Good morning, and welcome to the Marinus Pharmaceuticals 2021 R&D Day. My name is Sasha Damouni Ellis, and I'm Vice President, Corporate Affairs and Investor Relations at Marinus. This morning, members of our leadership team will discuss the company's clinical development programs, pipeline expansion opportunities, commercial strategy, and reformulation initiatives. Our CEO, Scott Braunstein, will lead with an overview of recent accomplishments, upcoming milestones, and overall corporate goals. Dr. Joe Hulihan, our Chief Medical Officer, will discuss our IV ganaxolone clinical development program as well as updates across the continuum in status epilepticus. Dr. Alex Aimetti, Vice President, Scientific Affairs, will discuss our oral ganaxolone clinical development strategy, including commentary on plans for the upcoming phase III clinical trials in Tuberous Sclerosis Complex. Dr. Ian Miller, Vice President, Clinical Development, will give an overview of the unmet need in pediatric epilepsies and potential expansion opportunities. Dr. Mark Paternoster, Senior Vice President of Development, will provide an overview of the initiatives underway to progress the second-generation formulation of ganaxolone. CFO Steven Pfanstiel will provide a financial overview and discuss the Orion Corporation collaboration. Our Chief Commercial Officer, Christy Shafer, will cover commercial strategy for the company's first potential launch and will highlight plans for our other programs. After our prepared remarks, we will move to a Q&A session. All questions will be answered then, but feel free to type in your questions into the Q&A box at the bottom of the webcast page. We would ask that only our covering research analysts participate in the Q&A session. Before we begin, I would like to remind everyone that some of the statements made today are forward-looking statements under the securities laws. These forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by 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 Forms 10-K, 10-Q, and 8-K. I will now turn the presentation over to our CEO, Dr. Scott Braunstein. Scott? Thanks, Sasha. Good morning, everyone. We greatly appreciate you joining us for this R&D Day. Before I turn the call over to the scientific team and our commercial team, I'd like to share a little bit with you my thoughts about where we are today as a company and where we would like to go. First and foremost, we are a company focused on the treatment of epilepsy. We are focusing our efforts on genetic epilepsies that have a high unmet medical need. Of course, our status epilepticus indication is the acute treatment within the hospital for status that does not respond to current therapies. We're in transition as a company. We have been a research company, and we are moving to becoming a commercial company. You're going to hear a lot from Christy today, who's going to talk about what she and her team have been working on behind the scenes. We are very proud of the efforts to date. It's an exciting time as we prepare for our commercialization in 2022. Let me talk a little bit about ganaxolone. We think that ganaxolone novel mechanism of action differentiates it in the treatment of epilepsy. It's got a compelling therapeutic profile. We've got a tremendous safety database, initial validation with our lead indication, and several new indications to come. We believe that creates a lot of excitement for this molecule in the future. We certainly believe that having both an IV and an oral formulation allows us to do things that other companies just cannot do in the epilepsy space. Next slide, please, Molly. This is a snapshot of our pipeline. Importantly, we have filed our lead indication, CDKL5, with the FDA, and we have an action date scheduled in March of 2022. Our phase III refractory status epilepticus trial is currently ongoing, and we expect that data in the second half of 2022. We are ready to initiate another phase III program with our oral formulation in tuberous sclerosis complex. We are gathering sites today and look for our first patient to be enrolled in that trial very early in Q1 of 2022. Early next year, we will add to the pipeline, bringing two additional IV trials to the pipeline, and we will add a new oral formulation, and we're very excited about those new oral formulations. I just want to highlight a little bit of what's happened for the company and what is new that we wanted to share with investors today. First and foremost, I really want to highlight a patent that was granted to the company last quarter, which is a method-of-use patent using IV ganaxolone, which specifies its dosing in the treatment of status epilepticus. That patent will give us protection until 2040 and allow us to fully value the IV franchise. We are already planning on how to best take advantage of that over the coming almost 20 years. We wanted to also give you an update today on the phase III RAISE trial. We are happy to report that after a difficult Q2 related to COVID, we've been able to initiate 10 sites in the RAISE trial. Our clinical operations team is doing a terrific job. We feel like site initiations for the trial is back on track. We expect top-line data in the second half of next year. On the oral franchise, I've mentioned that the CDKL5 application has been filed with the FDA. We are happy to report that the FDA at this time is not requiring a panel. We are having terrific dialogue with the agency. We believe our interactions to date have been very supportive of an approval. We are looking forward to that action date early next year. We are expecting to have validation from the EMA by the end of this month with a similar action date or CHMP opinion by the second quarter of next year. Our goal is to have ganaxolone available commercially, both in the U.S. and Europe, by the middle of next year. We're happy to announce today that we are increasing our expanded access program to the major European countries. We are hopeful that by early next year, we will have our first European patients on that expanded access program. On the TSC front, you're going to hear a lot from Alex today, but we're happy to announce that we have submitted our amended phase III protocol to the FDA in the month of September. We are now anticipating the first patient to be enrolled early in Q1. We are giving top-line expectations for our dataset in the first half of 2024. However, we have a lot of interest from clinical sites, and we will do everything we can to bring in those timelines. The team is already working on contracts as we speak today. Finally, we're announcing today that we've received a positive CHMP recommendation on ODD status in Europe, and that was based on clinical data from the phase II. The Europeans have recognized the value proposition of patients taking everolimus or EPIDIOLEX in combination with ganaxolone and that unmet medical need. This slide is really a shout-out to our regulatory and clinical teams. It's been a great 2021 for the company. We hope 2022 is even greater. We now have ODD status in all three of our lead indications. We've received priority review status for CDKL5, and of course, on approval, we are expecting to receive a rare pediatric disease voucher. We've recently received accelerated assessment, which moves our CHMP recommendation to the first half of 2022 in Europe, and we could not be more pleased with where we stand from a regulatory position today. Let me move to a little bit of a bigger strategic picture in terms of our regulatory and patent exclusivity. As I mentioned, our new intellectual property in the U.S. will give us protection for the IV franchise through 2040. In Europe, ganaxolone as a molecule is protected for at least 10 years with market exclusivity, and we believe we have the ability to expand that to up to 11 and a half years. We have recently filed new intellectual property based on what we believe will be a more efficacious paradigm for the use of ganaxolone in treating both CDD and TSC, and we'll be excited to share those patents with you. Our hope is that they're granted sometime next year. Let's talk about the year. It's been a busy six months. It's going to be an equally busy next six months, and I just wanted to highlight a few of the things that have kept us quite busy. In May of this year, we did a credit financing with Oaktree Capital Management. The Oaktree team has been a terrific partner to us. They have a dedicated healthcare team and have reviewed our CDD filing and our pipeline in detail, and we're hopeful that we will partner with Oaktree in further ventures in the future. Over the summer, we ran an extensive process for a partnership and collaboration within Europe, and we were thrilled that we could finalize a deal with Orion Corporation. The Orion team understands the oral franchise, our IV franchise, and culturally, they have been terrific to work with. We are hopeful to get together live soon and no longer have to work together via Zoom calls. They've just been a great partner, and we look forward to their commercialization efforts that will occur over the middle of next year. This past quarter has been filled with regulatory updates, and I've shared many of them with you, so I'm not going to go through them again. What I'd really like to highlight is the American Epilepsy Society meeting in December of this year. We've had multiple abstracts accepted. We will have several presentations, and our medical affairs team will lead a symposia to educate the medical community, more specifically on CDD and TSC. We will have a great amount of interaction with the medical community as we prepare for our action date in March, and we hope we can join you for an update at that time. Finally, in 2022, we have quite a bit of new clinical trial work. We have important regulatory milestones which will keep us very busy moving into 2022. This is one of the most interesting projects we have in 2022. This is our second-generation formulation. I'm incredibly appreciative of our shareholders who really supported this effort, and we've made great progress in about 12 months, maybe 15 months time. Our goal with a second-generation formulation is to make better clinical outcomes for patients. We are going to take the best properties of ganaxolone and hopefully improve upon them. There are a few pillars to do this. It's critical that we improve bioavailability. That will lead to reduced variability. To make this product incrementally better, we have to give physicians the ability to dose titrate. Those are all critical objectives for this program. It would be very nice as well to improve patient convenience, and we are committing research efforts in 2022 for a sustained-release formulation. That's a new objective that we're adding to the agenda. Again, we're happy to announce that we'll be starting this work in Q1 of 2022. We expect a second program to enter the clinic in the middle of 2022. Importantly, we continue to work on our prodrug efforts and believe that we will have a candidate selected by year-end or early next year. I don't want to steal Mark's thunder. He's going to do a great job walking you through the second-generation programs. I wanted to talk a little bit about our strategic initiatives with the advocacy community, and I want to give a shout-out to Sasha and her team for the work that they are doing with the advocacy community. First and foremost, our view is that every patient matters, particularly in the orphan disease work, and patients are at the core of the work that we are doing with the advocacy community. Our goal is to help educate, engage, and empower patients, their families, caregivers, and the advocacy community. This is a partnership that we will continue to support over time. Next slide, please. Thank you. What have we done to date, and where do we want to go? First and foremost, we want to be a strategic partner to the advocacy community. We have spent a tremendous amount of time working with the community, understanding their view of what patients need, what the alliances need, and how we can best serve the needs of our patients, our families, our caregivers. These disease states are quite complex and require several different efforts to gain access for patients. Next slide, please. I wanted to wrap with a little bit of how we're thinking about the future for the organization. First and foremost, we want ganaxolone available globally to patients. As many of you know, certainly in the rare genetic epilepsy world, there is genetic screening going on globally. We have the Loulou Foundation to thank for many of those efforts, and I think it's our responsibility to make sure that ganaxolone can be shared with patients across the globe. Our partnership with Orion was our first international effort. Our strategy and business development team is looking forward to engaging partners in China to try to finalize a partnership in the first half of 2022. We will look to a strategic partner in Japan by the second half of 2022 and look at other important markets by 2023. Once those commercial partnerships are in place, we will look to expand our access program to those patients. Equally important, we are committed to the scientific rigor that's required, whether it's through phase IV work, collaborations with investigators. As we look at new indications, new therapeutic uses of ganaxolone, we have to drive the research if we want to be successful. With that, I'm going to turn the meeting back to Sasha. Thank you, Scott. Next, we're going to run a short video on Keith and Amanda's status epilepticus journey with comments from our Vice President of Clinical Development, Dr. Henrikas Vaitkevicius, who was the treating physician at the time. After the video, we'll go through our clinical section, where Dr. Joe Hulihan will go over our IV program. With that, let us get started with the video. [Presentation] [Presentation] Good morning, everyone. I'd like to review the activities with status epilepticus in our IV franchise. First, some background. Status is the second most common neurologic emergency in the U.S. There are about 150,000 cases per year of status, and it's defined as prolonged, continuous, or near-continuous seizures, or repetitive seizures without recovery of consciousness in between. For convulsive status, anything longer than 5 minutes is defined as status epilepticus. Status can be caused by any number of etiologies: brain tumors, stroke, head trauma, infection, metabolic causes, drugs, alcohol, and so on. The progression of status is defined by failed treatments. Initially, the first treatment is benzodiazepines that's given in transit to the emergency room or in the emergency room. If a patient fails benzodiazepines, they're considered to have established status