NeuroPace, Inc. (NPCE) Earnings Call Transcript & Summary

Greetings, and welcome to the NeuroPace IGE PMA Supplement Update Call. [Operator Instructions] Please note, this conference is being recorded. I will now turn the call over to Scott Schaper, Head of Investor Relations. Please go ahead.

Good afternoon, and thank you for joining today's conference call. On the call, you will hear from Joel Becker, NeuroPace's President and Chief Executive Officer; and Dr. Martha Morrell, NeuroPace's Chief Medical Officer. Patrick Williams, NeuroPace's Chief Financial Officer, is also on the line. Earlier today, NeuroPace issued a press release providing an update on the status of the company's PMA Supplement seeking to expand the indication for the RNS System to include patients with antiseizure medication-resistant idiopathic generalized epilepsy or IGE. A copy of the press release is available on the Investor Relations section of our website. Before we begin, I would like to remind you that certain statements made on today's call may constitute forward-looking statements within the meaning of federal securities laws. These statements include, among others, comments regarding our expectations and beliefs with respect to regulatory matters, including FDA review of our PMA supplement through IGE, our submission issue request process, our intent to amend the submission of supplemental information, our ability to place the PMA Supplement in approvable form, potential labeling and post-approval study approaches, timing of future interactions with FDA, time lines for FDA review of PMA Supplement amendments, the potential approval of an expanded indication, the potential clinical and commercial opportunity in IGE and our expectations regarding operating performance and growth. Forward-looking statements are based on management's current expectations and assumptions informed by the information that is known at the time the statements are made, and they are subject to risks and uncertainties that could cause actual results to differ materially. A discussion of these risks and uncertainties can be found in today's press release and in our filings with the Securities and Exchange Commission, including our most recent Form 10-K and Form 10-Q. We undertake no obligation to update or revise any forward-looking statements, except as required by law. With that, I'll now turn the call over to Joel Becker. Joel?

Thank you, Scott, and good afternoon, everyone. As Scott mentioned, this afternoon, we issued a press release providing an update on the FDA review of our PMA Supplement seeking indication expansion for the RNS System into drug-resistant idiopathic generalized epilepsy or IGE. Let me begin with the headline. We received communication from FDA on the status of our PMA Supplement indicating that our submission was not approvable in its current form due to additional information requested regarding the clinical evidence supporting the submission. Having reviewed FDA's written communications and had subsequent discussions with the agency, we believe there is a path for approval of the submission. Our interactions are now focused on providing the information needed to answer FDA's remaining questions. While we are disappointed with not receiving an initial approval, we were encouraged by our subsequent discussion with the agency and importantly, their interest in engaging interactively, their request for additional information to address certain questions and their willingness to work collaboratively to bring the RNS indication expansion for drug-resistant IGE patients to market. We view our subsequent interactions with FDA as a constructive step in clarifying the path forward in the regulatory process. As I mentioned, following receipt of the communication and at the agency's invitation, we met with FDA to discuss their feedback. The review team and Office of Health and Technology Management, consistent with the letter indicated that providing additional data from the NAUTILUS trial and additional clinical context could help address the agency's remaining questions. Importantly, the submission not being approvable in its current form was not based on any new safety concern. The primary safety endpoint in NAUTILUS was met and the FDA communication did not identify any new safety signals with the RNS System. From a forward process standpoint, based on the strong recommendation from the agency, we are in the process of submitting a Submission Issue Request or SIR to further discuss our planned approach. A Submission Issue Request is a process that allows the sponsor to engage with FDA on specific issues in an active application. We expect to meet with the agency over the next few weeks, and this meeting gives us an opportunity to discuss our planned approach with FDA before submitting an amendment. We believe that is the right next step because it can help us align with FDA on the content and structure. Following alignment with the agency as part of these interactions, we intend to amend the submission with supplemental information, including additional data and analysis regarding the patient populations evaluated in NAUTILUS, real-world evidence and context with regard to the clinical meaningfulness of seizure reduction. I want to emphasize that we continue to believe in the strength of the NAUTILUS data set and in the potential of the RNS System to address a significant unmet need for patients with drug-resistant IGE. These patients have no approved neuromodulation or surgical treatment options. For patients who continue to experience uncontrolled generalized tonic-clonic seizures, the status quo is not without significant clinical risk. And Dr. Morrell will walk through the clinical data in more detail. To close, we are working with urgency and discipline to develop the supplemental package, align with FDA on appropriate data requests through the submission issue request process and move the application forward to approval. I will now turn the call over to Dr. Morrell to discuss the clinical context and data. Marty?

