thank you both. Incredibly valuable from our perspective, and we really wanted this to be a Q&A session. Again, I'm gonna do my best not to talk at all and let our clinicians do the work. Question? Jay Olson, Oppenheimer. Thank you, Dr. Koenig and Dr. Rajaraman, for sharing your impressive work with us here. Can you talk about the long-term prognosis for TSC patients? Can they expect to work and have a family and normal lifespan? And what could a drug like ganaxolone have on the long-term prognosis for these patients in terms of the impact? Thank you. Sure. Go ahead. Tuberous sclerosis, the lifespan can be even a normal lifespan. So, like, a lot of patients with tuberous sclerosis, you wouldn't be aware that they have tuberous sclerosis. Their seizures possibly could be minimal. We have families where they didn't know they had tuberous sclerosis. They have a child with TSC, and then we do genetic testing on the parents, and they find they have tuberous sclerosis, and they never were aware, or they, they have headaches, and they do an MRI, and, "Oh, look, you have evidence of tuberous sclerosis." The lifespan itself is, can be the same. In terms of children and adults who have severe seizures, often it's not specifically the seizures that could cause mortality. It could be other things like respiratory pneumonia, other kind of sicknesses as well. I would say the lifespan could be typical. In terms of ganaxolone helping with... What was the second part of your question? Also, can these patients expect to work and have a family? And I guess what potential impact can you have on a patient's lifestyle and ability to function with a drug like ganaxolone? Thank you. Yeah, you know, seizure reduction, and we talk about seizure reduction, but seizure intensity, if you're able to reduce that as well, which often doesn't get captured in clinical trials, but if your seizures are shorter, less severe, that definitely impacts the quality of life of patients. So, that can drastically change a person's lifestyle, make them more comfortable going back to work and different situations. So, I never say, "You have. You know, your seizures are never going to get better. You're not gonna. You just have to deal with seizures." There's always something that we could do, and having more medications in our armamentarium only helps, so. Yeah, I'll follow that a little bit. That, you know, 50% of patients with tuberous sclerosis have normal cognitive status. They're as smart as you as I. 50% of them are not autistic. So, and even the ones that are autistic, a lot of them are mild, and there's a lot of people out there in the workforce who have mild autism, especially in the pharmaceutical industry or neurology. So, you know, that leaves a good chunk of them that are capable of joining the workforce and living completely normal lives. So, the thing that I always think about, especially in the children with TSC, is if you are having multiple frequent seizures every day, how are you supposed to learn anything? It doesn't matter how smart you are. If someone is continuing to interrupt your day all the time by short-circuiting your brain, you can't learn anything because I'm trying to retain something, but you keep snapping in my ear with your seizures, and I'm constantly distracted by them. So having a medication that can stop those seizures, delay them, prevent them, shorten them, give me five seizure-free days instead of, you know, having seizures every day, anything like that is going to greatly impact their long-term success and their ability to be a productive member of society. Hi, there. Joseph Thome from TD Cowen. Maybe in those nine patients that were followed up that saw that 56% reduction within two years, is there anything that you were able to pull out that was, kind of specific to those patients, whether it's baseline disease severity or age? And between the two physicians, it sounds like you both have treated quite a few patients. Are you able to see anything in your patients of those that might respond better to, ganaxolone than those that maybe don't? You want to take the last half, and I'll try to take the first half? Yeah. So I'm not privy to a lot of the specific data, but I've had extremely good success with this. I think one of the things that my staff does very well is that we communicate really well with patients. And so I think this whole titration thing is going to end up playing a big role in it. So it's not that we didn't see the sedation in the Phase 2, we saw it, but my staff is really good at communicating with the patients and up and down the titration. And so I think that that's why we had such good success in getting people through the study, getting them on the right dose for them, and really seeing the success. This is a therapy that does work, if you can get them to the dose they need to be at. And that's true for a lot of seizure medicines. You have to start low, go slow. That's what they teach us. You have to get them to the dose they need to be at. And so I think that changing the titration schedule has made a big difference, and I think that that's going to be the key to success. Yeah, the thing in common that I saw with these patients, I would say, is that they've all failed lots of medications. So, which makes clinical trials harder and harder, right? Because you've failed so many meds previously, and that's why you do a clinical trial to try a new medication, and these people responded really well. So, I'm always pleased to see that because where, you know, families have optimism, I have to come in with an optimism that they'll respond. But these are very refractory kids, and even more in the CDKL5 population, those kids have tons of seizures, and they've responded really well during the Phase 3. And I'll add, just Joe, from the Phase 2 standpoint, you know, remember, we created an artificial scenario. We only treated patients for eight weeks in that study. You needed a certain seizure reduction to go into open -label, and so we limited the number of folks who went into that open- label. I think differently in the Phase 3, we're seeing all comers going into that open -label, staying on that open -label. And so to this discussion, you know, the excitement about seeing that long-term data from our standpoint is incrementally greater than what we could even see in a limited number of patients in the Phase 2. And certainly, look, we have two great physicians who take a lot of time with their patients, and we know that's not the case everywhere. Adjusting this titration schedule and dumbing it down for the 90 sites that participated in the trial, I think is going to be critical to our success. So thanks for the question. Jude? Thanks for taking our questions, and thanks for hosting this event. I'm also intrigued by- Do you want to tell all the people on the webcast who you are? Oh, Joon Lee from Truist. I'm also intrigued by the continued improvement on seizure reduction, the longer they are on the drug, especially as you've seen from the CDD long-term extension trial. Is that typical of other ASMs, or would that have something to do with the fact that you're targeting, like, this extrasynaptic GABA receptor that has more tonic effects? Go ahead. The only other ASM that shows that in TSC is the mTOR inhibitors. And that's because we believe that it is altering the synaptic pathways and connections. The reason you would see that would be an alteration in the synapse or the synaptic milieu, per se. Yes, I believe it goes back to exactly what Alex was describing, where you're altering the level of receptors present in the synapse. You know, Dr. Raj can probably explain this better than me, but you know, there's this process of epileptogenesis. Once someone's seizing, it's easier for them to seize. Once you start slowing the seizures down, it becomes harder and harder for them to seize. You do start altering that pathway. Before I turn it over to Dr. Raj, I'll just share that we've had some really exciting investigators who have been particularly excited about ZTALMY and have requested the drug off-label in patients less than the age of two, and we expect some of those presentations to be at AES, where we're enthusiastic that they're seeing some unique findings, which were somewhat unexpected in terms of neurocognitive improvements. So that's something to look forward to at AES. Dr. Raj? Yeah, I think the endurance of the medication is most likely due to those receptors still being available extrasynaptically. A lot of the GABAergic meds work on those synaptic or internal receptors, and those receptors involute or internalize or disappear over time. So, I haven't seen, like, a tolerance issue or kind of, getting used to it or a honeymoon period with the med. Doug, Charles, whoever is closer. Yeah. Thanks. Good morning, everyone, Charles Duncan with Cantor. Thanks to the team for hosting. Thanks to the KOLs for sharing your thoughts. I had one two-part question, and that first part is for Dr. Koenig, and that is... I think Scott actually just alluded to this coming up at AES. But are you able to detect anything with regard to TAND in addition to seizure reduction in the patients that you had in the Phase 2, or perhaps you could see ongoing in the Phase 3? That's part one. Part two is for Dr. Rajaraman. Dr. Rajaraman, you alluded to the titration schedule, and I guess, is that something that you can implement easily within your practice? You suggested it would do, and would it be useful not only for TSC patients but also CDD patients? Thanks. I'll address part one. I'm actually glad you asked me that because the answer is a very simple yes. I can only give anecdotal stories, but I have this one young man that we started in the Phase 2 study, who, he's, we call him a gentle giant. He's this giant young man. He's, like, six-three, and he, you know, weighs 250 pounds, and he's severely autistic, and he was extremely withdrawn into himself, and he was having very frequent seizures. His father used to describe how he couldn't go to family events because it was too overwhelming to have all the kids running around and all the family members. So, like, for Thanksgiving or something, he would just go sit in a corner and just be overwhelmed. And yet he's someone who does speak in a one-on-one setting, and he's actually quite pleasant and usually very calm. And there were two things that were very striking, well, three things. One, he became seizure-free on the therapy very quickly, and he's still seizure-free four years out. Two, my receptionist pointed out to me after he'd been on therapy about three months, she said to me: "You know, he's different." And I said: "What do you mean different?" She said, "He says hi to me when he walks in now, and he starts speaking to me and engages me." And we were trying to figure out whether that was just that he knew her now, and so he was more comfortable with her, or whether it was more of a durable effect. Then his father started saying, "You know, for Christmas this year, he engaged with the family. Instead of going and sitting in the corner, he decided to sit there when everyone was opening the presents, and he played with the little kids." That was such a change in their family, and that one little thing, that this person could now become part of the family, where he had never been part of the family before. My answer is yes. Yeah, for the