Greetings. Welcome to the NeuroPace Update Call. At this time, all participants are in a listen-only mode. The question-and-answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. Please note this conference is being recorded. I will now turn the conference over to Scott Schaper, Head of Investor Relations. Thank you. You may begin.
Good morning, and thank you for joining today's conference call. On the call, we will hear from Joel Becker, Chief Executive Officer, and Dr. Martha Morrell, Chief Medical Officer. Earlier today, NeuroPace released preliminary one-year results of the two-year NAUTILUS study, supporting an expanded clinical indication for idiopathic generalized epilepsy. A copy of the press release is available on the company's website at neuropace.com. Before we begin, I would like to remind you that throughout this call, we will make statements that include forward-looking statements within the meaning of federal securities laws, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Any statements made during this call that relate to expectations or predictions of future events, results, or performance are forward-looking statements.
All forward-looking statements, including those around NeuroPace's projections, business opportunities, commercial expansion, market conditions, clinical trials, top-line results and regulatory submissions, and those relating to our operating trends and future financial performance, expense management, estimates of market opportunity, and forecast of market and revenue growth, are based on current estimates and various assumptions. These statements involve material risks and uncertainties that could cause actual results or events to materially differ from those implied by these forward-looking statements. Accordingly, you should not place undue reliance on these statements. For more detailed descriptions of the risks and uncertainties associated with our business, please refer to the risk factor section of our public filings with the SEC, including our quarterly report on Form 10-Q for the quarter ended March 31, 2025, filed with the SEC on May 13, 2025, and any other reports that we may file with the SEC in the future.
This conference call contains time-sensitive information, which we believe is accurate only as of this live broadcast on May 27th, 2025. NeuroPace disclaims any intention or obligation, except as required by law, to update or revise any financial projections or forward-looking statements, whether because of new information, future events, or otherwise. With that, I will now turn the call over to NeuroPace's Chief Executive Officer, Joel Becker. Joel.
Thank you, Scott, and good morning, everyone. As mentioned, this morning we issued a press release announcing preliminary one-year data from our NAUTILUS trial evaluating the safety and effectiveness of the RNS System for treatment of individuals with drug-resistant idiopathic generalized epilepsy, or IGE. The trial met its primary safety endpoint and did not reach statistical significance in its primary effectiveness endpoint. However, overall, we are encouraged by the totality of the data, particularly regarding safety and the observed efficacy in a clinically meaningful subgroup of patients. We are also pleased with the improvements that patients experienced over time.
As we have consistently seen in patients with focal epilepsy, our preliminary analysis indicates that the median percent reduction after one year of RNS treatment compared to baseline is higher than what was observed in the randomized controlled trial in focal epilepsy that led to initial FDA approval of the RNS System. This is an important step forward and a meaningful milestone in our mission to expand access to personalized therapy with the RNS System. The strength of these preliminary results not only underscores the potential of the RNS System in IGE, but also reinforces our confidence in the platform's ability to drive long-term growth and deliver life-changing outcomes for patients with few alternatives. For the IGE community, where treatment options have historically been limited, the data discussed today offer new hope.
We are energized about the opportunity to redefine what is possible for people living with epilepsy, especially in a population that has waited far too long for meaningful innovation. Dr. Martha Morrell, our Chief Medical Officer, will walk through the preliminary results and provide context on the unmet clinical need in this patient population. I will then return with closing statements before opening the call to Q&A. I would now like to turn the call over to Dr. Morrell.
Thank you, Joel, and thanks to all of you for joining this morning to discuss the preliminary results of our NAUTILUS trial. As Joel noted, we are very encouraged by much of the data and believe it contributes meaningfully to the growing body of evidence that supports the safety and effectiveness of the RNS System as a treatment for persons struggling with drug-resistant epilepsy. To start, I'd like to comment on the trial design. NAUTILUS is a prospective, multi-center, randomized, single-blind, sham-simulation-controlled study that enrolled 100 participants, with 87 undergoing implantation of the RNS System. There were 23 epilepsy centers that participated within the U.S. Patients had drug-resistant idiopathic generalized epilepsy with a high burden of generalized tonic-clonic seizures, the most severe and dangerous seizure type. All subjects were required to have two or more generalized tonic-clonic seizures over a three-month baseline to be eligible for implant.
