Tech analyst here at RBC Capital Markets. Welcome back from our afternoon lunch panel. Our first presenting company of the afternoon is Marinus Pharmaceuticals, featuring their CEO, Scott Braunstein. Scott, thanks again for joining us. Thanks for having us, Brian. Appreciate it. So, Scott, it's been an eventful year at Marinus, and I know there's a lot that's going to be going on in the rest of the year. But maybe just kicking off with the recent update on RAISE. You recently reported that the Data Monitoring Committee recommended continuation of your Phase III study of IV ganaxolone in refractory status epilepticus following interim look. I know there was some hope that the study might be stopped early. What are the next steps now, and what are you going to be looking for in the final data that we get in early summer from the full 100 or so patients to make a decision on potential continued development of the program? Yeah. Thanks, Brian. Well, we really believe the study was very adequately powered for the DSMB to recommend stopping the trial early. And so the fact that they did not recommend that... Can you just lower the volume a little bit? I'm getting a little feedback. There's some feedback on the mic. Yeah. Yeah. Thanks. The fact that they did not stop the trial early really raised a question of how big a therapeutic effect we were seeing, at least on the primary endpoints. And therapeutic effect is probably the wrong word, but effect on the specific endpoint around the avoidance of IV anesthesia. And as a result of that, we really felt as though it was best to stop the study at 96 patients who will be double blinded, four additional patients who are dosed for safety, and evaluate those outcomes. And what we believe will be the case, looking at the totality of that data, is that the end will be less important than the outcomes that the patients actually have. So we aligned with the FDA 3+ years ago that we wanted to prove that our drug worked quickly, and we looked at a 30-minute endpoint, but also had some durable effect. And what we chose as our durable effect was what we believed to be was standard of care is when physicians would move to IV anesthesia. We still believe the drug is having a durable effect, but did not achieve the benefit of avoiding IV anesthesia in a statistically different manner than standard of care. All that being said, we are still firm believers, and I think the literature would, would support, that if we stop status epilepticus, that these patients are going to do better. So we've decided to stop the study at 96 patients, who will be double blind, 48 per arm. I think we believe there's a small chance, probably 10, maybe 20%, that we could hit statistical significance on both primary endpoints. But probably more important than that, in our minds, is: how are these patients doing? And so when we unblind the data, we've decided to clean the entire database. We will have primary outcomes, hospital outcomes, EEG outcomes, and all the health economic outcomes to compare how we are doing versus standard of care. And it's our belief that the drug is being dosed appropriately, that patients' status will be stopped, and quickly in most cases, and that will have a meaningful outcome for patients. And if we see that, we will report all that data publicly by the end of June, no later than the first week in July, and we will go to the FDA with that package and argue quite strongly that the drug should be approved on the clinical benefit that it brings to the table. The last thing I'll just comment on is, I think, you know, when we went to the FDA, we went with a really an endpoint that was in and of itself associated with better outcomes, that is the avoidance of IV anesthesia. But clearly, with these patients, you know, are they actually doing better? And I think we're going to fight hard if we see a signal that is meaningful, that the drug should be approved on that basis. Got it. And so do you have any hypotheses as to why the trial may not have shown strong enough benefits to stop at the interim analysis? I know there were some differences in dosing, patient population, and practices among the sites, maybe, and perhaps, you know, versus the Phase II, that could have contributed. And are there it sounds like there's also aspects here that, you know, the IV, the progression IV anesthesia endpoint, may aspects of potential benefits that that particular endpoint may not pick up on in this population. Can you speak a little bit more about that? What was sort of, I guess, the postmortem to the interim? Yeah, and, you know, we're still blinded to the data, but we have been open in discussing that we are seeing the blinded EEG data as we're putting together our hypotheses. And I think we're seeing some, some behaviors in the blinded EEG data that's surprising us. Hmm. Some patients who are having abnormal EEG activity for 36 hours, which was not supposed to