Thank you, Joel, and thank you to everyone joining this afternoon. Let's begin with the patient population that is central to our conviction in this indication and our commitment to advancing a therapy for these patients who have a meaningful unmet clinical need. Patients with drug-resistant idiopathic generalized epilepsy who continue to experience generalized tonic clonic or GTC seizures face a substantial life burden and risk to safety. GTC seizures are among the most severe and dangerous seizure types. Each GTC seizure is a serious medical event that can involve sudden loss of consciousness, a fall and convulsive movements of arms and legs often leading to injury. Recovery may be prolonged and rescue medication is often required. Additionally, patients with uncontrolled GTCs have the highest risk of sudden unexpected death in epilepsy or SUDEP. Reducing GTC seizures can meaningfully improve patient safety, independence and quality of life. For these patients, as Joel said, there are no approved neuromodulation or surgical treatment options available today. That is the unmet need that the NAUTILUS study was designed to address. I will not review the study design in detail, but I want to remind you of a few points. NAUTILUS is the first prospective multicenter, randomized, single-blind sham-stimulation controlled study evaluating responsive thalamic stimulation using the RNS System in patients with drug-resistant IGE. Importantly, this study met its primary safety endpoint. While the primary effectiveness endpoint did not achieve statistical significance, the prespecified additional analyses, comparing seizure frequency during treatment with baseline seizure frequency, demonstrated statistically significant improvements. FDA has requested information to help them understand whether these improvements are clinically meaningful with a focus on certain patient subgroups. FDA wishes to consider this using the totality of evidence. This includes the entirety of the data from the NAUTILUS trial, including additional effectiveness data at 24 months, analysis of response according to patient baseline seizure frequency and detailed information on patient-reported outcomes. Additionally, published literature will be provided that supports the clinical meaningfulness of the response to RNS System treatment. The clinical data generated in the NAUTILUS trial that was provided in the initial submission and what will be provided in the amendment consistently shows what we believe are meaningful and lasting improvements in outcomes that matter to patients and their physicians. The initial submission provided data to 18 months. At 18 months, patients treated with RNS System experienced a 77% median reduction in generalized tonic clonic seizures compared with baseline. 40% of patients experienced GTC seizure freedom at that time point. We also saw rapid and sustained reductions in other generalized seizure types, including absence and myoclonic seizures. The 18-month data also showed benefits beyond seizure counts. More than 90% of patients reported improvement on the Patient Global Impression of Change and 80% of their physicians reported improvement on the Clinical Global Impression of Improvement. Responsive stimulation treatment was also associated with an approximate 30% reduction in seizure-related injury events and 44% lower odds of use of a benzodiazepine as a rescue medication for a generalized tonic clonic seizure. Those data are now peer-reviewed and recently published in Epilepsia, which is important both scientifically and clinically. The publication provides Level 1 evidence supporting responsive thalamic stimulation as a potential treatment approach for patients with drug-resistant IGE. Since that 18-month analysis, the data set has continued to strengthen. At the request of the FDA during the review process, the company provided 24-month data, which showed patients continued to improve with stimulation. Among the evaluable patients who have completed 24-month post-implant follow-up, those who had received stimulation for 23 of 24 months post implant achieved a median percent reduction in GTC seizures of 100% compared to baseline. This continued improvement over time is entirely consistent with what we have observed with RNS therapy in focal epilepsy. FDA is asking us to further support benefit in subpopulations of patients evaluated in NAUTILUS and to help characterize the clinical meaningfulness of benefit, including in patients with different baseline generalized tonic clonic seizure frequencies. NeuroPace will provide evidence from the NAUTILUS trial to illustrate the magnitude of the clinical benefit of RNS therapy in these various subpopulations and the meaningfulness of that benefit as reported by the patients and their physicians. This will be supplemented by the literature describing the potential consequences of each single GTC and the patient recognized benefits of reducing that seizure burden. Another example of feedback from the agency was that there was limited representation to support an indication for individuals 12 to 18 years of age. NeuroPace will work to identify pathways to support an indication for use in this age group. We understand FDA's request for additional information and for the context they have requested to help to understand the clinical meaningfulness of RNS treatment. We appreciate the opportunity to interact proactively and are working to provide that information to FDA in a structured, comprehensive and expeditious manner. I will now turn the call back to Joel.

