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spk04: Good day and thank you for standing by. Welcome to the Praxis Precision Medicine's first quarter 2022 corporate update question and answer conference call. At this time, all participants are in the listen-only mode. After a short remark, there will be a question and answer session, and to ask a question during that session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0. And now, it is my pleasure to hand the conference over to your first speaker today Alex Gain, Vice President, Investor Relations and Corporate Communications at Praxis. Thank you. Please go ahead.
spk09: Thank you, Paul. Good afternoon, everyone, and thank you for joining us today for our first quarter 2022 corporate update Q&A call. With me on the call is our President and Chief Executive Officer, Marcio Souza, our Chief Medical Officer, Bernard Ravina, and our CFO, Tim Kelly. Following the press releases and video update issued this afternoon, we will focus today's call on your questions. We ask that you keep to one question initially, and then please feel free to rejoin the queue for follow-up questions as needed. Before we proceed, I would like to remind you that during today's call, we may make certain statements that are beliefs, forward-looking, and subject to various risks and uncertainties. For additional detail on forward-looking statements and the risks associated with our business, I encourage you to consult our SEC filings. With that, I will now pass the call over to the operator to open up the line for Q&A. Operator?
spk04: Thank you, sir. We will now begin the question and answer session. If you would like to ask a question, please press star 1 now. Again, that's star 1 on your telephone keypad. Please stand by while we compile the Q&A roster. Your first question is from Yasmin Rahimi with Piper Sandler. Please go ahead.
spk07: Hey, guys. Thanks so much. This is Lauren on for Yas. I have a couple questions. So the first one, what are some of the key lessons you guys learned from PRAC 944 data that could impact your views into the essential phase 2B study? And then speaking a little bit to the enrollment, how that's going into that study, and do you think that the essential population will capture a similar demographic? Thank you.
spk08: Thanks so much for the question. I would say maybe I'll start through the end there. The enrollment population for essential 1 is is slightly different than 944-221 that we're just very proud and very excited to have released today. The key components there that is different is that we did not allow for patients with Tetris upper limb score less than 10 on essential one, which is also kind of related to your first question. That's what we learned conducting these studies and looking to other data in this space as well. there has to be, in order to be a little bit more homogeneous, a certain level of tremor at baseline. So we went through a fairly broad, as 944221 was, to a little bit more restrictive, so on the higher than 10, and that would allow us, we expect, to show even more clear results, not that we believe we need it, based on today's data, on the essential one coming up. And the enrollment on the trial is going pretty well. We reinforced today and we continue to reinforce the results by the end of the year. But I'll hand over to Bernard for any other comments here about the lessons.
spk05: Yeah, the point about the population is a key one. And then I think a couple of the other key lessons. One is we learned that we could get most people up to the high end of the dose range. And we've previously shown we've got a very well-substantiated dose range based on that mechanistic biomarker of quantitative EEG. So it really confirms we've got a 20x dose range that we can work in where the drug appears to be active and has potential to improve tremor. And then I think we've learned a lot about the endpoints, too. And we agree with the agency's suggestions about ADLs and particularly modified ADLs, and we've seen what a responsive measure that is, you know, including in the randomized withdrawal, that blinded period. And so I think it really helps us focus in on function and understand that that is a reliable measure that integrates a lot of tremor in activities that patients come across every day.
spk07: Thank you so much for that information. Sorry, just one more question. What were the reasons for the three discontinuations in the PRAX-144 study?
spk05: Yeah, so there was one person who had a discontinuation totally unrelated to PRAX-144. So they needed a procedure for something that they you know, had medical conditions they had going in. So it was totally unrelated. And then the other discontinuations, one was dizziness and the other was primarily fatigue. So all the AEs there were mild to moderate. There was only one severe AE, which was worsening of tremor when drug was withdrawn. So overall, really well tolerated.
spk07: Great. Thank you so much, guys. Thank you.
spk04: Your next question is from Laura Chico with Wedbush. Please go ahead.
spk03: Good afternoon. Thanks very much for taking the question, and I'll stick with one here. I guess I just wanted to verify or clarify some of the comments you had in the video with respect to Essential One. You're updating the primary endpoint to this modified ADL, and it sounds like you have agency support here. I'm just trying to understand, could Essential One serve as a registrational study? I believe enrollment is around 115, 120 subjects. Just trying to understand, A, does this become a registrational study? And also, B, are there any mechanics behind changing the endpoints and how that might affect enrollment? Thank you.
