This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk08: Greetings, and welcome to the Marinus Pharmaceuticals first quarter 2023 financial results and business update call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. And now it is my pleasure to introduce your host, Sasha Damouni-Ellis, Senior Vice President of Corporate Affairs and Investor Relations. You may begin, Ms. Damouni-Ellis.
spk01: Thank you, and good morning. With me from Marinus Pharmaceuticals are Dr. Scott Bronstein, Chairman and Chief Executive Officer, Christy Schaefer, Chief Commercial Officer, Dr. Alex Ameddi, Chief Scientific Officer, and Steve Samsell, 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, Scott Bronstein.
spk14: Thank you, Sasha, and welcome to our call. During the first quarter of 2023, we made important progress advancing our oral and IV Ginexalone programs, further establishing Marinus as a leader in the development of innovative treatment options for patients with rare genetic epilepsy and refractory seizure disorders. We continue to make considerable strides with the launches of Ptolemy, are pleased with our first quarter sales of $3.3 million, and are on track to meet our previously stated full-year 2023 guidance of $15 to $17 million. Christy Schaefer, our Chief Commercial Officer, will be reviewing some of the key initiatives for 2023 that we believe will support the continued growth of the Ptolemy. We've also made significant progress in our commitment to bring Ganaxalone to more patients around the world. Let me start with an update on our European TDD marketing authorization application. As part of the day 195 assessment report, the European Medicines Agency communicated that the major objection related to the choice of regulatory starting material has been resolved. We expect to receive the CHMP opinion for Zotami and CVD by the end of May and are confident with the progress that we have made to date. As a reminder, in August of 2021, we entered an exclusive agreement with Orion Corporation for the commercialization of Ganaxalone in Europe and have been collaborating with them to prepare for the potential launch. We look forward to sharing the formal CHMP opinion with you later this month. Furthermore, we are pleased to have entered into an exclusive distribution and supply agreement with Biologics for Zytalmy in several markets in the Middle East and North Africa. Biologics is a multinational pharmaceutical company based in Dubai. We hope to have Zytalmy available for patients in the MENA region in early 2024. In parallel, we are working closely with Tenacia, our partner in China, and expect them to file a new drug application by the end of this year. We are engaged in active discussions with several strategics who are interested in bringing our products to market in Japan. Our current and future SUS partnerships are a central part of our commitment to reach the global patient community. Moving to our clinical pipeline, we are excited to announce our plans to conduct an interim analysis for the Phase III RAISE trial in refractory status epilepticus later this year. Alex will discuss the process in more detail shortly, but if the results meet the predefined stopping criteria, we expect to report interim top-line data in the second half of this year. Our leadership continues to prepare for a potential RFC filing, including a growing effort from our commercial, regulatory, CMC, and medical science teams. Additionally, we are gratified that physicians across the U.S. are requesting the use of ibuprofen for their most severe super refractory patients, and some have seen important clinical improvements. We are actively recruiting for the Phase III TRUST TSC trial in the U.S., Europe, and Canada, and expect the vast majority of clinical sites will be ready to enroll patients by mid-year, including new sites in Israel, Italy, Belgium, Australia, and China. Due to administrative and regulatory delays in certain ex-U.S. countries, many of these which have now been resolved, we expect top-line data no later than the middle of 2024. Importantly, we learned with CDV, efficacy and tolerability are key attributes to success in the refractory epilepsy population, and we are confident that the current protocol design maximizes our opportunity for a clinically meaningful outcome. Let me conclude with a few additional business updates. We continue to advance our IP portfolio and recently received a notice of allowance from the U.S. Patent and Trademark Office for a new method of use patent for Ganaxalone in TSC. When granted, the term of this patent will run through 2040. We have spent considerable time and energy broadening our patent portfolio and look forward to the final issuance of both this new method of use patent for the oral franchise in TSC and an additional dosing method of use patent for our IV franchise in the treatment of RFC. We believe that there are additional opportunities to expand our patent portfolio based on our scientific advancements in the next several years. We look forward to our upcoming phase three data readouts and the clinical progress in our second generation platforms. We expect a number of additional milestones before the end of the year, including enrolling our first patient in the RAISE-2 trial and completing enrollment of the first cohort of patients in the RESET trial in established status epilepticus. We believe our second-generation formulations have the potential to be the future of the Denasalone franchise and are planning to initiate a multiple ascending dose study with our first new formulation in the third quarter with preliminary results expected by year-end. If these results are consistent with the single ascending dose modeling, this formulation would be utilized in a future trial in Lennox-Gastaut syndrome with the clinical program design expected to be finalized in the first quarter of 2024. Finally, we are pleased to welcome Marvin Johnson to our Board of Directors. Marvin has over 34 years of diverse commercial operations experience at Merck and will be invaluable in supporting the Zetalny commercial efforts while preparing for potential hospital launch of IV Ganaxilone. Now, I would like to turn the call over to our Chief Commercial Officer, Christy Schaefer.
