Good morning, everyone. Welcome to Google Announced's second annual Healthcare Innovation Conference. Our next presenting company is Praxis Precision Medicines. From the company, we have a few executives here. We have the Chief Executive Officer, Marcio Souza, here. We also have SVP Finance, Lauren, and Matt Krogo. Thank you so much, Marcio and Lauren, for joining us. I do have prepared a few questions that I'll run through, but. Yeah. A few, yeah. Too many. Marcio, why don't you, I mean, obviously, a lot is happening at the company. I think most people are just focused on, let's say, one or two assets. You have a much deeper pipeline. Why don't you give maybe like four or five minutes' update on what are some of the key things that we should be focusing on over the next, let's say, three to six months? Yeah. We'll go into each of the programs. Yeah. I love thanks again for inviting us once more to be here. I find it actually funny. It always starts there. Yeah. If that's OK, our calendar is like three to six months. That's like, tell me how many things are happening there. It has been a little bit of the story of the company. Take advantage of that to talk about something super important for us and maybe oftentimes get lost, right, is really to execute on the commitments we have, first and foremost, to our patients. Of course, not too far second to all of us here that can enable drugs being brought up to patients. ET is the golden goose in the room. Like, I think it used to be the elephant, but the chained animal is there. We're going to talk a little bit about that. I'm sure we do have a number of things happening, right, where like final preparations for the potential NDA to be filed in the next few months. That is incredibly exciting. Of course, now we have to consider what are the key commercial prep items that we need to get ready, some of them out of the door and so on. Quite importantly, procedurally and for investors, is the upcoming meeting with the FDA to discuss the NDA in general. For that ET, we are going to be discussing what is next for ulixacaltamide as well on a similar time frame, since you put it in three to six months. It's quite obvious, and it's been for a long time, that modulating these incredibly important channels in the brain, like CaV3.1, 3.2, and 3.3, can play a huge role in other conditions. We've discussed that privately many times. I think now is the time with such positive and overwhelming results from the E3 program, as we call internally the Essential 3 program, for all of you to take that leap and that step forward there as well. Obviously, it does not start on ET. When you're looking from a value perspective, like if you were all unrestricted, unbounded by internal compliance policies, you name it. Particularly on the banking side, with all due respect, I think that part of the sum of the parts would be probably multiples of what is for everyone. The reason being, the markets are not met at all right now. If we had 10 drugs for essential drugs, each one of them would be multi-billion dollar assets. I think eventually, I certainly hope that we're all going to get to that realization. Getting that understanding in the next three to six months for us is going to be quite important. Moving on to the rest of the company, there are clinical stage and preclinical stage drugs that are going to be moving, or candidates are going to be moving quite quickly here. Last week, we announced that we're moving full steam ahead with SCN2A with our EMBOLD program. We've tried with Rich a very good alignment with the agency on how to bring this faster to patients. That was as part of an interaction, type B interaction, but it's really a breakthrough designation-like meeting. It is classified as a type B that we had not that long ago. Subsequently of that, we had multiple interactions with the agency in relation to the same meeting in regard to an agreement of what generally a package for submission would be. Not only having that interim analysis happening in the next few weeks, since we only have a few weeks left in Q4, also having a potential NDA submitted there being positive early in the year. By, let's say, three months from now, give or take, it's likely there are going to be two new drug applications filed for Praxis. A question I get quite frequently is like, it's hard enough for companies to do one. How can you guys do like to have two submitted in such a short period of time? We haven't stopped. Once we had the entire year, multiple, many, many interactions with the FDA, we're very, I would say, happy with the fact that there is very good continuity on the neurology, on the Office of Neuroscience, and particularly on DN1, where Ulixacaltamide resides, and DN2, where most of the epilepsy drugs reside. We have good continuity there, which should allow us to go full of that. I can keep going on and on, but I'm going to stop there because. Yeah. That's already a lot. That's already a lot. Let's focus on let's start with essential tremors. I don't want to go into the data because you already presented a lot, a lot of sensitivity that you have highlighted. I think the key for us and for investors is to really understand the relevance of this FDA meeting that you're going to have. What exactly are you outlining to them or asking them to get an alignment on so that you can move forward and file? What exactly are the things? Pre-NDA/PLA meetings are intended to be very boring. OK. Because one, and I know it's everyone's minds on recent history that they turned to be not boring at all for some companies. They are meant to be quite procedural. I'm