All right. Good morning, everybody. Nice to see you all here in person. Welcome to the Marinus Pharmaceuticals 2023 Investor and Analyst Event. We're super excited about this because this is our first in-person event to do something like this, and so it's super exciting. And I just want to extend additionally, a really warm welcome to everybody that's joining us on the webcast. My name is Sonya Weigle, and I'm the Senior Vice President of Investor Relations, Human Resources, and Corporate Affairs at Marinus. I also want to introduce our newest colleague to the IR team, Jim DeNike, our Senior Director of Investor Relations. Welcome, Jim. So today, I'm pleased to introduce today's speakers to share our agenda and to make some opening remarks. Before we begin, I'd just like to remind everyone that some of the statements made today are forward-looking statements under the securities laws. These forward-looking statements include substantial risks and uncertainties that could cause our clinical development and uncertainties, and the risks associated with our business are described in the company's reports filed with the Securities and Exchange Commission, including Form 10-K, 10-Q, and 8-K. During today's programs, members of Marinus's leadership team will provide an update of the company's late-stage clinical programs and commercial planning activities. Marinus speakers include Dr. Scott Braunstein, Chairman of the Board and Chief Executive Officer, Steve Pfanstiel, Chief Financial Officer and Chief Operating Officer, Dr. Joe Hulihan, Chief Medical Officer, Christy Schaefer, Chief Commercial Officer, Dr. Alex Aimetti, Chief Scientific Officer, Lisa LeJeune, Senior Vice President and Business Unit Lead of Rare Genetic Epilepsy, Dr. Henri Vaitkevicius, Vice President of Clinical Development, and Kristin Rudisill, Vice President and Business Unit Lead of Acute Care. We're also so very pleased to be joined by 3 external experts who are leaders in the field of SE and TSC. Dr. Dhar, Professor of Neurology in the Section of Neurocritical Care at Washington University School of Medicine in St. Louis, and Attending Physician in the Neurology and Neurosurgery Intensive Care Unit at Barnes-Jewish Hospital. We're also joined by Dr. Koenig, Director of the International Center of Epilepsy at Ochsner Neuroscience Institute, and Associate Professor at Ochsner Clinical School at the University of Queensland. Both will discuss the SE treatment landscape, unmet medical needs, and burden of illness on our hospital systems. Dr. Koenig, Professor and Associate Vice Chair for Clinical Research, Endowed Chair of Mitochondrial Medicine, Director of the Center for the Treatment of Pediatric Neurodegenerative Disease, Co-director of the TSC Center and Department of Pediatrics, Division of Child and Adolescent Neurology at the University of Texas McGovern Medical School, will highlight the unmet medical needs that exist for patients and families with TSC and the impact of refractory seizures on daily life. We are grateful for Dr. Dhar, Dr. Koenig, and Dr. Koenig's participation, and for all who are joining us 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 our commercial strategy, ganaxolone science, and our work in SE. We will then have the first of 2 Q&A sessions, which will be focused on the RSE discussion and will include Dr. Dhar and Dr. Koenig. After that, we'll break for 10 minutes before coming back together for an overview of our work in TSC, our 2nd-generation product development program, a financial overview, and concluding remarks. We will close out the day with a second Q&A session, which will be focused on the TSC discussion and will include Dr. Koenig, as well as Marinus' very own Dr. Ian Miller, Vice President of Clinical Development. Virtual attendees can submit questions via the Q&A box on the webcast at any point during the presentations. We will be running microphones for those of you who are here in person and ask that you limit your questions to 1 per session. A copy of today's presentation is available in 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. Scott? Good morning, everyone. Mic on? Sorry about the technical issues this morning. Ah, there we go. That's a little, that's a little too loud, guys. Did you lower the mic? Okay. Morning. Nice to see everyone live and- Good reminder of what it actually means to run a program live and how you have to get this stuff right. So, I'm gonna stay here. I normally would walk a little bit, but with the webcast on, we wanna make sure that folks can see me, for better or for worse. Thanks for being here live, and thank you all on the webcast for dialing in, and we won't forget about you. We promise that we'll take your questions and do our best to keep you engaged. I wanna start off by thanking our 3 physicians, Dr. Husain, Dr. Koenig, and Dr. Dhar for joining us. We're incredibly appreciative of your attendance. So we know how much you do for patients, and stepping away from your patient care responsibilities to be here means a lot. W hat are we gonna talk about today? Well, I guess I have to go to the next slide. What are we gonna talk about today? We're going to do a deep dive on our clinical trials. We're gonna spend quite a bit of time walking you through the thinking behind the RAISE trial and the TrustTSC trial. We're going to give you a little insight to the future for our commercial organization, both on, for our oral and our IV franchises. And certainly, you're gonna see some. We're gonna give you updates on how we're progressing. As you saw in the press release, we've had a great month of enrollment in the RAISE trial in the month of September, our strongest to date. And we reiterated that we will have top-line data in the Q1 of next year. We're incredibly excited about the recent progress in the study and where we stand today in terms of activated sites. And Joe and Alex will talk about that in a little bit. We'll also hear from Henri, who will walk you through our experience in super refractory status epilepticus, where physicians have requested the use of ganaxolone in emergency INDs, and we've now amassed a significant number of patients who have received treatment. So who are we? Marinus, we, as a team, are dedicated to improving the lives of patients with rare and refractory epilepsies. Ryan is a patient who suffers from CDKL5, and our goal as a company is to help families like Ryan's, who suffer from CDKL5, TSC, or other rare forms of epilepsy and refractory epilepsies. That is our mission. That is our focus. The good and bad of ganaxolone, as a neurosteroid, it has broad activities, and I think in the past, many have been misled and pushed down the wrong road of where this molecule can be most effective, and we'll talk a little bit about that. We also believe, as a company focusing on refractory epilepsy, we have a fantastic business model, and that business model will really lead the company to profitability over time and hopefully create quite a bit of shareholder value. The tricky part about being the first in a field is that it requires a lot of education, so we spend quite a bit of time with our scientific advisory board, our thought leaders. We are thoughtful about our publication strategies. We meet with advocacy groups. We meet with payers, and as the first in class, it takes a little bit more time, but we think that effort is unequivocally worth it. So what do we want you to take away from today? Really, there are 3 messages. We've built a fantastic commercial organization. We've executed, in the 1st year of the launch, and I could not be prouder of the team's execution to date. And as an example, I think our reimbursement success is just 1 piece of the puzzle. We've done an incredible job in educating the community through our marketing efforts, our website, our speaker programs, and we could not be happier with the traction that we've seen in the CDKL5 market. We consider our science quite novel. Remembering 3 years ago, we were the 1st company and are the only company that has aligned the FDA and the EMA on a strategy and a registrational path for patients suffering from non-convulsive status epilepticus. That is not a small feat. It took us 2 rounds at the FDA. It took a lot of help from Henri to get the FDA there, but we were able to get there, and we're quite proud of the fact with a single registration study, the RAISE study, we've now gotten Ztalmy approved in both the U.S. and Europe. I think the 3rd box is: Who do we wanna be as an organization? We wanna be a leader in refractory epilepsy. Our view is that of being very patient-centric focused. We see this as a great business opportunity with limited competitors, very strong reimbursement dynamics, and we are confident that we can do it again in a larger market opportunity. And you're gonna hear a lot from Lisa about that in the H2 of the program. So what's our winning formula? It's about the people, the science, and our approach. We're a small but mighty company. We have roughly 165 employees, yet the experience in this purple box is quite impressive. And without that scientific knowledge, we wouldn't be where we are with our clinical trials today, and without the commercial expertise, we would not be where we are in our commercial launch today. Our goal, moving forward, is to continue to bring in quite a bit of expertise throughout the organization, whether it's specialized in the hospital space, the orphan space, or as we build out our scientific team. We continue to follow the science, and without question, in my mind, the strongest preclinical data for ganaxolone lies in the world of refractory epilepsy. The drug has worked where no other compounds have worked, and it's shown durability in preclinical models where no other drugs have shown such durability. We've seen that in our clinical trials to date, and we believe that is a critical feature of differentiation....Our approach, as we mentioned, is one of science, thinking about a publication strategy, bringing in the right, right leadership, and interacting with payers, physicians, and the advocacy, advocacy community to be 1 voice. And again, I think we've done that incredibly well in the CDD market opportunity to date. So here's a snapshot of our pipeline. You're gonna get a deep dive today into our TrustTSC trial, into our RAISE trial, and Joe's gonna spend some time on our new formulation work, which we're all incredibly excited about. We're spending roughly $100 million in research and development on an annual basis. And our goal today is to not only walk you through those trials, but give you a sense why we believe there is a high probability of success in all of our programs, and we could not be more excited about that. So what's our goal today? Our goal is to really show you the value proposition of ganaxolone and what our plan is to maximize that value. If you start on the left side of the slide, 2019, when many of us joined Marinus, a little less than 5 years ago, we were a pretty small company. We were a little bit lost with what we were going to do, but our phase II data and status really allowed us to fund the company and rebuild the company from scratch. For those of you who supported that fundraising, thank you. I think where we've come today has been just a great journey in less than 5 years. Since that time, we met with the FDA, have aligned on a global strategy for super... for non-convulsive status patients. We had a great outcome with the Marigold study. We've gotten Ztalmy approved in both the U.S. and Europe, had a great commercial launch in the U.S., and we're excited about our partners in Orion launching early next year. But in those 4 years, we've done a lot of strategic deals that we hope have brought value. We've brought non-dilutive capital to the company. We've partnered not only with Orion, but Tenacia, and Tenacia is going to be an important piece of the TSC puzzle. Their enrollment in China has been quite robust and been extremely a positive influence on our thinking about clinical trial work, particularly in China, and BARDA has been just a terrific collaborator. The BARDA team goes with us for every meeting at the FDA. They, they've been supportive of our actions, and they've actually accelerated much of their funding to the company, which is allowing us to invest in long-term solutions and a U.S., a U.S. product from beginning to end, which will be really exciting over the next few years. So you see the green dot where we are today and everything to the purple side of the slide of what's to come. And I'm sure many of you are asking, "Can a small company successfully launch a drug in the hospital space?" I think it's our job today to show you that we think differently, and we can do that, and we will plan on doing that. I think spending some time with Kristin today, you'll get a sense of just how prepared we will be at the time of launch. On top of that RSE launch, we plan to launch a new indication in TSC, and you'll get an opportunity to hear from Lisa, who will talk about her plans expanding the CDD business to a much broader oral business. Our goal is to have you walk away that we are thinking about this the right way and doing the things that we need to do to be prepared for 2025. Now is the time to get on the bus and watch our journey progress. So what is our vision for the organization? It's one about people, about science, and potentially expanding our portfolio. We love being a leader in the rare orphan disease space. We still see a tremendous amount of unmet medical need. We think there are great assets out there that have novel mechanisms of action. We'd love to be a leader in this space over the next 5 years. As of today, our heads are down, and we are focusing on the clinical trials and the commercial readiness that's going to be required for us to be a leader in this space over the next 3 years, next 3 to 4 years. And with that, I'm gonna turn it over to Christy Schaefer, our Chief Commercial Officer, who's going to walk you through a little bit of her vision for the organization and how she is preparing for these significant launches in the near term. Christy? Welcome to an in-person meeting here, and certainly welcome to those who are joining us on the webcast. We'll be sure to keep you as engaged and on the edge of your seat. For those of you that I have not yet met and had the opportunity to meet, I'm Christy Shafer, our Chief Commercial Officer. I have been building and leading the commercial function here at Marinus for the past 3 years. Prior to that, I spent 2 decades in the hospital space, launching new innovative therapies and now, for the past 5 years, launching drugs in the ultra-rare disease space. It was those 2 things together that were made Marinus such an exciting opportunity to kind of marry those 2 worlds that I've spent so much time in. Today, I'll give you a general overview of where we've been highlighting our success and a lot of the plans that we have for the future. But I will say, I'm most excited to introduce to you 2 of my most senior commercial leaders, and they'll take a little bit of a deeper dive for you into our plans and our progress to date. Before I do that, at the heart of everything that we do and the progress that we've made, all of those things are in support of the patients that we aim to serve. It's been a very great privilege to collaborate with the advocacy groups like the IFCR, to amplify the voice of these patients. Let me introduce you to Gigi. Gigi is an inspiring 8-year-old little girl. She lives with CDKL5 Deficiency Disorder. Her remarkable progress is a testament to the positive impact that we're making on patients. We'll have an opportunity to share and hear a little bit more about Gigi's journey with Ztalmy later this morning, but be sure, her story is just the first of many. We plan to bring you lots of stories of the progress that we've made with the Ztalmy launch and the impact that we're making on patients. Gigi gives us a really great opportunity to highlight what better days look like with Ztalmy, and that better days can have a significant impact on not just patients, but their families and the entire CDD community. So moving on to the business side of things. The commercial team is united by a common mission of enhancing the lives of patients. Scott talked a little bit about that as a corporate mission as well, but we highlight these regularly. We've determined that this mission requires a very tailored approach. To do this effectively, we have franchised the commercial team into 2 very, very distinct models: rare genetic epilepsy, which is our oral formulation, and acute care, which is everything IV in the hospital. We knew there were areas where we could scale our success, but more separate and distinct teams specialized in their respective areas would be able to provide us with the dedicated expertise that they each require. When launching into CDD, we did something a little unusual. We went off script and took the rare approach. We believed having and building a team with rare disease expertise was our main priority. With a dedicated rare disease expert at the helm, we knew that ultra-rare disease populations needed something different, different than typical epilepsy launches and the epilepsy launches that came before us. Now, we feel very confident that we could build and execute upon this mission, and the swift and very steady uptick of Ztalmy in the CDD community underscores this specialized deployment model, and now we know that we were right. Continuing on this path, importantly, we built this strategy knowing that we needed to be focused on efficiency and scalability, but most importantly, growth. Now, turning your attention to the acute care side of the business, we likewise believe in this very tailored approach. We have been deliberate in building the specialized niche expertise required for success in the hospital. Hospital dynamics, total value proposition, and launch strategy are just a very few of the details that scratch the surface here, but the acute care team is poised for rapid success under very expert leadership. Now, we're confident in the sequencing of these events, the strategic approach, and timing of this execution. The key takeaway here is that this dedicated focus for both of these franchises strategically positions us to expand our presence just ahead of Marinus's next growth phase, and ultimately prepare us to compete effectively in the marketplace. Now, to validate that rare approach that I spoke a little bit about, I wanted to give you some highlights of our progress today in CDD and our Ztalmy launch. I want to direct your attention quickly to the lighter blue bar here on the right. We're thrilled to announce this morning and highlight our expected Q3 finish in the range of $5-$5.2 million, which confirms 4 quarters of growth from our launch date. And as a reminder, this is coming off the heels of our Q2 announcement, where we increased it, our total 2023 revenue guidance to between $17-$18.5 million. Take a little bit of time just to highlight some of the metrics attributed to this success. Our patient reach extends to over 225 million lives, and we're proud to have 120 unique physicians writing for Ztalmy today. With approximately 140 patients active on therapy, we've seen a broad range of patients, including some young adults, and the median age of around 9 years old. In the rare disease community, swift and smooth access to care is paramount. We continue to showcase a super impressive fulfillment process. Now, at just under 10 days in Q3, we have 90% approval rating with the patients enrolling in our programs. So looking into the future, our advancements in patient identification and capture, along with new enhanced analytics, will be the cornerstone to our continued success. On the commercial team, our constant has been our progress. Since the positive phase III data readout in 2020, we've expanded our reach, supported our ex-US partners, and secured EU approval in CDD... all while executing upon the launch of the first and only treatment for seizures associated with CDKL5 deficiency disorder in the United States. This very steady cadence of activity and these major milestones continue to build on our momentum. As we look into 2024, our very meticulous preparations for both data readouts in TSC and RSE reflect our dedication and efforts towards continued launch execution. This is our ladder of opportunity here in the U.S., and I'll have to say, this is my favorite slide because what we see and are hyper-focused on is exactly what you see here in this large gray circle, a $3 billion total U.S. market opportunity, with $2 billion attributed to our rare genetic epilepsy franchise and an additional $1 billion in the IV ganaxolone franchise. There's close to 60,000 patients who could benefit from ganaxolone in either its oral or IV formulations. We continue to invest in market research that routinely confirms these assumptions, and our confidence only grows as we get closer and closer to these milestones. So what does that translate to for the business today? Look, CDD has undoubtedly offered us a springboard into our future launches. And to remind you, 4 quarters of growth and increased annual guidance with positive payer acceptance across the board. This early success has created a very strong foundation that allows us to expand our footprint from lessons learned and a refined approach. Now, while CDD has been successful, looking into the future, anticipation into the investments we're making in both development programs gives us great confidence in the expanded launch into TSC and our hospital debut. All of this together gives a very clear path to a combined $1 billion revenue target by 2030, and that, we feel, is very within our reach. What's interesting and not included is our ongoing scientific and clinical research. That is honestly the fuel to driving early adoption and a potential label expansion, and that will only drive that number upward. Which is a fantastic segue, and it offers me the great, great opportunity to introduce my colleague, our Chief Scientific Officer, Alex Aimetti, who will expand further on our development and our progress. All right. Thank you. Thank you, Christy. It sounds like we have some fantastic opportunities right in front of us, and certainly the confidence to execute on our mission to really help patients and grow the business. In addition to the experienced team that we've already talked about, one of the real reasons why we have confidence in our ability to execute on this mission is truly the science behind ganaxolone, which we believe is truly unique and differentiated from what currently exists on the market for seizure disorders today. And why is that? Well, that's because ganaxolone is part of a novel class of compounds called neuroactive steroids, which exhibits a GABAergic mechanism of action, which is distinct from other compounds on the market. Now, neuroactive steroids get their name because they're derived from steroid precursors and have that classic 4 -ring structure, but they do not act on classical steroid hormone receptors, and rather, neuroactive steroids modulate neuronal excitability by modulating GABA-A receptors. Now, ganaxolone specifically targets sites on the GABA-A receptor that are distinct from other GABAergic compounds such as benzodiazepines. A key differentiating feature of ganaxolone is that it modulates both synaptic and extrasynaptic GABA-A receptors, where compounds such as benzos only act on synaptic receptors. Now, why do we think this matters? First, it's critical to understand the normal neuronal synapse, which contains a distribution of both synaptic, shown here in blue, and extrasynaptic, shown here in green, receptors. There's evidence that suggests that during chronic, prolonged, uncontrolled seizures, there's a trafficking or internalization process of synaptic GABA-A receptors, making them unavailable for drug targeting. This evidence comes from both a chronic temporal lobe epilepsy model, where we see a downregulation in gamma-2 subunits, which are representative of synaptic GABA-A receptors, and an upregulation in delta subunit containing extrasynaptic receptors. Also, it's phenomena like this that give us reason to believe that ganaxolone could potentially exhibit durability of response clinically in chronic epilepsies and not be susceptible to tolerance. We've actually, as Scott alluded to, seen this clinically in our long-term extension study in CDKL5 patients, where we've observed meaningful seizure reductions out to 2 years and beyond, which is not common based upon clinical evidence and current existing literature. M oving back to preclinical evidence, we see a similar pathophysiological process occur in a rat status epilepticus model, where synaptic receptors represented by beta-2/ 3, and gamma-2 subunits are internalized. And similarly, we see a maintenance to potential upregulation in delta-containing extrasynaptic receptors. So ultimately, it's these combinations of experimental evidence that gives us confidence in ganaxolone's unique mechanism of action, and may play a critical role in the treatment of a variety of different refractory seizures, from chronic epilepsies all the way to acute seizures. And we feel that our different formulations really enable us the opportunity to study ganaxolone across these broad patient populations with high unmet medical need. So now I'm going to start off our pipeline presentations by talking about the opportunity of IV ganaxolone and status epilepticus. I'll... Clinical background, then we'll have our 2 external