Praxis Precision Medicines Inc (PRAX) 2022 Q1 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines First Quarter 2022 Corporate Update, Question and Answer Conference Call. (Operator Instructions)

And 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?

(Operator Instructions) Your first question is from Yasmeen Rahimi with Piper Sandler.

This is Lauren on for Yas. I have a couple of questions. So the first one, what are some of the key lessons you guys learned from PRAX-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?

I would say maybe we 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 ADL score less than 10 on a central 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 like a little bit more homogeneous a certain level of tremor at baseline. So we went through a fairly broad as 944-221 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 need it based on today's data on the Essential1 coming up. And the enrollment of the trial is going pretty well. We reinforced today. 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.

Yes. The point about the population is a key one. And then I think you had a couple of 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 -- got a very well substantiated dose range based on that mechanistic biomarker of quantitative EEG. So really confirms we've about 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 ADL and particularly modified ADLs. And we've seen what a responsive measure that is including in the randomized withdrawal double-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.

Sorry, just one more question. What were the reasons for the 3 discontinuations in the PRAX-144 study?

Yes. So there were -- there was one person who had a discontinuation totally unrelated to PRAX-944. So they needed a procedure for something that they had medical conditions they had going in. So it's 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.

Your next question is from Laura Chico with Wedbush.

I guess I just wanted to verify or clarify some of the comments you had in the video with respect to Essential1. So 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?

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. So we'd be informing all of you about the those mechanics. Also specifically was, there are so many alternatives right now, as you can imagine, with such a robust rebound after we move the drug. It gives us a lot more confidence on some of the aspects that were unclear, like which dose should be targeting and things like that. So we're working all of that. In terms of the endpoints, the agency was incredibly clear with us and with others as well as in the space on measures that very clearly affect function for those patients.

So when you look into the ADL originally as designed, we're working pretty good assessment assumption. The loss, the ability that that's 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 reduced 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 say, the way that it's being done right now.

So we're very convinced by the feedback to-date that the end point is very clear. Now, whether or not the new design will be registrational, that's a matter of discussions with the FDA after we done that design. I think what we're going to be very clear driving shoes for clinically and strategically significant change and then have a discussion with the agency once the results are ahead, whether or not that could serve as 1 of 2 trials or if you have to run 2 more trials, which would be incredibly easy to do it as well with the drug they selected.

Your next question is from Ritu Baral with Cowen.

I want -- now that you've gotten last patient, last visit in Aria, I just wanted to check in on final conduct data retention, etcetera. And can you tell us when last patient last visit is? And then further, just given GABAA PAM precedent showing deltas of 2 points in sort of larger Phase 2, Phase 3 trials you've mentioned that you powered this for a 3-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?

Yes, of course, appreciate the questions. So a couple of things here. One, we're wishful that the clinical trials that go post would 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 5, 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 was supposed to -- and so we were able to complete the study by itself. Now, the next phase here is obviously clean up all the data, making sure that we can lock the database in due time and then report.

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 data basis not a lot, but it gives us great confidence that from a conduct perspective, we are in (inaudible). 2 aspects here. Every time we run a control trial, both the drug and placebo have to be 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 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 food, without a cheeseburger before bad time, they're going to get the exposures that are necessary. That is fundamental, right? There's no drug in the brain, no effect and no carryover to the next day. So the appearance to those, the drug, what we've seen from a side effect profile and the conduct itself being obsessed with conduct from day 1, not changing the endpoints. We're sticking to the conduct, sticking with fuel sites, being really adamant and a little bit of CD about how to conduct get us to this point step now we are just cleaning the data, and we're going to have the results to discuss in due time.

Your next question is from Douglas Tsao with H.C. Wainwright.

Just maybe it would 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 Essential1 and the 2 way study are?

Sure thing, Doug. I'm going to hand this over straight to Bernard, so he can walk you through that.

So I think one of the previous questions on what have we learned? I think we -- the reason we're changing it to essential into 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 is the right population and who can you measure a response? And we talk about people with adequate baseline severity? Do we understand the dose range? We do, 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, 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, has served 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 within the footprint of what we already have going in the Essential1 study.

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 -- change that can stick to that 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 right as a [CGP] to the agency. They specifically noticed what would have to do in order to make Essential1 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 change 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 there by end before the SAP is finalized.

Your next question is from Myles Minter with William Blair.

You're going to hate me but back on an Essential1 and the potential trial modifications here. Are you looking at increasing the patient enrollment 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, but it's not aligned with the stats plan, technically is not a positive trial. So what are your thoughts all around that?

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 of which dose should be the most used. And we're going to hold that a little bit closer to the vest right now. You're going to hear that soon. So there are ways to prioritize what dose if we choose to do that and make the other ones as 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 it 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 sent to the agency, wait for comments and so on. We're not very fortuitous because one may we know all of this right now. We have plenty of time to consult with the agents while we continue to grow and make the adjustments to Essential1, but very, very good points as we are learning more about the type of dependence of the effects, which kind of dose that would saturate the effect, I think this is going to be very straightforward, but we're going to -- we're not going to cross -- we're not going to cut any corners. We're going to cross every T and dot every I towards the end of this time.