epilepticus. That affects about half of all the patients, about 75,000 patients per year in the U.S. The next line of treatment are what are called second-line IV AEDs, such as levetiracetam or fosphenytoin. If a patient fails the first of those second-line AEDs, they're considered to have refractory status epilepticus. A patient who's failed one drug, one IV AED, who has convulsive status will generally progress right to IV anesthesia. However, patients who have non-convulsive status may receive two, three, or more sequential IV AEDs in an attempt to control the status. If several IV AEDs do not control non-convulsive status, those patients will also most likely progress to IV anesthesia unless there's some contraindication. Our current studies are investigating refractory status epilepticus, which affects about 35,000 patients per year. I'm also going to talk about our studies in established status. Our Phase II study in established status, which we plan to start next year. In addition, we've been supplying ganaxolone in response to emergency IND applications for super refractory status. We've had about 11 cases treated so far in super refractory status. A third of patients with refractory status will progress to super refractory status, which is defined as a failure of IV anesthesia, of one course of IV anesthesia for treatment of status. Our Phase III study intends to demonstrate both a rapid onset of action, but also prevention of progression to IV anesthesia. Treatment with IV anesthetics is associated with considerable morbidity and mortality and disability. We also wanted to look, in advance of starting this study, at the burden of illness of status epilepticus in terms of hospital and medical outcomes. Previous studies had looked at medical records to get subtypes of status epilepticus using algorithms based on diagnosis and procedural codes. Next slide, please. We took a bit of a different approach. We looked at medications administered and the site of care within the hospital, as well as other parameters. We looked at about 44,000 hospitalizations in the U.S. related to status epilepticus between 2016 and 2018. We categorized patients into three cohorts based on the administration of anti-seizure drugs given during the hospitalization and whether or not the patient was treated in the ICU. Cohort one considered low refractoriness, received one second line IV anti-epileptic drug or less. Cohort two, moderate refractoriness, more than one IV anti-epileptic drug or ASD anti-seizure drug. Cohort three, high refractoriness, at least one second line anti-seizure drug and more than one IV anesthetic, and had been admitted to the ICU. These were not exact correlates of the stages of status, established refractory, and super refractory, they were close analogs now for those levels of care. The outcomes I'll present include hospital length of stay, ICU length of stay, and costs. Here are the patients categorized by cohort, and I'll focus on cohort three, again, a rough analog of super refractory status. That affected more patients, 19,000 patients, compared to 14,000 and 10,000 in this analysis. Their length of stay was longer, with a mean of 12 days compared to four point seven for low refractoriness status epilepticus. Their ICU length of stay was a mean of six point six days compared to two point seven for cohort one. The most notable difference is the hospital cost. Almost $42,000 per admission in cohort three for patients admitted to the ICU receiving IV anesthesia, compared to much lower costs for cohorts one and two. Treatments that prevent progression to super refractory status have the potential to reduce medical complications, reduce mortality, and also reduce length of stay and hospital costs. Next slide. We want to expand our program in status epilepticus. We've got two trials in refractory status that I'll talk to you about. As I mentioned, we'll be starting a trial in established status epilepticus. In addition to these, we'll be moving into pediatric patients, targeting patients less than 12 years old. The current U.S. study enrolls patients 12 years old and above, and children make up about 15% of the total status population. In addition to those, we intend to fund a phase IV program or a post-approval research program to better define the clinical utility in status epilepticus and support relevant phase IV research. The RAISE trial, the refractory status trial in the U.S. I've talked about this before. It's a randomized placebo-controlled trial. 124 patients with status epilepticus who failed benzodiazepines and at least two second line IV AEDs. The drug is given as a bolus followed by 48-hour infusion. It's a 36 hours of ganaxolone at progressively lower doses, followed by a 12-hour taper. If you recall, in our phase II study, we maintained the ganaxolone infusion at a rate to keep a blood level of 500 nanograms per ML or above for eight hours. We've extended that to 12 hours in the phase III study with the intent of getting the maximal efficacy. The infusion of ganaxolone isn't limited by ganaxolone, but it is limited by the excipient, Captisol, and we're limited to 50 grams a day of Captisol. We keep that regimen at a level of 500 nanograms per mL as long as we can and then lower the dose a bit, and that is intended to "break the status epilepticus." The U.S. study has co-primary endpoints of the proportion of patients whose status stops within 30 minutes and not progressing to IV anesthesia. We have to hit on both of those endpoints for the study to be positive. The RAISE II study is being done for European registration, and it differs in some key ways from the U.S. study. The U.S. study patients have to have failed a benzodiazepine and two IV AEDs. In RAISE II, they have to have failed benzodiazepines and at least one IV AED. In the RAISE II study, ganaxolone is administered at the same time as a concurrent standard of care IV AED. The second or greater IV AED is given with ganaxolone or placebo. It's an adjunctive study, as opposed to the RAISE study, which can be given either with or without another IV AED. The primary endpoint is different, too. It's a responder analysis, and they have to hit on both components of the endpoint, cessation within 30 minutes and no escalation of care within 36 hours. In the EU study, it's no escalation of care, not necessarily IV anesthesia, because the rates of IV anesthesia use are much lower in Europe than they are in the U.S. The RAISE II study will be done in Europe, U.S., and U.K. We've had some challenges from COVID-19, as Scott mentioned, with enrollment. Our site initiations in the second quarter were slow as a result of site personnel changes. Primarily, physicians have left the institutions. There's been high nurse turnover and clinical coordinator turnover. Several hospitals in COVID hotspots are still overwhelmed by COVID-19. Not just clinical resources, but research resources are diverted either to COVID research or to clinical care, and admissions continue to exceed ICU capacity in these COVID hotspots. We've been very focused on countering these challenges. We're collaborating with individual sites to support their unique resource demands. We've had very well-received case presentations by our physicians to the investigators and coordinators, residents and fellows at the participating sites. Even more in-depth training and protocol refreshers for sites. We're also developing some novel enrollment initiatives in collaboration with key study sites. This is a map of our RAISE study sites in the U.S. The purples are the ones pending site activation, the green are the activated sites. We have some of what we anticipate will be our high enrolling sites coming online, including Brigham and Women's, Cleveland Clinic. We have two Mayo Clinic sites participating in this study, Yale, Columbia, and so on. We are focused on getting enrollment boosted in the third and fourth quarter of this year, and we anticipate that these are going to be successful in doing that, these efforts. Next slide, please. I mentioned our trial in Established Status Epilepticus. Unlike the RAISE trials, this study, the site will be in the emergency department rather than the ICU. Virtually all the patients in the refractory status studies will come from the ICU. These patients will be in the emergency room. We're going to be studying patients with convulsive status epilepticus. Most of the patients in the RAISE studies will have non-convulsive status. Because established status may be more treatment responsive and convulsive status may be more treatment responsive, we need to find the dose we would use in established status. A 48-hour infusion in the emergency department is not practical. They want to get the patients admitted and up to the floor of the ICU. We've got alignment from the FDA on the overall study design, and we plan to start the study in the first half of next year. One important piece of this study, that we need an exception from informed consent or EFIC. This allows patients with urgent treatment needs to receive investigational treatments. There are several requirements. The requirements for this are stringent. They have to urgently need care. They need to be critically ill. They need to be unable to provide consent themselves and not have a legally authorized representative to provide consent. Part of getting a EFIC approval is doing a community outreach. We need to inform the community with meetings with community leaders and key organizations in the communities, publicizing the study in these communities. We need to do that in every area where we're going to be performing the study. The IRB approves the community outreach plan, then they review the results of the community outreach. It's not just to inform the community, it's to get their feedback on the protocol and their endorsement for the study. The IRB reviews all of that before approving the study to proceed. I could go to the next slide. This is the design of the Established Status study. It's a two-part study. The first part is a dose optimization phase. This uses a sequential cohort design, a Bayesian sequential design. Cohorts of five patients are treated with a given dose and infusion rate and duration of infusion. They first receive one infusion. If they're still having convulsions, they progress to a second infusion, and then potentially a third. We're going to start with an intermediate bolus dose and an intermediate infusion rate. We'll be administering ganaxolone along with the first, second-line IV AED, levetiracetam, fosphenytoin, whatever the patient gets. Concurrently, they'll begin their ganaxolone. The idea is that ganaxolone is an adjuvant to the standard of care IV AED. Reducing the time to onset, it gets into the brain much faster than many of the standard IV AEDs, and also increasing the overall durable efficacy of the standard of care IV AED. Based on the results of that first five patients, a predetermined algorithm will be used to select the dose for the next cohort of five patients. Until we get to an optimal dose, based on, again, dose and duration of infusion, we'll continue to evaluate cohorts of five patients. We anticipate about 40 patients in that part of the study. The optimal dose will progress to the phase II of the study, which is double-blind, placebo-controlled comparison of the optimal dose of IV ganaxolone and placebo. We anticipate about 80 patients for that phase of the study. Our development program in status epilepticus, to summarize, we're committed to developing IV ganaxolone in status epilepticus across the SE continuum. We've got two phase III studies in refractory status, a phase II study in established status that's in development, and we're supporting emergency IND requests for super refractory status. These studies are being performed in the most relevant treatment settings. Additionally, we plan to support research beyond the pivotal trials. We feel that supporting research beyond the pivotal trials is going to be important to support the research community, the scientific community, to further define health economic and clinical outcomes in status epilepticus. We'll be developing an integrated evidence plan to inform appropriate use of the drug and get to some of these outcomes that I've discussed, as well as supporting independent phase IV research. With that, I'd like to introduce my colleague, Dr. Alex Aimetti, Vice President, Scientific Affairs. Great. Thanks, Joe, and good morning, everyone. I'm Alex Aimetti, VP of Scientific Affairs, and I'm excited to provide a clinical and scientific update pertaining to our oral ganaxolone franchise. First, I wanted to remind you how we got to where we are today. Just over a year ago today, we released positive data in CDKL5 or CDD, and these results really gave us confidence in the ganaxolone molecule to treat highly refractory rare epilepsies when dosed three times a day. The pharmacokinetic data from that study, coupled with the confidence in ganaxolone, suggested opportunities for reformulation efforts aimed to improve key product attributes that will be discussed later in this call. With that said, we recently announced our NDA filing for CDD was accepted with priority review with a PDUFA date in late March of next year. Next, we are currently studying ganaxolone in another rare genetically defined epilepsy associated with tuberous sclerosis complex, where these patients primarily have focal seizures. We recently presented top-line phase II data a while back, and are planning to initiate our phase III global study in the first quarter of 2022. In addition, I'm going to spend the majority of my talk here today reviewing those phase II data and expanding on the lessons learned and what alterations we're making in phase III as a result of those learnings. Lastly, we're currently in the planning phases of a Lennox-Gastaut syndrome, or LGS, clinical development program. LGS is a phenotypically defined rare epilepsy that is highly treatment refractory, and we really believe it's critical to study this indication with a new and improved oral formulation aimed to address the needs in this difficult to treat patient population. Before I dive into TSC, I wanted to briefly update you on what our medical and scientific initiatives are related to CDD as we approach a hopeful launch. First off, we have a fully staffed MSL team that's focused on identifying key thought leaders and treaters of CDD. We're primarily targeting centers of excellence in major academic centers to understand patient population, patient journey, and referral patterns. Most of the team is already out in the field, and I'm using the term loosely as most of the interactions have been virtual, really gaining these key actionable insights. Next, we've developed a