Greetings and welcome to Marinus Pharmaceuticals' Fourth Quarter and Full Year 2023 Financial Results and Business Update Call. Today's call is being recorded, and all lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during that time, simply press the star key followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one a second time. Thank you, and it is my pleasure to introduce your host, Sonya Weigle, Senior Vice President, Investor Relations, Human Resources & Corporate Affairs. Ms. Weigle, you may begin. Thank you and good afternoon. With me from Marinus are Dr. Scott Braunstein, Chairman and Chief Executive Officer, Christy Shafer, Chief Commercial Officer, Dr. Joe Hulihan, Chief Medical Officer, and Steven Pfanstiel, Chief Financial Officer and Chief Operating Officer. Before we begin, I would like to remind everyone that some of the statements we are making today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by such forward-looking statements. These risks and uncertainties and 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. I will now turn the call over to our CEO, Dr. Scott Braunstein. Thank you, Sonya. Marinus concluded 2023 with a strong finish across all fronts: commercial, clinical and operational. On today's call, I'll provide a brief overview of some of the key areas before turning it over to our leadership team. Starting with an update on Ztalmy, we finished 2023 with another strong quarter of enrollment and robust quarterly growth. As a result of the progress made by our commercial team, we expect to achieve profitability on our Ztalmy commercial investment by the second quarter of 2024, ahead of our previous 2-year target. Christy will provide a summary of our revenue results in her remarks, as well as an update on our investments to continue to grow the CDD business and our launch plans as we prepare for 2 critical phase III data readouts in the second and fourth quarters of this year. Our commercial partners in the EU, China, and MENA regions continue to make important progress to support Ztalmy launches around the globe. In China, the Tenacia team has been granted priority review of the NDA submission in CDD, as well as contributing to the enrollment of the TRUST-TSC trial. In Europe, Orion continues to plan for the launch of Ztalmy in select European countries in 2024. Finally, in the MENA region, we are targeting that our partner, Biologix, will begin their distribution strategy in the second half of this year. Concurrently, we are expanding our manufacturing investments to ensure that we can adequately supply not only our global partners, but the broader market opportunities for Ztalmy over the coming years. Turning to our clinical pipeline, I'll first share an update on our phase III RAISE trial of IV ganaxolone in refractory status epilepticus. As we announced in our press release this afternoon, we are pleased to report that we have met the enrollment criteria for the interim analysis and now have more than 90 patients enrolled in the trial. We expect to deliver the interim results to the Data Monitoring Committee over the coming weeks and plan to announce the outcome within the first half of the second quarter. Based on continued strong enrollment seen over the past six months, we project approximately 100 patients to be included in the secondary endpoint analyses. This growing data set should drive a robust package for both the FDA filing and our health economic outcomes. We expect to have the comprehensive trial results over the summer and to present this data at a series of medical meetings in the fourth quarter. We are currently planning for an NDA submission in the first quarter of 2025 and are expecting a priority review. We see the recent uptick in enrollment as a strong reflection of the potential market opportunity for the IV franchise. Domestically, we believe the addressable market for RSE is approximately 35,000 patients per year, and we have the unique opportunity to bring a novel therapy to physicians. We plan to build our leadership in the hospital by continuing to invest in future status epilepticus research while making the appropriate commercial investments, with the goal of ascertaining value-based pricing and broad physician adoption. Let me move to an update on our oral pipeline. Approximately 85% of the patients have been enrolled in our TRUST-TSC trial, and the discontinuation rate is below 7%. Due to some minor delays in screening, we expect to complete enrollment in the TRUST-TSC trial during the first half of the second quarter. As a result, we now anticipate our top-line phase III results in the first half of the fourth quarter of this year rather than the end of Q3. We could not be more pleased with the baseline demographics of the patients enrolled, the high percentage of patients rolling over to the open label portion of the study, and the low overall discontinuation rates, which are substantially different than what we saw in phase II. We believe the quality of this data set will support a compelling pricing strategy consistent with what we've seen to date for Ztalmy. The commercial team continues to make the appropriate investments to prepare for a potential launch in 2025, and we are eager to offer patients suffering from refractory TSC a novel anti-seizure therapy. Based on our market analysis, the addressable patient population in refractory TSC is projected to be about 10,000 patients in the United States. By leveraging our current commercial organization, we believe successful expansion of this opportunity will require a modest incremental investment. As a result, our goal is to drive profitability for the entire Ztalmy franchise within 6 months -12 months of the 2025 TSC launch. 2024 will be a pivotal year for the company as we have built a solid foundation that has us well positioned to drive future growth. Together, the CDD, RSE, and TSC markets represent a multi-billion dollar opportunity, where we believe we can take a firm leadership position for these disease states and other refractory epilepsies. With an established commercial and clinical track record, we look forward to building our momentum for Ztalmy, while also reporting on these key data milestones later this year. I'll now turn the call over to our Chief Commercial Officer, Christy Shafer. Thank you, Scott, and good afternoon, everyone. In my remarks today, I will share an update on our Ztalmy launch, the progress we are making to grow our CDD franchise, and an update on our commercial readiness planning for potential launches into TSC and RSE. Starting with Ztalmy, in our first full year of launch, we generated net product revenue of $19.6 million for the full year 2023. This solid performance is a result of our strategy to establish Ztalmy as a critical treatment in the comprehensive management of seizures associated with CDD and to ensure that patients have seamless access to Ztalmy from prescription through fulfillment. We ended 2023 with more than 165 patients active on therapy. We continue to see swift payer approval, with time from enrollment to patient fill of approximately 2 weeks in the second half of 2023, representing a consistent