This is Gavin Clark-Gartner, the Evercore ISI Biotech Research team. I'm really happy to be here with Scott Braunstein, the CEO of Marinus Pharmaceuticals. So thanks for joining us, Scott. Thanks for having us, Gavin. Absolutely. So maybe just for some of the people who are less familiar, why don't you give us an overview of the company, including some of the updates that you announced today? Sure. To Marinus, we have one lead compound, ganaxolone, but we're studying it in two unique formulations. Our oral formulation, Ztalmy, is approved for CDKL5 deficiency disorder, the seizures associated with that. We have been selling the product for roughly a year and a half. We've had a really fantastic launch, and I think we've seen the unmet need in rare and refractory epilepsies. We're also studying Ztalmy in tuberous sclerosis complex. We're in the middle of a phase three trial, and we're on track to finish enrollment by the end of the first quarter of next year, and to have that top-line data in the summer of 2024. So an exciting year ahead for our oral franchise. And while we see the CDKL market roughly at between $100 million and $150 million in the U.S., we think the TSC market can easily be 3x-5x that, given the significant number of refractory patients who suffer from seizures associated with TSC. The other side of our business is the IV ganaxolone franchise, and we are in the middle of our first registrational trial, the RAISE trial, which is all that's required for U.S. approval. And the RAISE trial is looking at a highly refractory population, who are suffering from acute status epilepticus, typically who have failed two, and often three, anti-epileptic therapies, and we're using ganaxolone really as an avoidance strategy to IV anesthesia, which can be effectively the kiss of death for any one of these patients. We announced this morning the study's now 80% enrolled, that it's been a really exciting study to run, but difficult and complex, so we cannot wait to get to the finish line. We expect to finish enrollment by the end of the first quarter, with the top-line data in the second quarter. So 2024 is a big year for us, and we generally see the refractory status market as one of roughly 30-35,000 patients. Street models have us pricing the drug at about $30,000 per patient. But really based on the data that we see, that will include not only avoidance of IV anesthesia, but other important health outcome measures, like the incidence of super refractory status, death rates, comorbidities, ICU stays. I think we'll make a determination on where we think the appropriate price is, and we certainly believe that's a billion-dollar franchise as well. So a big year ahead. Yeah, definitely. All right, so let's zoom in on RAISE a little bit more in RSE. So just remind us, what exactly is the trial design, primary endpoint, and when does this interim happen within the trial? Sure. The phase three, as agreed upon by the FDA, is a 1:1 randomization, where patients are enrolled after typically failing two IV anesthetic agents, and are still having more than a 20% seizure burden. And seizure burden is defined as the minutes in an hour that you're seizing. So these patients are seizing more than 12 minutes in an hour. And what we've seen thus far in the phase three is most patients have been doing this intermittently for 24 hours-36 hours. They've received multiple medications. Physicians now believe that the next line of therapy would be IV anesthesia, and that patients are then randomized to our drug or a placebo. This study is designed initially to have 124 patients with a 1:1 randomization. But we have spoken with the FDA and have agreed with them that we can perform an interim analysis after 82 patients, and much of that decision was driven by our confidence in a low placebo rate and our original thinking about a 30% delta versus placebo being quite conservative. And at an interim look, we have a 90% power... actually, a 94% power to show a 40% delta. Of course, that is an interim look, and so after we hit that 82nd patient, we clean the data, we will send it to the DSMB, and they will inform us whether we should stop the trial, and that's what we'll report on in the second quarter. For that 94% power you noted, is that for both of the co-primaries together or for each individual one? We will look at each primary individually, as agreed upon with the FDA, and that 94% power is for each of the endpoints, respectively. Okay, got it. Have you said what your latest assumptions on the placebo arm are, whether that's where any of the blinded data is tracking, kind of some of the discontinuation rates and how we interpret all that? Sure. And there's never been a study like this, so we went into the placebo rates, like others who have, you know, create the first studies, somewhat blinded. But what we had received in terms of feedback from physicians was that after failing two agents, they were more than likely to use IV anesthesia in 75% of patients within the first 24 hours, and actually about 80% of patients within 36 hours. If you look at the literature, there's only one study, which is almost 20 years old, a VA study, which has about a 9% success rate as a third-line agent. Now, that's for resolving status, but not every patient will move to IV anesthesia, and that—I think that's where we had to be careful. So our initial assumption allowed up to, in our minds, a 40% placebo rate-... Looking for a 30% delta. But I think as this study has progressed, and we've seen the blinded data, and what we've seen in the blinded data is the average patient is actually failing close to three antiepileptics rather than two. The average patient is being monitored and consented for somewhere between 24 hours-36 hours. The average overall blinded death rate is about 30% thus far in the trial. And so everything that we're seeing in this blinded data set, as well as a protocol amendment, which specifically called out to physicians to enroll patients only if IV anesthesia was their next line of therapy, it's given us a lot of confidence that we believe the placebo rate will be certainly south of 20%, and very possibly