calling them then boring, meaning you got to a point that there is a lot of previous agreements, procedural or otherwise, that you get to the agents. You're really checking the boxes on a few items, right? This list can be very big and can or can be incredibly short. I think we are on the short side of that spectrum, particularly because we took advantage of the last year or so to ask a number of questions for you through the agency. The key question on the table really for all of us is whether or not the current package, which is constituted by three major studies, right? The essential one as the Hypothesis-Generating study, where we've seen drug being better than Placebo on an eight-week study prospectively in a little bit over 100 patients in the U.S. That being hypothesis-generating, whether or not the confirmation of the hypothesis on essential 3 program is adequate with the two studies to submit an NDA. That is the real main question of this meeting, right? Whether or not the package constitutes substantial evidence of effectiveness that would allow the agents to make an approval decision. That is the key question. The other questions are mostly procedural, like, and I can't even say what they are, like, is the full pharmacology package the way you want to review? It is more like the way you want to review versus whether or not they are adequate for that, and a few other things here and there. That is the core of this question. Yeah. In terms of the hypothesis, I think you have presented like four hypotheses to us, right? Yeah. Like here are the four. I think that's the similar presentation. Correct me if it's wrong, you're doing to the FDA. Will the FDA tell you, or will they guide you to which of these hypotheses you are leaning to? From those four hypotheses, do you have an agreement on any one of them already? Yeah. June 2023, two things, or a hundred things, but two things I want to highlight happened there, which I think are quite important for this discussion. One is we decided on what would constitute a priori the substantial evidence of effectiveness. There were the two studies they were conducting in the Essential 3 program. That was the discussion there. There are a few other things there, like the size of the SAFES database, which were important as well. Of course, the discussion on a meeting like that, on an end-of-phase meeting, is quite important as well. It's not only what ends up on pen to paper, but whether or not the agents understand their unmet needs, understand this is the very first program to reach phase 3, right? There is a responsibility on both ends. We wanted this to be properly designed and work and so on. A point I might not have made explicitly clear before, I'm going to make it right now, is the people who are in that meeting and the people who are in this meeting coming up, they are the same ones. I think that's quite important at this day and age. The continuity at the division has been really good there. It was really what I would now call hypothesis 1 and hypothesis 2. I think what is actually quite incredible is the fact that we could design a study on Essential 3 that allows for other hypotheses to be tested that would bring a lot more comfort to the agency, right? Replication of effect has been a big deal, right? You look into reviews, and they're like, can we replicate the effect you've seen on study X, on study Y? Normally, that question comes because patient population might be different, sites might be different, times might be different, concomitant medications. It is a beautiful thing that we actually can go with that here because it makes the decision making. The regulators are not trying to harm the U.S. public. Quite the opposite. They're trying to protect us, right? It is very important for the FDA, and I wholeheartedly support that mission to make sure that those drugs are helping us as Americans. That is really what they're trying to do here. When you bring more certainty to that decision, as we believe we're bringing a whole lot of certainty, that helps. The cherry on top, if I may just say that way, is the fact that when you look back to essential 1, that data is consistent as well. There are multiple sequential studies that are showing basically the same thing. Of course, that is incredibly helpful. Yeah. I mean, FDA is generally going to do that anyways, right? When you give them the data, you just basically made our job easier to say, hey, look, here are the four scenarios they could, and potentially there are more ways to look. Yeah. OK. Yeah. OK. Now, when will you communicate to us? Do you need to wait for the minutes? Just help us understand. The $5 billion question is a little more. You mean double, right? Current. Delta. That's what I meant. The additional $5 billion question. I know companies tend to say, let's just go through this and let's get to the other side. We know we're a little bit more forward-leaning than that, right? There are really two major scenarios here. I'm going to start with the most likely scenario. The most likely scenario is that when we get the pre-minutes answers to the questions, which I know it's not new to anyone here, but you receive that before the meeting, right? They're going to say, oh, please discuss A, please discuss B during the meeting. They're going to discuss the A, B during the meeting. Incredibly common, bread and butter, I would say. If that's the case, I believe it should be appropriate to wait for the minutes, to reflect what happened, to have pen to paper. That does not change, by the way, any of the timelines we just discussed. Having the