improvement throughout the year and demonstrating payers' understanding of Ztalmy's impact on patients in need. Additionally, payer approvals of CDD prescriptions remain at nearly 100%, indicating strong payer recognition of the value of Ztalmy for these patients. To date, discontinuation rates are still well within our anticipated expectations. Looking ahead, we continue to expect full year 2024 U.S. Ztalmy net product revenues of between $32 million and $34 million. The midpoint of this range represents growth of nearly 70% versus 2023. We are executing a number of strategies to maximize CDD market penetration. We are utilizing new data sources and analytics to better identify patients who are not billed with the CDD ICD-10 code in third-party claims and identify patients who may have CDD, but have yet to have a confirmatory genetic test. Leveraging these data, we have also rolled out a genetic testing initiative, which will help accurately diagnose patients. And with the open label extension data published late last year, we are able to emphasize Ztalmy's sustained efficacy and safety profile, supporting the use of Ztalmy as a proven treatment for combating seizures associated with CDD. We are excited for the opportunity to bring Ztalmy to more CDD patients in need and believe our commercial strategy has us well positioned to realize the potential of this novel treatment. Our experience with Ztalmy provides Marinus with a solid foundation for two potential commercial launches in 2025. These include Ztalmy's expansion into TSC and the IV formulation of ganaxolone for RSE. Launch planning is well underway for both TSC and RSE in anticipation of two key trial readouts later this year. Let me take a few minutes to summarize our commercial planning in support of each of these programs. Starting with TSC, our rare genetic epilepsy business is led by Senior Vice President Lisa LeJeune, a 30-year veteran in ultra-rare disease. We are planning to build on the strong foundation we have established with Ztalmy and CDD and expand our proven strategy to capture the larger TSC market. We believe there is a strong business rationale and market opportunity for the expansion of our Ztalmy business into TSC, where we know there is a significant unmet need in refractory patients. We plan to take advantage of synergies with CDD and TSC while leveraging market data that will further support an additional commercial launch. Research suggests that there is a potential strong overlap with CDD rare disease treaters, and unlike CDD, TSC patients may be easier to identify through a well-established ICD-10 code, which has been in use for more than 30 years, and the physical TSC attributes, which may be identified at birth. Our early plans to expand into the TSC market include disease state education for payers, engagement with very active and supportive advocacy partners, including the TSC Alliance. TRUST-TSC data education with payers and formulary decision makers in advance of an sNDA submission, and an enhancement of our patient services and specialty pharmacy model. Turning to RSE, with enrollment criteria now satisfied for the interim analysis and the RAISE trial, and data anticipated in Q2, let me take a few moments to summarize our commercialization and launch plans. We have assembled a team with extensive commercial experience in the hospital setting under the leadership of industry veteran, Kristin Rudisill, our Vice President and Business Unit Lead for the Acute Care Franchise. In 2024, our acute care business is focusing on aligning development and execution with key milestones. Driving access post-approval is pivotal to our launch strategy, and this year, we are aiming to complete key access strategies such as channel and distribution plans, NTAP filing, and pricing. In addition to strategic planning, we are preparing for execution with the build and deployment of a field access team, entering the market as early as this summer. Activating this team under the FDAMA 114 guidelines is designed to address key access stakeholder and payer groups with information that addresses their key value drivers. These teams are permitted to disseminate healthcare economic information that is critically important to these financial decision-makers, who often control or influence formulary decisions for new therapies. With corporate and system-level financial decision makers, we believe engaging with these key stakeholders can accelerate access and awareness, leading to more favorable formulary placements, and will ultimately provide patients with earlier access to treatment. The combination of our team's leadership, the commercial plans we have outlined, and the success of Ztalmy, gives us the confidence that ganaxolone has the potential to become a blockbuster franchise across CDD, TSC, and RSE. I look forward to providing further updates on our progress and plans throughout the year. At this time, I would like to turn the call over to our Chief Medical Officer, Dr. Joe Hulihan, for an update on our clinical programs and development. Thank you, Christy, and good afternoon. I'm pleased to share an overview of our pipeline progress, which includes two key upcoming phase III data readouts and initiatives to support our continued clinical and scientific understanding of RSE and TSC. Starting with the RAISE trial of IV ganaxolone and refractory status. After a strong end to 2023, I'm excited to report that in January, we hit our enrollment requirement for the interim analysis. With this critical milestone achieved and date scheduled for DMC review of the data, we continue to expect to report top-line results in the second quarter of 2024. Now that we've achieved the required enrollment target for the interim analysis, the clinical operations team has been hard at work ensuring the integrity and completeness of the study data to be provided to the DMC for their review. Here's what you can expect next in the process. Presently, the clinical operations team is focused on data cleaning in anticipation of generating the interim analysis data set. Once the preparatory steps are complete, the data will be provided to the DMC for a determination of whether the studies met the pre-specified efficacy stopping boundaries on the co-primary endpoints. If the study achieves these pre-specified stopping rules, the Marinus leadership team will then evaluate the data and share top-line results publicly soon thereafter, including both the co-primary and key secondary endpoints. Successful results would serve as the basis for submission of a U.S. regulatory filing. While preparation of data for the upcoming DMC is ongoing, as Scott mentioned, we'll continue to enroll patients in the double-blind phase of the study. Data from these additional patients will be pooled with the interim analysis data set and will serve as the basis for analysis of other secondary and healthcare utilization endpoints. If double-blind enrollment is stopped based on the interim analysis results, we'll then enroll new patients in a planned open-label extension to collect additional safety data that will support upcoming regulatory filings and future discussions