Good morning, everyone. Wonderful to kick off our healthcare conference, and excited to have Praxis Precision Medicines here with us. We've lots to cover over the next 25 minutes, so let's get started. Want to congratulate you on the epilepsy announcement today, and we'll get to talk about it- Thank you. -in a second. But maybe let's start off with ET, and then move into epilepsy. I think the first question on Essential ET, that you're kicking off, which is amazing, is I think during the last R&D Day, this late fall, you talked about how you have 600 patients that have been identified and ready, and they have been in the screening process. So could you maybe talk to us a little bit about how the screening process is going? Mm-hmm. What percentage of the 600 patients are in the queue being reviewed? Yeah, yeah. We'll start there. Yeah, absolutely. No, thanks for the invitation, again, for being here, and always, it's very nice to talk to you. Yeah. The... Maybe I will expand a little bit further- Mm-hmm. On that question, right? What we mentioned on R&D Day, a few months ago, was that we were able to, through a consenting process, like, Mm-hmm ... what we'd call a small study, that was on request for a number of patients- Mm-hmm ... and over 600 of them- Mm-hmm engaged with us on how was their tremor, how willing they were to participate in a trial. Mm-hmm that we would sponsor. So it was very specific. Mm-hmm Praxis study, and a number of other questions that would help us understand how many of them would qualify- Mm-hmm to this study. Now, the source of those 600 patients were a larger database that we built on the last, Mm-hmm ... 12 months or so, as we're enrolling Essential1 - Mm-hmm As we continue to engage on interest on clinical studies from qualified patients, coming primarily from healthcare providers. Mm-hmm or Praxis that believe patients would be eligible, and from the Tremor Foundation. That totals to a little bit over 2,000 patients. Wow. Right? So that was our base. So our recruitment strategy on the beginning of this study- Mm-hmm was going back to the 600, of course, and then slightly- Mm-hmm -uh, up that- Mm-hmm to the 2000, and now we are already there, and beyond there. So far, without giving specific numbers- Mm-hmm -we're going to keep that a little bit close to the vest. We're being very overwhelmed- Mm-hmm like, positively, with the interest, with the engagement- Mm-hmm I'll, I would argue, as well as the suffering- Mm-hmm that goes through here, right? This is a very serious- Mm-hmm -disease, been neglected for so long. These patients are very engaged with us. The process is going very well. Mm-hmm. I'm incredibly happy, absolutely not satisfied- Yeah ... which is what our team here, every day, the number one priority for us- Mm-hmm Is to screen the right patient. Yeah. To get the right patient for the process. So the process is severalfold, but the first one is a formal screening and then the- Mm-hmm -eligibility review, for these patients. That gate- Mm-hmm makes sure that the right severity, the right diagnosis. Mm-hmm concomitant medications, lab results Mm-hmm All are wrapped up, so they, they can randomize. Mm-hmm. So the commitment we had is to get this right enrolled by the first half of next year. Mm-hmm. And I'll tell as it stands here today, I'm very confident. Mm-hmm that, that's what we're going to be able to deliver. Could you maybe talk about the process of the screening? Because some investors that I've been speaking with lately, they have this thought process that you get a patient in, you screen them, and tomorrow you can get them on drug, right? So I think it's important to understand that's not the case. There are many steps and assessments that are put in place, and the average... So if you could just kind of- Yeah ... capture what truly goes into screening. What's the time range it takes for screening just one patient on average? Yeah. So people have a real expectation of these processes are moving. So from the time we engage- Mm-hmm with a qualified patient, and I'll call him qualified patient. Yeah -someone who already has Essential Tremor coming from us, like a verification system that we have, to the time that a given person- Mm-hmm could randomize, is about a month. Okay. and that goes through both collection of medical records- Mm-hmm -which we'll review, and a few other things, assessments, screening assessment for, for different endpoints- Mm-hmm - and things like that. We do have multiple assessments- Mm-hmm -for baseline. So the, what you're trying to learn from the previous- Mm-hmm study that was done in this space is, probably getting more than one assessment before the baseline. Mm-hmm Is a good idea to reduce variability. Mm-hmm. and that's what we did here. So all that process, about 28 days- Okay to get the patients on this study. So not overnight whatsoever. Yeah. No, that's helpful. And then, who is screening? Is there a central committee that reviews all this and then- Mm-hmm, mm-hmm And then assesses