Q2 2026 Stoke Therapeutics Inc Earnings Call
Speaker #1: After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press *11 on your telephone.
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Speaker #1: It is now my pleasure to introduce CFO Thomas Leggett.
Speaker #2: Good evening, and welcome to Stoke Therapeutics' second quarter 2026 business update conference call. I'm Thomas Leggett, the Chief Financial Officer of Stoke Therapeutics. Joining me on today's call are Ian Smith, our Chief Executive Officer; Dr. Barry Teko, Chief Medical Officer; and Jason Hoy, Chief Patient Officer.
Speaker #2: As a reminder, today's webcast presentation is available in the investor section of our website. This webcast is being recorded and will be available for replay later this evening.
Speaker #2: Before we begin, please note that today's discussion includes forward-looking statements. These forward-looking statements are subject to risks and uncertainties, and actual results may differ materially.
Speaker #2: Please refer to our filings with the SEC for additional information. On today's call, we will review recent progress across the breadth of our business.
Speaker #2: Ian will start with an overview and share an update on the ongoing Phase 3 in-person study. This study is progressing nicely toward a data readout in the third quarter of 2027.
Speaker #2: Barry will then provide additional detail and input on our longitudinal dataset from our ongoing open-label extension studies, also known as our OLEs. He will also review the advancement of other pipeline opportunities that we are progressing, including our investigational medicine for autosomal dominant optic atrophy, or ADOA.
Speaker #2: We'll then hear from Jason on our commercial planning activities to deliver Zoriva Nursen to all patients who may benefit in the U.S., following a potential FDA approval by early 2028.
Speaker #2: I will review our financials, and specifically the strength of our balance sheet, and then we will open for Q&A. I will now hand the call over to Ian.
Speaker #3: Thank you, Tommy, and thank you to those joining us on the call tonight. Starting with our Phase 3 in-person study, the recent completion of enrollment of 162 patients in just 10 months speaks to the awareness and enthusiasm for STK-001 and its potential to change the course of Dravet syndrome by addressing the underlying genetic cause of this disease.
Speaker #3: Patients in the study are advancing through key study milestones, and importantly, there have been no treatment discontinuations. We are now within a year of our Phase 3 readout—data that would support the completion of our NDA.
Speaker #3: We continue our discussions with the FDA and have scheduled a pre-NDA meeting later this year as we prepare to initiate our rolling NDA submission in the first quarter of 2027.
Speaker #3: The meeting will focus on further educating the agency on the long-term safety and efficacy of Zoriva Nursen, using prior and ongoing analyses from our Phase 1, Phase 2, and OLE studies.
Speaker #3: We will also cover the details of our NDA submission, including the data to be included, the statistical analysis plan, and the timing of each module.
Speaker #3: Beyond Dravet, we have a unique opportunity with our platform and additional disease areas. We continue to advance STK-002, our investigational medicine for ADOA. Our Phase 1 study recently completed dosing of the first cohort of patients, and we have moved into a higher dose in a second cohort of patients.
Speaker #3: While continuing our work in SYNGAP1-related disorders, we are also expanding our early research efforts with new targets in haploinsufficient diseases, mainly focused in the CNS, given our expertise in the field.
Speaker #3: Consistent with our investment in other pipeline opportunities, in July we strengthened our leadership team with the addition of Tom McCauley, our Chief Scientific Officer, who will help guide the next phase of platform expansion and translational research.
Speaker #3: And from a financial perspective, our business investment is well supported by our pro forma cash position of approximately $420 million, providing a runway through to the potential U.S. launch of Zoriva Nursen by early 2028.
Speaker #3: We have entered a period where execution is increasingly important, and we remain focused on delivering the data and completing the regulatory and commercial readiness activities necessary to bring Zoriva Nursen to patients as quickly as possible.
Speaker #3: With that, I now pass you to Barry, who can provide more detail as to our progress.
Speaker #2: Thank you, Ian. Tonight, I will start with an update on the progress with the in-person study. In-person is a global, double-blind, sham-controlled, Phase 3 study of Zoriva Nursen in patients with Dravet syndrome.
Speaker #2: In June, we announced completion of enrollment of 162 patients in person. This puts us on track for our Phase 3 readout in the third quarter of 2027.
Speaker #2: Data from these patients are expected to be the final data necessary to complete our rolling U.S. NDA submission, which we expect to submit in the second half of next year.
Speaker #2: As Ian mentioned, the study is progressing well. To date, more than 140 patients are through Week 8 of the study and therefore have received either the two loading doses of 70 milligrams of Zoriva Nursen or sham.
Speaker #2: More than half of patients have only one dose left in the 52-week treatment period. Approximately 60 of these patients have also completed their Week 28 visit, the time point at which the primary endpoint of percent change in major motor seizure frequency is measured.
Speaker #2: The study will remain blinded through 52 weeks, given the key secondary endpoints measuring cognition and behavior will be assessed at that time point.
Speaker #2: In a couple of weeks, the first patients in the study will reach that milestone and have the opportunity to progress into treatment extension beyond week 52.
Speaker #2: Thus far, no patients have discontinued treatment in-person. When we designed in-person, we made several assumptions that are relevant when evaluating the study's statistical powering.
Speaker #2: First, in-person was powered to detect statistically significant effects on the secondary endpoint measuring improvements in cognition and behavior. This resulted in substantial powering for the primary endpoint.
Speaker #2: Second, the study design assumed a certain percentage of patient discontinuations. And as previously mentioned, we have had no discontinuations to date. Finally, our enrollment target was at least 150 patients, and we ultimately enrolled 162 in our primary analysis population.
Speaker #2: All of this reinforces our confidence in the study powering and the overall likelihood of demonstrating statistically significant effects on the primary and key secondary endpoints.
Speaker #2: Beyond the 162 patients intended to support our NDA, an additional cohort of approximately 30 patients in Europe is expected to complete enrollment this month.