comprehensive publication strategy that focuses on key themes or knowledge gaps related to the CDD disease state, ganaxolone's unique mechanism of action, the pharmacokinetic and pharmacodynamic relationships observed, and the clinical safety and efficacy data. We currently have multiple manuscripts in development that address these areas, including the Marigold primary manuscript, which has been submitted and is under review. We're excited and ready to engage with the medical community at upcoming medical meetings. As Scott mentioned, we have multiple abstracts accepted, including eight that we're planning to present at AES this December, and we're working through plans to maximize the productivity of our engagements at these meetings, whether they be in-person or through virtual. A group of us were actually just up in Boston at a Child Neurology Society, and it's really great to see medical meetings slowly having an in-person component come back. Changing gears, I did want to spend the rest of my talk on TSC quickly reviewing the phase II data that we previously announced, expanding on some additional findings that I think were critical to discover in phase II and really helped inform our phase III program. Briefly, just wanted to take you through the open label phase II study design with a classic epilepsy study design, inclusive of a four-week baseline period where patients or caregivers tracked the seizure frequency. Patients underwent a four-week ganaxolone titration phase, followed by an eight-week maintenance phase. Inclusive of a 12-week treatment period. At the end of the treatment period, the primary endpoint of the percent change in 28-day TSC-associated seizures was assessed relative to baseline. Next slide. The study enrolled 23 patients at seven clinical sites. The table on the left shows the baseline demographic information, a median age of 11 years old, with the majority of the patients being pediatric, with a 60/40 gender split between male and female. The table on the right highlights some of the key clinical attributes. These patients experienced a median 36.6 seizures per 28 days during the baseline period, despite the trial and past use of a median of three anti-seizure medications while being on a median concomitant three anti-seizure medications, really underscoring the refractory patient population enrolled in this study. I also want to note that this past study, to our knowledge, was the first time that some of the newer indicated anti-seizure medications were included in a study. The Afinitor study was conducted when EPIDIOLEX was not in the clinical development for TSC, and the EPIDIOLEX phase III program excluded mTOR inhibitors, including Afinitor. Again, highlighting a potentially more refractory patient population in this phase II study. On this slide here, I'm showing the primary efficacy endpoint in a waterfall plot to the left showing patient-level seizure responses. We observed a 16.6% median reduction in TSC-associated seizure frequency. That's also displayed on the figure to the right as a point estimate with the 95% confidence intervals of that median. As a reminder, and as we presented previously on the previous slide, we also did an interim analysis where we showed a 47.6% median reduction in TSC-associated seizures in the first 12 patients enrolled. I do want to comment that the median reduction of 16.6% was certainly a lower point estimate than we hoped to see, but there were some key learnings that I'll discuss in more detail that we believe are critical for phase III, and we may have missed those learnings if we move forward after those initial 12 patients with the higher median seizure frequency reduction. With that said, we still believe that there were some very compelling efficacy signals from this phase II study when turning to some secondary and exploratory analyses. We first looked at a responder rate defined as the proportion of patients with more than a 50% reduction in TSC-associated seizures. In the ITT patient population, we saw approximately 30% of those patients achieving a responder rate. This is in comparison to what we saw was about a 25% responder rate in our phase III CDKL5 Marigold study for comparison. When we looked at some key subgroups, we looked at patients on newly indicated anti-seizure medications and saw meaningful responses in those patient populations as well. In addition, we wanted to look specifically at the effect of focal seizures, which are the prominent seizure type in TSC. In fact, more than 85% of all the documented seizures in this study were focal seizures, and in the group that reported these seizures, we saw a median 25% reduction in these seizure types. Turning to safety, ganaxolone was generally well-tolerated, with somnolence reported as the most common adverse event. However, what we did notice was a higher discontinuation rate due to AEs and a higher rate of somnolence-related adverse events, which we define as inclusive of both somnolence, sedation, fatigue, and lethargy. In fact, 17 of the 23 patients reported a somnolence-related AE during the study. We thought it was critical for us to better understand this frankly surprising finding. We conducted multiple analyses to see if there were predictors of somnolence-related AEs, including demographics or other clinical attributes. After reviewing the complete set of data in 23 patients, two key variables rose to the top. Not surprisingly, the graph on the left, patients that reported somnolence-related AEs had a statistically higher average ganaxolone plasma concentration compared to patients that did not report these AEs. Of note, I just wanted to comment that the difference in sample size here is related to missing PK data. In addition to the average ganaxolone plasma levels, patients on concomitant EPIDIOLEX reported these adverse events at a higher frequency than patients not on concomitant EPIDIOLEX. This finding was also significant using Fisher's exact. We now wanted to understand if and how these two predictive factors were related. What we found was that patients that were on concomitant EPIDIOLEX had higher average ganaxolone levels when compared to those that were not. Looking deeper into the 11 patients on EPIDIOLEX with PK data, we saw a statistically significant positive correlation between average ganaxolone levels and the daily dose of concomitant EPIDIOLEX. This finding here strongly suggested a likely interaction between ganaxolone and EPIDIOLEX. It's important to compare, on the previous slide, those levels to the ganaxolone levels that we saw in the Marigold study. As a reminder, only about 5% of patients that were on ganaxolone in that study had average levels greater than 200 nanograms per mL. In this EPIDIOLEX cohort here, we see approximately 50% with blood levels greater than 200 nanograms per mL. We firmly believe that ganaxolone blood levels and concomitant EPIDIOLEX and the relationship between the two contributed to the increase we saw in somnolence-related AEs. We then wanted to explore the relationship, if any, between tolerability and efficacy. Although the subgroup numbers are small, what we saw was a directional improvement in the primary endpoint in patients that did not report these AEs compared to patients that did report somnolence AEs. It was approximately a 28% reduction versus a 16% reduction. Separately, we qualitatively observed that patients that experienced a beneficial seizure response had fewer dose adjustments through the 84-day study period compared to those that were deemed non-responders. Although the mechanism for these findings are still being understood, the combination of these data give us strong confidence that if we're able to improve tolerability in phase III, then we believe that this would translate to a meaningful efficacy improvement. Now, to move on to how we believe we can improve tolerability in phase III, we think the first place to start is with the ganaxolone titration. What I'm showing you here on this graph in the black solid line is the current titration schedule. We step up the dose in equal 25% increments until the start of the fourth week when the target dose is achieved. In the dashed purple line, we show an illustrative example of a desired output where we linearly increase ganaxolone plasma concentrations over a four-week period. However, we recently conducted a pediatric population PK analysis as part of our CDD NDA submission, and what we discovered is that there is a ganaxolone absorption limit that correlates with body weight and occurs at approximately 50% of the max target ganaxolone dose. How does this finding impact the design titration schedule? On the next slide. When we adjust the titration schedule to the percent of the max absorbed ganaxolone dose, we believe we're giving 50% of the absorbed dose during the 1st week, and then the full absorbed dose by the start of the second week or day eight. In a similar illustrative case here, we believe this could result in high acute ganaxolone exposures, which we believe could lead to tolerability issues. In fact, when we looked at when these somnolence-related AEs were first reported, all were during the titration period, with approximately 90% being first reported within the first two weeks of titration, further supporting this hypothesis. Next slide. To take it a step further and include the potential impact of concomitant EPIDIOLEX, the green dashed line represents the suggested faster titration as a result of the PopPK finding that I just spoke about on the previous slide. Based on the data that we shared earlier, and to the graph on the right, where patients that were on concomitant EPIDIOLEX had a higher ganaxolone blood levels than those that were not, we hypothesized with the dashed blue line that EPIDIOLEX exacerbates this finding and leads to further increased levels more rapidly. As a result, we think a revised titration schedule needs to solve for two findings. First, the PopPK finding, and second, the concomitant EPIDIOLEX finding. On this slide, I'm showing you again in the black solid line the titration schedule used in phase II, which steps up ganaxolone dose in equal 25% increments week over week until the max dose is achieved by day 22. Based on the learnings from the PopPK analysis, we don't think equal increments, especially early on, make sense. We've designed a titration schedule in the light blue solid line, where the initial dose on week one starts low and the incremental ganaxolone dose increases week over week. Essentially, rather than a linear titration schedule, the revised titration schedule takes on more of an exponential function and achieves the max dose at the end of four weeks or day 29. Based on the findings in EPIDIOLEX patients, we've designed a titration schedule number two that is conceptually similar to number one in terms of the shape of the curve, but only achieves two-thirds of the max dose of patients not taking EPIDIOLEX or on low dose EPIDIOLEX. We feel that these titration schedules meaningfully address the tolerability issues observed in phase II, and again, feel confident that if we're able to improve the tolerability with these titration adjustments, that it will lead to improved efficacy in phase III. What else are we doing to improve phase III based on the lessons learned in phase II? First, we plan to partner more closely with The Epilepsy Study Consortium. The Epilepsy Study Consortium is a central group of epileptologists that play a critical role in ensuring accurate and consistent seizure classifications. We want to collaborate more closely with the consortium in clarifying the descriptions and definitions of our countable primary endpoint seizures, and want to make sure that we're leveraging all of the relevant clinical and diagnostic data to ensure the accuracy in those classifications. In addition, we'd like to develop educational resources that the site can deploy to the patients and caregivers around best practices when documenting and counting seizures. Lastly, we're implementing an electronic seizure diary that can be used on the patient or caregiver's existing mobile device and provides real-time alerts for missed entries aimed to minimize missing data or the need for paper diary backups. We hope that this provides improved patient convenience, which ultimately could lead to patient compliance. As a result, here is our phase III TrustTSC study design. It consists of, again, similarly, a four-week baseline with the new titration schedule that I just presented, followed by a 12-week maintenance period where patients would be randomized following baseline one-to-one to either ganaxolone or placebo on top of their existing anti-seizure medication regimen. The primary efficacy endpoint would be assessed at the end of the 16-week treatment period. We're looking to enroll approximately 162 patients at 60 clinical sites in the U.S. and Western Europe. The primary endpoint would be the percent change in TSC-associated seizure frequency, with key secondary endpoints being the percent change in TSC-associated seizure frequency during the maintenance period relative to baseline as a preferred EMA outcome, the 50% responder rate, and CGI. We're looking to initiate the study in the first quarter of 2022. In parallel to starting the phase III study, we're looking to better understand what we believe to be an interaction between EPIDIOLEX and ganaxolone. We do know from the literature and prescribing information that cannabidiol is reported to have interactions with other anti-seizure medications. One of the more well-known interactions is with clobazam, and primarily its active metabolite, N-desmethylclobazam. Cannabidiol is known to inhibit CYP2C19, which leads to approximately a three to five -fold increase in that active metabolite. Although we believe ganaxolone to be primarily metabolized through CYP3A4, there also appears to be some contribution to CYP2C19 that potentially could play more of a prominent role clinically. First, we are actively conducting in vitro metabolism experiments between ganaxolone and cannabidiol to see if this interaction can be better understood, and the results of this in vitro study will help guide potential follow-on non-clinical or clinical studies. In conclusion, we're really excited about the potential for oral ganaxolone, and it started with the positive phase III data with TID dosing in CDD, which is a highly refractory rare epilepsy. We then expanded our clinical development pipeline into TSC to evaluate ganaxolone's effect in a different patient population with primarily focal seizures. I spent a lot of time today reviewing those phase II data and the key lessons learned that have led to the phase III modifications, which now give us increased confidence in the