I guess we'll get started. We're a minute into this, so I'm going to have to hurry up. Charles Duncan, I'm a senior analyst at biotech, and it's a pleasure to introduce the next presenting company, that is Marinus Pharmaceuticals. I have said that I think that Marinus is one of the deepest value names that I cover, and it is the case. It's both from market cap standpoint, but also untapped potential, and so it's exciting for me to introduce the management team, Dr. Scott Braunstein, who is the company's CEO, and some of you know him well as an ex-investor in biotech, a successful one, and Mr. Steven Pfanstiel, the company's CFO. Scott, why don't we kick it off with a seemingly softball, but it has been a tough year. I wanna ask you a question about a positive from the last year for Marinus, and when you think about the last year, what are you most proud of having achieved there at Marinus? We're... You know, we've had Ztalmy on the market for now over two years. We have over 200 patients who are currently on therapy, and CDKL5 is just a really difficult disease. Parents are effectively giving 24-hour care to their kids. Kids have significant neurocognitive deficits. Many are wheelchair-bound. Many have feeding tubes. And our drug now, two years into the market, is showing incredible durability. We have over 70% of patients who start the drug still taking it, and we do a company call every week, every other week, and we share experiences of our patients. And it is incredibly gratifying to hear about success stories of the drug, where families and patients' lives have been dramatically changed by just having that improved quality of life. So this has clearly been a year of introspection for me, seeing our company's market cap change quite dramatically, but certainly that's something I'm incredibly proud of. I'm incredibly proud that we've had the wherewithal to now complete what really comes out to be about a $40 million trial in kids and young adults with TSC, who are also entering the study failing four prior antiepileptics. Many have had surgery for their tumors, and they're seizing over 50 times a month. That's two seizures a day, and we've been able to create the opportunity for a new indication for all of those children and young adults, and I think we're on the precipice of doing that, so we're quite excited. You know, we're going to learn a lot more. You are conducting an analyst meeting tomorrow, and I suspect that there'll be some new, you know, incremental takeaways from that, and I'm gonna ask you about them today. So not to steal your thunder, but the one thing that has been said about change is that it happens, and so market caps go down, as you know, unfortunately, but they could also go up. So out of the TSC readout, which is coming up here soon, maybe a couple of weeks or so. Mm. W hat is the first thing that you'll look at as a CEO and an ex-investor to say, "Okay, yeah, we nailed it"? What's the first thing you're looking for? Well, you know, the nice thing about a seizure study is it's pretty straightforward. Yep. The FDA sets the rules, and they... It's one of those places that, from a statistical standpoint, you don't use mean, because the outliers can really change your data set, so it's all about median. Yeah. Out of the 65 patients in each arm, interestingly, what drives the primary endpoint is, how does patient 32 and 33 do? Mm-hmm. And how do they do with Ztalmy, and how do they do in placebo? And so it's as simple a calculation as one can have, and I think what we have heard over and over again in the three or four years that we've been doing market research and talking to clinicians, is clinicians want a drug that really one in four patients will have a robust and durable response. Mm-hmm. When you look at almost every anti-seizure therapy, the median seizure reduction is really a goalpost for whether a quarter or a third of patients do really well on the drug. Mm-hmm. I think really well, typically, in my mind, is greater than a 40% seizure reduction. We use the 50% seizure reduction as a nice secondary goalpost. Yeah. But time and time again, it's about, are there a good number of patients that are having a response, and is it durable? And, you know, we will be sharing some of our durability data. I think what makes this molecule, ganaxolone, so unique is its pan-extrasynaptic activity- Mm-hmm. ... appears to really counteract what's going on in the brain and the reestablishment of the GABA receptor, both synaptically and extrasynaptically, and that, in our minds, is linked to the durability of the drug. I was gonna ask you that. Basic pharmacology, what happens with this drug over time? Do patients see tachyphylaxis, or do they stay on the drug? Do you, do you see them continuing to benefit in the case of Ztalmy in CDD, but also as it may read on the TrustTSC result? You know, it's interesting, when you go to