Speaker #2: Planning is also underway for a new study of Zoriva Nursen in infants and toddlers under 24 months of age. We expect that study to initiate later this year to support our goal of enabling early intervention with this potentially disease-modifying therapy.
Speaker #2: Earlier this year, we presented data out to four years from our OLE study, which I'll briefly review this evening. I'll begin with our data on seizure frequency reduction.
Speaker #2: Here we see four years of data in which all patients received treatment with Zoriva Nursen. These effects are demonstrated on top of the standard-of-care anti-seizure medicine patients were already taking.
Speaker #2: These data include all patients across dose levels, including various levels of loading doses evaluated in the first year of treatment in the Phase 1/2 studies.
Speaker #2: As well as various levels of maintenance doses used in the OLE studies. The orange line most closely reflects our Phase 3 dose regimen. The blue line represents patients who received a variety of doses during the Phase 1, 2, and OLE studies.
Speaker #2: By month 29, all of them had transitioned to receiving 45 milligrams every 4 months, which is consistent with the anticipated commercial regimen, pending the results of in-person.
Speaker #2: While durable seizure control is the most immediate and obvious clinical need, we know that Dravet syndrome is not only a seizure disorder. It is a severe neurodevelopmental disease in which children develop normally until approximately 24 months of age.
Speaker #2: When they begin to stagnate in development, with minimal improvements in skills and activities such as communication, interpersonal skills, and mobility, this means that, regardless of chronological age, gains in cognition, behavior, and daily function are meaningful.
Speaker #2: To evaluate potential gains in cognition and behavior, we use VINDEM-3, a standardized assessment of adaptive functioning. Here are the 4-year VINDEM data from our ongoing OLE studies.
Speaker #2: These data demonstrate statistically significant improvements in cognition and behavior each year through 4 years of treatment, compared to the OLE week one. Similar to the seizure data I just showed, these OLE data include patients across all dosing regimens evaluated in our Phase 1/2 study, including loading doses that were lower than the 270 mg doses we are evaluating in our Phase 3 study.
Speaker #2: Importantly, all improvements in VINDEM scores shown here are measured against patients' baseline scores when they entered the OLE study, and therefore do not capture any benefit that may have been observed during the earlier Phase 1/2 treatment period.
Speaker #2: Alongside these efficacy findings, we continue to build a long-term safety dataset for Zoriva Nursen. Of the 81 patients enrolled in our Phase 1/2a studies, 93%, or 75 patients, continue treatment in the OLE studies.
Speaker #2: Of those, 57 patients remain in these studies. More than 930 doses of Zoriva Nursen have been administered to date, with some patients receiving treatment for more than five years.
Speaker #2: Overall, no new safety findings have emerged, and Zoriva Nursen continues to be generally well tolerated. The Phase 1, Phase 2, and OLE safety and efficacy data provide a substantial dataset that supports the design of our Phase 3 in-person study, and also a detailed understanding of the benefits to patients and how this potential medicine could change the course of Dravet syndrome for patients and their families.
Speaker #2: These long-term longitudinal data, which include patients who have received up to 16 doses over a five-year period, offer insight into the ongoing benefits with chronic dosing.
Speaker #2: Analyses from this clinical dataset have been well received at major medical conferences, and were published earlier this year in The New England Journal of Medicine.
Speaker #2: Our educational efforts will continue throughout the rest of 2026 and into 2027, with new analyses including effects on seizure severity, improvements in seizure freedom, and quality of life.
Speaker #2: We'll also continue to share these insights with the FDA. The data generated to date and the successful advancement of STK-001 in-person reinforce our belief in the potential of our platform to address the underlying cause of a number of severe genetic diseases.
Speaker #2: We are particularly focused on diseases caused by haploinsufficiency, where we believe we have a unique opportunity to use our proprietary scientific approach to restore protein expression from the healthy copy of a gene.
Speaker #2: In the near term, we are advancing STK-002, our investigational medicine for ADOA. ADOA is a progressive genetic disease that leads to degeneration of the optic nerve and loss of vision, starting in the first decade of life.
Speaker #2: It is the most common inherited optic nerve disorder. The majority of cases are caused by mutations in one allele of the OPA1 gene, resulting in haploinsufficiency, or 50% of the OPA1 protein.
Speaker #2: There are currently no approved treatments for ADOA. SDK-002 is designed to increase OPA1 protein expression, with the aim to improve vision in people with ADOA.
Speaker #2: Phase 1 dose escalation study is ongoing in the UK and Europe, and recently completed dosing of the first cohort of three patients. Dosing for our second cohort is scheduled to begin this week, with the third and fourth dose cohorts to follow.
Speaker #2: Subject to ongoing safety assessment. We anticipate early safety and efficacy results in the first half of next year to guide our next steps for development.
Speaker #2: We are encouraged by our preclinical data, as well as emerging data from the field, demonstrating that upregulation of OPA1 protein has disease-modifying potential. We look forward to sharing additional updates as the program advances.
Speaker #2: With that, I will turn the call over to Jason.
Speaker #3: Thank you, Barry. Today, I'll focus on three areas: the market opportunity in Dravet syndrome, how we think about label and access, and the progress we're making toward a potential US launch.
Speaker #3: I'll start with the patient population. There are an estimated 38,000 patients with Dravet syndrome across the seven major markets where we're running the in-person study.
Speaker #3: The US, UK, EU4, and Japan. Including approximately 16,000 in the US alone. Our estimates are based on an epidemiology analysis that scaled annual incidence to prevalence using country-specific live birth rates over the past 85 years, which was then adjusted for Dravet-specific mortality.
Speaker #3: In the U.S., the Dravet population is highly concentrated around centers of excellence and other key treatment centers. Approximately 50% of identified U.S. patients are cared for by the top 50 sites.
Speaker #3: All 50 of those sites are experienced in administering intrathecal medicines. Half of them are already participating in a Zoriva Nursen trial. This provides a strong foundation for early adoption and allows us the ability to maximize this opportunity with a lean commercial infrastructure.