probability of phase III success. Lastly, based on our increased confidence in ganaxolone as a molecule, but acknowledging some of the existing formulation limitations, we believe there are meaningful opportunities to improve the formulation that could potentially enable further indication expansion, with LGS being a possible next indication. With that, I'd like to thank you for your time this morning. I'd like to introduce Dr. Ian Miller, who will talk from a clinical perspective on the unmet needs of refractory epilepsies. Ian? Thanks, Alex, for that introduction. Thanks to the audience members for the opportunity to speak to you about the unmet need in epilepsy. My background is important to this talk. I spent about 15 years in clinical practice of pediatric epilepsy. I was lucky enough to participate in several recent clinical trials looking at intractable epilepsy in kids, including the cannabidiol trial, the fenfluramine trial, and more recently, the STXBP1 trial. As a result of that experience, this talk contains content that's a little bit unconventional, I think, in comparison to other talks that you've heard from drug development companies. The goal is to provide a unique perspective from the standpoint of a pediatric epileptologist and to kind of understand the disease in a way that you can't by reading about the facts that relate to epilepsy, tuberous sclerosis, LGS. It's one thing to understand a list of facts, it's another thing to really kind of understand what the families deal with and kind of what their circumstances are in a high-level way. That's what we're going to try to do, is understand epilepsy. I think epilepsy is a tremendously difficult disease to understand well. I'm embarrassed how long it took me to kind of learn some of these lessons that I'm going to share with you. My goal is really to help you take a shortcut to understand some of the subtleties that relate to epilepsy. One of the biggest of which is the fact that epilepsy is not one disease. Epilepsy is, in actuality, thousands of different genetic diseases as well as a symptomatic disease which is related to any injury that affects the brain, such as stroke or brain injury or infection. Another subtlety of epilepsy, which took me a long time to understand, is that seizures are important, but they're only one dimension of brain dysfunction. Brain dysfunction comes in many flavors and types. Seizures are one, but there's also developmental impairment, there's cognitive impairment, there's social impairment. One of the most profound things a parent ever told me about their disease course is the observation that when they received the diagnosis, they were really heartbroken about the seizures, and they were fixated on the seizures. They never realized that it meant that their child would never have a friend. Related to that, parents and patients report the fear, the unpredictability, and the medications all being miserable aspects of their disease process. Kind of in combination of all those facts above, the point that is really driven home when you talk to patients and families is that it's the last seizure that counts. If you think about it, if you have one seizure a month instead of 10 seizures a month, that's a 90% improvement. How much better is the fear? How much better is the unpredictability? How much better are the medications? Probably not all that much. If you're able to achieve seizure freedom, that is life-changing. Even a single breakthrough seizure infrequently occurring is tremendously debilitating. I'd like to talk a little bit about epilepsy on the whole. For context, there's about 3 million people in the U.S. that have epilepsy at any given time. That's a tremendous burden. One percent of human beings have epilepsy, and 10% of human beings have one seizure in their life. We're going to talk about that entirety of the 3 million people that have epilepsy, and we're going to be talking about when they first present and when the diagnosis of epilepsy is first made. This is in contrast to the deep dive that we often make in terms of intractable epilepsy. I want to provide that context upfront and be clear about that. If you have 3 million people with epilepsy, it is essentially true that we have a lot of medicines. How many are there in common use? Gosh, I would say at least 20. It's also essentially true, we don't have head-to-head data that provides really concrete quantitative numbers, but from clinical practice and you look at the data, it's clear that these medications are approximately equally effective. If you choose any one of those many, many medications at random, you'll have about a 75% chance of taking that new onset epilepsy patient and making them seizure-free. Thank goodness. That's fantastic. Let's take those facts as provided, and let's walk through a little bit of a thought experiment in terms of how that shakes out when you treat 1,000 patients, for example. We've provided a pie chart of 1,000 patients. If we choose one medication at random from that long list, we'll end up with 250 patients that respond to that first medication, which is pretty good. Looking back at that list of facts, it would be reasonable to conclude that we have a second chance with our second medication, and that it should work for about 75% of patients. If we take that 250 who didn't respond and treat them with a second medication, we will end up with only 63 patients that didn't respond to the second medication. Then we can take that 63 patients and treat them with a third medication, and we'll end up with only 16 patients that didn't respond to any of the first three medications. On for the fourth and the fifth. You can see that if we started with 1,000 patients, and in reality, keep in mind, we're starting with 3 million, so the numbers are significantly higher than these, obviously, but you end up with only 1 out of 1,000 patients that don't respond to the first five. You can see we're making tremendous gains with every step. You would think that at the end of this, the three million patients would be tremendously happy with the medication options that exist. I would argue that this idea and this set of mathematical calculations doesn't square with, my guess is what you've heard in other presentations about the need in epilepsy, and it certainly doesn't square with my personal experience in the treatment of intractable epilepsy. The question is why? How do we resolve this tension between our experience and what seems like we should be seeing when we run through the math? That tension is resolved by the realization that we could satisfy those facts that we started with if there were lucky patients who responded to absolutely every one of those 20 medicines, and then 25% of unlucky patients who responded to nothing. In that case, if we had that circumstance, we'd end up with the other side of the extreme. Next slide. That other side of the extreme is the example where you take the 1,000 patients and you have 250 that respond, and when you try the second and the third and the fourth and the fifth, you don't gain any incremental improvement because the response to the first medication completely predicts the response to the second and subsequent medications. That extreme is if they were completely dependent events, right? You have independent events on the top, dependent events on the bottom. The question is, what is the universe that we actually live in, right? What's reality for us? The truth is that reality is far, far, far on the extreme of dependent events. As a result, when you fail the first medication, it is highly predictive that you will fail the second and subsequent medications. Rather than having a 75% each time, which was the independent event example, you end up with about a 75% chance no matter which medicine you choose first. About a 10% chance, no matter which medicine you choose second, and about a one percent chance of being seizure-free, no matter which medicine you choose third. I hope that that's perspective and maybe made a light bulb go off in terms of why we are where we are with respect to how effective our medications are. I'd like to offer two data points in terms of the fact that this is real and legitimate. It's not just one epileptologist's opinion. Here is a citation from Chen et al. that talks about this fact that our medications tend to help the same individuals, and that outcomes in newly diagnosed epilepsy have not improved. If we're talking about outcomes in newly diagnosed epilepsy, the same can be said for intractable epilepsy, because if anything, that's an even harder problem. The second piece of data that I'd like to offer on the next slide, and it relates to a survey that was done by Marinus. When we asked healthcare providers how satisfied they are, from one, being not at all satisfied, to seven, being extremely satisfied with the current treatments for LGS in this example, we came back with a very lukewarm and kind of ambivalent review of the treatment options as they exist in LGS. It becomes crystal clear that as happy as we are to have effective medications, we recognize the deep shortcomings that that entire toolbox has when we bring it to bear for patients that have intractable epilepsy. Next slide. I'd like to talk briefly about how this nuance in epilepsy compares to intractable epilepsy by talking about a few specific epilepsy syndromes. The first is tuberous sclerosis. We know that epilepsy is common in tuberous sclerosis, and some citations report that rate as being as high as 90%. I think that's a bit of an overestimate because of the rate of undiagnosed tuberous sclerosis not being included in that number, but for sure, the point is that epilepsy burden is high in TSC. In TSC, you can divide those patients with epilepsy into approximately three categories, roughly equal. The first third of patients have complete control with a single medication and are lucky enough to have responded. You can note here that one-third is much less than the 75%, which I kind of promised you on the first thought experiment that we did, and that's because tuberous sclerosis is, on average, harder to control. When you take all comers, tuberous sclerosis does not have that great of a chance compared to the take all comers, which include mild epilepsy. About a third of the patients in tuberous sclerosis have moderate control, where they might need multiple medications or have occasional breakthrough seizures. About a third of the patients with tuberous sclerosis have hardcore intractability, where they're on multiple medications and having breakthrough seizures in spite of that. I'd also like to talk about intractable epilepsy as a whole, which would include tuberous sclerosis, but it also includes diseases like CDKL5 deficiency, Lennox-Gastaut syndrome, or infantile spasms. In intractable epilepsy, by definition, these individuals have tried multiple medications in every single case. Typically, they've tried more than eight medications over the course of their disease, and the appetite for how many they're willing to try kind of depends on the individual and the patient's family's preferences and how willing they are to try multiple medications over and over again. Because, again, with diminishing return, you rapidly feel a sense of futility when you're in the patient's shoes. Finally, I'd like to talk about the implications. The biggest point is that we need medications that have one of two important qualities. One is that they help the non-responders. I think recent pharmaceutical trials are exciting in this regard because they're doing trials in intractable epilepsy. That's a uniquely challenging group to demonstrate efficacy, and that's the kind of population that we want to prove ganaxolone can be helpful. It's also satisfying if the medication which is being developed has a compelling benefit, like safety or tolerability. It's important to remember that the safety profile isn't just what adverse effects that medication causes directly, but all of the indirect causes by virtue of medication interactions, et cetera. If I cause a medication level to increase that causes sedation or hepatic injury, adding that medication still has the downside of that, and that disincentivizes patients to try other medications and to continue that diagnostic exploration of trying to find something better. Then the final point I'd like to make is that this is not a zero-sum game where you only get to try one medication, or you only get to be on two medications. Really, patients with epilepsy and their families keep trying to find something that will really be a breakthrough treatment for them. They will keep medications that have a substantial demonstrated clear-cut improvement in their experience and have a reasonable side effect profile. If it doesn't have those two properties, then they'll move on as they continue through that exploratory trial. I'd like to highlight the fact that in the Marigold example, patients had failed seven prior AEDs and at the time of enrollment were on a mean of two point four AEDs. That highlights the idea that it's not a zero-sum game. In order to bring all of this back to our original point, since the last seizure carries the most burden, the existence of other treatments really doesn't lessen families' desire to consider another medication. With that, it's my pleasure to turn it over to Mark Paternoster, the Senior Vice President, Development, to talk about second-generation product development. Thank you, Ian. Good morning. I joined Marinus in May, bringing 25 years of pharma experience, including leading a number of development teams for refractory pediatric-onset epilepsy products that have achieved regulatory approvals around the world. Here, I lead the development team for oral ganaxolone, as well as functional management of development operations. I'm pleased to be presenting an update today on our second-generation product development. To add to Scott's introductory comments, a second-generation product that increases bioavailability and improves the PK profile has substantial benefits. Achieving higher blood concentrations, prolonging that exposure, and reducing peak-trough variability has benefits in achieving efficacy, mitigating peak concentration-related adverse events, notably somnolence, and the chance to reduce dosing frequency from the current 3 times a day administration to once or twice daily. New technologies also drive benefit in terms of intellectual property and the possibility of reduced cost of goods. Better bioavailability also drives less variability. This consistency is desirable in achieving a predictable response to treatment. These improved product characteristics could help us address new areas of unmet need. To remind you why we are currently dosing three