titration schedule for clinical practice and for CDD, I think it's definitely reasonable. I think that's the way to go because with clinical trials, you are trying to have it regimented across all sites, and you're trying to get results within a certain amount of period. But in clinical practice, you do have a little bit more luxury of time. So I would probably apply this titration schedule to how I do clinically? Correct. Thank you. We will look when we file our NDA to update the label for CDKL5. Okay. We think there'll be real advantage there for folks who are less experienced than you. Doug? Hi, good morning. Thanks for taking the questions. Douglas Tsao from H.C. Wainwright. I'm just curious to the two doctors, and thank you for your time and your perspectives. And obviously, we have to see the Phase 3 data, but I'm just curious how you would anticipate utilizing ganaxolone in terms of slotting it into your sort of treatment algorithm. You know, how far up and down the sort of, you know, scheme of drugs that are using. Obviously, they're testing for patients who are, you know, have already been treated with mTOR inhibitors or and Epidiolex. So I'm just curious how you sort of think about where you would fit that relative to the other drugs. So when I look at TSC treatments, there's a lot of factors that go into, you know, that whole laundry list of drugs. Why do you pick one over the other? There's a whole lot of reasons why you pick one over the other. So with TSC in particular, there's been a lot of evidence that GABAergic drugs, in particular, are more effective in TSC than other drugs. There's a lot of research that's been done showing that the GABAergic system is disrupted in TSC. Vigabatrin shows particular effectiveness in TSC. And I like ganaxolone because of its lack of adverse effects and its lack of drug interactions. It's easy to use. The titration is not a problem. We titrate all the seizure medicines. They all get titrated, so whatever, we have to do that. Sedation is a very common side effect. You can manage that pretty easily by titrating. So for me, I'm gonna put it pretty high on my list of drugs that I'm gonna use. It's gonna be up there in the two or three. I think it's very similarly high on the list. You know, we're a secondary, tertiary kind of center, but so we do get patients who have already been on several drugs and whatnot. But I think a nuance at patient, you know, it would be early. You know, there are certain drugs like certain conditions. Like infantile spasms have certain indications and medications for that ganaxolone doesn't, but I would definitely probably use it early on. And like Dr. Koenig mentioned, if it's worked on the GABA receptor, but it's not causing as much sedation as some of the other GABAergic benzo medications, I'll probably use it early on. We're at time, but I would take one more. Not sure any others or...? Hi, Joe from RBC. Are there any specific patient population, say, different seizure types that you find harder to treat with everolimus or Epidiolex that could benefit, have better results, with the ganaxolone? Say that one more time, the question. Sorry. Any specific type of patient pool or the patient population that you find harder to treat with everolimus or Epidiolex that could see better results with the ganaxolone? So, though the medication you mentioned do have interactions, so, you know, everolimus and Epidiolex, they do have interactions. So I do lab kind of monitoring with, so that's just something to keep an eye on in terms of levels. And if a patient has severe kind of agitation, autism, and they are not comfortable getting labs, it becomes difficult to sometimes kind of monitor. So I think a strong standpoint of ZTALMY is that the lab monitoring is not a major issue. You don't really have to. So, that makes it a little bit easier to, in terms of dosing drug-drug interactions, makes them a little more comfortable. Yeah, I second that. The side effects we're seeing with ZTALMY are just so minimal compared to a lot of the other anti-seizure medicines that I think it is just. Compared to everolimus, the mTOR inhibitors, and Epidiolex, it really, the side effect profile is very pleasant here. And the fact that you don't have to do any monitoring, really nice. And it doesn't interact with other drugs. I mean, come on, you can't get much easier than that. We like it. I mean. Thank you, thank you, both. Both Dr. Raj and Dr. Koenig have agreed to stick around for our last Q&A at the end of the session. But again, thank you both for joining us and sharing your thoughts with the audience. Thank you. We'll keep the program moving. Thanks, Scott. Yeah, thanks, Dr. Rajaraman and Dr. Koenig, for your clinical insights. My picture is not up there. I'm Joe Hulihan, the Chief Medical Officer. I know many of you. Oh, here we go. Thank you. Still not up there, but that's okay. I'm very excited about the potential for this study. I've been working on clinical trials, designing and executing clinical trials for about 25 years, and this one, I think, is really interesting in terms of some of the design features, but the potential to show a robust treatment effect, the potential for patients with this treatment, and hearing some of these anecdotes and hearing anecdotes from other physicians, I'm very excited about it, so I'd like to tell you a bit about the program. First of all, the Phase 2 study that we talked about, one of the great values of that study was how it informed the Phase 3 in terms of somnolence, in terms of the titration schedule. The data from the study, as well as insights from pharmacokinetics that I'll talk about, helped inform the titration schedule. And, you know, so we're on track for top-line data in the first half of the fourth quarter. And I'll talk a bit about the study powering a bit later in the presentation. So first of all, an overview of the Phase 3 trial. The TrustTSC study is a Phase 3 double-blind, placebo-controlled trial. It has an eight-week retrospective baseline, so not just enrolling patients in a prospective baseline. They have to have at least eight seizures for 28 days, for two months prior to coming into the screening, and no more than one week each month seizure-free. And then they come into a prospective baseline, where they need to maintain that. They need to have at least eight primary endpoint seizures during the baseline. And then they go into the double-blind phase. They're randomized 1-to-1, and there's a 4-week titration and then a 12-week maintenance period. Then patients have the opportunity to enter an open-label extension. The primary endpoint is the percent reduction in TSC-associated seizures from the prospective baseline through the entire double-blind phase. And we've got three key secondary endpoints. It's the seizure reductions during the maintenance phase, and then also, the 50% responder rate, and then a Clinical Global Impression of Improvement that's done at the end of the double-blind phase. There are a number of other secondary endpoints we think are important. Seizure-free days, which we looked at in the CDD study as well. We know that those are important for patient quality of life. We're looking at efficacy within different seizure types, and then, Dr. Rajaraman alluded to seizure intensity. We have a measure called the Clinical Global Impression of Seizure Intensity and Duration. That's a single-item scale that asks, are the seizures improved in terms of how long or how severe they are? And that, I also agree, is an important clinical measure, and we saw an effect in the CDD study of ganaxolone in reducing seizure intensity and duration. The primary endpoint seizures. These seizures, one of the requirements for these seizures, they have to have a motor component so that we can count them more reliably. So for the focal seizures, these seizures can be focal motor with intact awareness, with impaired awareness, focal seizures that then generalized to tonic-clonic seizures. What are excluded are seizures, say, with impaired awareness, where the patient just stares, and that could be a behavior, that could be a seizure, so those are excluded. And then simple sensory seizures. Sometimes patients just have a sensation. One of the typical ones is an upward sensation of burning in the chest, but those strictly sensory seizures are excluded. And then in terms of the generalized seizures, generalized tonic-clonic, and then tonic, atonic, and bilateral clonic. The most common of those in the study is tonic, but I'll talk a little bit more about what we're seeing in the baseline characteristics. So I'm going to go back to the titration schedule a bit. In his presentation, Dr. Rajaraman reviewed the revised titration schedule. But one of the things that informed the titration schedule was pharmacokinetics. And I'll just mention, you know, start low and go slow is a truism in clinical epilepsy. But usually, what that means is you just cut the dose increments and you prolong the titration schedule. And this is a bit different, and the pharmacokinetics helped inform this. This is data from a Phase 1 multiple-ascending dose study in healthy volunteers. And one thing you can see is once you get to a total daily dose, around 800 milligrams, higher doses don't increase the blood level any further. And on the bottom is the results of a population PK model that we did for pediatrics in connection with the CDD study. And what that shows is the maximum absorbed dose by weight. So that trend line is the maximum absorbed dose at each weight. So, for example, a 20-kilogram child would only absorb a 200-milligram dose, and further doses above that wouldn't create an increase in the plasma concentration. I just mentioned that these are population data, so it's on average. Individual to individual varies. Some individuals may not have a ceiling on absorption, some may have a lower one, but this is the population average. To go back to the titration schedule, just to say a little bit more about it. The original titration schedule just started at 25% of the total daily dose and went up by 25% a week. The revised titration schedule starts at a third of the starting dose of the old titration schedule and then goes up in slower increments until the patient gets further along in the titration, until day 14, and then it ramps up more quickly. And again, that's because of the pharmacokinetics and the maximum absorbed dose that we saw in the PK modeling in the Phase 1 study. That patients overall, patients are on 900 a day by day 7 with the old titration schedule. And so that really, based on the Phase 1 data, that would suggest that the patients are already at the maximum dose they're going to absorb. So by day seven, they're on the maximal, have the maximal blood concentration of ganaxolone. And this is another way of looking at it. This is a PK model for dosing during titration with the old titration schedule and the current titration schedule, the former titration schedule in black and the new one in blue. And what this shows, again, the same effect. It validates the idea that by day seven, patients are on their, the dose that's going to give them their maximal concentration. Here, by day seven, with the old titration, between day seven and 10, they reach the highest concentration they're going to get to, and it doesn't go higher with further increments. The new tri-titration schedule