with payers and other key stakeholders. As a reminder, the interim analysis will include results of the co-primary and key secondary study endpoints, which measure both onset of action and durability of effect in controlling status epilepticus. The co-primary endpoints are status cessation within 30 minutes and prevention of escalation to third-line treatment with IV anesthetics. For the key secondary endpoints, we are looking at another measure of onset of action, the time to status cessation analysis, and a further measure of treatment durability, lack of progression to IV anesthesia for 72 hours, which encompasses the 24-hour period following the end of the ganaxolone infusion. Following release of the top-line data, analysis will continue and will yield results on other secondary endpoints and important healthcare utilization outcomes, including time on mechanical ventilation, days in the ICU in the hospital, and discharge destination. The results are anticipated by the fall, and we plan to present them at major medical meetings later this year. Turning to our second refractory status trial, RAISE-2 is a phase III double-blind, placebo-controlled registration study targeting enrollment of 70 patients who have failed first-line benzodiazepine treatment and at least one second-line IV anti-seizure medication. In this study, we're evaluating IV ganaxolone in a population that's earlier in the continuum of refractory status, in whom IV anesthesia is less likely to be an imminent next step in treatment. We believe this study, which is expected to complete enrollment by the end of 2025, will support a European approval and can be used to expand the U.S. label. Data presented at AES last December, as well as other published research, suggests that earlier treatment intervention in patients with status improves clinical outcomes. At that December meeting, we presented results from a 5-year analysis of status epilepticus treatment dynamics in the U.S. This analysis showed that even in the absence of IV anesthesia, refractory status that was treated with two or more IV antiseizure medications had worse outcomes and longer lengths of stay. The RAISE II trial is designed in a way that will allow us to assess the impact of IV ganaxolone on clinical outcomes and healthcare utilization in this subgroup of patients. Moving to super refractory status, or SRSE, we continue to supply IV ganaxolone to physicians upon request under emergency INDs for these patients, whose life-threatening condition has high rates of morbidity and mortality. To date, over 25 patients have been treated for SRSE with ganaxolone under EINDs. Preliminary data on outcomes have been encouraging, particularly since we implemented a dosing regimen tailored to the treatment of SRSE. This regimen incorporates a higher daily dose of approximately 1,000 milligrams of ganaxolone with 63 grams of Captisol. Based on the outcomes we've observed, we intend to conduct a proof of concept study of IV ganaxolone in approximately 50 patients with SRSE. We plan to go to the FDA in the second quarter of this year with this modified dosing regimen and begin the study before year-end. Turning to our Ztalmy franchise, first with TSC. Seizures in TSC are often treatment resistant, despite the availability of newer disease-specific anti-seizure medications. To address this unmet need, we're evaluating ganaxolone in TSC patients with refractory seizures in our ongoing TRUST-TSC trial. This is a global, phase III, randomized, double-blind, placebo-controlled trial of adjunctive ganaxolone, which will enroll approximately 128 patients with TSC-associated seizures. As Scott mentioned, we've achieved over 85% of the target enrollment and are confident that we'll complete full enrollment early in the second quarter of this year. As a reminder, the trial provides 90% power to detect a 25% difference in seizure reductions between ganaxolone and placebo. As discussed previously, the titration schedule has been modified in consideration of the pharmacokinetics of ganaxolone and the timing of side effect onset in prior studies. Currently, the discontinuation rate in the study is below 7%, giving us confidence in the potential benefit of the revised titration, not just on tolerability, but potentially on efficacy as well. In addition, we're seeing over 85% of patients who complete the study transition into the open label extension, a rate as high or higher than observed in the Marigold study. We're targeting submission of a supplemental NDA in the first half of 2025, with a priority review expected. Additionally, we plan to expand our investment in Ztalmy to explore its potential in the treatment of other rare epilepsies. Planning is underway for a clinical trial that would assess oral ganaxolone for the treatment of a broad range of epileptic encephalopathies. Many patients with seizures and neurodevelopmental disorders don't satisfy diagnostic criteria for Lennox-Gastaut syndrome or other well-defined developmental and epileptic encephalopathies, and we feel there's a substantial unmet need for seizure treatment in these patients. We plan to initiate a proof of concept trial assessing ganaxolone in approximately 100 patients in the fourth quarter of this year. In closing, helping patients and families suffering from severe refractory seizure disorders remains at the core of what we do. Our clinical team is motivated and focused on ensuring these lives are transformed with new, safe, and effective treatment options. I'd now like to turn the call over to our CFO and COO, Steven Pfanstiel, for a financial update. Thanks, Joe, and good afternoon, everyone. I am pleased to be able to provide a financial update as well as share our financial results for the fourth quarter and full year of 2023. First of all, I am proud of how we managed the business in 2023. We ensured that we remained focused on our critical investments in the RSC and TSC trials and on the commercialization of CDD. On the latter, we now project a break-even on our CDD commercial investment in the first half of 2024, which is ahead of our projections and less than two years from the launch. We were also not afraid to make tough decisions, such as discontinuing the established status epilepticus trial and making other cost reductions, to ensure adequate cash runway headed into two significant data readouts. As a result, we ended 2023 with cash, cash equivalents and short-term investments of $150.3 million. This is expected to provide cash runway late into the fourth quarter of 2024, and importantly, we project a cash balance of greater than $100 million at the expected RSE readout. We announced early in the quarter that we project 2024 US Ztalmy net product revenues of between $32 million and $34 million. As Christy mentioned, this increase from 2023 represents continued strong and steady execution on the launch. Unlike 2023, we are not providing full year 2024 operating expense guidance at this time, as the level of investment will depend on the outcome of the RSE and TSC phase III trials. However, we expect operating expenses and cash burn in the near term to be consistent with the 2023 trends. I'll