times a day. When we had studied dosing twice a day in the phase III study of the now discontinued focal onset seizure program, plasma trough levels of around 40 to 45 nanograms per milliliter were associated with inadequate efficacy. Comparing that to the earlier positive development work in focal onset seizures and our Marigold CDD trial, both employing three times a day dosing, the higher trough levels of around 85 nanograms per milliliter were associated with a positive outcome. That exposure was consistent across all age groups in Marigold, as you can see in the table on the right. That correlation between dose levels and the percent change in major motor seizure frequency in the CDD trial is further illustrated here on the left. When split into tertiles of plasma concentration in the graphic on the right, you can clearly see what the second-generation product is trying to solve for. That highlighted low exposure group that does not achieve sufficient seizure control. Next, I'd like to briefly describe the specific target PK parameters we will be addressing with the second generation formulation. In this illustration, the black curve is representative of our current ganaxolone formulation, and the dashed purple line our goal. The aim is to increase absorption to achieve greater exposure, AUC, and to increase the proportion of time that the plasma concentration exceeds the nominal minimally effective concentration or MEC. This would result in a prolonged duration of action and enable the target of once or twice-daily dosing. It is likely that the increased absorption also results in increased peak concentration, Cmax, but we want to limit that increase so that we do not exacerbate somnolence. This is a challenging combination of goals in selecting a new formulation, so our development approach has been to assess a broad range of technologies from many sources, more than 20, and to progress many shortlisted candidates through technical, CMC, and pre-clinical evaluation with the aim of taking multiple candidates into early clinical development. This thorough investigation and early-stage investment keeps the option of multiple shots on goal as far into development as possible. We shortlisted five candidate technologies for the CMC and pre-clinical stages and are pleased to report that two of these have been selected for first-in-human studies early next year. Additional shortlisted candidates will complete the preclinical evaluation to provide fast followers into the clinic, should that be necessary. We will now bring these formulation projects fully into my development team so that we can build upon the clinical and regulatory plans, manufacturing and sourcing plans, and commercial and life cycle plans that are already underway. The next slide is showing some results from one of the shortlisted formulations. You can see here the PK data from a study in rats, which is a model very translatable to human dosing in our experience with ganaxolone. Comparing the current ganaxolone suspension with two variants of this candidate formulation. The new formulations six-10-fold increase in Cmax and two to five-fold increase in AUC shows the potential for breaking through the bioavailability barrier with increased exposure that we're seeking. You may note this does not meet all the criteria set out earlier, so this would be an example of a formulation requiring optimization, potentially including the sustained release approach that Scott noted we will research next year. Our approach in clinical development is to maintain the flexibility to quickly evaluate multiple candidates in the first-in-human study, which will assess the key target PK parameters described earlier. After that study, depending on the results we see, we will be ready to initiate a phase II study in LGS next year in which further dosing exploration could be done or to undertake additional phase I work. The latter path may reduce the need for a phase II study and instead offer a rapid path towards a pivotal LGS study. In making that choice, we will also take into account any need to optimize the formulation to produce the commercially representative batches necessary for pivotal trial conduct. At this time, we have a number of pivotal study designs in mind, a range that will be refined as we progress through early clinical development. Moving on to the prodrug project. The opportunities are those of the new formulation project, but at another level. Greater flexibility to design the ideal combinations of active ingredient and formulation to address PK and therapeutic needs across both oral and IV franchises with the benefit of composition of matter IP protection for new compositions. Our review of the patent literature would suggest there have not been any companies successful in producing a prodrug of ganaxolone that converts to ganaxolone in the bloodstream. We are pleased to report good progress with multiple prodrug candidates. Observed improvements in solubility that should eliminate the need for certain excipients used in the current formulations. Different candidates will show different rates of conversion to ganaxolone, supporting the achievement of key target PK parameters. Together, the improved characteristics of the active ingredient and the choices of formulation will give us the multiple shots on goal with prodrug, as we have with new formulations of the existing molecule. We look forward to sharing further details of prodrug candidates next year when we make the selections for IND-enabling preclinical and technical development in the first half. Thank you. I now turn the call back to Sasha. Thank you, Mark. Greatly appreciate all the presentations thus far. We are tracking a little ahead of time, but we would like to still take a five-minute break. It's currently about 10:16 now. Let us resume around 10:25, and then we will continue the remainder of the day with the financial overview, commercial strategy, and Q&A portion of the day. Thank you very much. Welcome back. Next on the agenda is Steven Pfanstiel, our CFO, who will provide a financial update and an overview of the Orion Corporation agreement, followed by our last formal presentation of the day, Christy Shafer, our Chief Commercial Officer, who will give an in-depth review of our commercial strategy. At the conclusion of Christy's remarks, Scott will be back to give a brief overview, and then we will open up to Q&A. Thanks, Sasha. Good morning to everyone. I am pleased to be able to provide a financial overview for Marinus and discuss several key events as they relate to our financial outlook. Let me begin by providing a summary of several key financial metrics. As of the end of Q2 2021, Marinus was in a strong financial position with $112.5 million in cash and cash equivalents. At the same time, we had $15 million in debt related to our recently signed credit agreement with Oaktree Capital Management in Q2. As a note, the debt in this facility is interest only for the first three years of the deal, with the outstanding balance due in 2026. To provide some additional background, the Oaktree deal was completed in May of this year and provides us with up to $125 million of potential funding. Of this amount, $75 million is accessible based on CDD regulatory milestones in the U.S. The remaining $50 million can be accessed based on achievement of specific development, funding, and commercial milestones. Importantly, this agreement enables us to monetize the proceeds of an anticipated priority review voucher upon a CDD approval. As well, the deal allows us the ability to execute a U.S.-based synthetic royalty monetization deal. As of June 30th, 2021, there were 36.7 million shares outstanding and 42.3 million on a fully diluted basis. For our full year 2021 guidance, which was updated as a part of our Q2 earnings call, we anticipate full year BARDA revenues of between $7 million and $10 million. As a reminder, we signed a deal with BARDA in Q3 of 2020, in which BARDA contributes $21 million of funding over a two-year period to support our phase III RAISE trial in RSE, as well as pre-clinical studies for ganaxolone in nerve agent exposure animal models. If successful, BARDA may contribute up to an additional $30 million in funding in support of further development in manufacturing activities. For the full year 2021, we anticipate operating expenses of between $113 million and $118 million, this total includes approximately $16 million of non-cash stock-based compensation. While I've touched on the details of the Oaktree credit agreement, I'd like to take a minute to dive deeper on our recently signed European collaboration with Orion. As a quick recap, we signed a license deal in Q3, which provides Orion with exclusive marketing rights to ganaxolone throughout Europe for the CDD, TSC and RSE indications. After going through a competitive process around European commercialization, we're absolutely excited to have Orion as a partner. One of the challenges and also opportunities of ganaxolone is that we have both an oral and an IV franchise serving different needs. This is where Orion is really an ideal partner for us and for ganaxolone. Their portfolio and expertise includes an existing commercial epilepsy portfolio, which ties in with our oral franchise, as well as expertise in an acute care setting. For example, they have PRECEDEX for ICU sedation, which ties in well with our IV franchise. Additionally, they have commercial leadership with strong orphan drug experience and pricing and market access expertise across Europe. Their commercial presence includes over 700 field sales personnel in 28 countries throughout Europe and CIS. Finally, Orion has strong experience in collaboration, and culturally they have proven to be a good fit with Marinus. From a financial standpoint, we are also pleased with the economics of the partnership. Excluding royalties, we have the potential to earn up to approximately $145 million from the collaboration, including a $30 million upfront, $8 million of R&D reimbursement, and $107 million of development and commercial milestones. Importantly, we also receive royalties ranging from the low double digits to the high teens for the oral franchise and from low double digits to the low twenties for the IV franchise. This provides us with significant and meaningful long-term value as a part of the deal. I also want to provide an update on anticipated events with the ability to significantly bolster our balance sheet over the next 12 months. In fact, two of these items have already occurred in Q3 of this year. As you can see from the green boxes in the bottom left. Combined, these two items have provided gross funding proceeds of approximately $60 million in the quarter. Specifically, we received the $30 million upfront associated with the Orion collaboration early in Q3 and recently drew an additional $30 million of funding from our Oaktree facility, which became available upon acceptance of our NDA filing for CDD. Upon an FDA approval for CDD, which currently has a PDUFA action date in Q1 of 2022, we become eligible to draw an additional $30 million of funding from our Oaktree facility. At the same time, through the designation of CDD as a rare pediatric disease, we are eligible to receive a priority review voucher upon a CDD approval. If received, we have the opportunity to monetize this and use the proceeds to fund further development and commercial activities. Recent benchmarks for PRV sales have ranged between $100 million and $105 million, and in fact, the two most recent transactions we identified were done at a price of $105 million. CDD in the near future, its approval has the potential to provide significant additional cash runway for the business. I'd now like to introduce our Chief Commercial Officer, Christy Shafer, to provide an update on our commercial strategy. Christy? Thanks, Steve, and hello everyone, and good morning. It's great to be here and quite exciting to speak to Marinus' first commercial launch and our future plans. Just a quick introduction of myself. I joined Marinus just shy of a year ago, as the first commercial employee. Prior to Marinus, I supported the build-out and launch of the neurology franchise at Alexion, where we launched eculizumab or SOLIRIS for MG and NMO. Prior to that, I spent the better part of two decades launching products in the hospital system between devices, biologics, and pharmaceuticals. My time here at Marinus has been the merging of my two worlds of rare disease in the hospital system. With that, I'd love to highlight the incredible amount of work that my team's been up to. Just to quickly reorient you to our development plan and pipeline. We'll focus on our pending first commercial launch in CDD, which, as you can imagine, is creating quite an exciting time here at Marinus. Outside of building our internal Marinus infrastructure, the development of our strategic launch imperatives were fundamental to our core strategy. To highlight them here, first, we really want to establish ganaxolone as central to comprehensive CDD management. We want to cultivate a patient support model that ensures efficient, rapid, and smooth access to care. We want to be able to prioritize the build of a commercial foundation that allows for scalability. Lastly, very importantly, we want to establish Marinus as a trusted partner in the CDD community. As you've heard, we're very excited to have an official PDUFA date in March of 2022. I wanted to quickly highlight our key activities and action items immediately after PDUFA. Like several other anti-seizure medications, we anticipate a DEA scheduling of a Schedule IV. The DEA scheduling period isn't initiated till after our FDA approval, and it usually takes up to that allotted 90-day period. We plan on taking full advantage of these 90 days. Let me walk you through exactly what that will look like. Several synchronized activities between the payer and sales teams will be happening. Our access teams will be focused on payer positioning, policy inclusion, and formulary status, while immediately after approval, we'll begin the onboarding process of our field sales teams, which will be followed by a concentrated training period. Once fully trained, we'll deploy our sales team into key accounts to initiate brand awareness and communicate the FDA approval while identifying appropriate patients in key institutions. As these patients are identified, we can introduce our complete patient services model in anticipation of the conclusion of that period. That stream of events will really allow a fantastic way for our patients to get onboarded after that 90-day period. Zooming out just a little bit here, you can see that each functional team is building out the launch readiness plans. We've got five functional