Stoke Therapeutics Inc (STOK) 2025 Q3 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Stoke Therapeutics third-quarter 2025 business and financial update. (Operator Instructions) Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today. Thomas Leggett, Chief Financial Officer. Please go ahead.

Good afternoon, and welcome to Stoke Therapeutics third-quarter 2025 conference call. I'm Thomas Leggett, Chief Financial Officer at Stoke Therapeutics. Joining me are Ian Smith, our Chief Executive Officer; and Dr. Barry Ticho, Chief Medical Officer. Jason Hoyt, Chief Patient Officer, will join us for the Q&A portion.

Today's webcast presentation is available in the Investor News section of our website. It's being recorded. It will be available for replay later today. Before we begin, please note that today's discussion includes forward-looking statements. These are subject to risks and uncertainties and actual results may differ materially. Please refer to our filings of the SEC for additional information.

With that, I'll turn the call over to Ian.

Welcome, everyone, and thank you for joining us today. I'm honored to have been asked to serve as the CEO of Stoke Therapeutics. This is an incredible company with significant opportunity ahead of it. I could not be more excited to be part of the team as we advance zorevunersen through Phase 3 and build the company to deliver long-term value to patients, our employees, and shareholders. On today's call, we will review our third-quarter progress. I'll start by summarizing where the company has come from, and how that has brought us to today. I will talk about what priorities are next for us.

Those progress in 2025 has put us in an important growth trajectory. There are several drivers of our momentum. With four years of zorevunersen clinical experience and two years of natural history data, we have compiled a wealth of data to support our understanding of Dravet syndrome and the potential for zorevunersen to treat this devastating disease.

In addition, to support the Phase 3 study, our long-term longitudinal data give us a clearer picture of the disease modifying potential of zorevunersen and the benefits it could provide for people living with Dravet syndrome, and the families and caregivers who support these people. One of our priorities for 2025 has been to bring broader and more consistent understanding of zorevunersen to clinicians, the patient community, and the investment community.

We have done so primarily through scientific and medical communications and our interactions at medical congresses. These activities, along with increasing awareness of the severity of Dravet syndrome, are contributing to significant interest in our Phase 3 study.

Back in August, we told you 150 patients have been identified through the investigator pre-screening process. That number has now grown to more than 200 patients. In a few minutes, Barry will share an update on progression of those patients through the formal screening process into enrollment and study randomization. As we continue to move forward with [borough], we are preparing to meet with the FDA to discuss potential expedited regulatory pathways to bring zorevunersen to patients as soon as possible.

This multidisciplinary meeting is part of the standard process for investigational medicines, granted breakthrough therapy designation. Although zorevunersen was granted breakthrough designation last December, we did not request the meeting until we have Phase 3 OLE longitudinal data. This now allows us to bring a comprehensive and current safety and efficacy data set to the discussion.

The breakthrough process was created to expedite the development and review of drugs that are intended to treat serious conditions. As part of that, the FDA commits to the involvement of senior FDA managers. The meeting will be guided by a briefing book that is submitted in advance by the company. We have submitted our briefing book, which includes data and a series of questions, one of which relates to the potential for an expedited regulatory pathway for zorevunersen.

With the growing awareness of Dravet syndrome and the data, to support the disease modifying potential for zorevunersen, the market opportunity is taking shape. As we move through our Phase 3, I'm prepared to potentially launch zorevunersen in the US. We are investing in foundational efforts that will enable us to rapidly scale our business to reach as many patients as quickly as possible.

Through 2025, we have prioritized leadership and our core areas of our business, namely medical affairs and commercial, as well as the executive team. The medical affairs field has increased the level and quality of our interactions with the clinical community. Our commercial leader team is now in place with experienced leaders in market access, pricing, marketing, commercial operations, and new product planning. PMC and supply activities remain on schedule to support the Phase 3 and potential launch.

We're in the initial stage of market shaping activities, starting with [unseen], a disease awareness campaign to increase awareness of diagnosis of Dravet's syndrome through genetic testing. You'll be hearing more about this effort, which is designed to confront the gap in disease diagnosis. Zorevunersen demonstrates the potential of our platform. We see a broad opportunity to develop additional disease-modifying medicines, particularly in [holu] insufficient disease areas of CNSI, and heart.

In terms of DNI, we recently presented data from our two year ADOA Natural History study that offer insights into underlying biology of disease progression, and clinical assessments that support clinical development of STK-002. Recruitment has begun for our Phase 1 dose escalating study of STK-002 as a potential treatment for Autosomal Dominant Optic Atrophy. Sites are active in the UK and European sites are expected to initiate in early 2026.

While moving through this dose-escalating study, the earliest we would anticipate potential efficacy data from Osprey would be toward the end of 2026 or early 2027. Next in the pipeline is our SYNGAP program. Similar to Dravet, SYNGAP is a neurodevelopment disorder that is primarily caused by a haploid insufficiency. Preclinical work continues as we work towards the potential nomination of a clinical development candidate in 2026.