physician thought leaders take the podium to talk more about the disorder and their clinical experience in managing these patients. Followed by that, we'll have Dr. Joe Hulihan, our Chief Medical Officer, review the existing clinical data and the ongoing RAISE study, including an enrollment update, where we've seen significantly improved trends in recent weeks. And finally, Dr. Henri Vaitkevicius, our VP of Clinical Development, will conclude with our experiences of IV ganaxolone and super refractory status epilepticus through our emergency IND cases and what this potentially could mean moving forward. So status epilepticus is the 2nd most common neurological emergency behind stroke, and describes when a patient has seizures that fail to self-terminate and become continuous or extremely frequent. It's believed that there's approximately 150,000 episodes of status epilepticus in the U.S. per year, and studies have shown that status has been correlated with increased morbidity and mortality, and that the care for these patients is often very costly and requires significant resources. So therefore, therapies that quickly and effectively stop status may play a critical role in improving outcomes and reducing healthcare utilization. So how is status treated today? First-line treatments include benzodiazepines. Patients that fail first-line benzodiazepines are what's called an established status epilepticus. This is the population that was studied in the ESETT study that was published in the New England Journal in 2019. These patients are treated with IV non-sedating anti-seizure medications such as levetiracetam, valproate, or fosphenytoin. Patients that fail at least 1 second-line IV anti-seizure medication are then described to be in refractory status epilepticus. Escalation of treatment in patients with RSE is commonly to third-line IV anesthetics to induce coma, with the goal of seizure suppression or burst suppression on EEG. Typically, these IV anesthetics are administered for somewhere between 24-48 hours and then removed. Those patients where status epilepticus returns upon removal of the IV anesthetic weaning are known to be in super refractory status. Now, what we know very well from the literature is that progression to RSE and SRSE is associated with significant increases in morbidity and mortality when compared to earlier lines of status. What we also know is that IV anesthetics themselves have been associated with increased clinical complications such as infections, hypotension, or the need for mechanical ventilation. As a result, this oftentimes leads to intensive healthcare utilization, such as increased hospital or ICU length of stay. D espite this established treatment continuum that's been reflected in a variety of medical society guidelines, there really has been a lack of level 1 clinical evidence to guide refractory status or super refractory status treatment, and really, a lack of innovation overall in this space. And that's evident through the fact that patient prognosis has not, not really improved over the past 3 decades. So we clearly believe that there's a significant need and opportunity to develop new therapies for these patients, generate robust clinical data to better inform and ultimately revise this treatment paradigm. So we believe that a new therapy in refractory status should accomplish most to all of these clinical goals, rapidly stop status. We believe that the term, "Time is brain," that was made popular in stroke, is highly relevant here as well and could lead to improved outcomes. Have minimal to no drug-related clinical complications that are commonly associated with current SE treatments such as IV anesthetics, such as infections, hypotension, and again, the need for mechanical ventilation. Lastly, demonstrate the ability to maintain status control when the drug is discontinued. We ultimately have confidence that ganaxolone has the potential to accomplish these clinical objectives, and we feel ultimately would provide a meaningful advancement in the treatment of refractory status. So some of the evidence that gives us confidence in IV ganaxolone comes from both preclinical and Phase I human volunteer data. First, on the preclinical side, we see rapid high exposures following an intramuscular injection in mice. What's even more important is that we see rapid attainment of high brain ganaxolone exposures, approximately threefold higher, which is likely due to the lipophilic nature of the compound, leading to rapid blood-brain barrier penetration. These findings were then translated to healthy human volunteers, where high ganaxolone plasma exposures were observed within 5 minutes following a 30 milligram bolus, which is very similar to how we're studying it in the clinic today in RSE patients. And then to the right, these favorable pharmacokinetic results resulted in similar pharmacodynamic responses, where we see rapid dose-dependent effects on an objective EEG Bispectral Index. Collectively, these findings suggest that IV ganaxolone has the ability to rapidly achieve high brain and plasma exposures necessary to have the corresponding rapid pharmacodynamic response, critical for a new therapy in refractory status. A ll in all, we think that the scientific and the clinical attributes of IV ganaxolone allow it to play a potential role across the status epilepticus treatment continuum, and we're committed to studying it in the appropriate trials, in the appropriate patient populations, to best serve the patient needs and ultimately maximize on ganaxolone's opportunity. First, we have the RAISE study in refractory status, and the key treatment objectives of this study is to demonstrate rapid cessation of status and the avoidance of IV anesthesia and hopefully the associated clinical complications. We believe that this study design really maximizes the potential to demonstrate IV ganaxolone's full value proposition in RSE. Dr. Hulihan, our Chief Medical Officer, will go into more details on this study. Second, we have our RAISE II study, also in refractory status, but earlier in the line of therapy. We believe that this study serves a unique objective to assess IV ganaxolone in a broader, more expanded RSE patient population who still have high unmet medical needs. This study is actively opening sites, and enrollment should begin here shortly. Third, we have a Phase II dose-finding study in established status epilepticus caled the RESET study. And lastly, although we don't currently have formal study plans for super refractory status, we have learned a lot through our physician-requested emergency INDs for IV ganaxolone in their super refractory status patients. Dr. Vaitkevicius will briefly review those findings and discuss a potential path forward to better inform IV ganaxolone's potential role in this patient population. A ll in all, we think that IV ganaxolone has some significant opportunities along the status epilepticus treatment continuum, with a real focus in RSE and SRSE patient populations, where we believe there's the highest unmet medical need and the highest healthcare resource utilization. So with that, I'd like to now turn it over to our external experts. It's my honor to introduce you to 2 of the clinical thought leaders with deep experience in status epilepticus. First, Dr. Dhar is a Professor of Neurology in the section of Neurocritical Care at Washington University in St. Louis, and an attending physician in the Neurology and Neurosurgery Intensive Care Unit at Barnes-Jewish Hospital. He specializes in acute brain injury, including stroke, subarachnoid hemorrhage, and head trauma. He is certified by the American Board of Psychiatry and Neurology in vascular neurology and from the United Council of Neurological Subspecialties in Neurocritical Care. He has served as Chair of the Scientific Committee for the annual meeting for the Neurocritical Care Society and Chair of the Organ Donation Research Council. Dr. Dhar is an associate editor for the Journal of Translational Stroke Research and guest editor for the special issue on AI and Big Data for the Journal of Neurocritical Care. Second, Dr. Koenig is a board-certified neurologist at Ochsner Medical Center in New Orleans. He specializes in epilepsy and seizure disorders, headache care, and dizziness. He completed his residency in adult neurology at the University of North Carolina Hospitals in Chapel Hill, North Carolina. Dr. Koenig completed a fellowship in clinical neurophysiology and epilepsy at the University of Michigan Hospitals in Ann Arbor, Michigan. He is the section head of the International Center for Epilepsy at Ochsner and the Neurodiagnostic Service Line at Ochsner Health. He's a fellow of the American Epilepsy Society and the American Clinical Neurophysiology Society. Dr. Koenig is a clinician researcher and is passionate about exploring innovative solutions to improve clinical care. Now I'll turn the podium over to Dr. Dhar. Thanks, Alex. So I'm going to provide my clinical perspective on, based on my experience and the existing data on the current landscape and the climate for patients experiencing and providers caring for patients across the continuum of status epilepticus, illustrated with patient vignettes, highlighting the limitations of the current treatment paradigms, and especially focused on refractory status as we try to prevent patients progressing into this long, dark tunnel. I'm going to discuss the need to balance the concerns about ongoing seizures with the risks of aggressive therapy, especially precarious given the lack of data, and the diminishing returns of escalating interventions for status epilepticus. And then we'll end with the unmet need for novel approaches to help escape or even avoid this dark tunnel. As you've heard, the status epilepticus is the second most common neurological emergency after stroke. 1/3 approximately of patients who come in with status epilepticus are refractory to initial interventions. And this important subgroup has higher mortality, longer lengths of stay, but also poorer outcomes and poorer long-term outcomes. And so a key challenge and target is to prevent patients from progressing to refractory status, and that's the that's a target that, that is largely unmet. So one way I like to conceptualize status epilepticus is really these repetitive uncontrolled seizures are the end result of a number of different diseases and processes and triggers. From epilepsy, genetic epilepsies, as you've heard, there's brain injuries from stroke, trauma, brain tumors, and then onto drug and alcohol intoxication, alcohol withdrawal. So all these processes can lead into status epilepticus, and if those seizures are not controlled, then you enter this, this hazardous tunnel with many dangers ahead. As Alex alluded to, a lot of the concerns and complications and costs of status epilepticus are related to being in that tunnel, to the ICU length of stay, the complications that can develop, and the long-term consequences of that. So we have an opportunity, just like there's a common on-ramp to this process from all these different processes that patients may experience, there's also a small early off-ramp before that kind of darkness sets in, that if we can treat early and effectively, that gives the patient the best chance for recovery without those morbidities and mortalities. Then the other way I conceptualize status epilepticus is from this iceberg metaphor, that many studies, including the ones you've heard in the past, have focused on convulsive status. That's what presents to the emergency department with convulsions and requires treatment. Until recently, less was known about non-convulsive status epilepticus, which is what's beneath the surface. It's not as easily seen. Primarily, it affects patients in the hospital. They may be in a coma, they may have altered mental status from brain injuries, but also from severe medical illness like sepsis, COVID, cardiac arrest. These are all things that can lead to status epilepticus that is beneath the surface. Until recently, this was really underappreciated, and somewhat more recently, with the increase in EEG monitoring in hospitals, we're now starting to see that really this represents the majority of patients who come in with repetitive seizures. In fact, 1 study recently, or several years ago at Columbia University, found that of patients monitored with EEG in the neurology ICUs, but also in medical ICUs, up to 40% were found to have seizures or status epilepticus. Again, highlighting this kind of under-the-surface need and frequency of status. The first vignette is a poster that we presented at the Neurocritical Care Society meeting a few years ago that highlights the diverse emerging threats that can lead to status epilepticus, but also the dire impact of repetitive seizures on the brain. Here, it's a young woman who had relapsed leukemia, and now we really have novel immunotherapies for cancer that you may have heard of, that can be very effective for very refractory oncological emergencies. I n this case, this woman developed neurotoxicity or brain toxicity, which is a known complication, became sleepy, and only because she had an EEG, was diagnosed with non-convulsive status. And this is a spectral analysis of the brain activity, showing intense bursts of seizures that were occurring basically constantly and probably had been occurring for hours before she was diagnosed. And this status epilepticus was not responsive to traditional treatments, to benzodiazepines, to multiple anticonvulsant medications, and so she required suppression of brain activity with anesthesia, with multiple anesthetics, including pentobarbital, as I'll come back to. But what this really highlights is that injury, along with the burden of seizures, led to severe brain swelling, which you see on a CAT scan here. Compared to her prior brain, this is much more swollen. O n MRI, you can see or you may see brightness on the surface of the brain. This is a cortical injury from that ongoing seizure activity. So just to highlight how status epilepticus in these novel situations can lead to a lot of injury and morbidity. So again, there's this continuum you've heard of from status epilepticus as you get more refractory to RSE and super refractory. But I think the way I look at it is there's also another pyramid. There's this inverted pyramid that as we go up and we have greater difficulty controlling seizures, we have less options. We have less agents that we can use to control seizures, and certainly less data on those agents. But also, the complexity and the complications and the difficulty of decision-making rises exponentially as you get to those increased stages of status epilepticus. We really want to prevent having to get to those stages. That's the key message that at least I've taken away from managing many patients in this situation, is if we can stop them before they get to those complications and complexity. We're always trying to balance, again, the risks and the benefits of those treatments... The main case I want to share with you, which is anonymized, very much simplified, but based on a real patient managed in our ICU for the last several months. This is a fairly typical case. A previously healthy young man who had a relatively innocuous infection and then developed some behavioral changes, more obviously, had seizures at home. The paramedics were called, was brought, as is very typical in status epilepticus, to the paramedics, gave some drugs. The emergency room gave more drugs. He was still having seizures, got another, very typical second, medication, lacosamide, and then came to our ICU. And so when he arrived in ICU, he had EEG monitoring to see if those seizures were ongoing. And what this shows is that in the right side of his brain, there was just repetitive spike activity that was going on. And on the lower panel, you probably see more easily the right hemisphere power analysis that shows these repeated red, seizures that were occurring every 2 or 3 minutes, lasting for about a minute. And this, as seems to be often the case, was despite giving more anticonvulsant drugs, giving more benzodiazepines. And so this timeline, I think, is really the key to highlight how difficult it is to manage a patient who develops refractory status. A t this point, he had transitioned from status epilepticus to refractory status epilepticus, and that's really the start of that dark tunnel. So at that point, the 1st key decision is whether to administer anesthesia. Do we have anything else that we can do to stop the seizures, or do we need to go to anesthesia? And because that's gonna require intubation, which is what he had, and the decision was made based on how aggressive these seizures looked and the hope of preventing brain injury from those seizures, to progress immediately to burst suppression, which is a very aggressive target to kind of put the fire out, to turn the brain off, into a coma. And he received propofol for that, which is 1 of the 3 typical agents, which is a lipid-soluble, very rapidly titratable drug. T he seizures did stop, along with other drugs that he got for a period of time. But this highlights a problem with those agents, so one of the problems, and he developed something called PRIS, or propofol infusion syndrome, which, especially with high doses of propofol, can be a fatal complication of those drugs, where he developed metabolic acidosis, lactate was elevated, and it can lead to cardiovascular collapse and death. So at that point, we had to immediately stop the propofol. And you see this mainly in status because we don't use these doses of propofol. Just, you know, if you have a colonoscopy or you have other kind of procedures, you might get propofol, but you don't get these doses of propofol. So PRIS is specific to... It's more likely in young patients as well, which obviously he was. As soon as we stopped propofol, he had recurrent seizures, and so then we had to think, what else do we have available? At that time, he got another anesthetic, which was midazolam, pretty typical agent, but also ketamine, which sometimes we can add along with the midazolam. In this case, those 2 agents, he kept on having repetitive seizures, those stars. We decided, and often, personally at least, I hold off on this as a last resort, even though it is very effective to go to pentobarbital, which is the most potent anesthetic that we have. That really did eventually stop the seizures, but has a very long half-life. It lasts for days and even weeks. H e was put into burst suppression for over a month in the end because he was actually having breakthrough seizures every time we would lower that, even by, what, 10%. Not turn it off, but go down by 10%, he would immediately relapse back into seizures. So this is just to highlight. Then during that time, you know, he had lumbar punctures, MRIs, and then it was really difficult to know what to do because he can't stay on pentobarbital for, you know, any—as I'll show you, the risks are pretty high. So he kept on having these recurrent seizures with weaning, so he went back on for another few days. Then he was obviously on this EEG monitoring, which is resource-intensive for that whole 1+ month, which is he was in ICU, he was intubated. T he decision was made actually to do immunomodulation, which is a new treatment for status of this type, which was basically to remove all the antibodies from his system in case there was something going on. So he had steroids, he has plasmapheresis, which is a way to remove antibodies. He even had other treatments that basically suppress your immune system totally. At that time, he underwent tracheostomy because there was no way he was getting off the ventilator quickly. Then eventually, because he just couldn't get off barbiturates, he had several investigational therapies that are extremely resource-intensive. We don't have data on them, and they're hard to achieve. For example, he underwent electroconvulsive therapy, he underwent the ketogenic diet, and eventually, with a combination of factors, his seizures were able to come under control after several months, and after about 3 months, he was able to leave the ICU. But still... 'cause actually, I wasn't on the ICU this whole time. It may surprise you, but I wasn't on for the whole 3 months. But, every single attending in our ICU took care of him, obviously, in this time, and I hadn't seen him, and then I came on, and he had left the week before, and that was a major achievement for our hospital, to get him out of the ICU, a major achievement. There was a party thrown. He went out, a very careful plan, 6, 7, 8 drugs, off pentobarbital, which obviously he can't leave the ICU, breathing on his own, sorry, through the tracheostomy. And then 1 day, 3 days later, he came back in, and what we figured out is somewhere in ordering his anticonvulsants from IV to oral, the timing had been changed from, you know, 9:00 P.M. to midnight or something. And that 3-hour delay in him not getting his medications led to him having seizures again. Now, thankfully, it wasn't status epilepticus. It was just a few seizures, and we were able to control it, but just highlighted how tenuous the situation was even at that point. A gain, stepping back from this case and from what I've been saying, the way I conceptualize our current situation with status epilepticus is that we do have some research in the early phases. So as you progress from benzodiazepines, which paramedics can give, anticonvulsant drugs, anesthetics, immune treatments, the research is really all on the front end. We don't have good research as we go to those more advanced and aggressive therapies. But also, the incremental benefit is less and less. It's not like you add pentobarbital, and you double your benefit. It's actually less and less as you get more aggressive. The chances of, you know, electroconvulsive therapy helping are not a hundred percent. And so you have diminishing returns, but you have increasing risk, and all those therapies have significant risk as you go up. This is highlighted by this one more way to look at it, that we're escalating our interventions but also escalating the risk to the patient. Nonetheless, even anticonvulsant drugs have complications. Drug toxicity, liver problems, cardiac arrhythmias can happen with our routine anticonvulsant drugs. But certainly, as you go to sedation, those patients need ventilatory support. Anesthesia can lead to the whole body shutting down, shock. You know, your bowel shuts down, your muscles shut down, and then if you add on immune system blocking, then you're at risk for pneumonia and infections. And so really, we're trying to be cautious in advancing in this path because ultimately, we want to control the seizures without leading to long-term damage from the treatments for the seizures. T hen finally, one other problem we have is when we're treating with this very aggressive burst suppression, and this is just an EEG showing a small bit of activity, and then the rest of the activity is flat. That's what burst suppression looks like. This study from Switzerland compared patients who achieved burst suppression versus those who didn't for status, and what they found is that, first of all, it was hard to achieve burst suppression. Second of all, there was more complications, as we would expect if you went more aggressive, but there was no better outcomes in patients who had burst suppression than who didn't. So it really raises, in my mind, a question: even when we wanna go to those levels, do we have good data? Are we doing the right thing for the patient? I'd finish by proposing what I think would be the preferred treatment pathway for patients with status epilepticus, and that is, you know, if we can break those seizures early, then not only do we avoid anesthesia with the risks for all the complications and the lack of even uncertainty of whether they work, but often we can get the patient extubated very quickly. When seizures are controlled, people can wake up, and then they can get extubated, or even better, we can avoid intubation in the first place. That would be ideal. And then in those cases, when I've seen that, patients can leave the ICU the next day. They can go home in 2 more days with their anticonvulsant drugs titrated. I think there's a definite unmet need for new ways, new approaches to address this gap and to assist patients getting out of that dark tunnel and to reemerge into the light. Thank you. All right. Thank you, Raj. Everyone, can you hear me? Well, I'd like to start by thanking the Marinus Scientific and Medical Affairs team. I congratulate their efforts for developing a potential solution for this greatly unmet need that I'll be sharing. So I'd like to do a little bit of a deeper dive into the clinical attributes and specifically talking about status epilepticus. This is what I do when I talk to my trainees and students. So status epilepticus is not just another type of epilepsy. It is a progressive phenomena. It is a medical emergency, and the fact is, this medical emergency can occur at any place, whether in the hospital or out of the hospital, for any patient, during a vacation, anytime. It's important to realize that anyone in this room, any patient who experiences a brain insult or injury, is susceptible to develop status epilepticus, and we need to take this with the utmost seriousness. So I wanna share 2 important facts. Number 1, like I said, everyone in this room most likely has some degree of blockages in their coronary artery. Why? Because we live in North America, it's our lifestyle. And with these blockages, as