Speaker #3: Including approximately 25 sales representatives, who will build upon our longstanding relationships with treating physicians established by our medical affairs teams. We're confident we know where 70% to 80% of the patients 25 and younger are being cared for today.
Speaker #3: Out of the estimated 16,000 total U.S. patients, we estimate 6,000 are under the age of 25 and likely under the care of a pediatric provider.
Speaker #3: These are patients who would be immediately addressable at the time of a potential U.S. launch. Pediatric neurologists and epileptologists tend to develop strong and lasting relationships with patients and families, and therefore continue to care for them well into early adulthood.
Speaker #3: As such, this group of clinicians follows the field closely and is typically the most well-informed about the disease and current treatment options. In addition, an ICD-10 code was established in 2020 and is used to track confirmed Dravet diagnoses.
Speaker #3: These data provide support for our assumptions, as well as insight into where patients are in their diagnosis and treatment journey, along with the providers who care for them.
Speaker #3: We believe diagnosis rates will increase over time as Zoriva, Nursen, and other genetically targeted treatments continue to advance. We'll continue to invest in targeted disease awareness and educational efforts to emphasize the importance of genetic testing to confirm a Dravet diagnosis.
Speaker #3: Looking ahead to our NDA submission, product labeling, and patient access, we continue to believe that the totality of evidence generated for Zoriva Nursen supports a differentiated value proposition in Dravet syndrome.
Speaker #3: By the time of our NDA submission, we expect to have approximately six years of safety and efficacy data available from our Phase 1, Phase 2, and OLE studies.
Speaker #3: Providing insight into the durability of treatment effects and the potential for disease modification over time. We intend to incorporate these data into our NDA submission for inclusion in the label.
Speaker #3: FDA guidance is clear that, in addition to pivotal study data, clinical study data that provide important information about a drug's effectiveness—and that would be useful to practitioners in their clinical decision-making—should be included in the label.
Speaker #3: We believe that the longitudinal data from our OLEs are relevant within that framework, and we know from market research that payers and healthcare providers already consider these data to be the most compelling evidence that we may have at the time of a potential approval.
Speaker #3: As Ian mentioned, we have a pre-NDA meeting with the FDA later this year. We plan to initiate the NDA in the first quarter of 2027, beginning with our Chemistry, Manufacturing, and Controls module.
Speaker #3: We recently completed commercial-scale manufacturing validation for both drug substance and drug product, and are currently finalizing product specifications. We continue to expect that, if approved, Zoriva Nursen would be granted a broad label for the treatment of Dravet syndrome, consistent with our breakthrough therapy designation.
Speaker #3: This broad label, combined with the existing concentration of Dravet providers and well-established infrastructure for administering intrathecal therapies, positions us for a smooth and efficient adoption with a lean commercial infrastructure at the time of launch.
Speaker #3: While we remain focused on accelerating access in our commercial territories in North America, our partners at Biogen are focused on expediting access in countries around the rest of the world.
Speaker #3: In addition, we plan to initiate a study of Zoriva Nursen in the adult population by the end of this year. This study is intended to expand clinician conviction for Zoriva Nursen in adults and support access among adults living with Dravet.
Speaker #3: Taken together, the strength of the clinical package, the continued positive feedback from payers and providers, and the progress we're making across commercial readiness activities give us confidence in our preparations for a potential U.S. launch in early 2028.
Speaker #3: With that, I'll turn the call over to Thomas.
Speaker #2: Thank you, Jason. I will remind you that all financial results can be found in our 10-Q. Today, I'll focus on the strength of our balance sheet position.
Speaker #2: We ended the quarter with $354.3 million in cash, cash equivalents, and marketable securities. Shortly after the close of the quarter, we raised an additional $65.7 million in net proceeds through our ATM program, selling approximately 2.1 million shares of common stock to a high-quality, long-only fundamental investor.
Speaker #2: This resulted in a pro forma cash position of approximately $420 million. Along with the reimbursement we received from Biogen for Zoriva Nursen-related expenses and a potential development milestone payment, we expect our cash position to fund our operations through a potential US launch in early 2028.
Speaker #2: In terms of our priorities, we continue to invest in advancing our Phase 3 study and preparing the organization for potential U.S. commercialization, while progressing our pipeline and maintaining a strong financial position.
Speaker #2: Thank you, and I will now ask for the line to be opened for Q&A.
Speaker #1: Certainly. As a reminder, to ask a question please press *11 on your telephone, and wait for your name to be announced. To withdraw your question, please press *11 again.
Speaker #1: One moment, please. Our first question comes from the line of Andrew Tsai with Jefferies.
Speaker #4: Hey, good afternoon. Thanks for taking our questions. The first one is, you guys have provided a lot of nice numbers this quarter. Where are patients exactly in the Emperor study?
Speaker #4: So, maybe bigger picture—what should we be taking away from these various data points as we track study progress and await the Phase 3 timelines?
Speaker #4: And then, secondly, it sounds like you have this pre-NDA meeting with the FDA in the second half, in part to talk about the SAP plan for Emperor.
Speaker #4: So may I ask what you guys are hoping to get alignment on? Is it kind of confirming the hierarchy of the five subdomains of Violin 3, maybe confirming which ones need to be Stat 6 for you to file?
Speaker #4: Just a little bit more color would be helpful. Thank you.
Speaker #5: Andrew, this is Ian, and thank you for the question. Good to chat to you again. We did provide a lot of, as you put it, nice numbers on the call.
Speaker #5: I'm going to ask Larry to reiterate those—there were a lot of them. But there are metrics internally for how we measure the trial every single week.
Speaker #5: And they're very important to us in terms of measuring the progress of the trial. So, Barry, why don't you provide those numbers again, and then I'll take the discussion on the NDA.
Speaker #6: Sure. Thanks, Ian. And thanks, Andrew, for the question. So, the study is progressing quite well, and patients are going through trial milestones. Again, as we said, enrollment is complete, and we enrolled 162 patients in the study.