spk08: Yes, Laura. There are a lot of mechanics behind it, and that's one of the reasons why we mentioned in the video we're working through it. We're going to be informing all of you about those mechanics. Also, specifically, there are so many alternatives right now, as you can imagine, with such a robust rebound after removing the drug. It gives us a lot more confidence on some of the aspects that were unclear, like which those should be targeting, and things like that. So we're working all of that. In terms of the endpoints, this was incredibly clear with us and with others as well in this space on measures that very clearly affect function for those patients. So when you look into the ADL originally as designed, it was already a pretty good assessment of function. The loss the ability to detect more of the floor. That's one of the reasons why the agency suggested very strongly, may I say, that we modify the way the floor was assessed. And I make a point that by doing that, we reduce the score by about 30%. If you were to have used that, the results today would be even more positive, not that they needed to be. but it's a lot more trustworthy, I would say, the way the analysis is being done right now. So we're very convinced by the feedback today that the endpoint is very clear. Now, whether or not the new design will be registrational, that's a matter of discussions with the FDA after we've done that design. I think what is going to be very clear driving to is for clinically and statistically significant change. and then have a discussion with the agency once the results are in, whether or not that could serve as one of two trials, or if you have to run two more trials, which would be incredibly pleased to do it as well with a director so active.
spk03: Thanks very much. Congratulations.
spk08: Thank you. Thank you.
spk04: Your next question is from Rita Baral with Cowen. Please go ahead.
spk01: Good afternoon, guys. Thanks for taking the question. Now that you've gotten last patient, last visit in ARIA, I just wanted to check in on, you know, final conduct, data retention, et cetera. And can you tell us when last patient, last visit is? And then further, you know, just given GABA-PAM precedent showing deltas of two points in sort of larger phase two, phase three trials, you've mentioned that you've powered this for a three-point difference. Is this mainly because you think that you've got better placebo concept, or do you think that this could be driven by just sheer differential efficacy? Thanks.
spk08: Yeah, of course, to appreciate the questions. So a couple things here. One, we're Wishful that the clinicaltrials.gov post will be up as we speak with you. You're going to see that hopefully in the next few hours or by tomorrow. But the last patient last visit was on May 5th, so last week. That is the safety visits. Obviously those was before that, a few weeks before that. So that's really the last piece of data we needed to be completed. The patient showed up at the day it was supposed to, and so we were able to complete the study by itself. Now, the next phase here is obviously cleaning up all the data, making sure that we can lock the database in due time, and then reports. From an underlying assumptions perspective, as we mentioned in the video, we're pretty happy with all the assumptions that went in. Now, this is blinded. We haven't seen the unblinded data yet. Of course, the database is not locked, but it gives us great confidence that from a conduct perspective, we are in good place. Two aspects here. Every time we run a controlled trial, both the drug and placebo have to behave as one expects. I think we're more confident than ever that placebo did behave the way we expected by everything we know. So that alone wouldn't give us the separation and the overall profile that we expect. Why are we so confident that drugs behave the same way? To our knowledge, this is the only drug in development that has predictable exposure. Once we give to the patient, without foods, without a cheeseburger before bedtime, they're going to get the exposures that are necessary. That is fundamental, right? There's no drug in the brain, no effects, and no carryover to the next day. So the ability to dose the drug, what we've seen from our side effect profile, and the conduct itself, being obsessed with conduct from day one, not changing the end points, sticking to the conduct, sticking with a few sites, being really adamant and a little bit of CG about how to conduct gets us to this point that now we are just cleaning the data and we're going to have the results to discuss in due time.
spk01: We'll have to talk about why you hate midnight cheeseburgers, but thanks for taking the question.
spk08: I don't hate them, but I'm also not depressed. Not every night. Not every night. Okay.
spk04: Your next question is from Douglas Chao with H.E. Wainwright. Please go ahead.
spk02: Hi. Good afternoon. Thanks for the questions. And congrats on the data. Just maybe it'd be helpful to just walk through the sort of implications, if you will, of changing the primary endpoint to efficacy. And also, if you could just remind us what some of the differences between essential one and the two-way study are?
spk08: Perfect, Doug. I'm going to hand this over straight to Bernard so he can walk you through that.