they progressively increase, that lumen becomes narrower and narrower, right? And then we hear of heart attacks. So what is a heart attack? Heart attack is not just progressive narrowing of this lumen, and then, ultimately, there's no blood flow. A heart attack is an acute process. It's... It is a medical emergency by nature of an inflammatory process that leads to the abrupt occlusion of that lumen, and that process occurs over minutes to hours. So it's important to understand that status epilepticus is a similar medical emergency, right? There's a state change that occurs in the brain, in each and every neuron in the brain, that leads to status epilepticus. So it's not just seizure, seizure, then progressive status. One way to look at this analogy, for all the economists in the room, is when you look at interest models, where you have simple and then compound, you see that exponential potentials of gain, right? So we see the same phenomena. That leads us to better understand this condition from an emergency standpoint. I want to focus on the clinical implications, the aspects, what drives our decision-making as clinicians, as we manage this condition, and then I'll zoom out and talk about some of the healthcare delivery aspects, utilization, and the economics of it. So when we drill down onto the patient, we understand status epilepticus as something that's been defined more than 30 years ago by the International League Against Epilepsy, as a condition where there's progressive seizures or repetitive seizures without enough time for the brain to have recovery. And what that means is that there's progressive, ongoing, irreversible damage. You know, our brain is not like these, the skin system, where, you know, you have repair that's ongoing and there's recovery. Once you have damaged neurons, you have damaged neurons. Why that's really important is because as status continues to progress and neurons continue to die on an exponential level, every second you see destruction of the brain and brain atrophy. Here's a case to illustrate that in the literature. This is a 19-year-old individual who presented with status epilepticus, was treated with IV anesthetics. In these images, as you can see, the first image is of a healthy brain, that age group. As time goes by, you see progressive loss of neurons, right? So that's 10 days, 30 days, and at 4 months, that brain that you see, that shriveled brain, that shrunken brain, is reminiscent to an advanced Alzheimer's patient. Imagine this 20-year-old living with this type of brain. I t's really important that we address this condition early before that neuronal damage continues to progress. Now, when we start to conceptualize status and try to understand the underpinnings of what's going on, this is a busy slide, and I want you to sort of ignore the first topic. We'll come back to that. But look at the bottom. Look at the mortality index over here. As time progresses, our risk for mortality exponentially increases with status, and also really illustrates here a small window where we can make a difference. This illustration came from the Yale group of internationally renowned epileptologists and scientists, and they proposed that the sooner we act, right, the better chances we have at reducing that risk of mortality as the brain starts to fail, as the other organs start to fail over time. Now we look at this model of sort of the pathophysiology, the different potential areas of targeting in this review, in Lancet, and we, we understand status as a progressive condition with different stages as it starts at the very beginning and as it progresses down to hours and days. When we look at this conceptual understanding, it really gives us an idea of where we can move the needle, where we can make that intervention, that change, to stop sort of that progressive downstream effects. Interestingly, here, we really can't do much at stage 1, right? It makes sense scientifically to go to stage 2, because it's a matter of milliseconds. If you look at stage 2, what they identified, some of the interesting target points is that first line talks about GABA- A, right? As Alex pointed out, neurosteroids are a phenomenal category of therapeutics that are available to us that sort of analogous to what the human body has already created to help protect the brain. And when we can develop synthetic analogs that can actually work on these same receptors, we have the capability to stop status as it continues to progress in that journey. So when we go back to that same paradigm, we go back to that understanding, and we say, "If we have the right target and at the right time, we have the best chance of mitigating that risk of mortality, of and, and, and any other downstream effects on the brain." So where you want to target is before that homeostasis in the brain starts to change. Now, we talked about the basic science component. Let's talk about some real world. What-- Why this matters and what we understand. It's a bit of a busy slide. This is real-world data from Europe, and this is more than 500 patients that were reviewed. We look at 2 key measures of outcomes, right? We look at mortality, right? Survival, death, and then we look at disability, which they study this as modified Rankin. We want to understand over here is that we want to reduce mortality, and we want to reduce disability. How do we accomplish that? When we look at the breakdown, they broke down patients categorically into those who responded to early treatment, those who responded to some of the second-line agents, those who didn't respond to second-line agents and required anesthetics, and then those who didn't require anesthetics at all. Looking at this from a bird's-eye standpoint, if you want to reduce the mortality, right, and keep it under 25%, right, you wanna work on that population. You want to do the interventions that you can where you do not require anesthetic. And if you look at disability, and if you want to keep that disability number, let's say, under 50%, then you wanna do the same thing, right? It's the same mirror effect, right? You wanna make sure that you treat these patients effectively with your first-line agents, your second-line agents, before the need of anesthetic. And that's a really critical point to understand we have this. We also have real-world data that comes to us from the American literature as well. O ne of the arguments that I face and I come across is: you're telling me it's a medical emergency, you're telling me that treating sooner makes sense, well, then why not just throw anesthetics at every patient that walks in the door at the very beginning and treat and call it a day?... Right? The reality is that there's-- there are complications and downstream effects that we want to avoid, and Dr. Dhar mentioned that, that long, dark tunnel. We know that when we treat these patients with anesthetics, right, we go on mechanical ventilation. The longer they're on ventilation, the longer it takes to get them off that ventilator, to get them back to regular breathing. It leads to more and more complications, ICU-related complications. Human body is not designed to be stuck in an ICU. It leads to delirium, neurocognitive complications, and then that scary picture of brain atrophy that we saw. So these are things that we don't want to happen. So unfortunately, throwing anesthetic at a patient at the beginning is not a viable option. We need to still go back and look at our first-line and second-line agents, and that's why there's a much, much greater need for better second-line agents to abort that process before it progresses. And as I talked about, we do have great, real-world data. This was published right before COVID. This was published in JAMA Neurology. This is a review and analysis of more than 43,000 patients in America, and I'll break this up for you. I f you look at on the left side, on the table there, what they did is they, again, categorically, put patients in 3 groups, right? The group low are the ones that came into the hospital with diagnosis status. They require 1 agent, and it was treated, right? Well, and good, this patient's recovered, right? So in terms of refractoriness, very low. Then the second group, moderate, are the individuals that might have required 1, 2, 3, or even more of these second-line agents to treat that status epilepticus, right? Because we're interested in refractory, we want to understand the outcomes of refractory. And the 3rd group are the ones that required anesthetics, some responded, and some didn't respond, right? So the highly refractory. Now, if you look at the distinction in terms of what the impact, the clinical implications of that, on the left, you see that table with regards to complications, right? When you're a hospital system, a health system, and you're worried about dollar reimbursement, you're worried about national ranking, this is what you want to keep low. Those numbers, you have chief quality officers, and their primary job is to keep these numbers low, right? As to the best of their ability. If you look at those patients who require anesthetic or refractory, those numbers are, obviously, very high, right? You want to do your best to try to treat these patients effectively. You're incentivized to treat these patients so that they don't become more progressively refractory. Now, on the other side, you'll see a table which explores the utilization and the health economics behind this, right? The more refractory the patient is, the longer they're going to stay in the hospital, right? So that's more hospital days, right? Obviously, that drives cost. In addition to hospital days, there's more likely that those patients will be consuming ICU beds, and we all know the scarcity of ICU beds that we experienced during COVID. And the fact that on a day-to-day basis, and Dr. Dhar can also talk about this, the fact that we are in this constant diversion, we just don't have enough beds, enough ICU beds in the hospitals, right? And so if we're trying to consume this and it's an overutilization, this is something that we need to certainly target and work on. T hen if you look at the cost, substantial increase in the totality of cost of care and also per day cost of care for those individuals who are more and more refractory. Again, this goes back to the approach that you want to avoid anesthetics as best as possible. You want to look at drugs that can target the system, that can prevent the progression of the disease before the stage where you require anesthetics, before the stage where you require drugs to essentially shut down the system, shut down the brain. And then you want to... The hospital system is also incentivized to give us the resources, the tools that we need in order to accomplish that. So that's what I have for you. Thank you. And I'll turn it over to Joe. Thank you. Thank you, Dr. Koenig and Dr. Dhar, for your clinical insights about status epilepticus. What I'd like to do is go over some of our own programs in status and start by discussing our completed phase II study that was published in Epilepsia. And as I recall, seeing these data for the first time over lunch with Scott in Philadelphia about 4 years ago, and was really very positively impressed by the data, and it's one of the reasons I joined Marinus, one of the reasons I'm glad to be here. So this study was an open label study, 17 patients with refractory status. They'd failed at least 1 second line, IV AED, but had not yet progressed to IV anesthesia. The dosing, there were 3 dose cohorts. There was a low dose cohort who received 500 milligrams per day of ganaxolone. A medium dose cohort that received 650 milligrams per day, and a high dose cohort that received 713 milligrams per day. Now, these patients differed not only in the total amount of ganaxolone they got during the day, but the way it was administered. Ganaxolone daily dosing is not limited by the drug itself, but by the excipient Captisol. We're capped at giving 50 milligrams per day of Captisol, so had to work within that constraint in developing the dosing. And at the time, we didn't know how much ganaxolone needed to be given or for how long. And so, these regimens differed not just in the total daily dose, but in how the infusion rates were varied. W ithin that, just high level in terms of the outcomes, the primary endpoint was lack of progression to IV anesthesia, and none of the patients in any of the dose groups progressed to IV anesthesia. An important concept in talking about treatment of status epilepticus is the idea of breaking the status. Dr. Dhar referred to that when he was talking about his patient, who had to be on pentobarbital for a month. The idea is that the effect needs to persist after the drug is stopped. You give a short-term treatment early on, it could be a benzodiazepine, 2 or 4 milligrams of lorazepam, and you break the status, and it doesn't come back. Or at the other end, super refractory status, where you have to give at least 24 hours of an IV anesthetic, in some cases, very long, and in Dr. Dhar's patient, a month of IV pentobarbital. So that is the goal. Unlike in chronic epilepsy, where treatment needs to be continued, there has to be a durability of effect after the drug is stopped. We measured that in the phase II study by seeing how many patients needed treatment escalation after the drug was stopped. We saw at the high dose group, none of the patients had treatment escalated for 24 hours after ganaxolone was stopped. The other notable finding was the time to status cessation. The median time to stopping status in these patients was 5 minutes, and if we can replicate that in the phase III study, that would be a big differentiator from the currently available drugs for status treatment. So I'd like to talk a little bit more about how the drug was given, the infusion regimens. So in the low-dose group... First of all, all 3 groups got an IV bolus of 30 milligrams. In the low-dose group, after that bolus, we maintained the rate of ganaxolone infusion that would give a blood level in the range of 750-800 nanograms per mL. And then for the next 2 hours, kept it around 500 nanograms per mL, and then it dropped to half of that and then continued until 12 hours before it was stopped. The last 12 hours was a taper. We're calling that 500 nanogram per mL level the target concentration. In the low-dose group, after they were at or above 500 nanograms per mL for 4 hours, that suppressed the seizures. As you can see, the line part of the graph is the seizure burden, and the gray boxes are the ganaxolone levels. Once ganaxolone dropped below 500 nanograms per mL in that group, the seizure burden increased again. It looked like potentially you would need to maintain that target concentration for a longer period of time. Another way to stay within the Captisol limit... Again, we didn't know whether it was duration of treatment or ganaxolone concentration. The medium dose cohort looked at, well, maybe it's just how long you give it. This patient group got a bolus, but then they received a more intermediate level of infusion of ganaxolone. The level was maintained at around 400 nanograms per mL. After the bolus, seizures came down quite a bit, but as soon as the regular infusion began, the seizure burden increased again. It appeared that that level of ganaxolone was not adequate to break the status. It had to be at a higher concentration, and it had to be for a longer period of time. In the high-dose group, again, a bolus, that first 2 hours, the left gray box maintained around 800 nanograms per mL, and then for an additional 6 hours, it was maintained at the target concentration of 500. This time, you know, after the bolus, the seizure stopped, but when the infusion rate was reduced, seizures remained, did not recur. I looked at the EEGs from the phase III study. This shows up to 14 hours. I reviewed up to 24 hours. In this high-dose group, the seizure burden was virtually zero, so for 24 hours. The status stopped, and it did not recur. It appears that you have to give ganaxolone at that target concentration of 500 nanograms per mL for at least 8 hours. Because of a change in the way the drug is formulated, we're able to give it at that high concentration, target concentration for 12 hours, to break the status and ensure that it does not come back. Pictures are worth much more than words. This is an example of a case from the phase II study. This was a 55-year-old woman. She had a left parietal stroke 2 years previously, and then she had an aneurysm clipping, the left middle cerebral artery aneurysm clipped 12th of April 2019, and then she was put on levetiracetam for seizure prophylaxis. She had not had seizures to that point, but to prevent the recurrence, she was put on levetiracetam. And then on 19th of April, 1 week later, she came in with a fluctuating aphasia, language deficit, and encephalopathy. Had an EEG, it was determined to be seizures, and those seizures increased in duration and intensity over 24 hours. They increased the levetiracetam dose, and then she received lacosamide and phenytoin. She received a high dose of phenytoin, 2,100 milligrams, higher doses of lacosamide. And what this illustrates is the EEG. This is an EEG rhythmicity spectrogram.... And seizures are essentially excessively rhythmic, high amplitude activity. And so each of those dark spots, dark bars on there, represents a seizure, and that goes back to 9 hours before initiation of ganaxolone. And so the patient's having 7-minute seizures, about 6 or 7 of those per hour. The triangles represent administration of medication. So at about 6 hours before starting ganaxolone, she received 400 milligrams of lacosamide, which is a high dose. That was probably a dose that was intended to abort the seizures. 100 milligrams of phenytoin, that was likely just a maintenance dose that was scheduled to be given. But then 2 milligrams of lorazepam with another attempt to abort the seizures, and there's no change in the EEG with any of those drugs. Ganaxolone is given, and you can see there's a rapid decrease in the seizures and a complete cessation of seizures after a couple of hours. And I'm not sure, I tried to figure out, you know, the cutoff for seizure burden that defines status as 20%. So that may have been an immediate cessation of defined status, but regardless, there were no seizures on the EEG, and that patient remained seizure-free. In terms of safety, again, this is a patient population that is seriously ill. Patients had a range of adverse events at a low frequency, leukocytosis, leukopenia, neutrophilia, and so on. S omnolence was the most common, and sedation. So 7 patients had either somnolence or sedation at some point during treatment. Most of the adverse events were considered mild to moderate in severity. 2 were severe, and there were 2 serious adverse events, sedation, assessed as treatment-related. A concern obviously with sedation is the risk of ventilatory compromise and the need for intubation. 9 patients came into the study non-intubated, and 8 were intubated upon entry. Of the patients who weren't intubated upon enrollment, 6 remained off a vent for the entire time. 3 required a period of mechanical ventilation, but were able to be removed from the vent. The intubation occurred not at the peak levels of ganaxolone, but later during the infusion. However, they were all able to be extubated. And actually, there were 8 patients who came in intubated. 3 more were intubated during the infusion, but all of the patients, all the surviving patients were able to be extubated. Now, most of those were for good reasons. There were some, you know, patient could be extubated, for example, for a tracheostomy. 3 patients during the study died, but the patients who survived with high function, which was most of them, they were able to be extubated. So, the summary of the Phase II results. Ganaxolone prevented escalation in all patients to IV anesthesia. There was rapid control of the seizures. The response was sustained, the effect was durable, and the safety was favorable in terms of the risk-benefit of ganaxolone for status epilepticus. Our ongoing phase III study, as we've mentioned, enrollment has picked up well after the summertime. We're on track. Right now, we have more than 70% of the patients enrolled that we need to get to the interim analysis, which is planned at 2/3 of the total enrollment, 82 patients. We're on track for that. Just to review the study design, the key inclusion criteria is patients 12 years of age or older with refractory status epilepticus. They failed at least 2 anti-seizure treatments, either a benzodiazepine and 1 second-line IV AED or 2 second-line IV AEDs. We made that modification to the protocol because we realized that some patients in the ICU may progress straight to the second line IV AED. They've gotten so much midazolam or other GABAergic drugs. It wasn't necessary to repeat a dose of a benzodiazepine. And another modification to the protocol that we included was that IV anesthesia would be the likely next step. If the patient fails study treatment, they would go to IV anesthesia. Previously, we had said that the patients that IV anesthesia would not be contraindicated. We strengthened that inclusion criteria to indicating that that would be the next treatment the physician would administer. Exclusion criteria, life expectancy couldn't be less than 12 hours. We excluded patients with anoxia as the cause of the status. And then, as I mentioned, the study treatment is an IV bolus followed by continuous infusion with 12 hours at or above 500 nanograms per mL. Then for the next 24 hours, it cuts back. The infusion rate's cut in half, and the last 12 hours is a taper of ganaxolone. So there are 2 co-primary endpoints, and we need to achieve statistical significance independently on each of those co-primary endpoints. One measures onset of action, and that's the percentage of patients where, in whom status ceases within a half hour without other treatments for status epilepticus. And we're measuring durability of effect as the proportion of participants who do not progress to IV anesthesia within 36 hours. We also have 2 key secondary endpoints: time to SE cessation, measured as a continuous variable as opposed to the categorical variable at 30 minutes, and then again, for durability of effect off drug, no progression to IV anesthesia for 72 hours or 24 hours off treatment. All of those endpoints will be measured within the first 72 hours of treatment. I'll get back to that when I talk about how we plan to conduct the interim analysis. There are a number of other secondary endpoints that are listed there, reduction in seizure burden and so on, discharge destination, and then healthcare utilization endpoints, time on mechanical ventilation, days in the ICU, days in the hospital. The interim analysis, again, I mentioned that that's going to be conducted when we hit 82 patients, and the way we're conducting the interim analysis is that when the 82nd patient hits 72 hours of treatment, we'll freeze the database at that point. Those patients will continue. There's a follow-up visit at 4 weeks. So the total duration of the study for the patients is 4 weeks. But we're gonna freeze the database when that 82nd patient hits 72 hours. At that time, we'll do the final data cleaning. We'll provide the data to an independent, unblinded statistician, who will generate tables for just the co-primary and key secondary endpoints, and then the patients will continue in the study. That data will be given to the DMC, who will make the determination of whether we've achieved statistical significance on the co-primary endpoints at that point. We're gonna continue to enroll patients during that time in the double-blind study while the data is being cleaned and analyzed. That will provide a few more patients that won't be part of the pivotal dataset, but we'll be able to analyze that additional N, however many patients that is, for the double-blind endpoints. Later, after the last patient has completed 4 weeks of treatment, whether it's, you know, 82 plus the few more that enroll while the data are being analyzed, we'll analyze the other secondary endpoints, and then those will be presented at medical meetings. We'll analyze those subsequently. So the top line will include the key secondary and key primary endpoints, and we have 94% power to detect a 40% treatment difference at the interim analysis. So the study is robustly powered, so that we have a high degree of optimism about the interim analysis. So if it is stopped for efficacy at the interim, we're on track to release top-line data from the interim in the Q1 of next year. W ith that, I'll turn the podium over to Henri. Actually, Henri came to us from Brigham and Women's Hospital. He's a neurointensivist, and he was actually the highest enroller in the phase II refractory status study, so very pleased when Henri joined us. So Henri, it's all yours. Thank you. Thank you, again. Before I get started with the super refractory status update, I just want to spend a little bit of time on the patient population that we have recruited thus far into the RAISE study. And before we do that, a review of who we are trying to recruit. For the RAISE study, we really were trying to recruit patients, a subset of refractory status patients, who are otherwise imminently going to IV anesthesia, i.e., they're seizing bad enough and failing enough therapies that they have the highest likelihood to progress to IV anesthesia. For that reason, I thought it was important to review who we have recruited thus far, and I'm really excited about