Our experience with zorevunersen and relationships with treating physicians and patient advocates have been helpful in our early planning for potential SYNGAP clinical development program. In addition to these programs, we continue to invest in our early-stage pipeline across multiple therapeutic areas. We look forward to providing updates as our pipeline programs advance.

I will now turn the discussion over to Barry for a brief review of key data and an update on progress of EMPEROR.

Thank you, Ian. I will focus my presentation today on a few of our more recent analyses that support our Phase 3 study and the long-term disease-modifying potential of zorevunersen. These data will be central to our discussion with the FDA later this year.

Here on slide 7, you see the reductions in seizure frequency observed among patients who were treated with zorevunersen for up to three years in the OLEs following an initial nine months of treatment in the Phase 1/2A studies. As a reminder, All of these patients were taking standard of care anti-seizure medicine. The orange line shows patients who were initially treated with 70 milligram loading doses followed by maintenance dosing in the OLE. Our Phase 3 regimen is two loading doses of 70 milligrams followed by maintenance doses of 45 milligrams.

Also notable, however, are the continuing reductions in seizures for patients in blue who are treated with loading doses of less than 70 milligrams. These patients were treated with different maintenance dose levels in the OLEs until approximately month 28, by which time all of them had transitioned to 45 milligrams. Of the 80 eligible patients who completed Phase 1/2, 94% were 75 patients entered the OLEs. Today, approximately 58 patients continue on treatment, providing important long-term longitudinal safety and efficacy data.

It's important to remember that Dravet syndrome is more than seizures. It is a complex, lifelong condition with devastating impacts on cognition, behavior, and quality of life for patients and families. What you see in the illustration on slide 8 is a representation of the anticipated trajectory for neurotypical development in green and for people living with Dravet syndrome in orange. Data from Natural History studies tells us that neurodevelopment plateaus within the first few years of life for people living with Dravet syndrome.

As time goes by, they fall further and further behind their neurotypical peers. Understanding the effects of Dravet syndrome beyond seizures is fundamental to the design and interpretation of data from studies of potential disease-modifying medicine. Our Natural History study and Phase 1/2A studies provide early insight into which clinical assessments would be most effective in the evaluation of neurodevelopment.

Vineland-3 emerged as a highly effective assessment for patients with Dravet syndrome because it evaluates key aspects of cognition and behavior that are impacted by the disease, including communication, motor skills, socialization, and daily living. These four domains are supported by a number of subdomains that are scored on a standardized scale. Vineland is conducted by a trained central rater, which reduces the potential for bias.

To help understand the scoring and what it means in real life, we conducted and published the study of caregivers and clinicians that helped define thresholds for clinical meaningfulness. At least half of respondents said that a 1 to 3 point change per subdomain per year was considered to be clinically meaningful, suggesting that even a small change can have a substantial impact.

Turning to slide 10, you see the most recent Vineland data from patients treated with zorevunersen in our OLE study. These are the same patients included in the seizure analysis I showed you earlier. As you can see, there are dramatic improvements in cognition and behavior within the first year, which continues through years two and three. These improvements are in addition to any improvements that may have been experienced within the first nine months of treatment in the Phase 1/2A studies.

As we designed our Phase 3 EMPEROR study, we went back to our data. Using clinical data from patients in our Phase 1/2A ADMIRAL Study and its corresponding OLE study, we conducted an analysis to guide our selection of dose regimen and key secondary endpoints. On the left, you see marked improvements across five key measures of behavior and cognition. These measures are now included in the key secondary endpoints of our Phase 3 study. On the right, you see an analysis that shows minimal changes among patients followed in our Natural History study and whose covariates such as age and baseline seizure frequency match the patients on the left.

Four years of data from our clinical studies of zorevunersen have provided a robust safety data set summarized on slide 12. Zorevunersen has been generally well tolerated across our Phase 1/2 and OLE studies. The most common treatment emergent adverse event was CSF protein elevations, which occurred in 14% of patients in the Phase 1/2A studies and 45% of patients in the OLE studies. Overall, 86% of patients in the OLE studies experienced CSF protein elevations.

No clinical manifestations have been associated with these elevations. One patient discontinued due to elevated CSF protein. Treatment emergent serious adverse events were reported in 22% of patients in the Phase 1/2A studies and 29% of patients in the OLEs. Across all studies, one patient experienced SUSARs. Overall, 81 patients have received at least one dose of zorevunersen. Some OLE patients have now been treated for more than four years with up to 15 doses. These data provide support for the Phase 3 EMPEROR study, which is offshore great start. Thirty sites are now actively recruiting patients in the US, UK, and Japan.

The first patient was randomized to zorevunersen in Norsham in August. More than 20 patients have been randomized and approximately 35 additional patients have entered the formal eight-week screening period that immediately precedes randomization. In total, more than 200 patients have now been identified by investigators as part of a pre-screening process.

We anticipate similar demand for EMPEROR in Europe, where we expect sites to initiate in the first half of 2026. We are on track to complete enrollment in the second half of 2026. Since June, we have received nearly 400 medical information requests, which is an average of nearly three per day. Half of these requests were related to site locations and eligibility criteria from interested caregivers.