areas, and just some highlights to draw your attention to would be our new branded campaign development. We've got a significant amount of attention focused on commercial data and modeling. Our payer and KOL engagement is off to the races, and certainly not least, our inventory build. I'd like to zoom back out quickly, and drill down to the activities of our proposed trade launch in June till the end of 2022. If approved and scheduled, ganaxolone will officially be available to patients drug in our channel in June. The continued identification of patients and enrollment activities will work in tandem with the access team's objectives with both our commercial and Medicaid plans. We will have a full launch of our patient services model, where patients will be enrolled in and pulled through an exclusive specialty pharmacy team. As well, there will be ongoing support to the clinical operations team to convert our open label and expanded access patients in the U.S. Typical conversion of trial patients can last anywhere between six and nine months, and we would expect any new patient starts beginning in about Q4. Early on in our commercialization development, we gained organizational alignment around the need for adequate resources for our first launch. Typically, in rare disease, the number 1 hurdle is patient identification. The ICD-10 code for CDKL5 deficiency disorder is just about a year old. Key research has dictated that the majority of patients are treated in a very small number of institutions. Nationally, there are eight centers of excellence devoted to CDD, and there are 40 accredited National Association of Epilepsy Centers, which that is 100% overlap with the CDD Centers of Excellence. Our research has confirmed that if we focus our efforts here first, there is an incredible portion of the CDD patient community identifiable and ready to convert. You'll see here that we've also drilled a little bit deeper into the data and have prioritized and will focus on approximately 265 accounts at launch. The first tier of accounts, which are about 40, that you see here on the left, those are the NAECs I just spoke about, with the largest number of claims, and they tend to be early adopters and have wide national influence. The B accounts are an additional 47 that also have a large number of claims, but the data suggests that there might be a slight delay in the adoption of new practice. They tend to also have very high influence across the United States. Lastly, our largest group in the C accounts, 178 to be specific, have a median number of claims. They tend to adopt new therapies, but they do definitely require a targeted commercial effort. The great benefit of a concentrated patient population like this is that we have the ability to have a targeted, efficient, and very, very high touch sales organization. We have a plan to have 16 very seasoned sales professionals in the field with an equally effective access team. Next slide. The patients that we will potentially be able to treat are at the core of everything that we do and every decision that we make. This community of patients and caregivers has inspired a purpose-driven brand realizing the profound effect that CDD has on families. You'll see a quote here from an excerpt of market research where a caregiver states, "Seizures are not just seizures. They take away a lot of things, family time, energy, emotions, physical work. If you can get control of the seizures, I would take that." Next slide. This market research confirms many things, most notably, that these caregivers take a very active role and are crucial member of the care team. We interviewed 10 caregivers of patients with CDD, and the key insights truly enforce our commitment to these families. Caring for a child with CDD is a 24/7 commitment. They tend to advocate and support and take a very selfless approach to their child's growth and development. Bad days are characterized by multiple seizure-related events and other complications. Ultimately, effective seizure control is paramount to improving the ratio of good to bad days. I'm the lucky one today because I'm thrilled to have the very, very distinct honor and pleasure of announcing for the very first time in public our proposed trade name of Xatomi. This brand name has been established and the trademark is registered. This branding concept represents a new hope for children and families experiencing seizures and CDD. The logo and colors are calming and supportive, while the open circles signify a community rallying around the champ, the child and family. You'll notice that we also have a complete packaging design in two different configurations that will support ease of use and convenience for families. Now that we have a trade name and our packaging is complete, our number one market access objective is to ensure patients have a seamless access plan from prescription through fulfillment. Because of the size of our patient population, we have elected to engage an exclusive specialty pharmacy partner. This partnership will support our efficiency objectives and strengthen our efforts to not overcomplicate this strategy. This coupled with high-quality headcount and a very compelling value proposition, we feel that the foundation for access is solid. There are several key strategic priorities and ongoing activity that take us up to and through our launch. Bucketing them here, we have pricing, distribution, value, and customer engagement. We collaborated with a global leader in pricing and reimbursement and have concluded our initial research. We are now under our strategic analysis phase and hope to have more information soon. Like I mentioned, we've engaged with and elected a specialty pharmacy partner. We continue to support and inform our Scientific Affairs team who's leading the effort in our burden of illness research. We've identified the national and regional plans that cover the majority of U.S. commercial lives. I'll remind you quickly that in our initial assumptions, we have a payer mix, that have our patients at approximately 60% Medicaid and 40% commercial. Now, although we have our hands full with a potential launch around the corner, we're simultaneously planning for the future. I'll just reorient you quickly to our development and pipeline here, and I'll highlight the more traditional commercial thoughts that we have to date. To round out our oral ganaxolone franchise, we executed similar research that you saw earlier to understand the footprint needed for an effective launch in TSC. I spoke earlier regarding adequate resources for launch, and assuming that TSC patients are diagnosed, there is clear data outlining where they're treated. Nationally, there are 10 centers of excellence devoted to TSC, and you'll notice by the table to the right that the incredible number of these claims are concentrated in that top tier. With similar characteristics to how we identified CDD accounts, number of patient claims, adoption rate, and national influence, you'll see close to 225 core targets needed for an effective launch strategy. Because our initial proposed footprint, we anticipate a minimal sales force expansion to just under 30 sales representatives and a commensurate expansion on the access team as well. Moving on to our proposed IV status epilepticus hospital needs. We believe that a few things need to be core to that success. First, we need to have a distinct and focused hospital sales force. Hospital promotion warrants a separate and distinct sales team. After working through several different analogs in an overlapping analysis, you'll see here on the left, we reviewed claims for status epilepticus. We also looked at the ability for hospitals to have 24-hour EEG monitoring, and then we also overlapped that with the national tertiary and quaternary care centers. This analysis yielded between 800 and 1,000 targeted accounts for launch. 800 and 1 more slide back, Molly. Thank you. With 800 and 1,000 targeted accounts, this dictates a hospital force of between 75 and 100 specialized representatives. Next slide. Given my background and experience launching products into the hospital, we're spending valuable time planning for a proposed launch. What's most important to know that that distinction that I spoke to and that differentiation is key to our strategy to an IV ganaxolone formulation. We have ongoing and in-depth reimbursement strategy development at work that's inclusive of the submission of an NTAP pricing work and a full evaluation of the associated DRGs. The distribution pathway will follow traditional direct or drop ship methods. While the value prop and HEOR work is being supported, we're developing concepts around the need for distinct protocolization, not only within the societies, but at the hospital level as well. Lastly, after finalizing a hospital target segmentation exercise that I just walked you through, we'll consider the impact of the larger IDNs and national accounts, and how we can effectively engage really important pharmacy and pharmacy directors early on in our development. With that, I'd like to turn the time back to Scott. Thanks, Christy. Great job. I want to thank everyone for being patient as we went through about 100 slides. I also wanted to share with everyone that you can now access all of the slides on our website under our R&D link. You can really take your time to go through some of the new data that we presented today. Before we move to Q&A, I just wanted to spend a minute or two to just walk through the next few years for folks who are on the call. As we've talked about, the end of 2021 is going to be a very busy time for us as we initiate our phase III TSC trial. As we move into early 2022, we continue to have several interactions with the FDA around our CDD filing as well as the EMA on our European filing. We have several major studies beginning in the first half of 2022, including two additional IV studies in our new formulation work. 2022 will keep us very busy. We look to our top-line RAISE data set, our U.S. pivotal trial for registration in the U.S. by the end of 2022. Certainly, that will give Christy ample time to start preparing her team for the IV launch soon thereafter. Our expectations is that data set would lead to a filing strategy in the U.S. I think importantly, we will continue our research efforts with our large phase III TSC program, looking for that data in the beginning of 2024. At some point in 2023, our expectation would be to move our new formulation programs forward with initial work in the LGS area in the second half of 2022, and studies that, as Mark talked about, leave some optionality for us of exactly what we want to do in 2022 and 2023, whether it's a more rapid move to phase III or a more detailed phase II program in an LGS indication. I hope you can all join us for American Epilepsy Society in December. We'll have quite a bit of data and presentations at that meeting. With that, I'm going to turn it over to Sasha to lead our Q&A. I'm going to ask all the Marinus folks to pop their cameras back on. Sasha, with that, I will turn it over to you. Great. Thanks, Scott. At this time, we would like to open the call to questions from our covering research analysts. I've already got a whole bunch of them that I'm going to throw out to the leadership team here. Figured let's just go with Joe, if you want to go with this one here on the status side. On the RAISE II trial design, what would be the expected placebo rate for interrupting status with an IV AED alone? Is 70 patients a large enough sample to power for a separation in a combination setting? This is from Brian Skorney at Baird. Sure, Brian. We're powering for an effect size of 35%, an anticipated placebo rate would be around 30%. That's based on a response rate from the ESETT study in established status that reported resolution within a half hour for about 50% of the patients who responded. That seems high to me, actually. We're looking at refractory status. Even if the patient responds, the brain penetration of the standard AEDs is slower than ganaxolone. We expect a higher response for ganaxolone. In the phase II study, 15 out of 16 patients had status cessation within a half hour. Even a very conservative estimate of 65% versus 30% would give us a 90% result, and that's just for the first endpoint. We actually have to hit on both. For the responder analysis, the endpoint is very robust for detecting a treatment difference from ganaxolone. I think that is mainly driven by the early response. In order to be a responder, it has to be rapid onset and a durable effect. We're confident about the powering at 70 patients. Okay, question from Joseph [audio distortion]. Can you discuss what physician education may be needed upon CDD launch around dose titration so that patients tolerate and stay on drug in light of the TSC findings? Did the TSC data alter your approach at all? Maybe I'll turn it over to Alex, but just to remind everyone, in our CDD study, we had no patients who discontinued therapy due to tolerability issues, and we had about 80% of patients who achieved maximal dosing in a CDD population. We feel very confident that the current titration schedule is adequate for launch in the CDD indication and extremely well-tolerated. We do think there may be future opportunities in the CDD population, but one that we're not at all concerned about in terms of launch. I do think it's critically important that at the time of launch, we can provide physicians with as much information as possible. Alex, you want to add to any of my comments? No, Scott, I think you hit on them. Just to, again, underscore the fact of how well-tolerated the drug appeared in the phase III Marigold study in CDD, low discontinuation rate with that existing titration schedule. As we continue to learn more moving forward, that may certainly adjust in terms of ways that we think could potentially lead to incremental increases or improvements in efficacy with modified titration schedules in the future. At launch, very comfortable with what we have. Maybe it's worthwhile, Sasha, for Joe to just comment on what epileptologists, or Ian to comment on what epileptologists in the field do when thinking about medication adjustments and adding new medications to patients. Ian, you want to maybe talk about that, or Joe? I'm happy to. I alluded to it a little bit in my talk, really, each medication that is trialed is kind of prioritized by virtue of side effects to a large degree, because initially when you're starting your first medication, they're approximately equally effective. Adverse effect profile is a tremendous consideration as long as it's indicated or approved for that form of epilepsy. If that first medication works, great, you're kind of finished. If it doesn't, and