Praxis Precision Medicines Q2 2024 Earnings Call Transcript

Quartr
Provided by Quartr
August 13, 2024

Key Takeaways

  • ESSENTIAL-3 Phase 3: Praxis is running two simultaneous 12-week studies (parallel and randomized withdrawal) of felixacaltimibe in Essential Tremor, with an interim analysis planned for Q4 2024 and full topline data by year-end to support an NDA filing in 2025.
  • ENERGY epilepsy program: Lead compound PRX-628 enters four late-stage studies—including the EMPOWUR observational consortium and the RADIANCE efficacy trial—with topline results for RADIANCE expected in H1 2025 and POWER-1/2 pivotal trials slated for H2 2025.
  • IMbOLD Phase 2 readout: PRX-562 (rolaltrogene) in pediatric developmental and epileptic encephalopathies (SCN2A/8A) is on track for top-line results this quarter, where the company expects to report placebo-controlled efficacy and extension data showing a 20–30% seizure reduction.
  • Ozanersen global registration: The ASO PRX-222 targeting SCN2A has initiated its first arm in Brazil and will expand into Europe and the U.S. later this year, building on Part 1 INBREX data that demonstrated significant seizure reductions and increased seizure-free days.
  • Strong cash runway: Q2 operating expenses were $37.8 M (R&D $27.3 M, G&A $10.6 M), ending the quarter with $433.8 M in cash and equivalents—fully funding key clinical readouts into 2027.
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Earnings Conference Call
Praxis Precision Medicines Q2 2024
00:00 / 00:00

There are 11 speakers on the call.

Operator

Good day. Thank you for standing by. Welcome to the Nephraxis Physician Medicine Second Quarter 2024 Corporate Update Conference Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer session.

Operator

Please note that today's conference is being recorded. I will now hand the conference over to your speaker host, Daniel Ferry. Please go ahead.

Speaker 1

Good morning, and welcome to Praxis Precision Medicine's Q2 2024 Financial Results and Business Update Conference Call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com. This call is also being recorded. Please note that remarks made during this call may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines and financial projections.

Speaker 1

While these forward looking statements represent Praxis' views as of today, this should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking on an obligation to do so. Please refer to Praxis' most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business. Leading the call today will be Marcio Sousa, President and Chief Executive Officer of Praxis Tim Kelly, Chief Financial Officer, will also be joining Marcio. After providing updates on our key programs, there will be a brief question and answer session.

Speaker 1

With that, it's my pleasure to turn the call over to Marcio.

Speaker 2

Thank you. Good morning, and welcome to the Praxis Q2 2024 Conference Call. Praxis is driven by our mission to therefore more as we discuss throughout the call today. We have organized today's call to provide you with a comprehensive update on recent progress on upcoming milestones for our key clinical programs. I'm very proud of the significant progress we have made so far this year, with ZEPRAXIS in a position to have up to 4 programs in a registrational phase by 2025.

Speaker 2

We continue to successfully drive our lead clinical program, ulyxicoutimide, towards registration, including the execution of our pivotal ESSENTIAL-three trials in ESSENTIAL TRAVEL, which expected top line results later this year. Additionally, following the positive EPR results in PRAX-six twenty eight, we have designed a comprehensive clinical program, including 3 interventional studies in epilepsy patients and a first of kind observational study in collaboration with the epilepsy study consortium. We look forward to building on the encouraging preclinical and clinical data generated to date with top line results from the first efficacy study expected in the first half of next year. Switching to the upcoming readout this quarter, we remain on track to report top line results for the Phase 2 IMbOLD study of rilatrogine or PRX-five sixty two in pediatric patients with developmental and epileptic encephalopathies. We're very excited about the upcoming readouts and the potential of rolatrogene in SCN2A and 8A.

Speaker 2

We also look forward to further exploring this pipeline in the molecule opportunity across a broad range of indications. With our strong cash position, we're fully funded throughout several key readouts, which will continue to position Praxis at the forefront of precision medicines for CNS disorders. Let me now spend a few more minutes on ELIXA. The unmet need for ET patients is undeniable with millions of patients in the U. S.

Speaker 2

In need of a therapeutic option that allows them to perform daily activities without the impairments created by the condition. With such a large market opportunity, the ET landscape has been ready for innovation. Itluxacaltimibe is a unique and highly selective small molecule inhibitor of T type calcium channels designed to block abnormal neuronal burst firing, which should lead, as you've seen and you're going to be looking into the new study to improvements of ETE symptoms in patients. It has been only a short 9 months since we started the biggest and most comprehensive ETE program conducted to date with Essential 3, comprised of 2 simultaneous Phase 3 studies, including a 12 week parallel design and a 12 week randomized withdrawal one. Essential 3 incorporates a decentralized design to reduce patient burden, which has been working super well, together with stratification of key parameters to maintain balance across groups and the implementation of a very comprehensive screening protocol to ensure suitable patients participate in the study.

