Praxis Precision Medicines - Earnings Call - Q2 2025 & Study Result

Executive Summary

• Praxis reported a deeper investment phase tied to epilepsy programs, with Q2 2025 net loss of $71.1M and EPS of $(3.31), versus $(32.7M) and $(1.74) in Q2 2024 as R&D spending scaled for registrational studies.
• RADIANT topline showed best‑in‑disease efficacy for vormatrigine: 56.3% median seizure reduction over eight weeks, ~60% achieving ≥50% response, and ~22% seizure‑free in the last 28 days; safety was generally favorable and discontinuations were largely manageable via background ASM dose adjustment.
• Guidance sharpened: POWER1 on track to complete in Q4 2025 (previously “2H 2025”), POWER2 to initiate in Q3 2025 with a new 40 mg arm and mood endpoints, EMERALD (relutrigine) and EMBRAVE3 (elsunersen) initiated; cash runway into 2028 maintained.
• Versus S&P consensus, Q2 EPS was a slight miss (actual −$3.31 vs consensus −$3.299*) and revenue came in at $0 vs ~$0.157M consensus*, reflecting the company’s pre‑commercial profile while R&D outlays rose for accelerated execution; EBITDA missed (actual −$76.0M* vs consensus −$68.7M*) as operating intensity increased. Values retrieved from S&P Global.
• Near‑term stock catalysts: additional RADIANT data at the International Epilepsy Congress (Aug 31), POWER1 completion in Q4 2025, and regulatory tailwinds from July FDA Breakthrough Therapy Designation for relutrigine in SCN2A/SCN8A DEEs.

What Went Well and What Went Wrong

What Went Well

• Vormatrigine delivered best‑in‑disease efficacy in RADIANT: 56.3% median seizure reduction; ~60% achieved ≥50% reduction; ~22% were seizure‑free in the last 28 days, with rapid onset and sustained benefit over eight weeks.
• Safety/tolerability was manageable; adverse events were mostly mild/moderate and resolved, and discontinuations were mitigated when investigators reduced background ASMs per protocol guidance: “when done (6 patients) no discontinuation was observed”.
• Strategic momentum: EMERALD (relutrigine) and EMBRAVE3 (elsunersen) registrational programs initiated; relutrigine granted FDA Breakthrough Therapy Designation enabling expedited development.

Management quotes:

• “We…believe we are positioned to revolutionize treatment in both common and rare epilepsy…vormatrigine has shown an impressive 56.3% reduction in seizures in 8 weeks…” — Marcio Souza, CEO.
• “We observed a median seizure reduction of over fifty six percent…sixty percent of patients achieved at least a fifty percent reduction…over twenty two percent…completely seizure free during the second month…” — Steven Petrou, CSO.

What Went Wrong

• Operating intensity increased: R&D expenses rose to $63.0M (vs $27.3M YoY) as clinical programs scaled; net loss widened to $71.1M (vs $32.7M YoY).
• Discontinuation rate in the open‑label setting was 23%; while comparable to peers, the company aims to reduce it via clearer background ASM dose‑reduction guidance and study design refinements (e.g., POWER2 dose arm, mood endpoints).
• No Q2 collaboration revenue vs $0.357M in Q2 2024, reflecting lapsed service obligations after UCB’s KCNT1 option exercise; revenue de‑leveraging accentuated EBITDA loss.

Transcript

Speaker 1

Good day and welcome to the Praxis Precision Medicines Radiant Top Line Results and Second Quarter 2025 Financial Results Conference Call. At this time all participants are in listen only mode. After the speaker's presentation there will be a question and answer session. Instructions will be given at that time. As a reminder, this call may be recorded. I would like to turn the call over to Dan Ferry of LifeSci Advisors. Please go ahead.

Speaker 2

Good morning and welcome to the Praxis Precision Medicines Radiant Top Line Results and Second Quarter 2025 Financial Results Conference Call. This call is being webcast live and can be accessed on the Investors section of the Praxis website at www.praxismedicines.com. 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 guidelines, and financial projections. While these forward looking statements represent Praxis views as of today, they should not be relied upon as representing the Company 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's most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the Company's business. Joining the call today are Marcio Souza, President and Chief Executive Officer of Praxis, Tim Kelly, Chief Financial Officer, and Steven Petrou, Chief Scientific Officer. After our prepared remarks, there will be a brief question and answer session. With that, it's my pleasure to turn the call over to Marcio. Marcio: Good morning everyone and welcome to the Radiant Top Line results presentation. We're incredibly excited to share this Best in Disease results with all of you. Before we begin, I would like to note that today's presentations contain forward looking statements. For complete disclosures, please refer to our latest SEC filings. Praxis is in an incredible position to bring innovative drugs to patients with CNS disorders.