meeting, having the minutes, and submitting Q1 are our base case. Now, there is another scenario. On that one, you are going to have to wait a few more weeks to hear our position. There is another scenario, and it happened actually on the EMBOLD and breakthrough meeting where the agents agreed to all the positions we presented. There is a written communication, and it says, yes, yes, yes, we agree, we agree, we agree. That is actually the statutes say you should cancel the meeting. I am not saying we are going to cancel the meeting. I am just saying that is what it says. It is like there is no reason to meet. You already got an agreement on everything. That increased the level of certainty to a very different level, right? Smaller probabilities, but high impact. There is no further disclosure after that. The minutes are going to be what the pre-comments are. If that's the case, we're likely going to say something to that regard. I would say probably even we'll disclose those comments in its totality. So we'll be able to see it. OK. And then that meeting is happening in the next four weeks or so? It's always trying to pin down exactly when things are happening. Well, yeah. One must look back to the calendars. Like, of course, the Thanksgiving week is not a valid week. Christmas week is not a valid week. There are only so many weeks between now and the end of the year, so. OK. Just quickly, I want to touch on the market opportunity because I think as we are doing more work on it, as we are talking to more, let's say, experts, it seems like it's a significant market opportunity. Just help me understand how you are thinking about it. Even just those 200,000 patients, right, that you've identified would imply a $10 million market. So how should we think? Who are the easiest one, or how many are identified? And if you can, touch on the pricing, just the not what you're going to charge, but just the ballpark. Yeah. For our fields, that is, has so much prowled on understanding behavioral economics, Wall Street seems to be lagging behind here in their own bias, right? The part of the issue is when you look into this market and you apply proper assumptions, it gets insanely big. There are 7 million Americans living with essential tremor. We understand to the level of detail of the patient level, there's at least 2 million of them actively seeking treatments. Let's just stop there. Let's not even go beyond three. When you look into the ex-U.S., I'm going to say this for the first time, there's about 30% in value of the U.S. value. Just keep that in mind for a second, right? Very conservative penetrations on the market. If we use a fairly reasonable analog, like if you get Ingrezza and, of course, if you look into both Neurocrine and Teva and you're looking like movement disorder, not primary, secondary, a few other things, and you're like, what is a reasonable haircut on the price? I will let you decide what reasonable is. We think it's about 25%-50% is a reasonable haircut to that price. You go for a very reasonable penetration at year one, year two, year three. I challenge anyone in this room or elsewhere to come up with less than $10 billion pick sales. I believe that that's part of the issue is that when you come to numbers like that, your brain immediately say it can't be possible versus trusting mathematics, which is the OG of all science. You need to trust. When you add, let's say, 30% ex-US, we're talking about $13 billion-$15 billion, and it becomes even harder to believe. That is the actual markets, right? I think it's time that we start ignoring our bias and start accepting the actual assumptions. OK. What do you need? Obviously, number one, when will you be able to file? How are you or what are you doing on the commercial front? Because we need to prep now. Oh, yeah, yeah, yeah. We sincerely appreciate many of you in the room who supported the last raise. A big part of that is we need to be able to build the infrastructure to acquire, I'm going to call these patients, do not make patients as commodity, but I mean in terms of understanding those patients even further. The beautiful thing about this, the head start we had is our recruitment campaign for Essential 3 was based on commercial understanding. Most companies, and nothing against them, go through the key opinion leader understanding of the markets. That is not the markets, right, when you're recruiting to studies. You can take a different approach, and that's the one we took, to ask what is the markets. Because we've done that, we're already foreseeing how to grow the market as well, how to understand these patients better. We just closed publicly. Before that we had over 200,000 patients in our own database. With the level of investments that are now supported by the cash we have in hand, I believe before launch we can get to about 1 million patients in our database. Now, I'll go back to the mathematics that we just discussed a couple seconds ago. The 10% of those patients at the first three months, that is already a $1 billion run rate for the first six months to one year. We're doing a lot of that. Of course, we're strengthening the commercial organization. We're lucky to have many of us, myself included, who launched multiple drugs before. There's a baseline understanding and building from there. You ask about the timing of filing. Our philosophy is to be ready day of feedback by the FDA. Of course, there's always little things here and there to adjust. You should expect that we'll be ready by Q1. OK. I'm going to jump to the other asset then. Actually, I'm going to focus on relutrigine because believe it or