Speaker 2

We knew going in ESSENTIAL 3 that the proper endpoint had to be the MAGE L11, as we discussed previously. And also the importance of putting in place the controls to minimize variability and placebo effect, and that was all done. While we are confident about the design and the execution of the program, we're also cognizant of being the first in a space like Essential Tremor and the responsibilities that are bestowed upon us to leave no rock unturned in order to maximize the proven top success of Elixir. With all of this in mind, we built in from the very beginning of the study from the onset of planned interim analysis for the parallel group study or Study 1 in the ESSENTIAL-three program. We have discussed this plan with the FDA, and we intend to complete the analysis in Q4 2024.

Speaker 2

The base assumption we've been using and we're going to continue to use at this point in time is that we would read out the study shortly thereafter. The strong participation we are seeing in Essential 3 continues to highlight the significant unmet needs for new therapies in Essential Thermo, and we really look forward to fulfilling these needs and filing our planned NDA next year. I'll now move to our highly differentiated epilepsy portfolio, beginning with PRX-six twenty eight. As a reminder, PRX-six 8 is a next generation functionally selective small molecule from our Cerebro platform. 628 is currently being developed as a once daily oral treatment for adults with epilepsy.

Speaker 2

Building up the strong results seen to date with 628 both preclinically and clinically, we have started a comprehensive late stage program in epilepsy, and we call this program ENERGY. ENERGY is comprised of 4 studies, aiming to build a strong base of patients for our trial, while generating multiple data points over the next 18 months to support the differentiated profile of BRAC-six twenty eight. We're very excited to be collaborating with epilepsy study consortium, a first in kind initiative to characterize a very large group of epilepsy patients and amongst other things, assess the appropriateness of participation in clinical studies. This initiative is conducted under a clinical protocol called EMPOWUR, which is expected to be up and running this quarter and to be active during the entire development program for PRAX-six twenty eight. Radian is the first of 3 planned efficacy and safe studies we expect to start in the coming months.

Speaker 2

RAZN will enroll patients with either focal or generalized epilepsy who receive 628 for 8 weeks. Site engagement and recruitment initiatives are underway, and we plan to enroll up to 50 patients and expect top line results in the first half of twenty twenty five. Regency is expected to provide important safety, PK and efficacy information about 6 rates and we're really looking forward to it. POWER-one and 2 are our 12 week Phase twothree studies in patients with full concept seizures. POWER-1 is expected to start enrolling later this year with results expected by the second half of twenty twenty five.

Speaker 2

We expect POWER2 to be initiated in the first half of next year, which we believe together with POWER1 will generate a robust efficacy package for PRAC-six twenty eight. With that, I would now like to turn to our erythrogene program for DEs, which are a group of severe epilepsy characterized by developmental delays with early offsets. Rilutrogene is a 1st in class small molecule preferentially inhibits persistent sorting currents, which has been shown to be quite a key driver in uncontrolled seizures in multiple The preclinical and clinical data we reviewed before for rilatrogine supports a differentiated profile in GEEs, particularly those without any effective NSAIDs available today. We look forward to the top line results from our proof of concept study in BOLD's this quarter. We have been particularly humbled by the severity of the patients in the study and the urgent needs they bring to the table for better therapies.

Speaker 2

At the time of the readout, we expect to be able to share the efficacy and safety of the placebo control part of the study as well as available data from the long term extension portion as appropriate. We believe rilutrogene has potential as a best in class option serving as a backbone therapy across multiple gene indications and really look forward to discuss that further with you all in the near future. Finally, I'd like to turn to Alzenirsen, our PRX-two twenty two, our ASO designed to selectively decrease expression of SCN2A gene and directly targets the underlying cause of early onset seizures in SCN2A DE. In the Q2 of this year, we initiated the first arm of the global registration study for Ozanersen in Brazil, which is expected to be followed shortly by the expansion of the program in Europe and in the U. S.

Speaker 2

Later this year. This study builds on the very encouraging data from Part 1 of INBREAK, where patients achieving significantly seizure reduction and significantly increase in seizure free days, while being generally safe and well tolerated. As we take all of the updates together, we anticipate all 4 programs to rapidly advance throughout late stage developments with multiple regulatory filings expected in the next few years, which is incredibly exciting. With that, let me now turn the call over to our Chief Financial Officer, Tim Kelly. Tim?

Speaker 3

Thanks, Marcio, and good morning, everybody. Thank you for joining today's call. I'll provide here a quick summary on the financials for the quarter. In Q2, our operating expenses were $37,800,000 with $27,300,000 of that for R and D and the remaining $10,600,000 for G and A. During the Q2, Praxis spent $27,400,000 in operating cash compared to $20,900,000 in the Q1 of 2024, with the increase reflecting more activity for the ESSENTIAL-three studies, while we continue to maintain a focus on optimizing working capital.

