Okay. Hey, Nancy. All right, welcome back, everybody, to our next session. It's Marc Goodman, one of the biotech analysts at Leerink, and we are lucky to have Marinus Pharmaceuticals here. I think everyone knows Scott Braunstein, who is the CEO of the company. Thank you for joining us, so. Thanks for having us, Marc. What, what say you these days? We are locked and loaded. I mean, I have all sorts of questions, but maybe I'll just give you a chance to, you know, make an opening comment on that. I guess I don't wish any first-time CEO taking over a company that has less than six months of cash and goes into a pandemic. But I guess if it was easy, anyone would do it. Makes you stronger. What, what doesn't kill us, but it's a big year for us. I mean, there are not too many companies that have two pivotal phase III readouts and expect to file two NDAs or sNDAs in, in really in less than a three-month window, and bring, bring hopefully what will be some really important therapies for patients. So, an exciting year ahead. Yeah. Exciting year ahead. Definitely. So let's start with RAISE. It's coming soon. I mean, it seems like the study's done, right? I mean, we're just. We've hit our interim analysis enrollment number, and we have been cleaning the 83 patients for over a month. It is interesting when you have to send a study to a DSMB, really, to tell us to halt the study. It has to be clean as a whistle because there's no one in the company who's going to be looking at that data. The tables that we send to the DSMB have to be delivered at least a week ahead of time. It has to work into their lives' schedule. The chair of our DSMB is on service the end of April, which made life a little bit more complex. But we have to do everything we can to make sure that what we deliver to them is 100% accurate. So it takes a little bit more time than I think some other studies might take to clean. But I think our team's done an amazing job thinking about what could go wrong, instituting some programs to allow us to check the data sets from primary endpoints to really the robustness of the full data set. And I think we are there, and we're very close. We've got two dates on the calendar for the DSMB, and what we've told folks is that the latter date won't be any later than the beginning of May, which kind of tells you the first date's likely to be in April. Yeah. So, we're hopeful to have data over the coming weeks. The team's preparing accordingly, and we couldn't be more excited about it. Let's just talk about the different scenarios when they come back, right? Sure. Scenario one is the DSMB says, boom, you've hit. You're good. Our DSMB scheduled dates are on Fridays, so we'll get a thumbs up or a thumbs down from the DSMB Friday afternoon. We've already made a commitment that we're going to work the weekend and let our sites know Monday morning to stop the trial and let the investor community know that we've stopped the trial by Monday morning. Mm-hmm. If the DSMB comes back and says, we think you should continue the study, we know from a statistical standpoint that the drug would have a less than a 25% benefit for patients. And we're not really convinced at that point in time that it's worth completing the study, and that it's less likely than not that we wouldn't have a path to FDA approval. So we've decided as a leadership team that if the DSMB recommends that we continue the study, by that time we would have approximately 100 patients enrolled, and we would stop new enrollment at that time, look to clean the entire database, give a topline readout by the summer. But our expectation is that we would fall short of filing for approval. I think importantly, we'd really want to understand and see that data set so that we would have the ability to adjust the trial that we've just started. That's why it's getting ready. A new trial and make sure that if we believe there's a path forward, we can institute whatever change is necessary, to really ensure that RAISE II would work or have a higher probability of working. My personal view, if the study fails, it's much more likely that this is a patient population that's just too sick to respond to a therapy. The average patient in our phase III has been treated actively for status for 24 hours. They've failed three to four drugs, and it may just be that these patients are too sick to respond. That being said, we think the drug has proven itself to have great efficacy where no drug has worked before. So we think that probability is low. I think if, in fact, the trial did fail, that would be my number one reason for failure, that these patients were just too sick. Just remind people, like, some of the things that you've done to ensure that you've got the right patients and, you know, just. Yeah. Well, I think most importantly, we have two amazing clinicians who screen every patient who's enrolled in the trial. They've played an active role in really educating our sites. Every site. One of the two physicians was our lead investigator from the Brigham, Henrikas Vaitkevicius. Every site that is participating in this study is a quaternary care center. They have 24-hour EEG monitoring. They can participate in a trial that requires 24/7 care, particularly over the first two days of therapy. But I think the team has really taken painstaking efforts to try to simplify a very complex disease. But probably the most important protocol amendment we made early in the study was really requiring that physicians be willing, on enrollment, to move to IV anesthesia almost immediately. The risk