We have four late stage assets, one of which we're discussing here today, and we expect five clinical readouts within the next year. That is no small feat. This progress is powered by our two robust platforms enabling current development and future CNS drug innovation. Our cash runway extends into 2028, supporting our ambitious clinical agenda. Today we'll discuss the Radiant results for PRAX-562, but it's worth taking a few moments to remind everyone of the rich in depth pipeline we have with multiple readouts coming out in the next several quarters, which will enable Praxis to stay at the forefront of CNS drug development. Focal epilepsy is a very serious medical condition impacting about 3 million U.S. patients. Contrary to common belief, most of the patients are not doing well. Over 60% of those patients require multiple anti-seizure medications, highlighting the inadequacy of existing therapies.

Patients need effective, tolerable, fast-acting, and durable treatments to avoid a constant ASM cycling, and we believe PRAX-562 can deliver on that. Starting with today's results, PRAX-562 is showing best-in-disease efficacy in the RADIANT study. That should be enough to be excited. We should not minimize the further differentiation of PRAX-562 with current and in-development therapies, being the only drug to combine once-daily administration, fast action, no food effects, ideal tolerability, and no meaningful drug-drug interactions, which importantly do not interfere with common contraceptive agents. Before I hand over the call to Steven to discuss the details of the RADIANT study result, I want to take a step back and talk about execution. We have executed the RADIANT study exceptionally well, initially setting an enrollment target of 35 patients with focal epilepsy and 15 with generalized epilepsy.

The strong demand for focal, even after we announced the closing of the enrollment through the site, demonstrates the effectiveness of our recruitment capability. The same engine is already at play for the POWER 1 and soon to be for the POWER 2 and POWER 3 studies. We have so far completed screening of 99 patients and dosed 61 as of July 25th. We expect to complete the study in the near future with approximately 75 patients dosed. Today we review data from 37 focal patients who completed the ACE study for efficacy so far. We also review the safety for the overall cohort of the 61 patients who have been dosed. We present more details from this initial cohort of patients at the upcoming International Epilepsy Conference in Lisbon later this month.

The full study results are expected to be presented during the American Epilepsy Society Conference later in the year. Let me now hand over the call to Steven to discuss the results. Steven.

Speaker 0

Thanks Marcio. Let me walk you through the design of the RADIANT study. We began with a 28-day observation period during which patients stayed on their existing anti-seizure medications while we monitored seizure activity. Following that, participants received 30 milligrams of PRAX-562 once daily for eight weeks. An optional two-week safety follow-up was also available at the end of the treatment phase. We're proud to have enrolled a representative sample of the refractory epilepsy population here in the U.S., predominantly female with a high baseline seizure burden. The median monthly seizure count was 12 and most participants were on multiple anti-seizure medications. Looking ahead, we expect the population in our upcoming POWER 1 study to closely reflect what we've seen here in RADIANT. That alignment gives us a strong foundation and confidence in how we're approaching the next phase of development.

Now let's turn to the part we're most excited about. The results PRAX-562 delivered a truly remarkable performance. In the RADIANT study, we observed a median seizure reduction of over 56% and, importantly, that effect came on quickly and was sustained throughout the treatment period. Even more compelling, 60% of patients achieved at least a 50% reduction in seizures. That's one of the highest responder rates we've seen in recent epilepsy trials and it speaks to the potential impact PRAX-562 could have for this community. What's especially striking is how quickly these responses emerged and how they continued to improve over time. By just week one, 54% of patients had already responded. That number climbed to 67% by week eight, showing a clear and encouraging trend of improvement. Even more notable, over 22% of patients, more than one in five, were completely seizure-free during the second month of treatment.

That kind of outcome not only underscores PRAX-562's potential, but also sets the stage for what we hope to see in the longer 12-week POWER 1 and POWER 2 studies. Looking more closely at the data, PRAX-562's efficacy held strong across all patient subgroups, regardless of baseline seizure burden. We specifically analyzed outcomes by splitting patients at the median baseline seizure frequency to explore whether those with a higher or lower seizure loads responded differently. As you can see in the figure, the drug performed consistently well across both groups. That kind of robust and uniform response is a strong signal of reliability in a heterogeneous epilepsy population. Taking a step back, it's important to remember what treatments these patients were already receiving when they entered the study. The bar in RADIANT was especially high. This was the first epilepsy study launched and reported in the U.S.

following widespread adoption of cenobamate. In fact, 30% of RADIANT participants were already on cenobamate, meaning PRAX-562 had to demonstrate efficacy on top of an already aggressive background regimen. That context makes the results even more compelling. When we looked at response rates based on the most commonly used background ASMs, the results remained consistently strong. Patients showed excellent responses whether they were on one or more sodium channel blockers, SV2A modulators, or even cenobamate. This level of consistency in both efficacy and tolerability across different treatment backgrounds speaks to PRAX-562's versatility. It reinforces the idea that this is a therapy with broad applicability, not limited by the complexity of background regimens. Turning now to safety and tolerability, PRAX-562 demonstrated a favorable overall profile. Most adverse events were mild to moderate and tended to resolve over time.