slowly builds up, and it's not really until day 21 that they achieve their maximal blood concentration. I'd point out that dotted line. That shows the average time to the onset of somnolence-related adverse effects in the Marigold Study, in the CDD study. The average was ten days, and that's that would be predicted by this model. That's when they get to the highest blood concentration, and that's exactly when we saw the onset of somnolence in the Marigold Study. So a little bit more about the study. There are some other things I'd like to highlight. The patients have to have clinically or genetically verified TSC. They have to have a genetic test with one of the two mutations or a clinical diagnosis based on standard diagnostic criteria to ensure that the patients coming into the study do have TSC. They have to have seizures that are uncontrolled after at least two adequate trials of prior anti-seizure medications. And then, as I mentioned, the retrospective baseline with eight seizures per month, and the same in the prospective baseline. And the primary endpoint seizures were required to have a motor component. So this is the first trial in TSC that will include patients that are already on Epidiolex and/or Afinitor. Some are on both. Patients on Afinitor were excluded from the Epidiolex study because of the drug interaction. So this will be the first to show the effect of a new drug on top of either or both of those drugs. The revised titration schedule I talked about. We're using electronic seizure diaries. This is standard, currently in trials. Paper diaries are notoriously unreliable. I've you know, had patients who fill out their diaries in the waiting room before their appointments. I worked on a trial on the industry side, where every day, the seizures occurred in multiples of five on the paper diary. So these recording of seizures is time-locked, and every day, the patient has to attest to the accuracy of that count, so that it's validated along the way. Okay, so anyway, to conclude, you know, that part of it, that the trial design is intended to maintain stability of seizures. So, you know, seizures can be variable in their frequency. We don't want patients coming into the study, and then patients enter studies when they're at their worst, so we don't want patients coming into the study and then regressing to their previous seizure rate. We've looked at some of the baseline characteristics of patients in the study, and they look like they reflect the epidemiology of TSC pretty well. The average age is fifteen. Most of the patients are in the adolescent age range or adult, and you can see, so 59% of the patients in the study are adolescents, 22 are children age 11 or younger, and then 45% adults, 3 are infants less than 2 years. Again, the inclusion criteria allow patients down to age 1. Sex distribution is about half and half. U.S. is the most, has the most enrollment, followed by Spain, China, Canada, and the U.K., and then some other countries enrolling a smaller number of patients. The baseline seizure rate's about 40. So this, you know, is, demonstrates the severity of the patients coming into the study, and the baseline seizure types, again, seem to reflect the epidemiology of tuberous sclerosis. Most of the seizures are focal. On the bottom is focal seizures with impaired awareness, that is occurring in 68% of patients, focal motor seizures with intact awareness in 23%, and then focal seizures that generalize to tonic-clonic seizures in 22%. And then at the top, you can see the generalized motor seizures, with tonic being the most common, occurring in 33%. The average number of failed therapies, the mean number of failed therapies is 4.8. So given the age of the patients, they've failed quite a few treatments before they already came into the study. Patients with prior or current exposure to the various drugs, everolimus, this is numbers of patients, 76, cannabidiol 38, vigabatrin 43, and cenobamate 15. There are 27% of the patients in the study have failed Epidiolex, and 58 had failed mTOR inhibitors, 58%. As we've talked about, the double-blind discontinuation rate is quite low, and especially low due to somnolence-related AEs, which includes somnolence, sedation, lethargy, or hypersomnia. Those are all verbatim terms that all code, coded terms that we've included in this bucket of somnolence-related adverse effect. 93% of the patients continued from the double-blind into the open-label extension, and the retention rate in the open-label study is also high. High study drug compliance, 94%. The modal dose, the mean modal dose, is 88%, and the median is 100% of the target dose. Again, the target dose, in children under 28 kilograms is 63 milligrams per kilogram per day in three divided doses, and for patients 28 kilograms or above, it's a fixed dose, 1,800 per day or 600 TID. So 81% of the patients are getting to at greater than 90% of their target dose. So in terms of the powering, with 129 patients, we intended to enroll 128, we enrolled 129. The study has 90% power to detect a 25% treatment difference. The powering assumptions are based on earlier studies in rare epilepsies, particularly the Epidiolex study. Now, the Epidiolex study had a 20% placebo rate. We expect and hope for our placebo rate to be lower than that. And then their treatment effect, they had 48% median reduction and 36% median reduction in the two treatment groups, respectively. The relatively higher placebo rate may have been due to high expectations about cannabidiol, patient expectation. You know, again, we're getting around that by the things I talked about, to make sure the seizure frequency is stable over time, and then site and country selection. The CDD study, there were particular countries that had very high placebo rates. We didn't go there for this study, and we've been very careful with our site selection. The last patient just completed the last visit. Top-line data in the first half of the next quarter. Of course, we'll present the data at upcoming medical meetings and are targeting a primary manuscript in 2025. We're on track for the sNDA submission in April 2025, and we do intend and expect to receive a priority review. So thank you for your attention. I'll turn the presentation over to our Chief Commercial Officer, Christy Shafer. Thank you, Joe. Good morning, everyone, and thank you for being here. Also, I just wanted to quickly thank Dr. Koenig and Dr. Raj. It goes without saying, but your insights are so powerful in the way that we serve the patients on the commercial side of the business, so thank you. As the commercial lead... Oh, let me advance this. Thank you. As the commercial lead for Marinus, I'm super excited. Today I'm gonna share our team's progress, and our mission has always been very clear. It's to improve the lives of patients with seizure disorders through innovative treatments. And over the past two years, we've done just that. We've been working closely with patients, caregivers, and healthcare providers to make a real difference. Today, I'll show you how our success with CDD has not only impacted patients, but it's also strengthened our ability to expand into new rare epilepsies, including TSC, so our work to advance treatment options for rare epilepsies has led to some significant progress. Since its debut, ZTALMY has grown rapidly, and over the past year, we've seen an impressive 87% increase in revenue. This growth highlights the strong execution of my commercial strategy and my team's ability to execute. This growth highlights everything that we've done for the CDD patients and their families. We now have approximately 200 patients on ZTALMY, which is a huge milestone in the world of rare disease. Caregivers and advocacy organizations have played a major role in spreading awareness and introducing ZTALMY to more families who need it. The support from the early adopters, both healthcare providers and caregivers and families, has been crucial to this success... We now have over 200 prescribers across the United States, thanks to a multi-channel approach that includes direct outreach, caregiver advocacy, and clinical peer experience. This has created broad clinical adoption, and it's laid a pretty strong foundation for future growth, especially as we plan to expand ZTALMY's use into TSC. On the access front, we've secured 83% formal coverage for commercial payers and 100% coverage for Medicaid. I'm pleased to announce that every CDD patient enrolled in ZTALMY One has received coverage, ensuring limited barriers. With ZTALMY's growing presence, we're more focused than ever in making a lasting impact on patients and their families, and I'd like to share a quick example that illustrates the real power of ZTALMY. I'm excited to introduce to you Evie. Evie is eleven years old. Every day, her family, her parents, her brother, and her sister live with the challenges of CDD, and like many patients, Evie spent years and years cycling through medications, hoping for something that would make a difference. After two years now on ZTALMY, I want to share one of these quotes here from her mom, Kelly: "ZTALMY was the right choice for our child. It was the right choice for our family. Evie now has fewer seizures, measured in weeks and months, and we're so glad we made the decision. Over the last eighteen months, it feels like we're getting to know our daughter all over again." Stories like Evie's remind us of the huge unmet need in the epilepsy community. Marinus has been, and always will remain, committed to developing treatments for refractory patients. With few new therapies on the horizon, our work has the potential to make a profound impact for many patients. Now, while we're super proud of the work that we've done for CDD patients, Scott mentioned earlier that this launch was more than just bringing a product to market. It was a very strategic move to lay the foundation for long-term growth. The investments we've made early on, driven by our vision, have set us up perfectly for the upcoming TSC launch. In recent years, we've built a very scalable organization that's fully operational. It requires minimal expansion, and with key personnel already in place, we're ready to make a move that's efficient into the TSC market. We've made large investments into datasets and advanced analytics that have refined our strategy, giving us a strong advantage in identifying high-value targets that optimize our commercial efforts, and we can make faster, more informed decisions. This data-driven approach, combined with insights from our field teams in the CDD launch, ensures we remain aligned with the needs of patients, caregivers, and healthcare providers. We've applied these learnings directly to the TSC launch, and that's shaped our strategy that fits the market realities. We have a proven market access strategy that I spoke to earlier that's adaptable and applicable for TSC. We've built strong relationships with payers and refined this approach to ensure that we have rapid uptake and minimal barriers. The trust we've built with healthcare providers and decision-makers reinforces our position as a reliable partner. Our ability to engage payers and advocacy groups, patients, and the broader medical community will drive a comprehensive and effective launch for TSC. And finally, we've synthesized all of this together, all of the key learnings, to optimize all of the systems