Speaker #6: Of those, 145 patients are through their week 8, which means they've received two loading doses of the 70-milligram or sham treatment. About half of the patients have gone through week 24.
Speaker #6: And so they have only one dose left in their 52-week treatment period. Importantly, 60 patients have completed the week 28 visit, and that means that they have hit the time point of the primary endpoint, which is seizure frequency.
Speaker #6: And we're also very pleased that, very soon, patients will start to be reaching their week 52 endpoint, which is the important part of the treatment period study.
Speaker #6: Again, no patients dropped out of the study, which is important. This progress gives us a lot of confidence in EMPEROR to date and is consistent with the data that we've had from the OLE studies as well as our Phase 1/2 data.
Speaker #5: Yeah. Thank you for that, Barry. Yeah, I'll just reiterate the data that we're seeing in terms of no discontinuations, given the large number of progress that these patients through the study, continues to emphasize that this medicine is generally well tolerated.
Speaker #5: That's also consistent with the five-year data we have from the Phase 1, 2, and the OLE, where we've dosed between 70 and 80 patients, and continue to show that the medicine is generally well tolerated.
Speaker #5: To your second question, Andrew, about the pre-NDA meeting, I'll kind of answer it in a broader way and tell you all about the meeting.
Speaker #5: So, firstly, the meeting will occur in early fall—so not too far away. This is ordinary course when you're at this stage of Phase 3 development.
Speaker #5: When you're in registration studies, and so we're going down to the FDA with three objectives, or three topics. The first is to discuss the sequence of submission of data for our rolling submission.
Speaker #5: We anticipate initiating a rolling submission in Q1 of 2027, and that would start with the CMC package, followed by the preclinical data, and then closing out that rolling submission in the third quarter of 2027 with the clinical data.
Speaker #5: And so that's the first piece. Second, as you point out, it is the SAP—the statistical analysis plan. Again, this is normal practice. Before you get to the end of your Phase 3, and certainly during your Phase 3, you don't want to leave it too late.
Speaker #5: You need to go down the line on the details of the SAP. The way that our protocol has currently been constructed is that our primary endpoint is not in discussion in terms of the detail, but we will talk about the secondary endpoints.
Speaker #5: And the way that the study protocol has been described so far is that we will look at the secondary endpoints in either a hierarchical analysis—which means taking individual violin domains in a hierarchical manner—or we will look at it on a composite basis, where you combine those individual violin domains.
Speaker #5: The study is designed and we've communicated that it is designed in terms of collecting both sets of data. What we want to do is we want to go to the FDA and discuss exactly how they would like us to present that data.
Speaker #5: I will just point out that, in terms of the hierarchical secondary endpoints, the first hierarchical secondary endpoint is actually continued seizure reduction.
Speaker #5: So I'll just point that out. And then it goes into the violin domains. And then the third topic is the OLE data. As you know, each year we've gone down to the FDA and discussed the OLE data.
Speaker #5: Last year, we were discussing with the FDA in the latter part of 2025. This year, we have access to the four-year data, being updated from last year's three-year, and we're going to discuss that again.
Speaker #5: Why are we doing that? Because it's important to show that this is a drug that is chronically administered, and that this data has now been collected in patients for up to a period of five years.
Speaker #5: And we've been able to measure both durable seizure reduction and the continued improvement each year of violin scores, which are just a measure of skill and task acquisition of these children that unfortunately have a I'm going to call it a Dravet age of approximately 24 months, but we're potentially providing them task acquisition and skill acquisition that then is more typical, more neurotypical, of the children that have a greater age and are healthy.
Speaker #5: And so the importance of that data, obviously, as we've just discussed before, is it does help us understand the effectiveness of the medicine. As Jason has described in his remarks, that will continue to be part of the NDA submission when we file our clinical data around the middle of next year.
Speaker #2: Thank you. Very clear.
Speaker #4: Thank you. And our next question comes from the line of Alyssa Larios with Lyric Partners.
Speaker #7: Hi. Good evening, everyone. This is Alyssa on for Mark Goodman. I was just wondering if you could walk us through what parts of the NDA you expect to submit, starting in Q1.
Speaker #7: And what will still be left? When does the Emperor data come in? Thank you.
Speaker #5: Alyssa, sorry, you didn't come through. Oh, so you're asking about the sequence of the NDA order of submission? Yeah, sorry—you just didn't come through, Alyssa.
Speaker #5: There's some background noise. So, as I just mentioned, we anticipate starting our rolling submission in Q1 of 2027. That will initiate with the filing of our CMC package. Jason had a number of comments in his prepared remarks where we've made great progress in that area, including quality.
Speaker #5: And so, that will be the initiation of the submission in Q1 2027. The final part of the submission will be the clinical data, which will occur in Q3 2027.
Speaker #5: And that data will conclude with the week 52 secondary endpoint measurements, to complete that submission in Q3 of 2027.
Speaker #7: Okay. Thank you very much.
Speaker #4: Thank you. And our next question comes from the line of Pete Stavropulos with Cantor.
Speaker #6: Hello, Ian and team. Thanks for taking our questions. First question that I have is, going back to the Vinland 3 subdomains and for the Phase 3 readout, what gives you confidence that the one-year time point is sufficient to see separation between the active arm and sham for the secondaries?
Speaker #6: And the second question I have is—one point of discussion has been the potential pricing of Zoreva nursing, if approved, specifically around what data may be needed to translate to a label that suggests or states disease modification, which will ultimately impact pricing.
Speaker #6: And so, can you just provide your thoughts and plans and possible scenarios for getting disease-modifying outcomes into the label? And, if achieved, how should we be thinking about pricing?
Speaker #5: Yeah, thanks, Pete. There were a number of questions there. Maybe I'll start by asking Barry to help you understand the powering of the study. I'll then talk about the data we have that informed us and supports our confidence in achieving both the primary and secondary endpoints.