spk05: Yeah, so I think one of the previous questions, what do we learn? I think the reason we're changing it to an essential one, to an efficacy study, is because we've learned what we need to know to conduct an efficacy study. And so Those big questions are who's the right population and whom can you measure a response? We talk about people with adequate baseline severity. Do we understand the dose range? We do, and we understand that we can titrate people up with good tolerability. We have a clear efficacy signal, which I think is remarkably clear from both the open label and the randomized withdrawal. and we understand the endpoint. And so the implications are, you know, we understand how to put together an efficacy study now. And then I think it's a matter of discussion with the agency, like Marcio said, will this serve as one of the pivotal studies. But it has all the key ingredients, and we'll come back with more specifics about what that amendment and redesign will look like. you know, within the footprint of what we already have going in the Essential One study.
spk02: And just as a follow-up, have you or do you plan to engage with the agency in terms of this switch just to ensure that there are elements that you might need to make sure that the sort of staff plan in particular is done appropriately so that it could function as a registrational study?
spk08: Yes, Doug, the interesting thing is when we submitted the original proposal for the program, right, as a CTP to the agency, they specifically noticed what it would have to do in order to make Essential 1 registrational. We chose at that point in time not to, but we have a very good idea of what the criteria is. and we would be adhering to it 100%, as we always do, and then have a discussion with them. Now, if we deem necessary, the changes are more than simply like in terms of the size or the actual order of the endpoints. We obviously would reach out, make sure we have their buy-in before the SAP is finalized. Okay, great.
spk02: I'll have that in the queue. Sure.
spk04: Your next question is from Miles Minter with William Blair. Please go ahead.
spk06: Yeah, you're going to hate me, but back on essential one and the potential trial modifications here, are you looking at increasing the patient enrolment number and also on the stats plan, considering it's now going to be an efficacy trial, how are you going to adjust for multiplicity between the doses there? I only make mention of that because there's been some recent FDA interactions in the schizophrenia space. where if not all doses are positive and it's not aligned with your stats plan, it technically is not a positive trial. So what are your thoughts all around that? Thank you.
spk08: Yeah, Miles, there are a number of ways to do it, right, as you well know. And this is still pretty much in flux right now. We do believe we have a very good understanding on which dose should be the most used. And we're going to hold that a little bit close to the vest right now. We're going to hear that soon. So there are ways to prioritize one dose if we choose to do that and make the other ones a secondary or even to combine exposures at a given dose at a given time point. So we're exploring different ways. I completely agree. I think we all here completely agree with your statements. Whatever you do has to be very clearly justified and spelled out in the new protocol because we're going to have to submit an amendment and subsequently on the statistical analysis plan and that's sent to the agency, wait for comments, and so on. We're in a very fortuitous period because we're in May. We know all of this right now. We have plenty of time to consult with the agents while we continue to enroll and make the adjustments. two essential ones, but very, very good points. As we are learning more about the time dependence of the effects, which kind of goals that would saturate the effects, I think this is going to be fairly straightforward, but we're not going to cut any corners. We're going to cross every T and dot every I towards the end of this study.
spk06: Great. I'll hop back in the queue. Thanks. Cheers. Cheers.
spk04: Once again, ladies and gentlemen, if you have a question, you may press star one now. Again, it's star one on your telephone keypad. Your next question is from Laura Chico with Bud Bush. Please go ahead.
spk03: Hey, guys. Sorry. Just one quick follow-up. I think cash runway actually changed from 2Q23 into 3Q23. I guess I just wanted to maybe take a step back. With the number of these studies still set to start in the second half of the year, I'm just trying to understand kind of what flexibility you might have in terms of prioritization of efforts but also further extension of cash runway. Thanks very much.
spk10: Sure. Thanks, Laura, very much for the question. And overall, we're very conservative when we look at our cash runway, and by that we mean we plan for success with our studies. When we looked at things like our portfolio prioritization with the 562 Saxuna indication falling out with a little bit of a delay in our PD study with the way we're looking at 222 now, it created just a bit more space in our runway. So we move now into Q3 of 23.
spk04: Your next question is from Miles Minter with William Blair. Please go ahead, Steve.
spk06: Yeah, just on slide eight of the data released this afternoon, it does look as if when those patients come off drug that they pretty much cannot draw in a circle, but they kind of could at baseline. So I'm wondering what your theory is there. Is there a dependency that's developing on 944? Or, like, why would a patient that's come off drug not be able to draw that circle if they could at baseline? And I know that that's just one patient. Did that happen for everyone who had a response to 944 on the trial? Thanks.
spk05: Yeah, thanks for the question, Miles. There's definitely... when you remove a drug in people with tremor, a drug that's working, there can be brief, you know, transient kind of overshoot, worsening, really not a physiologic dependence. There's nothing like that. There are no signs of withdrawal. It's just kind of the tremor rebounds. And so they see, like, that's a, you know, day 56. At day 70, they kind of go back to their baseline. So No, it does not happen in everybody. It is not unique to this class because you see it with other medications, including clinically, and it's transient. Thanks.