all the preclinical data from this compound, the animals become tolerant of side effects, so their somnolence goes away. The rodents stop knocking into the walls. They're not drunk sailors. But they never lose efficacy. They don't tachyphylaxis to efficacy. And certainly we think that it's been seen since our early phase II CDKL5 data. I think what we've seen in the real-world experience in CDKL5 is that robust. You know, I think when we all see data sets, phase III data sets, we wonder, "Is that going to translate into better or worse efficacy in the real world? Mm-hmm. And that was kind of our biggest challenge, or certainly what I lost most sleep about. And we've I think what we've seen in the real world is the drug has performed as good, if not incrementally better. And I think a lot of it has to do with education about the drug, taking it with food, a better manufacturing process, where we're seeing, I think, more reliable blood concentrations across patients. Our titration schedule that we're using in TSC, I think can actually improve outcomes on the margin in CDKL5 patients, too, and with a positive study, we'll look to change our label to this newer dosing titration across the board. But we see no signs that the drug loses efficacy over time, and in fact, we have a lot of case reports of the drug being given very early in life, having impact on neurocognitive outcomes. Oh, excellent. You know- Yeah. ... and there's some nice preclinical models out there showing that the drug truly does have neuroprotective effects. You know me, I'm pretty hardcore, so I kind of pooh-poohed a lot of that, but the case reports are growing in number, and I think our... You know, one of the things that I love about working with the TSC Alliance, they are a scientifically motivated group, and nothing would make me happier about doing an early intervention trial- Mm-hmm. ... with the TSC Alliance, and not only affecting seizure outcomes, but really looking to affect hand outcomes, developmental outcomes, and certainly, we'll have a great case report at AES this year that would certainly suggest that's a possibility. Yeah, interesting. So before we dive deep into TrustTSC in the future for potential TAM expansion for Ztalmy, let's talk a little bit more about the commercial setting for Ztalmy and CDD. You're getting traction because of new patients. Are you getting traction in terms of new patients because there's a lack of other alternatives, or because patients and caregivers really feel like they are doing better, not only in terms of seizure reduction, but perhaps, other quality-of-life factors? Yeah. You know, CDD's a tough disease- Yeah. ... and we knew going into this launch. The typical parent is taking their child to about a dozen physicians a year, and the typical patient is on more than 10 drugs, and so epilepsy is really only one of many significant problems that these kids have and their parents have to deal with. So we always expected the launch to be a bit of a slow and steady launch- Mm-hmm. ... given those issues, and I think that's played very true. I think we expected that our centers of excellence would be incrementally more involved in the day-to-day care, and I think in CDD, the centers of excellence are seen as referral centers and really seeing the patients- Okay. ... less commonly. So I think our success to date has really been able to work with the CDKL5 community. I think the patient experiences have been very positive. I think patients are, and family members in particular, are prioritizing seizure disorders on their list. But certainly, I think it's one. It's a very difficult area, and we're certainly proud of our results to date. But I would contrast that with the TSC community, which we'll talk a lot about tomorrow, where seizures are far and away the vast issue with TSC patients. Okay. Some patients in their 30s and 40s suffer from lung disease, kidney disease. Yeah. ... women have particular issues around pregnancy, but in general, seizures are front and center and really the biggest detriment to a patient's daily life. And so to be very frank, we're super excited about expanding into a market where it's all about seizure control. Yeah. I think it'll be a luxury for our sales organization to not only have a bigger market, but to really align with patients and physicians on the number one reason why families and patients come to see the physician, that is, looking for seizure control. Now, let's talk about TSC. I mean, obviously that's the big, new TAM expansion opportunity that hopefully will get green-lighted soon with some good data or at least the next step. But you alluded to... I mean, I asked you a question of what you'd like to see out of that study, but it seems like you've already seen something that you would have liked to see, and you alluded to a new titration paradigm. And so the past data required some