spk09: Thank you, Scott, and good morning. I'm pleased to provide you with an update on our continued progress as we execute on the U.S. commercial launch of Zotami. Today, I'd like to focus on three topics, how the Zotami launch is progressing, what we're doing to accelerate growth and adoption of this important new medicine, and how we are preparing for a potential IV launch of Ganaxolone in the hospital and an expanded indication in TSC. Net sales of Zotami in the U.S. in the first quarter were 3.3 million, with approximately 100 commercial patients active on therapy by the end of the quarter. We continue to see a steady build of treatment-naive commercial patients with prescriptions coming from a growing and diverse prescriber base of over 100 unique physicians. Total payer coverage for Zotomi increased to approximately 225 million lives, including both commercial and government programs. Zotomi has received favorable coverage determinations from over 40 payers, representing approximately 130 million commercial lives. And Medicaid access has been confirmed in all U.S. states, as well as Washington, D.C., and Puerto Rico, representing approximately 95 million lives. We've received meaningful uptake in all CDKL5 centers of excellence, with encouraging trends persisting in surrounding areas where patients are managed routinely for ongoing treatments. Using sophisticated data sources, we've seen an uptick in the usage of the ICD-10 code, G4042, and continue to see this trend rising with educational efforts and awareness campaigns with over 700 unique patients since 2020. We're evolving our commercial efforts in response to what we've learned. This includes investments in higher quality data sources, more sophisticated analytics, new educational materials around genetic testing, and training in ultra-rare market dynamics. Understanding the crucial role of the caregiver, we continue our commitment to providing ongoing support to the CDKL5 community. Recently, we hosted an educational webinar featuring Dr. Raj Rajaraman, a prominent pediatric neurologist from UCLA, a CBD center of excellence, and Dr. Alex Ameddi, Marinus' Chief Scientific Officer, to address questions received from the community. Additionally, we are in the process of kicking off our Caregiver Engager Program to educate patients and families by sharing experiences of families who have initiated treatment with the TAMI and what that experience has meant for them and their loved ones. These stories will be incorporated into our branded promotion for CDD And we'll also include healthcare providers who can speak to the clinical profile of Zytomi. We continue to plan for and are making significant progress as we look to expand our oral franchise and build out our acute care franchise in preparation for a potential hospital launch of iVegan Exelon. For our expansion efforts, the remainder of 2023 will be focused on building on our robust and comprehensive understanding of the US TSC market. These efforts will include initiating an emotional and functional patient journey market research project, treater identification analyses, and a US TSC landscape assessment to identify leverage points, existing behaviors, and beliefs to create a brand strategy that enables the optimization of the introduction of Zotomi to the US TSC market. For IV, our commercial planning investments are ramping up significantly with priority on strategies that we believe will drive early launch success. To maximize the total market potential, we are in the final stages of an innovative data project that is first of its kind as it relates to the identification and tracking of status epilepticus patients. Leveraging data across four distinct claims providers to generate patient progression through each episode resulted in a sophisticated and comprehensive look at inpatient pathways and outcomes associated with usual care. These key findings and insights deepen our understanding of the specific unmet needs as patients progress along the status continuum and will shape our commercial strategy. Finally, we are preparing to address the inherent challenges with inpatient reimbursements and complex DRGs and do plan to pursue an NTAP as one component of our access and reimbursement strategy. As a reminder, the NTAP, or the new technology add-on payment designation enables additional payment to hospitals above the standard Medicare severity diagnosis-related group payment amount. Under this policy for eligible technologies, Medicare pays the applicable MS-DRG payment rate up to an additional 65% of the cost of the approved new technology. The team is closely monitoring CMS proposed changes to filing requirements while also determining an optimal filing approach that allows our hospital customers to maximize the NTAP period post-approval. We look forward to providing more details in our Investor and Analyst Day in September, which Sasha will discuss in more detail at the end of the call. We feel there are many opportunities to continue to grow our brand and are committed to supporting CDD families in new and meaningful ways while expanding our commercial infrastructure in line with our clinical development programs. I'll now hand the call over to our Chief Scientific Officer, Alex Ametti, to discuss our ongoing development program.
spk03: Thank you, Christy, and hello, everyone. I'm pleased to step in for Dr. Joe Houlihan, our chief medical officer, to provide an update on our clinical programs today. Joe is currently in China meeting with our strategic partner to further strengthen our R&D collaboration. He will be participating in a local CDD advisory board, attending a TSC investigator meeting, and connecting with doctors around the country who have expertise in CDD, TSC, and status epilepticus. I will now provide an update on our clinical programs. As a reminder, the TRUST TSC trial is a 162-patient, double-blind, placebo-controlled trial in patients experiencing a minimum of eight countable seizures per month, despite adequate treatment with existing therapies, including recently approved anti-seizure medications. This is a highly refractory pediatric and adult population, and we believe the estimated number of patients with refractory seizures to be between 25 and 40,000 patients in the U.S. Based on our observations from the Phase II open-label TSC trial, where we saw a higher rate of reported somnolence than our Marigold study, we developed a new titration schedule for this Phase III study. The new titration schedule is designed to slowly increase the dose early on and increase more rapidly towards the end of the four-week schedule to successfully titrate TSC patients to target doses. We believe that slower titration initially will optimize tolerability and lead to improved efficacy. The low discontinuation rate observed in the TRUST TSC study to date gives us increased confidence that the changes we made to the phase three dose titration are having the desired effect. We continue to actively enroll patients in the TRUST TSC trial at sites in the U.S., Europe, and Canada. Due to administrative and regulatory delays getting certain ex-U.S. sites up and running, we now anticipate top-line data mid-2024. The team has been working hard to overcome these country-specific delays, and we are confident that the vast majority of sites in the trial will be ready to enroll by the summer. We expect to begin enrolling patients at new clinical sites in Israel and China this quarter with additional site activations planned in Italy, Belgium, and Australia by mid-year. With these new initiations, we expect to see increased enrollment across our global sites. To further support study recruitment and enrollment, Marinus has sponsored two educational webinars in the US and Europe featuring prominent key opinion leaders. The first was held in April for US families and hosted by the TSC Alliance. And the second one will be hosted by the TSC Association with a European focus and will be recorded later this month as we continue to build and strengthen our relationships with global TSC advocacy groups. Now I would like to provide an update on our clinical programs in status epilepticus. Our phase three RAISE trial studying intravenous or IV Ganaxalone in refractory status epilepticus continues to advance. We have dedicated considerable cross-functional resources to prioritize site engagement and scientific education and are confident that it has had a positive impact on enrollment and overall study awareness. Today, we announced that we are planning to conduct an interim analysis in the second half of the year. The RAISE study protocol provides for a pre-specified interim analysis to evaluate the co-primary endpoints of status epilepticus cessation within 30 minutes and no progression to IV anesthesia for 36 hours, when two-thirds of the patients, or approximately 82 patients, have completed the trial. The interim analysis is more than 90% powered to show a 40% treatment effect. We continue to enroll patients in the RAISE trial that are representative of the Phase II patient population which gives us strong confidence in a robust and clinically meaningful treatment effect that can be observed at the interim analysis. We expect that successful achievement of the co-primary endpoints would serve as the basis for submission of a regulatory filing in the US. I would like to review the process of the interim analysis. Upon completing enrollment of 82 patients, we plan to clean and lock the database and an unblinded statistician will supervise the running of tables and quality check to maintain integrity of the data. These data would then be provided to the Data Monitoring Committee, or DMC, to evaluate for efficacy and safety. The DMC would then inform Marinus as to whether or not the study met the pre-specified efficacy stopping boundaries on the co-primary endpoints. If the study does achieve the pre-specified efficacy stopping rules, the Marinus leadership team would then have the opportunity to evaluate the data and share top-line results soon after. If the trial is complete at the interim analysis, we will continue to enroll new patients in a planned open-label extension to collect additional safety data, which we believe would be supportive for regulatory filings. We also continue to progress our other trials in status epilepticus. Enrollment in our Phase III RAISE II trial in RSE for European registration is anticipated to begin in the second half of 2023. On a successful interim analysis, we would plan to transition a significant number of our U.S. RAISE sites to the RAISE II trial in an effort to expedite enrollment. We also expect a complete enrollment of the first cohort of our phase two reset trial in established status epilepticus before the end of the year. Finally, we continue to provide iVEGAN Axalone to physicians who request it for their severe patients in super refractory status epilepticus under an emergency IND mechanism. To date, 16 patients with super refractory status have been treated with iVEGAN Axalone. Some cases have already been presented at major medical meetings or as case reports in the literature, and we anticipate additional cases to be published in the future. I would now like to turn to our second generation product development efforts. We have completed our single ascending dose study in healthy volunteers with our new oral formulation. The new formulation exhibited linear pharmacokinetics at single doses of 100 to 1,200 milligrams, overcoming some of the limitations of the current suspension. Model data suggests effective trough levels can be obtained with BID dosing with this new formulation, enabling Ganaxilone to be studied in additional rare epilepsy patient populations. Our multiple ascending dose study is expected to initiate enrollment in the third quarter of 2023 with preliminary data by the end of the year. In parallel, we are aiming to finalize the clinical program designed for Lennox-Gastaut syndrome in the first quarter of 2024, pending results of the MAD study. Our prodrug development continues to advance, and a lead oral candidate has been selected. We are targeting phase one data in 2024. On the scientific affairs side of the organization, we continue to generate relevant and compelling data aimed at addressing the needs of the medical and caregiver communities. We're excited about the datasets we have planned to share with you all this year. First, we are planning to share the two-year data from the CDD Marigold Open Label Extension Study at this year's International Epilepsy Congress in Dublin, and then expanded data at the American Epilepsy Society meeting in Orlando. In addition, we are planning to present multiple abstracts, including the complete single ascending dose study data, some early real-world data on zetalamy use in the U.S., as well as new preclinical data of IV Ganaxolam in a severe status epilepticus model. The Marinus scientific and medical teams will have a considerable presence at this year's Neurocritical Care Society, Child Neurology Society, and American Epilepsy Society's annual meetings as we continue to educate about Ganaxalone and the disease states in which it's being studied in, as well as raise Marinist scientific awareness. All in all, I'm excited about the progress we're making on our clinical programs, and it's shaping up to be a very exciting year with multiple data catalysts along the way. I would now like to turn the call over to our CFO and COO, Steve Phansteel, who will provide you with a financial update.