Speaker #5: And I'll ask Jason to comment on the work we've been doing, which is extensive, to understand the value of the medicine AKA pricing.
Speaker #3: Yeah, thanks. So the powering of the study, then, was based on our Phase 1, 2, and OLE data. And the confidence that we have in showing a difference from sham is based on the fact that the secondary endpoints—the Vineland endpoints—are powered at 90% or greater than 90% to show a 0.01 or less p-value. And so those results were based on 150 patients enrolling in the study.
Speaker #3: And as we mentioned, we now have 162, so that increases our confidence that we'll be able to show a significant difference from sham in the study.
Speaker #5: Yeah, thanks, Barry. I'll just pick up from where Barry mentioned. I would say increasing confidence with the 162 versus the initial powering calculations of 150.
Speaker #5: What I would also add is, in that 150—that was the initial powering assumption—it did also assume a 15% discontinuation rate in that Phase 3.
Speaker #5: As Barry mentioned in his prepared remarks, we have seen zero discontinuations to date in the study. So, if you work the analysis back, it was powered, as Barry says, to a 90% confidence level for a p-value of 0.01 for the secondary endpoints from approximately 125 to 130 evaluable patients.
Speaker #5: At this point in time, we have 162 enrolled, still in the study, and zero discontinuations. The data that we use to power the study, frankly, was data from the Phase 1, 2, and the OLE data.
Speaker #5: But notably, you asked about the confidence, Pete. And this time last year, we provided data to help understand the impact of a regimen that had similar dosing to that in our Phase 3 study.
Speaker #5: That data was provided at EPNS last year. I believe we showed it on our Q2 conference call. If not, there was a disclosure that was very close to August of 2025.
Speaker #5: And that data showed that in Vineland scores for the five key domains that we've been discussing, showed Vineland scores of between 8 and 11 in terms of Vineland scores of each of those domains.
Speaker #5: And I would just point out that our Phase 3 study secondaries are powered for a 2 to 3 point delta in Vineland scores. So we have high confidence of hitting these secondary endpoints given the data that we have, both from the Phase 1, 2, and the OLEs, and in particular, that dosing regimen that is consistent with the Phase 3 dosing regimen of 270 milligram doses and 245 milligram doses, which accumulates to approximately 230 milligrams of dosing.
Speaker #6: Yeah, and then on your last question, Pete, around pricing and the implications around pricing, it's timely that you asked the question because, just earlier this year, we conducted some pretty extensive market research across our constituent audiences, including healthcare providers, payers, caregivers, etc.
Speaker #6: Specifically for healthcare providers and payers, we wanted to understand the potential implications of different label scenarios, and how those audiences think about the data that are included in the label versus other data that may be available and in the public domain.
Speaker #6: Published, presented at scientific conferences, etc. And I think the long and short of it is that the data to be included in the label are going to be most important for promotional purposes, right?
Speaker #6: So how are commercial teams able to educate healthcare providers on the efficacy and safety of Zoreva nursing at the time of approval? And when payers and healthcare providers, talking about the different potential scenarios, what could be and would be the most compelling pieces of evidence that they would have at their disposal to drive in the case of healthcare providers prescribing for their medical policies that support reimbursement for a broad population of patients with Gervais syndrome, across the board, the five-year open label extension data and one Phase 1, 2 data that we anticipate having at the time of approval, were the most compelling piece of evidence.
Speaker #6: So when you think about payers, it's less important that it's included in the label and more important that the data are disclosed in peer reviews.
Speaker #6: So payers are going to look at the totality of the evidence. They'll look at published manuscripts, data presented at scientific congresses, the Phase 1, 2, and OLE data that we've generated to date, right?
Speaker #6: Four years of OLE data, plus the Phase 1 and 2. And I think it's not all anchored to the secondary endpoints. One of the things payers told us loud and clear is that the additional seizure reductions that you're seeing on top of the best standard of care medicine will drive significant value.
Speaker #6: But with that being said, they will look at the totality of the evidence. They'll look at the data that are published in, for example, the New England Journal, right?
Speaker #6: That comes with a significant amount of credibility. And so we're feeling really confident in how we think about the value proposition and value story for Zoreva Nursing, and that it really should command rare, genetically targeted, disease-modifying pricing potential consistent with what we've been talking about over the last few months.
Speaker #6: So hopefully, that answers your question a little bit, Pete. It.
Speaker #1: Thank you. And our next question comes from the line of your own Weber. With TD Securities.
Speaker #4: Great. Thanks so much, and congrats—really terrific progress. Maybe I have a couple of questions. The first one is, given that you're going to have six-year data from the OLE, which potentially can be label-enabling, how does that sort of jive with the Phase 3 data?
Speaker #4: Can they be sort of synergistic? Do you need to hit all the same points in the Phase 3 that you showed in Phase 1 or 2?
Speaker #4: I mean, you noted to us, obviously, that the delta that you're looking for is a lot smaller, and you're obviously very overpowered. And then secondly, I know you don't know exactly how you're going to rank order, hierarchically yet, in the SAP.
Speaker #4: The secondary endpoints—but maybe from you, based on your data, what is sort of your wish list? Which endpoints are the most important? Thank you.
Speaker #5: Hi, you're wrong. Thank you for the question. As I mentioned in my earlier comments, we're heading to the FDA to discuss the pre-MDA and to have a pre-MDA discussion.
Speaker #5: One of those topics will be the six-year data or the five-year OLE data. You asked whether it was synergistic. Absolutely—yes, it is synergistic.
Speaker #5: It is also additive. The importance of that data is that it demonstrates how the medicine is benefiting these patients, as well as safety, but it is benefiting these patients over a chronic period.
Speaker #5: This is a chronic disease, and our medicine is a chronically dosed medicine. And so the OLE data allows us to understand the benefits these patients are gathering, with seizure reductions being durable through a five-year period, and also to see these cognition and behavioral periods.