eligibility? How is that controlled for? Yeah. So there's a number of steps, and I'm not going to bother you- Yeah with all of them. But the most important one is when all the information is collected, is the same group of physicians. Mm-hmm like there is an eligibility review committee. They're looking through every single- Okay One of them. That comes from a standardized exam- Mm-hmm -that we developed. It, it's, I would say, a little bit more advanced than the regular, exam to measure different- Mm-hmm aspects of the disease... to assess stratification factors, and so on. Mm-hmm. So that, that's what happens. Once they give the okay, I'll have to assume everything else- Mm-hmm. remains the same, then the patient can be randomized. Mm-hmm. Okay. Sorry about that. Okay. The other question that we get is, you've also publicly said that you will announce enrollment updates. How do you visualize sort of the cadence of sort of the disclosures over the next first half of 2024? Yeah. I think we're trying to balance, give enough confidence- Yeah To all of you, who Mm-hmm are being, and we're very grateful Mm-hmm investors in the company to... On the other side, right, to the certainty. Mm-hmm on the ends. Mm-hmm. So what you're going to see moving forward from us is more increasing the certainty on the end of the process. So this is not going to be, like, every couple of days- Yeah -or every 15 days, but, we're going to give periodic updates. Mm-hmm. Probably more in large increments. Yeah. So you can see really it's moving on the proper direction here. But, if I can measure by the start- Yeah of the process, I think we're going to be all very pleased to how we do that. When you say increments, increments of what? Increments of the hundreds, potentially, or? Yeah, that wouldn't- Okay ... be unreasonable. I think we're going to see the time of disclosures- Yeah reg recalls like this one. Mm-hmm and others, and how we can get there. No, that's, that's, that's great. The other question I want to talk about is, you guys, once you connected your phase IIb, you really stepped back and really reviewed the execution of the study, and you really implemented many aspects in Essential3 to really ensure success. Very briefly, like, maybe talk about three or four of the main strategies that were implemented. We talked about the screening, we talked about the committee, the eligibility committee, but what else has been implemented that you think is important for investors to understand? Yeah, well, the nice thing about the way we operate as well, quality is not negotiable- Mm-hmm. Yeah ... at Praxis, right? So if you look into the way we run this trial- Mm that's never been in Yeah ... the way we operate, it's never going to be like- Mm-hmm ... like a quality issue. So we keep that quite fixed- Mm-hmm ... as a parameter. So everything will go back and say: Can we do something- Yeah ... even better here? But that, that was never a, an issue for us. So the other aspect, you just talked about refining- Mm-hmm ... eligibility, refining, and by refining, I mean reducing- Mm-hmm ... the number of people who touch the process and keeping the same group. Mm-hmm. So reducing the intra and inter-rate variability, there was quite important for us. We learned couple aspects, for example, family history- Mm-hmm ... as an important covariate. Yeah. Now it's a stratification factor. Intention tremor- Mm-hmm ... was an important- Mm-hmm ... covariate, so it's a stratification factor. So those learnings were put as the- Mm-hmm ... arguably one of the biggest learnings, that we only need one dose. Yeah. So that, the one dose- Mm-hmm ... going in, into the study as well. So all of those came to play. And maybe the biggest of all is the- Yeah ... the fact that we know how to recruit this patient- Mm-hmm ... very well, that allow us to keep the trial moving quite nicely. Okay. Maybe just walk us, I think, just as a reminder, your primary endpoint, powering assumptions- Mm-hmm ... and what's considered clinically meaningful in this patient population? Yeah. Yeah. So, just to remind everyone about Essential I- Mm-hmm ... there were two endpoints that were combined. The largest proportion of the combined endpoint was the TETRAS-ADL- Mm-hmm ... and then a smaller proportion from the performance scale. But those are two endpoints, right? Mm-hmm. When you separate the endpoint, we had a number of conversations with the FDA about the performance of- Mm-hmm ... the performance scale, not on drug. Mm-hmm. The performance of the scale, and I think we got to an agreement that the scale- Yeah ... really doesn't work Mm-hmm ... for studies like this, so we abandoned that. So if you go back to Essential1 and look exactly what we collected for- Mm-hmm ... the current endpoints, it's incredibly clear, right? Mm-hmm. It would have been like that sick, like clinically meaningful- Mm-hmm ... and so on and so forth. So we're getting... and I'm not talking about- Mm-hmm ... the population. I'm talking about- Mm-hmm ... the actual