We did observe a 23% discontinuation rate, which in many cases was linked to a lack of background ASM dose adjustment despite protocol guidance. Importantly, in six instances where investigators proactively reduced background ASMs, both adverse events and discontinuations were avoided entirely. We see this not as a safety signal related to PRAX-562 itself, but rather a manageable interaction dynamic that can be addressed with appropriate background therapy management. I'll close by saying how proud we are to share these results today. RADIANT was a high bar study in a complex and underserved patient population. We believe the data clearly support PRAX-562's potential to make a real difference for people living with refractory epilepsy. With that, I'll now hand the call back to Marcio.

Speaker 2

I'm sure you are as excited as I am about the strength of the RADIANT data Steve just reviewed. As we move forward, we must remember that one of the key motivations to conduct RADIANT was to better inform the final design of POWER 2. In that regard, one of the key aspects Steve did not discuss was the preliminary modeling for dosing and efficacy. We have concluded that it would be beneficial to add a dose arm of 40 milligrams to the POWER 2 study, bringing to life the potential of even greater efficacy. We also intend to be more deliberate in our instruction to CPI on how to dose reduce the background ASM for even better management of patients. Another incredibly interesting piece of information we learned in the RADIANT study is the reported positive impact in moods observed in patients.

With that in mind, we decided to include depression and mood endpoints to the POWER 2 design. We're ready to start rolling out POWER 2 and it goes without saying that the full force of the Praxis recruitment engine would be at it. The final design of POWER 2 will enroll approximately 400 refractory epilepsy patients testing PRAX-562 doses of 20, 30, or 40 milligrams against placebo over 12 weeks. The enrollment is expected to complete in 2026. I want to now focus the next few minutes into a very important and often neglected aspect of drug development in epilepsy. As you can see here, we're presenting some data from a very large U.S. claims analysis in patients with focal epilepsy conducted by Praxis, which covers almost half a million patients' worth of data. The message is very clear.

The majority of the patients are not doing okay and virtually 2/3 of them fail their first-line treatments and after that a very improvised layering of multiple agents begins. This is not good for patients or the healthcare system. Clearly there's a critical need for simpler, more effective treatment like PRAX-562, ones that combine the fast-acting mechanism with minimum restrictions and high effectiveness. With that in mind, we'll be launching POWER 3 which aims to establish PRAX-562 as standalone therapy enrolling refractory epilepsy patients transitioning off currently used ASM. This study leveraged historical understanding, benchmarks, and safety measures to protect the integrity of the patient and the results of it. We plan to initiate POWER 3 in early 2026 to wrap up the call about PRAX-562.

It's incredibly exciting to be at the point where we can confidently say it has emerged as best-in-disease ASM, distinguished by rapid seizure reduction, favorable safety, ease of use, and sustained effectiveness across diverse patient groups. The RADIANT study results significantly bolster our confidence in the ongoing and upcoming studies for PRAX-562. Before we move to Q&A, and reminding that today's result is about celebrating PRAX-562, I want to emphasize that Praxis remains deeply committed to revolutionizing epilepsy treatment from common focal epilepsy to rare DEE conditions. I'm sure you have seen the fantastic news of luterigine being granted breakthrough designation here in the U.S., which will allow us to move even faster towards registration in patients with SCN2A and SCN8A. Lastly, we extend our sincere thanks to our investigators, patients, site staff, and Praxis team for the contributions to the success of the epilepsy program overall.

We now open the call to Q&A, operator.

Speaker 1

Thank you. If you'd like to ask a question, please press star 11. If your question has been answered and you'd like to remove yourself from the queue, please press star 11 again. Our first question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Team, congrats really to the outstanding data, both in treatment response as well as seizure-free, especially as the majority of the patients are on background therapy. I guess the first question is, if you looked in terms of the background therapies, were you able to look at if there was a difference in response rate if they were on different products, that's sort of question number one.

The question for number two is just given the incredible execution into RADIANT and you provide a color around POWER 2 reading out in which I POWER 2 finishing in the back half of 2026, could you maybe help us understand sort of, you know, I think we get that question a lot. What were sort of the nuggets that leads you to execute really strongly through the study and then the timing of POWER 1. I think a lot of it sounded like you're interactive finish POWER 1 at year end. If you could just reconfirm guidance around timing of POWER 1, that could be very helpful.