Speaker #5: So it is absolutely consistent, additive, and synergistic with how we think about the Phase 3, and it will supplement the Phase 3 data in our submission.
Speaker #5: That's why we continue to discuss it with the FDA, so it fits—really important. And as Jason says, the OLE data is also important in terms of how we, one, educate payers as they look at the totality of the data.
Speaker #5: But I'll also say, for prescribing physicians, a really important piece upon approval of this medicine will be having physicians understand not only how to use the medicine, but what benefits it provides to patients beyond the one-year registration trial and those clinical endpoints.
Speaker #5: So we're in great shape with that data. And as you said, our own—we'll have six years of data by the time that we start our NDA submission of that clinical data package. You asked about the importance of the secondaries and the hierarchy.
Speaker #5: We have, at this point in time, looked at the hierarchy of endpoints. Number one in terms of the primary and secondary endpoints is actually continued seizure reduction.
Speaker #5: But once you get beyond there, you get into the Vineland points. But we've included communication, receptive and expressive communication, as being the key measures that are in terms of the hierarchy.
Speaker #5: That's on the basis of physician and caregiver feedback, and we're fortunate that that's where we're seeing benefit through our OLE data as well. Just to give you an idea: when we talk about Vineland as a measurement tool of cognition and behavioral benefits, what that actually means is these children who unfortunately stagnate at the age of approximately 24 months don't acquire other skills while they chronologically age.
Speaker #5: But we appear to be providing benefit where we're giving them function and giving them skill. And in the communication area, for example, we appear to be helping these young children who can barely talk and have a minimal number of words they can use.
Speaker #5: We're providing the ability for many more words, to actually use sentences, and that's a progression they wouldn't otherwise see. We're also seeing them receiving communication, which allows them to respond—and respond to their parents as a real-world example.
Speaker #5: And then when you go on further and look at some of the motor skill acquisition, you're seeing children that improve their motor skills. And that includes non-ambulatory becoming more ambulatory, frankly.
Speaker #5: And this is data that's from our that's been collected from our OLE study. And we've shared that well, it's been shared with videos that are in the New England Journal of Medicine.
Speaker #5: So I have that validation and credibility. But that's what Vineland means. And it is for us now to turn these Vineland scores into what real-world skill and task acquisition is for a Dravet child that otherwise would stagnate at the unfortunate age of 24 months.
Speaker #5: And we want to provide them skill and acquisition based on the use of our medicine.
Speaker #4: I might just add, this is very those despite the wish list that we have, the powering of the study for the key secondary endpoints is for each of the individual Vineland subdomains.
Speaker #4: So we put power to the one that we think may even be the least likely to achieve. But each one of those has its own high degree of power.
Speaker #1: Thank you. And our next question comes from the line of Laura Chico with Wedbush.
Speaker #6: Good afternoon. Thanks very much for taking the questions. Maybe just one for Jason on commercial. You previously indicated most U.S. Dravet cases are managed at centers of excellence.
Speaker #6: How should we be thinking about site capacity to treat? That’s an intrathecal ASO program, and I guess I’m thinking a little bit more about logistical constraints, like procedure slots and imaging.
Speaker #6: How do you think about site capacity and the impact on a commercial observing nurse and launch? We obviously saw that this was important for drugs like Spinraza.
Speaker #6: I'm just trying to understand how things might have changed in the landscape. Thank you.
Speaker #2: Yeah, it's a great question, Laura. And I think we provided some additional details here this afternoon around specifics for the top 50 sites, for example.
Speaker #2: So if you think about those top 50 sites, all of them have 20 or more patients that are under their care, but all 50 of those sites also have experience administering intrathecal therapies, most of them Spinraza.
Speaker #2: And so, given the efficiency that they've developed administering other intrathecal products and their familiarity with the procedures and processes that go into it, we feel like they are really set up incredibly well to handle the capacity that comes through at the time of a potential approval, which we expect to be robust if based on nothing else, based on the speed with which we recruited the MPERS study.
Speaker #2: But it's also consistent with what we hear in market research. So, we still have more work to do around site readiness and site qualification over the course of the next year or so.
Speaker #2: But going in, we're definitely benefiting from the fact that there are other intrathecally administered antisense oligonucleotides available in the commercial context, and that institutions have protocols already in place with how they're administering those therapies, which gives us a huge advantage going into a launch like this.
Speaker #6: Thank you.
Speaker #1: Thank you. And our next question comes from the line of Sumant Kulkarni with Kinnick Orgenuity.
Speaker #5: Good afternoon. Nice to see the progress, and thanks for taking our questions. On slide 11 in your presentation accompanying this update, you mentioned that HCPs and payers indicate that OLE data may be the most compelling data at the time of approval.
Speaker #5: You alluded to this a little bit, and we understand that reduction in seizure frequency on top of standard of care and the totality of evidence matters.
Speaker #5: But what specific components of the OLE data resonate most, and does the relative importance of the components of the OLE data vary for HCPs and payers, or are those factions looking at them largely in the same way?
Speaker #4: Sumant, thanks for that question. Obviously, Jason's going to take this question. To reiterate what Jason's about to tell you about the importance of that data—yes, it's our belief, but this is feedback from prescribers and payers.
Speaker #4: It's what they're telling us. It's not what we are telling you. It's actually what the payers and the prescribers are telling us, because we've gone out—as you appropriately should be doing at this stage of drug development—and you should be doing diligence with your payers and your prescribers, and helping them understand the medicine.
Speaker #4: But Jason, yeah.
Speaker #2: So it's a great question, Sumant. Thank you for it. When we and I'll take those two audiences in sequential order there. So starting with the healthcare providers, I think it goes back to when you ask healthcare providers and caregivers specifically, what are the greatest unmet needs that exist in Dravet today?
Speaker #2: First and foremost, the number one thing that you hear is persistent seizure burden—the fact that very few patients ever reach seizure freedom. It is number one.