and be fully prepared to scale for a solid foundation. We're ready to execute, and with precision, ensuring a smooth rollout for a fast market capture for TSC. We know that this is critical to our continued growth, positioning us to deliver significant returns. Now, while we stay focused on delivering for CDD patients and preparing for the launch in TSC, we're confident that our mission and the expertise that we've built will keep driving us forward. Right now, we hold about 7% market share in CDD, and we expect faster adoption and a larger market share in TSC, which is very consistent with the market research that we've performed. The overall market opportunity is clear. With, excuse me, with the potential to be more than three times larger than just CDD and TSC alone. Again, this foundation that we've built has given us great confidence in our abilities and that we know that these new opportunities into new rare epilepsies and other DEEs are on the horizon. As we now focus on to TSC, we're ready to build on this momentum, and the opportunity in TSC is very exciting. With that, I'm honored to introduce to you Lisa Lejuwaan, whose leadership has been at the center of this crucial effort. Thanks, Christy, and thanks to all of you for being here to be along with us on our journey. When we think about what we've been able to do with ZTALMY for CDD, our incredible team is very excited about making the same difference for patients in a much bigger market. As you can see from the funnel, it's widely accepted and documented in the literature that there are approximately 48,000 TSC patients, 75% of whom have been diagnosed, and 84% of those are epileptic. Of those seizing, close to 50% of those patients are considered refractory, still seizing despite generic and branded therapies to treat the seizures associated with TSC. I will share how we're thinking about this market of 12,700 refractory patients. As Christy mentioned, we're a data-driven organization. The funnel I just showed you can be validated by claims data. Of the patients we see in the data, approximately 26% of them have three or more anti-seizure medicines in their history, which is in line with just over 12,000. These are our addressable patients. They have tried and failed two or more medications, and they are still seizing. A significant portion of the TSC patients continue to seize despite the myriad of treatment options, just like Dr. Koenig and Dr. Raj mentioned. We hear from the TSC Alliance and market research that reducing seizures is a number one priority in these patients. I'm gonna read these three quotes because I think it's important to understand what these families want, and more importantly, what they need in their lives to make their lives better. Until you get the seizures under control, not much else can be worked on actively." "That's a catastrophic word, seizure, and it completely changed the trajectory of his development. He's got the stuff on his face, he's got the other stuff, but the hardest has been the seizure activity, because it's daily." These emphasize that parents and patients prioritize seizure control, and they do not currently have it. Our market research is very consistent with Dr. Raj and Dr. Koenig's comments earlier. We know that there's a significant opportunity for improvements in anti-seizure medicines. We hear the concerns from the HCPs, from the caregivers, and the patients, that in-market options require too much work for too little impact. Managing DDIs, adverse events, and lab monitoring are all part of the current treatment options. There's a constant cycle of managing side effects, dealing with contraindications, and yet we still see patients having too frequent and too severe seizures. Balancing this with tolerability concerns, it's a heavy burden to get it right. So how does ZTALMY fill this gap or provide an option that's more palatable? You saw something similar from Dr. Raj earlier. This visual calls out why the current therapies are insufficient in TSC and why there is not only room in the market, but a need in the market for ZTALMY. These patients are complicated. They have tuber burden, tumors. They're on multiple therapies simultaneously. These therapies have not been widely studied in conjunction with one another, and they have not all been studied in both children and adults. This disease spans a lifetime, and ZTALMY is a safe and concomitant-compatible drug. So why ZTALMY? The last slide showed you the gaps. Let's talk about how ZTALMY fills those gaps. First, ZTALMY will be one of a very few therapies with a TSC-specific label, studied in a real-world way alongside other branded therapies, mTORs, Epidiolex, and others. TrustTSC is the first study to look at this concomitant usage of therapies, which paints the picture of real-life TSC patients. In market research, the key differentiators that HCPs most respond to are: one, the GABAergic mechanism that is perceived as more directly related to seizure control than other ASMs' mechanisms of action. We heard that from our physicians this morning. No drug-drug interactions or contraindications that might require dosing adjustments and/or monitoring. ZTALMY checks those boxes. We had strong uptake in CDD, as Christy shared with you, but we're confident that uptake in TSC will be even stronger due to a few key factors. First, TSC is far more common and far more easily recognizable. We see 25 times the number of coded patients in the data. The awareness of the TSC ICD-10 code is considerably higher, contributing to a higher data capture of known patients. TSC is much easier to diagnose. We heard this from Dr. Raj. Diagnosis does not require a genetic test. Diagnosis is typically done by MRI, clinical exam, and most are identified as early as in utero. There's a three-prong diagnosis that's widely accepted, all clinical and obvious features of this disease: seizures, skin lesions, tumors, and cysts. Additionally, there is a strong foundational support for patients and families through the TSC Alliance. I've been in rare disease for a long time, and one thing that I've learned over time is identifying the patients is often the challenge. That is not the case with TSC. In rare genetic epilepsy, where there's a high unmet need, there's a clear pathway to predictable access. We saw this exemplified in CDD, where all patients have been approved for therapy. We know through payer research that payers, both commercial and government, are reluctant to significantly increase restrictions for a novel TSC therapy, given a high disease burden and a true need for more to gain seizure control. Clinical unmet need and a small budget impact equals access to therapy. As we experienced in our CDD launch, we expect prompt and broad payer access. The payer channels will be similar, with slightly more Medicare and a reminder, anti-seizure medications are a protected class under Medicare Part D. Our specialty pharmacy partner has done a fantastic job serving our current ZTALMY patients. They will be upsizing appropriately for a larger launch and will evolve to meet these patient needs as well. Efficient growth in our sales team is the key point I'd like to make here. So rare genetic epilepsy treaters treat multiple kinds of rare genetic epilepsy. We'll add an additional 3,200 targets to our HCP focus, primarily additional adult treaters. You can see the overlap on the map between TSC COEs and clinics with the CDD COEs. There are significantly more TSC clinics than COEs, and the majority of patients will be there or in the close vicinity. Two-thirds of our current targets, primarily pediatric neurologists, are also TSC treaters, meaning we've built solid relationships already with this base of physicians. Marinus is now a known entity amongst the key treaters of these diseases. This wasn't the case at CDD launch, CDD launch. We needed to build that, and we did. Our partnerships and relationships with the epilepsy community have grown substantially as a result of our CDD launch, which was our goal. We'll double our targets and approximately double the sales force to 30 to 32 regional account managers to sufficiently touch our prescriber base. Christy talked to you about our CDD success and infrastructure build with CDD. We'll leverage that strong foundation. We built a fit-for-purpose infrastructure with CDD, and for that $25 million dollar spend, we will generate approximately $32 million in year two. At the two-year mark with TSC, we expect $210 million-$240 million for the incremental $25 million more that we will spend in the build. We will continue to grow, share, and revenue with each subsequent year thereafter. In summary, we're poised and well-prepared for a successful launch in TSC. We have a proven foundation and infrastructure in place. There is significant unmet need in TSC. I don't see how anyone can deny that after hearing Dr. Raj, Dr. Koenig this morning, and the data that we've seen in market research. Current therapies have limitations. ZTALMY fills those gaps. We hear loud and clear from patients and families that they're, that they are waiting, and that HCPs are excited about the possibility of utilizing ZTALMY, with its novel mechanism of action, as their next ASM in treating TSC. Our market access strategy is clear. All CDD patients since launch have been approved for therapy by payers, both government and commercial, with quick policy development and with a quick turnaround, with less than seven days to fill a prescription. We anticipate the same with TSC. Most importantly, as we head into our next chapter at Marinus, efficient spend can potentially yield seven times the revenue in two years. Greater results for patients equals strong returns for shareholders. Thank you, and we're excited to have you watch this journey with us. With that, I'll turn it back to Dr. Joe. Thank you, Lisa. Now I'd like to turn from the near term to the longer-term plans that we are developing. So we're looking at several options for further development of ganaxolone, and what we're targeting is the successor to ganaxolone, a ganaxolone prodrug. The plans we're developing will give us flexibility in how we develop both ZTALMY and the prodrug, and as Scott mentioned, we have a longer IP pathway with ZTALMY now as a result of the titration patent. So that recommends that we think more about what we can do, not just with a successor, but with ZTALMY itself. And so the development programs we're talking about encompass a wide range of epilepsies with developmental disabilities, what we're calling neurodevelopmental epilepsies, focusing on DEEs, but incorporating patients with non-DEE neurodevelopmental epilepsies. Our goals for generation of a successor to ganaxolone are straightforward. We want to reduce the ratio of the Cmax and AUC. We want to lower the AUC to have a beneficial effect on lower the Cmax, so that there's a benefit on side effects, and increase the Cmin. So we want to lower peak trough variability, and on the minimum side, on the trough side, that would give us a higher, a longer time during a day above a minimum effective concentration. And, you know, that's why we need to give ganaxolone three times a day, is to keep an efficacious level, keep it within the therapeutic range. Ideally with a successor compound, increasing the AUC, stretching out the pharmacokinetic profile would allow us to use twice daily or perhaps or even