you're in that unlucky group of people that tend not to respond to medications, it's essentially a step-by-step decision with each subsequent medication in terms of whether it's convincingly effective to that family, right? Families don't care what the aggregate effect size was or what the literature showed. They want to know, am I convinced that it's really helping my child have fewer seizures on a daily or weekly or monthly basis? With that benefit in mind that they personally see, they will make a judgment based on the AE profile that they're seeing, again, in their child. Here, they do get nervous and pay attention to things that are reported in the literature, because if there's a risk of permanent vision loss or a skin rash or something with bone marrow suppression, they're going to pay attention to that because they know that's a risk, and they definitely factor that in. They want to make sure that it's pulling its weight and it's generating enough benefit for their child relative to the risks that they know about and are educated about by their clinician. I don't know if you have anything to add, Joe. Yeah. I'd add that neurologists and epileptologists are well-versed in managing drug interactions. Really, as Ian alluded to, treatment's individualized. A drug is titrated to efficacy and tolerability. The target dose in the package insert is a guide, but they don't slavishly follow a titration schedule. They'll individualize therapy and are always aware of potential drug interactions. With the drugs being used with EPIDIOLEX, they'd be particularly aware. Okay. You touched on this, Joe, so it's worth asking from Joon Lee at Truist Securities. Regarding DDI between EPIDIOLEX and ganaxolone, can you talk about interaction of both with cytochrome P450 and other liver enzymes? Was there any evidence of DDI between ganaxolone and Afinitor? Can you talk about the current backbone standard of care in TSC? Could ganaxolone displace EPIDIOLEX as the preferred combination drug due to DDI of EPIDIOLEX? I'm going to ask Alex if he wants to comment on the first part of the question. Yeah, sure thing. Thanks, Joe, and thanks for the question. ganaxolone does not really appear to be a perpetrator, inducer, or inhibitor of any of the key P450 enzymes. In a human DDI study, when it was administered with a CYP3A4 substrate clobazam, it didn't materially impact the levels of that 3A4 substrate. In terms of EPIDIOLEX, certainly would guide you to the prescribing information. Appears to be metabolized through 3A4 and 2C19. As I had mentioned in my talk, there is a well-known interaction with the clobazam and its active metabolite, believed to be impacted through the 2C19 pathway. The question becomes in terms of, we believe ganaxolone to be inhibited, or excuse me, metabolized primarily through 3A4 in in vitro studies. In terms of what may be happening here clinically, again, I think some of these in vitro studies that we have ongoing could help better inform this potential interaction. To the second part of the question, in terms of any interactions with Afinitor, in the 11 patients in the phase II study, we did not see any interaction with Afinitor, either on ganaxolone levels or reverse. This is certainly something we're going to continue to look at in phase III. Just briefly, I'll touch on the last part and pass it back to Joe. We're very confident in the refinements that we made to the phase III protocol, that we believe that ganaxolone could be administered concomitantly with EPIDIOLEX, since it does play a role in standard of care of TSC patients. Joe, anything you'd like to add? In terms of the backbone of care for TSC, I think EPIDIOLEX and Afinitor are clearly part of the standard of care these days, in addition to one or more of the standard AEDs, levetiracetam, valproate, so on. Of course, clobazam. I think it's the standard of care AEDs with the addition of Afinitor in particular, and also EPIDIOLEX. Although Afinitor is primarily, I think, of interest for its disease-modifying properties in terms of CNS tumors, rather than an anticonvulsant per se. In terms of, I think Alex alluded to it, whether or not ganaxolone displaces another standard of care drug, I think will depend on the results of phase III. I think that the study is designed so that there wouldn't be a need to discontinue EPIDIOLEX. With the titration we're using, I think that it'll be well-tolerated in combination. Sasha, I would only add to Joon's question. Thus far, we've screened about 40-50 sites in the U.S. and asked specifically about EPIDIOLEX use in their TSC population. Thus far, our screening would suggest only about 30% of patients or so are currently on concomitant EPIDIOLEX, and we're specifically asking about the refractory population. Clearly, physicians are thinking about that EPIDIOLEX interaction with Afinitor or other reasons that we're not seeing more widespread use of EPIDIOLEX in the U.S. I think those numbers are going to naturally increase in the U.S. To Joon's question, I do think that does create, in the future, an opportunity based on our phase III results and tolerability across the board. Which, to remind folks, this drug has no interactions from a cardiovascular, renal, or hepatic standpoint, which I think makes it quite attractive. We've done that same probing for the European sites in the trial. We see about 33% use of EPIDIOLEX in Germany, where the EPIDIOLEX TSC indication has been approved. We see very little use in the rest of Western Europe, less than 10% across most countries. Certainly, we are expecting greater utilization with the U.K. recently approving the use of EPIDIOLEX in TSC. Given the mix shift in our phase III, our expectations is that EPIDIOLEX use will really wind up being seen in somewhere between 25%-50% of patients. I think to Joon's point, it really will create a very interesting data set for us. Okay. Question from Douglas Tsao at H.C. Wainwright. Beyond hospital costs, can you provide a sense of the total cost, post-acute and rehab, for treating patients that advance to ESE and RSE? Presumably, cessation of the SE episode has long-term cost savings as well. Alex, you want to take that? Or In terms of total hospital costs, I'm not sure if I'll address the question directly. In terms of the research that Joe presented, that only looked at hospital costs and clinical consequences during the inpatient stay. We think there are certainly additional opportunities to demonstrate and realize the potential value proposition of ganaxolone beyond what just those numbers show. One thing in particular we saw in that study, that a lot of these patients were discharged to long-term care or skilled nursing facilities. Specifically those that were in Cohort three are more severely impacted. We think if we can arrest or terminate status earlier in the treatment paradigm, that their discharge disposition could be improved, reducing overall long-term costs. Second, though, I wanted to comment that it excluded patients that were referred to the hospital for that inpatient stay. We also think there's an opportunity to minimize potential referrals if the effective treatment is delivered at the site of initial care. Those are two areas that we're potentially looking to expand out in our value proposition development. Does anyone else want to answer? Well, we're good. Okay. We'll move on to the next one. Joon Lee at Truist. This is again on status epilepticus. You have guided to RAISE top-line data from RSE in the second half of 2022. What's baked into this assumption? Also, you have guided to RESET in established status epilepticus starting in the first half of 2022. Is the start of RESET trial in ESE contingent upon enrollment completion of RAISE, given RESET is testing IV ganaxolone in the frontline setting? Let me kick it off, and then I'll turn it over to Joe. So, June, the critical piece of our assumptions around the RAISE trial is really having sites up and initiated, and then our expectation that most of our active sites, and particularly our high-enrolling sites, will average somewhere between three or four patients over the course of a year. We were really happy to share the list that Joe highlighted, that many of our key sites and what we expect to be our high-enrolling sites are now up and activated, many of them in Q3. Our current expectation is that those sites, over the course of the year, will enroll three to five patients. That has been the major stumbling point to this date, and that's been really unexpected around physicians leaving their jobs, nurse coordinators leaving their jobs. I do want to shout out that our clinical operations team has just done a tremendous job of countering very unexpected turnover and I think unprecedented in the industry. I think this study has raised physicians' interest in being a part of it. Our clinical team, Joe, Alex, we're all mobilizing every effort we can to keep folks engaged while they are very busy with COVID. I think we're finally seeing some improvement in that regard. Right now, once the site is up and active, that is the critical piece, the way we're thinking about the enrollment timelines and why we feel comfortable about the second half of 2022. We'll make sure that we update folks on a quarterly basis, and we'll do that again early next year. Joe, you want to talk about the difference in populations in the RESET trial and any other key points that you'd like to highlight? Yeah. A site being in the RAISE Study for refractory status doesn't preclude its involvement as a site for the RESET Study in established status. The RAISE Study, the patients are coming almost exclusively from the ICU. In RESET, it'll be done in the emergency department. It's really, in most ways, a different population of patients. I think we are, in fact, using some of the same sites, but they're different PIs and different sites of care. Okay. Next question is from Joe Hulihan, accounting company. Is a formal CDKL5 mutation necessary for reimbursement in CDD? Do you anticipate any necessary prior treatments for identified patients? A step three, for example. Well, that's a tough question. I think we have to really wait for our label and our expectations. Maybe I'll just remind the viewers, and Christy, you feel free to add, is that genetic testing is almost universal in the U.S., and our numbers would suggest there is strong genetic testing globally in 80%-90% of patients. Remember, these patients are presenting typically before the age of one. The vast majority of these patients will be genetically tested. We had an extremely high correlation in our phase III study with presumed CDKL5 deficiency disorder or prior genetic testing, and we validated all of those testings in the phase III. That was not at all a major source of losing patients in the phase III study. The vast majority of patients that were screened for the study, Alex, I am correct, right? They were genetically validated as part of that process. We don't see at all genetic testing as a stumbling block. Maybe Christy, before I have you chime in, Ian, may be worthwhile for you to chime in with your experience around genetic testing and that process overall. Yeah. I agree that when infants with epilepsy present, they get tested early. I think in other forms of genetic epilepsy, we are seeing very high rates of genetic testing. I don't think we're at 100% yet, especially as the folks get older. I definitely think we still want to try to get it done earlier, because the earlier that we can figure out why the child has epilepsy, the more specific and thoughtful we can be about the treatments. I definitely don't think it'll be a stumbling block in terms of identifying these patients because of how early they present. Although, I do think that it's a different group of patients relative to LGS. Obviously, LGS doesn't have a genetic diagnosis. It's a syndromic diagnosis. If the question relates to how concrete and discrete is the boundary around the patients that are on label, it's much more clear-cut for CDKL5. Basically, without a genetic diagnosis for CDKL5, it's challenging to make that as a diagnosis because there's a lot of infantile-onset epilepsies that are equally severe. I hope that answers the question. Christy, maybe it's just worth commenting on the payer discussions we will have focused on CDD. Sure. Just to highlight what's already been said, though, because we feel our patient population, our proposed label will potentially be for patients two and above. By the time they get to us, really dictating what Ian Miller spoke about, even if there were step edits included in the access plan, we believe they would have already gotten to that point where those step edits would have already been taken care of. I think that I would expect, and again, I don't believe it's a giant hurdle if genetic testing confirmation was needed at that point of access. That, again, that would not be a giant hurdle for us. Again, the payer discussions will be primarily focused about identifying those patients and their specific plans. We talked a little bit about the epidemiology and the patients that we'll be focusing on, we'll be looking at between 2,000 and 4,000 patients nationally. These payers, that's not a lot of patients compared to some of these therapies that they're looking at. It will be more education around what CDKL5 is, who those patients are in their payer systems, and then really dictating what a smooth access to care will look like for them. Let me just add, Sasha, as Christy pointed out, there are some key centers of excellence in the CDD world, and I think it's pretty likely that all of those patients come with genetic testing before they're referred to a CDD center of excellence. Why don't we move on to the next question? That's leading quite nicely to Charles Duncan from Cantor Fitzgerald. Her question, what percent of patients are treated in these centers of excellence? Do you think initial new starts will be driven by center use or more a certain patient profile that might reflect the highest unmet need? Christy, jump right in. You're on mute. I clicked it. I apologize. Charles, that's a fantastic question. If I'll refer back to what I spoke about, the ICD-10 code is only about a year old. Unlike some of our other disease states like TSC or status, we don't have a specific number. What we did do is build a cohort of patients that really dictate what a CDD patient will look like, and that's what's focused on those top-tier accounts that about 260 accounts. What we did is we provided another bit of core research of really looking at these larger centers. The market research over and over in these larger centers gave us numbers that were very confirming and really dictated this strategy and underscored the need to have a