Speaker #2: And I think that, from a caregiver perspective, it relates back to watching your child undergo a seizure, for example, right? And so, not far behind the persistent seizure burden is the lack of efficacy across the non-seizure manifestations of the syndrome and the lack of any targeted medicines that address the underlying genetic cause.
Speaker #2: And so, when we talk to healthcare providers and they talk about what's most compelling to them, obviously the long-term data are the most compelling, because as a clinician, they're sitting across from a patient where they're thinking about prescribing a chronic, lifelong treatment.
Speaker #2: They want to understand what the implications are of administering this medicine to these patients over a long period of time. And so I think they're reassured by the long-term safety profile now going out four years, of OLE plus the phase one/two.
Speaker #2: They're reassured by the persistent reductions in seizures that they're seeing, and the durability of that seizure response. And they're certainly reassured by the fact that you see consistent gains in adaptive behavior and the neurocognitive endpoints, as measured by the Vineland Adaptive Behavior Scale.
Speaker #2: And then, in addition to that, it's quality of life measures, right? As you think about what matters to families—the ability for a child to continue to, or a child to be able to communicate with their family, the ability to, for example, feed themselves—all of those little activities of daily living and acquired skills, as Ian mentioned, really matter a lot.
Speaker #2: And then, when you think from a payer perspective, payers matter less. Payers care less about, for example, the nomenclature associated with disease modification. What they care about more is, is this new treatment offering something that what I currently have at my disposal for my members isn't?
Speaker #2: And so it's what we're doing in the non-seizure manifestations of Dravet syndrome, above and beyond the seizure suppression. So, they're seeing the additional seizure suppression on top of the best standard of care as being a real value driver. But above and beyond that, the fact that we're affecting other elements or other manifestations of the syndrome really goes a long way with payers in driving that value proposition associated with certain things.
Speaker #1: Thank you. Thank you. And our next question comes from the line of Kevin Strang with Goldman Sachs.
Speaker #6: Good afternoon. Thanks for taking the question. Just a quick one: you mentioned a study for infants and toddlers under 24 months of age, as well as generating new data in adults.
Speaker #6: I just wanted to ask about those two bookends. Anything on trial design or potential timelines for both of those? And then, for adults specifically, is there any data that you can leverage from your OLE in terms of patients that have crossed over into adulthood?
Speaker #6: Thanks.
Speaker #4: Yeah. Thanks, Kevin. I appreciate the recent initiation and the data you sent us this week about some analysis you've done of the market.
Speaker #4: So first of all, the infant-toddler study is part of the requirement for a PIP in your so we're running that study there. It's really a straightforward as that.
Speaker #4: Although the data will help us potentially expand the label and treat even younger patients. And obviously, with genetic medicine, the earlier you can treat a patient, the more potential you have to put them back on a more neurotypical pathway, as well as prevent those seizures.
Speaker #4: So, it is a very important study—to get to these children, these Dravet children, as early as possible. For the adults, it's a different rationale.
Speaker #4: The adults, we anticipate that on successful data and approval, that our label would be for two years and older. And therefore, we will have access to be able to have prescriptions to adults.
Speaker #4: What the adult study will do, though, will help us understand the benefit for adults and help provide access and reimbursement for those adult patients.
Speaker #4: And you are correct, our studies have been run so far for ages two through 18 years of age. And in the OLE, it does have patients that have progressed—that started in their late teens and have progressed into their early 20s now.
Speaker #4: And we continue to track that data. That data continues to show seizure reduction—durable seizure reduction—and cognition and benefit from the first start of dosing.
Speaker #4: We're measured to their baseline when they're in their teens. And our own principle on this is, given that the root cause of Dravet is the lack of expression of normal expression of NAV 1.1, whereas we upregulate NAV 1.1 protein, and therefore, there should be no difference in providing benefit to a, let's say, a 15-year-old versus a 21-year-old.
Speaker #4: And so we'll use all that data, but we will also run an adult study that begins later this year. You also asked about the design of those studies; they'll initiate later this year.
Speaker #4: And as they initiate, we'll provide you study design at that time.
Speaker #6: Great. Thank you.
Speaker #1: Thank you. Our next question comes from the line of Joseph Stringer with Needham and Company.
Speaker #5: Hi, thanks for taking our questions. Just a follow-up on the market opportunity in Dravet syndrome. You estimate the prevalence in the U.S. is around 16,000.
Speaker #5: What do you estimate the current diagnosis rate is in the U.S.? And if there is a disease-modifying therapy available, such as Zoravanir, how significantly do you think the diagnosis rates could improve in the U.S.?
Speaker #5: And maybe as a follow-up question, I guess, what are the most appropriate drug comps that we should think about that have a similar setup to what there is for Dravet syndrome now?
Speaker #5: Just multiple approved drugs on the market for several years, but no disease-modifying therapy available. Thank you.
Speaker #2: Yeah, so thanks for that, Joey. So maybe taking the first part of your question—of the 16,000—when we look at claims data, we have a pretty good idea where about up to 80% of the 25-and-younger patients are being cared for today.
Speaker #2: I would say that the genetic testing landscape in the US has really grown dramatically over the course of the last 5 to 10 years.
Speaker #2: And so I would say that pediatric epileptologists and pediatric neurologists are doing a really nice job at diagnosing pediatric patients even earlier. But the gap—there is a gap that still remains for the older patients.
Speaker #2: And so, the disproportionate—I would say majority—of the diagnosed patients today are the diagnosed patients that are 25 and younger, of whom we expect there are about 6,000 that will be immediately addressable at the time of a potential approval.
Speaker #2: That's based on both epi and what we're seeing in claims data. So if you look at total unique claims, across all ages, you get pretty close to that 6,000 number in the US, but then when you break it down and you apply machine learning where you're looking at that peridiagnostic period, looking at concomitant meds, concomitant procedures, CPT codes, that are commonly used for Dravet patients and apply that to the total claims universe, that's how we get to knowing where approximately 80% of the patients are being cared for.