once daily dosing. The other thing we want to achieve is consistent dose exposure. We want to be able to give a patient, you know, what concentration the patient is going to have based on the dose they receive. So consistent dose exposure and the ability to go higher on the dose for patients who tolerate the drug and need more seizure control. Again, as I mentioned, we have an absorption ceiling on ganaxolone, and it looks like the prodrug would not have that limitation. I'd also mention, you know, lower cost of goods is a goal, and also further IP protection beyond what we would have otherwise. A little bit about how these prodrugs are developed, which I'm sure you're familiar with, but we have a candidate that we've nominated for development. In order to get that candidate, it had to go through several steps. Obviously, synthesize the compound, but then make sure it has drug-like properties that are suitable for a prodrug, and those include. This is for any drug, you know, make sure it's soluble in gastrointestinal fluids. Make sure it's metabolized to ganaxolone, first testing in human liver microsomes, and then in vivo, in experimental animals, to make sure it's converted. And converted, you know, we want a conversion that's going to give us those pharmacokinetic properties, so not automatic conversion. We want it to be a bit slower. And so the bottom left is simply that, that's just a validation. It's an experimental study to show that we get the formation of ganaxolone from administration of the parent compound. Parent compound's in the blue, and then we see ganaxolone in the circulation a little bit later. So right now, for the prodrug, we're in the midst of IND-enabling studies. We want to submit an IND by the end of 2025 and then begin a clinical program, begin the Phase 1 studies for development. A little bit more clinical background on DEEs. I mentioned this term, neurodevelopmental epilepsy. 20% of children with epilepsy have intellectual disability, so a significant proportion, and these fall into two large buckets. We talk about the DEEs, developmental and epileptic encephalopathy. Those are patients who have intellectual disability plus seizures, and the seizures actually contribute to the progression of the intellectual or neurodevelopmental problems. There's another group of patients we don't talk that much about, and these, in a recent paper, were termed intellectual disability plus epilepsy. Some of these terms get a little bit, you know, awkward, but these are also sometimes called static encephalopathies. These patients have brain abnormalities, usually a focal lesion, postanoxic encephalopathy, cortical malformation, and they have seizures as a result, but the seizures actually don't contribute to progression of the disease. These are patients with, say, cortical cerebral palsy, is another way to look at that, and they make up a pretty big percentage of these patients who have epilepsy and intellectual disability. The yellow line is overall, the combined incidence of both DEEs and this other group, and combined by age 16, the incidence overall of both of these is about 300 per 100,000, and the non-DEE patients make up more than half of that. Now, our development programs are going to focus on DEEs. I just mentioned this background to explain when I talk about inclusion of static encephalopathies in some of these studies, what I'm talking about. We've looked at a number of different development pathways and have three leading possibilities for development pathways that differ slightly in how we would look at things, but they incorporate DEEs and these other encephalopathies and Lennox-Gastaut syndrome. As you know, Lennox-Gastaut syndrome is a syndrome with intractable seizures, intellectual disability, and a characteristic EEG pattern called slow spike and wave. They're grouped with the DEEs, but a large proportion of patients with Lennox-Gastaut have these static encephalopathies from anoxic brain injury and so on. One approach has us doing an open-label proof of concept in DEEs and neurodevelopmental epilepsies while we're going through the necessary steps to get to clinical supply for the prodrug. That would give us. We'd get earlier to this is an end of Phase 2 meeting, and then we would select, do we want, you know, the ZTALMY in LGS and the prodrug in DEEs? I think that's probably more likely, but we still have the flexibility to segment these two drugs based on data that comes in along the way. Another possibility is a combined LGS Phase 3, also enrolling patients with DEEs. That would give us a higher level of evidence, proof of concept for DEEs, but it would take us a bit longer with a double-blind study incorporating both populations. And so the upside is that higher level of evidence, the downside is taking a little longer to get a prodrug study in the DEEs. You know, kind of a compromise between that, we could do a parallel double-blind study for ZTALMY in Lennox-Gastaut syndrome, do an open -label, proof of concept study in the DEEs, that would get us data on the DEEs as we're going for an indication for Lennox-Gastaut. That, so we'd have proof of concept data to guide design of a pro-drug trial, and this would be published, so we'd be able to get data out on DEEs earlier than if we did a blinded study. So all of these are under consideration. Our next steps are to meet with our business development and regulatory colleagues, and finance, Steve, to chart the path for the next steps. And we'll be doing that shortly, and we'd really like to start whatever studies we choose, in 2025 and get moving on that. The last thing I'll mention, just some of the upcoming presentations that we have. I mean, obviously, the TSC top line data we'll present. We want to present other data cuts for the TSC study about the modified titration schedule, the open -label, its two-year follow-up from the Phase 2 study, effective concomitant medications in the TSC study, and we want to look at some of the non-seizure outcomes that we've talked about. We have quality of life scales, in the study, and so we want to take a closer look at those. In CDD, we're actually, we're looking at a, an LGS subtype analysis. There was a paper published that listed clinical characteristics where you could retrospectively look to make a presumptive diagnosis of LGS when you don't have EEG or all the detail you would have prospectively. And so we're going to look at that, not just in the CDD study, but in our other studies as well, to give an idea of how much LGS is lurking within those studies that we don't know about. Effective concomitant medications in CDD, we will be presenting that shortly. And then ZTALMY use in clinical practice, from a study we've been doing of post-marketing use of ZTALMY in CDD, that'll be at our scientific exhibit at AES. Now, we haven't talked about IV ganaxolone. We've been focused on the oral formulation, but I just want to mention the RAISE study in refractory status, the results of that will be a platform presentation at the Neurocritical Care Society. And then we're going to do another. The EEG was important, turned out to be quite important in this study. We're going to do a separate presentation on the EEG findings from the study, so I'll turn it over to Steven Pfanstiel, our Chief Financial and Chief Operating Officer. Thanks, Joe. It's a pleasure to be here today at our second Investor Day. The potential ganaxolone has to impact patients' lives is what brought me to Marinus three and a half years ago. I'm proud of what we've accomplished, and I'm just as excited about the future. It's also a pleasure to be the last person to talk today. I think the team has done a really great job laying out the rationale, why we're well-positioned scientifically and commercially to expand ZTALMY's impact beyond CDD and drive significant value. The four key factors I've laid out here represent why we are so bullish on our future. We have a combination of, one, rare disease, and two, a ready and waiting refractory patient population. That creates an attractive market. Our proven commercial team has driven an incredibly successful CDD launch, one where we've raised revenue guidance multiple times, and we have a team that's primed and ready to expand rapidly with the TSC indication. We also see significant value creation from our partnerships outside the U.S., with a launch for CDD in the near term and the potential for TSC not far behind. Organizationally, we have an efficient and cost-effective business model, and with the leverage and growth the TSC launch provides, we can drive to profitability in the near term. All of this exists with an expansion into TSC. However, as Christy and Joe showed, we have the potential to drive further significant value creation beyond just CDD and TSC. Refractory epilepsy, as a rare disease market, represents a unique opportunity. We know that a significant unmet need exists for these patients. They've tried and failed multiple therapies, yet are still suffering. The needs of these patients are broadly recognized by the payer community. As you've heard from the team today, the TSC market has several favorable attributes, including a large refractory patient population, six to seven times CDD, easy identification of patients, a primary patient need focused on overall seizure reduction, and broad payer acceptance for refractory patients. We have the potential long term to impact as many as another hundred and fifty thousand epilepsy patients with similar needs. We've proven that the business model for refractory epilepsy, even in a small patient population, can be successful. In just two years since launch, and with an annual conservative commercial investment of just $25 million, we've been able to drive to a revenue target of $33 million-$35 million in just our second full year of launch and achieve profitability on that commercial investment. With continued long-term adoption of genetic testing, increased use of ICD-10 codes, and further HCP and patient experience with ZTALMY, we see long-term potential for U.S. revenues greater than $100 million annually in CDD alone. Our CDD commercial model provides significant leverage with a TSC launch. With significant call point overlap, we see a need for only a modest expansion of sales force to a total commercial investment of $50 million annually between CDD and TSC combined. This is incredible cost leverage when you consider the potential revenue expansion with the TSC indication to be $700 million or more annually. Without the same patient identification and genetic testing hurdles that we have in CDD, we expect a faster launch in TSC. Additionally, we can build upon the market access for ZTALMY already established with CDD. And at the time of CDD launch, we contemplated pricing with further expansion into other refractory epilepsies. This pricing, along with our continued focus on refractory patients, should enable a generally positive payer environment. We spent a significant amount of time and effort over the past few years to ensure we could expand patient access beyond just the U.S. market. This led us to seek well-respected partners who share our passion to deliver therapies for epilepsy patients. And we're especially excited as two of our key partners, Orion in Europe and Tenacia in China, are preparing to launch in CDD shortly. As the TSC trial was a global trial, we also