the fact that we are at the stage of this trial that we actually can look at these numbers and then provide some meaningful outputs. Just for sake of comparison, I'm gonna take some time to compare the phase II open label study, particularly in the table on the left to the currently recruiting patients in a RAISE-III double-blind, placebo-controlled study. So to start with, they're very similar age population, which makes sense. About half of the patients in both trials have history of epilepsy, and that's important because sometimes history of epilepsy makes people more susceptible to treatments and have different kind of reactions to treatments. Next thing is seizure burden. We have 60% ictal burden, electrographic ictal burden in our open-label study, and it dropped down to 33% in a PIP episode in the RAISE study. That is not unexpected, and the reason for that is that our inclusion criteria switched from 50% to 20%, and that is consistent with the change in the guidelines. So guidelines from ACNS specifically decreased the ictal burden as being toxic and diagnostic of electrographic status from 50% to 20%, which made this inclusion criteria consistent with clinical practice, and therefore, as expected, decreased ictal burden in the study recruited. In addition to that, just to dive in a little bit more, I'm gonna point you towards the table on the right there. What kind of status did we see? As expected, majority of the patients had no motor symptoms, so these are non-convulsive status epilepticus patients, about 70% of patients. The people who have motor symptoms, otherwise convulsive motor symptoms, they are largely focal motor symptoms. So again, we are recruiting focal status patients with convulsive or non-convulsive patient population. Next thing is STESS, which is really a score to measure the severity of status at presentation. As you can see, the STESS score is identical between the open-label study and double-blind, placebo-controlled study. The next thing is severity of the disease, as measured by refractoriness to treatment, and that's how many IV anti-seizure medications these patients failed before receiving investigational product. In the open-label study, it was 2, and which matches the phase III double-blind, placebo-controlled. It's also 2. Just to clarify, even though the median number of an IV anti-seizure medications in these patients were 2, many patients received more than 2. More than 40% of patients in the RAISE study have received 3 or more anti-seizure medications before receiving investigational drug. As a matter of fact, the median total on the anti-seizure medication exposure in this population is actually 3, and that includes oral medications that are beyond IV exposures. As Joe mentioned, in our trial, we are not requiring patients to receive benzodiazepines. So I thought it was important to understand that despite that, 80% and 90% respectively of patients receive benzodiazepines as one of the treatment options before receiving investigational drug. These are sick patients. The mortality in the phase II, open-label study was 18%. The mortality in double-blind, placebo-controlled study is 27%, which is again consistent with what would be expected from the epidemiological studies. As for etiologies, the etiologies are matching completely between the 2, between the 2 studies, and they're really consistent with what I would expect being at the bedside and seeing patients in your ICU. In addition to that, I, I just wanna mention that these patients are refractory for some period of time, and again, we are asking the clinicians to recruit patients when they're ready to start IV anesthesia as another alternative. That means that they are really trying to do all things possible before initiating investigational drug, because their only next step is IV anesthesia. Indeed, the last escalation of care prior to initiation of IP was 10.5 hours, the median time to last escalation of care. The 2nd escalation care before that was 28 hours, and beyond that is 54 hours. So after the diagnosis of status epilepticus to initiation of IP, on average or in median time, was about 24 hours. So these patients are sick in the intensive care unit, being taken care of by clinicians, escalating care throughout the time, waiting until they're ready to go to IV anesthesia, and really only then entered into the trial for the treatment with an investigational product. At this point, I will transition to a super refractory status. Alex went through the definition of super refractory status, but I'll just remind, remind you that super refractory status population are the patients who already failed IV anesthesia. So these patients are really the most refractory patients, most sick patients presenting to our institutions with status epilepticus, and actually carry a substantial degree of mortality, up to 40%, and represent about 4%-13% of all status patient admissions. Now, as we mentioned, when status become refractory and they progress to IV anesthesia, one of the important aspects is introduction of artificial ventilation, and not just short-term artificial ventilation, but the long-term and the long-term defined by longer than 24, 48 hours. What that introduces is a substantial increase in length of stay, both in ICU as well as hospital. It introduces unfavorable outcomes and increases mortality specifically. Now, if we look at the outcomes, again, SRSE patient outcomes carry substantial mortality. 40% of these patients die. The 35% of remaining patients, they have substantial neurological deficits going forward, and only 25% recover back to the baseline going forward. So these are sick patients with dramatically impressive outcomes. As we started our program in the RAISE study, as well as started recruiting into our open label, as well as our phase III study, shortly after that, we started receiving requests from the physicians to help us to help them treat super refractory status epilepticus and the IND process. Now, under that process, to date, we treated 19 patients, and they were spread out throughout kind of all age groups, including substantial number of pediatric patients, as well as adult and adolescents.... Many diagnoses were there that are representative of these refractory patients, and that's including NORSE, FIRES, Lennox-Gastaut, PCDH19, the autoimmune encephalopathies, infections, vascular disorders, as well as mitochondrial disorders. Out of those 19 patients, 9 recovered, 3 were considered partial recoveries, and then 7 did not recover. I think it was important to recognize of how we approached this patient population. To start with, we treated patients very similarly, how we treat patients in the RAISE study. We treated them as if they're actively seizing at that particular time. In contrast, what we actually recognize that SRSE patients at the time of starting of them actually don't need to be seizing because they are on IV anesthetics. The goal is not necessary to acutely stop seizures, but actually effectively withdraw anesthetic. I think in that sense, we had to change the way we dose these patients, and hence we introduced kind of a new way of dosing. A few things were achieved. First of all, since we don't need to stop seizures acutely, we can decrease the Cmax. There's no reason to slam them with high doses of ganaxolone up front. So we decreased the Cmax, but then we know that from phase II study that Joe presented, that we need probably somewhere in the range of 500 nanograms per milliliter concentration exposure in order to prevent seizures from coming back. So we would like to maximize that period of time in the range of 500 nanograms per milliliter. And we actually were able to... Each individual case applied for FDA under EIND was able to be exposed by a 20% higher level of both Captisol and ganaxolone than we're currently dosing in the RAISE study. So therefore, the AUC overall exposure was substantially increased per day. In addition to that, these are chronic patients. We really know it would be unrealistic to expect a patient to be better after a month in Dr. Dhar's ICU, receiving pentobarbital, and in 48 hours, coming off anesthetics. That was really unrealistic expectation, and therefore, we really expanded the length of treatment to 5 days, introduced 2-day additional taper onto oral medications, which were often requested by the physicians as a kind of late 3-month taper. So really a new way of trying to treat these patients. As a matter of fact, out of 19 patients that were treated under this EIND process, 5 were treated with the new dosing paradigm, and 4 out of 5 of those patients successfully came off IV anesthetics. What is potential future for this program? We don't know yet, but still trying to learn things. But we're really excited about encouraging, you know, encouraging results from the EIND learnings. And therefore, we're still considering what's the plan going forward. But certainly, we'll continue to support the EINDs. We're considering investigational-driven kind of a... or collaborative efforts by the tertiary centers. We are considering an open-label study. In any case, in addition to all this, we definitely needs to engage the community, engage the societies, and affect the guidelines of this disease therapy. Let's take some time to understand what we're trying to say here, since, since we're starting this program. I think I'm hoping that we communicated sufficiently that status epilepticus is a common emergency that carries substantial risks, including morbidity and mortality, and really does not have sufficient therapy available to us at this time. Ganaxolone, in turn, has potential and has a mechanism that would make sense to try to utilize in treating these patients. As a matter of fact, PK/PD profile of this drug is very favorable towards use in ICU settings with IV protocols. Our phase II study that was reviewed by Joe seemed encouraging and really defined how we should use those treatments in the ICU patients, in actively seizing patients, and really informed us about how to dose patients in the RAISE study. Then finally, IV ganaxolone has the potential to be a significant advance in treatment of both RSE and SRSE. At this time, I would like to introduce Kristin Rudisill, VP of Business Development of the Acute Franchise. Thanks. I messed up the last line. Thank you, Dr. Vaitkevicius. Good morning to each of you. My name is Kristin Rudisill, and I'm the Vice President of the Acute Care Franchise and the commercial lead for our planned launch in refractory status epilepticus. Marinus's first market entry with our IV formulation of ganaxolone. I'd like to move the conversation forward, really with the primary objective in in framing our market opportunity alongside the strategies that we're putting in place to unlock that potential.... I also plan to share some new insights from a real-world data project that we just completed. Our commercialization plans are well underway, and with the groundbreaking science and our IV formulation of ganaxolone and a wide-open market awaiting us, our commercial potential is further bolstered by the Marinus team's expertise. Our team's comprehensive knowledge of both the inpatient hospital setting and the status epilepticus patient population are really intrinsic to the strategies that we're developing. This strong and powerful combination positions us to deliver on what is a substantial commercial opportunity, addressing the unmet needs of patients along the status epilepticus continuum, but also serving as a partner to health systems, fully supporting how they realize the potential of the clinical and economic benefits of a new therapy. So let's get started with a little bit more about the market that we're planning to enter. The hospital market is wildly different than the specialty or outpatient space, and the franchise approach that Christy mentioned this morning really supports a commercialization plan that's tailored to these nuances. Now, I've got a really deep set of experiences in the hospital market. With more than 15 years working directly in this space, I've had a front-row seat to the evolution of the healthcare model, from the change from fee-for-service to value-based care, all the way to some of the nuance and new dynamics between sites of care in a hospital as it relates to adopting a new product, especially inside the 4 walls of different types of hospitals. Now, let's talk a little bit about what some of this orientation means and how it's showing up in the strategies that we're building for the launch. The United States is a complex network of more than 6,000 hospitals, 3-quarters of which serve acute and emergent patients today. Now, these hospitals are in a constant state of evolution. Particularly, we've seen an increasing number of hospitals that are becoming part of large health systems and IDNs. Over 80% of U.S. hospitals sit inside of one of these systems, where we've seen a really growing and an increasing number of consolidations within the integrated delivery networks. Now, for hospital members of these IDNs, they serve as really good... They provide a significant amount of buying power, right? And also supply supports and services to their hospital members, but they also add a layer of decision-making for corporate and system-wide formularies. Now, our market segmentation and targeting strategies are being built with these considerations in mind, both in how we target specific hospitals within that larger universe and how we think about leveraging the emergence of these large mega systems to drive top-down support or adoption of the product that can be pulled across and down through their hospital networks. A lso driving bottoms-up demand by addressing the needs of the hospital administrators of those individual hospitals. Now, for health systems and hospitals coming out of the pandemic, we know that, you know, reduced reimbursement rates, as well as increasing costs, have really driven tight hospital margins. And what that's done is it's really increased, how stakeholders are expecting new products and manufacturers to bring products to them that drive real value creation. You'll see that we're making really clear and strong investments in the curation of a value story that will resonate across access decision-makers, and modeling tools that will enhance how a hospital really personalizes the product into their own system, creating confidence that once they put the drug on formulary, their system will be able to actually translate the value into their own real-world applications. We've also seen other companies really underappreciate the disparate set of stakeholders that's involved in both formulary access, adoption of a new product, and then uptake and utilization across the health system. It's why we're preparing to ensure our value proposition addresses their unique value drivers, while also maximizing areas of interest that span across systems and stakeholders. For example, I had the opportunity to meet with senior and executive hospital and pharmacy leaders back in May. I had over 30 encounters with these health systems and hospitals, and each of them spoke about the ICU as one of the most labor-intensive and resource-driven sites in the hospital. Frankly, they each expressed a clear willingness to really explore new therapies and technologies that would allow them to improve outcomes for these critically ill patients, while also driving efficiency and effectiveness along the patient population. Hot buttons for them were the ability to demonstrate reduced ICU stays and overall length of stay, avoidance of invasive treatments, and accelerated discharge readiness. Finally, you cannot underestimate the complexity and the often bureaucratic nature of hospitals and the resulting challenges that they face, when trying to adopt a change in protocol. We want to take extra steps to ensure that the access that we earn in each of these accounts is able to be translated into adoption, utilization, and accelerated uptake…. You know, it's true that this is a complex marketplace, but we've assembled a really dedicated and seasoned team who is laser-focused on steering our launch readiness and strategically investing in the places where it matters most. With that, let's go ahead and get into the data. It's worth noting that the real-world data project I'm about to share represents a first-of-its-kind analysis, where we combined 4 distinct datasets to really cover over 141,000 status episodes, inpatient in the U.S. over the last 5 years. The project has yielded a substantial number of meaningful insights, a few of which I'll share now to show you how we're advancing our thinking about RSE. All right, so I'll remind you that patients diagnosed with status who have not responded to 1st- and 2nd-line therapies are, by definition, refractory. However, once they reach this refractory status, we wanted to better understand how patients in this cohort differ across their progressions with different third-line treatments. Now, what the real-world data showed us was 3 clear cohorts of patients within the RSE population, which you can see projected here across the estimated 35,000 annual RSE patients. First, on the left, in the dark purple, some patients simply do not progress to extensive treatments for third-line therapy, either through treatment response or frankly, withdrawal from care. These patients do not go on to additional interventions. But for the majority, on the 2 boxes in the right, 70% of RSE patients, we see a high level of refractoriness and progression to additional interventions in 2 basic pathways. First, in the blue, 30% of these RSE patients progress to additional anti-seizure medication cycles, but never receive IV anesthesia for their status treatment. And then in the green, the majority or 40% of RSE patients do progress directly to IV anesthesia at third line for a therapeutic coma to treat their status. Now, inside of each of these cohorts, you know, what could the data tell us about where the unmet need sits, given the outcomes with usual care? For that, let's take a look across the cohorts. Now, overall, as you would expect, a patient's progress along the SC continuum shows that outcomes significantly worsen. Keep in mind, these are really complex and critically ill patients. As Dr. Koenig mentioned, there's no real rigorous data to support a pathway to take for patients at the third line, which leaves HCPs with a really difficult decision and a balance of the risk to benefit options. Now, across these 3 cohorts, you will also see that baseline outcomes in the purple aren't great, but it only gets worse from there on the right, with 70% of patients on average, spending 2 weeks in the hospital, with half of that spent in the ICU. Now, remember, that's a full week in one of the most labor and resource-intensive sites of care in the hospital, where patients are undergoing intense treatments and specialized care from a number of multidisciplinary stakeholders. Despite all of those efforts, we see significant mortality in both cohorts, both with high, but with higher levels, excuse me, in the IV anesthesia group all the way on the right, with a devastating quarter of patients experiencing inpatient mortality during their status episode. What's not shown here is for patients that progress and go on to meet the criteria for super refractory status, the mortality quickly escalates to over 40%. Now, across these patients in the right who progress, 60% of the patients who do survive are not able to go home at discharge. These patients are transferring to long-term care rehabs, skilled nursing facilities, to hospice or palliative care. While one of the limitations of real-world data is its inability to capture if a patient returns to functional baseline, the trends that are depicted here really provide compelling evidence for conveying an urgency to treat message, aligning with the medical community's time is brain philosophy for patients experiencing neurological emergencies. Now, considering that these overall outcomes are from the last 5 years of patient data, and that they closely resemble some of the historical outcomes that you've heard earlier this morning, it's really clear that suboptimal outcomes and bleak prognoses for these patients have persisted for several decades with no real improvement. Now, let's take a look at what the outcomes mean and how they can be translated as we think about costs to the hospitals and the health systems treating these patients. Of course, as these patients progress along the continuum, the costs rise significantly. Progression to any extensive treatment at third line is associated with a doubling of cost, and those who progress to RSE associated with a threefold increase. Now, these numbers are conservative and represent averages, but keep in mind, as you're looking at these costs, there's no real prognosis indicators for progression, and severe forms of refractory status are associated with substantial outlier costs. Inside of our own real-world data, we were able to demonstrate costs exceeding over $400,000 for a single inpatient episode of a patient in SRSE. Expenditure buckets, or what comprises the purple bar here are total length of stay or inpatient stay, a special carve-out for ICU stay, anesthesia costs where appropriate, and RSE-related drug costs. So across the cohorts, it's important for us to understand what are the primary drivers of cost, and does that differ across the patient cohorts? The primary driver of costing these patients really sits within and inside of that ICU stay. Not surprising, then, that this is an area that the hospitals are looking to drive efficiencies in. These are real costs to hospitals, and they are looking to improve not just outcomes, but to really reduce the cost burden and the financial burden of treating these patients. Leading with the science of ganaxolone, we believe that our IV formulation has the potential to provide early control, preventing progression along the status continuum. We believe strongly in our potential to improve clinical outcomes, providing rapid and sustained control, seizure control, which in turn will translate to reduced healthcare resources and frankly, diminishing use of invasive interventions that frequently drive a sequelae of complications and result in costly, lengthy hospital stays. Now, as we eagerly await the completion of RAISE and the release of top-line data to substantiate this potential, I'll direct our focus towards some of the specific commercial preparations. We have a bold ambition with this launch, but this is where our expertise will begin to pay dividends. Drawing from our past experiences and lessons learned, we're strategically directing investments across key areas of the business that are critical for launch. So how are we charting this new and unique path into the market? First, which accounts we target at launch are, is really, really important to our overall success. And we're making really informed decisions about where to enter by utilizing advanced analytics and account profiles to identify our strategic entry points. More to come on segmentation in the next slide. But with the right targets in hand, we're gearing up to engage both clinical and financial decision-makers to ready themselves to embrace a new opportunity for status patients. Next, investments that support how we construct, curate, and deliver a compelling value proposition that resonates strongly with both key clinical and financial decision-makers. And where others have missed the mark, we are not going to ignore really part of the care teams and the critical decision-makers that sit inside of pharmacy and quality initiatives. Third, once approved, market access in the hospital market is really largely driven by formulary inclusion and availability to HCPs through institutional stocking. We're actively exploring a number of strategies and avenues, including channel strategies, distribution methods, and contractual agreements, to facilitate rapid and sustained access through our targeted accounts. Now, furthermore, as an uptake accelerator, we are also preparing to submit a new technology add-on payment. This aims to support hospitals in establishing reimbursement pathways for the adoption of IV ganaxolone in the initial 2-3-year period. Lastly, we know better than to assume that access equals adoption and uptake or utilization. We have an appreciation for the operational hurdles that hospitals face when trying to bring a new therapy on board, and we have a number of different initiatives that are really designed to support how they ready themselves, how they operationalize the product, and how they drive utilization in the early launch period. Now, in one of those, I'll remind each of you that we made an important investment in changing the size of the bottle, shifting from a 500-milliliter bottle to half the size in a 250-milliliter offering. Now, at face value, the change to this smaller bottle really helps to serve as a way to keep the drug closer to the patient. When minutes matter, we don't want our product to be stored in a centralized or a disconnected location in the hospital, simply because that's the only place where they can store and house a larger vial size. What's more important is that the smaller or 250-mL vial gives early adopters the chance to evaluate the product clinically. Market research tells us that there will likely be an increased number of trialists who are willing to initiate therapy with a smaller 250-mL offering, waiting for the patient to respond as they begin to go through that course of treatment, and with