Speaker 3

We ended Q2 with $433,800,000 in cash equivalents and marketable securities compared to $81,000,000 of cash in December. The increase of $352,500,000 is primarily due to net proceeds from Praxis January 2024 and April 2024 follow on public offerings. Our cash reports a runway into 2027 and includes funding all studies that Marcio discussed today to their readout. With that, I will pass it back over to you, Marcio.

Speaker 1

Thank you, Tim. We're now

Speaker 2

going to open the call for Q and A. Thank you. Operator?

Operator

And our first question coming from the line of Yasmeen Rahimi with 5% line. Your line is open.

Speaker 4

Good morning team and congrats on kicking off the energy program. Team, few questions. First one is you alluded to that, I guess, could you comment whether enrollment, I guess, it seems like it's still sort of finishing up, if you could quantify sort of where you are in the cadence of getting essential done? 2nd is you spoke about an interim analysis. Could you maybe talk about what this interim analysis is referring to?

Speaker 4

Because it's maybe a new word that we just picked up on, would love your thoughts on that, what that analysis is and what will be unveiled. And then the third question is, could you maybe talk to us about given that Radian will read out in the first half ahead of the POWER studies, how predictive is going to be the Radian study in terms of read through to POWER I and POWER II, given that it has maybe a more broader population and how you're thinking about enriching that group?

Speaker 2

Absolutely. Good morning, Yas. Thanks for the questions. So on the first one, right, if you can, as we look into our slides like 8 in our corporate equity posted this morning, you're going to see we're clearly maintaining the guidance that we had before. So it's by no mean like a delay here introducing the interim analysis.

Speaker 2

What I wanted to be clear here was going to segue to our second question. As we're looking for the study from the get go, from the very beginning of the prepared remarks, we have the possibility of adding unentrained analysis and we did that was properly discussed and being on the very first portion of the protocol statistical analysis plan and so on. Primarily for two reasons. 1, obviously things can go better than we expect, number 1. And 2, things could happen along the way, that might consider depending on the for us to do this analysis.

Speaker 2

Now, in terms of the data, nothing happened along the way. We have considered phase of enrollments, type of patient, characteristics of the patient, apply the data, it's all looking exactly as we expected here. So that is a check and that will not be a reason to conduct an interim. But externally, there are factors that being happening and that might have influenced like the way we think. So the when the costs of something is very small as it is the case here, but the upside is very large And it is the case here, meaning, if you were, for example, to exercise the ability to increase the sample size in case just like a recent readouts from another competitor program, seems like placebo is slightly higher than expected, not what we are seeing, but we remain more in diligence here.

Speaker 2

We might have the opportunity to do that because we have tremendous interest to the trial that wouldn't be really problem for us whatsoever to do that at points and continue to stay steady. So a big insurance policy on one hand and not really an indicator that there is anything happening with either the enrollments or the problem itself. On the other hand, felt appropriate for us considering the responsibility that we have right now to deliver this program, not only for all of us at practice for all the investors like you are representing here, but patients, right, that don't really have any other option in development now for them. So when you put that all together, increasing the probability of success of the overall program was a key driver and we believe we're doing that by conducting this analysis. So that is on the second.

Speaker 2

On Radiance, so Radiance is, I think, a phenomenal study to be conducting right now. It adds an intermediate readout for us, which obviously continue to build excitement of 6 to 8 to generate data. There are a couple of points to generate more. 1, again, continue to build the success we're seeing now with patients that have non controlled seizures, both with full concept and generalized. But the second is we want to and we believe that since we're accelerating pretty quickly to a potential NDA, not in then far in the future to continue to characterize PK in this population, which is not something fancy or something that we often discuss that needs to be done, but it needs to be done and conducting that on my study that is operationally far easier.

Speaker 2

It's the second parameter and is our first foray on patients with generalized where we're going to get like an even potential for a second indication here in the future. So understanding that as well. All of that done an incredibly efficient way, right? The excitement from all the investigators we talk to is incredibly high. I think everyone really looking forward to having their thoughts on something as efficacious as it looks like 6 to 8 is going to be.

Speaker 2

So it was an open in between. Of course, we're going to learn things as well on this study that is going to help higher package. So when you look into a potential package for registration here, POWER I, POWER II and whatever we learned from safety and exposure relationships and so on on Radient should be that package in the near future. Sorry for the long answer there and hopefully I answered everything you asked.

Speaker 4

That was great. Thank you, Marcio. I'll jump back into the queue.

Speaker 2

Thanks, Jens.

Operator

Thank you. And our next question coming from the line of Jun Lee with Drew. Your line is open.

Speaker 1

Congrats on the progress and thanks for taking our questions. And I think interim is a good it's part of good housekeeping. But if you do decide to resize the trial any reader that could potentially push out the timeline for Study 1, with the randomized RYJAL trial, which I believe is Study 2 still readout by year end, I don't think that there is an interim for Study 2, I believe. And I have

Speaker 5

a follow-up question. Thank you.