Drawing from our experience in the focal epilepsy trials, patients were given three months for the implant effect to subside and for RNS programming to be optimized. In the fourth month, patients entered an effectiveness evaluation period where they remained until their second seizure, after which they entered an open-label period where all patients were unblinded and able to receive stimulation. This study design was modified from an earlier successful anti-seizure medication trial for IGE and is novel for a medical device trial. The intent of the design was to reduce patient risk of seizure-related injury and of sudden unexplained death in epilepsy by allowing patients who were randomized to the sham arm to transition to active stimulation therapy as soon as was possible. This trial design was supported by FDA and the physician investigators and was acceptable to patients, resulting in very rapid enrollment.
Anticipating that there could be progressive improvement with treatment over time, pre-specified effectiveness endpoints included metrics to assess change in seizure frequency at one and two years after implantation, as well as additional measures of quality of life. Now, moving on to the data, I am pleased to report, as Joel said, that the study met its primary safety endpoint, which was defined as the percentage of patients experiencing serious device-related adverse events through 12 weeks post-implant. Secondary safety analysis demonstrate safety at the one-year endpoint as well. When combined with the extensive safety data that we have from the trials in focal epilepsy, this further supports the safety of the chronic implant and of responsive stimulation. Moving on to effectiveness, the study did not reach statistical significance for the primary endpoint.
However, a strong signal for efficacy was seen in a large subpopulation of patients who had a lower baseline frequency of generalized tonic-clonic seizures and whom the time to the second generalized tonic-clonic seizure was statistically significantly greater in the treated patients compared to the sham. While the study is not powered to show effectiveness in subgroups, this analyses suggests there is a meaningful therapeutic and clinical benefit from the use of the RNS System in a substantial population of patients with IGE. Other pre-specified analyses are being performed right now as are analyses to better understand patient characteristics that differentiate this response. Data on longer-term seizure outcomes is highly encouraging. Pre-specified additional effectiveness endpoints include median percent seizure reduction, responder rates, which are the percentage of patients with a 50% or greater reduction in seizures, and improvements in seizure-free days.
Each one of these endpoints shows numerically robust and clinically meaningful improvements over the first year of responsive stimulation treatment. These continue to increase in those patients who have progressed into the second year. The median percent reduction after one year of RNS System treatment compared to each patient's baseline is higher than what was observed in the randomized controlled trial in focal epilepsy that led to FDA approval. These endpoints are highly relevant to physicians treating patients with drug-resistant idiopathic generalized epilepsy. In this chronic and disabling epilepsy for which there is no treatment beyond medications, patients and physicians choose treatments that deliver a reduction in the severe seizure burden over the long term.
The progressive benefit evident in these patients with intractable IGE and generalized tonic-clonic seizures aligns with all of the clinical data in focal epilepsy, including data from our FDA-reviewed three-year post-approval study, which showed median percent seizure reductions at one year of 62%, improving to 69% at two years, and reaching 82% at three years, with 42% of patients experiencing at least one six-month period of seizure freedom. This was data generated in the NAUTILUS trial reinforces the sustained real-world efficacy and contributes to a growing body of evidence supporting the utility of the RNS System in the treatment of drug-resistant epilepsy. It also highlights how physician experience with the therapy enhances the ability to optimize programming for the personalized therapy that is possible with our treatment approach.