now take a few minutes to summarize our financial results for 2023. We recognize the Ztalmy product revenues of $6.6 million and $19.6 million for the three and twelve months ended December thirty-first, 2023, as compared to $2.3 million and $2.9 million for the same periods in the prior year. The full year total of $19.6 million exceeded our revised Ztalmy revenue guidance range of between $18.5 million and $19 million. Separately, we recognized BARDA revenues of $0.6 million and $11.4 million for the three and twelve months ended December thirty-first, 2023, as compared to $1.8 million and $6.9 million for the same periods in the prior year. Our actual 2023 BARDA revenue of $11.4 million was within our guidance range of between $11 million and $12 million. Research and development expenses were $26.4 million and $99.4 million for the 3 and 12 months ended December 31, 2023, as compared to $21.4 million and $79.9 million for the same periods in the prior year. The year-to-date change was due to increased costs associated with our API onshoring effort, increased TSC and RSE clinical trial activity, and increased headcount. As a reminder, the API onshoring effort is approximately 70% funded by BARDA, so the increase in R&D expenses is partially offset by the increased BARDA revenue. Selling, general, and administrative expenses were $15.4 million and $61.2 million for the three and twelve months ended December 31st, 2023, as compared to $14.7 million and $56.8 million for the same periods in the prior year. The primary drivers of the change on a year-to-date basis were annualization of the U.S. Ztalmy launch costs and increased headcount. Full year 2023 GAAP operating expenses, consisting of both SG&A and R&D expense, was $160.5 million, which was within our revised guidance range of between $158 million and $162 million. Interest income was $1.7 million and $8.1 million for the three and twelve months ended December 31st, 2023, as compared to $1.7 million and $2.4 million for the same periods in the prior year. The increase in interest income was driven by the overall increase in cash, cash equivalents, and short-term investments, and increased yield on those balances. Interest expense was $4.3 million and $16.9 million for the three and twelve months ended December 31st, 2023, as compared to $3.7 million and $10.7 million for the same periods in the prior year. The increase is driven by drawdown of an additional $30 million of credit under the Oaktree agreement in March 2022, and non-cash interest expense related to our revenue interest financing with Sagard. The company reported a net loss before income taxes of $41.8 million and $142.9 million for the three and twelve months ended December 31, 2023, as compared to a net loss before income taxes of $32.7 million and $16.4 million for the same periods in the prior year. As a reminder, the prior year's results included the one-time sale of our priority review voucher in the third quarter. These totals include non-cash stock-based compensation expense of $3.9 million and $15.6 million for the three and twelve months ended December 31st, 2023, as compared to $3.8 million and $14.9 million for the same periods in the prior year. Cash used in operating activities was $118 million for the 12 months ended December 31st, 2023, as compared to cash used in operating activities of $112.9 million in the prior year. Before we move to the Q&A, I will make a few concluding remarks. We are very pleased with our progress to date, all of which has led to a number of potentially transformational milestones in 2024. We have two key data readouts in RSE and TSC that, if positive, could drive significant growth for our ganaxolone franchise, and we look forward to sharing these and other important updates in the months ahead. Thanks again for your continued interest in Marinus. Operator, you may now open the call to questions. Thank you. As a reminder, if you would like to ask a question, press star and then the number one on your telephone keypad. To be able to take as many questions as possible, we do ask that you please limit yourself to one question. We will pause for just a moment to compile the Q&A roster. We will take our first question from Brian Abrahams with RBC Capital Markets. Your line is open. Hi there. Good afternoon. Congrats on the enrollment completion and of the interim cohort, and thanks for taking my question. I guess on TSC, as we think about the potential future commercial opportunity there, I'm curious how the reimbursement dynamics that you're seeing with Ztalmy, both for on- and off-label use, are shaping your view of what the ultimate, what the future dynamics might look like commercially, in the TSC indication. Thanks. ... Thanks, Brian. I'll kick it off. This is Scott. Thanks for the congratulations, and then I'll kick it over to Christy. You know, we're incredibly proud of what the job that Christy's team has done. Within 6 or so months of launch, we had every state Medicaid program reimbursing Ztalmy. We currently have over 80% of commercial plans with relatively straight guidelines, and we've yet to have a patient who's been denied a therapy. Equally interesting, since launch, we've had a meaningful number, about 10% of our current sales are coming from spontaneous use, refractory epilepsy or DE patients. And we're seeing overall, about two-thirds of those scripts, those prior authorization forms, being reimbursed by the payers. So I think we really understand that the payers recognize that there are not a lot of therapy for these refractory patients. We have a limited data set, and we're very pleased with the reimbursement dynamics as of today. I think going into TSC, we will have a second randomized control study showing the value proposition. We'll have a patient population in TSC, which in many ways mimics the CDD population, a highly refractory patient population that has failed multiple prior therapies, a patient population currently getting standard of care, either Epidiolex or Afinitor or mTOR inhibitors. This will be the first add-on study ever with Afinitor that's randomized double-blind placebo control. So I think we're going to go into all of our discussions with a high level of, I would say, a high level and high expectations that what we will share with payers will be equally compelling to that of the data in CDKL5 for Ztalmy. Christy, you want to add any? I know I rambled on, I apologize, but anything you want to add? Nothing additional that I want to add, but I think the most important thing is that we regularly are confirming assumptions that in the refractory patient population, payers have a very, very distinct appreciation for what these patients have gone through. So it's a different disease state than CDD, yes, but I do think that data is suggesting that although these patients have gone through many, many different medications, they still are significantly at need in the refractory patient population. If CDD is an indicator of that success that we've had in the CDD population, we'll be thrilled to see that again in TSC. Got it. Thank you. Thanks, Brian. We will take our next question from Peyton Wansak