spk07: Thanks, Alex, and good morning to everyone. I am pleased to be able to share our financial results for the first quarter of 2023. Before going through the details of our financial performance, I want to touch on a few key updates for the business. We are very pleased to have initiated significant startup work related to our API onshoring initiative. As you may recall, BARDA exercised its option late last year to support this initiative, which included funding of up to $12.3 million. Importantly, this work is expected to provide a second domestically sourced manufacturing capability for a Ganaxalone API and has the potential to drive a greater than 30% reduction in API supply cost, which represents a significant portion of the overall manufacturing costs for Ganaxalone. We have also been active in our dealmaking over the past two years, partnering with Orion for the European markets, Dinesha for China, and now Biologics for MENA. We remain active for further expansion with a current focus on Japan. As we continue to advance in excellence development in ex-U.S. markets, such as Europe, we have the potential to see royalty and milestones contributing to our cash inflows in the near term, in addition to ongoing R&D reimbursement. For the fiscal year 2023, we are maintaining our guidance with U.S. Atomi revenues projected to be in the range of $15 million to $17 million, and BARDA revenues to be in the range of $8 million to $11 million. We continue to project our GAAP operating expenses, inclusive of SG&A and R&D expenses, to be in the range of $165 million to $175 million, of which we expect approximately $16 million to be non-cash, stock-based compensation. We expect that our current cash, cash equivalents, and short-term investments of $199.2 million will be sufficient to fund our operations into the second half of 2024, inclusive of maintaining the minimum required cash balance of $15 million under our credit agreement. I'll now move into our financial results. For the first quarter of 2023, we recognized product revenues of $3.3 million for the three months ended March 31st, 2023. These revenues consist of Zitomi product sales, which was launched in the third quarter of 2022. Separately, we recognize barter revenues of $7 million for the three months ended March 31, 2023, as compared to $1.5 million for the same period in the prior year. The increase is driven primarily by activity associated with startup of our API on-shoring initiative and increased RAISE trial activity. Research and development expenses increased to $27.9 million for the three months ended March 31, 2023, as compared to $18 million for the same period in the prior year. The change was due to increased costs associated with our API onshoring effort, increased TSC and RSC clinical trial activity, and increased headcount. As a reminder, the API onshoring effort is approximately 70% funded by BARDA, so that the increase in R&D expenses is partially offset by the increased BARDA revenues reflected in the first quarter. Selling general and administrative expenses increased to $15.2 million for the three months ended March 31, 2023, as compared to $11.7 million for the same period in the prior year. The primary drivers of the change were increased headcount and commercial support for the U.S. launch of CITAMI. Interest expense was $4.1 million for the three months ended March 31, 2023, as compared to $1.7 million for the same period in the prior year. The increase is driven by drawdown of an additional $30 million of credit under the Oak Tree Agreement in March 2022 upon FDA approval for CITAMI and non-cash interest expense related to our revenue interest financing with CIGARD. Interest income was $2.3 million for the three months ended March 31, 2023, as compared to less than $0.1 million for the same period 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. The company reported a net loss of $34.7 million for the three months ended March 31, 2023, as compared to a net loss of $19.4 million for the same period in the prior year. As a note, the 2022 net loss includes the one-time gain of $12.7 million related to our recognition of a portion of the upfront payment associated with our Orion partnership. These totals also include non-cash stock-based compensation expense of $3.7 million for the three months ended March 31, 2023, as compared to $3.4 million for the same period in the prior year. Cash used in operating activities was $41.5 million for the three months ended March 31, 2023, as compared to cash used in operating expenses of $27.7 million for the same period in the prior year. Now I'll turn the call back to Scott, who will provide concluding remarks.
spk14: Thanks, Steve. 2023 is off to a strong start for Marinus, and we are thrilled to have a strong balance sheet to support the continued positive momentum of our Zitomi launch, the advancement of our two late-stage clinical programs, and our second-generation product development. We are committed to delivering shareholder value and expanding opportunities to serve patients that may benefit from Zutomi and iVegan Axolotl. I would like to thank our employees for their hard work and dedication to advancing our mission and our investors for their support. Sasha, I'll turn it back to you.
spk01: Thanks, Scott. Planning is underway for an investor and analyst event in September, which we will share more details about in the coming months. We look forward to diving into our commercial planning in RSE and providing color around how we're advancing our strategic goals to prepare for a successful launch. Operator, can you now open the call to questions?
spk08: Thank you. At this time, I would like to remind everyone, in order to ask a question, press star, then the number one on your telephone keypad. We'll take our first question from Andrew Tsai at Jefferies.