To close, we are highly encouraged by these results in a patient population with the most dangerous seizure type who have failed to respond to medical therapy and have no other treatment options. FDA recognized this when granting a Breakthrough Designation for this trial. We remain absolutely committed to helping persons with intractable IGE, to build on this evidence, and to engage with the FDA as we move forward. We plan to submit the full data set in the second half of this year and to engage with FDA on the possibility of utilization of the pre-specified data on median seizure reduction, among others, as well as the possibility of an indication with labeling aligned with the substantial subpopulation of patients that showed a therapeutic and clinical benefit. I will now turn the call back over to Joel.
Thank you, Marty. Thank you to all the patients, clinical investigators, clinical sites, and the NeuroPace clinical team for these important contributions and dedication to advancing the field of research in epilepsy. At NeuroPace, we are deeply committed to being the leader in the field, including the leader in evidence generation, to move the standard of care forward. This means not only advancing innovation, but also learning from every patient and every data point. What did we learn? We learned that responsive stimulation targeting the thalamus with the RNS System is safe in patients with intractable idiopathic generalized epilepsy and generalized tonic-clonic seizures. We also importantly learned that for the total study patient population, we saw meaningful and sustained improvements in seizure burden and seizure-free days at a rate that is higher than what was seen in our focal epilepsy pivotal trial that led to an FDA approval.
These are critical clinical outcomes that matter deeply to physicians and to families. Additionally, our previous findings regarding continued improvement over time were again supported and confirmed by this data. Finally, we learned that effectiveness is evident and most pronounced in patients with one to two generalized tonic-clonic seizures per month, the most dangerous type of seizure, a group that likely represents a large portion of the real-world drug-resistant IGE population. Regarding next steps, we plan to continue the NAUTILUS trial to its predetermined endpoint of two-year follow-up, which many patients have already reached. This will allow our teams to collect additional data and conduct further analysis across a broader set of safety and efficacy measures. As Dr. Morrell mentioned, we will be engaging with the FDA regarding this one-year interim review and plan to submit this data in the second half of 2025, consistent with timelines we've shared previously.
As noted in our press release, our 2025 financial guidance provided in the first quarter earnings call on May 13th remains unchanged. We view the totality of the data in the NAUTILUS study as a meaningful catalyst that adds to the growing body of evidence and momentum in our business. We're committed to leadership in this field, and this is another example of our leadership and of advancing our mission to help patients who suffer from debilitating seizures. Our long-term strategy is clear and underway. Our base business is growing over 20% year- over- year, and we are excited by the opportunity ahead. This concludes our prepared remarks. I would now like to turn the call over to the operator, who will open the call for questions. Operator? Operator, can you hear us?
Ladies and gentlemen, the floor is now open for questions. If you would like to ask a question, please press star one on your telephone keypad. Our first question today is coming from Frank Takkinen of Lake Street Capital Markets. Please go ahead.
Great. Thank you for taking the questions. I was hoping to start with one on just kind of understanding that subgroup of patients with the lower tonic-clonic seizure rate. I think you called out one to two per month where you saw the highest outcomes. If you kind of look at the larger market that you've quantified at, I want to say around $800 million in the generalized population, what portion of that market do you believe is in that subset that you saw the highest clinically meaningful benefit in the study?
It's a great question, Frank, and thanks for joining us this morning. When we think about the IGE population, if we zoom out a little bit here, we just think we all understand it's 60% focal, 40% generalized. Of the generalized, about half of that is IGE, so a total market of about 20% of the total market. While it's early in the data, our data would say that that population is likely a majority of the patients in IGE. That would be a meaningful, even if a somewhat narrowed total GTC incidence population, and we don't know if that's where we'll end up. Even if our population looks like the normal population, that would still be a majority. A significant group and a significant revenue opportunity and a significant available market and untapped patient population.
Got it. That's helpful. Oh, sorry, go ahead.
Oh, I just wanted to add that the patients in this trial had particularly severe idiopathic generalized epilepsy. We did not put a max on the numbers of seizures that people could have. As Joel said, the majority of people with IGE have fewer generalized tonic-clonic seizures. They represented 58% of the patients in our trial, the two and fewer. In the real world, that would be a much higher percentage of the population.
