Welcome, everyone. It's my pleasure to introduce the President and CEO, Marcio Souza, and the CFO, Tim Kelly, of Praxis Precision Medicines. My name is Kevin Kuang. I'm one of the biotech analysts at Goldman Sachs. Yeah. Welcome. To start us off, maybe for those that are newer to the story, would you mind giving a brief introduction and maybe what you view as your core competencies and philosophy as a company? Yeah, absolutely. I appreciate it. I appreciate the invitation and being here today. I'm Marcio Souza, Tim Kelly, our CFO, is here with us. I think what we're trying to do right now, arguably done part of this going to be hopefully finalizing the next part, then there's going to come the next and the next and so on, is to address a fairly large number of markets in CNS. When you think about essential tremor, for example, which is our arguably largest part of this, has really been nothing maybe Tim can talk a little bit about the size of the market. I'll go back and talk a little bit about the science and so on. Everything else, I would say, fades when you think about ET. When we talk about essential tremor, it is one of the largest movement disorders, a prevalence of roughly 7 million patients in the U.S., about 2%-3% of the population. There's never been a drug designed for this population, which is staggering given the size of it. Another movement disorder much better known is Parkinson's, that has a prevalence of about 1 million. To get a sense of just how large the essential tremor opportunity is, while there's a prevalence of 7 million, our initially addressable market is about 2 million. We get to that number from a longitudinal claims analysis that we did a few years ago, that the conclusion out of that was there's about 1 million patients currently on treatment, and propranolol is the only approved drug. They're taking a number of other things off-label, then there's an additional 1 million patients who have tried treatment but come off of it. When we look at as we're launching, we're not going after the full 7 million. We think there's definitely opportunity down the road to bring market share to that group. Initially focused on those 2 million patients who are currently sub-standardly treated or have tried something and gone off. Then there's an additional about 200,000 patients who are diagnosed every year as well, particularly as this is an aging population, and it is a disease that progresses with age as well. We talk about 2%-3% of the broader population. It gets to be about 6%-8% of the 60+ population also. There's quite a lot for us to focus on and target. What I think we'll go through in the next few minutes is the strength of our drug, ulixacaltamide, to address this market. We are in a phase right now where that's under NDA review with the agency. A lot of what we're doing right now within the company is to prepare for the launch and the upcoming PDUFA date in late January of next year. I think why I wanted to talk a little bit about the numbers and get Tim to speak about that is we normally start with studies and the FDA process and things like that. In a sense, the reality is there is no other market where you have 2 million, 3 million, I think we've been putting this on the lower end of 2 million or 3 million patients with basically absolutely nothing for those patients. When we think from a market opportunity perspective, it is completely different than any other market. When you think about competency, as you said, we proud ourselves for really thinking very deeply about new markets. As you probably just heard, not only on the understanding on the next phase, but before that. There are reasons why on a market that large, no one but us to this point succeeded. Really on our relationships with the agency and making sure at moments like now, particularly in drug development, I think we have to be very thoughtful about how we engage with the FDA and with the other entities. On top of all the work Tim just mentioned about that we've done with physicians and understanding the market and so on. We did a very deep understanding of the payer, again, how they view the drug and therefore what kind of process and particularly support for these patients we need to put in place. There's no place we look into that does not result into a very large, and I think sometimes when we put numbers like $10 billion peak revenue for this drug, it sounds for some people a little bit absurd because we just haven't had a lot of $10 billion drugs. If you actually take the very simple mathematical way with known competitors, millions of patients, a drug that is very clearly effective and safe for these patients actually becomes, in a sense, a conservative number, if I may. Got it. Sort of to bookend that, 2 million is somewhat of a conservative number in that they've already been diagnosed and treated and are either currently on therapy or have come off. I guess for ulixacaltamide, can you talk at a high level about how you can address sort of this unmet need for those patients, the efficacy benefit that you're seeing? I guess we can start there. Yeah, absolutely. There are very few times, I think, in drug development, particularly when you're looking for a new indication, that you not only have a large indication, as you just talked about, but what you measure and what patients actually are asking for are the same thing. When we talk, and you can imagine we talk to thousands of patients at this point in time, including a very recent survey we put a little bit in our corporate deck on really trying to understand w hat do you expect from a drug, number one, and how does this condition affect you? It's so common, I think one of the biggest features, unfortunately, I may say, of essential tremor is that people just try to hide. As you go through life, the vast majority of the patients start having symptoms in their teenage years, and that's one of the misconceptions. Most people think about an old people disease, but it's actually very early in life that it starts. 