spk10: Hi, everyone. Thanks. Good morning. Appreciate you taking my questions. Appreciate all the progress as well. So maybe two questions on RSE today. First question is, you know, I'm just curious, how do you envision the interim top line release to look like? Presumably, it'll be quantitative numbers, drug versus placebo on the co-primary endpoints. but it sounds like the DMC may look at safety as well. So would you share safety and would you also share some details on the secondary endpoints as well? So, you know, the bottom line is just trying to gauge how robust of a kind of top line release we can expect at the end of the day. And number two, only to the extent you can share, can you remind us, what you are monitoring on a blinded basis in the phase three, whether it's around the baseline characteristics, I don't know, making sure you're enrolling the right patients, or maybe even looking at the actual, you know, blinded efficacy outcomes, or even overall safety, or are you looking at all three? Just any color would be helpful. Thank you.
spk14: Thanks. Thanks, Andrew. Let me take the second question first, and then I'll pass. what will provide the DMC. Remember that we have a central EEG reviewer who is looking at the patients who are enrolled. And I think most importantly, that EEG reviewer is sharing with us the consistency that the patient being enrolled from a baseline characteristic are hitting the appropriate seizure burden to be enrolled in the study. That's really the only data point that we have access to. We're really not looking at the overall blinded data sets in any way. Certainly, we want to keep the integrity of the study. So, in our minds, it's really about what that baseline EEG looks like, the severity of the patient entering the study, And of course, the other piece of the puzzle that we see regularly are patients who fail screening. And so we are still seeing about 50% of patients from first line to second line who are responding to an anti-epileptic. Interestingly, it can be hours. Sometimes it's 8 to 10 hours before a patient is no longer considered a candidate for the study. So that's a number we expected. I think as we look to the future, particularly with the RAISE-2 trial, we'll really be focusing on that window of seizure resolution compared to standard of care today. So that's an important measure for us because we want to ensure a low placebo rate, and we think those numbers have been very consistent. So thanks for the question. Alex, you want to talk a little bit about what we'll provide to the DMC and most likely what we'll have in our top line?
spk03: Yeah, sure. Thanks for the question, Andrew. As mentioned, at our interim, we will have pre-specified efficacy stopping boundaries in place for our co-primary endpoints. Also included in our formal statistical testing hierarchy will also include the two key secondary endpoints that look at no progression to IV anesthesia at 72 hours, as well as time to status epilepticus cessation. We would plan to include our key secondary endpoints in our interim top line data release if that interim does meet the pre-specified stopping boundaries. In regard to the other secondary endpoints we have, those secondary endpoints are all planned to be descriptively analyzed. And, you know, that includes a lot of various clinical outcomes, functional outcomes, a CGI modified ranking scale, as well as very important healthcare utilization metrics. And our plan at this point would be to present those at upcoming major medical meetings. And then just quickly, yes, absolutely safety will be included in that as well. That's a critical component to our data release at that time point.
spk10: Great. Thank you guys so much. Very clear.
spk15: Thanks, Andrew.
spk08: We'll move next to Charles Duncan at Cancer Fitzgerald.
spk06: Hey, good morning, Scott and team. Thanks for all the update and congrats on the progress. I had a couple of questions at CUS and so wondered if you could provide any additional color on the resolution of the objection for the starting material, the regulatory starting material. How was that resolved and Yeah, what's the process there and what gives you confidence in the upcoming positive opinion?
spk14: Thanks for the question, Charles. You know, just to remind you and everyone on the call, our process for creating Ganaxalone, creating that API was agreed upon with the FDA about three to four years ago. Gosh, maybe even a little bit longer. And that is the same process that we suggested to the EMA. And interestingly, in the last three to five years, we have made this process incrementally better. So as an example, when we started making the NAX loan five, six years ago, the purity on the API was about 97%. Now it's well north of 99.8%. And quite honestly, our scientific team, and I've learned now more about starting materials than I ever cared to, really walked me through our process. And we were just having a scientific debate with the EMA and our rapporteurs. And we continued to provide the scientific rationale around our starting material, the quality that was associated with it, this very high purity. We tested for multiple impurities. I think most importantly, we really walked back the agency step by step through the process. And I think with that, we got our rapporteurs and the CHMP comfortable with this starting material in terms of safety. It was one we always believed in. It was one that I was very willing to escalate if necessary, but at the end of the day, we are a scientific team. I think both the U.S. and European regulatory bodies are scientific teams, and we were able to come to a conclusion that we believed was the right one, and now we have support in multiple regulatory agencies. So, in our minds, that was the biggest issue. There was a lot of other work we had to do, Charles, to satisfy the European authorities that were substantially bigger in scope than the U.S. And we've climbed those mountains. So, the team at Marinus has put in hundreds of hours to get there. And we're incredibly excited with the upcoming opinion. We're enthusiastic about a launch in the near term. And, you know, I think this means a tremendous amount to families in Europe, validation of our platform, you know, and the opportunity to really help additional patients in European markets and soon thereafter in MENA markets. and soon thereafter in Chinese markets with Ganax Loan, initially in CBD, and then our expansion. So it's a big milestone. It was a very strong and healthy scientific process, and one I'm incredibly proud of our team. So thanks for the question.
spk06: Congratulations on that process. Let me ask you about incidence and prevalence, XUS. You mentioned MENA, you mentioned China, obviously EU. I guess I'm wondering how do you see CDD ex-US versus US? Are there any geographic, you know, call it drivers to increased incidents or even prevalence? And then can you provide any other color on the Japanese partnering process? Are you having ongoing discussions and could that actually come to fruition yet this year? Thanks.
spk14: Thanks. Let me take the second part of the question, Charles, and then I'll let Alex answer because Alex is our expert epidemiologist when it comes to the instance of CDKL5. On the Japanese front, our teams really started the engagement process recently. We've seen a lot of interest from several companies. I can't promise you a deal this year only because we have some big data sets coming up, and I could imagine some companies waiting for those data sets. That being said, There is, I think, very distinct interest around the orphan part of our disease relative to the hospital side of the disease. And certainly, we would love to see a deal done before year end. That's our corporate goal. But understanding that, you know, sometimes some companies get a little bit nervous in front of data sets. So we're pushing hard. I think we've seen more interest than I would have initially expected, which is exciting. I think the U.S. revenue trajectory and now the European approval will be very supportive of how much strategic in Japan. I'm going to push our business development team to get something done over the next few months. I'm excited with those prospects. Alex, how about I turn it over to you to talk a little bit on the epidemiology?
spk03: Yeah, certainly. We believe that the birth rate or the incidence XUS is very similar to how we think about it here in the U.S., which is approximately 1 in 40,000 live births. I think what is a really important driver to think about is the rate and adoption of genetic testing to identify that patient population. And I really think we're at a really exciting time in the field of epilepsy genetics. And there continues to be increased momentum in the adoption and the realization of the clinical impact of providing a proper etiological diagnosis. So a lot of the countries in Western Europe, for sure, have been genetically testing their patients for many years, and we continue to see that rise. And we're continuing to see it grow throughout the global regions.
