Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines' First Quarter 2022 Corporate Update Question and Answer Conference Call. At this time, all participants are in a listen-only mode. After a short remark, there will be a question and answer session. To ask a question during that session, you will need to press star one on your telephone. If you require any further assistance, please press star zero. Now it is my pleasure to hand the conference over to your first speaker today, Alex Kane, Vice President, Investor Relations and Corporate Communications at Praxis. Thank you. Please go ahead.
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?
Thank you, sir. We will now begin the question and answer session. If you would like to ask a question, please press star one now. Again, that's star one on your telephone keypad. Please stand by while we compile the Q&A roster. Your first question is from Yasmeen Rahimi with Piper Sandler. Please go ahead.
Hey, guys. Thanks so much. This is Lauren on for Yas. I have a couple questions. The first one, what are some of the key lessons you guys learned from PRAX-944 data that could impact your views into the Essential1 Phase IIb study? And then speaking a little bit to the enrollment, how that's going into that study, and do you think that the Essential1 population will capture a similar demographic? Thank you.
Oh, thanks so much for the question. I would say maybe I'll start through the end there. Like the enrollment population for Essential1 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 TETRAS upper limb score less than 10 on Essential1, which is also kind of related to your first question. That's what we learned conducting the studies and looking to other data in this space as well. There has to be in order to be like a little bit more homogeneous a certain level of tremor at baseline.
We went through a fairly broad, as PRAX-944-221 was, to a little bit more restrictive, so on the higher end of them. That would allow us, we expect, to show even more clear results, not that if we need it, based on today's data, on the Essential1 coming up. The enrollment on the trial is going pretty well. We reinforced today, we continue to reinforce the readouts by the end of the year. I'll hand over to Bernard for any other comments here about the lessons.
Yeah, the point about the population is a key one. 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 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. I think we learned a lot about the endpoints, too. 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.
I think it really helps us focus in on function and understanding that that is a reliable measure that integrates a lot of tremor in activities that patients come across every day.
Thank you so much for that information. Sorry, just one more question. What were the reasons for the three discontinuations in the PRAX-944 study?
Yeah. There was one person who had a discontinuation totally unrelated to PRAX-944. They needed a procedure for something that they, you know, had a medical condition they had going in. It was totally unrelated. And then the other discontinuations, one was dizziness and the other was primarily fatigue. All the AEs there were mild to moderate. There was only one severe AE, which was worsening of tremor when drug was withdrawn. Overall, really well tolerated.
Great. Thank you so much, guys.
Thank you.
Your next question is from Laura Chico with Wedbush. Please go ahead.
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 Essential1. 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 Essential1 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.
Yes, Laura Chico, 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 gonna be informing all of you about those mechanics. Also specifically what. There are so many alternatives right now, as you can imagine, with such a robust rebound after removal of the drug, it gives us a lot more confidence on some of the aspects that were unclear, like which doses should be targeting and things like that. We're working all of that. In terms of the endpoints, I think this was incredibly clear with us and with others as well in the space, on measures that very clearly affect function for those patients.
When you look into the ADL originally as designed, it was already a pretty good assessment of function. The loss, the ability to affect 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. 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. It's a lot more trustworthy, I would say, the way the analysis is being done right now. We're very convinced by the feedback to date 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 we're gonna be very clear to drive and choose 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 we have to run two more trials, which we'd be, incredibly pleased to do it, as well for a drug that is so active.
Thanks very much. Congratulations.
Thank you. Thank you.
Your next question is from Ritu Baral with Cowen. Please go ahead.
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. Can you tell us when last patient last visit is? And then further, you know, just given gabapentin precedent showing deltas of 2 points in sort of larger Phase II, Phase III trials, you've mentioned that you've powered this for a 3-point difference. Is this mainly because you think that you've got better placebo control, or do you think that this could be driven by just sheer differential efficacy? Thanks.
Yeah. Of course, to appreciate the questions. A couple things here. One, we're hopeful that the ClinicalTrials.gov post would be up as we speak with you. You're gonna see that hopefully in the next few hours or by tomorrow. 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. That's really the last piece of data we needed to be completed. The patient showed up on the day he was supposed to, and we were able to complete the study by itself. The next Phase here is obviously clean 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. 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. That alone wouldn't give us the separation and the overall profile that we expect. Why are we so confident the drug behaved the same way? To our knowledge, this is the only drug in development that has predictable exposure.