Speaker 2

Sounds great. Thanks, Yaz. Like incredibly enthusiastic. Right. As we come out here, when you look into focal epilepsy background in general, I think your question is exactly on the specifics. The first question on the specifics for the background. If you look across Keppra or any of the FB2A's and it's on our slide 13. Right. We saw incredibly robust effects on sodium channel blockers in general. Some patients were on one, some patients were on two. You wouldn't expect much of an effect there. I think that was some of the skepticism before. We're seeing incredibly robust effect as well with over 57% of patients having a response. Maybe the most striking result on that same slide is patients on this study, over 30% of them were on 300 milligrams or even more, sometimes 400, 450 of cenobamate.

This was not your mildly treated like a run of the mill epilepsy patient. On those patients we've seen over 55% response. If there is any doubts on the placements in terms of refractory, I think that should be no more. We did talk as well on what we believe to be the proper way for this drug to be used. It's really moving towards first therapy and first line and that's why we're starting the POWER 3 study. I'm sure we can discuss that soon. Going back to your question, right. We set up to recruit a smaller group of patients and we end up recruiting. That should be a big check mark on our ability to recruit this population. As you've seen on the demographics slide, it's your classical refractory seizing a lot multi treated patient population in the U.S. and in Europe. I'm pretty happy with that.

Not happy for the patients on being treated with those drugs, but happy on the fact that we can recruit them. That is already happening on POWER 1. The acceleration we did in our corporate release in our form 10Q which should be filed right now and you can refer to like reinforce the guidance that we previously gave on finalizing POWER 1 this year. POWER 2 is not off the ground yet, so one should always be careful on making predictions of studies that have not started. Based on our engine, particularly here in the U.S., what are really able to get high quality sites and to help the sites with their own recruitment efforts, with our own recruitment efforts to get more patients.

We believe more patients in a site is a good thing because then they have more experience, the quality is higher, the overall operations run smoother. That is going incredibly well. We are going to transfer that enthusiasm towards POWER 2 and pretty soon in the future POWER 3 as well. It is on and off. It is not only a phenomenal result as we see for patients today, but in general it brings us a step closer or an inch closer to completing POWER 1 and to getting POWER 3 and getting that registration. It is particularly sad as others struggle here to recruit on the same population. One must ask why. In our case, we are incredibly happy of our execution and our team's focus on getting these patients on these studies.

Speaker 1

Thank you so much. Congrats again.

Speaker 2

Of course.

Speaker 1

Thank you. Our next question comes from Ritu Barel with TD Cowen. Your line is open. Hey guys, good morning and congratulations on this, on this really, really good data. I've gotten a bunch of questions this morning, just being driven by this 22% seizure-free rate and this sort of large percentage of patients that responded very rapidly. Marcio and Steve, what do you think is driving this increase in efficacy on all these measures? Excuse me, even after steady state plasma is achieved in patients. Do you have any exposure response analysis done which is contributing to the 20 milligram dose that you now plan on including in POWER 2? I've got just a quick housekeeping follow up. Thanks.

Speaker 2

Yeah, no, thank you so much. Ritu. We do have the exposures and I would say that the raw exposures are already quite well processed and the preliminary exposure response is well underway as well. I'll make a couple comments about that and then I'll hand over to Steve to talk about why we were expecting and we are seeing these phenomenal results. We do see steady state being reached quite quickly here between the first and the second week of treatment. As you've seen, all these slides off the gate get very good results. It deepens quite considerably. We thought the most scientifically relevant way to present was actually feeding the loas to the charts because we know epilepsy is not a weekly process, right? The patients don't see. Otherwise, we would observe them for a week and then just treat for a week or two afterwards.

It's the overall month, I think, the metric here. We do see less. I think the overall concept is that less seizures leads to less seizures. We see this deepening over time, which bodes incredibly well for POWER 1, which is 12 weeks long. POWER 2 is going to be 12 weeks long as well. On that regard, the 20 milligram dose that we are using for the first six weeks of POWER 1 is right into the range where you're seeing this incredible efficacy, clearly the 30 as well. What you've seen is a potential for a fairly significantly higher when you go to the two much higher sides of the exposure on these patients to get even bigger results here. Not that we need it. Not like this is the highest seizure reduction ever seen on an epilepsy study. Not that we need any more.

I think these patients do deserve more and we're going to drive that. That's why we added the 40 milligrams. In a sense, it's going to be stepping in into POWER 2, expecting all three doses to be quite effective and giving this flexibility for the patients. Maybe Steve can talk about why we think the jiponing is granted.

Speaker 0

Yeah, it just speaks to the issue you raised, Marcio, about fewer seizures causing fewer seizures. The same thing, the old saying in epilepsy is seizures beget seizures. That's a process of really resetting the activity level of a neuron. That's a molecular process that takes time to occur. Conversely, when you give an agent like PRAX-562, you immediately decrease activity and that's actually starting to reset the level of neuronal activity. That process takes time to unwind as it took time to wind up. We just think it's really the opposite corollary of increasing seizures as a patient first presents. There are well known physiological mechanisms, homeostatic plasticity, et cetera, that are known to underlie this phenomenon.