with TD Cowen. Your line is open. Hi, guys. Good afternoon, and thanks for taking our questions. I guess, looking forward to potentially if the data is positive, what remains to be, done for the NDA package? How quickly do you think, besides the, guidance that you've given? And is there anything outstanding on either the safety database that needs to be completed or, CMC? And, that's it for me. Yeah, let me kick it off, Peyton, and then I'll pass it over to Joe. So, for everyone out there, as a reminder, this is the same API material that we have approved in Ztalmy, so a substantial proportion of the NDA package has already been effectively blessed by the FDA. Certainly, the process from API to an IV product will be new. As many of you know, we made a formulation change over a year ago. We did that with guidance from the FDA. About half of the study will actually be in patients who have received that new formulation, and over the coming weeks after positive data, we will set up a meeting with the FDA, a pre-NDA CMC meeting, very similarly, what we did with Ztalmy, and that was an incredibly successful strategy. For the filing, we will want to gather all of the data from roughly 100 patients to provide that to the FDA. Although our expectation is the label will be driven from those from the interim, and just to share with folks, we actually will have 83 patients in the interim. We had two patients enrolled in the same day to finish the study, because we're Marinus, nothing is ever simple. But so that interim will be based on efficacy on 83 patients, but we will and we are expecting a label around those 83 patients. But certainly, we'll provide all of the safety data and all of the double-blind data from all 100 patients as part of the filing. We will keep our sites open, and we will enroll patients, should the interim be stopped for efficacy, we will continue to enroll patients, in an open-label fashion to continue to allow physicians to experience using the drug, and we'll also file that additional open-label data with the FDA. Certainly, the regulatory team is expecting to have a pre-NDA meeting with the FDA soon after the top-line data, with our current plan for filing the NDA in the first quarter of 25, early in the first quarter. And that's really aligns both with the data that we have to compile, but equally important, with our commercial team's best thinking about the time of launch and when we're thinking about major reimbursement, including NTAP in 2026. So the wheels are in place from our standpoint to be 100% prepared, and we'll walk you through as we go through these processes through 2024. Joe, anything that you want to add on the data set? No, I mean, there, as Scott mentioned, I mean, the pivotal data set for efficacy is gonna be the 83 patients from the interim analysis, and then we'll be supplementing that. Especially the secondary endpoints, we'll be looking at. We expect somewhere around, I don't know, we'll continue to enroll until the DMC meets, but that full data set of 100, who knows how many patients, enrollment has picked up quite a bit. We'll analyze healthcare utilization endpoints and secondary endpoints on that larger dataset. And so that'll give us more patients with those secondary endpoints, and we'll have a good size safety data set as well. As Scott said, especially with continuing to enroll open label if the DMC stops the study for efficacy. Hey, thank you, guys, so much- Thank you. for taking our questions. Thank you. We will take our next question from Andrew Tsai with Jefferies. Your line is open. Hey, thanks. Good afternoon. Congrats on the enrollment completion as well as the other updates. So, maybe an open-ended question for you guys. If an investor were to ask you, what are maybe one or two things that keep you up at night with the phase III RSE study, you know, that what, what things could have been done better or on an execution or a trial design standpoint, what would they be? And then really quickly, if the stopping criteria is not met, would you still provide some type of update right away to the street? Thank you. Yeah. Yeah. Thanks, Andrew. I'll take the second one. We will unequivocally update you all on should the DSMB suggest that we continue the study. So you should expect some update from us in the first part of the second quarter. I think one of the things probably in the last few weeks that was keeping me awake, these are very complex patients. Some in our phase II, we had one patient who was on 100 different drugs, and just collecting all of that data can be, it could create issues. I'm gonna really give a shout-out to our clinical team, who several months ago started to create, really, computer-generated checkpoints for the data to make sure that the individual datasets were aligning with our primary endpoints accordingly, and, and with the, what physicians were filling out and what was being filled out at the sites, and, and, and we could do that in a way to really ensure high quality of the data. I would say, you know, as Joe, as Joe mentioned in his prepared remarks, we, you know, we finished enrolling the study at the end of January. We've now had several weeks to start cleaning the data, and so I feel, you know, what was keeping me awake at night was the integrity and the complexity, but I think the team has really worked hard to get us there. You know, and we're confident in delivering the dataset as we talked about, and probably even more excited about sharing some of the secondaries in the fall as well, Andrew. So, the last few weeks, you know, the team's made great progress, and we are looking forward... You know, this has been a three-year project, a labor of love. I think our clinical team has done an amazing job at enrolling the right type of patients for this study, and I think we're gonna unequivocally know that not only does this drug work, but can it have a material impact in the treatment of refractory status patients. And I was just at a meeting in Orlando this weekend. I met with five investigators, and it was, there was a lot of excitement about the dataset from the investigator team, and I think they're equally excited to see the results as well. Thanks for the question. Great. Yep, fingers crossed. Thank you. Bye. Thanks. We will take our next question from Charles Duncan with Cantor Fitzgerald. Your line is open. Yeah. Hey, good afternoon, Scott and team. Congrats on completing that enrollment and commercial progress in the year. I had a question regarding RAISE I granular, if you could just give us some guideposts. And then, also, I didn't hear anything about second-generation oral ganaxolone. Do you have any color on the progress there? Thanks. Thanks, Charles. I'm gonna pass over the stopping criteria to Joe, but I'll just quickly say, we didn't talk on this call. We were trying to keep the call brief, number one, so we kept it to 30 minutes. On the second gen program, I would tell you all that we're really thinking about our prodrug program now being our lead candidate. We are doing IND-enabling work. We have a very high reason to believe that the prodrug, both ganaxolone and the cleavage of the