Once we give to the patient, with or without foods, with or without a cheeseburger before bedtime, they're gonna get the exposures that are necessary. That is fundamental, right? No drug in the brain, no effects, and no carry over to the next day. The ability to dose the drug, what we've seen from a side effect profile, and the conduct itself, being obsessed with conduct from day one, not changing the endpoints. We're sticking to the conduct, just sticking with few sites, being really adamant and a little bit OCD about how to conduct gets us to this point that now we are just cleaning the data, and we're gonna have the results to discuss in due time.
We'll have to talk about why you hate midnight cheeseburgers, but thanks for taking the question.
I don't hate them. I'm also not depressed.
Not every night.
Not every night.
Your next question is from Douglas Tsao with H.C. Wainwright & Co. Please go ahead.
Hi. Good afternoon. Thanks for taking the questions. 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. Also if you could just remind us what some of the differences between Essential1 and the IIa study are.
Sure thing, Doug. I'm gonna hand this over straight to Bernard so he can walk you through that.
I think, one of the previous questions, what did we learn? I think the reason we're changing it to an Essential1 into an efficacy study is 'cause we've learned what we need to know to conduct an efficacy study. Those, you know, those big questions are, who's the right population and whom can you measure a response? We talk about people with, you know, 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. We understand the endpoint.
The implications are, you know, we understand how to put together an efficacy study now. I think it's a matter of discussion with the agency, like Marcio said, will this serve as one of the pivotal studies. 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 Essential1 study.
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 change to make sure that the sort of stat plan in particular is done appropriately so that it could function as a registrational study?
Yes. Doug, the interesting thing is when we submitted the original proposal for the program as a CDP to the agency, they specifically noticed what we'd have to do in order to make Essential1 registrational. We chose at that point in time not to. We have a very good idea on what the criteria is, and we would be adherent 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. I'll hop back in the queue.
Sure.
Your next question is from Myles Minter with William Blair. Please go ahead.
Yeah, you're gonna hate me, but back on Essential1 and the potential trial modifications here. Are you looking at increasing the patient enrollment number? Also on the stats plan, considering it's now going to be an efficacy trial, how are you gonna adjust for multiplicity between the doses there? I only make mention of that 'cause 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. What are your thoughts all around that? Thank you.
Yeah, Myles, there are a number of ways to do it, right, as you well know. This is still pretty much in flux right now. We do believe we have a very good understanding of which dose should be the most used, and we're gonna hold that a little bit close to the vest right now. You're gonna hear that soon. 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. We're exploring different ways. I completely agree. I think we all here completely agree with your statements.
Whatever we do has to be very clearly justified and spelled out in the new protocol because we're gonna have to submit the amendments 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 agency while we continue to enroll and make the adjustments to Essential1. Very, very good points. As we are learning more about the time dependence of the effects, which kind of goes, that would saturate the effect. I think this is gonna be fairly straightforward, but we're not gonna cut any corners. We're gonna cross every t and dot every i towards the end of this study.
Great. I'll hop back in the queue. Thanks.
Cheers.
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 Wedbush. Please go ahead.
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 a 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.
Sure. Thanks, Laura Chico, very much for the question, and overall we're very conservative when we look at our cash runway. By that we mean we plan for success with our studies. When we look at things like, you know, our portfolio prioritization with the 562 SCN2A 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 2023.
Your next question is from Myles Minter with William Blair. Please go ahead, sir.
Yeah, just on slide eight of the data release 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. I'm wondering what your theory is there. Is there a dependency that's developing on nine four four or like why would a patient that's come off drug not be able to draw that circle if they could at baseline? I know that's just one patient. Did that happen for everyone who had a response to nine four four on the trial? Thanks.
Yeah. Thanks for the question, Myles. There's definitely, when you remove a drug in people with tremor, a drug that's working, there can be brief, you know, transient, kinda 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. They see like that's a, you know, day 56. At day 70, they kinda go back to their baseline. No, it does not happen in everybody. It is not unique to this class 'cause you see it with other medications, including clinically, and it's transient.
Thanks.
You bet.
Your next question is from Ritu Baral with Cowen. Please go ahead.
Hi, guys. I think you mentioned that eight of the 11 patients, I believe, if I was reading my notes correctly, eight of 11 patients were able to complete the open label at full dose. Can you talk about why the three had to dose reduce? What were the symptoms that drove it and what dose they had to dose reduce to?
Yeah, maybe just a reminder here, right, Ritu, and I'll hand over to Bernard this. We allow for dose change until day 36 on this study, and after that, they had to be stable to enter into the randomized withdrawal day 42. That's one important phenomenon here. The second is when you look into our PD 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.
Yeah. As you pointed out, Ritu, thanks for the question. Overall, really well-tolerated. 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, difficulty paying attention, focusing. For the most part, those AEs occur early, so if people are gonna have them, they tend to have them early. You know, once they're titrating up, they generally do fine. What we've done in Essential1, 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. We believe that that's going to help.