Speaker 1

Super helpful. Marcio, you knew this was coming. The upcoming POWER 1 data, you mentioned you would finish enrollment and have data by end of year. Is there any more granularity that you can give us around where enrollment currently stands? Will you announce completion of enrollment for that study?

Speaker 2

Yeah, we probably will announce the completion. I would say at this point today is the day to celebrate RADIANT. Yes, I could see this coming. I appreciate you prefacing with that. The enrollment is incredibly strong. I just had a call this morning with most investigators, and the enthusiasm of everyone that is on POWER 1 is really great to see. I know it was in these lives and I reinforce it. One of the things on RADIANT that we were not expecting was really this overwhelming feedback from patients and investigators on their improvements in moods, on their ability to cope better with their day. I think investigators like that a lot as well. That is certainly helping with even more patients being funneled towards this study versus other things going on out there.

Speaker 1

Great. I'll hop back in the queue. Thanks.

Speaker 2

Thanks.

Speaker 1

Thank you. Our next question comes from June Lee with Truist Securities. Your line is open.

Speaker 2

Hey guys, congrats on the data and thanks for taking our questions. Can you elaborate a little bit more on the discontinuation rates in the RADIANT and how that was inputted into seizure reduction data, if at all, and also for the forthcoming POWER 1, would it be fair to assume the placebo rates will be lower than those reported for cenobamate and XEN1101, a drug given the more refractory population in POWER 1? Thank you. Yeah, no, thanks. Thanks, John. We think we can do better on the discontinuation, right. If you look into competitively or other studies, it's fairly similar as I'm sure you already done the comparison in overall, so not quite completely satisfied there yet because we've seen what happens when investigators actually follow the bullets they had on the protocol. It doesn't happen, right, or happens at a very low rate.

I think that's what we're going to see moving forward. Having talked with some of them already over the weekend and so on, I think some regret they wouldn't have removed some of the drug. Not as much on the impact to your question on the ability to reduce seizures, but just that is a lot on top of these patients. I think that that's what is leading primarily here for patients not want to stay. That's what needs this study to come out as well. When you are in the open-label setting, it's certainly more reports of side effects in general and easier to discontinue. I'm not completely surprised. Was a little bit higher than we expected, but it's still lower than cenobamate comparative to other drugs in the market with lower efficacy. Oh, and you mentioned what we should be expecting for POWER 1. I agree on.

In general, what you're seeing, this patient population are two things, right. One is the background, as you mentioned, very difficult, very refractory in general. The second is really the quality of the sites, the quality of the patients are coming in, the stability of these patients on their seizures beforehand. I think when you get like higher number of patients per site, higher quality of assessment, good level of stability in terms of the seizures beforehand, that all contributes to lower potential placebo rates. Thanks, Kash. Of course.

Speaker 1

Thank you. Our next question comes from Douglas Zhao with H.C. Wainwright. Your line is open.

Speaker 2

Hi, good morning. Congrats on the data. I guess as a starting point, in terms of the added effect of increasing efficacy that we see over time, that was something that we saw with the luterigine as well. I'm just curious, the two molecules are similar in many respects. Do you think that is a function of how they interact with the sodium channel uniquely, that you get the de Kindling effect, which I think Steve talked to, I think in response to Richie's question, and then have a—just.

Speaker 0

Maybe just to further what I said before, Doug. That's very specific and different to how any other molecule interacts with the sodium channel, their biophysical profile. We think that's got a lot to do with this effect because they target the activity more than they target normal function. They target the epileptic activity, and that profile leads to this rapid and then this growing because we're having such good acute efficacy that encourages this longer term efficacy to grow over time. Very much associated with their biophysical character.

Speaker 2

Okay, great. I guess on the side effect profile, I'm just curious, Marcio or Steve, to the extent that you've been able to sort of detangle the effect that some of the side effects or AEs were related to PRAX-562 versus the background therapy. As you look to the POWER studies, sort of thinking about enabling some sort of reduction in dosing in background ASMs, which obviously probably contribute to many of the side effects experienced by patients. Yeah, absolutely right. Maybe before that, I'll ground us on the table in our slides 23, the PRAX-562 treatment emerging is over 20% lower than any other drug out there, 20% less patients. If you're talking about any other therapeutic area, this is like 100 miles from anything else on CNS related, it's about 20% as well.

We're already in that other universe when it comes to these other drugs that are unfortunately in the background. We can't disentangle what these other things are doing. What we know because we ran the experiment is it gets reduced or removed when the background drugs are reduced, which ultimately is what these patients do and what the physicians do. We see that as incredibly positive not only for patients continuing RADIANT, since we have a significant more now and for open label extension as well, but for the POWER 1 and POWER 2 and potentially POWER 3 studies as well.