Okay. That's helpful. Maybe on just kind of optimizing treatment and understanding that a little bit better, I'm sure it's challenging to really quantify the puts and takes there. Based on the learnings throughout the procedure, how much of it do you think is really related to optimizing that therapy for a specific patient versus just the higher tonic-clonic burden for these patients? Really just trying to understand. I know with focal, you had, when you ran the real-world post-approval study, you saw a faster reduction in that median percent seizure as you understood how to kind of optimize the therapy for the patient better. Just kind of trying to parse out the difference in those.
Yes. Thank you. As Joel said, NeuroPace is always the leader, meaning we're always doing things the very first time it's ever been done. We definitely did learn during the trial about what should be detected and how treatment should be delivered. I think we started out at a better place given what we have learned from the focal epilepsy. This is a very different epilepsy, and the types of intracranial EEG patterns are different. The way we have approached stimulation is different. There was learning going on. Having said that, this effect of time is really striking. As Joel mentioned, the absolute numbers from every time point in terms of seizure reduction compared to baseline are higher than focal epilepsy. The slope of improvement is remarkably similar to what we saw in both our pivotal trial and our real-world trial.
I would just repeat myself. I think it's both. That time effect is something that even once we have refined stimulation and detection and feel like we're where the patient needs to be, there is still this continued improvement.
For some further context there, Frank, and of course, as Dr. Morrell mentioned, the trial's still ongoing, and we're still monitoring data. The data beyond 12 months is still, as of yet, incomplete. That work is ongoing. The preliminary signals based on the subset of patients that have gotten out to that 24-month point, to the point of learning and the time effect, for the group that's gone out to that 24-month mark, among those patients, we're seeing a median seizure reduction rate exceeding 80%. It is important that we emphasize that we're still working on that data, and we're not drawing statistical conclusions from that data just yet. We're seeing greater than 80% median seizure reduction rates in that population.
Again, speaking to the learning effect as well as the impact over time of the chronic nature of RNS as a therapy, we saw it in the focal population in the pivotal trial. We saw it in the post-approval study. Again, here we're seeing it. We're seeing it over time. As we've mentioned in our earlier comments, we're seeing it at a higher rate than in the pivotal trial for the focal population that did lead to an indication. When we say on the totality of the data that we're encouraged by it, those are all parts of it.
Got it. That's helpful. I'll stop there. Thank you.
Thank you, Frank.
Thank you. The next question is coming from Mike Kratky of Leerink Partners. Please go ahead.
Yeah. Hi, everyone. Thanks for taking our questions. Maybe just one to start. In terms of the overall primary efficacy endpoint, can you provide the p-values from the overall study population at one year? Any reasons you can provide as to why that endpoint may not have been achieved? Was it higher than expected placebo response or just minimal response in a certain subsegment? Any early findings?
Yeah. Thanks. We are deeply analyzing this. Of course, this data is very, very new to us. We are trying to understand characteristics. I would tell you that they do seem to be different. They are different in terms of the variability in their baseline seizure frequencies. I do not feel that we are in a place where we can say something that we are confident about, except that there are various characteristics that appear to separate the two groups as well as seizure variability. I think we are going to hold off on giving you the p-value other than saying that it was highly significant for the 58% of patients in the group that were two or fewer. Of course, we will be providing this information to FDA very soon today.
We want to make sure that they're aware of these results before we make them public.
Thank you, Marty.
Okay. Yeah. Understood. Maybe just a separate one. Some of the efficacy rates that you're mentioning, over 80%, I think you said at two years for median reduction from baseline in the active group. Can you talk about the placebo response, either the one-year median reduction versus baseline? How did that compare with the focal study or any kind of relative difference between active versus placebo on that endpoint specifically?