happen. Some patients who appeared to have improvements in their EEGs and are still moving to IV anesthesia, which really should not have happened. Hmm. We're seeing some physician behaviors- Hmm. on a blinded basis that are not making a whole lot of sense to us. Hmm. I think you always have to worry in a study like this about site bias, where I would expect in our top 4 or 5 sites, our clinical data will be very consistent. But when you have 30 other sites that it's enrolling one patient, we do, we've clearly looked to be running the risk of how that site bias plays out, that one fellow who's on call at 2 A.M., him or her, that even though we did a tremendous amount of training for the physicians, they all had to take EEG tests. We had 300 live site visits with our MSLs. Every patient that was enrolled was screened by our clinicians, whether it was 2:00 A.M. or 10:00 A.M. So we had huge oversight to the study, but I think what we're seeing is behaviors that just don't make a lot of sense to us from what we've been talking about for the last three years in terms of the paradigm. Yeah. The one other comment I'll make, Brian, is that the Europeans treat status epilepticus very different than we do. Their view is that IV anesthesia is as big a risk factor for mortality as not treating. So they allow their patients to sit in the hospital seizing for 2-3 days, rather than using IV anesthesia. And what our hope is, is that whether you choose that path or IV anesthesia, neither of them are great solutions, and stopping status quickly, we believe, is going to lead to the best outcome. So we're still hopeful that that paradigm will play out in the totality of the data. And I think we're learning, the companies do, when they are the first to run a trial, that physicians' behaviors are not what they always say- Right ... it should be. Maybe shifting gears to the commercial franchise. Tell us more about the latest commercial metrics that you're seeing on the ground for Ztalmy, and its currently marketed indication, CDKL5 deficiency, and maybe the types of patients that are being put on. What surprised you the most in this two years since the launch, and where do you see things going from here? Yeah, you know, it's been a really interesting two years of launch. We're very fortunate. We've raised guidance several times since the beginning of the launch. Understanding that these patients are rare, there's roughly 100 newborns a year. We thought about 2,000 pediatric patients would be eligible for the drug. And even though there are centers of excellence, I think what we've learned, one of the things we've learned, the centers of excellence tend to behave more like a referral center and allow local neurologists to do most of the treatment. That's really led to a little different strategy, where we've been much more driven by data collection, ICD-10 codes, and following patient journeys to really find our patients for therapy. Now, the great news is that there's only been an ICD-10 code for about 3 years, and the codes have gone from about 200 to about 1,000 patients. And they're growing about 30% a year. There's not 30% more patients, but physicians are starting to code with more genetic testing for CDKL5. So I'd say there's a few things that have surprised us about the launch. Where we thought most patients would be pediatric around genetic testing, about a quarter of our patients are adults. Hmm. I think what we're learning is good doctors genetically test, and they treat accordingly. There are a lot of doctors who are still not genetically testing. However, it's clearly changing as more and more doctors are recognizing that they should be coding for CDKL5, and so they clearly have to be genetically testing. So we're seeing that pivot in the community, and we're able to chase those patients a lot more directly outside the centers of excellence. I think, you know, we've continued to see healthy growth in the marketplace. We believe that growth will continue. I think what we're learning about the CDKL5 market is going to be incredibly applicable to our second launch in TSC next year. And we have learned that safety really matters in this marketplace, and we've got a drug with that does not require cardiac monitoring, blood monitoring, and has no major drug interactions. That's pretty damn good in the seizure world, and it's a reason why the drug's done really quite nicely to date. And I think the other is the medical community wants to see the next study for this drug. We know this drug works in generalized seizures. They are eager to see this drug replicate its success in either the same or different indications. So for us, TSC will have a meaningful implication, not only for TSC patients, but hopefully- Hmm ... on how physicians view the drug more broadly in refractory epilepsy patients. So a potential halo effect more, more broadly, it sounds like. You know, yeah. Look, we'll never market