intent-to-treat, modified intent-to-treat population. Mm-hmm. There's no change to that. We just use that endpoint now- Mm-hmm ... to power this study. Essentially, it was powered at 80%. We obviously learned- Mm-hmm ... a fair bit there. We're powering this study at 90%. Mm-hmm. Give a little bit of a hair there as well- Mm-hmm ... for anything we might not know, so higher them. And I'm saying now, remember, there are two studies. Mm-hmm. There's a parallel group study and a randomized- Mm-hmm ... a withdrawal one. Both of them are powered at 9%. For what treatment effect? Yeah. We also published something at MDS on our website- Mm-hmm ... you might be able to see it, showing that the minimal clinical importance- Mm-hmm ... difference, is, two points- Mm-hmm ... for these patients on the Modified ADL, and we are aiming for larger than- Mm-hmm ... for the criteria. Mm-hmm. But one could argue the actual separation on the meaningful- Mm-hmm ... that starts at 0- Yeah ... which is quite interesting- Yeah ... because it means they really need an improvement- Mm-hmm ... to be meaningful. We don't see that in many diseases here, but. Mm-hmm. Okay, very helpful. Could you maybe tell us, is there any secondaries that it's powered for and what the hierarchy of the powering is in the secondary? Yeah, we haven't disclosed hierarchically what we're looking- Mm-hmm ... but, it's a sequential- Mm-hmm ... testing. We, the TETRAS-ADL, by definition- Yeah ... is powered, if anything, like larger numbers- Yeah ... difference there, right? So one more item, the Patient Global Impression- Mm-hmm ... is quite important, as well. And the Clinical Global Impression is quite important. Those are the four things, together with the primary, that we should be looking into. Mm-hmm. They're not formally powered in a sense that, that we are reserving alpha to them- Mm-hmm. we do expect to be successful. Mm-hmm. Given that your product looks highly safe, is there a third - and you talked about the 2-point difference, and the- Mm-hmm. Modified ADL is considered, you know, clinically meaningful. Is there a need to show that type of a treatment to file for approvability, given the time and need, or is any statistical separation sufficient to- Yeah. to file? Yeah. Pretty interesting question. We actually had that conversation with the agency, and- Mm-hmm. our interpretation of the- Mm-hmm ... the conversation is, they are probably more interested on a separation- Mm-hmm on the parallel group. I think for the randomized authority- Yeah It's slightly different because we have a threshold. Yeah. They have to match the threshold and then be. Yeah -withdraw. Because we suggested, and I believe they were happy with- Mm-hmm The combination of two designs. When you put them together. Mm-hmm. It becomes very clear. Yeah if the patients are benefiting, so there was not as much of a- Mm-hmm - obsessional call- Yeah for that one number, one study Mm-hmm -uh, there. That's very helpful. Another question that we get quite a bit is, I think there's a competitor program by Jazz- Mm-hmm, mm-hmm. that's also going to be reading out. Mm-hmm In 2024. Like, what is your expectation from that program? Remind us what the differentiation between the two molecules are. Yeah. The mechanism of action is the same, right? The number of isoforms- Mm-hmm. There are three isoforms of this channel that both drugs have. Mm-hmm. They're similar. I think there's a number of details that we wouldn't have time, Yeah -right now to go through, including the, the fact that, the other drug has a very significant- Mm-hmm -active metabolite, for example. Mm-hmm. Which is not necessarily an issue, but it's a factor- Mm-hmm to consider. That seems to be- Mm-hmm an impression out there, that selectivity in terms of the- Mm-hmm states of the channel matters, it doesn't. Yeah for this disease. Those are bursting fires- Mm-hmm not open Mm-hmm -closed states like sodium channels, for example. So that is a little bit of urban legends. We have pushed the dose all the way to double of- Mm-hmm the dose what we have right now. Mm-hmm. There is no additional benefits. Yeah. So what I expect to see there is an effect. Mm-hmm. The mechanism work. Mm-hmm. So we do expect to see an effect because it's diluted in multiple- Mm-hmm -dose, is likely smaller- Mm-hmm -in certain geographies that have not been, actually any trial- Mm-hmm or a potential trial run before. I think there are a couple areas of variability- Mm-hmm that might be expected, but I firmly expect the- Mm-hmm The study actually to show quite promising results as well. Great. Maybe now would love to transition to the epilepsy program. Before we go into specific questions, you announced multiple presentations across the epilepsy programs that are going to be presented at this- in the month of December- Right ... at significant conferences. Is this gonna be just an opportunity to educate the physicians, or is there new data gonna be coming out at the conference? I think it's all of the above. Okay. Right. It's a