confidence in the response that they see, continue on with the rest of the duration of the dose. The other piece that we know that's important, as a critical follow-up to an NTAP and other reimbursement pathways, is to ensure that we do the research to find out what type of support they'll need to ensure proper billing, coding, and the ability to activate the reimbursement pathways that we build. And we're actively exploring a white glove service to see what hospitals really need, where, in areas where they need support. Let's take just a double-quick look at market segmentation. So we've initially narrowed the broader U.S. healthcare organization market to around 3,000 hospitals. And now what we're doing, we're in the process of further evaluating this 3,000-hospital segment to either do additional refinement-... on removing them from the target list or to characterize the properties of them so that we can better understand what their patient volume potential is, as well as what the operational complexity holds by way of timing to formulary access, adoption, and uptake. One of the things that's really important as we think about launching with the prioritized strategy is really to ensure that we create a matrix opportunity, whereby we want the opportunity to capture the highest patient volumes to drive early clinical experience. But inside of the academic medical centers, tertiary, and quaternary centers, there are long cycles for access, lengthy formulary processes. We plan to balance what the real-world data showed us by, by including in our target list, mid- and large-sized hospitals that are not academic medical centers, but that hold a volume of patients that can be easily addressed because their operational barriers or the steps to access and adoption are reduced. Simultaneously, the team will both drive early adoption in these sites while working the lengthier processes at the tertiary and academic centers that have a longer sales cycle. Another one of the access and uptake accelerators that we're looking to deploy is NTAP. As many of you know, this is a statute that's granted to certain applicants by CMS and was really designed to provide financial support to hospitals, helping them offset the additional expenditures associated with innovative therapies, incentivizing them to adopt these products, whose price is not yet covered under the inpatient, MS-DRG system or bundled payments. NTAPs often serve as a really important reimbursement pathway that ensures that patients have access to the most advanced care and effective medical treatments, while that inpatient DRG system catches up. Now, CMS evaluates applications for manufacturers in really 3 critical areas or criterion: newness, cost, and substantial clinical improvement. With an additional check that the new technology that you're filing for really addresses the unmet needs within their patient population or the Medicare patients, as demonstrated by this population's inclusion in your phase III program. Now, our access strategy includes an NTAP submission, and we have increasing confidence in our ability to meet the criterion that are outlined by CMS. Our newness is substantiated by our unique mechanism of action and the lack of similarity to any other products that are on the market for status. In addition, the real-world data also confirmed bimodal distribution of RSE patients, demonstrating a significant percentage of patients will be in the Medicare population. And from a cost standpoint, you, you've just seen the high costs in these patients per episode, decreasing any likelihood that the current DRGs are adequate enough to cover, cover RSE care that's inclusive of the price of IV ganaxolone alone. We look forward to the RAISE data to demonstrate the 1 box left open that shows significant improvement compared to usual care. Now we're finalizing our NTAP filing timelines to really ensure that we can both meet the target dates for the annualized application process, but more importantly, strategically timing our filing to ensure that if the NTAP is approved, hospitals and systems will have enough time to drive formulary, bring the drug into the hospital system, and adopt it inside of their hospitals, with enough time to maximize their use of the NTAP code across the eligibility time period of 2-3 years. With an appreciation of the stakeholders that are involved across the access process and an enormous amount of respect for the healthcare providers and care teams as experts who treat status patients each day, we really spend time building a well-defined engagement plan that bolsters our preparations and really fully appreciates the insights and the distinct role that different HCPs play in the treatment pathways for patients. Too often, we've seen companies start engagement too late, wasting valuable time at commercial launch, doing work that could be done ahead. And frankly, for those that do start early, we've seen a blanketed approach to engagement that doesn't really empower stakeholders or health systems to be ready to receive a new therapy. Now, the purple at the top really represents ongoing, activities by the medical affairs team. They've been working diligently to both engage the healthcare community, as well as to provide disease state education and the burden of illness across this patient population. Then, as we're planning for the commercial team's introduction into the market, you can see a series of engagements that are really built to drive momentum along the filing process. At top-line data, we'll initiate a field-based market access team that will be able to initiate payers or, excuse me, initiate education to payers on the RAISE trial, with a really specific effort in targeting our most valuable hospital formulary decision makers. At NDA filing, we'll be able to continue those in-depth conversations, establishing target patient populations across these health systems and payer markets. And then shortly after approval, the opportunity to provide personalized budget impact model discussions, really giving the tool to hospitals, again, to determine and support how they'll be able to bring the therapy on, realizing its full economic and clinical benefits. 2 of the uptake accelerators are also demonstrated here, where you can see that we're doing the filing development now, and we'll plan our application filing with PDUFA. We are planning for a 250 milliliter exclusive launch. So what does disease state education look like? If I might, I wanted to give you a recent example of what it looked like in August at the Neurocritical Care Society's annual meeting in Phoenix, Arizona. Our medical affairs team sponsored, as part of the society meeting, a non-CME event. Now, this event was held at the same time as 3 other programs at this targeted group of neurocritical care specialists from around the world, and it was met with high attendance. The Marinus team was really delighted to see a standing room only crowd and a room that that was almost at fire code. And while the program was met with, with wildly positive feedback from the attendees, I think for us, what's more, it was a strong signal that this is a medical community that's eager to come together to drive a change for these patients. And we could feel this organic movement, if you will, around urgency to treat and time is brain, that will really serve to catapult us in our pre- and post-launch efforts, creating a burning platform for change as we ready to enter into the market. What I'd most like for you to remember today is that we all view the opportunity to introduce IV ganaxolone into the hospital market as a true privilege. Our solid foundation, formed by the ideal trinity of good, strong science and the market potential, and our dedicated team, really serve as the basis for our commitment to serving status epilepticus patients. We are resolute in our approach, tailoring strategies that align with the realities of the hospital market, and we're making targeted investments that have been carefully considered. Our commercial strategies, priorities, and efficiency will allow us to have a successful launch, with the ultimate goal of enhancing the lives of refractory status patients and the healthcare systems that serve them. It's really exciting times ahead. With that, we'll now transition to the Q&A portion from this morning's presenters. I'm fine. I'm fine. My mic's not on though. You want to turn my mic on, please? Mic on, please. Thank you. Okay, Q&A. Should we, should we go, Hi, there, Joe Thome from TD Cowen. Thank you for the presentations. Maybe just a quick one. You know, debating a little bit what the placebo response is going to be on the escalation to IV anesthetics at 36 hours, and it seems like the data that Kristin presented suggested that 30% of patients don't progress. Just curious, because of how the trial was designed, the next step is supposed to be obviously IV anesthesia. So how—where do you expect that to fall, maybe for the company, and the physicians? And then is that 40% delta, clinically meaningful, that the trial is, powered for? Joe, I'm sorry. You are asking this because I'm a little confused by your question. So I think the number that Kristin showed, about 30% effectively responding to current therapies, different than our trial population. So I just want to make sure I'm clear what your question was. Sorry. Yeah. A lthough, so I guess, okay, then maybe that was my misunderstanding. So what is the expectation of the placebo-treated patients that would progress to IV anesthesia- IV. -in the RAISE trial? I guess, what is your expectation? Sure. Yeah. So, the question is, what's our expectation for the placebo rate for progression to IV anesthesia? And really happy to have Dr. Dhar and Dr. Koenig talk about what your normal practice would be and your expectations for these patients that you're enrolling. I mean, I think, given the way I think Henri outlined the selection strategies for the study, you know, being part of the study and understanding this population, we're waiting for that last stage when you really do feel like your options have been exhausted. And whether whoever's taking care of the patient, we're touching base with them and saying, "Is anesthesia your next option?" And, you know, we give it a little bit of time, but there's time for response to happen. But in my sense of these kind of patients, the proportion that don't—they just suddenly stop seizing after not stopping, I mean, you see these repetitive seizures for hours and hours. Not many will stop seizing, you know, without receiving an effective treatment in the next 1-2 hours. I don't have a number, or maybe the Marinus has people to comment, but I think it would be fairly low. Yeah, sure. W e have this population that we're enrolling that have already failed first line and second line agents, right? So I guess your question is regression to me, right? How many patients who receive placebo, just saline, will not progress to anesthetic? And that's a very, that's a very low number, right? Because when you're enrolling these patients, you have to understand these patients are already gearing up towards refractoriness. And we know from data, from epidemiological data, natural course of disease, these patients will continue to progress. Now, they will progress to the point that they will require further and further intervention, and as they continue to fail first and second line, then as best clinical practice, we go ahead and move on to the third line, right? Which then obviously is accompanied by, you know, IV anesthetic and then the ICU stay. So that number will, will, you know, just looking at the natural progression of the disease, will actually be quite low. Joe, we've always talked about the assumption that we'd have at least a 40% treatment effect, where when we designed the study, roughly a 30% placebo rate, 70% effect, efficacious rate or efficacy of the drug. And certainly, I think what you saw from Henri is that we've seen a very consistently sick population, patients who are getting 2-3 anti-epileptic therapies, plus a benzodiazepine. So our confidence, given not only the physicians on the panel, but the job that Henri and our other physician does to screen every patient that's enrolled in the study, continues to give us very high confidence on where placebo rates will fall. Next question. Go ahead, Joon. Thanks. Hey, thanks. Joon Lee from Truist Securities. Are you noticing any difference in response to ganaxolone, depending on whether the patient got benzodiazepine or not, as a prior therapy? And also, is there a set maximum dose of benzo that is allowed in the trial, and how does that compare with what is done in the real life? And I have a quick follow-up. J ust to be clear, Joon, the question. The second part of your question is, in general, how much benzos are patients getting in the trial? And I'll let Joe handle that question. But your first question was a little bit more related to response rates in a blind trial. Yeah. I just want to be clear. I just realized that not everybody got the benzodiazepine in phase II. I'm sorry, one more time, Joe? My understanding is that not everyone got the benzodiazepine in phase II. Well, remember, in the phase II study, and Henri showed the slide, about 80% of patients- Right ... got a benzo, and about 90% of patients. Exactly. Our general understanding is that there is a small subgroup of patients where they are contraindicated for benzodiazepines, often patients who have a neurosurgical procedure, but I will... I'll pass it back to the physicians. So Henri, do you want to talk about maximum benzo use in the phase III? Yeah. W e do not describe maximum use of benzo from the dose perspective, and it's really from the fertility perspective. There is multiple trials over and over again, demonstrating that despite the ceilings that we create, despite the guidances we did provide, the physicians will still do what they think is right at the bedside. And that's certainly supported by the agency to allow the physicians to do whatever is necessary at the bedside. So that's from the maximum dose, dose perspective. As for not utilization of benzodiazepine, in this 20%, the big group of that is the people who've had some exposures to, anesthetics. So, for example, a person who was briefly on propofol, it seems unnatural to say, "Now we force them to give them benzodiazepine," as they had similar class medication that they already failed. That's subpopulation. Yeah. Maybe Dr. Khan, have you start this time. Do you expect differences in response rates in patients who have received or not received benzodiazepines? Yeah, I think mechanistically, the way neurosteroids work, I don't think it's gonna matter whether or not that patient is naive to benzodiazepines or received benzodiazepines in the course. And, you know, this is a heterogeneous population. You might find patients coming in the door who are allergic to or have an adverse reaction, and so they don't receive benzodiazepines upfront. You might find patients who are already on oral benzodiazepines as part of their standard regimen, and so intuitively giving more benzodiazepines doesn't make sense, as you know, as the disease is rapidly progressing. So instead of... You know, each time you give an agent, especially a benzodiazepine, right? In most health systems from a pragmatic standpoint, you know, you look at the EEG, you look at the patient, you order that, that comes in, the nurse delivers it. The reality is that's an hour-long process. If you're looking back at that timeline that I showed you, you don't have that much time. So you want to be very strategic and be quick about what you're going to use. In many situations, benzo may not be the first thing that comes to your mind, and so that's not standard of care. Yes, it's among the first-line, sometimes the second-line agents, but it's not the first go-to thing. Dr. Dhar, do you want to add anything? I think, I mean, the only thing I would add is that the variation in benzodiazepines, in my mind, is partially, is mainly driven by the side effects being sedation. Which is a key issue here that we've kind of alluded to, is that when you're limiting, apart from what Henri said, maybe from a pharmacological, giving benzodiazepines is because the patient is already tenuous from a respiratory point of view. So that's usually when, at least I would avoid benzodiazepines and maybe go to, you know, another IV agent that's not as sedating. So some patients might get none because of that reason. Patients who are maybe already on a ventilator or more stable, maybe they could tolerate more. So I think the variability is probably more driven by that. The counter side to that, but also maybe didn't come up so far, at least in my talk, was that you give a drug that's maybe slightly sedating or not sedating. Most are, have some sedative, but the hope is that if you give a benzodiazepine or any agent, if it controls the seizures, the benefit to wake the patient up will be greater than the downside of the sedation. So you're always kinda weighing those factors, like, will this tip the person over, or will it control seizures? And the sedation will be balanced because, you know, so I think that's why there's a lot of variability in the dosing. Q uickly, you know, are you seeing- Dude, we really have to move on. Yeah, sorry. Just be respectful of others, but thank you. Brian? Yeah, thanks. My questions are probably for Dr. Dhar and Dr. Khan. Just trying to get a handle on the actual practical structure of the ICU, and who would make the call to write a third-line prescription. Is it pretty consistent across ICUs? Is there always a neurologist on call? Do some ICUs not have a neurologist on call for treatment? And is it, you know, is it the attending physician? Is it their fellow who's on call? Just trying to get an understanding who actually writes the prescription and is the target audience here? You wanna, you wanna start? Sure. No, that's a good question. I think when we're talking about early status epilepticus, you know, obviously an emergency room or coming to the ICU, you know, benzodiazepines and these things, yes, I think there's a variability that a lot of providers are taking care of those patients, you know, whether emergency physicians, general ICU doctors, fellows at nighttime. I think the difference, at least I see, is once you get to refractory status, one, there's a little bit of a... What's the word? Not homogenization, but you know, into limited care places like ICUs. Not only neuro ICUs, but certainly ICUs with some neurological involvement, even if it's not a neuro ICU. At that stage, not necessarily earlier, but I do think that mostly it'll be a neurologist or someone else who's had experience with those agents, which is somewhat more limited, I would say, once you get to third line. You know, certainly when it comes to anesthesia, because we don't have great 2nd and 3rd-line agents, the ED may start propofol, so those decisions are being made early. The question is: how do you get someone off propofol? And those decisions are made at a more specialized level, at least in my opinion. And, you know, we would usually have that discussion, even for anesthesia, with an attending-level person saying, "Do you wanna use propofol, midazolam? Is there another drug you'd like to use?" And if someone's not intubated, I would usually at least try to use another non-anesthetic. I think, like Dr. Khan said at all costs to avoid the anesthesia. So that usually does come back to, mainly, the neurologist, maybe other ICU doctors, maybe in some institutions. That would be my sense. Before you go, I'm surprised you didn't mention the growth in neurocritical care, the fellowship programs, and so many of the hospitals we work with have expanding neurocritical care units. So maybe, Dr. Khan, you can chat a little bit about that as well. Yeah, I completely agree, Scott. It's like you have small, medium, and large cap. We have the Cleveland Clinic, and then we have the small county hospitals. It's a huge variation, right? So the team-based approach, which is a neurointensivist, a neurologist with expertise in epilepsy, a pharmacist, entire team coming together and making those decisions in a cohesive manner. And then you have sometimes a breakdown where it just there's availability of just the intensivist, and then a small community hospital, it's the ER physician or the on-call person who's just available. So really, it depends on who's actively managing this. You know, we have the concept of a primary team, and then we have consultants, at least in the United States. I t's a primary team's, you know, in their wheelhouse to make these decisions and make these judgment calls in whatever time of the day it is. Now, if you have trainees and residents, then obviously you rely on them, but it does go up the chain. If there's situations where they're scratching their head, they always reach out to consultants for help. But that's how essentially care is there, especially in an ICU setting, where care is not Monday to Friday, 24/7. Doug? Hi, Jason Butler, JMP Securities. I guess another question for Doctors Dhar and Khan here. When you think about the enrollment criteria in the RAISE trial, essentially directing physicians to wait as long as possible or wait until you know that that, IV anesthetic is the next step, how is that gonna translate into clinical practice versus, the thought process behind how quickly you would just make a decision to treat after a patient progresses from the second IV, I think, anti-epileptic? There's a window there. So can you maybe just talk about how that, you know, may differ from the trial to the real world? Thanks. Yes, I think, I think the, the trial is a blended mix of not too conservative, not too liberal, right? So you have these overly conservative trials, which say: "Here's this criteria. You meet this criterion, that's the decision-making point." And that becomes really hard because we've seen that in our predecessors in other clinical trials, that fails. The, the model fails because it's not a reflection of real-world practice, right? We see too much heterogeneity. There, you know, there's all these society guidelines on how to manage status, but it's a lot of variation if you actually look out there. And so you wanna have a trial that focuses on the decision-making power to the investigator or the clinician, and that's what the RAISE trial allows you to do. It's also liberal in the sense that it doesn't. It allows you to spend some time, understand the patient, and wait. And that's very important in the way you execute a trial, right? Because if you have those. If you don't have those guardrails, right, then you're gonna get all these all-comers into the trial. It's not gonna be systematic, and you're not gonna see the outcomes that you want. And we've seen that, you know, just looking at neurosteroids, right? We know this, this category of medications is very effective. We've looked at it in depression, for instance, right? So the studies that were done on postpartum depression, very well structured, gave autonomy to the investigators, and looked at the disease state, as opposed to let's look at major depressive disorder at large, and it failed. That outcome failed for that very reason. So you wanna have sort of a blend, and I think the way this study is designed, it really works in collaboration with the investigator, and that's really what's important here, in my mind. ... Thank you. Dr.? I think if I understand your question, and I can just give, you know, my opinion of what could happen. You know, going back to what I said earlier, we use second-line AEDs, and by that I mean drugs like lacosamide or now brivaracetam is a new agent that's out there, that's on our formulary. Not with a high expectation they're gonna work, but with a hope they're gonna work because of what the alternative is. So I think to your question, would we really wait for the RAISE trial criteria? My opinion, if we had an agent that actually wasn't like another second-line AD, where you're hoping but really are thinking, "I'm gonna go to anesthesia," I would not wait for that. I... If that's what you're asking, I would not be waiting. I think the use of an agent like that would be much broader in the sense of you don't have that same sense of futility, if, you know, if obviously that is the situation. That's my opinion, at least. We're gonna take 2 more questions in the audience, and we're gonna go another 10 minutes to make sure we get people on the webcast. Doug? Thanks for taking the question. It's Doug Tsao from H.C. Wainwright. Just one of the differences in the patient population between RAISE and the phase II study is the seizure burden. Just for Dr. Khan and Dr. Dhar, just be curious if you could just help us understand what that sort of moved down from, I think it's like 50% to 30% or so percent or. And also just the enrollment criteria, and what that actually clinically means and how that could impact the results for the study. Thank you. I think, Doug, a lot of investors... To add to Doug's question, investors worry that a lower seizure burden may not lead to as sick patients or higher placebo rates. So you can frame it in the context of Doug's questions and what some folks worry about. Yeah. And I'll let Dr. Khan talk more about the epilepsy side. He's really the specialist there. But from the ICU perspective, you know, my opinion is 20% is a lot of seizures. That's my honest opinion. When I see patients who are having 25, 30% of the time, like the patients I showed you, their burden was not 