Thank you, Marty. Let me close by describing where we go from here. Based on our interactions with FDA, we view this as a delay and a waypoint in the regulatory process and are working to address feedback on patient populations, real-world evidence and labeling as we continue pursuing approval of the RNS System for a drug-resistant IGE indication. We have already met with the FDA review team to discuss the agency's feedback. There have already been further interactions this week, and we are in the process of submitting a Submission Issue Request to further discuss our planned approach with the agency over the next few weeks. We believe that this is the right next step because it gives us the opportunity to align with FDA on the content and structure of a supplemental package. If we are able to align with FDA on the clinical evidence package through the SIR process, we plan to submit an amendment shortly after the SIR meeting. FDA will determine the appropriate review classification for the amendment and the agency has the ability to treat an amendment as a major amendment and extend the review clock up to 180 days. Based on our breakthrough device designation, the interactive nature of our ongoing dialogue and the agency's handling of prior amendments during this review, our current expectation is that the amendment could be reviewed without requiring a restarting of the full 180-day review clock. We will provide more specific timing as we gain additional clarity following the SIR meeting. As previously communicated, our full year 2026 guidance did not include any contribution from the expanded IGE indication, and we plan to provide full financial results and any updates to our full year outlook on our upcoming earnings conference call scheduled for August 11, 2026. Stepping back, while disappointed by FDA's recent communication regarding our initial application, we are encouraged by the agency's continued engagement, their interactive collaboration and interest in working on a path for approval. We are focused on doing the work required to address FDA's feedback. We will do that with urgency, discipline and a clear focus on the patients and physicians who need new options for drug-resistant IGE. NeuroPace has consistently led the field by generating high-quality clinical evidence and advancing neuromodulation into patient populations that have historically had no device-based treatment options. And we remain committed to that leadership as we continue working toward an IGE indication approval. This concludes our prepared remarks. I will now turn the call back to the operator to open the line for questions.

[Operator Instructions] Your first question comes from the line of Anthony Petrone with Mizuho Group.

So maybe we can start with the -- I guess, a little bit more detail on the clinical side from feedback in the initial conversations with FDA. And then again, you had the 18-month and then the supplemental 24-month follow-up data, which certainly showed a good median control seizure rate for generalized tonic clonic seizures. One option here was to get the GTC-only clearance. So a little bit more detail on what the feedback was on why the company and the data that's submitted did not get this over the goal line here for GTC only?

Thank you, Anthony, and it's obviously a very good question. Glad to have you here on the call. Wish we were under a little bit different circumstances and welcome you to the call for the first time, but thanks for being on, and thanks for your interest in NeuroPace. And you're exactly right, we had provided the 18-month data and some of the 24-month data. And Dr. Morrell Marty is very close to both the data that has been submitted as well as the data that we plan to submit the new data, the incremental information that we're looking at. So I'm going to ask her to say a little bit more about that, answer your question.

Yes. Thanks. So with our initial submission, we provided the 18-month data. FDA then came back and requested some of the newly completed 24-month data. But they asked for a subset of that data only, they were not provided the entire data set. What they've requested is to have that entire 24-month data set. And their intent is to look at the overall benefit as well as the response in certain subpopulations. They also have a great deal of interest in seeing more detail on the patient-reported outcomes. And they've asked us for the literature that comprises the real-world evidence for treatment of the RNS system as well as the literature establishing the clinical meaningfulness of a reduction in generalized tonic clonic seizures. They are obviously wanting to engage interactively and quite intensely with us to truly understand this patient population and what the RNS System brings.

I guess the only thing I'd add to that, Anthony, is that as their analysis has gone on, and remembering this is the first time the device group has ever reviewed a study for drug-resistant idiopathic generalized epilepsy patients, they have also come up with additional questions. And as their analysis has also continued, specific questions come up too. And so in addition to the things that Marty mentioned here, exactly the 24 months of subpopulations, the patient outcomes, et cetera, and the clinical meaningfulness of the generalized tonic clonic seizures, there's also a temporal element here where their knowledge of the study and the analysis also has continued to progress over time.

And I'll say that we internally have performed these analyses, and we see that in the subpopulations, there is consistency and the directional improvement and then the magnitude of improvement. So we believe that we'll be able to satisfy their questions and assist their understanding.

If I could sneak one quick one in. I know it's early here, but you have the submission issue request and there'll be another follow-up meeting with FDA. But just -- is there any way to just give a little bit more substance on timing? When do you think the initial meeting with FDA will be? And if you had to handicap what timing on a resubmission could look like, that would be helpful, and I'll get back in queue.