spk04: Your next question is from Rita Burrow with Cowan. Please go ahead.
spk01: Hi, guys. So I think you mentioned that eight of the 11 patients, I believe, if I was reading this, reading my notes correctly, eight of 11 patients were able to complete the open label at full dose. Can you talk about why the I believe the three had to dose reduce? What were the symptoms that drove it and what dose they had to dose reduced to?
spk08: Yeah, and maybe just a reminder here, right, Richard, and I'll hand over to Bernard. We allowed for those chains until day 36 on day 30, and after that they had to be stable to enter into the randomized withdrawal day for each year. So that's one important phenomena here. The second is when you look into our PG curves versus concentration, which is the sigma bands, We tap out around 80 milligrams, between 80 and 100. We wanted to push to 120 to make sure you are safe and if other patients needed to go there. Now, we knew all along that some of them would and some of them would not. We're actually very pleased with the proportion of patients that were there. But I'll get Bernard to talk a little bit about the optionality here and what we've seen.
spk05: Yeah. So, as pointed out, Ritsu, thanks for the question. Overall... really well-tolerant. Most of the people were able to get up to the highest dose there. The people who down-titrated or just didn't titrate up, it was a range of kind of common AEs that you see with CNS drugs. Dizziness, there was difficulty paying attention, focusing. For the most part, those AEs occur early. So people are going to have them they tend to have them early. And so, you know, once they're titrating up, they generally do fine. And so what we've done in Essential One, and we plan to continue this, is we've lowered the starting dose so that people can get just a bit of a smoother ramp. And we believe that that's going to help.
spk01: Got it. Thanks. Thank you.
spk04: Once again, if you have a question, please press star 1 now. Or if you do have follow-ups, please press star 1 now. Your next question is from Douglas Tao with HC Wainwright. Please go ahead.
spk02: Hi. Thanks for taking up the follow-ups. Just quickly, I mean, obviously, it's a small number of patients, and the ADAL score improvements are really impressive. I'm just curious if if you have a sense of what proportion of the patients responded with sort of clinically meaningful responses and how much variability across the patient population was there in terms of improvements. Thank you.
spk08: Yeah, Doug, that is an incredibly important question and one that was one of the first things that we looked into this data when it got like the last few days. So the vast majority of the patients responded on the ADL. And all the patients, once you remove the drug, lost response. And I think that's quite important because obviously they didn't know if they were on drug. And this is a seven-day look back on their lives, on the things that they were able to do or not do. One of the interesting things about the future, when the FDA asked us to rescore the ADL, is that by removing the zero in each one of those items, you make every other item clinically meaningful. Because now every change is from not being able to do something to being able to do something. Or unfortunately, in some cases, after they removed the drug, they lost that ability. So what we're seeing is a very clear gaining functions back on their life, And then when you remove the drug, progressively losing those functions. The half-life of 9-4-4 is fairly, I would say, short. It was by design that way, so we can get coverage during the day. But it's very clear it's necessary to continue dosing. Otherwise, it gets like a worse. So it's unequivocal in our view that any change on the ADL would be important. And the vast majority of the patients got those changes. The ones that did not respond at all, which were a few of the patients in this study, they really didn't respond throughout, which gives us confidence, one, if it was on the open label, that there are responders and non-responders, but now we have the benefit of randomizing these patients, right? They wouldn't know, once more, if they end up on drug or placebo. There is no functional unblinding here, as Bernard just mentioned, that the AEs happen at the beginning of the treatments. So at the time they got to day 42, there's really not a lot going on in terms of adverse events. So they really didn't know. And then when you remove the drug, such a dramatic change on the ADLs and not happening the same on the ones that keep on the drug, that just gives us confidence that now it just runs to the next year to race to make sure we can get this drug to patients in the markets.
spk05: A nice thing to add about ADLs is, right, that the adverse events predominantly CNS, but the ADLs really integrates any side effects you might have along with the benefit on tremor because of how they're functioning with that. So to see that really marked upside improvement in function tells you a lot about the benefit risk.
spk02: Great, thank you so much.
spk04: Once again, if you have a question, please press star 1 now. Your next question is from Myles Minter with William Blair. Please go ahead.