spk06: And cell phones.
spk14: Charles, we're now seeing the first centers of excellence in several countries throughout Europe. We know there are over 600 patients identified through the global CDK Alliance. In China, we know that there are several patients in China. United Arab Emirates waiting for the drug. So we get a lot of inbound calls and nothing that we are seeing from our discussions globally make us believe that the incidence is any different across the globe. I think the one kicker for me with Japan will be the birth rate. And the lower birth rate in Japan I think will have an incremental impact of the size of the Japanese orphan disease market, not necessarily status epilepticus because it's an aging population, but I think on the orphan side, just from a modeling perspective, I think it is a little bit smaller than the U.S. given the birth rates.
spk06: That's a key nuance. I appreciate the insights on genetic testing. It makes sense to me. Thanks for taking the questions.
spk08: We'll take our next question from Brian Abrahams at RBC Capital Markets.
spk05: Hi there. Good morning. Thanks for taking my questions and congrats on all the continued progress. I just had a few questions on IV Ganaxalone. I guess maybe first off on the mechanics around the interim, I wonder if you could expand a little bit more on the gating factors and timelines we should be thinking about for getting to the 82 patients, cleaning the data, and getting to the DSMV evaluation. And if this doesn't hit the stopping criteria, what would be the implications for the program, both the RAISE trial and the other studies, And then lastly, just as a follow-up separately, I wonder if you could speak to any learnings or observations you can take away from those 16 EIND patients recognizing that they're in a different stage and using a different protocol. Thanks.
spk14: Thanks, Brian. Some great questions. I think, again, I'll start backwards and then I'll turn it over to Alex where the question started. I think the super refractory patient population is increasingly interesting to me. I think I've been pretty transparent with investors that it's a very long road for a phase three double-blind placebo-controlled child. That being said, we continue to get requests and have incredible outcomes for a patient recently who had been, we'd been the last line of the resort, they had been transferred to a tertiary care center. We believe that had they not gotten our drug, they would have been discontinued from their ventilator. And that patient was able to be discontinued from anesthesia and left the ICU as a result of Ibogainex alone. Our team is working on some new suggestions to physicians when they request EIDs on dosing. Slightly a different dosing regimen than we're using in RSE. Those regimens are being filed as we speak, so I can't talk much more about it, but we would expect, you know, by the time of AES to talk about that a little bit more. And I think what we're really thinking about is there, from all these learnings from EIDs, is there an opportunity for us to do, you know, a single-arm study and really help the field. So, I think it's very exciting, and we certainly know this is a population that needs help. It's just the best way how to attack it from an organizational standpoint. I actually forgot your middle question, Brian. I'm having a little phone service, so I'm not taking notes. So, Alex, why don't you talk a little bit about the process of data cleaning? And the only thing I'll say is, you know, really the key point is when we get to that interim number, that's when we make the decision to lock and load the data set. And, Alex, I'll turn it over to you to just talk about those mechanics a little bit more specifically.
spk03: Yeah, certainly. Thanks for the question, Brian. I think one part of your question was, you know, how do we get to 82 patients? And I can just say that there's, again, a lot of significant momentum in our enrollment in this study and really confident in us getting to that number here soon. Again, we've really dedicated a significant amount of cross-functional resources to really make sure that we are engaging actively with our clinical sites. and making sure that all the key stakeholders within the hospital system have the right amount of information to help identify a potentially eligible RAISE patient and, if eligible, get them enrolled. And a little bit more about mechanics. Once we have the 80-second patient in, there's a 30-day follow-up, so about four weeks to continue to collect all of the safety data. From there, we think that we can clean and lock the database in potentially three to five weeks. So call it seven to 10 or so weeks from 82nd patient in, that data set will be shared with the DMC. The outstanding question is how long the DMC will take to fully evaluate and assess that data set and provide that information to Marinus, whether, yes, the pre-specified efficacy stopping rules were met or to likely proceed as is. on that. And at that point, as mentioned earlier, if the stocking criteria is met, then we would look at that for a few days and announce those top line data. I'll pass it to Scott to answer that last question that you had about if the interim does not hit.
spk14: Yeah, thanks. Thanks, Alex and Brian and Sasha for reminding me about that question. So I think Brian there's no question that we can still hit statistical significance if we don't hit the interim. And maybe just to add on to Alex, When we begin that interim process, we'll continue to enroll patients in a double-blind fashion. If the DSMB said to continue the study, we can do so. We think that would take a few additional months to complete the study. We still have new sites up and running, and we're allowing new sites to come on board through about the middle of the year. So I expect to be at 75-ish sites. by the June timeframe. A lot of reasons for that, which I can go through, but to your question specifically, we would enroll the study and then unblind the data at 124 patients. That being said, given the fact that this study has a very high probability of hitting at the interim, Should it not? I think the likelihood that we have a clinically meaningful drug at the end of the study without stopping at the interim is a low probability. So I think we generally believe where we set the bar for the interim, and Alex talked about a greater than 90% power to show 40% clinical benefit versus placebo. You know, we think that's where the drug needs to come in to have important clinical outcomes associated with it. So we're making a very strong bet that this drug is working. We will see a low placebo rate, and we will have more than sufficient data to file at the interim. And I think that's where our head's at today, Brian.
spk15: That's really helpful, Scott and Alex. Thank you guys so much. Thanks for the question.
spk08: We'll move next to Joseph Tome at TD Cowan.
spk04: Hi there. Good morning, and thank you for taking our questions. Thanks for walking through all the different steps here. I guess just in terms of what you're going to be telling the street, I guess what is your disclosure strategy? Will you say when that 82nd patient is enrolled? Will you say when you are taking the interim, or will we kind of just know once the results of the DMC review are available? And maybe on RSE, as you see it from a CMC and safety database perspective, How are you thinking about timelines of having everything together, assuming the positive ?
spk14: Yeah, thanks, Joe. You know, I haven't necessarily made a final decision. We have a team that haven't made a final decision on our communication strategy. I think we try to be as transparent with you guys as possible and keep you up to date. As everyone knows, you know, this is an instance trial, and there are great weeks, and there are quiet weeks. um and then again it is a complex data set so i just want to make sure that when we communicate uh we not only have hit our our number of patients but we have good confidence that we can clean and and lock the database as alex uh described so we're gonna what we're doing joe is we're we're doing our best to clean and monitor the the data as it comes through but it's a big process these are sick patients And I think I'll feel very confident by the summertime that the timelines that Alex walked people through, we can hit those and look to exceed them, particularly in terms of a data cleaning. So, bear with us. Give us a few more months. We will get there and we'll finalize our disclosure around, you know, exactly when we're starting this process. Would you mind repeating the second question?