Got it. Thanks.
Kim?
Once again, if you have a question, please press star one now, or if you do have follow-ups, please press star one now. Your next question is from Douglas Tsao with H.C. Wainwright & Co. Please go ahead.
Hi. Thanks for taking up the follow-ups. Just quickly, I mean, obviously it's a small number of patients and the ADL score improvements are really impressive. I'm just curious 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 improvement? Thank you.
Yeah. Doug, that is an incredibly important question and one that was one of the first things that we looked into this data, when we got like the last few days, right? The vast majority of the patients responded on the ADL. All the patients, once you remove the drug, lost response. I think that's quite important because obviously they didn't know if they were on drug, right? 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, right, in each one of those items, you make every other item clinically meaningful.
'Cause now every change is from not being able to do something to being able to do something, or unfortunately in some case here, then after they removed the drug, they lost that ability. What we're seeing is a very clear gain in functions back in their life and then when you remove the drug progressively losing those functions. The half-life of 944 is fairly, I would say, short, 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 worsens, yeah. It's unequivocal in our view that any change on the ADL would be important, and that 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. 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. 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.
When you remove the drug, such a dramatic change on the ADLs and not happening the same on the ones that it keep on the drug, that just gives us confidence that now we just run to the next year of the race to make sure we can get this drug to patients in the markets.
To add is about ADLs, right, that the adverse events predominantly CNS, but the ADLs really integrates any side effects you might have along with the benefit on tremor 'cause how they're functioning with that. See that really marked upside improvement in function tells you a lot about the benefit risk.
Great. Thank you so much.
Once again, if you have a question, please press star one now. Your next question is from Myles Minter with William Blair. Please go ahead.
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, they got randomized to placebo? 'Cause theoretically, you know, those patients should be flat over the 56-day period with their tremor, right? I'm just wondering how much they actually contributed to the data that we're seeing here. Thanks.
Yes. Myles, the patients, there's no objective measure of response, right? 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. The one interesting thing is every one of them returned towards baseline. There was no super responder or super loss of responder and others that stayed flat. While the ones that stayed on nine four four, they manifested more like the typical group that stay on drug, which made this incredibly clear that the drug was still active.
We're just seeing small variabilities here and there on the one with 944, but very large change, or virtually all of them moving back to baseline or even overshooting, a little bit, which is not uncommon with CNS active drugs, as you all know.
Cool. Thanks for the color and all of the questions. Appreciate it.
Once again, if you have a question, please press star one now. Again, that's star one on your telephone keypad. You have a follow-up or additional question from Yasmeen Rahimi with Piper Sandler. Please go ahead.
Hi, guys. Thanks again. One last question. How is, or I guess any comments on screen failure rates or the screening protocol, going into the Essential1 study, to help to understand to capture a homogeneous population? Any color on that would be helpful. Thank you.
No. Thanks for the question. Again, we haven't discussed that before, but it might be a good point to discuss how we do it, right? Just like Aria, and you all heard myself, Bernard, Tim, the entire team here at Praxis reinforcing how strict our screening criteria is for MDD. It's not any different for Essential1. 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 there's not necessarily critical mass with 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, like, 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 comfort, 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 gonna 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.
Yeah. As I'd add that the way we do the reviews here, we do video. It is paired with the history of their tremor. It helps us confirm the diagnosis, which I think is very important because you can get. You wanna screen out the mimics, just like we've talked about in Aria. You wanna get the correct diagnosis, and we confirm severity. We said that central review, you lose a little granularity in the amplitude, but you could still confirm that it's you know above at or above 10 points upper limb.
Great. Thank you.
Once again, if you have a question or a follow-up, please press star one now. Again, it's star one 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.
Thank you so much, and thanks for 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 promised to deliver those results in May. Here we are. We delivered. We promised to deliver the results for Aria in June, and there we're gonna 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 hand, so we can deliver those drugs to more and more patients. 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 nine four four, and we will. If it was not the case, we would be serious as well about not continuing. We believe strongly here at Praxis to stay to our pillars. Every drug, screen for genetics, very good translational data. I wanna remind everyone, we have beautiful translational data for our nine four four that was presented at AAN last month. Here we are, translational data, giving clinical data to these patients. We have beautiful translational data for one one four, and we're all excited to be sharing that soon as well, and many more drugs to come in the future. Thank again for all the patients that participated in the trial, for all investigators, and for all the Praxians that work day and night to get to this moment.
Talk to you all soon.
This concludes today's question and answer session. Thank you for participating. You may now disconnect. Have a great day.