prodrug, structurally looks incredibly safe. We will have that data over the summer, which in my view is a de-risking event. For those of you who are not too familiar with what we've talked about in the prodrug program, the, the data looks to have a once-a-day dosing regimen, a blunted Cmax, will have new intellectual property, will have improved cost of goods, and there are some other important business, issues that we will talk about over the coming months on the prodrug program. And so our hope would be that we will finish that IND-enabling work by year-end and, and be able to take that program into the clinic next year. And I think, quite honestly, that's going to align great with TSC data and the additional study that we're going to start in the fourth quarter in other refractory epilepsies. Joe, you wanna talk about the stopping criteria? Yeah, sure Charles. I mean, we're glad to share what the details of that are. So the stopping criteria are based on the co-primary endpoints, cessation within 30 minutes and lack of progression to IV anesthesia within 36 hours. They're co-primary endpoints, so both of those need to hit on the statistical significance independently. And the way, you know, the power, the powering is based on an alpha spending function. The p-value, required p-value at the interim is 0.0293, and that with that p-value, we have over 90% power to detect a 40% treatment difference. You know, with that said, if we get deltas, you know, 25%-30%, it will still be statistically significant. The analysis is very robust. And so we have a lot of power at the interim analysis based on the 83 patients. And then we'll also be looking at the key secondary endpoints at the interim, but the stopping rules depend on the co-primaries. Very helpful. Thanks for the added color. Sure thing. Thanks, Charles. We will take our next question from Joon Lee with Truist Securities. Your line is open. Hey, congrats on the enrollment as well, and thanks for taking our question. You know, good to hear that you're already planning for launch of Ztalmy and IV ganaxolone next year. You know, as you do the market research in preparation for launch, is there a specific efficacy profile that patients are looking for and the docs are looking for? And is that consistent with your pre-specified stopping criteria? Thank you. So I just want to be clear, the market research on the IV form of ganaxolone? Yeah. Ztalmy for TSC? I wanted to be clear. Yeah. IV ganaxolone? Both, actually. Both, actually, but IV ganaxolone- Oh. Would be nice. Yeah. Christy, I'm happy to pass it to you. Yeah, as Scott mentioned, you know, one of the things that keeps him up at night is that these patients are quite sick. And I think what we've learned in our market research is, yes, these patients are quite sick, and the value that we believe that IV ganaxolone can bring is quite extensive because everything is confirmatory. Everything that has been done in RAISE-1 to identify these patients is really what we've seen in real-world evidence as well. So they really mirror each other, and quite frankly, that's super supportive of the commercialization efforts that we're trying to build. Similarly, on the Ztalmy side of the business, I think that it is really important that we realize that this is the refractory patient population, and in TRUST-TSC, it is exactly what they have been doing there as well. A little bit different from CDD, but again, it's super refractory patients. And so again, exactly who we'd be commercializing for. Yeah, and the only I'll add to Christy's comments is that, you know, the literature is quite clear that IV anesthesia leads to increased morbidity and mortality. And I think we designed that Phase Three trial specifically to replace a treatment paradigm which is antiquated and really deleterious to the patient's outcome. So that, in my mind, the study design in and of itself is exactly what physicians told us they wanted. And certainly, I think it's going to be critical for the IV launch. Thanks, thanks for the question, Joon. Looking forward. Thank you. We will take our next question from Marc Goodman with Leerink Partners. Your line is open. Hi, good afternoon. This is Basma on for Marc. Thanks for taking our question. I have a question regarding Raise. So if Raise is successful and ganaxolone is approved in RSE, how much of label use would you expect in the RSE and SRSE settings? And along the same lines, what... You mentioned that there are 10% of Ztalmy sales are coming from off-label use. Would you expect this percentage to stabilize or to increase? Thank you. Well, let me start with the second question, and then we'll work our way to the first. Look, I think we, as a company, will never predict nor give specific estimates about off-label use. It's, you know, our sales organization is hyper-focused on the CDD population, hyper-focused on educating physicians about the use of genetic testing, and we would be the same with TSC. That said, traditionally, I mean, you know the market better than us. When GW was an independent company, we saw Epidiolex sales as high as 20 or 25% in the spontaneous use category. I think we will focus on doing additional studies, either with Ztalmy or second generation and drive for label expansion over the coming years. But I think it's pretty clear that there's a significant number of patients with needs in the refractory epilepsy population. So you know, I think it's great to see that physicians are asking payers to try Ztalmy. It's great that payers are reimbursing, and we're seeing about the same discontinuation rates in CDKL5 patients, low 20% range. So that's also encouraging on the efficacy side. On the IV side, the commercial team will be hyper-focused on the refractory status population. I think that is our best strategy for reimbursement, for formulary acceptance. I think we really believe that there are three major parts of the refractory population, and we will start with the most difficult to treat and continue to focus on the importance of earlier intervention, where there is-... Significant data in the literature that the later you treat status patients, the worse their outcomes, the longer status patients are in status, the worse their outcomes. And we have good justification for moving up the treatment paradigm, starting with the RAISE 2, but other studies that we are considering today. I think we find equally compelling is the super refractory opportunity. We think there are about 5,000 patients in the U.S. today suffering from super refractory status. The typical EIND patients that we are seeing today are spending about 30 days in the ICU as physicians ask to use our drug on a compassionate use basis. We continue to get 1-3 requests a month. We've had two more requests this month as EINDs, and I think a critical goal for us is to go back to the FDA and align on a dosing strategy, which would change from the RAISE dosing of 830 milligrams and 50 grams of Captisol to a daily dose of about a little over 1,000 milligrams of ganaxolone and 63 grams of Captisol. We think there's adequate safety there, but we do want to go to the FDA, get their alignment, and Joe is working