spk04: Yeah, and the second part was just on the CMC components and potential safety exposure. Is that, I guess, gating to anything or on a positive interim, would you be ready to go?
spk14: Yeah, no, great question. Thank you. So, CMC, we're super excited. We have filed, you know, the amended IMD to start using our citrate buffer. And yes, we're disclosing that the new buffer is citrate today. So, woohoo! But, you know, so all those science geeks who want to look up the solubility of citrate buffers rather than phosphate buffers. You know, we wanted to give you something today. We're expecting that the FDA will basically say, you're free to use that product in the study. We have batches with that ready to go. So, we'll incorporate that new citrate buffer product into the clinical study within the next few weeks. We will start RAISE2 100% with that new buffer. But as a good housekeeping measure, as we did with Zytalmy, we will ask for pre-NDA CMC meeting to review the package with the FDA and say, look, here's what we got. Do you have any, and here's our questions. Is this sufficient? Is this sufficient? Is this sufficient? As an example, with the TAMI, we asked, the FDA 10 questions, and they said we'd like to see more on two of the 10. So we had six to nine months before the filing to add some additional analytical testing. So we'll do the same on the CMC side. I'm incredibly proud of the progress that the CMC team has made. They've made so much progress. We've added a new formulation bottle size for launch, and we'll talk about that more in September. It may be a few months after launch, but it really, we think it's going to be really important commercially. So from a CMC perspective, I think we are locked in and loaded. And I'm sorry, Joe, you asked me one other piece beyond CMC that I forgot as well. Oh, no, just the safety database component. Oh, yeah, yeah. No, that's a great question. So I'm not losing sleep over safety. I think any drug has to have an efficacy-safety balance. We know the safety. We've had a DSMB. You know, we've had the DSMB reviewing the Phase III We've seen nothing new that we're aware of, nor have been informed by the DSMV. We've got a ton of now open label data with 20% higher doses than super refractory patients. We've seen nothing unexpected in that population as well. But to make sure that there is not an issue in terms of patient number, We have every intention of keeping our sites open, rolling probably half of our sites into open-label treatment with Ganaxalone. Again, building that ability for physicians to use the drug in these very sick patients. And of course, we'll have additional double-blinded data in the several weeks from the time we choose to lock the data to unblinding. Of course, once we unblind the data, we move every site to either open label or to RAISE 2. You know, and people ask me a lot, well, why, you know, why would you cut the study at 82? Well, one, you know, we think we can get there without an issue from an efficacy and outcomes standpoint. And two, we think RAISE 2 is a really important add-on to the franchise and we want to accelerate those time runs as well. So we have a lot of reasons to be enthusiastic about this interim and the future expanded patient numbers. So I'm not at all losing sleep from an FDA perspective on safety. Thanks for the question.
spk15: Excellent. Thank you.
spk08: We'll go next to Douglas Tao at HC Wainwright.
spk16: Hi. Good morning. Thanks for taking the questions. Scott, maybe first on the second generation product development, I think in the release you said that you're close to advancing or you have oral candidates selected. I'm just curious from the, you've talked about developing a pro-drug IV formulation. I'm just curious what the update or how far along, what progress you've made on that front.
spk14: Thanks, Doug. Does Hercules have a question?
spk16: No, he's napping.
spk14: He's good. Hercules is sitting on Doug's lap. He just sent us a picture. It's awesome.
spk16: He's looking up now because there's talking.
spk14: We disturbed his nap. We're moving aggressively on the IV side as well. We really do believe that a formulation with No or significantly less capsaicin will have a lot of advantages in the pediatric population and super refractory status. And, of course, if we could substitute the entire franchise, we do have a 3% to 5% royalty stream with Ligand that was negotiated before our team came to the organization. And Ligand is a great partner today. But capsaicin is hard work. We have an IV candidate, a pro drug selected. It looks beautiful in the human cell models. The problem right now is we don't have, we don't see normal metabolism of that pro drug in any other animal model. So we're scratching our heads of how to do the tox work when you don't have the appropriate animal model. Lots of companies run into this. I've just run into this problem with another company that I've seen it several times in my career. We're going to talk to a few consultants to figure out how to advance that compound. At the same time, our chemistry team, our chemists are working on new formulations that effectively look and smell like the one we have now, but would also have the same metabolism in animal models for us to do the tox work. But, you know, we know that the pro-drug is 80%, 90% canaxolone. We know what that cleaved particle looks like and the safety of that particle. So in my mind, there's got to be another way we can overcome this to move this a little bit more rapidly into the clinic. That being said, we've made tremendous progress in the two years that we've been working on this behind the scenes. And, you know, I'm hopeful we're going to have a lead candidate chosen by year end. And, you know, then it's about 18 months from lead candidate to INDs. But once we get to IND, Doug, I mean... Similarly to the oral formulation program, we know what blood levels we need to hit, and we would expect the pro-drug to behave very similarly to our capital X alone today, IVG and X alone. So thanks for the question.
spk16: Can I ask one follow-up? I think on RSC you mentioned that you'll continue enrolling even after you sort of move ahead with the interim analysis. If you ultimately do read out that study and you've enrolled patients, Can you switch those patients into RAISE-2, or do you just sort of continue to follow them as part of the RAISE-1 data set?
spk14: Yeah, great question. So let's just say, you know, day X, we internally decide to – we've hit our 82 patients. We're going to clean that database. That 82 patients are going to be the basis of our filing and what we expect to be in our PI. But again, to Alex's point, it'll take eight to 10 weeks from the time we choose to unblind to data. And so in that 10 weeks, we'll still continue to enroll as a double-blinded fashion. And to an earlier question, in case we don't hit at the interim, then we would just continue to enroll to finish the study. on the news from the DSMB that we should stop the study because there's a clear efficacy signal, we would then stop all enrollment, no longer enroll double blind, and either enroll those sites into single-arm, open-label Ganaxalone use or into RAISE 2. And I guess today it'll be 30 plus sites that go into each study. But I think we wouldn't, those additional patients, let's say 10 or 15 that are enrolled in this window while we're waiting for data, would just be part of the safety data set for RAISE. We wouldn't expect it as part of the but we would submit it to the FDA as part of the safety. We've been having a lot of discussions about this, and I think that is the most likely outcome and the way the agency typically handles you know, these additional data sets. We've had some discussions like, well, when you look at oncology studies, you can unblind at PFS, but then outcome, you know, outcomes and survival later on. But I think for the purposes of being conservative, we're going to assume that the 82 patients are going to be the basis of the label with additional safety data in those 10 or 15 patients who are in that unique double-blind portion while we're unlocking. Does that make it clear?