outside of label, but- Yeah ... historically, anti-seizure drugs are, have about 20%-25% of their business that come in spontaneous use. Yeah. We're at about 10% today, a little bit higher than that, primarily for refractory DE patients and some kids who are below the age of two. But I think ultimately, if, if we are successful in TSC, as we expect to be, we will make the investment- Mm-hmm ... to study the drug in other refractory DEEs. But certainly, I think physicians are already thinking about how to treat their highly refractory patients. And the one thing, you know, that really intrigues me about this space is so many companies have focused their efforts on focal epilepsy. And those patients are important, but those patients are having one or two seizures a month, or a quarter, or a year. We're trying to treat patients who are having 50 seizures a month, and very few, if any, companies are really developing drugs for those patients. ... Maybe speaking of TSC, I know we're gonna see data in October from the phase III TSC study. In the prior data, you saw some signals of activity. You've done a lot in the phase III trial design to optimize the population and the dosing paradigm. Can you talk a little bit more about how those optimizations have gone, what you're seeing out of the, the, the conduct, the blinded data, baseline characteristics, and, and sort of how you're feeling on confidence-wise about a potential positive outcome based on all the implementations that you've done? Yeah. Well, I would start with the Marigold study, the CDKL5 study. That study was about a third enrolled when I took over as CEO. Given the history of ganaxolone and really the failed trials and the high rates of discontinuation, I asked all our investigators, "You know, we're a third into this, you're blinded, but are you seeing tolerability issues?" And we really had no major tolerability issues in the Marigold study. I think in fairness, you know, we are recognizing that kids with CDKL5 have significant neurocognitive deficits. Many are not communicative, many have hyperactivity, and so maybe not surprising that not only was the drug efficacious, but extremely well-tolerated and certainly minimal complaints of somnolence. Statistically significant, but certainly not that required dose adjustments. We start the phase II TSC study with a very similar dosing titration, and we, we took a look about halfway through the trial, and we saw a 48% response rate, and we said, "We've got this. We've got this nailed." We finished the study, and we saw that median seizure reduction drop dramatically from 48% to 17%. We said: What happened? And what we saw was about 26% of patients discontinued in our phase II. More than 50-60 required dosing adjustments. And just about the time we got that study, we completed a population PK data study that was required for the CDKL5 approval, an FDA requirement. And what that pop PK data told us was that patients were hitting maximal doses from a plasma concentration, in most cases, at day 8 of the titration schedule. So a 1-month titration that was tailored for tolerability was really practically delivering maximal blood doses at 8 days. So now we're left with a peak, a pop PK data set that says we're titrating improperly. We have a Phase II data set with a high discontinuation rate, lots of dosing adjustments, and really mixed efficacy, and we put those two pieces together. And before we did so, we went back and looked at the Marigold data, and we saw a similar phenomenon in Marigold. That is, highest of complaints of somnolence, day 8, when we were adjusting the dose, and a disconnect between efficacy and tolerability. So patients who had more somnolence reported in Marigold actually had lower efficacy, which is a bit counterintuitive for a GABA product. So we took all those pieces of the puzzle, put it together, and realized if we adjust our titration schedule to align over four weeks with plasma concentrations, we should have a drug that's much better tolerated and drive the same efficacy signal that we believe that we had in Marigold, and we believe this drug can deliver in, in chronic epilepsy. And since... And now we have a real-world test of that. We've enrolled over 120 patients in the study. We'll complete enrollment tomorrow. Tomorrow is our last day of screening. We'll finish with either 128, or 129, or 130 patients. We'll, we'll, we'll know, we'll know that by end of day tomorrow. And we've only had two patients thus far who have discontinued for tolerability issues. That's a far cry from what we saw in phase II. We've had over 85% of patients remain in the study and go into the open label, and we've seen very few patients discontinue since open label. So we have a lot of tools telling us that what we've done in terms of adjusting the titration and the tolerability is working, and we are very comfortable making the bet. If you titrate the product right, you get to