Speaker #2: But not surprisingly, one of our focal points right now is enhancing and increasing genetic confirmation of diagnoses in that young adult into adult cohort of patients.
Speaker #2: With that being said, we feel like the DMT introduction, with the potential approval of Zoravanir, will dramatically increase the volume of genetic testing in the US.
Speaker #2: And we've actually asked that question of healthcare providers, and healthcare providers themselves anticipate that genetic testing will increase 85% to 90% compared to today with the introduction of a disease-modifying treatment.
Speaker #2: So the foundation is there. Our hope is to be able to drive those earlier diagnoses and, in the case of the adult patients, intervention before approval with additional diagnoses and genetic testing.
Speaker #2: Oh, and then from a comps perspective, in terms of Joey, from a comps perspective, with I think Spinraza, the SMA market is a good comp.
Speaker #2: I think even potentially the CF market is a good comp, where you had symptomatic treatments available before the introduction of the first disease modifiers.
Speaker #1: Thank you.
Speaker #5: Great. Thank you so much for all the color.
Speaker #2: You bet.
Speaker #1: And our next question comes from Jessica Fai with JP Morgan.
Speaker #6: Hello, this is Adam on for Jess. Thank you for taking our question. I really just want to talk about the Syngente program and am just curious about timelines here.
Speaker #6: When could we expect a candidate to maybe enter the clinic?
Speaker #4: Adam, thank you for joining the call. So I'll start with Syngente remains a very important disease area for us. Just why? Because there is a lot of closeness of Syngente to Dravet, in terms of being an oral development disease.
Speaker #4: Our platform that upregulates the effective gene to create protein in these patients is applicable to Dravet, as we talked about today. But it also goes to Syngap.
Speaker #4: And so, Syngente becomes a very important area that we are focused on. We currently have five potential drug candidates that we are studying preclinically. We're working through our animal models.
Speaker #4: And in 2027, we hope that we will pick a development candidate to move them towards the clinic. But I want to reiterate that it's a really important disease area for us to continue our efforts, now that we have success.
Speaker #4: And using Dravet as a proof of principle that our platform can work in these kinds of disease areas, we will continue our efforts there to do the best for the patients.
Speaker #6: Great. Thank you.
Speaker #1: Thank you. Our next question comes from the line of Delma Khayati with Guggenheim.
Speaker #7: Hi, good afternoon, and thank you for taking our question. On the 80-way program, the SentinelCore dosing is now complete. Can you give us any color on how many patients were dosed and at what dose level?
Speaker #7: And what did the Sentinel safety review show that supported the decision to escalate? And then for the readout in the first half of ’27, what magnitude of change would you consider as a proof-of-concept threshold?
Speaker #7: Thank you.
Speaker #5: So, Delma, thanks for the question. I'm going to have Barry summarize the program more holistically to help you understand the decision we made to go into the clinic, which was based on preclinical data, obviously.
Speaker #5: But then, where we are in advancing is a dose-escalating study, where we're already into the increased doses. So, Barry, please.
Speaker #3: Yeah, thanks. And thanks for the question, Delma. So, just as a reminder, ADOA is due to a haploinsufficiency—meaning half the normal amount—of OPA1 protein, which is required for mitochondrial function.
Speaker #3: And we do have preclinical data in an NHP that has a genetic mutation that's similar to what patients have and has a similar phenotype to patients.
Speaker #3: And there, when we administered 002 to those animals, they showed an improvement in their mitochondrial function, as well as an improvement in the function of the optic nerve.
Speaker #3: So that gave us a high degree of confidence moving forward into the clinic, as well as other data that have come in the field.
Speaker #3: So the study is a typical dose escalation study—a single ascending dose study. The first cohort had three patients in it. The safety monitoring committee reviewed those data.
Speaker #3: And are approving the escalation to the next dosing level. We have, right now, four dosing levels that are planned, and each of those is being reviewed for safety on a variety of levels after the injection.
Speaker #3: And we'll also be looking for potential improvement in vision because, since we are improving the mitochondrial function in the patients, we expect that the retinal ganglion cells that are important for vision will be improving in their function as well.
Speaker #3: And that will allow for better visual acuity, as well as improvement in the measure of mitochondrial function, which is what we call the SPF.
Speaker #3: So, those data we anticipate being able to discuss next year.
Speaker #5: And Delma, I would just point out that as we progress through these four cohorts of increased dosing, we anticipate, based on our preclinical work, that we may start to see efficacy in Cohort 3 or 4.
Speaker #5: And that's why Barry is referring to data readouts that would be in the first half of 2027.
Speaker #7: Great. Thank you.
Speaker #1: Thank you. And our next question, and last question, comes from the line of Rudy Lee with Wolf Research.
Speaker #6: Hey, thanks for taking my question. As we've finished enrollment of the Phase 3 trial, can you maybe provide more color on the patient population and baseline characteristics as expected?
Speaker #6: Any notable difference versus the Phase 1/2 trial? Thanks.
Speaker #4: So the patient population for the EMPIRE Phase 3 study is consistent with the patients that came into the Phase 1/2 and progressed into the OLE study.
Speaker #4: And just to ensure that, we had an eight-week screening period that required certain baseline characteristics to be tested through that eight-week screening period before they were allowed into the Phase 3 EMPIRE study.
Speaker #4: Characteristics, obviously: age, had to be screened for the SCN1A depletion gene, and also a certain number of seizures. So there is a similarity and a consistency between the phase one/two OLE patients and those that are in our phase three.
Speaker #6: Cool. Thanks for confirming.
Speaker #1: Thank you. I'll now hand the call back over to our CEO, Ian Smith, for closing remarks.
Speaker #5: Yeah, thank you. I just want to say thank you for taking the time out to join us this evening. We look forward to talking to many of you throughout this week.
Speaker #5: And probably next week, we'll continue to update you on the progress of the company. Thank you for your time this evening.