you run in a trial like this is that these patients are incredibly sick, but physicians know if they move from an antiepileptic that's failing to an IV anesthetic to treat a patient's status, they're raising the risk that that patient will never come off mechanical ventilation and anesthesia. They're contributing to effectively ending that sentence to for many of these patients. There is a mental game here that physicians see an abnormal EEG. They see a very sick patient, but they are unwilling to commit to IV anesthesia. By putting that in the protocol, it's clearly driven a 12-hour observation period that was only six hours in phase II. It's driven about a third of our patients getting three antiepileptics on top of a benzo, where in phase II it was two antiepileptics. And that type of trial design and our physicians handholding physicians through every one of these cases, I think we're seeing the level of severity really quite meaningfully different than we saw in the phase II. So we feel very good that we are studying the right patients who are not responding to standard of care and have a high probability of poor outcomes. When we started this study, the numbers would have suggested we would have seen three to four super refractory status patients, roughly a 4%-5% incidence of super refractory status. And right now what we've revealed publicly that about 20% of patients as an outcome are being diagnosed as super refractory status, and about half of those, about 10 patients, are having prolonged episodes of super refractory status. That, in my mind, is many more patients than we ever could have expected in a trial this size. And I'm eager that we now have a chance to show a numeric and possibly a p-value, in terms of the outcome of super refractory status. And to give people a little bit of flavor of what that means, we've treated almost 30 patients via our EIND route, who suffer from super refractory status. Those patients are failing six to seven attempts on weaning, and on average they've spent 30 days in a neurocritical care unit still seizing, any time their anesthesia is turned down. And most of those patients do not go home. And by getting our drug via EIND, about 2/3 of those patients have gone home. So that's, that's what we're trying to do. I mean, that should give you a little confidence that something's working. It gives me a little bit of confidence that we have the right drug, the right dosing paradigm, and we're really treating a disease state that, that has really poor outcomes. And that's, that's why this is such a critically important trial, but a complex one. Yeah. Because the physician knows the moment they move to IV anesthesia, the patients are unlikely to do well. These are more severe patients than you predicted at the beginning, I suppose. You're saying that's, that's good. I think. But at the same time you're saying. That is the risk. The more severe patients might just be too severe to treat. I think that's always the risk. So that's what you're saying, like the fine line that we're trying to kind of squeeze into. Exactly. Exactly. And I think if we didn't have the confidence on the efficacy side for the drug. Yeah. I'd be more nervous. I'd be losing more sleep. But that being said, I mean, we're still going to look at this data set and recognize that every patient in this trial, whether or not they get our drug, are seizing for almost 24 hours before they are enrolled, which tells me medical care is terrible. And that is not what our physicians told us. Our physicians told us that they advance care every two to three hours with these patients, and that's just not true. Mm-hmm. Right. So, so we now have the ability in our second trial, the RAISE-2 trial, to intervene much earlier and really change the paradigm of treatment in this disease state. And I think we're thinking about hiring a psychiatrist and a psychologist to help us with a publication strategy that looks at the behavior around status treatment. But I think in fairness to physicians, their options in terms of treatment are really not very impressive. And protocols are different at every hospital. I mean, we talked to one hospital that's completely different than another. I mean, you know, I shouldn't say completely different, but. Well, it reminds me early in my investment career when I was looking at multiple myeloma and every transplant center did something else. And I swore I could never make an investment in the myeloma space. But, you know, you get a great drug like Revlimid or Velcade and. Yeah. Practice patterns can change pretty quickly. That's our hope in this disease state. Talk about the discussions you've had with the payers and the hospitals, such that if you do get a positive study, you know, how quickly you think that they, you know, will agree. Uh-huh. This is an important study. Let's add it to the formula. You know what I mean? Well, there is a recipe or a playbook in the hospital space. 