adequate blood levels, the drug is going to deliver more than adequate efficacy. I guess on the efficacy front, what do you see as the bar for clinical meaningfulness for seizure reductions? Now, it's interesting. Our Marigold study showed a 27% delta versus placebo. GW showed a 23% delta. On an absolute basis, it was 25% versus placebo. Yet, you know, GW only has about 9% market share in TSC. Yeah. So the numbers don't always tell the story, but what clinicians tell us regularly is that we wanna see a percent of the population that has a meaningful and durable response, somewhere in the 40%-50% range. So we think anything north of a 20% delta, with the certainly, the study is powered for a 25% delta, puts us in a highly competitive position. We know from our Marigold open label study that this drug has a durable effect. Certainly, that's differentiated in CDKL5. We've got some nice durability from our phase II patients in TSC. And so we think we can have an extremely competitive profile in the TSC population, which, by the way, we've now looked at the claims data, and there are 12,000 U.S. patients today who have failed two prior therapies who suffer from TSC. That is... 5-6x the market population that we're going after. Yeah. Can you talk about that more? I'd love to hear more about what you guys have learned about the TSC opportunity and just, you know, compared to CDD, and then just how much leverage you could potentially get out of the sales infrastructure? How much expansion would you need, and investment would you need to launch this TSC? Well, it's interesting. So when I took over the company, five years ago, and I went to my first AES, you know, my chief scientific officer set up about 10 meetings for me with clinicians, and they said there's two big areas of unmet need: LGS and TSC. And so that was one of the big reasons that we started to look at TSC patients, and making a bet whether or not there would be a value proposition for ganaxolone. We saw some early scientific signals that led us down that road, but I think what we heard from clinicians five years ago has not changed. And if you look at TSC patients, they're treated all over the map. They get an mTOR inhibitor as a disease modifier, but those drugs are moderate at best for seizure control, and 90% of TSC patients have significant seizures. Many will get vigabatrin, which again, is a good but not great agent for seizure control, but lowers the incidence of infantile spasm. And beyond that, it is player's choice on what a physician will use to treat these patients. And our hope and goal is we are going to be the first company ever to have a global Phase III trial that uses mTOR inhibitors as baseline. GW didn't do that. You cannot give Epidiolex safely with Afinitor without checking Afinitor blood levels. You can have significant bumps in Afinitor levels that can put patients at risk for with neutropenia and greater, a greater infection. So this is a real-world study with the best standard of care across the board, and we're gonna fight very hard for that second- and third-line patient. I think with the safety profile and a strong efficacy signal, there's no reason we can't be the drug of choice for any refractory patient. Maybe just in the last two minutes, latest status of the prodrug, what you're seeing there, and the go-forward plan. Yeah, so you know, when I had the opportunity to first think about how we wanted to extend the franchise, we knew that Sage had done quite a bit on the chemical modification side of ganaxolone, and allopregnanolone, and we love ganaxolone. It's got a great efficacy signal, and it's got a very safe profile. So I didn't want to change ganaxolone, so we went down the road of creating a prodrug program that would really improve the half-life of ganaxolone. We have a lead candidate. That candidate looks to be once a day. Importantly, it looks to have a blunted Cmax, so tolerability will not be an issue or should not be a significant issue. And our goal is to really drive that prodrug program into the clinic next year. We're running all the preclinical work, the pre-IND work now. We know ganaxolone is safe. Chemically, the prodrug that is cleaved looks incredibly safe. So to a large degree, the work we're doing now, in our minds, is to check the box to bring that program into the clinic. And if we see those safety signals play out and we dose the drug in humans, and we replicate the PK that we see in mice, which has always been the case for ganaxolone, the mouse PK has really been a great harbinger of human PK, then I think we are gonna be off to the races with an LGS indication, with a once-a-day drug, and one that a physician can titrate and drive blood levels higher than they can today with ZTALMY. Scott, unfortunately, we're out of time, but always a pleasure. Thanks so much for the updates. Thank you, Brian. Look forward to all the data. Thanks. Thank you for the time. Thanks.