50%. Their burden was very high. Even that, the young gentleman I showed probably was 30-40%. So that, in my experience, and I wasn't involved in the phase II studies, is a very high seizure burden. And as I said, that applies to that seizure burden, a very low expectation of response. I think if you get down to, you know, obviously 5%, that's different. I think what I've seen in the patients is this 20%-40% range. I think that fits with what Henri was showing in the data, I believe. I hadn't seen that before today. But to me, that is, just at the bedside, not a lot of time between seizures. We're talking 30 seconds. So usually the seizures might be 30-60 seconds, and then you have 2 minutes in between, that's 33%. That means that you only have a 2-minute break between continual seizures. So just as a clinician, that's how I look at it. I don't know from an epilepsy point of view, how you view the seizure burden. Yeah, I agree, Dr. Dhar. You know, if you get caught up in the numbers, you're looking at an absolute moment in time, right? The seizure burden is something that's dynamic. It's gradually evolving. And so when you look for either a higher or lower seizure burden, you're looking at your threshold, your individual threshold. So where do you wait to treat? And like Henri mentioned, the science has evolved, our understanding has evolved each coming year. Presented recently at the Neurocritical Care Society meeting. We realize and recognize that treating sooner, and sooner means our bar starts to change, right? So when we get to lower burden, we start to aggressively manage that because we want to improve the outcome. It's really the entry point of what you're treating, as opposed to looking at the individual patient, because that patient's gonna range over that spectrum. That change wouldn't really impact the likelihood of some kind of placebo response or reciprocity from your perspective? No, because you... You know, that's like a running train, right? It's at what point do you catch that running train, right? Now, if you saw a variability disease and you're measuring something over months, I understand there's a lot of confounding variables. Yes, it's an ICU setup, but then in the short period of time, the confounding variables are so limited that you're actually not gonna see that. So it's actually, to that point, it's actually easier to power a study in that manner. Thank you. Last question from the audience. Thank you. I just had a quick question looking at the recent demographics cut that you had from September. So assuming 70% of the IA has been enrolled, that's about 57 patients. I'm curious, Henri, why you said that the 20% mortality being slightly increased in the phase III so far, based on these demographics. Why is that expected? Why is that higher than what we saw in phase II? Well, I'll kick it off, and then I'll turn it over to Henri. Remember, in the phase II, every patient was treated with ganaxolone, and what we saw in the phase II was a shorter ICU than historical controls, and that 18% or 19% mortality rate is as low as 50% of what would be seen in a normal population. So I would argue quite strongly that we saw a treatment effect in phase II beyond seizure, beyond just treating seizures. So it would be logical to me, in a study where 50% of patients are getting placebo, that they should have up to a 40% mortality that would be seen in a normal population. These patients are all failing 2 to 3 therapies. I do the math and say a blinded mortality rate of 30% is exactly what we would hope to see if the drug hasn't any impact, and the study is not powered, nor is it designed to show a mortality benefit. But certainly, thinking about a mortality rate closer to historical controls in a blinded trial... is extremely logical to me, and it would be illogical in a blinded study for that number to be similar to a fully treated population. Henri? Yeah, I mean, I agree with that. At the same time, keep in mind, that's 17 patients in the high tertiary centers, as opposed to, you know, this is now approaching global studies. So the diversity of patients is bigger. So, that, the mortality data doesn't match what other numbers showing about from literature as well as what Kristin presented. A mong what Kristin presented, there was like this 3 groups, right? Yeah, I think we need to move on, but the only other point I'll make, is that we've talked about this from the phase II, that when you look at the phase II population, about 1/3 of patients have disease states like glioblastoma, that were ultimately not gonna have a huge impact on their mortality. So you have to remember, there's acute therapy, there's getting patients out of the ICU, there's worsening, and they're more minimizing the morbidity. But there are going to be patients that may die 3 weeks later from a glioblastoma or other etiology. Let's, let's move to the webcast, just to be fair to folks who are out there. Thanks, Scott. So the first question is in 2 parts. 2 parts to this question. For the Marinus team, have you seen SRSE- Is there a specific analyst, Sonya, who- There's no analyst name for this. No, no name. Have you seen SRSE in the blinded EEG data? And then for Doctors Dhar and Khan, have either of you treated SRSE patients with IV ganaxolone under EIND, and if so, can you speak to your experience? N ot surprisingly, we have seen patients in the RAISE III trial develop super refractory status. That number today is slightly above 20%, and about half of those patients, greater than 10%, are having some extended case of super refractory status. So certainly consistent with what we think is a highly population that we have the opportunity to show a benefit. We are seeing patients who are progressing and having prolonged courses within this study design. And as Joe mentioned, that is certainly something that we'll be looking at in one of our key secondaries. It's a small study, no promises on that number. Unfortunate for patients, but we believe that gives us the potential opportunity to show a meaningful clinical benefit beyond the primary endpoints. Dr. Dhar, do you want to talk about any EIND experience? I have had experience with the EIND process. Thanks to Henri and Maciej and the team for getting us the drug. Actually, it was the patient I described in the vignette. I didn't share that during the case because I was trying to focus on the earlier stages, but we actually used that in the new protocol, I believe, that you heard about for this patient, and you know, it's a complex situation. I'd. Like I said, at the end of the day, the patient's seizures settled down through a number of interventions that we did, including you know, open label ganaxolone, following the protocol you heard about. And you know, many other seizure medications that they were already on at the time, and we were able to come off pentobarbital. We were able to get them out of the ICU, but I mean, based on that, I certainly couldn't make any statements about the efficacy of that experience, but it was a positive experience in general. But, you know. Dr. Khan, I'm not sure if you've seen any IV, but you were part of the phase II trial, so you can talk about any open label experience you saw in the phase II. Yeah, I was not part of the super-refractory, but we were included in the phase II. We saw really positive results, you know, ranging from an 80-year-old female whose family was adamant that they did not wanna go down the route of mechanical ventilation and anesthetics. We were able to obviate that and provide relief, you know, very soon control of the status epilepticus. So I think, you know, from our standpoint, one of the great rewards in this is that every time we give an agent to an individual, we look at the EEG. We rush to the EEG and look for responses because we want objective responses. Then when we give the drug and we see that, we know that the brain's responding. So that's just been our sort of, you know, positive silver lining in this. Okay. This one comes from Jay Olson at Oppenheimer. Can you describe your expectations for the healthcare utilization endpoints in RAISE? How important are favorable economic outcomes for reimbursement? Alex, you wanna take a stab at that? Yeah. I mean, we were very thoughtful when we designed the RAISE protocol to make sure that we were capturing as much relevant data as we thought possible, to both inform clinical use and to help with formulary decisions down the way. I think some of the endpoints that we're gonna have a keen eye towards are time on positive pressure ventilation, and then as Kristin mentioned, certainly days in the ICU, days in the hospital as well. Evidence would suggest a very strong correlation between use of IV anesthesia as it relates to some of these healthcare utilization endpoints. A lthough the study is not powered on those endpoints, again, I think we have a lot of confidence going into the data readout, coupled with some of the demographic data that Henri showed, to really ensure that we're enrolling the right patient population that we ultimately intended. Why don't we take 1 or 2 more questions from the audience, from the webcast? This one's from Michael Higgins at Ladenburg. At launch, what percentage of RSE patient hospitalizations are you going to target? And is there an adoption plan predicated on that initial target group's adoption before expanding? Can you share? Kristin, you wanna jump in? Yeah. I think if you think back to the 2 cohorts that we saw on the right-hand side, right? The patients that progressed to ASMs and IV anesthesia. We believe that because of the unmet need, especially, you know, given what, what's happening with outcomes, with usual care, that we believe that we will have, a strong ability to target both of those patient populations. And we believe that that'll be further substantiated, especially in the group that progresses only to IV, ASMs with, RAISE-2 data. But what I'll say is that early market research and hearing from clinicians, the safety and the efficacy profile of RAISE is going to offer some of them significant confidence to go after both of those patient groups. Remember that those 2 who progress are really sort of what we would consider highly refractory. With additional top-line data, we'll continue to do market research to establish that. But in terms of phasing the launch, I think the reality is that part of why we're spending so much time investing in allowing hospitals early on to begin to personalize IV ganaxolone into their system is because we'd like them to dictate for us where they have the greatest unmet need and burden of illness in their system. And I have a strong suspicion that that will fall across both of those cohorts. Kristin, will you be targeting any groups of hospitals where you think formulary access will be somewhat easier, let's say, than academic hospitals? Yeah. How do you think about- Yeah. formulary acceptance? I think that's probably a big part of this question. Yeah. Absolutely. If you think about 4-by-4 or 2-by-2 matrix, I think we are looking at institutions across sizes that have, you know, a significant number of addressable patients, but along the spectrum of operational complexity, because we do want to drive early clinical experience and not wait for these larger, more bureaucratic systems to take, you know, 9, 10, 12 months to get the product on formulary. The real world data did substantiate that there's a significant number of patients in, you know, mid to large-size, non-academic facilities, especially those in urban centers. So, we feel really excited about the continued work there to target those hospitals and those patients for early uptake, and to get some positive noise about the next one into the market after launch. Why don't we take 1 more? Okay, this one is unattributed, but can you remind us of the RAISE-2 strategy and opportunity? Alex, why don't you take that? Yeah. T he RAISE-2 trial was originally designed to really support European registration, but I think as time has gone on and as we've looked at the patients enrolled in the RAISE trial, we think it offers much more than that. Again, I think looking at some of the patient segmentation that Kristin presented, I think that there's a meaningful cohort of patients out there in the RSE patient population that are treated earlier, that, again, have significant unmet need, increased hospital stay, ICU stay, that might not necessarily progress to IV anesthesia. There is not a requirement that IV anesthesia is the next imminent treatment step in RAISE-2. So I think that that study really provides another opportunity for us to, again, generate some robust clinical data in an expanded refractory status patient population, which potentially could have some labeling implications in the future to be determined. Great. Molly, how long were we scheduled for break? It'll be 5 minutes. So 12, you wanna just say 12 o'clock? It's 7 minutes. We'll kick off at 12:00 P.M. Kick off at 12:00. Thanks, everybody. Thank you all. All right, we're gonna go ahead and get started here to the next section. It is my pleasure to introduce our next key thought leader, this time in tuberous sclerosis complex, Dr. Mary Kay Koenig. Dr. Koenig is a neurologist and co-director of the TSC Center of Excellence at McGovern Medical School. She's been working with TSC patients for close to 20 years, was previously the chair of the Department of Defense Panel on TSC Research. She also was a member of the expert panel to develop consensus recommendations for treatments for TSC, and also sits on the TSC Alliance Advisory Board. It's my honor to now welcome Dr. Koenig to the podium. Thank you. Thank you. I'm so happy to be here. I love talking about tuberous sclerosis to anyone who will listen. So today I'm gonna talk with you guys about tuberous sclerosis complex. So tuberous sclerosis complex is an autosomal dominant genetic disorder, which means that a parent will pass it on to 50% of their children. It is the leading genetic cause of epilepsy and autism, and it affects multiple organs throughout the body, including your skin, where it can cause abnormal skin pigmentations. It is a rare disease. It affects 1 in 6,000 people, which comes to 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. There are 2 genes we know of that can cause tuberous sclerosis complex, but about 10%-15% of people are genetically negative. We believe they likely have changes in those genes. We're just not able to detect them by our conventional methods right now. About a 3rd of cases of tuberous sclerosis complex are inherited, and about 2/3 of them are sporadic, meaning there's no family history. There's currently no cure for tuberous sclerosis, but the research has been expanding a lot in the last 15 years, which is why it's so much, so much fun to be in this field right now. Manifestations are typically treated as they arise, and patients are typically on multiple drug therapies for their disease. O ne of the characteristic findings and one of the things that people see, are hypomelanotic macules or white spots on the skin in patients with tuberous sclerosis. They also have these characteristic facial lesions called facial angiofibromas. They can get tumors in their eyes, called retinal hamartomas. They get tumors in their heart, called cardiac rhabdomyomas. This is one of the first things that's recognized in people. They get a lung disease called lymphangioleiomyomatosis, which is similar to COPD and causes very severe cystic degeneration of the lungs. They get renal cysts or cystic changes within their kidneys. They also develop tumors called angiomyolipomas in their kidneys. In the brain, there's multiple findings. One of the things that's seen in almost everybody with tuberous sclerosis are these white lesions called cortical tubers. These are areas of malformation within the brain, and they are very epileptogenic. They trigger seizures very commonly. They can also have larger areas of malformations. This is actually one of our patients that we followed. She has something called hemimegalencephaly. Half of the brain is bigger than the other half. This is not a good thing. It actually ended up having to be surgically removed when she was less than 6 months of age. You also see something called subependymal nodules, these little black spots within the ventricular spaces, and about 15%-20% of patients develop something called a subependymal giant cell astrocytoma, or a type of brain tumor. TSC is typically diagnosed in early childhood after the onset of seizures. It's actually becoming more and more diagnosed perinatally because of the frequency of ultrasounds, and so we're starting to recognize the cardiac rhabdomyomas more and more often, and many children are being born and diagnosed right at birth. 85%-90% of people with tuberous sclerosis complex have epilepsy, and over half of them start having seizures before the age of 12 months. 2/3 of them have what we call intractable seizures, which means that no matter what we do, we can't make the seizures stop. Nearly all patients with tuberous sclerosis are associated in some way by what's called tuberous sclerosis-associated neurocognitive or neuropsychiatric disorders, or TAND. They have aggressive behaviors, autistic spectrum disorders, intellectual disability, psychiatric disorders like anxiety and depression, sleep problems, or social communication, school, and occupational disabilities. So I was asked to talk with you guys about the impact of t uberous sclerosis complex and how it affects people living with it, or people caring for people who live with it. And like Alex mentioned, I'm the co-director of the Tuberous Sclerosis Center in Houston. I've been involved in this community for many, many years. I follow hundreds of patients and their families who have tuberous sclerosis complex. Because this is an autosomal dominant disorder, it runs in families, so sometimes we follow whole generations of people who have this, and we get to know their families quite well. As part of the Tuberous Sclerosis Alliance Scientific Advisory Board, I worked very closely with them, and back in 2017, they wanted to see what the patients thought and what the families thought about what was going on, and what they felt like was important and lacking in their disease care. So they did a survey, and it was an international survey to try to understand better the perspective of patients and their caregivers with tuberous sclerosis complex. And one of the things that they found, not surprisingly, was epilepsy and TAND, were the TSC manifestations that were found to be the most disruptive to daily living in children, and they were the least likely to be controlled by existing treatment modalities. Seizures, behavioral problems, and sleep disorders of children with TSC impacted a caregiver's ability to work and impaired their ability to spend time with their other children. The effects that this have on someone's day-to-day life, it's more than just the seizure. It's not just someone having a seizure. It's the fact that they can't work. They can't spend time with their healthy children because their child or they are having a seizure. 82.6% of caregivers reported that their ward or their child suffered from epilepsy, and 72% of them replied that they had had to make moderate to large changes in their lifestyle to care for the patient's epilepsy. Many people reported that the epilepsy made them fearful for their child's well-being. I don't think most of us could imagine what it's like to live in fear every day that your child's going to have seizures, and that it's gonna impact your ability to be able to do things or their safety or their well-being. Many participants also indicated that their definition of seizure control was different than what their doctors thought or even what the pharmaceutical companies thought. If you talk to a doctor, they will tell you the only type of seizure control that's acceptable is no seizures, and when I was in training, that's what I was taught. You aim for seizure control. You must stop all the seizures. Well, what the parents and caregivers tell you is that, "My child has hundreds of seizures per day. If I can find a drug that reduces the seizure frequency to 2 or 3 seizures a day, I would welcome that, and I would consider that seizure control, because that's much better than hundreds of seizures a day." And so their definition of seizure control is very different than maybe mine or the FDA's or a pharmaceutical company's. So it kinda makes you rethink what it is that I'm doing as a physician or we're doing when we're trying to find seizure control. It's not always about stopping them altogether. Sometimes it's, it is really just about making them better. Several participants mentioned frequent seizures and problematic behavior required a level of flexibility that is incompatible with normal life. This is a quote from one of the patients, or one of the caregivers: "I'm no longer able to work as her seizures persist and require monitoring. There are no caregivers available who know what to look for or understand." Trying to find a babysitter for your child with intractable seizures is really hard. As a parent, it's hard to find a babysitter, period, but now tell the babysitter that your child is likely gonna have seizures while they're babysitting them, and try to go out to dinner with your spouse. It's really hard, and imagine how much that impacts your life. Avoidance of seizure triggers often shapes what a family can do. My TSC child is not allowed to laugh hard because she will have a seizure. She cannot have too much ice cream because she will have a seizure. Being out in the heat or the sun causes an increase in seizures. Caregivers of TSC patients emphasize that although the complete elimination of seizures would be ideal, a more realistic but still valuable outcome would be a reduction in seizures. I see this over and over again. 95% of these patients have seizures. 66% of them are intractable. By the time they're in my clinic, they don't care about making the seizures stop anymore. I shouldn't say that. They'd be happy if I could make their seizures stop, but just as important to them on a day-to-day basis is making the seizures better. This is a story I found written by a young woman named Courtney. She said, "When I was 20, I had my first child, a baby girl with beautiful blonde hair and blue eyes. I named her Mary Sue. Like me, she was diagnosed with TSC before birth. She was learning, picking up on things, perfect. All the things a healthy 15-month-old should be until the seizures came. She's been on many medications. She's 2 now and has seizures almost every day, even with 3 medications she takes twice a day, and they're only getting worse."