You bet. So we're in the process of preparing that SIR submission. And then once that goes in, the agency has a period of time in which to respond. In general, you could think about it as we expect to be having the SIR meeting with the agency over the next few weeks. Then coming out of that, there's obviously some different scenarios. Ideally, what we would see and what we're working to and most expeditiously is we would file an amendment following that if we have good alignment with the agency on what they're looking for and the answers to their questions, we would file an amendment. And from there, then the agency has some further discretion. They could evaluate that information, and this is what we're working to. They could evaluate that information and move forward with a decision based on what has gone into that submission without -- based on our current understanding, our expectation is that would not require a full restarting of the 180-day clock. So they have discretion within that. They do have the right as a case here, too, to treat the submission as a major amendment, which could extend up to 180 days after submission. But again, based on the breakthrough device designation, the interactive nature of our ongoing dialogue, the way the agency has handled prior amendments during this review, our current expectation is that our amendment could be evaluated without requiring a restarting of the full 180-day clock. So hopefully, that gives you a little bit of extra color.

Your next question comes from the line of Michael Kratky with Leerink Partners.

Maybe just to follow up on that last one. But could you give a sense of what specifically within the current evidence package the FDA found insufficient? Any specific questions they asked in terms of the efficacy and what remains unresolved? And then maybe just to ask a follow-up upfront, but can you confirm how many patients completed that 24-month data that you mentioned in the press release?

You bet, Mike. Thanks for those questions. And I'll ask maybe, Marty, if you could just say a little bit more about the different categories of incremental information that we're planning on providing there as well as then to the specific question on patient completion of the 24-month time frame?

Yes. I don't think that FDA had any issue with the data that was provided. They knew that we had 24-month data. And so wanted to see that and wanted some additional analyses performed that were not prespecified. The patients were all followed for 24 months post implant. But because of the way they were randomized early on, not every patient received that full 23 to 24 months of stimulation. Some received stimulation later and therefore, did not have the complete 24 months of treatment. So we're looking at everybody at every point that they were receiving stimulation, every month of stimulation, including those who completed with that 23 months. So that represents 41 of the patients in the trial for whom we have data to -- stimulation to 23 months and then 84 patients for whom there is data with some period of stimulation.

And then the first part of Mike's question was maybe you say a little bit more about the incremental data, the new information that we're going to be providing. You touched on that previously, but.

The new information is really more of what we had already provided. And so that would be the 18- to 24-month data. We also had provided patient-reported outcomes. They would like to see that in more detail. They're interested in the programming, how detection and stimulation were programmed during the study. Understandably, we obviously can provide that to them. And then we had not really spent much time providing literature to them about what it means to have a generalized tonic clonic seizure and what it means to be medically intractable and how much of the change is necessary to be clinically meaningful to a patient. So we're very happy to provide the extensive literature that describes the clinical need.

And Mike, just to emphasize a couple of those points there, and Marty mentioned it earlier, but I just want to make sure that it came through here as you listen to all the kind of the data coming at you here. An incremental piece of the analysis is going to -- that we had not provided and will be new is the subpopulation analysis. And just it will be supportive, I think, of looking at the indication and potential claims around seeing what we see is a consistent and directional effect across populations. It's not a subpopulation benefit. Marty, would you?

Yes. So these -- as I mentioned, these analyses were not prespecified. And FDA's question is this benefit -- substantial benefit being driven by a particular subpopulation. And so asked us to look at these subpopulations to see if they derive equivalent benefit. And we're very comfortable with the outcomes of those analyses.

The last thing I'd add here, Mike, is just that -- and you didn't ask it, but just as we talk about the incremental data that we'll be providing, et cetera. Our discussions with the agency have really focused on data from the NAUTILUS trial as well as published literature. We have not been discussing with them any data that would require a new trial. And so I just -- again, you weren't asking that specifically, but just to the point of as we think about buckets of data and in the discussion, everything has really been either around the trial, around additional real-world evidence and meta-analysis of publications for patients having been treated or publications around the clinical meaningfulness of GTCs, et cetera. Nothing that's been outside of the trial or current publications.

No, that's really helpful. So I appreciate the color there. And Joel, maybe just to follow up on that last point quickly. But did it seem like the FDA expressively greenlit this path that you guys are taking? Or did it seem like they maybe do want to see another study at some point? Like how explicit were they in terms of approving this path that you guys are pursuing now?

There was no discussion or mention of an additional study.

Yes.

It was really pulling additional information and performing post-hoc analyses on the data that exists. The literature is there. And so we will provide that to them. But there was no discussion about a new study.