Speaker 2

Yes. So thanks so much, John. So Study 1 and Study 2 now are allotted to readouts together, right, as you know. We're still expecting to be the case as we do expect as you properly for there, the insurance is just going to be a housekeeping exercise. But in the case, which we're not expecting to happen, but it could happen that we need to slightly increase the size of Study 1, then they would be separated.

Speaker 2

We don't believe by a very large period of time because we do have sufficient patients who are not going to be closing the screening and pre randomization work for the Study 1 will be quite fast if that happens. It was one of the motivations to be honest on our end. So we have like enough patients that wouldn't be a delay and creates like a significant cohort effect.

Speaker 1

Great. That's a fascinating setup there. The follow-up question is, as we look forward to the ROLUTRAGE data in BE, help us set some bar for what you think is a good data and what you from FDM2A and 8A? And are you saying that the opportunity in 2A and 8A could be just the tip of the iceberg for future application? Can you elaborate on that a little bit?

Speaker 1

For example, what other types of DEE did you have in mind? Thank you.

Speaker 2

Yes. No, that's and thanks for that. So we continue to monitor the progress here. We are really very, very close to that readout, right, incredibly excited. But there are 2 things there that I mentioned on the prepared remarks, just going to want to bring back.

Speaker 2

So one, those patients were far more severe than we originally expected. And I think that is quite interesting from the agency to actually drive some relief for themselves, for their family, which is exciting for us. We guided before, we're going to continue to guide at this point in 20% to 30% seizure reduction. We think that would be quite phenomenal from the sample size we have from the type of patients in enroll. Of course, we want to see patients doing as well as possible.

Speaker 2

You might have caught as well the fact that you're going to have a significant number of patients crossing the long term extension. So we're going to be able to talk about what happens when they continue taking the drug and so on. So that is the answer there. Then when you open, I would say the horizon here and to other these amount for something like 300 genetically defined epilepsies at this point in time, right. Like incredible the growth that existed on understanding since the pioneers on this field like Steve Petro or Dave Goldstein and others started like looking to this in detail and Sam and other folks.

Speaker 2

But the use of ferritoxic, but it's too efficacious, so I didn't channel modulators. It's pretty wide. So if you think nothing else, but like patients trying to control mechanism that give them some relief, but they really can't because there are limitations on both efficacy and safety, That alone, it is probably the largest opportunity in TE that anyone ever talked about. And as we look into that, what you're probably going to be hearing from us, it's a broader approach in terms of like patients who have very severe uncontrolled and pediatric ID because that is the key here, right? So very different manifestations they get older, probably not as severe as when they are young.

Speaker 2

That number is pretty big, not only from our market opportunities, but from our unmet needs opportunities and I think that that's focusing on right now.

Speaker 1

That concludes our question.

Speaker 2

Thank you.

Operator

Thank you. And our next question coming from the line of Francois Pizarro with Oppenheimer. Your line is open.

Speaker 6

Hi, thanks for taking the questions.

Speaker 2

So just first of all,

Speaker 6

so you mentioned that 20% to 30% seizure reduction would be great, especially with this size of a trial. But should we be expecting a P value here? Just want to make it clear for expectations into the data.

Speaker 2

Yes. So thanks, Patrick, for the question. So we are like again, we keep guiding here, we're going to continue to 4 20% to 30%. I think what I would like to see on top of that is the distribution of the patients, right? And I think we're going to be talking about that.

Speaker 2

Like that are things that are more common, like variable sample in some of those patients that are things that are probably uncommon like significantly reduction potential part periods like without seeing and things like that. So we're kind of weeks away, I would say, since we guided for Q3. So I'm going to continue to look into that. When you think about scalability, the go to hypothesis on this study is that we would see a lot of issues with these patients. They are unknown for having very poor to with any agents they take.

Speaker 2

And I can say because tolerability is not blinded, right, for all the study, that is not the case. We're seeing very good tolerability with this drug, which gives us even more encouragement on how it can be used and explored for controlled and uncontrolled case. So stay tuned. It's now our footstep. It's very close for us to be talking about this.

Speaker 2

So we're going to be having a fulsome discussion as the results are out.

Speaker 6

Okay, thanks. And then just in terms of the study design, just differences with others terms of essential tremor, can you just help us understand maybe the differences in the thought process between doing parallel and randomized withdrawal and just overall just maybe going through the differences that make you feel comfortable with the readout or more comfortable than what others ran into here? Thank you.

Speaker 2

Yes. So the thoughts from the GAAP goal on the I'll start with the randomizer draw here because I think it's quite interesting, right? The way drugs are used in the market is patient takes drug and if they respond, they stay on the drug response, they just continue. The way and I know it sounds insanely odd what I just said, but it doesn't feel like when we have questions like this on how obvious it is. Then you go back to how we test drugs and you just assign them to groups that would never actually behave that way, right, like parallel groups and other designs.