70% of them have family members, that's normally the second or third or fourth person in the family has it. It slowly progresses on losing function. The reason why that's important is it's an increasing disability disease, where you're feeling some internal tremor and then a lot more external, and then you can't quite write very well. It progresses to full-blown not being able to do anything, like no dressing, no eating, of course, never leaving the house to socialize and things like that. The FDA gave us a very strong advice a few years back that they had no interest, in a sense, in measuring the tremor itself. It was very wise, and at the time, we didn't think it was so wise, but now we realize why it was, because it varies a lot throughout the day. What it does not vary is the impact on life. It would be incredibly difficult for those patients to be here and drinking their coffee as we are, or even having the breakfast as you just asked us if we had this morning. That's not possible for them. Compound that with age, and then you see this really big problem with an aging population as we have in the U.S. The results of the Essential3 program, we had anywhere between, I would say, the mean on about five functions on the ADL restored, dropped away to zero, meaning the ADL goes to zero. No function affected. Looking to the American Academy of Neurology, we had a plenary meeting for clinical research. Over 20% of the patients had more than 12 functions restored. When you put that together with we're talking about the size of the market, this is not a small change. I would argue that even if it was small, it'd be quite important for us to judge what's important for our patient. Those are very large changes in their lives every single day that gives independence in a sense to some of those patients. Got it. That's helpful. You've highlighted sort of the distinction between tolerability and safety when it comes to the profile of the drug. Can you characterize the tolerability profile that you're seeing? Yeah. The drug acts on an incredibly important part of the brain, primarily on the thalamus. I think what we learned as well is there are certain patients, like about 70% of the patients, you can go very quickly to maximal efficacy, and they tolerate the drug really well. For about 30% of the patients, it's a little bit too much to go that fast. Of course, we could just say, let's ignore this 30% or so because with a market with a multi-million number of patients in the U.S., from an overall financial perspective, it's irrelevant, but that's not how we think. Every single one of those patients is important to have the drug. Why would you then have any safety concerns? I think it's incredibly important to highlight this. When you are studying a population that the average age is in their 70s, in our study it was 68, you're concerned about major safety issues. Like hepatic, renal, you name it, that. We didn't have any of that, but we did have a lot of dizziness that led to discontinuation on about 30% of the patients. When you take a step back from that, our understanding very clearly now is that if you keep the patients for a few more days, they tend to basically stay, so it goes away, the dizziness. One of the conversations we had with the FDA, where they proposed for us that we try to come up with a label that, and analysis supporting the label, of course, that would allow for a lower number of patients to have this continuous dizziness. We did propose something for them based on the phase II, where the discontinuation was about 10%. We have that knowledge. We're able to propose, and it's actually incredibly simple, at least a priority, where you keep the patients for a longer period of time at 20 mg, and they tend to resolve. We give them the opportunity to, one, not to have the dizziness that leads to discontinuation of this, I'm going to call it small just because it's a minority of the patients, a small part of the patients. At the same time, give the best possible benefits once they continue on the drug. Again, a great outcome in general the way we see. Where would you say you are in terms of that strategy, your confidence in being able to implement that, and then what flexibility do doctors have in the real world and sort of holding? Yeah. I'm going to start by the last part there, Kevin, if that's okay. The irony is that when we present this to a very large number of doctors, they say, Oh, this is just like every drug I have every single day in neurology, and I'm just going to figure that out, and I'm going to titrate them to effect when they need to. They were never the actual issue here, and doctors are going to do what doctors do when the drug's available in the market. I