Speaker 0

So.

Speaker 2

I think the trajectory, while we should ground on the numbers and be happy about being best in class and here in best in disease, that is a space to get better. That's where we're moving forward. Okay.

Speaker 1

If I can, one follow up.

Speaker 2

I'm just curious on the mood benefits that you saw. I'm just curious, was that based on sort of anecdotal feedback or was there any kind of sort of inventory on emotional state taken? Yeah. It was systematically reported by sites, but unfortunately we had not designed an instrument to collect that from the very beginning. That's where we are incorporating on the POWER 2 design. It's not completely unexpected, right. I think there's other drugs in this class that have approval for bipolar, e.g., biplo metroidine, but they just can't be used broadly because of the other issues, including the allergic reactions to the drug. Not completely unexpected, but also very welcome comments that we got across the board from the investigators. Okay, great, I'll hop over to you. Thank you.

Speaker 1

Thank you. Our next question comes from Yatin Suneja with Guggenheim. Your line is open.

Speaker 2

Hey guys, thank you for taking my question and let me add my congratulations. Very nice results. Again, congratulations to the team. So a couple for me. The first one is could you talk about the kinetics of response in the sense that are you seeing improvement in efficacy over time for most patients and then when you do a 12 week study, you probably get more benefit. The reason I ask is because I couldn't get it figured out from the chart that you have. Are you seeing sort of deepening of this efficacy throughout the period? That's first. Second one is, you know what should be the read through to generalized data that you will have for the same asset. What should be the expectation there?

Finally on the safety, which I'll ask, I mean you should be very comfortable with the safety, especially the tolerability if you are going with the 40 milligram in the future study. Yeah, those are the three questions. Thank you. Yeah, thanks Yat. On the kinetics of the response it is very clear like we thought it would be disingenuous to just get a straight line there to fit like a linear. If that was the case and you can do yourself, since the data you would see it's a very significant deepening between the first month and the second month, which we expect to continue as we treat this patient further. For POWER 1, the translation should be even deeper response there. Of course we're going to have to wait for that study to read out.

That is the expectation based on the data we have and that is kind of the read through. That was the second part of your question. When you look into safety as we're very comfortable going to 40 milligrams, we really see this association being a lot more related to the time and type of management by the investigators than the drug itself. We do see, as I mentioned one of the previous questions, on the higher end of the exposure response, we see even further efficacy response or deepening. When you combine that with another month of treatments, we should expect significantly better results here. Once again, not that it's needed. Right. This is already the best results in an epilepsy study.

Speaker 1

Thank you. Our next question comes from Ami Fadia. I'm sorry, Ami left the queue. One moment please. Our next question comes from David Hong with Deutsche Bank. Your line is open.

Speaker 2

Hi there. Congrats on the data and thanks for taking my questions.

Speaker 0

I just wanted to ask about some of these other work that you.

Speaker 2

mentioned you're doing with the program here in terms of, I guess, mood endpoint and POWER 3, looking at a role for monotherapy. How do you envision some of these other endpoints and additional studies here? Are you looking, I guess, to enhance?

Speaker 0

The label or get some label differentiation versus what's currently available, you know.

Speaker 2

What else is in the pipeline. Thanks, thanks. Thanks, Dave. On the mood benefits, right, that mentioned a couple of minutes back, that is an expectation that a drug that reduces the seizures makes these patients feel like more relief from that hyperoxyl pellets overactivity and with this mechanism that is known for in a specific way to improve mood in general to be positive. We are looking for adding that as an endpoint, potentially a label claim. Of course, based on the results there on the POWER 3 switch to monotherapy study, I think that is a game changer. We haven't really had a drug for many, many years that is able to move to those 100% of the patients there at the beginning versus the 30% on the bottom.

When you're talking about the refractory hyperrefractory patients, like 4th, 5th line, as we show on the charts on the slide, we're talking about a $2 to $3 billion market opportunity there. When you move up to the first line, second line, we're talking about several folds. That's potential. From a market opportunity perspective, it makes a lot of sense, number one. From a drug profile, it is the only drug that makes sense. Let me remind everyone that Keppra, which is now the drug that people use off the gate, showed an efficacy of like 30%, basically no seizure freedom and with very similar pharmacological properties and overall toxicological properties of format regenerative. We're not talking about a high bar to replace that. We're just talking about the fact that no other drug was able to.

That is expected to get off the ground pretty soon and to, if completed before the NDA submission, beyond the NDA, potential NDA, if not, to be a quick add on to the label there.