Speaker 2

So when we discussed with the agency, when we discussed internally, that was quite important to establish like what happened with these patients. They maybe remind everyone that patients with essential tolerates anything. They are giving like a lot of other potential therapies and they continue all of them like the terminal rate is like single percent of retention on treatment. So that was quite important. Now that study is pretty straightforward in a sense that we size that significantly higher than we believe we need.

Speaker 2

So that's why we'll continue that. That's why from the beginning we never planned to do any potential adjustments with that. The Parcel Group,

Speaker 7

the key

Speaker 2

are influencing that from the beginning is as being many, many discussions in the fields, essential tremor never had a pharmacological approved. We did a very comprehensive study and analysis of ESSENTIAL-one. If we understand the groups really well and we power the trial and conducted a trial based on those learnings. Now as we move forward to a much larger study, I think what's important and continues to be important to understand how this heterogeneous group of patients since there's not a one determinant of essential tremor behave when you expose them to a relatively long period of time, like 3 months now. And I look into what's happening in the study right now, it's pristinely done and it's done exactly the way we're expecting and all the indicators as we're expecting.

Speaker 2

But we still have that unknown of Virginia's population that might influence things as likely one way or another. That's why we're planning that we are planning right now. This is a registrational package and we want to make sure as you heard in our disclosures, as it is in our slide deck in our website, to file an NDA next year. And to file that NDA, we need a study to be definitive and that we're doing everything in our power to get the 1st pharmacologically approved treatments in recent decades for essential tremor patients. So that's how the product is designed.

Operator

Thank you. And our next question coming from the line of captain Suneja with Guggenheim. Your line is open.

Speaker 5

Hey guys, thank you for taking my question. Just a couple of clarifications from me. So with regard to the interim analysis in Study 1, could you tell us what will be the sample size that will trigger it? So that's one. What exactly are you looking for?

Speaker 5

Is there a particular M8811 delta you're shooting for there? And then is there an alpha loss there since you do an interim analysis and what sort of an alpha loss? And then I have a follow-up on the other program.

Speaker 2

So the interim is based and while I'm not going to give you the information points here, right, you have to and I'm sure you do that and believe that it has to be sufficient for the estimation of the entire study. We are using like a promising zone approach to understand where we are. So the re estimation one exists, right? It's just a reminder that not our base assumption. The base assumption is situation without re estimation.

Speaker 2

Re estimation happens, it's going to be based on the boundaries, the recommendation of the independent IDMC that we have. Now it's all within the range of things we believe we can randomize quite quickly to like increase the progress of success of the final trial. One of the constraints we've been working on and one of the reasons why we didn't discuss this before is, like final cohort enrollment is incredibly fast. So when you have a situation like that, the redial potential entrant as we're doing and the final are pretty close together. So we are considering that as well as work on this study.

Speaker 5

Okay. For the final analysis or let's say for the study readout, is there what is clinically meaningful in terms of MADM both on from the absolute size or on and also on the placebo adjusted delta?

Speaker 2

Yes. When you look back, most of the work, if not all of the work that for clinical meaningfulness follow the recent like last year's FDA guidance on patient driven drug events and historical guidance in terms of how you anchor these endpoints. Intrinsically, when you anchor the MATL to a known like disability endpoints like global impression. What you see is a perfect alignments between chains on the ATL and on the global impression. It's actually quite obvious for us because when you talk to patients and you ask them to describe what will be important, talk to physicians and you ask them what would think to be important on their patients, they all describe the gain or maintenance of a function.

Speaker 2

When you go back to the ATL, that is one point. When you transform that to the MATLAB 11, that is required on this study, that is obviously dropped below one point. This study is well powered beyond that, but that would be the logic and proper answer is if we can drink properly from a cup and now you can, I challenge anyone to tell me that that's not to our patients? It's incredibly me, that's a point or less. Now, what we are planning to see on this study is obviously more than that.

Speaker 2

But it's quite important as well that the proportion of patients gaining one points, 2 points, 3 points whatever are pretty high. So it's not only a point estimation, but I was like the proportion of that and we are monitoring of course and even continues to talk about that. If you look into our corporate deck, we talk about the treatment of 3 points. We talk about like proportion of patients that are there and so on. So it's very clear that this is going to be a quite meaningful treatment for patients with essential tremor, especially the ones that are like with significant disability due to their condition.

Speaker 5

Got it. Maybe one more multiple parts like a classic cell site question. So for the interim analysis, this is an efficacy analysis, not futility analysis. 2, how you will disclose or what exactly are you willing to disclose to us when this interim happened and when exactly is this happening? Is it a Q3 event or Q4 event?

Speaker 5

Thank you so much.