think it's important as well that we have as much data to inform in the label, to inform those prescriptions, and to inform the proper use. The combination of the phase II, as I just mentioned, understanding that the tolerability is significantly better if you just slow down some of those patients With the FDA, really, I'll say supporting at this point in time, including that in the label. Of course, it's going to be a matter of label review in the coming weeks as we're entering that phase with the agency. It seems to be a very good setup right now. One other thing I might layer in, when we talk to physicians as well, and the neurologist population in particular, they're very aware of the disease, but also that they have not been able to treat their patients efficiently with the existing drugs, propranolol being the only thing that's approved. Other things that they're using, it's not enough for what they want to do to provide their patients some relief. A lot of awareness about the disease and a lot of interest in ulixacaltamide as a therapy for these patients as well. Got it. I want to talk about what you're assuming for sort of long-term persistence on the drug in the real-world setting. What are your assumptions going to that? What data points do you have in how long patients could actually stay on this drug? Is there sort of like a benefit threshold that they need? Just how do you think about that? I assume it's a factor going into your $10 billion peak assumption. It is. Lowell, take a step back here as well. I find it super interesting. When you go back to the studies, right? The way we've done the studies was understanding that no one succeeded before. What was the key features we needed here? We made it incredibly simple for patients to come in to the study, which at the same time, made it incredibly easy for them to leave the study. That was one factor here. When you look into the number of patients right now, like on drug. The study ended, of course, last year. We reported the results was before. It's pretty much everyone that completed. Of course, there is some life goes on, again, with age and so on, it's a very high number of patients that were on the drug at that point in time are still on the drug right now. We have patients for years now receiving ulixacaltamide hydrochloride, which is, in our view, incredible. Maybe quite importantly as well, we really haven't had discontinuations that due to lack of efficacy, directly to your point. By whether or not they were for lack of efficacy and then the patient then reports, of course, I cannot attest to that. In a lot of studies you see this, right? Like lack of efficacy as one main reason. The patients really see the effects. In our rather limited but important open-label extension from the previous study, we see an increase in the response as they stay for three more months at the end, and that is when we measure that, which is very encouraging. Of course, we are talking here about the progressive disease on their 70s. The fact that we are seeing multiple functions regained is nothing short of fantastic, I would say. The fact that they see that response, they tolerate the drug well after the discussion we just had about how to get to that point, and they stay for multiple years, it is fantastic. Are we counting for any of that on the forecast? No. Because I think again, I said simple math before, but if you actually go and do the simple math, this is not 10, right? It is probably more like $20 billion. We are taking a conservative approach, and I know it sounds oxymoronic to say conservative and $10 billion on the same sentence, but it is. We are taking the clinical study discontinuation rates as kind of the worst case that we have seen so far, even knowing that we can do better than that. That was without supports. We are using the lower ends of what the pricing can be, maybe even less than the lower end, one could argue here, and a nice lower curve to get there. In the recent work that Tim mentioned we did with a few thousand physicians in the U.S., we haven't done a lot of work in the fields. As you know, in terms of didn't have a large MSL group and going there and exchanging scientific information with these physicians. It was incredible to see, one, the level of awareness on ADEs. Things that we haven't really talked to them, so how much they know. The second that was the most fantastic for us was their day of launch intention to prescribe is about 2.5x our peak intention to prescribe expected. I think we are in very good territory when we think about the forecast in general. Now, your next question could be, do you actually have supply for all of this, right? That is something we are always being very careful on building the inventory to make sure we can on a one we would call like a best case scenario. Not trying to inflate launch expectations, quite the opposite. I think we have to be responsible for what we are seeing. It is, I will say, using all of this, as you can see, we know very deeply these markets. We are very happy with how things are shaping up. Got it. I just want to do a quick question before we get to that commercial aspect. Just to bookend the label and how you're thinking about it, where do you anticipate from now on the most discussion with the FDA? I guess just how should investors think about the titration