... In January, we gathered with the baby's neuro to talk about possibly plucking out the active tumors that were firing off seizures. It would be a long process that included an external EEG and an internal EEG. So we go in for the EEG, and they told us 9 months ago they were on the right side, and now they're all over, and we can't do surgery because they don't know where the seizures are coming from. And now we're stuck, giving a medicine that won't work and a little girl fighting through seizures almost every day. This is a story I hear over and over again in the Tuberous Sclerosis Clinic. Although these patients do have TAND and they have a significant amount of neuropsychiatric burden, a lot of these patients live lives. They have jobs, they have families, they go to school, and yet the seizures are a huge impact on their ability to function. And if we could do something to reduce that burden of seizures for them, it would be very impactful. Thank you. All right, great. Thank you, Dr. Koenig, for that wonderful overview. Now I'm going to walk through the opportunity for oral ganaxolone in seizures associated with tuberous sclerosis complex. I'll very briefly review our phase II data, where we only saw a modest reduction in seizure frequency, but more importantly, I'm going to spend some time really focusing on those key learnings from the phase II study and why we have confidence moving forward into our ongoing phase III study. Since Dr. Koenig gave us such a fantastic, comprehensive overview, I'm going to be very brief here on this slide. I think the real key take-home message here is that TSC is one of the most common genetic epilepsies, and despite there being some clinical development in this space in recent years, there's still a meaningful proportion or number of patients that still have highly refractory seizures. And we believe that providing ganaxolone with its differentiated and unique MOA could play a really critical role in this patient population. So as a result, we did conduct an open-label phase II study. Very briefly, it included a 4-week baseline period, followed by a 4-week titration and an 8-week maintenance period. I think on the tables below, the 2 things to highlight is that the patients enrolled were very representative of the TSC patient population. And then on the table on the right, it really highlights, to Dr. Koenig's point, the severity of epilepsy in some of these patients, where we're seeing patients fail a median of 3 prior anti-seizure medications and come into the study on a median 3 concomitant anti-seizure medications. Despite all of that, are still experiencing about 35 seizures per month during the baseline period. The other thing about this study is that patients were allowed to be on newer generation, recently approved anti-seizure medications, including Epidiolex and Afinitor. So when we look at the results from the phase II study, here we have patient-level percent reduction in TSC-associated seizures, where we see a median of 16.6%. When we look at some of our secondary and exploratory endpoints, we look specifically at focal seizures, which are the predominant seizure type in TSC, we see a median of about approximately 25% reduction. Then when we look at our responder analysis, and this is the proportion of patients that have greater than a 50% reduction in seizure frequency in the ITT patient populations, we see approximately 30% achieving the responder level, which is similar to maybe even slightly better than our phase III CDKL5 study. But then also equally as important, when we look at some of our subgroups of patients that were on concomitant Epidiolex or Afinitor, we again see some pretty robust response levels. Now, with all of that said, we certainly did not feel that the 16.6% really reflected ganaxolone's potential in this patient population. W hen we look at some of the responder levels, we noticed that there were a proportion of patients that had some really strong, clinically meaningful responses, and really prompted us to dig into the data a little bit more deeply to better understand what was going on here. One of the results that we noticed first was that there were a higher proportion of patients in this study that reported a somnolence-related adverse event, defined as somnolence, sedation, lethargy, or fatigue. In fact, about 74% of patients in this study did report a somnolence-related AE, and that's compared to about 35%-40% to what we saw in a phase III CDKL5 study. Now, we certainly don't believe that ganaxolone is having a different AE profile in this patient population, but potentially rather that these patients are less cognitively impaired and perhaps more able to report somnolence. Nonetheless, these reports of somnolence often resulted in dose adjustments and dose reductions for these patients. As a result, one of the things that we noticed is that patients that did not report a somnolence-related adverse event, we saw improved efficacy in that, albeit small, subgroup of patients. One of the things that we noticed was that somnolence was most commonly reported during the titration schedule, typically around the 2nd week. And so this really guided us to look at that titration schedule and the resulting predicted ganaxolone levels. A s a result, we have revised the titration schedule, shown here in black, from what was studied in phase II to this very linear, stepwise adjustment, to a more, and shown here in light blue, more of an exponential approach, where we start low and increase the dose week over week to still the same target dose. Now, why we have confidence, and why we believe this revised titration schedule will have the positive impact, really comes from some of the PK modeling work that was done. Around the time that we conducted the phase II study, we also were completing some of our pediatric population PK modeling. And what we learned from that was that there were some patients that reached maximum absorption at around 50% of dose. Fifty percent of dose. When you go back and look at the old titration schedule, that occurred around day 8, probably not surprisingly to when we saw most commonly that report of somnolence. So what I'm showing you here from the modeling is now with the revised titration schedule shown here in blue, we see again what we ultimately were aiming to accomplish by this stepwise increase in ganaxolone plasma concentrations week over week, which we believe will lead to improved tolerability and hopefully thereby improved efficacy. So that gave us. Again, with those learnings, that gave us the confidence to move forward into phase III. Here's the study design, called the TrustTSC trial, which it comprises of a 4-week baseline, followed by the revised, 28-day titration schedule and a 12-week maintenance period. Following the announcement that we made this morning, the study is now designed to enroll 128 patients. We feel very confident in this sample size as it's 90% powered to detect a 25% treatment difference. In fact, when we use some realistic assumptions, statistical significance could be achieved at treatment differences as low as 15%. We think that these statistical assumptions are necessary to ensure that we have a clinically meaningful and viable drug, with these powering assumptions. And, and these sample sizes also align with those of recent rare epilepsy clinical trials in, TSC, Dravet, LGS, and even our own phase III CDKL5 study, which was powered on a 30% difference, where we enrolled 100 patients total. The primary endpoint is the percent change in, 28-day TSC-associated seizure frequency, with the key secondary endpoints listed below. W hat I want to share with you now for the first time, is some early insights into the patient demographics from the ongoing blinded TrustTSC phase III study. What we see here is the average age of patients being enrolled is 15 years old, with approximately a 50/50 male-female gender split. Looking at the box in the middle, again, really similar to what we studied in phase II, really highlighting the unmet need here. These patients are entering the study on an average of 3.1 concomitant anti-seizure medications. Many of those, approximately 41% on Fintepla and about 25% on Epidiolex. Despite this, these patients are still experiencing 52 seizures during that baseline period leading up to randomization. Now, what I'm also really excited to share with you is the blinded discontinuation rate, which to date is less than 10%. Now, as a reminder, this is in comparison to about a 25% discontinuation rate that we observed in phase II. And of those discontinuations, only 1 patient discontinued due to a somnolence-related adverse event. It's this data point right here that gives us some confidence that the revised titration schedule may be having the desired impact it was designed to achieve and we believe should translate to improved efficacy. So in summary here, before I pass it over, again, TSC is one of the most common genetic epilepsies with, again, with high unmet need, despite recent clinical development in this space. Currently have the ongoing phase III TrustTSC trial that we're on track to read out data in the middle of 2024. And as discussed, I mean, we, we believe that the revisions to the titration schedule should have a meaningful impact on tolerability and efficacy. And in fact, we believe that also these findings that I just presented to you could have broad utility when we think about how we could study ganaxolone in other rare epilepsy populations as well. With that, it's my pleasure to turn the podium over to Lisa LeJeune, SVP, Business Unit Lead of Rare Genetic Epilepsy, to talk more about the commercial opportunity in TSC. Thanks, Alex. I'm Lisa, and I'm here to talk to you a little bit today about our commercial opportunity in TSC. Before I do that, I want to show you a short video clip that shows you the why behind what we do every day at Marinus. Gigi started having seizures not long after she was born. I recorded it and sent it to her pediatrician. They could not figure out what was causing the seizures. Her neurologist suggested that we do a genetics panel, and at that time, that's when we got our initial diagnosis. Bad day for Gigi. A lot of seizures. A lot of seizures, just screaming. When you see a tear come down her face, it kills me. There was a point where she was getting rescue medications every other day, so it was really scary to see her sedated like that, not able to eat or drink or, or wake her up. Yeah, I just... I'm grateful for good days. I'm glad you had the opportunity to meet Gigi and her family, her parents, Jasmine and Jesus. She has a sister, Ally, too, who adores her. This family, for them, Ztalmy really made a big difference in their lives. It has the same potential to make a big difference in TSC. I'd like to thank Dr. Koenig for the work she does with these families, and she painted a wonderful picture of what these families go through on a day-to-day basis. The one thing that was clear is there's a need for better seizure control. I've spent the last 25 years of my career in rare and ultra-rare disease. I've launched 7 or 8 drugs into rare disease, and for those of us that grew up in the world of rare disease, we think differently. We think about Gigi and her family every day. When we make a decision, when we sit in a room and decide how we're going to execute on something, we think about Gigi and her family. We spent the last 3 years preparing for our launch into CDKL5 deficiency disorder. We were very intentional in our decision making, and I'd like to highlight 3 key things we did to ensure a successful launch. These same ideas will establish a foundation in TSC as well. First of all, it's about the people. We hired incredibly passionate people. I hope you've felt that from the leaders in this room. But our broader team that is out there, doing this work every day, are extremely passionate about helping patients with rare diseases. We put together a comprehensive strategic plan that would have a compelling message. We had effective and targeted promotion, and we had a sales and marketing strategy that would lead us to the right people at the right place, at the right time. I'm gonna brag on us a little bit. We executed pretty flawlessly. We followed the data, we listened, we learned, and we pivoted when we heard something new that would make a difference in our strategy. We came into our CDD launch with a clearly defined value proposition, a responsible pricing plan, a robust publication strategy that represented our scientific progress with ganaxolone, and we developed a patient support model to meet the needs of the patients and caregivers. We'll do the same for TSC, with a few key differentiators to meet the needs of this broader population. The point I'd really like you to take away today is that our success with CDD can and will be replicated in TSC. Marinus aspires to be the market leader in rare genetic epilepsy. Here's how we think about what's ahead. Our market opportunity, first of all. TSC is a larger market. One of the common problems in rare disease is actually finding the patients. We don't have this issue with TSC patients. The ICD-10 code has been around since 1994. It's widely used amongst treaters. There's no genetic test required to make a diagnosis of TSC. These patients have physical characteristics that present in utero or shortly after birth, which makes it easier to identify them. And from what we've heard this morning, I hope you have the understanding that a large percentage of these patients still have seizures. We're gonna expand upon the CDD launch. Families like Gigi's, living with TSC, need the same opportunity for a new option for more good days. Marinus has taken a distinct, rare approach. This was not just another epilepsy drug launch, and nor will TSC be. We take the values of a rare disease launch into everything we do. We listen, we learn, and we design to meet the needs of the community. So let's talk about the opportunity. We're looking at a 4-5 times growth opportunity for Ztalmy in the TSC population. It's widely accepted that there's a prevalence of about 50,000 patients in the United States, the 1 in 6,000 incidence, as Alex mentioned. 80%-85% of those patients have seizures to begin with. Another 60%-65% are refractory to the treatments that are out there. Another 40% are what we consider highly refractory patients. A population of 9,000-11,000 is our addressable patient population. You can see in CDD, we've talked for a long time about the 2,000 addressable patient population. With this 4-5 times increase in growth, in the market growth, we only have about a 2 times incremental spend. Our CDD foundation and our commercial infrastructure will only require a modest build in our field force. We have about 18 people out there that are field-facing right now. We anticipate this will double to reach the expanded targets of CDD and TSC. We'll have an incremental build in marketing and market access, deploying a commercial and government payer strategy to open doors and access for the TSC population as well. There are distinct centers of excellence for each of these diseases. There's 10 for CDD, 13 for TSC, and about 50 additional TSC clinics. These are places where rare genetic epilepsy treaters live, and that's where we'll spend our time. There's a solid 50%-60% overlap in our targets, and we anticipate an additional 400-500 targets added to our list for our sales reps to address. This geographical overlap between the 2 will allow us to reach both key opinion leaders and community physicians where the patients are. As Christy mentioned earlier, we have over 120 unique prescribers of Ztalmy. We know that will grow between now and launch. Our success stories in CDD will jumpstart our launch in TSC. We started with the video of Gigi. Their goal as a family, as Dr. Koenig mentioned, is to just live as normal a life as possible, just like every one of us in the room wants to. What Gigi's mom said to us was, "We just didn't know how good it could be until she started having good days." That incremental movement in seizures can make a big difference to a family. We want this for the TSC community as well. Let's talk a little bit about how this will work. I'm gonna take you kind of behind the curtain and show you how the synergies between CDD and TSC exist. We touched briefly on patient ID and customer targeting, patient finding. Again, the TSC patients are easier to find than in many rare diseases. There's an established code, no genetic test required, and the data is much more straightforward. This allows us for laser-focused targeting and an appropriate sizing of a team to meet this market. It also allows for a strong behind-the-scenes, non-personal promotion strategy for digital engagement with our treaters. So we found them. How do we move them to Ztalmy? So CDD, Ztalmy was the first and only drug indicated in CDKL5 deficiency disorder, specifically studied in this patient population. That's not the case with TSC. We weren't the first specifically studied in TSC. However, what we've seen is significant seizures still exist despite generic and brand drugs that are already on the market. We are the first in our trial to study, Ztalmy with both Epidiolex and Fintepla, the other 2 branded products on the market, creating a real-world picture of the numerous therapies that our patients cycle through. Dr. Koenig told the story of 1 mom there at the end, Courtney, and her struggle to find help for her child. Many TSC families have this cycling through therapies experience. They're left with treatment-resistant seizures in spite of it. They need another option. Building upon our highly successful team will ensure adequate market reach. Our unstoppable team, with a patient passion for the patient, will execute on our strategic plan that incorporates the voice of the patient and the caregiver. This is where many rare disease launches go wrong. The drug companies, physicians, as Dr. Koenig mentioned, don't always listen to what the families are saying. We're listening. These patients are very, very sick. They require a lot of care. The need is obvious. So much so that when we went to payers early and well-armed with scientific rationale in CDD, over 80% of the payers covered this drug immediately, and that number continues to increase. I've never seen so few barriers to access in my history of rare disease. This same paradigm, significant need, a drug that makes a difference, responsible pricing, and early engagement with payers will lead us to similar success in our next launch with TSC. We will continue to evolve our patient support model to meet the needs of a growing population. We're currently doing this with our CDD population, evolving to meet their needs, and we will obviously broaden our offerings from a patient support perspective as we launch into a broader market. There's a lot going on behind the scenes right now to prepare us for this launch. This timeline demonstrates a timely and effective plan already in place for engaging with the key stakeholders. You can see the advocacy, clinicians, caregiver, community, all of those are underway as we speak. We'll effectively be the voice to the clinicians who make the treatment decisions as we educate on TSC and Ztalmy. Engagement early with payers and financial decision-makers will define our population and spell out our strong value proposition, responsible pricing, and authentic branding. Just like Ztalmy made a difference in CDD, we have the opportunity to broaden the TSC treatment landscape with Ztalmy. TSC is a complex, rare genetic epilepsy. Dr. Koenig showed you multiple facets of this disease. While it's complex, we're solving for the same problem in TSC as we did in CDD: treatment-refractory seizures. Ztalmy has a unique mechanism of action, a favorable safety profile, and the potential to bring the same hope it brought to Gigi's family, to those living with TSC. We met with the TSC Alliance recently, something we do often and will continue to. 1 mom shared with us, "For me, it's about the next seizure, the unknown of the next seizure. I'm afraid that seizure might be the one that takes my child from me." I could feel her frustration, her fear, and her desperation, and I can only imagine how challenging that must be. We'll continue to prepare for a TSC launch with these words ringing in our ears. We've proven ourselves in CDD, and here's what's most critical about how we'll take on TSC. We'll establish a payer strategy that will ensure positioning of our drug is optimal, given the evolving market, the competitive landscape, and the emerging data from the TrustTSC trial. We'll continue to engage with KOLs and patient advocacy groups in both CDD and TSC to educate and to stay informed as to their evolving needs. The TSC advocacy community is a highly developed advocacy and research organization. Our relationship with them is strong and will continue to grow as we move toward a new treatment option with Ztalmy. Most of all, we'll continue to listen to the patients and the caregivers. We take this responsibility seriously, and we'll consider it our privilege to bring Ztalmy to both CDD families now and potentially to TSC families in the future. With that, I'm going to turn it over to Dr. Joe Hulihan. Oh, wait, am I right on? Great. Thank you, Lisa. So I'm going to talk a little bit about our 2nd-generation formulation work. You know, one of the cornerstones of epilepsy management is the ability to individualize treatment depending on what the patient needs. And that depends on the ability to predict a predictable exposure with changes in dose and predictable responses based on exposure. And we've learned a lot about ganaxolone over the past few years and now understand that success is associated with adequate exposure to the drug. It's a potent and effective anticonvulsant when we get it into people in the right way. So we're developing a reformulation of ganaxolone, and the goals of that are to reduce the variability between peak and trough levels. We want to lower the Cmax re- re, in reference to the AUC, presumably, CNS-related side effects or Cmax related... and, exposure correlates with AUC, and so we want to improve that part of the profile. Ideally, reduce dosing frequency. Right now, TID, as you know, we want to get to at least BID dosing with the reformulation and potentially with our prodrug to once daily dosing. And consistent dose exposure through the dosing continuum. We've completed a single ascending dose study at doses from 100 to 1,200 mg in healthy adult volunteers, and the results of that are encouraging. On the left is the graph of AUC versus dose, and you can see from 100 to 1,200 mg, there's a linear dose-response relationship. We've seen in previous studies of the oral suspension that above 600 or 800 milligrams, you get a plateau in exposure, so giving doses greater than that, doesn't give you increased exposure. We see a hint of that in the data, but we have a lot of data from, historical data with the oral suspension to, to support that. In contrast, the AUC, once you get to about 600 milligrams, you don't see the same increment and exposure, with increasing dose. And looking at it in a bit more detail, between 600 and 900 milligrams, the AUC goes up, 41% or 38% actually with the historical suspension, but 41% and 31% in terms of AUC increases, but only 18% and 14% in terms of Cmax. If that carries through and potentially could have a benefit in terms of Cmax-related side effects, relative to increases in efficacy with increasing dose. That being said, it appears that, you know, Alex showed the slide on modeling of the effect of titration. It may be that the titration is gonna be the key to solving reduction in side effects, but this certainly wouldn't hurt. So the next step is to do a multiple ascending dose trial with the reformulation. Again, we want to show that it has linear kinetics. Looking at data in CDD and elsewhere, it appears we want to get blood levels at steady state in the range of 100-200 milligrams and minimize again the peak trough variability and have BID dosing while maintaining an adequate trough level. Looking at the data, you know, we've pored over the data from prior studies, and it's clear that when the trough level falls below a certain point, that's when you don't see the efficacy to be as good. So we want to maintain an adequate trough level. The study has kicked off. This is a study in healthy adult volunteers. We're gonna do 36 subjects in 6 equal cohorts. Subjects are gonna receive ganaxolone at doses of 600-1,200 twice a day. We're also incorporating assessments of food effect, high fat versus standard diet and vehicle, various, you know, yogurt, applesauce, different types of food. And we're gonna look at the first few cohorts and then make a decision about what to do with the dosing for subsequent cohorts. So depending on the response, PK response and safety, we have the opportunity to adjust the dosing for subsequent cohorts. We're also working on a prodrug that, of course, is earlier in development. We have an oral prodrug. We're working on oral and IV prodrug candidates. We have an oral candidate selected and are working on selecting an IV candidate. The goal is to optimize for the oral. We want to increase absorption to a greater extent than the suspension, but for the IV, increase solubility and perhaps get away from having to use a excipient like Captisol for the IV solution. We're planning the preclinical, the IND enabling studies, and IND filing is planned for the end of next year. We're also kicking off a target engagement study. We don't have a PK/PD study with the oral formulation. We've done it with the IV, the data that Alex showed earlier, but we have not done that with the oral. We're going to do a study using transcranial magnetic stimulation and EMG. This has been used to a limited extent in drug discovery. It's been used in a lot of disease state research, neurodegenerative diseases and others. T he way it's done is utilizes a transcranial magnetic pulse over the motor cortex and then measure surface EMG over the thumb, and it correlates. There's a consistent correlation between, in this case, CNS inhibition and the response we see on the amplitude of the effect with the EMG. We're gonna do a multiple crossover design, planning, again, doses to mirror those used in the ascending dose studies, and we'll measure detailed pharmacokinetics and pharmacodynamics over a 24-hour period. And this should help us quite a bit in terms of supplementing our confidence in dose selection for clinical trials, as well as better inform the PK/PD relationship that we should see in terms of efficacy. Our first planned program for the reformulation is in Lennox-Gastaut syndrome. Again, we've completed the development of the formulation. Completed the single ascending dose study. The MAD is ongoing. Depending on the results of the MAD, we would potentially go straight to phase III. If we need more information on dose selection, we would do a phase II-B and then phase III. Historical Lennox-Gastaut trials are interesting. All different kinds of endpoints, and the consistent—the terminology is inconsistent in terms of what's a drop attack. Is a drop attack something that makes you fall? Is it an atonic seizure? We are looking carefully at the previous studies to see which are the best in terms of demonstrating a response, and we'll select our own clinical trial endpoints accordingly. That's a summary of the reformulation. I'll turn it over to Steve Pfanstiel to give a financial overview. Thanks, Joe. It really is a pleasure to be here today at our Investor and Analyst Day. The potential ganaxolone has to impact patients' lives is what brought me to Marinus 2 and a half years ago. I'm proud of what this team has accomplished, and I'm just as excited about what we have in front of us. As Christy and Lisa described, we've proven our ability to successfully launch a rare disease product with a clear path to a near-term return on investment. The RSE and TSC indications in our global partnerships have the opportunity to significantly expand the impact of ganaxolone to many more patients on a global basis, while also driving long-term value for Marinus. As we're demonstrating with CDD, focusing on rare diseases provides us with a unique and attractive business model. With a focused commercial investment, a deep understanding of our markets, and a product with transformational impact, we