expect Europe and China to launch soon after the US market with positive data, and these markets represent significant patient populations. Importantly, we're poised to receive greater than $25 million in milestones from potential CDD and TSC launches in Europe and China. We're also capturing long-term value in these markets, with double-digit royalties in both, as well as the potential for greater than $300 million of revenue-driven milestones. Our partners are very excited about both indications, and we take it positively that they've increased their estimates for supply forecasts. Outside of these markets, our partnerships continue to move forward with the MENA market and Russia markets, and we recently launched our managed access program to enable patients to gain access in non-partnered markets. Japan also remains a significant unpartnered opportunity, and we expect acceleration of interest upon positive TSC data. With expansion into TSC, we see the ability to derive an efficient, rare disease business model, one that we started with CDD. ZTALMY dosing is weight-based. For the TSC market, we expect a higher patient weight on average of 10%-20%. This is based on our experience in the Phase 2 TSC trial compared to the real-world CDD experience. We also expect similar gross -to -net deductions between CDD and TSC, averaging approximately 20%. This is based on our expectation that government payers will continue to represent greater than 50% of all patients, and by remaining in the refractory position, we expect continued broad commercial payer acceptance of our current pricing. Currently, our cost of goods average is 10% of our U.S. net price. We're focused on expansion of our capacity first and foremost, with both a second API supplier and a second manufacturing facility underway. We expect these initiatives to enable lower cost of goods, including up to about 20% on our API costs and the potential for manufacturing scale to reduce COGS further long term. As discussed previously, the expansion into TSC is expected to require only an incremental commercial investment of around $25 million. This results in an expected annual total SG&A investment upon TSC launch of less than $100 million. R&D expense is expected to reduce in the near term as we have limited future IV investment. We completed the RAISE trial and are nearing completion of the TrustTSC Phase 3 trial. While we see continued development opportunity for ZTALMY and ganaxolone, we will remain disciplined in our portfolio investments. As Lisa mentioned, our recent success with ZTALMY and CDD provides us with a great analog for how to assess a potential TSC launch, and we see the potential for an approximately $200 million annualized revenue run rate within 18 months of launch. If you look at the chart, you'll see our actual revenue trajectory for ZTALMY over the first eight quarters of our CDD launch in blue. If we then take the sixth quarter, which represents months 15 through 18 of the launch, you'll see we had $6.6 million of ZTALMY revenue. If you then adjust that amount for a refractory TSC population that's six to seven times larger and factoring in the TSC dosing, we see an annualized revenue potential of between $170 million and $220 million for TSC at 18 months into launch. This analysis does not include any factor to account for a potential faster ramp of market share in TSC relative to CDD. There's rationale for this, and it would represent upside. It's also worth noting the $170-220 million revenue at eighteen months into launch. We expect continued growth for several years. And finally, CDD's revenues are annualizing at $32 million as of Q2 2024, and we expect continued growth there as well. As a company, we've continued to challenge ourselves to set and drive to meaningful corporate targets. We did that with our goal to become profitable on our commercial investment in CDD within two years of launch, and we accomplished that a quarter early. Similarly, we are targeting total company profitability within eighteen months of our U.S. TSC launch. We see this occurring at an annualized revenue run rate of approximately $200 million, inclusive of both CDD and TSC sales. Specifically, $200 million of U.S. sales drives a gross profit margin of approximately $180 million, based on our cost of goods at 10%. With annual SG&A investment of $100 million or less and a modest R&D innovation level of $50 million, we would see $30 million of net operating profit. That's more than adequate to cover our expected ongoing royalty financing cash costs of around $22 million. Bringing us back to where we are today, our restructuring activity early this year enabled us to dramatically reduce our overall operating expenses, with combined SG&A and R&D expenses projected to be down 30% from the first half to the second half of 2024. This has left us with an organizational and cost structure appropriate to our oral rare disease focus, one we can effectively leverage for a future TSC launch and beyond. From a financing standpoint, our cost reduction activities have extended our cash runway into Q2 of next year. Our current debt balance with Oaktree is approximately $15 million-$58 million, and we have relatively modest principal payments over the next eighteen months, less than $2 million per quarter in 2024 and less than $4 million per quarter in 2025. Our current Sagard financing, royalty financing includes a modest 7.5% royalty on U.S. net sales through Q2 2026. As a reminder, the total Sagard investment was only $32.5 million, and it includes an early buyout cap of 1.6x through October of next year. As mentioned previously, our outside the U.S. partnerships also have the potential to provide meaningful capital for milestones for both CDD and TSC, as well as ongoing double-digit royalties. Finally, our intellectual property continues to strengthen, providing us with the potential for long-term protection of our innovation and overall business. Protecting our R&D investments and the innovations we developed is vital. For the oral franchise specifically, we have multiple patents, both granted and pending, covering CDD and TSC, with the potential to extend protection beyond 2040. Importantly, a new patent for ganaxolone, encompassing the titration schedule utilized in the TrustTSC Phase 3 trial, is expected to issue soon with protection through 2043. This patent will cover a broad range of epilepsies in addition to CDD and TSC. And for our next generation formulations and prodrug, we are already driving an IP strategy to protect those innovations long term. With that, I'll bring Scott back up. Great. Thanks, Steve. We are actually running right on time, which is fantastic, and just a quick wrap from me. As you've heard today, we are feeling extremely good about the future of the organization. I think our clinical team has done an amazing job in running an extremely high-quality clinical study. We are in the home stretch. It is very nice to be looking at a Phase 3 trial where we are not the first, where we have executed on this in the past, and we've been able to actually learn from what was a very successful trial and to build on that learning process. I think what we've done on the commercial side and how we're preparing for TSC is almost identical. That is, what have we learned and where will we go? I think it's pretty clear from the discussions today there's a meaningful opportunity in terms of differentiation, so I want to thank everyone for your time in speaking today, and we're going to bring the entire senior management team and our physicians back to the table. We have a good half hour for Q&A. We've got some Q&A on the call. Sonya, do you want to remind people on the Q&A, exactly how they can pop in their questions? Sure. Just as a reminder, you can submit your online questions on the webcast. There's a button to do that, and we do have a couple queued up already- Great When you're ready. Terrific. Folks, you want to come on back up? No assigned seats, so just... And folks in the audience, we're going to take one or two from the folks on the line, just so we make them feel loved, because I think that is important. All right, Sonya, let's kick it off. Okay, so first one that came in online is: Can you help us understand the correlation between somnolence and effect, efficacy? You know, I would love to pass it over to Dr. Raj and Dr. Koenig to take first stab. Dr. Raj, you want to kick it off? The correlation between somnolence and efficacy, so in the Phase 2 study, they showed that the patients who had increased sedation and somnolence had increased seizures, and that can be seen because some people just have seizures during sleep or during nocturnal periods of time. So if we have decreased sleep and decreased sedation, you're more awake, more alert, and that's usually a time period in which you have less seizures, so if ganaxolone, the new titration schedule reduces your sedation, you are already ahead of the eight ball in terms of treating your seizures because you're not sleeping as much, and additionally, the compound itself will help with the seizures. So I think the new titration schedule, reducing your sedation, gives you less time sleeping, less time having seizures, and then while being awake, the medication is going to help your seizures anyway. Dr. Koenig, anything you'd like to add? I don't have much to add. Less sleepiness means less seizures. That's true for anyone. Joe, I'm not sure we've talked about it, but do you want to talk about the post hoc that we did on Marigold and the association between seizures and efficacy? Yeah. Once we saw what we did about related to somnolence and efficacy in the TSC study, I went back to the Marigold Study and looked at that. As it turns out, in that study, we saw the same thing. Patients who had somnolence-related side effects, the efficacy, it was a bit lower. It wasn't as dramatic as it was in the TSC study. That was another thing that motivated us for the new titration schedule and pushed us in that direction when we went back and saw it in the CDD study. You know, I think what Dr. Raj mentioned, we've also been talking about that internally. Why would that happen? Of all the explanations, that does seem to be the most likely. Thanks, Joe. And certainly, I'll reiterate, we really do believe it's critical to update the label for the entire franchise. We'll take one more, maybe from the webcast, Sonya, and then we'll go to the room. Sure. This is from Andrew Tsai at Jefferies. What is the minimum placebo-adjusted delta needed in Phase 3 for ganaxolone to be meaningfully prescribed? It's the first part of the question. And the second is, what kind of net price should we expect for ZTALMY in TSC relative to CDD? Before we talk about either pricing or our statistics, I mean, maybe Dr. Koenig and Dr. Raj, you'd like to talk about what do you need to see to have a drug that you think is important and viable for patients? Yeah, so statistics are something that physicians don't like to talk about because it was really the least favorite class in medical school. So what I know is that statistically significant is important. So we want to see something that's statistically significant. Clinically meaningful is different. So what I want is to see something that means something to me. So if you tell me that there is a statistically significant difference between placebo and your therapy