south of 15%. Again, I think that's giving us a lot of confidence in stopping the study at an interim look, and feeling like 40% is really the minimum bar that we would expect to see in this study. Yeah. And sticking on some of the stats for the interim, let's say that it's not successful. I mean, how much alpha spend is there, and how much beta circle? The alpha spend is pretty small. It literally will cost us the effect of one patient being successful. The last alpha spend we talked about was about a.036 alpha spend, to, to, to hit that primary. But I think in reality, the way this study is designed, and the way the primary outcomes are measured, we could have as low as a 25%-26% delta, and still have a p-value. So our general view today is that if this study is not stopped at an interim, we'd very likely stop the study soon after, with our expectation that there was not a clinically relevant differential. Now, one or two investors have asked me: "Well, Scott, isn't a 30% delta still very meaningful?" And absolutely, I think it is, but I think in all probability, we would see that at the interim regardless. Got it. And, like, also gaming out scenarios in the future, too, what if only one of the primaries is positive? What do you do in that scenario? But it's very positive, maybe. Yeah, look, I think we'll look at the totality of the data. These patients are incredibly sick. They have very long hospitalization stays. If you look at the average data set, these patients, non-convulsive status patients, will spend 10-17 days in an ICU. So I think in our minds, avoiding anesthesia is the greatest way to show a value proposition in these patients. However, could there be a scenario where we stop status, but the same number of patients move to IV anesthesia, but they do better with ganaxolone, shorter ICU stay, lower mortality, lower incidence of super refractory status? It's possible, but I think from our standpoint, to make this a value-add drug, you need to stop status quickly, and that's critical to this discussion, and it has-- and the drug needs to have some durable effect. That durable effect is really helping avoid IV anesthesia and all its complications. So we'll look and see what all that data could look like. But I think, again, given our experience with this drug in phase two, and our experience in super refractory status patients, we know that we are hitting the right blood levels to see efficacy. And we have every reason to believe, going into the study, that the drug could be 80%-90% efficacious. So, right now, our focus is on all of those other critical endpoints, and today, we're not losing a lot of sleep about a 30% delta being the bogey. Yeah, I think that's well put. All right, so thinking through commercial considerations then, maybe just frame on ICUs and hospital stays, like, how much does one night saved or one day saved translate to in health economics? Yeah. I think ICU stays today are somewhere between $5,000 and $10,000 per day. Probably even more impressive is patients who suffer from super refractory status can spend months in an ICU, so you're literally talking about 30-180 days of ICUs. We've treated 25 patients who have suffered from super refractory status, where physicians have requested EINDs, and I would say their average length of stay, requesting our drug as the last line of defense before life may be terminated, has been on average two-three months. So I think we're incredibly focused on the ability of this drug to reduce that incidence of super refractory status. When you look at the use of IV anesthesia, that is independently associated with a 20%-40% higher rate of mortality, and comorbid conditions, so we'll look at nosocomial infections. So we think there's a very strong health economic story we can build, and for those of you who don't know me, my last operational role was at Pacira, and so I met with COOs and CFOs and CEOs of Pfizer and Intermountain Healthcare every day. And I thought long and hard about what we needed to include in this study to make those CFOs happy to put this drug on formulary, and I think we've been pretty thoughtful proactively about building in the HEOR story. And just to round that story out, what's kind of interesting about us doing an interim analysis is the-... that interim will focus on the primary endpoints, but it will allow us to continue to enroll patients blinded. When we publish our HEOR outcomes, it will not only include the interim patient analysis, but the additional patients that are enrolled over the last two months. So I would expect our HEOR publications to have closer to 90 to 100 patients, just incrementally larger and a larger story to tell. So, you know, when we went into the study, we did not expect to get any HEOR in the label. It just doesn't happen. I think we'll fight for one or two critical pieces when we see the data sets. We may get them, we may not. We certainly think we'll get the primary in the label, the key secondary in the label. That's why we chose them respectively. But much of the health economic data is really gonna be driven by our larger database, and the publication processes are starting now for us. Great. And for reimbursement, is this all going to be within the inpatient and the DRG system, or is there the opportunity to get some into the outpatient? This will be a hospital drug, so it'll be within the DRG system. There's two current codes for status, complicated and uncomplicated, roughly $45,000 for uncomplicated, $65,000 for complicated. But we certainly have the ability to apply for an NTAP, and an NTAP will provide, through CMS, 75% reimbursement of the drug effectively for the first two-three years of launch. So that NTAP program is really based on an unmet medical need, a clinical study that shows value add, and we have to file that data roughly middle of the year, for CMS. We'll think very carefully about the timing of our launch and the timing of NTAP reimbursement, and then what should happen over the course of the first three years of the drug launch, and let's just say we choose a $40,000 price tag. CMS will look at the drug price plus the cost of patient