scientific conference, so- Yeah We're trying to focus. Mm-hmm The discussion with the scientists. Some of those presentations were late breakers. Yeah. As you know, for AAF, specifically for our conference, we have to have something new. Yeah. One of that is our predictive model for drug activity in the brain. Mm-hmm -using EEG. It's the first time we showed with three molecules- Yeah -not only one. So we're gonna see, in a week, we can project- Yeah Whether or not it's gonna have an activity in the brain using something we developed in-house. Mm-hmm. Quite exciting. One of the authors- Mm-hmm -and I'm gonna be there, helping present- Mm-hmm that and more data on 628 to increase the confidence. A little bit more data on 222 as well, like the Mm-hmm final four patients, and so- Oh, so the two... all four, four patients- Yeah are gonna come also. Are gonna be there? Okay On the, like, the wrap-up of what- Yeah We expected the trial to be. I think in general, what you're gonna see in a week or so is confirming to improving. Mm-hmm -the confidence- Yeah in the drugs we have in epilepsy, and we're very excited- Mm-hmm to participate in the conference. No, that's great. So let's maybe, like, go through each one. Mm-hmm. Maybe start with 562, since that you're gonna show 4 patient data. 222. 222, sorry. Yeah. PRAX-222. I apologize. On PRAX-222, so you're gonna show four patient data. What, have you had a chance to engage with the agency to discuss, or is it just more the whole data set that we're gonna see among- Yeah -each patient, to assess the next program? No, it's just a wrap-up. Like, we had three. Yeah, now 4. Now we just- Mm-hmm finalize that for 4 dose, 4 patients. Mm-hmm. 3 dose before, 4 patients- Mm-hmm -4 dose now. That was what the cohort was meant to be. Mm-hmm. I think it's very straightforward, and as I'm sure you're gonna see next week as well. It does not change whatsoever- Mm-hmm -our view. We have, I'm gonna give a little, two-way answer to your question. Yes, we have engaged. No, we haven't had the meeting- Mm-hmm Yet, which are sometimes different things. Yeah. We're very pleased with the fact that. Mm-hmm There is a pre-engagement and a meeting, which is scheduled right now. Mm-hmm. I'm not gonna guide for when. Mm-hmm. We did say we were trying to get this meeting as quickly as possible with the FDA. We will have that. It was as quickly as they could- Mm-hmm give us a date... and we believe that they're gonna, like- Mm-hmm. -part with us on understanding, the benefit for these patients- Mm-hmm. and work together for the next steps. Mm-hmm. For 2-2. That is a gate for us. Mm-hmm. I wanna be incredibly clear, we have very high expectations- Mm-hmm. -from those engagements, because any investments in any- Yeah program has to be justified by a very clear- Mm-hmm path forward. And, Okay. Maybe now on focal epilepsy, PRAX-628. Yeah. You have noted that you're gonna have POC data by year-end. That's gonna be year-end, that's not gonna be at the conference, right? Yeah. Okay. So separate data disclosure. I guess as we look at, you know, I guess, what additional data are we gonna get at year-end? Mm-hmm. What is sort of the next steps that you need to take post that data to really come back to us and guide sort of the- Yeah phase 2 design in the first half of 2024? Very quickly, what we've shown with 628, right? Mm-hmm. Praxis, in focal epilepsy, I was gonna say best in class- Mm-hmm but really best in focal epilepsy, therapeutic index. Mm-hmm -on very predicted model. If you go across the industry, if you look into other drugs- Yeah Everyone is using the same benchmark. Yeah. I would argue that it should go and compare- Mm-hmm those multiples to the ones we are showing. Mm-hmm. They all tap out- Mm-hmm -between 2-4 folds on the MES EC50 equivalent. We're talking about 15- Mm-hmm -18, with 628. So we're very comfortable there. Then we show it's safe on the health volunteer study. Mm-hmm. It's present in the brain- Mm-hmm It alters the EEG. So one could argue, just jump straight- Mm-hmm -into a phase 2, 3. We chose to run this- Mm-hmm PPR study. The original cohorts was planned to be increments of 4. Mm-hmm. We over enrolled a little bit. Okay. On that, so we're wrapping up as quickly as possible- Mm-hmm but we're really gonna be- Mm-hmm Try to give as much as a full sum, or- Mm-hmm I would say, excited. Mm-hmm about that. That, that's gonna give us a further guidance from activities in patients, right? Mm-hmm. This is no longer. Yeah -a biomarker in healthy volunteers. Now, we have a biomarker, translational marker- Yeah -in patients, so, stay tuned for that one, but not at the AS. Okay. Maybe moving to 562. Mm-hmm. We hear quite a bit. You shared really exciting data at the analyst event this fall. So, and I guess the question now here is, you're gonna have more data in this population, given it's a high unmet need. Yeah. You're also gonna engage with the agency. So could you maybe talk about the type of data that will come in the first half of 2024? Yeah. What is