showing a 50% reduction in seizures, then that means something to me. But when you talk about P values and delta values and things like that, I get lost. I don't know. Maybe you're- Yeah, I would agree that what we're looking for and families are looking for is not just seizures decreasing, but decreased intensity, decreased duration, and some of those things are difficult to capture in a clinical trial, or days where you're seizure-free. Those are often not the primary outcomes, and that's just been historically how clinical trials have ran. So there is more in terms of effectiveness just than the seizure reduction. But in conversation with families, we look at kind of all aspects, and even if the seizure reduction hasn't been as robust as we wanted, if the family's telling me: "Hey, our seizures are better, it's not three minutes now, it's like 30 seconds," that's a win-win. Joe, you want to talk about the actual statistical power of the study? Yeah, that's right. Where we could hit a p-value, and then, Christy, I'll turn it over to you for the pricing question. Yeah. So, I mentioned the study is 90% powered to detect a 25% treatment difference, but actually, a delta down to 15% would be statistically significant. And so, the 25% is not an absolute, and I agree with Dr. Rajaraman and his comments about drug selection and effect size. And before I turn over to Christy, I will remind Andrew that you really snuck in two complete and distinct questions. But thank you, Andrew. We'll remember that going forward. Christy? It's, it's sneaky, but it worked. It did. So, just talk about pricing. I'll kick it over to Steve just to talk about gross -to -nets, if that's important as well. But, a few years ago, when we priced ZTALMY, similar to how we were thinking about foundational with CDD, we were also with a nod towards TSC. So a few years ago, when we priced CDD, it was—there were a few drivers that were similar in CDD and TSC. One was data. We knew that a clinically meaningful data set was going to drive promotion in this product. Second was the very, very profound unmet medical need. Those two things together in an ultra-rare disease population got us to where we are for price today. With this data set that we believe keeping price where it is from a growth standpoint, is going to stay static, and we have no plans to do anything proactively with payers today. Yeah, Andrew, I'll just add, I think we gave the dosing. We did that in Q2, and we just said it again here. But the average CDD dose is between eleven fifty and twelve hundred milligrams per day, and that's kind of our actual CDD real-world experience. When you then look at what we saw in the Phase 2 TSC trial, we see dosing that's about 10% to 20% higher. So that's generally what we've used in all the projections that we've shown today. These patients in TSC are just gonna be less kind of developmentally delayed, as you know, both of our panelists talked about today. So we do expect that kind of increased dosing on average per patient. Gross -to -nets, we don't expect a big difference. Really, we're gonna see Medicare, Medicaid being the bulk of the patients, over 50% of the patients. We know, Medicaid's a 23%, kind of mandatory, statutory discount. The Medicare is gonna be close to a 20% gross -to -net discount as well. So those are really gonna drive it, and when you think 20%-23% discounts across, you know, 60%-70% of your scripts, that's how you get to this 20%, gross -to -net deduction along with our pharmacy fees. Thanks. Why don't we take one from the audience? Joon? Thanks for taking our question. Joon Lee from Truist. I have a question for Joe and one for Lisa. Joe, there were quite a few patients on vigabatrin, which also works through the GABA mechanism path, but maybe at a different point along the pathway. Would you say that vigabatrin and ganaxolone works synergistically, and how the patients on vigabatrin do on ganaxolone in Phase 2 relative to other combinations? And for Lisa, you mentioned that ASMs are a protected class under Medicare Part D. Can you elaborate on that a little bit? And, do commercial payers have similar approach to coverage of ASMs? Thank you. Joe, you want to talk about vigabatrin? Yeah. You may want to remind folks of the subanalysis from Marigold as well. Yes, that's what I was so I'm more familiar with the Marigold analysis. The numbers in the Phase 2 study were smaller and maybe not as meaningful in terms of looking at subsets. But in the Marigold Study, which we're presenting again at AES, I believe, the concomitant medication effects. The patients on vigabatrin had more severe epilepsy. When we looked at the effect size, we saw a lower effect size on ganaxolone and vigabatrin than the overall population, but we also saw more of a plus, a lower placebo effect. The curves were about the same. And so the way they looked indicated that it's not any effect of the drug. It was actually the patients coming into the study on vigabatrin had more severe epilepsy. You know, we didn't randomize to these different drugs, and that's the problem. One thing I'll mention is clobazam. Clobazam and ganaxolone, and that subanalysis looked good. More patients, I think, were on it than on vigabatrin. And so the looking at the concomitant medications was confounded by not randomizing the patients to the different concomitant medication. But overall, we expect very little difference in outcomes. A little difference between the drugs, and the safety was good, comparable between the different concomitant medications. Lisa, Christy, who wants to take the pricing question? I'm happy to take it. So payers are reluctant to put restrictions on seizures. When you think about seizures can kill patients. Seizures can be deadly. Payers are reluctant to put a restriction on coverage for this in a very severe patient population with a serious unmet need. Commercial payers tend to follow suit. We've seen that across the board with ZTALMY and with other anti-seizure medications that have come before. Joe? Oh, or. Jay Olson, Oppenheimer. Thank you again for hosting us here today. Can you talk about how positive results for ganaxolone and TSC would inform your thinking about LGS? And what is the overlap in terms of LGS patients who are also TSC patients? And then what other DEEs would you potentially expand into, in the event of positive TSC results? Thank you. Is John Platt here? I think 25% of patients with LGS or TSC, what's the percentage? I have to ask you, is it 10, 20? Dr. Koenig. Dr. Koenig, why, why don't I ask you? Sorry. You're sitting right here. There is a big overlap in LGS and TSC, so a lot of TSC patients meet criteria for LGS. I do not know what percentage of LGS patients have TSC. Was that the question? Yeah, it's one of the more common etiologies, but the exact percentage, I don't think there's great data, and maybe I was flipping it around, but, you know, a lot of LGS patients have TSC. In terms of what DEEs we would look at, I think we'd have a pretty open door. It depends. If we did a parallel open -label study at the same time as an LGS double-blind study, whether or not we'd include LGS in the DEE open -label study is uncertain, and we would exclude TSC and CDD, just because we have double-blind, placebo-controlled data. But pretty much everything else. I can't think of anything we'd exclude. Alex, you want to talk a little bit about the analysis we're going to have at AES around our Marigold Study? Yeah, I think Joe alluded to this earlier, but again, a lot of the patient population that we've already studied exhibit the LGS phenotype. And so we're retrospectively going back through the data to identify cohorts of patients that fulfill LGS criteria and looking at safety and efficacy, both from our CDKL5 Marigold Study. We expect to combine that with the TSC study and even include some of our placebo-controlled small data set, but PCDH19 study, to identify this LGS cohort and do a combined analysis. And hopefully, that can help inform us a little bit more as we're in the planning stages of what that next study would look like. We plan to present at least the analysis from the CDKL5 Phase 3 study at AES this year in December. Dr. Raj, what would be your guess in our Phase 3, TSC study that you think we'll see a representative LGS phenotype and/or associated EEG? I would. To be honest, I would think it would be fairly low, 'cause often in clinical practice, if you identify a patient as TSC, you're gonna call them TSC. Mm. They might have features of LGS, but I don't know if you would ICD-10 say this patient has TSC and call them an LGS, 'cause you'll be like, "Oh, this is a TSC patient." So I think if we're pursuing a LGS or DEE indication, it would definitely be a larger umbrella. I can share, as we've looked at the seizure types, as Joe shared with you, we really have a relatively small number of drop seizures- Right I n the Phase 3, so I think consistent with Dr. Raj, kind of a separate population. And again, I think as others pursue DEE indications, we feel really good about having a 130-patient dedicated study in TSC and the drugs that those patients typically take, and we think that is unequivocally the best clinical strategy to pursue. Yeah. Hi, Brian Abrahams from RBC. Thanks so much for putting this together. This is super helpful. You guys talked about the modeled ganaxolone exposures for patients in TrustTSC using the new titration scheme. Relative to the Phase 2, how does this change the time at which the average patient will be above the predicted therapeutic threshold, knowing what we know about the baseline characteristics, baseline seizure burden for the Phase 3 patients? Yeah, you know, it's interesting, Brian. I'll kick it off, and then I'll turn it over to Joe and Alex. But the first analysis we looked at, or I wanted to see in the Marigold Study, was: Did we see a difference in the maintenance phase of the Phase 3 in terms of seizure reduction versus the titration phase? Because I would have presumed that we were giving up efficacy in that first four-week period. And what we saw when we analyzed the data, that there was no difference between zero to four and the maintenance phase, which told me we were probably giving too much drug in that study early on, too. To your point, I think one of the things we had to balance in the Phase 3 is, do we look at an eight-week period or a twelve-week period, where the twelve-week period really gives us at least twelve weeks at a therapeutic level. But generally, patients are going to hit that 50% mark, which is going to be significant receptor occupancy, on day 20 of the titration. Right, Joe? Week three, effectively. Yeah. You want to talk a little bit more about it? Yeah. In terms of that PK modeling that I showed for the revised titration versus the old titration, that wasn't really indication-specific. That was just based on the kinetics. Now, we haven't looked at it in detail. You know, the modeling gives you more consistent results than you see in real life, so there may have been a lot of variability. But the onset of somnolence suggests that it was the same profile in the CDD study, and so that would apply to CDD or anything, really, with ZTALMY. The thing where Brian may be going, and we've certainly heard from other investors: Are we at a subtherapeutic dose for too long, and does that put the study at risk in terms of seizure