spk06: Yeah, thanks. Last one from me. On slide 6, are you disclosing, I guess, how many patients actually had a response to 944 and then got randomized to placebo or, for that matter, didn't respond and got randomized randomized to placebo because theoretically, you know, those patients should be flat over the 56-day period with their tremor, right? So I'm just wondering how much they actually contributed to the data that we're seeing here. Thanks.
spk08: Yes. So, Miles, the patient, there's no objective measure of response, right? But I'll give you a little bit of an idea of what happened here. We had one more patient randomized, as you know, to one group than the other since it was an odd number. The patients that were randomized to placebo had a numerically bigger response before. It should be obvious by the numbers. We're just reinforcing that. But the one interesting thing is every one of them returned towards baseline. So there was no super responder or super loss of responder and others that stayed flat. While the ones that stayed on 944, they manifested more like the typical group that stayed on drug, which made this incredibly clear that the drug wasn't still active. We're just seeing small variabilities here and there on the one with 944, but very large chains, virtually all of them moving back to baseline or even overshooting drugs a little bit, which is not uncommon with TMS active drugs, as you all know.
spk06: Cool. Thanks for the caller and all of the questions. Appreciate it.
spk04: Once again, if you have a question, please press star 1 now. Again, that's star 1 on your telephone keypad. You have a follow-up or additional question from Yasmine Rahimi with Piper Sandler. Please go ahead.
spk07: Hi, guys. Thanks again. So one last question. How is, or I guess, any comments on screen failure rates or the screening protocol going into the Essential One study to help to understand to capture a homogenous population? So any color on that would be helpful. Thank you.
spk08: Thanks for the question. Again, We haven't discussed that before, but it might be a good point to discuss how we do it. Just like Aria, and you all heard myself, Bernard, Tim, the entire team here at BRACS is reinforcing how strict our screening criteria is for MDG. It's not any different. For essential one, we have a central reviewer of severity, It has to be general concordance. Otherwise, the patients are excluded. We are seeing a number of patients getting excluded because they are not stable or they're not severe enough. I think we just saw here how important it is that we stay true to that measure. It's ramping up. I would say that it's not necessarily critical mass that I would start talking about exactly what the ratio is. I think once we started talking about for ARIA, for example, we are like three-quarters of the enrollments and gives us better confidence on the numbers, but it's not small. We are excluding a significant number of patients from coming to trial because they cannot show that they are severe enough to participate, which gives us great comforts, actually, that that's the right thing to do. We might now be able to provide other alternatives to these patients through, like, different mechanisms, but to be able to show this drug is efficacious meets the regulatory statutory definition and get the drug approved, I think we have to stay the course. Enrollments, though, was going pretty well before. I'm sure it's going to continue to go even better now that we have the majority of the sites in the U.S. open, recruiting patients, screening them actively every week.
spk05: Yes, I'd add that the way we do the reviews here, we do video, so it is paired with the history of their tremor. So it helps us confirm the diagnosis, which I think is very important because you want to screen out the mimics, just like we've talked about in ARIA. So you want to get the correct diagnosis, and we confirm severity. We've said that central review, you lose a little granularity in the amplitudes, but you can still confirm that it's at or above 10 points upper length.
spk07: Great. Thank you.
spk04: Once again, if you have a question or a follow-up, please press star 1 now. Again, it's star 1 on your telephone keypad. As there are no additional questions or follow-ups, I'll now hand the conference back to Marcio Souza, CEO, for any final comments.
spk08: Thank you so much, and thanks, everyone, for joining, for supporting us and all those patients throughout their journey here. A couple of points I wanted to make, just to close. We promise to deliver those results in May. Here we are. We deliver We promised to deliver the results for ARA in June, and there we're going to be delivering those results and then four more results after that. All of this taking very good care for the shareholders, all the other stakeholders, and for the cash we have in hands. So we can deliver those drugs to more and more patients. So we haven't changed anything in terms of just how disciplined we are. on the use of capital, use of resource, being serious and clear with the science. The science today is speaking volumes for us to continue 944, and we will. But if it was not the case, we would be serious as well about not continuing. And we believe strongly here at Praxis to stay to our pillars. Every drug screams for genetics. Very good translational data. I want to remind everyone. We have beautiful translational data for 944 that was presented at AAN last month. Here we are, translational data, giving clinical data to these patients. We have beautiful translational data for 114, and we're all excited to be sharing that soon as well, and many more drugs to come in the future. So thank you again for all the patients that participated in the trial, for all investigators And for all the practices that work day and night to get to this moment. And talk to you all soon.
spk04: This concludes today's question and answer session. Thank you for participating. You may now disconnect. Have a great day.
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