80% of the business is going to be driven by 1,000 hospitals, the top 20% of hospitals. And that will be our focus. And, and, and out of those 1,000 hospitals, about a third are going to have relatively simple and straightforward formulary access. About a third will take six to 12 months. And the other third, like the Kaisers of the world, undoubtedly will need a 12-18-month window. So our goal today as a team is we're, we're building that list of hospitals. We have that list created internally, and we're thinking about how do we accelerate, particularly that middle tier to early adopters. Mm-hmm. I think what has worked incredibly well for us as an organization. We have hired four PharmD MSLs who have helped us with our phase III trial, have brought some amazing KOLs into the study, and have introduced me to more pharmacists than I've ever met in my life, while in the middle of our phase III. So we'll have a two-pronged strategy from the time of data. We will hire a PharmD MSL team to start, really educating the pharmacist and to understand exactly how the formulary process works in a hospital. The other part of the strategy will bring in what are FDAMA 114 reps. And those are commercial individuals who can actually educate the C-suite on the disease state, and the process, and the economic value. We'll bring on about a dozen of those people from the time that the data is positive, and they'll have a year to really help us plan for our launch. It's a critical part of doing this the right way. Right now, you know, we have 60 of the best sites in the U.S. that are participating in the trial. I feel strongly that every one of our neurocritical care intensivists or epileptologists will be our biggest champions at places like the Brigham, Mass General, WashU, Tampa, University of Miami. Florida has been an outstanding state for the trial. We've got some great sites across the country, so we expect those folks to be champions for the drug. We're purposely going to extend open label treatment until the time of approval. Not every company does that because they're fearful of their NDAs. We think this drug will have a great impact for patients, and we want to have a robust experience going into launch and a robust safety package to share with the agency. So we're very confident about not hurting our chances of approval by having the drug in the community. We're planning on starting two additional studies in the U.S. We'll expand our RAISE trial to include U.S. sites. What Joe talked about on the call is we'll start a third status study, which will be a single arm open label study that will look at the use of IV ganaxolone as monotherapy in the second line versus standard of care, whether that be Keppra or levetiracetam as a second line agent. We'll offer ganaxolone as a rescue after 24 hours. And for the first time, we're going to actually transition patients from IV ganaxolone to Ztalmy as part of a bridging strategy. We've done that with these super refractory patients. Every patient that has gone home from the hospital with super refractory status has gone home with a three-month tail of Ztalmy. And it's been a huge win for, I think physicians to be able to transition from an IV to an oral. Yeah. Neurologists love it. Yeah. They love it. All doctors love it. We want, and we think, on the margin it can only improve the efficacy of the drug. So, you know, I think, you and I have seen a lot of billion-dollar drugs in our career. You, you can't build a brand without the right research investment, the right real-world studies. And we have every intention of doing that with this drug. Secondary endpoints here, are they important at all? Like, how important to the payers? Because obviously, you know. The critical part for the hospital space is building the health economic models. Yeah. And so we're in the process of building the model now. The inputs for the model are going to be multifactorial. There is plenty of health economic data out there that avoiding general anesthesia will be a huge cost savings for a hospital. Days of mechanical ventilation will be a huge cost savings for the hospital. Certainly we're going to be looking at ICU days. We're going to be looking at the patient, the percent of patients who respond, get out of the ICU quickly. We'll be looking at the instance of super refractory status. We'll be looking at nosocomial infections. If you look at the literature now, about 50% of patients who get IV anesthesia require pressors. A significant percentage have nosocomial infections, whether respiratory, GI or other. So we have a, for lack of a better, a plethora of secondary endpoints that we'll be looking at helping us build this HEOR model. But we're quite confident that this was part of our thinking 3+ years ago when we designed the study. We're looking at the right patient population and we're eager to build those into our pricing assumptions. And I would say, you know, we have no idea where all that data will fall, but I think that every data point that falls in the drug's favor, the numbers that are in your model and street models, I think are extremely conservative. That's a good segue. What. Yeah. Maybe you can comment. Look, most of the streets in the $30,000 range plus or minus. That's it. You know, we think about there's two, there's two ICD-10 codes, there's two DRGs for status, uncomplicated and complicated. And they fall in the $45,000-$65,000 range. And so we generally softly guided folks a few years ago to about a 30% discount to that DRG. I think we're really thinking very differently today. What's the value proposition that we can bring? And that will be driven by the primary efficacy, these HEOR endpoints, the instance of super refractory status. And so, you know, my, my expectation for our team as we think about pricing is, you know, what's the value that we're bringing? What's the cost savings that we can bring to a hospital? And I think every, you know, every data point that falls in our direction gives us the opportunity to think as much as 2x pricing where the street is today. We want to design a study in super refractory patients. And those patients, as we've talked