nice, small, nimble organization. Some of these larger organizations look at between 40 and 60 patients on the upper level, which is a lot of patients when you're looking at ultra-rare orphan diseases. In those second tiers, we're having 20 patients. When you're looking at these national centers, that will be our first place to go to really get the low-hanging fruit, if you will. Those patients who are truly refractory, they need to follow the thought leaders in the community. We feel very confident in those 260 and of course, those top 80, 8-40 accounts for the first tier. Thank you, Christy. Next question is from Douglas Tsao at H.C. Wainwright. You've made great progress on new formulations and a prodrug. As you learn more about the mechanism, are you looking into making changes to the molecule itself? I guess I'll kick off that one. Doug, thanks for the question. I think we feel that there is a terrific therapeutic window for ganaxolone. Quite honestly, both our approaches, that is using a new formulation or a prodrug approach, we are replicating ganaxolone in the blood level. I think we feel very confident from the Marigold dataset that the higher blood levels we can achieve over a period of weeks will maximize the therapeutic effect. Just as a reminder, we saw great sensitivity in our IV studies between blood levels of 400 nanograms and 500 nanograms in the acute setting. I think we believe that if we can get all patients on ganaxolone to blood levels between 100 and 175 nanograms, we have an incredible opportunity to drive greater efficacy. That being said, I will throw in that if we can improve bioavailability, that will really allow us to look at sustained-release formulations. We're committing to that work in 2022, and I think driving a 12-hour PK can really create opportunities not only in the chronic epilepsy space but in other chronic neurologic disorders. We're still keeping an eye on those opportunities, but right now, our lead horse, ganaxolone, we feel great about the therapeutic window. Joe, anything you want to add there? No, Scott. I think nothing substantive. I agree with you. I think if we can get consistent delivery of the drug, especially in epilepsy, titrating to effect is important. If we can get dose proportionality and reduce the variability in absorption, I think that's going to do as much to increase efficacy as anything and increase the utility of the drug in epilepsy. I would just add one other piece, Sasha. I think what we learned in the phase II TSC study is we can't get there immediately. It's got to be a slow titration. I think really we will target all of our work to allow us to really create a very steady titration period for the patients. We could go back to the preclinical work that Dr. Michael A. Rogawski has performed, showing in animal models the tolerability around ganaxolone improving over time while efficacy remains unchanged. That is one of what we believe the great differentiators in the drug. Again, to some degree, the drug You're really better situated for chronic disease states rather than disease states where you need to give a lot of drug quickly to create an immediate effect. I think status is the exception to that or other acute medical emergencies. We continue to look and study where the drug could play an important role in other acute indications, primarily in the hospital setting. I think we're thinking about infantile spasms as being one of those potential indications where the IV formulation, acute high blood levels can be quite important within a chronic phase oral dosing to follow. Okay. We'll shift temporarily away from development, clinical development over to Steve. Can you talk about your plans and progress to monetize the PRV you would get on approval in CDD? Yeah, sure. I think, obviously, the PRV presents us with the opportunity to significantly bolster our balance sheet if we monetize that. I would say, we anticipate and expect that that's the path we will absolutely go down. We're still six months away from a PDUFA action date. There's certainly plenty of time to work on the detailed plans with that. Essentially, that's where I see this headed. We'll continue to just make progress as we go over the next few months. That was from Jason Butler at JMP, I'll continue his questions. As you advance the novel formulations, how are you thinking about the potential to develop different formulations for certain indications or groups of indications? I'll take it. I think, Jason, we're really focused on what will be the best formulation for the treatment in chronic epileptic patients. At the end of the day, I think more likely than not, we're going to look to one specific formulation to be that anchor. I think our belief today is that LGS will be that anchor indication. Then we'll be very thoughtful about where that new formulation may play a role in a CDD population, TSC population, or other new indications. That's a process that Christy's team is highly involved in, our strategy and business development team, as well as the clinical team will be involved. So we're going to continue to think about all of those programs. I think to a large degree, 2022 is about picking the lead horse, moving the program forward, and setting ourselves up to move that program through the clinic quickly. I think what's more important or equally important from our standpoint is we know what we need to achieve. We know we need to target specific blood levels with that adequate titration. As of today, our data would suggest if we can do that in all patients, the probability of our success is highest. One of the things Joe, Alex, myself did early days of preparing for the NDA was to go back and look at some of our failed clinical studies. Not only did we see extremely low blood levels in the failed focal onset study, but in the small study that was run in LGS, for example, several years ago, the vast majority of those patients had blood levels less than 50 nanograms per ml. We've seen a consistent theme in the oral development of too low a blood level chronically will not be an efficacious dose. I think right now that's our focus. Okay. Jay Olson at Oppenheimer has a very detailed question, so bear with me. Since epilepsy is heterogeneous and 25% of patients tend to be refractory, are there any predictors of response to new therapies? What are the current diagnosis rates for CDD, TSC, and LGS? Does the availability of new treatment options improve diagnosis rates? How much additional clinical efficacy do you expect to achieve by increasing the bioavailability of ganaxolone? I'll stop there so that you can answer the question, and then I'll continue. Well, that's a lot. Sasha, maybe you want to take one at a time with Ian or Joe. Ian, you want to kick it off? Sure. My understanding of the first part of the question is whether there's predictors that help you make an educated guess about which medication might be the best, either out of the gate or based on the first few medication trials. I think that's really hard. I think there are some clear-cut associations, especially related to etiology. If you have a person with SCN1A, we know even before you try your first medication that you want to steer away from carbamazepine or oxcarbazepine or phenytoin because they will make seizures worse. I think as we get better genetic testing and are able to identify where the different etiologies are and how they respond to medications, we will develop some associations like that. I have to say that that level of association is very atypical. I think to a large degree, anticonvulsant medications have relatively broad applicability, and it's a symptomatic treatment, and it's rather challenging to know and have a crystal ball about what will work. I think the question was insightful, but I think it's more challenging than I wish that it was in 2021 to do that. I think the second part of the question was diagnostic rates of LGS and CDD. I think they are both very high. I think it's a clinical judgment in terms of identifying LGS populations and therefore, due to the awareness, especially related to recent medications that have been approved to treat LGS, I think LGS is top of mind on the part of the treating clinicians. The patient advocacy groups do a great job pounding that drum also, because it's important to identify the patients that fit a certain phenotype, if that phenotype is a marker for what medications you might respond to. Related to CDKL5, like I mentioned earlier, because it starts so early and because child neurologists are so desperate to understand what's going on and really give parents prognosis about what the future holds, that future can be very different if you're dealing with CDKL5 versus if you're dealing with some other genetic disease that might be progressive or degenerative. Those tests get done early, and I think as a result, the detection rate and the diagnosis rate of CDKL5 is high as well. Sasha, I need your help to hit anything else or remember what the rest of the questions were. Just in terms, you covered the first two. How much additional clinical efficacy do you expect to achieve by increasing the bioavailability? I might turn that one over to Joe, just because of his longitudinal experience with blood levels and seeing the rates. Definitely, that was a question that I had when I joined Marinus. I've only been with Marinus since March, and I think the credibility of that answer was really important for me to be satisfied of when I joined. Joe, anything else you want to add? Yeah, no, I think it's going to improve it quite a bit. As I mentioned, there is variability in absorption. Patients could take the same dose and get anywhere from a level of 50 up to as high as 300. In the CDD study, we saw a very clear PK/PD relationship in terms of blood level. Making that consistent and being able to predict the dose, I think, is going to be very important for ganaxolone. I might just make one other comment on the diagnosis rates. I think in children, for something like CDD or the other genetic epilepsies, the diagnosis rates now are high. I think an available treatment that's specific to a certain disease does motivate physicians to diagnose. CDD, I think is probably, with the availability of genetic testing, especially in the U.S., high. One caveat to that might be adults. Institutionalized adults, or adults living in group homes who've had long-term disability, developmental disabilities. There's not great motivation to do genetic testing. I think there are undiagnosed patients with CDD and other genetic epilepsies that may not declare themselves clinically. Tuberous sclerosis usually declares itself clinically, but milder patients go undiagnosed. Patients can have tuberous sclerosis into adulthood and not have it diagnosed unless someone does a skin exam. I think it does vary a bit by syndrome and population. Okay. Michael J. Higgins at Ladenburg asks, "Is there an identifiable difference in the Cohort two and three patients before ganaxolone would be started?" His second question: "According to your most recent 10-Q, it looks like we'll see an update in Q1 on the work on the M2 metabolite. Any updates for us on their ongoing work there? I could start and take the burden of illness study. In terms of ganaxolone use, I think that Cohort two would be the population in which it would be used. They're the closest analog to refractory status and ideally prevent progression into something like Cohort three, super refractory status. If a patient had failed IV anesthesia, that would be possibly outside the indication, although refractory status is defined as greater than two IV AEDs. I think that remains to be seen. The only way we're exploring super refractory status at this point is through these emergency INDs. Cohort two would be the most appropriate population. I don't know if Alex or Scott or anybody has other comments on that. Building on what you just said, Joe. Oh, go. I'm sorry, Alex. No, go ahead, Scott. I was going to take the second part of the question on the micronucleus test. We have now continued to make the M2 metabolite. It's a little bit of a lengthy process for us. The micronucleus test is on track to be performed this quarter, and we will be updating the investment community as soon as we have the final results. We certainly still believe that this test is going to not show any concern from a safety standpoint. All of our outside experts have given us that opinion, and our hope will be that this will be very informative in the future. We'll be happy to update the investment community when we have those results. Looking forward to it. Just one final question to wrap up, since we are planning to wrap up at 11:30. For RFC, for the RAISE trial, as you are activating more sites, are you still seeing a similar level of placebo rates in general? Last time, I believe you noted your sites have indicated that 75% of patients progress to IV anesthesia after two or more IV AEDs. Yeah. Well, I couldn't comment on the placebo rate because the study's blinded. We don't yet have data on overall progression to anesthesia in the study. There's going to be a data safety or a data monitoring committee who will evaluate that, and their first assessment is going to be after 25% of the patients are enrolled. Joe, let me clarify because from the question standpoint, that was a survey that we did for sites as they entered the study. We wanted to make sure the sites that we enrolled had a reasonable conversion to IV anesthesia. What we saw in that survey work was that 75% of patients progressed after two prior anti-epileptics. That was the foundation for choosing sites. We're no longer surveying sites as we are now getting all the sites up and activated. Again, that was a pre-screening qualification for us starting this or entering a site into the study, and we shared that data set with the investment community. We feel very confident that those sites will behave as we would have expected. That's the critical piece of the story that we want to be clear about. Great. That question was from Andrew Tsai at Jefferies. Just one more to point out. Just to confirm, you think the low-hanging fruit will be from the eight centers of excellence plus 48 accounts? Christy. I will say that there is 100% overlap between those eight centers of excellence and the 40 NAEC. Let's go with the top tier being 40 NAEC that we'll target to start. I will say with a small sales organization, we can get to all 265. Fantastic. Okay, great. We will close the event today, and we'd like to conclude the meeting. We thank you for your time this morning, and we appreciate your interest in Marinus Pharmaceuticals. Should you have any questions, please feel free to reach out to info@marinuspharma.com. Thank you very much, everyone.