on that final clinical trial design. Christy, on the commercial side, do you want to add anything? You know, honestly, Scott, I think you hit on all points wonderfully. Thanks. Good. Thanks so much. Thanks for the question. Thank you. We will take our next question from Douglas Tsao with H.C. Wainwright. Your line is open. Hi, good afternoon, and thanks for taking the questions, and congrats on all the progress. Maybe starting with Ztalmy, just given, you know, now we're, we're entering our, I guess, our third year of commercialization, I'm just curious if we've seen a shift in where new patients are coming from and how that's evolved and, and how you expect to see that sort of change over the next 12-24 months? And then I have a follow-up on the IV franchise. Sure. Christy, you wanna jump in? Absolutely. Thanks for the call, Doug. You know, over time, we're—we launched this drug in September of 2022, and there were a couple of interesting things to start, but after we really leveled off, patients are coming from a myriad of places. We get an enormous amount of patients from our centers of excellence. I'll remind you, there's 10 of them across the United States, but these patients also are being seen by their their local or community physicians on a regular basis, and so we tend to see great involvement from pediatric neurologists or pediatricians in some sort of function around these patients throughout. So what we do know is that the targeting that we've done has been very, very good from 2022 to now. We've now given that a little bit more of a, of a kick, if you will, and it's a little bit more robust for 2024, and we've, we've broadened our scope a little bit on who we're targeting. But I don't see us targeting differently, just a little bit more broad going into 2024, and there's not wild shifts on who's writing for the drug. Okay, great. That's really helpful. And then just to understand, a little bit what you're trying to do in SRSE, Joe, you spoke about, and, and Scott as well, about getting alignment with the FDA in terms of the higher dosing. Mm-hmm ... I, my guess is you're not planning on sort of doing another sort of placebo-controlled study in SRSE. I'm just curious in terms of the language or sort of on the dosing, would it be sort of just because RSE in theory should be on label to what you, your label would be in terms of SRSE. Would it just be labeling to give specific guidance for that 1000 milligrams dose for an SRSE patient? Or would it just be sort of providing looser language that you can dose up to 1000 milligrams a day? Thank you. Let me kick it off, and then, Joe, I'll pass it to you. Yeah, Doug- Yeah. I mean, you know, we're expecting our label is going to be the RAISE regimen, which is that 830 milligrams over 24 hours, which contains 50 grams of Captisol. So we want to unequivocally align with the agency that that higher dose can be studied safely. We don't think it'll be an issue. Almost all of these EIND patients have gotten 63 grams of Captisol. We've not seen a renal signal. We've never asked the agency because we've never had to go that high for RAISE. So we want to get their buy-in, and along with that buy-in, we will be doing what will be a single-arm study, and I'm gonna pass it over to Joe. And, yeah, I don't think there's any reason that we need to do a double-blind placebo-controlled trial in this population. I think we need to show safety in this population, but all of those patients would have failed multiple therapies. And I think that's the way we're approaching it. I think we also wanna really create a more robust dataset for the drug outside of simply our RAISE and RAISE-2 populations. Joe, you wanna talk about what you're thinking about for a trial design? Yeah. We've been working on this with Henrikas Vaitkevicius, you know, our former Brigham ICU doc, who's been really leading the design on this. And we're looking, as Scott mentioned, single-arm, open-label trial. The dosing regimen is different. It's whereas RAISE is 48 hours, it's been several days. This dosing regimen we've implemented more recently for the emergency INDs, and without as much of a bolus upfront, it's really a different approach. We start the drug while the patient's on IV anesthesia, continue it for a period of time, and then bring it down. And a dose of total highest daily dose is 1,050 milligrams per day, and as Scott mentioned, with 63 grams of Captisol. As I said, you know, we, we've treated over 25 patients with this regimen, including children, and we haven't seen any safety signals from this higher regimen. And it looks like this higher dose regimen, it's hard to say based on the EINDs with 100% certainty, but it looks like it's having an effect beyond the regimen that we had used previously, which was basically the raised regimen. So we really want to make sure that, you know, if docs are going to use it, that they use it appropriately. It's not anything we promote, but I do think potentially they'd use it. So the dosing regimen is different, and we wanna get some data on that from a clinical trial. Joe, just as a final clarification, so would you anticipate having that new dosing regimen on the label itself, or would it just be to get the higher, dosing limits, sort of on the label? I mean, this is a first step. It's a proof of concept study. So I think it depends on what we see there. But I mean, we're just taking it a step at a time. We really need to see, you know, kind of safety and preliminary efficacy from a proof of concept study. And Scott, I don't know if you have any more comments about the dosing and- No, I think you're right on target, Joe. Yeah. I think, Doug, after we have this data, we'll go to the FDA, the team's ready to go, and we'll hear what they have to say, and we certainly see it as next steps. I mean, I think I'd love to see us get safety into the label, but we haven't had those discussions with the agency yet. But certainly that would be our goal, our hope, and our plan. Okay, great. Thank you so much. Thanks for the question. We'll take our next question from Jason Butler with Citizens JMP. Your line is open. Hi, thanks for taking the question, and let me add my congrats on all the progress. Just one about the proof of concept study for oral ganaxolone and Lennox-Gastaut and the other rare epilepsy. Can you maybe just speak to the amount of data you would need to generate from that study before moving into a registration study in any specific patient population? And would there be any opportunity in that study to introduce the next gen formulation, the prodrug formulation, or when would be the first time that you could bring that formulation into this patient population? Thank you. Joe, let me kick it off, and then I'll pass it over- Yeah, to you for the trial design. Jason, what we're really thinking is that this will be a Ztalmy study, and I think, quite honestly, five years ago, I would have felt crazy to run this study. But given now what we understand about Ztalmy, the PK, the PD, the blood levels, and what we've seen over the years, a consistent improvement in serum concentrations of the drug. And by the-- and when we finish