about in these EINDs, are in the hospital for 30 days or more. So thinking about pricing that is 3x-4x in the super refractory setting based on 20% more drug, about three times longer dosing paradigm, I think is still going to be a great, great cost savings for the hospital. So we think we've got quite a bit of pricing flexibility based on where the data comes out. Yeah. You know, we're excited that we built all these endpoints into the study so we can really make the strongest case for pricing for the drug. Yeah. Good. Good, good. I want to make sure we have some time to spend on the base business, so to speak, the product that's on the market right now. Talk about Ztalmy just a little bit in its base indication and, you know, what we're seeing this year and how much more room there is to grow. You know, well, it's interesting. I think we always believed that this would be a very steady launch. And I think it has been. These kids are incredibly sick, and moms and dads are amazing. Most kids with CDKL5 will have 10 or 12 doctors and will be on 15 different medicines. And even though they may be seizing 30-40 times a month, mom and dads know what to expect. And so as a result, any new therapy comes with a barrier to a lifestyle change. And so what we've seen is very steady adoption of the drug. We have now, you know, captured about 10% or so of the CDKL5 market in the first 18 months of launch. We've continued to see new prescribers. We continue to see centers of excellence grow the business. We ultimately believe that we can treat 600-700 patients, creating, you know, slightly over $100 million-$150 million opportunity in CDKL5. We've seen now about 10% of patients receiving the drug off-label. It's primarily developmental encephalopathies, highly refractory patients. Interestingly, the payers are paying for the drug in the majority of cases. They're recognizing the unmet need. And at least from the data that we see, which is really only through our third-party vendor, that folks who are even suffering from developmental encephalopathies are staying on the drug about 80% of the time, which is pretty encouraging. Yeah, that's good. But I think, you know, we are firm believers. This This has been a great first indication. It's allowed us to, you know, jog before we run. We've done it with a small team. We'll make this business profitable about a quarter or two quicker than we originally guided towards. We're absolutely convinced that we can launch successfully into our second indication, TSC, in a little bit more than a year, and make this a profitable business almost immediately and bring this drug to another 5,000-10,000 patients, relatively quickly. You know, when we first showed up at AES a few years ago, no one knew who Marinus was. No one knew what Ztalmy was. Now people are waiting for the next indication. They're waiting for the IV data set. But again, I think when you have a chronic epilepsy drug, the more clinical studies you do and the more p-values you show physicians, the greater confidence they will have. And our strategy was to add a focal epilepsy indication to a generalized motor epilepsy indication and really giving physicians confidence that you can treat a broad number of patients with this drug. Scientifically, there's no reason that should not be the case. And as we've talked about, we're, you know, we want to commit to a proof of concept study in LGS patients and a basket-like study for other anoxic patients, other genetic disorders in epilepsy. And so we're really looking forward to the future of the oral franchise as well. Your thoughts on enrollment on the TSC right now? Yeah, we're in the home stretch. We have about 15 patients to enroll. A little less than half of those are already in screening. We have another 10-15 patients that are set up for screening over the next four weeks. So we will finish, and in a TSC study, in any epilepsy study, a physician has a patient that he or she identifies for having more than eight seizures a month. They're brought in for a visit and they go through a one-month screening where they document in a seizure diary that they're having more than eight seizures a month. So we've lost about 10% of patients who are not achieving eight seizures a month. We think that's going to dramatically, in a positive way, lower the risk of placebo effect or drug effect. And we've stuck to that. There are lots of folks who do epilepsy studies and they lower that threshold to four seizures a month. My CMO, Joe, who's an epileptologist, is deathly afraid about regression to the mean and having an impact. We've stuck to that eight seizures a month. But the patients, we've, we've got more than enough patients at sites that are just coming in for a visit. We'll have the study fully enrolled in the May timeframe. It's a 16-week study. So we're really targeting data in the month of October. We want that data for AES in December. We will. We have already started the planning for the SNDA, and you should expect that we will file that SNDA within three to four months of the data set, which will put almost two NDA filings on top of one another in Q1 of 2025. But my regulatory team is ready. They're excited. There are two distinct teams working on that filing. We could not be happier about the TSC study. We are looking at a disease state that hasn't had a drug approved in five years, Epidiolex, where the average patient in our phase III has failed four anti-epilepsy therapies. They're averaging 45 seizures a month. About 1/4 of the kids and young adults in the study