reduction? Ultimately, I mean, the proof is when they get to the maintenance dose. But again, even though the patients got to a higher level more quickly, we saw absolutely no difference between titration and maintenance in the Marigold Study. So I don't anticipate that that would be anything clinically important, a difference between titration and maintenance. These patients have chronic seizures, and it's better to have them tolerate the drug and stay on it long term than... I'm talking like a clinician, right? Than have them drop out because of an early high blood level. Thank you. Hi there, Joe Thome from TD Cowen. Thank you for taking my questions. Maybe for either of the prescribing physicians on the panel, do you see any meaningful prior authorization requirements for Epidiolex or Afinitor in your TSC population? And has this changed since the drugs were initially approved? And then secondarily, once these drugs do have multiple indications on the label, are you able to get successful reimbursement for maybe some off-label DEEs? Go. I will say prior authorizations are the bane of our existence, so we all have people in our offices that do this. It depends on the insurance company. It depends on the drug. But if you're working with this patient population, you have to have someone in your office that does this, and you have to have someone who's good, and they are able to do it. To answer your first question, yes, there's problems, but we're all very capable of dealing with that, and we're all very good at getting them approved. Does it get easier? Sure, it gets easier with time. Can we get them approved off-label? Sure, we can. You know, there's a lot of factors that go into that. Time is just one of them, because you get more evidence, you get more people publishing papers, you get more information out there that it works for this other patient population, and then you have to argue it, you know, once with the insurance company and then twice with the insurance company, and then in two years, it's very easy because you've argued it a hundred times, and now you have a form letter, but it happens. Yeah, so I don't anticipate it being any more difficult than any of the other therapies. Dr. Raj, any other comments? I would say, I feel like I do more paperwork with everolimus. I'm not certain why. I've not had issues with sirolimus in terms of paperwork or anything like that. I would say, clinicians, if there's difficulty with... If you had to do repeated denials and peer-to-peer and stuff like that, your preference is to prescribe medications, which is easier to get approved, right? So, no issues here, but prior auth is day-to-day thing. And maybe, Joe, I'll turn to Lisa or Christy. I think we've been very fortunate with our specialty distributor, but we recognize that the volumes will be significantly higher, and we want to be prepared for that. So I know, Lisa or Christy, one of you want to take how we've been thinking about it? Our specialty pharmacy partner has been amazing, and when I even think about this prior auth process, I was going to raise my hand and say that without Scott even asking it. That, you know, they are there to help through the process with these physicians and the patients and caregivers. So, they've been a really strong partner and are already scaling up. We sat in a room with them a couple of weeks ago, where the actual president of our pharmacy partner sat in there with us and said: "What can we do? How can we make it better? What do you need? What do these patients need that are different?" They've got a whole team that is bent on figuring out how they need to scale up and do things slightly differently to meet the needs of this patient population. Yeah. Hi, this is Basma Radwan from Leerink. We have a question to follow up on the relationship between somnolence and efficacy. You mentioned that the less sleepiness is usually correlated with better efficacy. So is that something that you observe across the broader DEEs, or is it only specific to TSC? And also, would that sort of analysis observed for other medications or only ganaxolone? So in seizure disorders, we always tell our patients there are certain things that are gonna increase your risk for having seizures. So if you have someone who has epilepsy that's well controlled, if you're tired, hungry, stressed out, sick, any of those things are going to make you more likely to have a seizure. So and the same is gonna be true for someone with refractory epilepsy. If you put them in any of those situations, they're going to be more likely to have a seizure. So whatever you do to someone to make them sleepy, you're going to make their seizures worse. If you sleep deprive them, that's gonna make them worse. If you give them a medication that makes them sleepy, it's going to make them more likely to have seizures. So, when you look at what it appears happened here was starting the ganaxolone at a dose that was making people sleepy, was actually increasing their seizures because they were sleepy. Although the drug was showing efficacy, it was being counterbalanced by the fact that they were getting sleepy, which increases seizures. So you didn't see the same degree of efficacy that you would have seen if you hadn't had the sleepiness. So when the second titration schedule came about, which decreases the sleepiness, you should expect to see improved efficacy because you're no longer having the sleepiness, making the seizures worse. You could have done the same thing if you made them hungry. Dr. Raj, anything you want to add? Yeah, I don't think it's a TSC specific. I think the titration schedule will help with and DEEs across the board. Yeah. I just want to be cognizant of time. We're already a little bit over, but happy to take one more question. Doug? Hi, Douglas Tsao, H.C. Wainwright again. Just maybe a question for the panel. I know you sort of, Steve, highlighted sort of the much greater revenue opportunity ramp that you sort of anticipate in TSC, just given the much larger patient population as well as the dosing. I guess I'm just curious to think about some of the pushes and pulls that are different than the CDD market, right? Where you were the only approved drug specifically for that indication versus TSC, which is more competitive and, you know, how that might affect the curve that we might see. I'm happy to take that. I mean, there's many of the things I mentioned earlier. This disease primarily is so much easier to identify, and that is, that's the crux of the, the answer right there. CDD patients have to be genetically tested. Many CDD patients are lumped into a category of LGS. The ICD-10 code with CDD was only came about in 2020, so many physicians didn't use it, making it more challenging to track them in the data. When you look at TSC, we have none of those hurdles. I think this will result in and of itself in a much quicker uptake. Great. I'll just- Oh, go ahead. Sorry. I'll add promotionally first, and then I'll give it to you, which is, we just finalized a very, very, very large market research project, excuse me, that really zeroed in on the fact that why ganaxolone is going to be so favorable in TSC specifically, is because there are, and Dr. Koenig and Dr. Raj have said this now multiple times, no drug-to-drug interactions, the safety profile, those two things rose above the need for seizure reductions, which was fascinating to us. And there was such favorability and such excitement for product X, of course, that it was really. We had to stop a couple of times and just say, "Okay, is this as good as we think it is?" And it's really driving a lot of how we are going to promote and how we're going to communicate this drug. But the lack of drug-to-drug interactions, the polypharmacy that we know happens with in TSC and other DEEs as well, including CDD, allows for ganaxolone to do so much more than these other drugs. Can I just make a comment, too? Yeah, please. So, you know, I've been in this TSC for 20 years, so I do TSC. I don't do refractory epilepsy, I do TSC. And when I started this 20 years ago, there were zero approved drugs for tuberous sclerosis. In fact, there were no therapies targeted for tuberous sclerosis. And we have gone through multiple new therapies that have been developed, and I've watched each one of them launch. And what I've seen is that the physicians in this field, we've adopted each one. We have welcomed them, we've taken them on because we're now expecting there to be these advances. We're looking for them, we're excited about them. And so this is a group of physicians that run these specialty clinics that have gotten used to now seeing things come onto the market, that have helped these patients. And so I think that that's something to consider as well. So we're expecting these therapies to come out now, and we've been through this a couple of times, and so we're ready for them, and we do see the benefit in using them. And, Doug, I would just add, I think we've been very fair with how we've portrayed the TSC patient population. We're not saying we're targeting 48,000 TSC patients. We've really taken that funnel and said: Hey, who are the refractory patients who failed those 2 to 3 therapies? These are patients who are looking for that next option. So, you know, I think that's a meaningful population. That's how we've defined it. And that 12,700, that's the 6-7X the CDD population, of the addressable CDD population, 2,000. But as we've said, we can't even identify all those 2,000 CDD patients. So, it's growing and the genetic testing is helping drive there, but it's six to seven from a patient population that we're targeting, but it's really in terms of identifying. It's probably ten X or more. Steve, Steve, we get a lot of questions about Epidiolex. You want to just walk through some of the pricing assumptions, anything that people may not always understand? Yeah, and certainly, you know, talking about Epidiolex, I think they've taken a broader strategy across, you know, multiple types of epilepsy, less of, I think, what I would consider to be a refractory epilepsy focus. You know, I think a 25 milligram dose would be around $50,000 WAC per patient. We know in what we see in the trials, not everyone doses up to that 25, and I think in the TSC trial, it may be, you know, ten to fifteen milligrams. So, you know, I think their pricing is likely then, you know, kind of a fraction of what we see by staying in that refractory epilepsy space. If it's $50,000 at, you know, 25 milligrams, it could be $20,000-$25,000, right? On more of a representative dose of what we see in some of the TSC patients, and that's not including, you know, kind of contracting and other discounts. Dr. Raj, were you gonna make comments? Right, yeah. No, in terms of new products for tuberous sclerosis, I think, there are a lot of TSC patients who are looking for a new compound or something available to treat their epilepsy. So, even though there are other drugs that are on the market, I think there's always, something that you're looking for in the next step in terms of treatment. So I think the effect will be promising. Great. Thank you all again, Dr. Raj, Dr. Koenig. Appreciate you so much making the trip. Thank you all for showing up live, folks listening in. We look forward to being back to you shortly with the Phase 3 results and a great AES ahead. So thanks so much for coming.