interpretation. You got some seizure control- Mm-hmm. -which was notable, but you have a lot of patients not do so well because they were overly somnolent, if you will. So help us understand what you did in the subsequent study, the TRUST-TSC study, to improve the side effect profile of oral ganaxolone. You know, and, you know, I'm gonna go back a little bit to CDKL5, because when I took over the role as CEO, we were in the middle of the Marigold trial, which was our registrational trial for CDKL5. And the history of the drug, from its failed phase III focal epilepsy study, was poor tolerability and high discontinuation rates. Yeah. And so one of the first things I did when I took over, Alex and I did a little road show with all our CDKL5 investigators, and we said... We asked them, "How's, how- you're in a double-blind study, but how's the tolerability?" And all those investigators said, "We're really not seeing an issue." And ultimately, when we unblinded Marigold, we had a low rate of discontinuation. We had a low rate of somnolence, and I think we were lulled into a false sense of security about the drug, for lack of a better. Most CDKL5 kids cannot communicate easily with their parents. They tend to be non-vocal. CDKL5 kids have hyperactivity. Mm-hmm A nd we actually saw some behavioral improvements, as reported by children's parents in that study, and I think we were lulled into the way we were dosing the drug was the right fit for everyone, and so we went into the phase II study thinking, you know, guns blazing. Yeah. We did an interim, and we had some great responses, and I think partly because we had good investigators who knew our drug. Part of it may have been luck in terms of tolerability. But as we concluded the study, we not only saw an efficacy signal that surprised us, but we saw a tolerability issue that jumped off the sheets on us- Yeah. ... with 70% of patients requiring changes in their medication, 26% of patients discontinuing from the phase II study. I mean, dramatically different than what we had seen- Mm-hmm. ... in CDD, and in fact, one site, a well-known site in Northern California, refused to participate in the phase III because the tolerability was so bad in the phase II. Ah. Unfortunately, none of that came to light to us until this, the phase II was completed. We unblind our phase II. We see it, this very different signal in terms of tolerability. Yeah. We recognized that this was not, this was not right. Around that time, we happened to get our population PK data that was required for our FDA filing in CDKL5, which suggested that the average patient was actually hitting maximal blood levels at 50% of the dose. Our titration schedule, although algebraically a quarter, a quarter, a quarter, a quarter over four weeks, we were actually giving 50% of the dose by day eight. Uh-huh. We thought we were titrating patients over a month, but in reality, we were titrating them aggressively in eight days. That led to this drastic rethinking and really creating a titration schedule that would match serum concentrations over four weeks, rather than matching an algebraic number. Sure. And we really believe that with an appropriate titration, we would see good tolerability to side effects and a strong efficacy signal. And we had originally planned on doing an interim analysis, that if we really had tolerability issues, we would discontinue the study and put those resources back into other programs. And what we saw almost from day one was we saw almost no tolerability issues, and we were so pleasantly surprised and saw very low discontinuation rates early in the trial. We decided to eliminate the need for an interim analysis because we really believed we had solved the critical piece of the puzzle. How can we get patients to the appropriate blood level without exhausting them and really creating hypersomnolence, and similar to a medicating patient, screwing up their lives and hurting them more than helping them? Yeah. And, um- Mm. ... and so that titration schedule has really been incredibly effective. We've, you know, we'll report the final discontinuation rates in the study, less than 7%. That's everyone. Yeah. That's 130 patients who are keeping... half the patients getting placebo, keeping diaries for 16 weeks, doing lots of follow-up visits. We could not be happier with that overall discontinuation rate, and we've said publicly we've only seen two patients discontinue the study due to tolerability issues. So even on a blinded basis, you know a lot about at least the titration schedule working. Is it something that you think will be translatable to CDD and TSC in the future and can be implemented by- I think- ... in the market. ... every patient we treat going forward- Okay. ... we are going to think about this titration schedule. When we file the TSC NDA- Yeah. ... we will ask the FDA to change- Yeah. ... the titration