Speaker 2

Yes, absolutely. It's currently scheduled to happen in Q4. Like just as a reminder, right, patients have to complete the whatever information points we determine, the data has to be clean, transferred to an external independence data monitoring committee and then the analysis should be to be conducted. So and coming back to us and so on. A little while that's why therefore the timeline.

Speaker 2

What we intend to communicate at a point in time is what we're going to do. It's a decision that is being held at that point in time with Dinex. So, I'll argue the likely decision here is we would update all of you with the readout when the full readout for this study is going to happen. And in the eventuality that we believe is appropriate as recommended by the IDMC to increase the sample size, what is the increase and we would be reading out that as well, which we believe Evinrna will increase. If that is to happen, we would have quietly quite shortly

Operator

thereafter. Thank you. And our next question coming from the line of Ritu Baral with TD Cowen. Your line is open.

Speaker 8

Good morning, guys. Thanks for taking the question. I have got one last question on Elixir and then a bunch on 628. So for the essential, the withdrawal study, I know that sometimes FDA imposes a official or unofficial requirement on the initial response rate for those patients going in that are defined as responders before the actual withdrawal portion is conducted and analyzed. Have you spoken to FDA around the design of the withdrawal study specifically on that initial open label responder rate sort of what they're looking for even if and if there is even a hard requirement or just

Speaker 7

a soft would like to have?

Speaker 2

Yes. No, thanks Ritu. The from the beginning as well, we've been actually from the Phase 2, we had proposed the randomized one of the studies there, right. The parameters as you wisely noted there is the definition, right, like we're going to randomize on these tables or stable with another criteria and things like that. And our proposal from the GAAP goal and what's being implemented in the Central 3 was that in the 1st 8 weeks, they will be exposed to drug with a response criteria, bilateral response criteria, meaning the criteria increase and decrease is identical.

Speaker 2

If they cross the boundary, we're going to be disclosing shortly. As you can imagine, that could influence some assessments. That's why we disclosed before. Then they can be randomized to stay on drug or to go on placebo and for the following 4 weeks. If patients are not to meet the criteria at week 8 and maybe that is what we haven't really talked much before, we are moved into the long term extension.

Speaker 2

Programmatically, right, they don't know that they were excluded as the entire system remains blinded for the entire duration of the trial. So only responders are randomized after 8 weeks and therefore they are the only ones at risk of losing the effect when they are randomized to placebo.

Speaker 8

But the original sort of open label response rate, going in, there was no criteria for what was required around that?

Speaker 9

They are all randomized under They're all blinded already. Okay.

Speaker 2

Yes, correct.

Speaker 8

Okay, understood. Moving to 628 and the RADIANCE studies, First of all, can we confirm that the RADIANCE and POWER-one-two, those are placebo controlled studies?

Speaker 2

Yes. So RADIANCE is not placebo controlled, POWER I and POWER II are placebo controlled.

Speaker 8

Got it. And then what doses are you using, just given the very good safety that you've seen, what doses are you using in RADIENT and POWER-two, the 628? Yes.

Speaker 2

So RADIENT, patients are going to start at 30 milligrams. Power 12, and updated the schematics in our PowerPoint and our website as well. Patients will start at 20 milligrams for 6 weeks and then 30 milligrams for the 4 other 6 weeks on POWER-two there is a lower dose as well just to fulfill potential requirements for a lower dose exposure there. The deal with regions that are more flexible, it's here as well. So maximum Alaska should be derived from day 1, but it's easier for investigators to make potential recommendations for adjustments, adjust other drugs that cannot be done in the setting of a double blinded study when you don't know if patients are on drug or which dose they are in because that could interfere.

Speaker 2

So that is the idea. It's also as you heard on the previous comments, right, we were collecting our extensive samples from this, so it becomes a lot easier to recruit them in general.

Speaker 8

Is there a minimum percentage of generalized epilepsy or maximum percentage of generalized epilepsy that you have in mind for Radient? We're asking just because when we did our doc checks, some of our KOLs were particularly excited about the potential for 628 in this population.

Speaker 2

It was I'm glad you bring that up because one of the motivations that I put forth includes originally, we thought about only conducting for ONSAT, but there is a very, very clear excitement about 628, on the investigators in general. When they look into highly translatable preclinical models across the boards, I think what they are imagining and that might be a for me at least is even beyond what we are imagining potential of this drug, potential for seizure across the board and things like that, that I think we're humbled by and about drug developments in general. So that is clearly a push. We do expect by the conversations we had with the sites that are going to be rolling and the investigators in general that are going to follow the general proportion of patients in the clinic. So about 30% or so should be generalized and the remainder of that should be focal.

Speaker 8

Got it. Got it. And then final question. Thanks for your patience. Other than the dosing, do you see in the design, are there any major differences between POWER I and POWER II of note?