Yeah. As you know, everybody, of course, was implanted with the device. There is a well-known implant effect. It is seen with any type of brain procedure, including diagnostic stereo EEG. In our focal epilepsy study, we saw that there was a reduction in everybody in seizures for three months. At that point, it appeared to subside. We saw that the sham implant stayed the same, had no effect, and the treatment started to emerge. In this study, we are doing additional analyses, but it appears that the implant effect is three months also. I will reserve the right to adjust that as we do the hardcore analyses of our data. Having said that, we did see a response in both groups that was very similar for the first several months, at which point there was a differentiation.
Now, as far as the study design is concerned, for safety and ethical reasons, we employed the design that allowed patients to exit once they had had their second generalized tonic-clonic seizure. There were very few people in the placebo group who reached one year without having that second generalized tonic-clonic seizure and many more patients who were in the active group. I can't answer your question exactly as you asked because the sham group exited as soon as they showed that they were not responding.
Got it. Okay. Thanks for the caller, and I'll hop back into Q.
Thanks, Mike.
Thank you. Our next question is coming from Rohan Patel of J.P. Morgan. Please go ahead.
Hey. Thanks for taking the question. You mentioned that many of the pre-specified endpoints like median seizure reduction over the one year—and I believe I heard a comment on 24 months as well—were better than the focal pivotal data. I just want to get a sense for given that the key value proposition of RNS is the benefit that patients get over time from therapy optimization. I guess, why did you choose to power the trial in the way that you did versus the median percent reduction that you did in the focal trial? Any additional context on magnitude of the reductions beyond that roughly 38% that you saw in the initial trial would be helpful. I have a follow-up.
The reason that we powered the study on, well, there are two reasons. Not knowing the implant effect, there were discussions with the FDA about if we did a standard trial, how long the blinded period would be. The discussions were even taking that blinded period out past nine months. In patients with such terrible epilepsy, there is a risk for death. That traditional trial design made many of us very uncomfortable knowing that patients were going to have convulsions during that time. This trial design was adopted from a very successful trial design of a medication, lacosamide, that was conducted in patients with idiopathic generalized epilepsy. That is what we did.
The secondary, but it was pre-specified that there would be secondary endpoints that would be the median percent seizure reduction, responder rate, which is percentage of patients with a 50% or greater reduction, and then also days that are free of seizures. Generalized tonic-clonic seizures are not the only seizure type for many of these patients. They also have SOMS and myoclonic seizures, which are hard to count. Those are incorporated in the metric of days without seizures. That is what we did. The primary effectiveness endpoint is, of course, not the only thing that FDA considers. As Joel said, the data is rather striking. In the focal epilepsy study, in our real-world study, we reached 82% reduction in three years and were there within two years. Not all patients have completed two years, as Joel said, but many of them have.
Of course, more do almost every day. I am certain that that data will have some meaning to FDA, a lot of meaning to FDA, and it will be extremely meaningful to the doctors who are making decisions about how to treat these patients who are at such severe risk.
Rowan, just to your question, and as Dr. Morrell indicated, and I mentioned previously, we're still working on that data, and all the patients aren't out there yet. The monitoring isn't entirely complete. The preliminary signals are really encouraging in that population, in particular in the median seizure reduction rates. Again, we're over 80% in that population, as well as showing positive effect on some of the other secondary pre-specified endpoints. Again, we're really encouraged by that data and look forward to talking with FDA as well as submitting the data for publication and presentation.
Great. Thanks. I guess just a follow-up on the potential kind of label in the subset of patients that responded well. I guess if you could just talk more about the identification of these patients heading into the procedure. Obviously, I think that that's going to play into just the overall efficiency and workflow. It would be helpful if you could talk about kind of what's needed as far as identifying the right subset of patients that are, I guess, good responders here. Thanks.