schedule for CDD, harmonize the label, a safer approach. I wish we had it in the label today, because I think on the margin, it would drive better tolerability and better efficacy in the CDD population. Maybe we would take those numbers from 70% to 80%- Okay. ... let's say, in terms of success rates in the- But they still are staying on the drug. The titration could be incremental upside in CDD. Absolutely. Absolutely. But with regard to TrustTSC, I assume you're still blinded to the data. You haven't seen it, you don't have the final data in-house. But you do know that more patients are in the trial than perhaps you would have anticipated, and you know something about what happens after the endpoint, right? What happens after the endpoint? So they go on, can continue on, correct? Correct. So, And have they been? We've been really pleasantly surprised. Look, this is a huge commitment for any family, any patient, right? A 16-week blinded study means that half the patients are gonna get placebo for 16 weeks, and remembering they're having two seizures a day on average. But they're hoping to get into that open-label period- Yeah. ... and get drug, and we're thrilled that well north of 90% of patients who have entered the study have not only rolled or stayed on drug, but have rolled over to the open label, and have stayed in the open label. So look, you know, placebo can be a powerful thing, but we certainly believe that the- Well, can it- ... the drug's efficacy. ... in TSC, can it? I mean, the whole point of seizures is it's hard to think, not having- We're taking a population that has really- You could change diet, I guess- ... failed every- or something. Right. Yeah. Look, I think, you know, the literature would suggest that placebo rates in the studies such as these will run somewhere between 5 and 15%. Uh-huh. When GW ran their study six or seven years ago the placebo rate was higher. I would say there was a ton of excitement about cannabidiol. I'd also say GW went to several countries in the Eastern Europe that historically have high placebo rates, and our SAB members strongly advise us- Yeah. ... to avoid countries where placebo rates could be falsely elevated. So we've been painstaking in not only site selection, but country selection, and Joe, our Chief Medical Officer, was dogmatic- Yeah. ... about sticking with eight seizures per month as a baseline. Okay. 'Cause you could imagine if we lowered that bar to four seizures a month- Yeah. ... natural variability, some placebo patients would go from four to three, and that could be a 25% placebo rate. It's... Yeah, that's a big hit. So Joe was dogmatic about us sticking at eight seizures per month as a baseline, and we think we've done everything in our power that, to drive a very low placebo rate- Yeah. ... in our phase III. So we're expecting the placebo rate to be about 10%. So early on, I think you mentioned something like 40-ish% would be a really neat number to see in terms of median seizure reduction. So, I assume that's not placebo-adjusted, but tell us about the statistical assumptions that you've made with regard to powering, and what you really need to be able to show. Yeah. No, we have a 90% power to show a 25% median difference. Difference. Okay. What's very nice about that is we'll hit statistical significance with a delta beyond the low 20% range. Yeah ... 21%-22%. Yeah. And those are typically the numbers where clinicians say to us, "This is a clinically meaningful outcome." So we purposely sized the study that with any P value, we would have a meaningfully important clinical outcome. We originally talked about powering the study to 160 patients, which would be 80 patients per arm, and we could have achieved. In that scenario, we could have achieved a P value in the mid-teens. Mm-hmm. But clinicians told us that wasn't really relevant. So to overpower a study just to hit a P value, we really think didn't make a whole lot of sense, and as you know, Charles, you make a study bigger, you're inevitably gonna get some patients who probably shouldn't be in the study. Yeah. Yeah. You know, we've looked at the blinded data. Quite honestly, I think 100 patients was more than enough to understand the drug effect, but again, you know, we went to 130 to feel very good about seeing what is real drug effect, what's real placebo effect, and to see that difference really shine through. I think equally important, the nice thing about 130 patients is we'll have more than half of those patients who are mTOR inhibitors. I was gonna ask you what standard care- Yeah, and that's critical. I mean, these patients should... Most TSC patients are on mTOR inhibitors, either for lesions in their brain, lesions in their kidney, lesions in their lung, and those drugs have shown a proven benefit in controlling the symptoms of TSC and the tumors associated with TSC. I mean, they are true anti-inflammatories, and if you are a patient, you need a drug that you can take with an mTOR inhibitor, and Epidiolex is not that drug. Even though it is the last drug that was approved, patients will have, for reasons that are not clear, there's no clean drug-drug interaction, but there are multiple case reports where mTOR levels go up tenfold as a result of use with Epidiolex. You dump a ton of that stuff into a liver. Yeah. And it take- Look, Epidiolex is a fascinating drug, and it has multiple effects on hepatic pathways. Mm-hmm. What we see in the real world is, in our phase III study with these patients taking a history of four prior drugs, only a quarter are coming in on Epidiolex, and they're coming in on half the dose. Oh, interesting. 