Speaker 1

Thank you. Our next question comes from Ami Fatia with Needham and Company. Your line is open. Hi, good morning. Thanks for taking my question and congratulations on this really strong and impressive data. I wanted to sort of better understand the discontinuation rates. If the physicians were allowed to discontinue any background therapies, why did they not do that? For the six or so patients where they were discontinued, was there any change? Can you kind of talk about the change in the efficacy as well as the safety adverse events that were noted after the background therapies were removed? Maybe a related question on POWER 3. What additional data do you think you need to generate perhaps in an open label portion to convince physicians to switch out patients from their existing background therapies and then move patients through omit regime? Thank you.

Speaker 2

Yeah, absolutely. On why people haven't done something, it's going to be kind of a speculation a little bit on my end, right, but inform the speculation since we had that conversation. I'll refer to one conversation, for example, I had with an investigator in the last few days who was a little bit slow to start reducing. I think his point to us was, and to me particularly, you know, we're so used to just keep adding and just doing nothing and then cycling these patients on that the reaction time for some of them, this is a big key opinion leader, someone very important, so they space at the number of patients on the trial. When you realize with the first few patients that was not the case, then for the following ones he was able to and it worked really well.

I think it's a timing thing and really people learning a little bit the drug at the end of the day. That's why we did this study as well. On the ones that did remove, I think we mentioned that on the slide as well, it's not only resolved the AEs, right, that was efficacy is not impacted like at all. In the long run efficacy is actually better on those patients. We should always be careful to talk about individual patient results on things like this. That's why we give us, it is not that reducing the background made the patients worse, which is the general concern, right. One would have in linking to your question about POWER 3, I think that would be concerning if that was the case, but it's not the case at all in a sense.

I think what we established is that the background therapy is not doing anything but causing side effects and PRAX-562 is getting these patients better. A monotherapy study of switch to monotherapy makes a lot of sense. We polled a number of physicians in the last few days as they are under CGA with us and I think there is incredible enthusiasm for POWER 3 because they really believe in PRAX-562, but they didn't have an opportunity to do something like that before with any other drugs. Not hearing a lot of concerns. Of course there are ways to do it, there are dynamics on this study, but not really an overwhelming concern about it. That's helpful.

Speaker 1

Thank you.

Speaker 2

Thank you.

Speaker 1

Thank you. Our next question comes from Jay Olson with Oppenheimer. Your line is open.

Speaker 0

Oh, hey, congrats on these impressive results, and thanks for providing the update.

Speaker 2

Since you mentioned the.

Speaker 0

Observation that seizures beget seizures, is there a way to.

Speaker 2

Show that PRAX-562 could potentially have a disease modifying benefit? Yeah, thanks Jay. I would again argue, and I'll ask Steve to comment here as well, that that's what we've already seen when we have the direct benefit of seizure control and then the indirect benefit of patients just feeling generally better. Better moods, better relationship with the site and with their own families and so on. Ultimately, I think what we are looking for here is to change epilepsy as we know it. Take a look at our slides when we're looking at people. People keep saying 30% of patients are refractory. One of the biggest BS that anyone can say in epilepsy is like over 60% of those patients are on several therapies. Right. That is just not acceptable. Those things are not benign as we know, so they affect the well-being of patients as well.

When you remove that, get an effective drug that not only reduces the seizures but improves their overall well-being and particularly moods as we discussed, I think we have an opportunity to really change everything here. Maybe we can talk about it.

Speaker 0

I think it's back to that earlier point about seizures. Begetting seizures is the disease that it's a new set point for the brain where a higher level of activity, a higher threshold for triggering seizures, becomes a new normal. This reduction over time in seizures that we saw and that we've talked about earlier is a sign that we're reversing that process. In that, it can be exactly what you're talking about, disease modification. All the attended things that happen if you've got a brain that's hyper excitable, mood disturbances and other things emerge. The fact that we saw changes in other domains, I think it's very encouraging that we are really tackling fundamental.

Speaker 2

Issues.

Speaker 0

Epilepsy is a disorder of seizures and excitability. We see this across rare severe epilepsies, and we see that common epilepsies like focal as well. Resetting that set point is key to disease modification and improvement across multiple areas. Thank you for that.

Speaker 2

Maybe if I could just ask one follow-on.

Speaker 0

Do these impressive RADIANT study results give you.

Speaker 2

Any hint that PRAX-562 potentially could have benefit in DE? In theory, yes. Right. I think we can. The good news is the luterigine is quite strongly set for these and RADIANT is off the ground that you might have seen on our corporate release a couple minutes ago enrolling patients. We do expect to have very strong enrollment and results there as well. On the DE side there are things, features that are important for DE patients that you might not be able to fulfill with like a solid form that is like PRAX-562. In theory, right, these drugs are dampening hyperexcitability on a hyperexcitable neuron that is seizing a lot. There is no reason to believe not, but we're really looking straight on and quite focused for luterigine for these and for PRAX-562 for adult epilepsy. Great. Thanks for taking the questions. Of course.