language, warnings, contraindications? What should they be looking for in the label? What are your expectations? Yeah. Think about it like page one or section one. There is no expectation for contraindications here, so I'm going to be clear there. The warnings that you would expect is the things we just talked about. Yes, people can get dizzy. It's important that they discuss that with their healthcare professional, particularly in general. I think the bottom line here of this indication as well, of course, we'll never be able to speak for the FDA. We've been multiple times now in multiple conversations with them throughout this program. December last year, after reviewing the final results, they granted us breakthrough designation. I think that point is important because all the safety, tolerability, the efficacy were there. It is incredibly hard for someone to look into the clinical results of this study, particularly the level of detail the agents have, and say it's not bringing benefit for the patients. You turn to the other side and say, okay, is this harming patients in any possible way? Like in normally the major organ systems and particularly liver here. The answer is no. The benefit risk has been and will continue to be, in our view, quite positive. The discussions now that we are entering, as just said, pretty soon, in terms of labeling, will likely focus on proper use. We know because we asked for the advice from the agents, they told us that they don't want to trade off efficacy for tolerability. They think that we can figure out both of them together, and the proposal at that point in time is for a second titration, right? The original titration, the titration, the label is 20 mg, 40 mg, 60 mg, one week apart, milligrams per day, and the alternative one is 20 mg, like staying for a long time. The good news there is that it's not that you have zero efficacy at 20 mg, it's not something that you're just not having anything. We switch to 40 mg, you see basically the top of the efficacy there as well. It's actually a pretty good benefit risk for the patients in general. We're very optimistic about it. Great. You talked about pricing briefly. I think you even talked about maybe $50,000 as sort of an annual target price. Is that a target? Could that be a floor? Sort of what analogs are you putting into that? Yeah. Not going to be disingenuous here, just said there is a space there, right? It's more of a floor, the way we're looking. The reason why is we did a lot of analog work. Number one, if you look into the initial population, right, what we're going for, the kind of benefits the drug gives, but particularly what payers are telling us, because I think at the end of the day, that is going to be how they ramp that up. I think there is basically no resistance or as we call, between, let's call it $50 and $100 or even maybe a little bit more than that. We have to ask ourselves what is the best for the patients and what is the best for the company and our shareholders. It probably is a number in between. The kind of service that we believe we should be giving here, particularly medical education in terms of proper use of the drug. There's no expectation we'll have anything more complex than just the label. There's no REMS expectation, there's no mandatory medication guides or things like that. We do believe that we should be educating. Those things cost money as well. We have to support and then the next developments. I think to guide between $50 and $100 is probably the place to be. Get some analogs too when we look at the tardive dyskinesia market. A little bit smaller, but it is a movement disorder. There are a couple players in that space. The price is low six figures. It does give an analog, and what we're talking about is a price that recognizes the value of the drug so we can support patients, but also gives a floor for where we can price. Great. On the commercial aspect and having facility with pricing, you talked about potential step-through requirements for propranolol, which is the only FDA-approved drug. Can you talk about your expectations for how that will work? Even though it is the only FDA-approved drug, not every patient is on it. How does that dynamic work in terms of getting access to the drug? I think when we're planning for uptake execution, it is more conservative for us to expect step-through as propranolol, work with that upside if there's not as much there. Rather than be surprised by it. With that, we don't expect much friction there. One of the issues with propranolol, it's a beta blocker. Given the age of this population, about half of them are contraindicated from it from the beginning. The other aspect of it is a number of them have already tried it. What we might expect is maybe there is some type of requirement for have they tried it in the last three years. I think a part of what we're looking at in terms of our commercial execution and rollout is how do we use data and systems as well to help support things like prior authorization and step-through and accelerate that aspect of the process. It would also be part of what our medical communication and information is as well. That we can support the physicians as they're going through this with all that's required there so that if propranolol is required, we do that, but we get patients onto the drug that can really help them, which is ulixacaltamide