16 mg on average. Yeah. So there is... And what our market research data suggests is they have about 8%-9% share in TSC, and I think the drug-drug interactions with mTOR inhibitors are far and away the biggest issue. Yeah. We feel we have a great opportunity. Yeah, and I mean, I think that's why, commercial, our team is very excited. We've studied on- I'm glad you brought this up- Yeah. ... 'cause that's where we're going. What are the implications for you? Right. So we're studying on top of standard of care. Yeah. You know, we hope to be able to show, you know, safe use with other medications. We're studying in adult and a pediatric population- Mm-hmm. ... so this can kind of be broadly used in those classes. Yeah. We've also been on the market for two-plus years- Sure. ... and continue to be on market, so HCPs will have experience with these patients, so- And to get to those docs, what do you need? Do you need to double the size of your sales force, triple it, or- Yeah, it- incremental? ... it's probably in that double category- Okay. ... 'cause there is a ton of overlap between CDD call points and TSC call points, and in fact, yeah, we know that these refractory TSC patients are fairly highly concentrated. There's 17 COEs and another 55 TSC centers. Mm-hmm. You know, we'll specifically target those, so 72 centers. There's plenty of other, you know, HCPs and targets we'll go after, but we know we can access the vast majority of these kind of 12,700 refractory TSC patients out there with a modest expansion of the sales force and sales activity. If you get data that you can interpret and press the Go button on, how quickly can you file a supplemental NDA? Is there any other data that you'd need to be able to enable that, and when, when can we see this all happen? Yeah, well, our NDA filing was 500,000 pages because we had to do a decade of cleanup work- Yeah. ... for every study that the compound had ever been used in, from the original textbooks that the drug was created, and the CMC piece of this was a huge project. And I will say not a single page was written before I was CEO, and which I thought was pretty fascinating, so it's a huge undertaking for our both CMC and our regulatory team. What were they doing before you? I'm not gonna answer that question. Maybe Alex should give that a try. We learned a lot, and we had a lot to do, but none of that is required. So our... You know, the CMC process, the drug substance, it is all approved, and so all the FDA wants to see is the phase III study and an update of our total safety database. Okay. ... which will include some of the IV data, what's happened in the real world in the pediatric study, any other study that we've done. So it's a relatively tight filing. The regulatory team and our head of regulatory, Kim McCormick, has worked in the CNS area for 25 years. She got Ztalmy approved in six months. We had a great pre-NDA meeting a year ago to, or at least the phase III meeting, pre-phase III meeting to discuss the clinical trial plan, and the FDA has been a great partner to us through this process, so we have every intention of taking the data set, finalizing the patient records, submitting the NDA by certainly no later than April, and we're hoping by March, with approval October 1. Our partner in Europe, Orion, who's about to launch in CDKL5, we own the registration, the filing in Europe, and it'll take about three more months to file, and it's not anything that we're doing, but the EMA requires three additional months of open label data. Why they want open label data, I don't have a clue, but they want it as part of the filing. Clinical value they're trying to establish. So we're out of time, unfortunately, but it sounds like a year from now we may be talking about TAM expansion for Ztalmy. You brought up IV. I won't go there right now, but more to learn at the analyst meeting tomorrow. Scott and Steve, thanks for spending time with us at the Cantor conference, and wishing you luck. Really look forward to a phase III result that is positive, and we can interpret, unlike what we saw earlier this year and this change in the stock. Thank you. Thanks to the audience.