Yeah. Absolutely. I've been an epilepsy doctor for a long time, and I still have an active practice. Somebody who walks into your office with idiopathic generalized epilepsy, you should be able to make that diagnosis with your clinical history, your 45-minute or one-hour discussion with the patient, and one EEG. It's very easy. You may or may not choose to get an MRI scan. That's it. That's the entire evaluation. We placed the leads in the thalamus, a particular nucleus called the central median nucleus. This appears to be a great target. It's a great target because—we didn't take this for granted. It's the first time it was done. It's a great target because we absolutely saw those seizures begin. Absolutely.
We were able to provide a response within about 100 milliseconds of the detection and then provide the response of stimulation similar to focal epilepsy in ways that were not at all perceived by the patient. I believe that the decision about whether a patient is a candidate is really simple. You ask them how many medications they've been on. You ask them how many seizures they're having. You can tell by the history what they have. Then you know what to do. There is no need for intracranial monitoring or even a requirement for scalp monitoring in the epilepsy monitoring unit. You have the answer.
Thanks, Rowan.
Thank you. The next question is coming from Priya Sachdeva of UBS. Please go ahead.
Hi, guys. Thanks so much for the question. Dr. Morrell, you noted that this lower baseline frequency subpopulation does represent a higher level of real-world patient population. Some of our KOL checks have indicated positive off-label use. Is there anything from a real-world data perspective or use case that can be leveraged when you're bringing this data to the FDA? Any thoughts with your previous work with the FDA and kind of getting this all together? One follow-up.
As you know, we're working with FDA actively on a number of studies. We have the same review group, and it has been uniformly positive with opportunities to have discussions. In addition, we have a breakthrough designation. FDA has identified this as a novel therapy that's meeting a—well, that's for addressing an unmet clinical need. As part of this, there are discussions rather than only written communications back and forth, and the timeline is much faster. For example, we are going to be giving FDA a high-level report of the results today. We called them, I believe it was on Friday, and got today. We will be scheduling a sprint meeting with other discussions. It is definitely a much more streamlined process than I'm used to with our other approvals.
I would also say that we're fortunate that our review group is very familiar with the RNS System. I think with this data, is completely comfortable with the safety, which is not trivial. The safety experience was really fabulous. We are really going to talk about what is meaningful. As Joel mentioned, we'll be sharing this data with the investigators beginning today. We'll be showing them the safety, primary effectiveness endpoint, the subpopulation of two or fewer, and then also the long-term data. It is that long-term data. These are people with chronic condition. You want a therapy that you can deliver chronically that will not lose its effectiveness. If you can find that it keeps getting better, that's extra.
Okay. Got it. That was super helpful. To ask, appreciate the reiteration of the 2025 guide, but obviously want to touch on the long-term guidance that you guys issued earlier this year where generalized was categorized as a growth driver. Any color on potential impacts to that long-term guide? At what point would you guys feel comfortable kind of reevaluating or updating those long-term guidance? Thanks so much.
Thank you, Priya. At this time, we're not making any changes to our LRP. We're, as Dr. Morrell mentioned, engaged with FDA in having these conversations. I wouldn't be making any changes while we're in those discussions. For emphasis, I would also just remind us all that within our LRP, there is a multi-pronged strategy here around growth drivers. Continuing to penetrate in adult focal, in existing L4 centers and with new prescribers, expansion into care, additional new indications. We've talked about our work in the pediatric space as well and our IGE work. None of what we presented at our LRP in January from a strategy perspective has changed. I continue to be—we continue to be excited about and encouraged by the role that we can play in providing an important therapy for idiopathic generalized patients.
We are encouraged by the data. Now we go into the process of finalizing that data analysis and engaging with stakeholders, including the agency. We plan to stay on track for our submission in the second half of 2025. The totality of the data, we are excited and encouraged about. It is better than what we had when we got a focal indication. Given where we are at, I do not see any changes being made to our LRP at this time. I do not see any changes being made to our LRP strategy. It is clear and compelling. I continue to be very confident in it.
Thank you. This concludes.
Thank you, Priya.
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