hydrochloride. We'll give you two data points there. One, in our forecast, we assumed everyone would step through propranolol. We'll think about how conservative we're being there. Tim just mentioned half of them cannot medically even do that. The second is we went to the private payers. We asked, what are you going to enforce? Any restrictions? Here is the population expecting full well that all of them are going to say yes, that they want. It was less than half that said yes to that. Understanding their population, right? We're talking about numbers like think about the UnitedHealthcare's of life. There's a lot of those patients, for example, which was surprising, to be honest. I think it's real just looking into how much utilization of the system these patients end up having with ancillary support and then ultimately really needing a lot of care. While the drug can give, delaying the treatment is probably not wise on a drug that gives its maximum treatments starting around two weeks. It's incredibly fast to get there as well and to help this patient. It was another interesting potential upside here in general. Sort of on the commercial readiness front, you've talked about maximizing your investment upfront in terms of maximizing the commercial opportunity. Can you talk about that investment, what that entails in terms of field force and sort of education perspective? I know you started some awareness campaigns. Can you talk about where you are today versus where you want to be in January? Yeah. I would say we're more than halfway through it. Our launch readiness expectation is in Q4. Some place in Q4. I'm not going to give the exact numbers. We're not trying to be ready by January, like the end of January as the PDUFA, but actually by relatively early in the fourth quarter. We have to be pretty advanced right now in order to be there. One, things can always be accelerated with the agency. I know we normally think on the other direction, but we need to be ready for the both directions. The second is just making sure we understand this market as much as possible. We start with a base of over 217,000 patients that were in our database. That's where we are starting from. Those all have physicians linked to them. Then as Tim just mentioned, we just refreshed the claims data sets, which we were able to really understand who in the last 12 months, 24 months, 36 months, actually seen one of those patients where is the largest concentration. When you put all of that together, it is about 13,000-15,000 targets in the U.S., or accounts that we want to cover. When you back calculate all of those things, we are about 200-300 sales reps to cover that. I think most companies would start with 200, I think we're making a decision that we'll start with 300, because we can cover everything we just talked about, the potential upside. A middle of the country particularly, there's a lot of large PCP practice covering the space for neurologists, They need attention as well. As we discussed as well, we want basically no patient left behind in a sense, so we want to make sure the physicians prescribing understand the drug and can guide the patient. The wave one of the launch is going to be neurologists and the top decile for PCPs on this disease. I think we're fortunate with the balance sheet that we have right now. We can invest heavily upfront into the commercial launch. The other thing I would say is relutrigine in January is our second launch over the next three quarters. Yeah. We'll have a little bit of time maybe to get through relutrigine, but we have that at the end of September as well. There's a lot of activity internally right now. That was my next question, actually. I know we can talk about that all day, but moving to relutrigine, this is actually potentially your first approved drug with a September PDUFA date. Can you talk about the opportunity and the initial genetic DEE indication, and then how you're preparing commercially for that, and then we can move on to potentially the broader opportunity. The SCN2A and SCN8A, which is intended to be the first approval here coming up September, I think my guess is on the 25th, just because the 27th is the weekend, but you can tell me I'm wrong when we get there and they actually do on Monday instead of on Friday. We'll see. We are preparing next month's launch readiness date for us. It wants to be launch ready in a few weeks. It's progressing incredibly well with the FDA. I think the reason why we focus a lot on ET is really people not even grasp the surface on ET, and I think it's a little easier on relutrigine to talk about that. The first launch itself, we should always think about the first indications over billions of dollars in potential revenue here for two reasons. One, 5,000 to 10,000 patients in the U.S., all of them need better drugs. This is not a matter of who is doing well, who is not doing well. No one's doing well on this condition. It's going to be the first approved drug for indications ever. Once again, just like we're discussing before, when you go back again to payers and so on, we're talking about not really having an upper limit, we're just trying to understand or maximize access here in general. The choice we took was to actually call for a little bit more than the centers of excellence, I'm going to call, at time of launch. We're going to hear us talking