spk16: Yes, that's very clear. Thank you so much.
spk14: Sure. We've had a lot of internal discussions about this now, so it's kept us pretty busy. Thanks, Doug.
spk08: We'll go next to Brian Scorny at Baird.
spk12: Hey, good afternoon, guys. Thanks for taking the question. I guess two quick ones from me. It sounds like there could be a few months between enrolling the 82nd patient and a response from the DMC, during which patients are still going to be enrolling in a double-blind fashion. I guess given where enrollment is right now, if you stop at the interim, how many patients do you actually estimate will have randomized data for the submission? If it takes three months for DMC to get back to you, do you think you could almost have that study fully enrolled at that point?
spk14: Brian, I just want to be clear. What we don't know is from the time we give that data to the DMC, how quickly they will turn it. We don't think it'll be three months for them to turn it. It could be a few days. It could be one or two weeks. But that, let's say, entire 10 to 12-week process includes us following a patient to 30 days, cleaning the database, then giving the data to the DMC. So I'm estimating now, we are estimating one to two weeks for the DSMV to come back to us and say, you should stop the study. I just wanted to be clear on that point. Sorry.
spk12: Yeah, sorry. I misspoke. I meant if it was like up, you know, three months from the 82nd patient enrolled to when the DMC gets back to you. Yeah.
spk15: Yeah.
spk12: Do you think that you, could you give us like an estimate in terms of how many patients you think will actually, you'll actually wind up having randomized data from?
spk14: Oh, I think, you know, look, I think if it's a three-month process, then I think it'll be, you know, roughly 15 additional patients, as many as 20 potential patients, right, from the So, you know, generally, you know, we think we'll be, and we've said this, we've talked about this publicly, is that generally we've been enrolling four to five patients a month, and we're still expecting acceleration as we open these new sites. So, you know, if it's three months at those type of enrollment numbers, it'll be roughly 15, as many as 20 patients or more.
spk12: Great, thanks. And then on the reformulated Ganax alone, if the profile holds up in this MAD study, I know your next stage is focused on Lennox-Gusto, but I'm wondering, have you explored if there's value to kind of looking into CDD and PSC with this reformulation and what sort of regulatory requirements you might need if you wanted to kind of reference labels on the current formulation for reformulations?
spk14: Yeah, no, it's a great question, and we met as a strategic team about two weeks ago in Miami, and this was the key topic. I think right now where we believe we will fall out from a regulatory standpoint is for this second-generation product, we will reference the current forms of Ganaxolone. We do believe as of today that that will allow us to do a single pivotal study for approval. That's our working hypothesis today, of course, that, you know, once we do the MAD study, we will go to the FDA and propose a phase three strategy. I'm comfortable saying that we would see as a single study strategy with an expanded database given that the 900 and 1200 BID formulations today have higher AUCs than our existing formulation, so we'd want to have additional safety data. We've thought long and hard about what's the right strategy with CDD and TSC. We haven't come to firm conclusions yet on those programs, but we do think if there's the potential to show stronger efficacy in those populations as well, it's logical to think about either studies, switch studies, or efficacy studies in those populations. So nothing's off the table at this point in time. I think I've spoken to lots of investors and publicly that we'd love to have a strategic involved here. I mean, my view of this is if we can accelerate this second generation program into multiple indications, we have an incredible opportunity to The 2nd, gen product with a much broader, deeper message for the rare refractory populations. And we know that there are lots of them out there that are that are hungry for a job where we're getting requests every day or several requests for the Tommy for these refractory patients. So we know they're out there and we think right now. We're spending more energy and time than anyone else in the space. So to your question, we think there's a real opportunity to expand this program. We recognize we can only do so many things. So stay tuned, and I'm looking forward to sharing that with you. We're a little disappointed about the slowdown, but I think we totally understand that we want this program to run smoothly from here. So thanks for the question. Thank you.
spk08: For the sake of time, please limit yourself to one question to allow everyone an opportunity to ask a question. We'll go next to Jun Li at Truist Securities.
spk02: Hey, congrats on the quarter and thanks for taking our questions. Apologies if this was asked, but if the study does not stop at interim and goes to full enrollment, what's the timing of the top one data at 124 patients? And is there any reason why you're not including futility? Thank you.
spk14: Yeah, to I think kind of To earlier folks, June, it will obviously depend on the monthly enrollment curves. I would expect by the time we're ready to unblind the study, we're enrolling seven to eight patients per month, so roughly a three to four month window from interim to full data set. From the time we elect to do the interim to the full data set. So the full data set should be done, at least the last patient should be enrolled, I would expect soon after the DMC would come back to us.
spk15: Got it. Thank you.
spk08: We'll move next to Mark Goodman at SVB Securities.
spk13: Good morning. So first question is, the off-label usage at all? There are 100 patients you said were on drug. Are they all CDKL5? I'm just curious on that first.
spk15: Christy, you want to take it or you want me to take it? What would it be like?
spk00: Yeah.
spk14: I mean, we've had Christy on the line. There's been no commercial questions. Put the girl to work.
spk09: Thanks, Scott. Yeah, I'm happy to take it. You know, as of Q1, we've seen greater than 100 patients on commercial therapy with the majority of them getting reimbursed. We have about a 90% reimbursement rate right now. I will say that we have only had a handful of non-CDD indicated patients to date. The majority of them would be for other DEEs. For example, LGS, again, very minimal at this point, but the majority of our patients do have a CDD diagnosis.
spk13: And since the drug's approved, are we seeing an increase in the actual number of patients out there with CDKL5? I'm just curious if, you know, all of a sudden now there's more testing and we're finding more patients, you know, since you'd mentioned it a year ago.
spk09: Yeah, there's great trends in diagnosis and identification today. At this point, we're still really cornered on that 1 in 40,000 patients and the 2,000 pediatric patients that we have in our funnel. But to that point, earlier here on the launch, there are, you know, really wonderful efforts surrounding genetic testing. It was probably the number one topic at AES last year in December. We have internal progress made just to continue to identify potential patients that do have other syndromic diagnoses. So we still feel very confident in the numbers that we've communicated, but we continue to uncover patients every single day.
spk13: And then maybe just quickly one detail on RAISE. Can you just clarify that? around the IV anesthesia protocol. Are you allowing IV anesthesia use if it was for intubation, or are you allowing it if it was attempted to be used as an anti-seizure medication? I know in the phase two, like, half the patients entered the trial intubated, and most of them received IV anesthesia for intubation.
spk15: Alex, do you want to take that, or do you want me to take it?