considered, like, further POC and validation in this? Mm-hmm. How could you work with the agency to maybe find a very innovative way for path for approval? Yeah. If you could tackle all three, that would be great. So 562, we're testing right now, it's a phase 2- Mm-hmm. in two cohorts of patients. Mm-hmm. That's in SCN2A gain of function, that's in SCN8A gain of function. Mm-hmm. They have to have a high seizure burden at baseline, and then we're dosing them for 16 weeks. Mm-hmm. Four of those weeks on placebo, for a group of patients, and the other one's on drugs. So the... what you expect there, and they're only standard of care- Mm-hmm best standard of care right now. So what you can expect from that study is a comparison, not only with placebo. Mm-hmm But what happens when they transition? Yeah in a blinded fashion, right? So a crossover- Yeah A one-way crossover there as well. We're excited because these patients have nothing. Mm-hmm. And they have a very high- Mm-hmm -burden at baseline. It's a relatively smaller study. Mm-hmm. It is a phase two- Yeah -so we're trying to learn as much as possible here. But what should enable us, once we do meet- Mm-hmm -with the agency, is to get a very efficient- Mm-hmm Confirmatory study that leads to approval, shortly thereafter. So that's what we're looking there. First half of the year, we should have that in our hands. Is there an opportunity that this existing dataset could be just increased in a cohort and you could deem it as pivotal? Is that also one of the optionalities? Yeah, I think it's always an option. We need to unblind- Yeah the study and then look into what is happening there. Yeah. I think what the agency being very clearly indicating- Mm-hmm They want more treatments of these patients. Yeah. The vast majority of these patients, if not all of them, die before- Yeah -like teenage years. Yeah. Uh, twenties. Yeah. So the unmet need, this is not an epilepsy. Mm-hmm. This is a fatal disease. Yeah. This is comparable to many other fatal diseases out there. Mm-hmm. So there is a very high- Mm-hmm Need from all sides perspective. So we believe they're gonna work with us to accelerate it. Another question that we get quite often now is: Given that you have a pivotal study reading out in the second half of 2024, you have pipeline updates across all epilepsy programs in the first half of the year. When you start these discussions with investors, could you maybe quantify what percentage of your time is sort of really digging into epilepsy versus—like, in, into essential tremor versus epilepsy program? Like, sort of what's, what's the hierarchy of— Yeah Discussion points at this time? So from an internal focus, it's pretty obvious, right? Like, essential tremor, it's larger- Yeah ... more complex, more important, larger inflection. Yeah. There's a lot of, like, disproportional- Yeah -amount of resource there. The other programs are not suffering from a quality perspective- Yeah But there's less resource allocated. The way we look financially for- Mm-hmm -for the resource allocation, if what we have right now, in the bank covers- Mm-hmm all those readouts and obviously some Yeah Because we, we need to get that on the other side. But we are very serious with the game. Mm-hmm. Right? So covering to success. Yeah. And then we make a decision- Mm-hmm. —like we're not taking risks for Mm-hmm. -beyond the- Yeah the proof of concepts or the phase 2 readouts for this. The priority is Mm-hmm to readouts and bring new source of cash. Mm-hmm. Our key initiatives right now are deals with- Mm-hmm Strategics, and I think we're gonna be able to continue to supplement the cash runway based on that. When you speak about strategics and partnership interest, is the thought process to partner in some of the epilepsy programs, or is the part to potentially entertain the idea of, like, actually give the, you know, ET programs? So, what's the hierarchy of interest in terms of partnership on which asset? The highest likelihood, I would say, on a short term. Yeah is, regional deals with Mm-hmm our ET, for example. They're pretty high on our radar. Mm-hmm Right now in conversations. I think what you're hearing from strategics about ET is, it's such a large market. Mm-hmm that it's hard to reconcile- Mm-hmm the potential up front or even Yeah full consideration with market cap right now. So, we're trying to balance that interest for a larger deal. Mm-hmm. But for the rest of the portfolio, it's very productive discussions to... We are not too precious about one or assets- Mm-hmm or another. We believe there's a lot more from where those came from. Mm-hmm. We can continue to move the company, and if we can bring more dilutive- Mm-hmm -source of capital, the better for all of us. Great. Well, we've come to the end of the fireside chat. What a great discussion, and really lots of excitement in 2024. Just wanna say thank you on behalf of all of us here at Piper Sandler for great discussion and participation at our conference. Let's thank Marcio for being here.