Speaker 2

So at this point in time, there are no major difference. The Power 1, the reason why we are really pushing that ahead before POWER-two as well is, 1, taking one study off the grounds or in the case of rates or one is obviously the operation is simpler. The second is that is overlap in terms of sites, expected places we want to go up or to. And we wanted to make sure we're underway on the enrollments on Parole 1 at the moment we start that, if not complete. So we wanted to staggered to give the maximum opportunity for patients to enroll on POWER-one.

Speaker 2

That was the main motivation

Speaker 8

here. Understood. Thanks for taking all the questions.

Speaker 2

Of course, our pleasure.

Operator

Thank you. And our next question coming from the line of Joe Vito with Baird. Your line is open.

Speaker 10

Hi, thanks for taking the questions. A couple on Essential 3. The first is, what's the next update for us to expect from the Essential 3 program? Would it be an announcement on the completion of the planned enrollment or would the next update be the implications from the interim analysis? And then as a second question, has the data from ESSENTIAL-three been able to be looked at on a blinded basis, perhaps to assess things like whether the variability of the data is in line with

Speaker 2

expectations? Yes. Hey, Joe. So I'll tackle the second question here first. So yes, we continuously look into the data in a blinded fashion and I'll tell you the variability is actually as expected and are lower in terms of the patients coming in, number 1 and then in the study, the randomization is actually lower sorry, is actually as expected, slower beforehand.

Speaker 2

So fairly stable patients coming in as expected patients during the study. So all systems are go, are green there. That is not the motivation for the plans interim to do. On the next update, we do have to talk about when we are when we have completed all the next stage program. And also you should see updates coming up soon, not only on enrollments, but on the initiation and completion of the interim analysis.

Speaker 10

Great. Thank you.

Operator

Thank you. And our next question coming from the line of Amit Bhatia with Needham. Your line is open.

Speaker 7

Hi, good morning. Thanks for taking my questions. Firstly, just a follow-up on 6 to 8. What is the gating factor for initiating a pivotal program for generalized epilepsy? And is Vadent meant to inform the dose that you would study in that epilepsy type?

Speaker 7

And then I have one or two other quick follow-up.

Speaker 2

Yes. The motivation here for including GENERALIESS, you might recall 628 quite broadly, so this is the first what we are trying to look into is the I would describe as the terminal value of this model here, right? So when we start with patients that are, I would say struggling to response, but likely to respond in our view and that's the way we're thinking about Radian. To understand whether or not we can really drive the efficacy of this drug. Now when we are powering double blind study, but really driving the potential maximum here, obviously that is safety collection here that would add to the safe database.

Speaker 2

That's quite an importance. But maybe even primarily, I keep going back there, but we don't want to throughout your study keep like collecting more and more PK samples from patients. And I know it sounds minimal, but as we're accelerating towards a potential NDA that becomes a quite important consideration as well. And as we want to expand the program right after POWER-two very, very likely running another study in generalized epilepsy. So we wanted to start getting some experience with that patient population.

Speaker 2

That was the motivation here. I think the bonus to all of us, particularly our investors is another milestone here and an intermediate like readouts before PowerOne, which should obviously be more confidence on the overall product, particularly on our end, right. We're having this program with a very high confidence on the results.

Speaker 7

Got it. That's quite helpful. With regards to PRAS-five sixty two, can you talk about how age and baseline severity impacts how much seizure reduction we could expect to see? Also how should we think about read through into other DEEs based on the data that you will share with us on the 2 DEE subtypes? And then maybe I'll just plug it in here.

Speaker 7

A quick follow-up on Alexa. Is the interim analysis likely to drive a statistical penalty or not? Thank you.

Speaker 2

Yes, sure. So we're looking to involve in the upcoming readouts. I think we absolutely should look into this and how it extrapolates to other The world of GEs being dominated by this by Dravet number 1 and then 2, by these buckets of unknown things that we call LGS or linorgastoid most recent of some instance. But there are far more patients that are have no alternative that was a reduction as little as it might look or not look, right. We're obviously not expecting for little reductions here expecting for significant reductions with significant change, one, their lives and their parents' trajectory, but the second is their survival.

Speaker 2

So we are absolutely sure that we're going to be talking during the pandemic and we'll be back to our first question about the age seizure burden there. I don't know, cephalopatis are disease of childhoods, right. When you look into the patients that enrolled in our study as you're going to see pretty soon, We're talking about pretty young kids, seizure burdens that are very, very high, and disabilities that are quite prominent. When you see gains there as we fully expect to see from these patients that is incredible because their bodies are still developing, they're developing and there's like a huge opportunity here to continue to help them throughout their lives. It's exciting to see that and we believe it's quite translatable to a very large number of these that don't really have any opportunities that have similar characteristics, young, high seizure burden, very low ability to treat, it's mostly because of safety and tolerability drugs.

Operator

Thank you. And our next question coming from the line of Doug Wisser with H. C. Renberg. Your line is open.