can drive robust operating profit margins while also providing for further investment in R&D. Backing up all of that is a strong financial and IP foundation, which sets the stage for near-term execution and long-term stability of our business. Going back, even prior to the positive phase III Marigold data, there were questions around the financial feasibility of launching Ztalmy, whether we could ever realize a return with such a small patient population. I'm proud to say our sales trajectory, as seen here, is on track to break even on our annual commercial investment of approximately $25 million within 2 years of launch or by mid-2024. By keeping a tight field focus on the pediatric CDD population and pricing appropriately, even below what our pricing research suggested, we've been able to drive steady uptake in a very short period of time. In fact, our 2023 sales guidance is now between $17 million and $18.5 million, which reflects an increase from our guidance at the start of the year. We are also pleased to see we're driving adoption of Ztalmy across the pediatric population with a median age of new patients of approximately 9 years old. Given the weight-based dosing paradigm, this is driving an annual net price of approximately $150,000 per patient. We are not content to limit the impact of ganaxolone to just patients in the U.S. We have exciting partnerships with the European market, with Orion, and in China with Tenacia. These partnerships are critical for several reasons. We've selected partners with the right expertise and resources to bring these products to market and expand the reach of ganaxolone. As a reminder, these partnerships have already provided upfront funding of approximately $40 million, with the potential for an additional $45 million of development and commercial milestones. We also share in the long-term value of ganaxolone in both markets, with tiered double-digit royalties and additional sales milestones. BARDA also continues to be an important partner for our IV development programs. They help fund significant preclinical and clinical investments for IV ganaxolone, including our current RAISE phase III trial and our API onshoring initiative. The total committed funding to date is $33 million, with the ability to expand that up to a total of $51 million as development progresses. Outside of the EU and China, we have recently signed a commercial partnership with Biologix for the MENA region and continue to evaluate opportunities for the Japan market. For other countries, we're implementing a managed access program to be launched within the next 6 months to ensure broader access globally. Our oral franchise with Ztalmy provides us with the potential for a significant and attractive return on investment. Rare diseases, by definition, have a low incidence and overall patient population. Investments in these spaces do provide higher pricing potential, but that's critical, given the cost it takes to develop a product through approval and to support it beyond. Our strong phase III data, our open-label extension data, illustrate our ability to build and maintain a patient base by providing a long-term durable response and a high retention of patients. As mentioned, our OUS partnerships also contribute to our long-term revenues through double-digit royalties and milestones. On the cost side, manufacturing costs and royalties paid to partners are each in the mid-single digits, which drives a robust gross profit margin, and we have the opportunity to improve this further through investments such as our API onshoring. With expansion into TSC, we see significant commercial overlap with existing CDD efforts. The overlap across these indications allows us to serve a market that is 4-5 times the CDD market, yet with more limited incremental investment. We expect to combine CDD and TSC commercial investment of likely just approximately 2 times our current CDD investment. We understand the hospital space requires a different investment profile. Successful products in the hospital have a foundation of a compelling clinical impact backed with strong health economic data. We're excited to reach the finish line soon with our phase III RAISE trial, as we believe we'll be able to drive a compelling pricing rationale focused on both patient outcomes and cost reduction. Similar to the oral franchise, our revenues in the U.S. will be augmented by royalties and milestones outside the U.S. IV manufacturing costs are expected to be in the low- to mid-single digits, as are our royalties paid to partners. That should also drive robust gross profit margins similar to the oral franchise, with a similar opportunity to improve that over time. Commercially, our market research and experience in the hospital is helping us to optimize our approach to launch and the overall investment. We are ensuring we're addressing all key aspects, including sales and market access, while making key investments such as the 250-milliliter IV bottle. We're also able to leverage many parts of the existing corporate structure, our knowledge of ganaxolone, so that we limit incremental investments outside of the commercial team. We've worked hard to provide a strong financial foundation for Marinus ahead of the phase III readouts of RSE and TSC. If you look on the left, we now project to have a cash balance in the range of $170 million-$175 million at the end of the Q3, which provides us with cash runway well into the Q4 of 2024. Earlier in the quarter, we did execute 4 discrete reverse inquiry transactions off our ATM facility, resulting in the sale of an additional 3.7 million shares, driving net cash proceeds of $26 million. These transactions further strengthen the quality of our shareholder base, providing us with another quarter of cash runway as well. Our guidance for 2023 remains unchanged from our Q2 earnings call, but I will point out that we continue to focus on our CDD commercialization efforts and our TSC and RSE phase III trials in order to maximize our existing cash runway. We also continue to look forward to future opportunities. With a successful RSE and TSC outcomes, we have several oral and IV programs that can further build the impact of ganaxolone. Our IP around both the IV and oral franchises continues to strengthen, providing us with the potential for long-term protection of our innovation and our business. As an example, we have invested greater than $50 million since just 2020 into our IV formulation of ganaxolone, including our RAISE trial. Protecting this investment and the innovations we've developed to advance the treatments of epilepsy and seizure disorders is vital. For the IV franchise, we now have method of use patents granted protecting ganaxolone into 2040, which speak to the specific unexpected finding of our RSE dosing paradigm being used in the phase III trial. We continue to expand our IP around the IV franchise, with additional pending applications on both dosing and formulation. For our oral franchise, we have multiple patents, both granted and pending, covering both CDD and TSC, with the potential to extend protection into 2040. For the next generation, formulations and prodrugs, we are already driving an IP strategy to protect those innovations long term. Now to bring everything you've heard together. As every speaker you've heard attested to, we are absolutely committed to being leaders in innovation. We have an incredible opportunity with ganaxolone to address significant unmet needs, and we're poised to expand that significantly beyond CDD. By addressing patient needs, we've shown we can build a growing and cost-effective business model, and we're ready to extend that. With 2 significant launches, we have the potential to drive blockbuster status for ganaxolone. As I just mentioned, we have a strong IP foundation, and we'll continue to defend that. We've also used our global partnerships and programs to impact more patients and drive long-term value. And finally, we've spent a great deal of time talking about the science and the approach, but it's appropriate to end this meeting by talking about the people we have at Marinus. This is an incredibly dedicated and knowledgeable team, fully committed to helping patients and delivering on the potential of ganaxolone and on Marinus. With that, I believe we're set to transition to the 2nd Q&A. Mic on? Oh, yeah. Okay. I just want to thank my team. We are trying to keep within that 1:15 time period, so I think we've done a good job at doing that. We have about 20 minutes for Q&A, so right on track. I will note that we also have Dr. Ian Miller, who joined the organization about a year and a half ago. Ian is a—was a formerly practicing pediatric epileptologist, who came on board and is really leading the efforts on the recruitment and the overseeing of the TrustTSC trial. Let's open it to Q&A. I thought it would be fair, Joe, and just go to the audience first, but we'll get right there. Okay, Scott, this question is from Charles Duncan at Cantor. Well, then let's take the next question. I love Charles, so... He says, "Congrats. Take it all back. Congrats on the Ztalmy progress thus far. With 140 patients on therapy, what percentage of these patients are previously clinical trial patients, or those that would have been on the trials? And what percentage are de novo and identified patients? What do you think it would take to reach 3x adoption, and could that happen in 2024 or by mid-2025? ...Lisa, do you want to talk about the breakdown of patients? Sure. About 20% are the clinical trial patients. Of the 140 patients that we have on therapy, we mentioned 120 unique prescribers. So think about it as if most of these physicians have had 1 or so patients on therapy. As we progress, we imagine that these treaters, with their good experiences, will expand their patient population accordingly. I guess I'll only add, Charles, I'm hopeful that this franchise will continue to grow. We've generally guided to about 2,000 patients out there in the pediatric population. A meaningful number of our patients are adults, and so we do think there is an opportunity for this market to continue to grow beyond those 2,000 patients. And we've talked about this molecule having what we believe is a $100 million-$150 million peak potential in CDKL5, which would equate to about 600-700 patients. So that's our target here over the next few years. I think we know in epilepsy that doesn't happen overnight, but we're incredibly happy with the success of the molecule. We are starting to share success stories every week on our company meeting. We've been very happy with the discontinuation rate, which is now lower than what we've seen in the phase III trials. Only a year into launch, but a lot to learn, and so we're excited about the future of the franchise. Joe? Thank you very much. 1 for the physician in terms of clinical practice. Can you talk a little bit in terms of what proportion of your TSC patients are you able to titrate successfully up to the top recommended dose in clinical practice? And is there anything in the phase III TrustTSC trial, you know, on a reduction in seizure burden that would make you definitely place this ahead of Epidiolex, I guess, in the treatment paradigm? Did you get that? I think so. So as far as what percentage of patients we're able to titrate to the maximum dose in clinical care, so we're not using this in clinical care for tuberous sclerosis right now. Oh, I'm sorry. Just basically, we've heard some physicians say they can't titrate Epidiolex up to the top dose in clinical practice. Okay, yeah. Are you able to? For Epidiolex. So right. So Epidiolex is a drug that has been approved for TSC. And yes, we are using it. There's a couple of reasons why, everybody's not using it. So one is it's not efficacious in everybody. There are patients who put on it, and it just doesn't work. It's just like other drugs. And then there's a lot of patients who are developing diarrhea, and the dose is limited by that. So as far as what percentage, it's really hard to say. You know, I'm not sure I could give you a number. I would say maybe 10%-15% of my patients are on it. Maybe a little higher, maybe a little lower. I don't know. Joe, were you curious about dosing in Epidiolex as well? What's typically the range of dosing? Are you using 25 mgs per kg or other dosing? Yeah. T he minimum recommended dose is about 15 mgs per kg, and we're going as high as 35. You know, I'm seeing efficacy anywhere as low as 10, and seeing continued increased efficacy up to 35, depending on the patient. And some people just seem to tolerate it, and some people don't. Did you have a second question, Joe? We have a little time, so... Just in terms of the level of seizure burden that you saw in the TrustTSC trial, then you would definitely reach for this before Epidiolex, given some of the concerns that you just mentioned. W ould I place this before Epidiolex? You know, people ask me all the time: "How do you decide what seizure medicine to start in what patient?" And I think there's a reason why computers don't do seizure control and people do. There are so many reasons why you pick 1 drug over another when you're trying to treat a patient with, with intractable seizures or with seizures in general. Every neurologist you meet will have favorite drugs that they use, and. The things you take into consideration are the type of seizures the patient has, what the known side effects of the medication is or are, what they've tried in the past that's worked and not worked. One of the things that ganaxolone has, that really is going for it, is the fact that it is a unique mechanism of action. When you've tried medicine after medicine after medicine that have failed, you really are looking for something with a unique mechanism of action. The other thing is the lack of side effects. That seems to be really impressive. Somnolence isn't always a bad side effect, especially when it's titratable. And it is - it does seem to be dose-dependent. A lot of patients are looking for something. Insomnia is very common in people with tuberous sclerosis complex. And there's ways in clinical practice that we can trick and play with it, give a higher dose at bedtime, a lower dose in the morning. I know we don't do that in clinical trials, but you can do that in practice. So insomnia, I'm sorry, so somnolence is not always the worst side effect to see. So where would I put it in my paradigm? Based on my experience right now, I'm actually gonna put it pretty high. I like it. It's working quite well in the patients that I have on it. I can't give you any specifics, but it's definitely going very high in my treatment paradigm because it, it's so far, has good efficacy with a very good side effect profile. We have another one from the webcast, Scott. Also from Charles. This time for Dr. Koenig. What is the key value proposition for ganaxolone? Seizure freedom, seizure control, or improved stabilized progression of comorbid conditions, especially TAND? That's a really complicated question. In tuberous sclerosis, always looking for improvement in seizures. It goes back to what the parents say. It's not always about seizure, seizure resolution as much as it is about seizure improvement. And one of the things we find is that seizures and tuberous sclerosis change over time. They change all the time. You can have a patient that's well controlled, and then the next week, all of a sudden, they start having seizures again. I've had patients that have been intractable for 5 years, who all of a sudden wake up one day and don't have another seizure for 3 or 4 years. So when I see a patient in clinic, I'm always looking to improve their seizures. So step number 1 is seizure improvement. I'm using a seizure medicine. I want to improve their seizures. Step number 2 is I want to try to improve their TAND-related symptoms. When you improve someone's seizures, you improve their TAND-related symptoms. If you're having seizures very frequently, it affects your ability to sleep, it affects your ability to think, it affects your mood and your behavior. So you're improving TAND-related symptoms just by improving seizures. Whether or not there's another mechanism that improves the TAND-related symptoms, I think that's yet to be seen. But certainly improved seizure control can improve TAND-related symptoms. Thank you. Questions in the, Okay, let's take it. Okay. Andrew Tsai from Jefferies. Thanks so much for the Analyst Day. How should we expect the phase III TSC placebo rate to trend? How would that placebo rate compare to the placebo rates of other TSC studies? Dr. Khan, you wanna, you wanna take a shot on what you expect in terms of placebo in this patient population? Anytime you do a clinical trial with epilepsy, you expect to see a pretty decent placebo rate. As far as how I would expect to see it compared to other TSC studies, I would expect it to be similar. Some people look at the 25% placebo rate in the Epidiolex study as unusually high. Okay. Any thoughts or comments? No. Not, not really, other than that people were really excited about the Epidiolex study because they were very excited about CBD, and they were very confident that it was going to work. Do I expect it to be higher or lower in this one? I don't, I don't really know. I would defer that to someone who does clinical trials. Hi, Joon Lee from Truist Securities. So tuberous sclerosis, Lennox-Gastaut, these are all chronic conditions, chronic epilepsies. Is there something about ganaxolone versus Epidiolex versus other drugs that you may prefer for chronic use? You know, is there, is there something about GABA targeting that you wouldn't want chronically as compared to endocannabinoid system versus... I'm assuming Afinitor will be, will always be a backbone, but, you know, just wanted to understand, based on CBD experience for chronic option, what would you prefer? What would you be looking for? In Tuberous Sclerosis, we're always talking about chronic. In epilepsy therapy, in general, you're always talking about chronic. So again, it goes back to the side effect profile, long-term side effects, short-term side effects, trying to maximize that side effect profile. So I'm always looking for something that has the lowest potential for side effects, the lowest drug-drug interactions. So I want something that's tolerated by the patients, and I want something that's not going to interact with their other medications, 'cause they're going to be on a lot of them, and I want something that's not gonna cause a lot of risks to the patients. Other things we think about is drug monitoring. Do I have to do a lot of drug levels? Do I have to check CBCs? These patients oftentimes are cognitively impaired, and they don't want to just sit there and say, "Oh, yes, please check my blood every month." So a lot of the medicines that are out there, some of the older medications, things like fosphenytoin, Depakote, you have to monitor drug levels. They have really nasty side effects. They make your hair fall out. Some of the newer medicines that are out there, they can interact with each other. Lamictal, you can't give Lamictal with Depakote because they affect each other's levels. It can start getting really complicated. So when you're starting to look at what medicines do you want to give, you wanna give something that is either going to beneficially interact with your other medicines or it's going to not interact at all. You want something that's gonna have a nice safety profile. As far as ganaxolone goes, it's got a unique mechanism of action, it's got a good safety profile, and the side effects are relatively mild compared to a lot of the medications that are out there on the market, and they're potentially manipulatable in order for me to use them in a beneficial way. Hi, this is Rudy from Leerink. Just a quick follow-up to the TrustTSC question. So in the open label phase II trial, I think ganaxolone showed roughly 17% seizure reduction in all comers and 25%-30% for patients without somnolence. So just curious, given that TrustTSC is 90% power to show 25% treatment difference. So what are your assumptions for seizure reductions in the drug arm versus placebo arm? Any color will be helpful there. Thanks. What are my observations? Your assumptions. Oh, what are my assumptions? So I- ... I believe that it is going to work. I wouldn't be part of the trial if I didn't think it would work. Can I, can I talk about my experience in this? Phase II, you can talk about. Yeah, I was part of the phase II trial. I think we had 5 subjects enroll in it. We had very favorable responses in our subjects. So I have 1 young lady who's still on therapy. She's seizure-free. She's seizure-free for the first time in her entire life. She's a cognitively normal young lady. She's in middle school and never been able to get her under control with anything else. Epidiolex, Fintepla, none of those worked. And so, you know, it's. I have very favorable feelings towards ganaxolone, and I believe that it will work, if not for everybody, at least for a lot of patients. I think from a company perspective, our assumptions are we expect the same efficacy delta as we saw in the Marigold study. We've actually powered the study incrementally with more patients relative to the Marigold study to show that benefit. In our minds as well, the biggest difference between Marigold and the phase II study in TSC was the discontinuation rate, the tolerability, and the side effect profile. As Alex mentioned, we feel very good that we've solved that particular problem. We've seen not only a low discontinuation rate, but if you remember that phase II slide, there were several patients who did significantly worse in that trial, had a doubling of their seizures, and we've had a very low discontinuation rate in the study as a result of worsening seizures. W e feel very good about some of the issues that we've resolved and hence our, our confidence in a phase III result that's very much in line with, with Marigold. Doug? Go. Hi, Joe from Brian... Or Joe, Joe from RBC, for, for Brian. So on TSC study, with the new, I guess, number of patients, that'll be enrolled there for a TSC study, what fraction of the patients do you expect to come from outside the U.S.? And, if you could highlight some of the key differences or similarities in clinical practice or drug that these patients are on from different regions, that would be super helpful. And if I could squeeze 1 more. How similar are the types of seizures between TSC and CDD patients? Joe or Ian, do you wanna talk about the seizure types? Sure. Please, go ahead, Ian, please. Yeah, I mean, tuberous sclerosis is pretty different from CDKL5 in terms of it being conceptualized as an intrinsically focal epilepsy. Dr. Koenig showed us the MRI with those white spots in different parts of the cortical ribbon, and that is where the seizures are thought to come from. Some seizures spread very quickly, and they look generalized. If you look at our data set, when the trials are real, see seizures that look like they're generalized from onset because they spread so fast. Fundamentally, clinicians think of it as a focal seizure disorder, like, very unlike CDKL5. Right now, about 1/3 of our sites are U.S. sites, and I think we'll see about 1/3 of the enrollment come from the U.S. Probably, 40+% coming from core Europe, where we've seen Spain and Germany really be the largest, where and the U.K.'s been a very nice contributor, and we're actually hoping that's going to continue. Where Israel, Canada, Australia will make up the bulk of the patient population. And as Alex mentioned, we're very happy with the baseline characteristics. This where we thought long and hard, was this trial worth lowering the seizure burdens more similar to other, LGS or Dravet-type studies? And we felt it was critical to keep that seizure burden at 8 seizures per month. The fact that we're seeing seizure burdens close to 50, 50 seizures per month, 3 prior medications, this is the exact refractory population that we're hoping to enroll in this study. So we are very pleased about the type of patients we're enrolling, that that will translate into a benefit that payers will understand and, and, and certainly patients and physicians will, will be, will be happy to see. Did we get all the parts of your questions? Great. Dr. Koenig, I'm just curious if the TrustTSC study works, you know, the ganaxolone will demonstrated efficacy in 2 distinct epilepsies. I'm just curious, would you, and do you expect some of your colleagues to be looking to use it in other epilepsies, understanding that reimbursement and access might be somewhat limited, but if you have patients who have failed numerous therapies, oftentimes payers are willing to grant access to something off-label? T hat's a really great question. The answer is very simply, yes. We are always looking for new agents with new mechanisms of action, and this provides that. So, yes, I do believe that it is something that would be readily accepted and trialed to the extent that we could get coverage for it. I think with that, we will thank you, Dr. Koenig, for sticking around today. Our earlier physicians, the panelists and earlier panelists, thank you all for coming. Appreciate everyone who listened in on the webcast. We had north of 150-175 people on the webcast, so thank you all for listening in, and sorry that we had to keep you here a little past 1:00, but we really wanted to showcase the future of the organization. As you can see, we have quite a bit on our plate, and the team is ready to execute and will continue to do so. We appreciate your support. Thanks so much.