spk03: Yeah, sure. I can take that. So the inclusion criterion in Amendment 3 is any exposure for IV anesthesia for less than 18 hours. We feel that at that time point, these are still patients that are not in super refractory status epileptic. It's critical that these patients are not in super refractory status. With that all said, though, too, they also have to meet the eligibility criterion of the seizure burden prior to study drug administration. So as IV anesthesia is weaned, again, less than 18 hours of exposure, they still have to meet the electrographic status epilepticus definition of at least 20% seizure burden. So we feel that these patients, despite any exposure prior to that, if they're still meeting that electrographic eligibility criteria, and we think that they are eligible patients for Ganaxilin and potentially could respond to Ganaxilin if that was administered. Thanks.
spk14: And, Mark, I'd add, I think that's very real world, right? Smaller community hospital has a patient in status. They give anesthesia. They intubate. They transfer to a bigger center. Those bigger centers, and we had this two weeks ago, patient didn't get enrolled, but the center basically got a patient in transfer. lowered the anesthesia, and patient had status, and that would be perfect for the trial and for the use of our drug. In this case, the patient had a contraindication, so wasn't eligible because they were on another drug. But I think very real world, those are patients we really want to capture, and we used an 18-hour cutoff because the literature really defines super refractory status as 24 or more, but we certainly believe that there's a meaningful role for the drug in the acute setting. So I think it would work quite well after 24 hours. Yeah, probably as well, but we want it to be safe, particularly for the purposes of this trial, and not enroll patients that were effectively, you know, super refractory in nature, not responding to anesthetics. So, yeah, I think it's going to help to study a lot. I think it's very helpful for the real-world commercial opportunity.
spk08: We'll take our next question from Jay Olson at Oppenheimer.
spk11: Hey, congrats on all the progress, and thank you for taking the question. Can you talk about the expected product lifecycle for Zitalny in the U.S. based on the new patents? and any other patents you have pending, and then also the timeline for getting an NTAP filed and approved, and how long would the NTAP be in place if it's approved, or does that require an annual renewal? Thank you.
spk14: Chris, do you want to start with the NTAP, and then I'll talk about the patents for Zotami?
spk09: I'd be happy to. Much of what we're doing right now is really discussing on maximizing the benefit for our healthcare providers and for the system, quite frankly, when we do file for an NTEP. Timing is very specific on how to maximize that. Current, the IPPS has proposed a change to the filing for the NTEP. That change will be, if it goes forward, that will go in August of this year, that decision. And it changes it just by a few months of when you would have to have PDUFA. So, again, we've got quite a few scenarios in line right now, again, to maximize that benefit because when you do have a positive opinion through the NTEP filing process, you do have that for three years. And if you don't have an approved product, you kind of eat into the time that the NTEP is active. So, again, we'll be looking at this, our patient numbers, our enrollment trends to see when we'd be filing. so that we can file at the exact amount of time that we would need to maximize the benefit.
spk08: We'll move next to Michael Higgins at Leidenberg.
spk14: I'm sorry. No, I didn't answer the question, operator, on the patent. Sorry about that. So, quick reminder, on the IV side, we have one method of use patent granted and another one that we expect to be issued Well, first is granted and issued, and the second is granted and pending issuance around the dosing paradigm and the resolution of status epilepticus with this high dosing for 8 to 12 hours. So we feel great about those methods of use. On the oral side, Of course, we have now method of use patents that we've been licensed from OVID for CDD that go to 38. We now have this new TSC patent method of use that goes to 40. We also, and we're really excited about the TSC, the new TSC patent, and we have some additional patents pending around CDD, around our new dosing titration schedule. And so we feel very confident about the growing method of use patents for the franchise and many of the unexpected findings that we've learned in the last three years. That said, what I'm really excited about as well with our second generation programs is that that will bring seven years of orphan drug, particularly if we follow that path in LGS. And so in my mind, that's just another alternative strategy to really guarantee that our oral franchise has strong IP and market exclusivity for many years to come. So I really couldn't be happier with how much progress we've made and the comfort that we have in and extending the IV and the oral franchise. And of course, if we're successful with pro drugs, that would add even different levels of protection to the franchise. So we're feeling pretty good about the longevity of the franchise all around today. And again, you know, many of you know, I sat on the other side of this and spent more time than I ever care to on patent cases. And, you know, we feel quite strongly that specific method of use patents are as strong as we can build our franchise, and all of them are scientifically driven. So that's what gets me excited. So thanks for the question. And, Michael, we'll take your question. It's got to be our last question. We've run over quite long, and folks have to get back to their day jobs.
spk17: MICHAEL TORRES- Yeah, I really appreciate it. Thanks, Scott. I wanted to look ahead at the data back after this year or into next year on RAISE. If you have an agreement with the agency to prospectively look at the patients and the outcome based on things like severity of neurological deficits, seizure burden, and other ways, or is this just everyone that's coming in? For example, if you really hit on seizure burden at 50%, but you completely missed somehow on 20%, or vice versa, can you still advance the program, or do you have to hit again on the overall? Thanks.
spk14: Yeah, the agreement with the agency is that we have to hit each co-primary endpoint at a 0.05. I think we feel extremely confident on both, but specifically when you think about the first primary being resolution within 30 minutes. Our Phase 2 data, we saw that in every patient by clinical bedside, 14 out of 15 by independent EEG reading. And as a reminder, the independent EEG reader is not how the primary is defined. It's defined by the clinical bedside read. The second endpoint, again, avoidance of general anesthesia, we were at 100% in phase two. We're giving incrementally, you know, a little bit more drug in phase three. We've bumped from 713 to 830, so we have 12 hours of high dosing. So, we feel very good about very sick patients avoiding general anesthesia with the use of our drug. Not going to be perfect, but we would expect efficacy in the 70% to 80% range, and we feel very confident about a placebo rate in this study. for the first primary being close to zero and the second co-primary being no higher than 20 or 25 percent. So, we expect the delta in both of these co-primaries to be north of 40 percent. I think that's our expectation, 50 or 60 percent on the second co-primary. And I think, you know, our expectation on the first full primary is that we're at least 50%. So, that's our expectation going in. If we don't hit that, we certainly will look at the data and understand what we have and whether or not there's a path forward. Of course, we don't hit that interim. We'll go to the full, we'll finish the study in its entirety and have a larger data set to review. But that's the way we're thinking about it right now, Michael. So, thanks for the question. And operator, I just want to say thanks to everyone for staying on the call. I apologize that we went 20 minutes over, but we did want to answer your question. I'm sorry we didn't put Steve to work on this call, but he's done such a great job helping us strengthen our balance sheet. I'm glad those were not issues that we had to tackle today and appreciate all your time and support. And we look forward to catching up live in the future. So thanks for dialing in.
spk08: And that does conclude today's conference call. Thank you for your participation. You may now disconnect.
Disclaimer