not, I think going into ET, there was a lot of focus on ulixacaltamide, but now I think it's mostly ET and relutrigine obviously ulixacaltamide we'll discuss. You have this breakthrough designation. Now you meet with the FDA. FDA agreed with this interim analysis, 70% of the patients. What exactly do you have to show in this study? I mean, for you to do an interim analysis, there has to be something you have to have confidence there to do that. What is driving it? Yeah. It's a front-loaded entry-in, right? I want to be clear about that. So we normally enter in, you have a lower chance of succeeding at the beginning and a higher at the end. We inverted that. We have a very high chance of succeeding, hypothesis being corrected at the first time we look into the data, 4% alpha. It made us very comfortable based on what we know about the drug, prior effects, made the FDA comfortable as well. We had a very extensive discussion with them on this. We agree on all the key elements here with the intent of filing an NDA on that data, right? That is quite important. It's happening right now in the next few weeks. If that study is positive to the 4% alpha level, right? If the p-value is equal or less than 0.04, that study would be declared positive. The study ends, and we make that the substantial evidence of effectiveness for SCN2A and 8A. What does that give us, right? Let's say we can file January-February. Like early, we said early in the year, early is not June, right? For the sake of the arguments, that would be an approval around September. The first thing that gives us access to the patients, absolutely nothing in the markets. The second thing is, of course, there's a PRV still in play here, and it's important. Any source of non-dilutive cash is important for us and for other companies in our space. It's a launch in 2026, if that's the case. Now, if there is some flexibility here on the time, even if it's early 2027, it's a really big deal. Of course, we felt comfortable, but also bought an insurance policy for the case that something happened to read out at final at the 1% level. OK. How big is that population? I mean, I recently have sort of updated my assumptions on it, but I'd love to hear from you how you think about that particular market and eventually going into broader DEEs. Yeah, absolutely. There are multiple ways to look into this. I was reading a number of analyst reports over the weekend on other rare disease, and I can't, it's 20 times the NALI for MPS II, a drug that, by the way, the first one I launched. When people look into that and say there are 250 patients in the US that can use this drug, just because it's top of mind, a lot of people think about, I think there is a huge need to accept that this is a large opportunity and to stop making up excuses to put these small numbers in models. That's why I'm saying this in such a straightforward way today. Differently, there are 5,000 patients, zero alternative. It's not a replacement market. This is a penetration market. We're talking about the lowest possible range here is $500,000,000 at time of launch. The most likely scenario is about over $1 billion for SCN2A and 8A only. Now, two things before our 23 seconds run, right? Here. Or more, yeah. Or 20 seconds. EMBOLD, that is the DEE general study, is recruiting incredibly well. Yeah. If there is one company who shouldn't have doubts about recruiting study, it's us, right? There's a lot of evidence out there. That would be shortly after the submission of the first NDA will have those results, if not about the same time in terms of overall review. When you sum the opportunities for the initial NDA and the actually very similar opportunities to the low end of the ET, when you put that in the model, you know what it does because you probably revised your model to include that already. I think it is proper that since that is so close that we focus a lot more on relutrigine as. I think the pricing is also more orphan-like, depending on how you unlock the broader DEE versus SCN2A. All right. We have about three more minutes. Relutrigine, so POWER1 is already completed, right? But we're going to get this RADIANT data at AES. I think for the first time you might share the data on in-generalized patients. Can you just tell me exactly what we should be expecting, what additional patient worth, how many patient worth of data we're going to get for FOS and generalized? Two things that, or three things I would say we're going to be discussing there that might be relevant. One is 37 patients on the initial cohort, over 60 now on the second cohort together with those initial 37. The question should be in everyone's mind, certain was one hour, is that consistent, right? Are we seeing consistent effects to what we've seen before? That question is going to be answered. I think the second question we want to answer here is like, is that consistent with whatever we are seeing on generalized? Generalized is a market of about 300,000 patients in the US, so it's quite important as well. The last one that was not on the original gamut here, but we included, is when you project potential effects on POWER1 and POWER2, understanding the exposure on RADIANT, what are we projecting? What is the neighborhood there? So all those, look forward to seeing a lot of you in Atlanta in like three weeks. In three weeks, indeed. All right. I think that's all. We didn't even go to your ASO pipeline or platform, but we'll keep that for next time. This was very good. Always funny, Atin. Thank you. Thank you so much. Thank you. Busy, busy time. That's good. I'll see you tonight. See you soon.