Speaker 9

Good morning. Thanks for taking the questions. Just maybe starting with Radient. I think given the PPR results, there was a lot of interest in terms of 628 effect in generalized epilepsy. I'm just curious why not just do that study with generalized epilepsy patients?

Speaker 9

And then also I'm just curious in terms of the dosing between RADIENT and the power studies. With power you're starting at 20 milligrams for 6 weeks and then moving to 30. Why in Radient are you going directly to the 30 without sort of a titration period? Thank you.

Speaker 2

Yes. Thanks, Doc. So we have a lot of flexibility on Radient to as we go for the study, we're going to provide periodic updates on how things are going on that study to potentially actually advance as a cohort. So we're not quite there, but your thought about why not just run a generalized epilepsy in 6 months that's what we're going to be talking about. We're going to be talking about starting that trial, that controlled study in generalize.

Speaker 2

I think first we wanted to understand the impact we could have, which we believe is going to be fairly large in both focal and generalized epilepsy. The second question on the dose, I mentioned before, we want to drive the maximum potential efficacy here with definition the highest concentration. At the same time, we have far more flexibility on Radian than we have on PowerOne 2. We do need to have some like data on the different concentrations and the reduction in seizures. For example, we do believe that 20 milligrams for 6 weeks is going to be efficacious and that's sufficient.

Speaker 2

And that is going to be a quite important discussion decision with regulators once that is significant and then the 30. So what is the start dose? How do you actually treat patients? But after Regent, if you see, let's call just scenario planning of very significant number of major threat. Then we must have to rethink what a labeling language could be in the near future.

Speaker 2

So it's all complementary. I think as drug developers, we need to think about the piece of the puzzle that are going to allow for the best possible decision by the regulators and the physicians and that's how Radia plays a role here.

Operator

Thank you. And our next question coming from the line of Cam Baskia with Jefferies. Your line is open.

Speaker 1

Morning team. For PRAC-six twenty eight, in terms of focal patient enrollment, how will you prioritize it between POWER-1 and RADIAN? And then maybe you can go into more details of the EMPOWUR observational study. And then for another program, elsinericin, what feedback did you receive from global regulators to initiate a pivotal study in Brazil and kind of what remains required to advance the program in the U. S.

Speaker 1

And Europe? Thank you.

Speaker 2

Sure. Thanks, Kenneth. So PowerOne and Radian are not, I would say, competitive internally from a first form or external. They just go through very it's a much larger initiative as you can imagine PowerOne. So all the administrative stuff that has to happen, takes a little bit longer.

Speaker 2

It's a smaller number of sites for Radient. So that's part of that as well. And the patient characteristics we might enroll is slightly different as well. So we were trying to actually triple our, I was going to be perfectly honest, on making that both studies recruits quite excellently as we expect to. So again, no competitiveness there whatsoever.

Speaker 2

I think your second question about as a nursing, we do have obviously a full feedback from Brazil. We're able to start the study there. We believe that cohort is going to be quite complementary to the initiatives that we are having outside of the U. S. We do have some preliminary and should be final soon from Europe as well, which are aligned with how we are thinking about this.

Speaker 2

And that's why we guided for more global parts including the Europe part of the U. S. Starting later this year and in the similar process with the FDA. We know it's a complex program with like multiple variables here. The most important of them is just how severe those patients are.

Speaker 2

So we're taking one step at a time on that program.

Operator

Thank you. And I'm showing no further Thank you. And I'm showing

Speaker 7

no further questions in the queue at this time. I will

Operator

now turn the call back over to Marcio Ceza for any closing remarks.

Speaker 2

Thanks, everyone. Sincerely appreciate joining the call and all the questions. We're having quite importantly as well the supports for Brexit and all the patients we serve. As you heard at the beginning, we do there for more and often times that materialize on actually looking our cells in the mirror and seeing what is best for the patients we serve. In the case of this call, it's really delivering successful studies for patients with essential tremor with Felix that compromised hydrochlorate as we will later this year.

Speaker 2

I hope everyone is as excited as I am of the upcoming readouts. And just a reminder, in a few short weeks before the end of the quarter, we're going to be talking about our readout for our previous 5, 6, 2 Relitrogen now as you're calling, which brings up quite important upside for all of us in terms of from the investor perspective, but most importantly, SNHUA, SNH8A have no treatments either available, approved or in development that are at the break of being potentially approved. So to have that discussion, to have that coming up in a matter of weeks in front of us is quite exciting. And then I'll say on how excited we all are by the number of questions in today's call of 6 to 8. 628 is moving at lightning speeds as you can all see.

Speaker 2

I have worked in many programs in my life. I haven't seen as much excitements about a program from the investigators perspective as we see with 6 to 8. And we're excited on not only getting that to the clinic potentially in the next few years bringing to market and revolutionizing the way epilepsy is treated. So again for the support, look forward to having follow-up calls with you and we'll see you soon.

Operator

Ladies and gentlemen, that concludes our conference for today.

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