care, and then readjust the overall DRG three years later when the NTAP goes away. If you look at some really successful drugs in the hospital, like Bridion for Merck, the disappearance of the NTAP has had zero impact on the growth of the product. In fact, some of the growth has been bigger post-NTAP. So NTAP kind of gets the drug on formulary, allows a physician to use it, but I think good drugs in the hospital space can be incredibly successful without NTAP reimbursement. Great. To round out the discussion on RSE, just remind us why did you discontinue the phase two RESET trial? What was the rationale for that? Yeah, I think, you know, we, we as a team are learning a tremendous amount about status, and being the only company that's truly dedicated to the space today. I've been amazed that we are now getting one request a month for eINDs for super refractory status. We know there's a demand and a need there. We've now adjusted our dosing paradigm. We're seeing very meaningful clinical outcomes for many of these patients. I think our team felt committed that we need to make an investment in super refractory status. I promise investors we will not run a $100 million four-year trial in super refractory status, but we think we can align with the FDA on a proof of concept study and get them very comfortable with 20% higher doses of ganaxolone, and more importantly, Captisol, our solubility agent. I think we are now really understanding that treating earlier is gonna be critical to the drug success and patient outcomes, and we want to effectively double down on the timing of RAISE 2, and really start thinking about enrolling U.S. sites in 2024. And I think there will be centers that will request additional HEOR outcomes. So from my job as CEO is to do the best we can for patients and to really maximize shareholder value, and I think our entire commercial team and our medical team felt very strongly we needed bigger investments on the refractory side of the business. And I think we had questions about the value proposition, how hospitals would deal with the value proposition on the earlier side of status. And to be very frank, it was a very expensive trial, and I think to run a business in biotech today, you gotta make some tough decisions, and the decision was, let's put the resources where we think the real value add for patients will be. And quite honestly, our entire team was aligned with this decision, and I was pretty happy that I didn't have to make it, because everyone around the room recognized that that was the right investment. I think shareholders see that as well. Yeah, that makes sense. I'm gonna, just in the last couple of minutes here, jump over to your second-gen oral, actually. It's in a MAD study right now, I believe, and also considering development in LGS. So I guess, like, the main question is, what makes you confident ganaxolone is gonna work in LGS? Well, it's interesting. If you go back to the history of the molecule, the company had a failed phase two study several years ago, 10 patients. But one of the things we had to do when we had a positive Marigold study was to understand why the oral franchise had such a checkered history. And when you go back and you look at the 10 patients who were treated in what was called the nine hundred study, eight of them had blood levels less than 50 ng, and all eight of those patients failed. The two patients that had higher blood levels had, had positive responses.... In the CDKL5 study, in the Marigold study, the average patient with TID dosing achieved a blood level of about 100 ng, and had about a 30% reduction in seizures. In patients who had blood levels closer to 150 ng, we saw seizure reductions close to 50%, 50. 50. Unfortunately, with the current formulation of Ztalmy, we can't get all patients to 150 ng blood levels. So that is the concept behind our second gen program. Better bioavailability, lower Cmax, higher trough levels. It's not rocket science work, and our expectation is we should see improved seizure reductions across the board. We did treat a handful of LGS patients in the CDKL5 study. They did have real responses in that small subgroup. So I think this is all about blood levels. It's what we learned with the IV program, it's what we believe for the oral program. I think we believe we have a very broad-based anticonvulsant, and I think we're gonna prove that in the TRUST-TSC trial, and I think after that, folks will feel very confident about us moving forward in LGS. Great. Maybe just to wrap us up here, you can just lay out the cash runway and all the milestones that are coming throughout 2024, and actually the rest of this year. Great. Well, Steve's in the audience, and he's done an amazing job managing. And I think everyone organizationally has really tightened their belts to get us to the finish line. We are gonna very comfortably finish 2023 with more cash than we expected. We ended Q3 with $175 million. Our average burn has been somewhere between $25 million-$30 million a quarter. Ztalmy sales are growing. And so we expect to have more than ample cash for our two clinical readouts in 2024. We have some other, I would say, tricks up our sleeve that we're working on, but I think it's... You know, we've used every tool available to us to minimize dilution for our shareholders. I think we'll be cognizant of that, moving forward. We certainly don't plan on doing any large equity raise until we have data. We'd love to have some new shareholders as we have successful data. And we have already proven our prowess in building a commercial business. So we are well positioned going into our data sets in terms of cash. We're gonna spend probably $10 million-$15 million less than we had originally anticipated, cutting out programs like RESET, and that's certainly gonna help us get to where we need to go. So we could not be in the tough environment that we're in. We feel really good about where we are, getting to data, and flipping our data cards with north of $100 million in cash, certainly for the RAISE study. Yeah. Sounds great. Well, exciting year ahead. Thank you. Thanks so much for joining us. Thanks for having us.