the TSC study, we'll be happy to share some of the, we haven't seen the blood levels in TSC, but we've seen them in other healthy volunteer studies, our SAD, MAD studies, and certainly we're feeling good about the discontinuation rates in the real world. So I have a heck of a lot more confidence today that in any study with Ztalmy, we can get the vast majority of patients to a therapeutic blood level. And I think our goal in this study is to really show that proof of concept, and I'll let Joe talk about it. I think what we also want to walk away is, where do we think ganaxolone as a molecule is most effective, if not only in LGS, but in other refractory DEEs. But we, I would not expect this study that we will kick off to really include that second gen. We'll use this study to help guide us on efficacy and where we want to go with the pivotal, and we'll take the next gen through the, the SAD, MAD studies, and hopefully, those will align in terms of what we want to do with the, with, with the, the prodrug program. And I think we have the, the luxury of a little time to get this right, to be thoughtful. We've got two launches that we'll be planning for in 2025, so that will keep us pretty busy. But that being said, I think, you know, there are not a lot of folks who are really thinking about these patients, and it is a priority for us to get there. Joe, you want to talk a little bit more about the trial design? Yeah. Or what you're thinking about the trial design? Yeah. Yeah. So, again, this would be the initial trial's proof of concept, single arm, open label. We have not yet done the detailed discussions about what statistical signal we'd want to see to say the drug is particularly effective in condition X. I mean, I think there are a lot of things we can get out of such a study, besides signal finding. I mean, we look at signals based on the genetic etiology, seizure phenotype, the type of seizure. We could also get information on non-seizure outcomes, some preliminary PK/PD data, and also information to inform other pieces of a study design, selection of the clinical endpoints, even, you know, how we collect the data, how we do the measurements, and a basis for statistical, you know, more than statistics within the study itself, a basis for statistical powering on any subsequent study we would do. The general comment would be, if everything, you know, if overall we get a good effect and every, you know, every subset seems to be trending in the same direction, you know, that'll tell us one thing. But if something happens to pop, you know, we may get patients in the study with specific disorders of GABAergic transmission that may show a differential effect. All of those things will be informative. In terms of how much of a signal, I don't think, you know, we haven't done the statistical powering on that yet. A lot of the statistical descriptions in the study will be purely descriptive statistics without a priori statistical powering. Okay, great. Thank you. Thanks for the question. Operator, we're gonna take one more question from the call-in, and then we're gonna have to cut the call. Thank you. We will take our final question from Brian Skorney with Baird. Your line is open. Hey, good afternoon, guys. I just wanted to ask a question and also on, on raise and sort of the powering assumptions there. It was originally powered for 40% delta, and I think you've been talking about as low as a 30% delta to reach that sig. I'm just wondering how to kind of think about that 30% delta. Is that based on blinded response rates overall in the study? Just kinda going through the powering analysis and how different results wind up hitting stat sig at 83 patients. So I don't know, is that informed at all by a blinded analysis, or is that consistent with the original analysis? Can you review any of the statistical assumptions underpinning the time to cessation analysis, as a secondary endpoint, since it's not binary outcome? Just what, what sort of separation do you need to see there to be statistic? Thanks. Joe, let me kick off, and then I'll turn it over to you. Mm-hmm. So, Brian, we have not looked at the blinded data. It's had no impact on our decision making here. I think when we started the study, we really could not get a very comfortable handle on where placebo rates would be in the study. I think it was very clear to us that once we started the study and we added a protocol amendment, and we had our physicians really screening every patient, our confidence continued to grow that we were seeing a highly refractory population that was very likely going to have a low placebo rate. You know, we've shared with you that blinded data, that the average patient in this study is failing 3.5 drugs, 3 to 3.5 drugs. They are being observed for 24 hours, compared to about 8 hours for our phase II. You know, giving us a lot of confidence that that physicians have run out of options, and our clinical team has pressed every enrollment, every physician on enrollment, making it crystal clear that if a patient was to be enrolled, the physician had to feel comfortable that IV anesthetic was the next drug of choice. Now, that being said, there are still gonna be some placebo patients that probably or drug patients that still are having epileptiform activity and are not getting IV anesthesia. Physicians are not perfect beasts, but we feel quite confident that the placebo rate will come in lower than our original assumption of 30%-40%. And I don't think we had any magical way to really think about that when the study started, given that the only publication suggested about a 9% response rate in third-line patients. So I think we have just seen this study progress. We feel very good about it. We feel that we're likely overpowered for a 40% delta where we were. And we think for the interim analysis, these 83 patients will be more than sufficient. Joe, you wanna talk about the secondaries, and then we're gonna wrap? Yeah. Yeah, yeah. Yeah, just real quick about, I mean, the power calculation. The hardest data we had was from a survey of the investigators. You know, when we presented them with the profile based on the inclusion criteria, they said that they would advance to IV anesthesia, 70% of the time within two hours. And so 70%, you know, advanced, that gives the 30% not advanced. There would be basically what we would translate to the placebo rate, 30%-35%. In terms of the secondaries, you know, the time to status cessation, we expect that actually to be, you know. It's a continuous variable, so even more robust than the responder analysis on the primary. The way status would stop, you know, in the phase II, it was a median of 5 minutes in the ganaxolone group. Patients in the placebo group aren't gonna stop spontaneously. When they'll stop, it's when they're treated. So that's gonna be a period of, you know, hours, probably in most cases. So that continuous variable is extremely robust in terms of statistical power. Great. Thanks a lot. Mm-hmm. Ladies and gentlemen, that is all the time we have for questions today. This will also conclude today's call. We thank you for your participation, and you may now disconnect.