Speaker 1

Thank you. Thank you. Our next question comes from Brian Skorney with Baird. Your line is open.

Speaker 2

Hey, good morning everyone. Thank you for taking the question. Let me extend my congratulations as well on the nice data. I like the chart on slide 13 you have breaking out the efficacy by background med. I'm just wondering in that vein if kind of pushing on some of the color on the safety profile, do you have a similar slide deck to kind of look at how safety breaks down by background ASMs? Obviously, some of these are pretty potent sedatives, so I wonder if there's just a driving force behind some of the dystopias and some nons that can be discombobulated from drug. Just to confirm, are these all focal onset patients in this data set or are there any grand mal patients here? Thanks. Yeah, so Brian, this is all focal onset seizures.

We're going to have the primary TLIs later in the year at AS here, so maybe get that out of the way. As you can see on both the demographics table and on that slide, this number sums to much more than 100% in terms of the overall. Patients are wearing a multitude of anti-seizure medications, which makes that analysis of what is actually the culprit a lot harder. I think what I can say is we look into not only the ASM they're in, but the actual ASM levels in their blood. When you look into that, it is very clear that a significant proportion of those patients are on toxic concentrations, meaning higher than the maximum allowed concentration in the U.S. You do see somewhat of an association on those cases. People are not monitoring from drug monitoring perspective too frequently and heavily.

These patients, I would argue they should and obviously they are a lot more prone to have side effects. One of the reasons why we're being a lot more proactive on the reduction of the dose of the background. Great, thank you. Of course.

Speaker 1

Thank you. Our next question comes from Rudy Lee with Chardan. Your line is open.

Speaker 2

Hey, thanks for taking my question. Congrats again on the strong results. Just a quick follow up to the question regarding background therapy. Can you provide additional color on the potential impact testing of current background therapies? I'm just curious how that impact changes your enrollment criteria selecting the right patient for the pivotal trials and what kind of additional data you think would be necessary to support its use in combination with other sodium channel blockers in practice. Thanks. I think what you're seeing here is the only real sample of how patients are treated currently. Unfortunately, I would say adjunctive therapy on this layering of ASMs is just a common practice. There is no reason to be worried. Concerns about the combination, if anything. Again, I urge everyone to look into slide 23.

This is the lowest rate of side effects on the therapies in development or developed for focal onset seizures, despite the fact that the combination was probably the most aggressive at baseline. No concern whatsoever. We need to deal with the markets as the market stands and that's what we are doing here, particularly with over 30% of patients on cenobamate. I would say that's what the market is. We're very confident that both the safety and the efficacy are incredibly strong there. No real expected change other than the instruction, as we mentioned before, for physicians to be more cautious about the reduction on the background ASM. Got it. Very helpful, thanks.

Speaker 1

Thank you. Our next question comes from Ritu Burrell with TD Cowen. Your line is open. Hi guys. Thanks for taking the follow up. I just wanted to ask a little more detail on the side effect profile and specifically the comment on the severe patients and this comment about recovered and resolved. Can you give us a little more detail on the moderate to severe and serious side effects and that recovered and resolved comment? I've got a follow up.

Speaker 2

Yeah, yeah. On the severe specifically, we do that. One of the patients had a dizziness. I would say that was clearly on target, and on target not only for therapy but for the combinations that they were in. The other ones were background illness, like particularly an infection that leads to aspiration pneumonia. Not too concerned about that. The fact that they all resolved, I think testing most important and resolved very quickly is the most important part here. Not too concerned. I think we want to be very transparent and show the rates there and show the results, but not anything we are very concerned about.

Speaker 1

Was it resolved with removal of drug or adjustment of background meds?

Speaker 2

Oh, very, very good question. Sorry for misunderstanding before. No, it was actually just resolved with conscientious dosing.

Speaker 1

Okay. That was the follow up question. Thank you. I'm showing no further questions at this time. I'd like to turn the call back over to Marcio for closing remarks.

Speaker 2

Thanks everyone for joining. We are thrilled on these results. I think it's important for all of us, but it's particularly important for patients living with focal seizures and with epilepsy in general. It's not every day that we got a field that's been going on for like 100 years, a little bit over 100 years since the first treatments, and you can deliver after more than 25 drugs in the market like over 50% reduction, 60% overall response rate patients. It's quite remarkable to put in context. Wanted to take a second to just show my appreciation for all the patients participating on this study and all the other studies and for everyone at Praxis and our investigators and site staff, thank you so much. Exciting days ahead of us. Appreciate the support and looking forward to interacting with all of you.

Speaker 1

Thank you for your participation. You may now disconnect, everyone. Have a great day.