have either had brain surgery to remove a tuber or they have a neurostimulator control their seizures, and they're still refractory. It's pretty amazing that there are that many patients out there. Ironically, only 25% of the study's patients are going to come in on Epidiolex. It's a big number, but it's not a huge number, whereas about 60% will come in on an mTOR inhibitor, which has really shown to be a disease modifier. And I'll remind folks in our phase II, our strongest responder data was on top of mTOR inhibitors. This will be the first study ever done in a TSC population on top of mTOR inhibitors. For those of you who remember the GW story, they did not study. They excluded patients who were in mTOR inhibitors because there is an idiosyncratic reaction that raises mTOR levels in these patients. And, and I think it's really affected the use of Epidiolex in the TSC community. Yeah. So we are the first company to run a modern study in a disease state that clearly still has highly refractory patients. We think that that baseline characteristics will drive equally powerful pricing. We believe this is a business we can successfully launch ourselves, drive strong operating margins, and will be a cash flow for the rest of our business by as early as 2026, if not in late. What do you mean by pricing, though? Because. Well, you know, one might argue when you go from a 2,000 patient population to roughly a 10,000, there are 50,000 TSC patients, but we think about 10,000 that are highly refractory. One would argue you have to give the payers discounts to have access. But we believe that the data will be robust enough to justify the same pricing without a significant discount. So we really believe that's a critical part of the. 100-ish K or whatever the number is for Ztalmy. Today, the maximum price is $300,000. We're averaging about $150,000. $150,000 to net. Remember, two-thirds of patients in the epilepsy world have Medicaid as a. And so there's a natural 23% discount. And in fact, pricing may be incrementally robust because in TSC right now, we're averaging about 15% more drug in the phase III than our average CDKL5 patients. So in fact, more likely than not, pricing on an absolute basis will be incrementally higher in the TSC population. You're saying the $150 is the average selling price after gross to net. Correct. Yeah, correct. That's really higher than where we thought it long. Well, you know, it's interesting. We really thought that, when we launched in CDKL5, the majority of new patients would be four-five-year-olds. Right. But what I think we've seen is we, like every disease state, there are doctors who genetically test and think about moving to the appropriate therapy for the appropriate patient. And I think that's independent of age, more so than age. So we're seeing an equal number of eight-12-year-olds being started on the drug than three or four-year-olds. I see. So it's. Ironically. Yeah. So it's really lifting that quite a bit. Correct. We have a couple of minutes left. Maybe you want to just comment on the next generation products you're working on just for completeness. Yeah. So when I took over the company five years ago, you know, I was watching what Sage was doing and had a good sense about ganaxolone and really believed that we have a drug that the scientific thinking around ganaxolone is that it is pan-synaptic and pan-extra-synaptic. And when you look at the creation of the GABA receptor, it's a constant cycling and there's a lot of risk that if you target a certain, a subset of receptor, that could lead to lower efficacy. So I wanted us to stay with ganaxolone. And so we started a pro-drug program several years ago, to really identify a compound that could dramatically improve the bioavailability of our oral franchise. We have that compound. The preclinical data has suggested a beautifully blunted Cmax and a 12-hour half-life that can lead to once-a-day dosing. We will have novel intellectual property. We believe that we will be entitled to an NME for the compound, not an NCE, because the moiety is one that's been defined by the FDA as an NME. We think we can create that compound at a significantly lower cost of goods. And so everything about this program smells good from a business standpoint, but from a scientific standpoint, what we saw in Marigold was that when patients can achieve a blood level of 150 ng, they have about a 50% improvement in seizures, and only about 1/3 of patients achieve that blood level today with ganaxolone. So my real hope and vision for the pro-drug is that we can get as many patients as necessary to incrementally higher blood levels, drive higher efficacy, and certainly once-a-day dosing would be a very nice plus, and have a significantly important drug for refractory epilepsies. Of course, we're going to target LGS as our key indication. Right, right. So it's been three years in the making. We'll get. We already know that when you split this pro-drug into its moiety and ganaxolone, the moiety looks extremely safe, but we'll run those pre-IND studies over the summer, confirm that. My hope is that we'll be in a phase I study early next year. My hope and expectation. We did have to put the program on hold a little bit when we had our delays. We had to make some tough decisions about what we could fund and what we couldn't fund. But we've now decided to, you know, reinvest in that program pretty aggressively and excited that that could be the future of the franchise. All right. Thank you. Thanks for joining us. Pleasure, Marc. Thank you. April it is.