(Operator Instructions) Your next question is from Laura Chico with Wedbush.

Sorry. Just one quick follow-up. I think cash runway actually changed from 2Q '23 into 3Q '23. 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.

Sure. 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. And so when we look at things like our portfolio prioritization with the 562 SUNCT/SUNA 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.

Your next question is from Myles Minter with William Blair.

Just on Slide 8 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 PRAX-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 in the trial?

There's definitely when you remove a drug in people with tremor or that's working, there can be brief, transient 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 at day 56, 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 its transit.

Your next question is from Ritu Baral with Cowen.

So I think you mentioned that 8 of the 11 patients, I believe, if I was reading my notes correctly, 8 of 11 patients were able to complete the open label at full dose. Can you talk about why this -- I believe the 3 had to dose reduce. What were the symptoms that drove it and what dose they had to dose reduce to?

And maybe just a reminder here, right, Ritu and I'll hand over to Bernard. We allowed for dose change until day 36 on this study. And after that, they had to be stable to enter into the randomized for day 42. So that's one important phenomenon this year. 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 milligrams. We wanted to push to 120 milligrams 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 actually very pleased with the proportion of patients that were there. But I'll have Bernard talk a little bit about the optionality here and what we've seen.

Overall, really well tolerating 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, 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 once they're titrating up, they generally do fine. And so what we've done in Essential1, and we plan to continue this as 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.

(Operator Instructions) Your next question is from Douglas Tsao with H.C. Wainwright.

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?

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 in the last few days, right? So the vast majority of the patients responded on the ADL and all the patients once you remove the drug lost the response. And I think that's quite important because obviously, they didn't know if they were on drug, right? So the -- and this is a 7-day look back on their lives on the things that the way we should 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 because now every change is from not being able to do something to being able to do something or unfortunately, in some case here, they actually removed the drug, they lost that ability.

So what we're seeing is a very clear gaining functions back on their lives. And then when you remove the drug progressively losing those functions. The half-life of my portfolio is fairly, I would say, short was by design the 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 year. So it's unequivocal in our view that the any change on the ADL would be important. And the vast majority of the patients got those change. 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 don't know once more, if they end up on drug or placebo, there is no functional unblinding here, as Bernard just mentioned that AEs happen at the beginning of the treatment. 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 raise to make sure we can get this truth patients in the market.

The nice thing to add is about ADLs is, right, the adverse events, predominantly CNS, but the ADLs really integrates any side effects you might have along with the benefit of tremor because how they're functioning with that. So to see that really marked upside improvement in function tells you a lot about the benefit risk.

Our next question is from Myles Minter with William Blair.

On Slide 6, are you disclosing, I guess, how many patients actually had a response to PRAX-944 and then got randomized to placebo or for that matter, didn't respond, they got randomized to placebo because theoretically, 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?

So Myles, the patients, there's no jacked up 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 a loss of responder and others that stayed flat. While the ones that is stable on 944, they manifested more like the typical group that stay on drug, which makes this incredibly clear that there was -- the drug was still active. We're just seeing small vulnerabilities here and there on the 994, but very large chains 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.

You have a follow-up or additional question from Yasmeen Rahimi with Piper Sandler.

So 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 homogenous population. So any color on that would be helpful.

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 strength our screening criteria for (inaudible). It's not any different for Essential1, we have a central reviewer of severity 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 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 3 quarters of 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 the 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 as efficacious meets the regulatory statutory definition and get the drug approved that we go have to stay the course. Enrollment, though, was going pretty well before. I'm sure it's going to continue to go even better now than we have the majority of the sites in the U.S. open, recruiting patients is screening that actively every week.

Yes. As I would 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 can get -- 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 said that central review, you lose a little granularity in the amplitude, but you could still confirm that it's above -- at or above 10 points upper limb.

(Operator Instructions) As there are no additional questions or follow-ups, I will now hand the conference back to Marcio Souza, CEO, for any final comments.

So thank you so much, and thanks for joining, for supporting us and all those patients throughout the 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 delivered -- we promised to deliver the results for our end June and that we are going to be delivering those results and then 4 more results after that. All of this taking very good care for the shareholders, all the other stakeholders and for the cash we have enhanced -- so 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'd be serious as well about not continuing. And we believe strongly here a practice to stage to our dealers, every drug screen for genetics, very good translational data. And I want to remind everyone we had beautiful translational data for our PRAX-944 that was presented at AM last month. Here we are translational data, giving clinical data to these patients who 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 again for all the patients that participated in the trial for our investigators and for all the [Praxisons] that work day and night to get to this moment and 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.