more and more about numbers, but you could easily cover this market with about 30 or so sales reps or personnel in the field and maybe about a third of that in MSLs. We're probably going to go a little bit on the higher end. As you can see, this is thematically how we're going for this. We're not believers that every three or six months just say, I'm going to increase, I'm going to increase, that you're chasing the demand is the appropriate way to launch drugs anymore. Rather to get the best possible experience from the get go, maximize the launch. Remember, we have EMERALD coming up in Q4 as a result, which expands the indication about 10 to 20 folds, depending on how we want to see here. We're incredibly confident about the clinical profile and what we are seeing from a blinded view on that study and what we're getting from the patients who already rolled out to the open-label extension. When you consider we should never launch for the second indication. I think we have to be ready for the fact that physicians are going to feel confident and are going to start wanting to have conversations with CMS so on, about that, we need to be there for them when they want to talk about it. Got it. Can you share what you're seeing in a blinded fashion that gives you confidence? Yeah. I think there's I'm going to call a shape of the distribution that gives you more or less confidence. We always have to be incredibly careful about blinded review. Like I think we've all been burned before. I have for sure. There are certain distributions I would call that they're just clinically impossible on a population that is so refractory. The more to very high response rates, I would say in large number of patients in the study, the more confidence one should feel. Particularly one that is associated with very good safety, as we are seeing on this study. We enrolled more than we were expecting initially on 160 patients here. I think we talked about it. We use very, very high-quality pediatric sites. It's a pediatric condition, we wanted to make sure we have those patients there. We wanted to make sure as well that there's no over-representation of some cohorts, particularly the ones we know there is efficacy already, like SCN2A and SCN8A, and we accomplished that. I would say, having basically looked into this every day for many weeks, that I'm as confident as one can get. Got it. About what we are seeing. Is there anything in terms of how you think about execution risks from going from that concentrated population to a more genetically diverse population? Yeah. The good news here, twofold. One, prescribers are the same. When we are talking about promotionally about SCN2A and SCN8A, if they have a question, we can get that to our medical team to answer the questions about the broader. We are right in front of them, which makes it incredibly easy. They are already coming to us and actually asking questions right now. Then on the second, of course, we're going to be pricing this, thinking about SCN2A and SCN8A. What we are hearing from payers in general is that we probably have two to three years to make adjustments if we need to. It allows for that very successful financial ramp on the following, three to four to two to three years, here without having to start considering price adjustments and things like that. When you're looking for recent price on the rarity space on drugs that actually have competitors, which is not the case here, we're talking about anywhere between $450,000-$650,000 per patient per year. I think that's a good place to start here as well. Great. I want to touch very briefly, you had a recent update for vormatrigine in focal onset seizures. What can you say about that at this point in terms of that program and w here do you go from here? Absolutely. We just had the results from the POWER1 study last week for vormatrigine. I think couple good news and couple bad news there. The bad news is that it's not the profile we wanted for that population. We did not meet the expectation from the seizure reduction that we wanted. There was positive on the responder rates on the 50%, that's one of the good news. I think there's a lot of other good news here. We see the drug at either 20 mg or 30 mg being really well-tolerated, sub 10% discontinuation, really no idiosyncratic events. A good dose response between 20 mg and 30 mg, which gives us what to go from here. Allow us to take a little bit of a step back right now and ask again, what is the drug for? I think the more we look into this and the distribution of the patients and where they're in, the closer it gets to the original profile of the drug that is really a great drug for the 60% or 70% of the patients. That's probably where we should be focusing the development moving forward. Yes, it's going to be used on the hyper-refractory patients. That's what this study was, the highest seizure burden ever in a study. That was the POWER1. Which is accomplishing the fact that we get a lot of very severe patients, but also talking about the limitations of getting very severe patients. A few things to tighten up for the next studies, but we are quite optimistic about how to move forward here. Great. Well, Marcio, Tim, I didn't even get to elsunersen and the rest of your pipeline, I apologize for that, but next time. Thank you very much for being here. Thanks for having us. Appreciate it.