The volume of inquiries and the length caregivers are willing to go for an opportunity to participate in EMPEROR are remarkable and support the significant and urgent need for disease-modifying medicine to treat Dravet syndrome. The impacts of this disease go beyond the individual patient. Dravet syndrome impacts all aspects of life for an entire family.

By addressing the underlying cause of the disease, we believe zorevunersen has the potential to change the course of the disease and the lives of patients and their families. The team and I look forward to taking our substantial data package to the FDA and to working with them to explore potential expedited pathways that would bring zorevunersen to patients faster.

I will now turn it back over to Thomas.

Thank you, Barry. I'll now provide the financial highlights from our third quarter. Stoke has maintained our strong financial position. We ended the third quarter with $328.6 million in cash, cash equivalents, and marketable securities. Subsequent to quarter end, we raised $48.7 million in net proceeds from our ATM by a single block trade. We expect our cash runway to fund operations to mid-2028.

Moving to the income statement, total revenue for the quarter was $10.6 million versus $4.9 million in Q3 2024. This increase in revenue was largely driven by a $6.7 million increase in revenue recognized as part of our collaboration on zorevunersen and with Biogen. This was partially offset by $1.1 million lower revenues from Acadia. Net loss in the third quarter was $38.3 million, or $0.65 per share, compared with $26.4 million, or $0.47 per share, for the prior year. This was driven by an increase in operating expenses.

More specifically, R&D expense was $37.7 million versus $22.2 million a year ago. This was driven by spend associated with our Phase 3 EMPEROR study, advancement of our early-stage pipeline, and hiring across the R&D organization. SG&A for the quarter was $16 million versus $12.7 million a year ago. This reflects increased investment in the growth of our commercial capabilities and team.

I will now turn the call back to Ian for closing remarks.

Thank you, Thomas. 2025 is shaping up to be a defining year for Stoke, and we are amid a significant transition of our company. Zorevunersen is an incredible opportunity, firstly for patients, but for our company as well. The data Barry just summarized make clear the severity of Dravet syndrome and the dramatic impact zorevunersen could have for patients and their families.

Given that, we see it as our duty to get zorevunersen to patients as quickly as possible. The primary way we intend to do that is to continue to activate more sites and enroll more patients into EMPEROR. We will also continue our educational efforts to bring greater awareness of Dravet syndrome and the understanding of the data that support the disease-modifying potential of zorevunersen. Our team will be present and active at the upcoming American Epilepsy Society meeting in early December, where we anticipate sharing additional clinical data.

In parallel, we are continuing our preparations for our meeting with FDA to discuss potential expedited regulatory pathways for zorevunersen in the US. Our balance sheet is in great shape with a cash runway that takes us into mid-2028. I want to thank everyone at Stoke for their hard work toward our mission. I also want to acknowledge the courage of patients, their families, and caregivers who are participating in our clinical trials. I look forward to a busy and productive Q4.

Operator, would you please open the line for questions?

(Operator Instructions)

Pete Stavropoulos, Cantor.

Hi, Ian and team. Congrats on the progress, and thank you for taking my questions. You know, first is, you know, you presented three-year OLE data at International Epilepsy Congress in August, and additional data in October. You know, I guess seizure data and cognitive and behavioral data. And I assume it's in the briefing book for the PTD meeting.

My question is, with that data in hand, what are some of the potential scenarios we might anticipate based on the PDD meeting with the FDA? And importantly, should it read anything across from the [Unicure] experience?

So thanks for that question, Pete. And maybe I'll take the second question first. First of all, yes, I saw that we all saw the Unicore -- Unicure information yesterday. I want to first of all say there's something there that's disappointing, firstly, and what I mean by that is disappointing for Huntington's patients and their families. I'm sure hope was rising there and so disappointing.

We at Stoke, obviously in a very different disease area, we're in a different division, and we're in a different process, and so that's why I wanted to just take the first -- the second question first. But the overall question in terms of our process with the FDA, yes, we are taking all of our data, which is now four-year data when you include the Phase 1/2 data and the three-year OLE data to the FDA, and it is in our briefing book.

It is extensive. It goes down to patient-level data, and I would say one of the most important things in the briefing book is actually the safety data that gives you confidence over a four-year period for some patients, and with over 800 doses now in all those patients. I do also want to take a moment to describe our process that we're going through with the FDA.

In my prepared remarks today, I did comment that we received breakthrough designation for zorevunersen in December 2024. We chose to wait to get our three-year OLE data, and also we had the Phase 1/2 data, both safety and efficacy, and take that to the FDA, to your question, Pete, and take that to the FDA. This meeting that we have is actually a perfunctory meeting under the breakthrough designated class of medicines. It's called a multidisciplinary meeting.

So it's standard in the process, and part of that is to go down to the FDA and educate around the pathophysiology of the disease itself. Educate around the methods of action of the drug and how that addresses the pathophysiology of the disease. And share safety and efficacy data with the FDA and discuss with the FDA how you may expedite regulatory pathways.

Now, one thing that is different than the usual multidisciplinary meeting is that we have four-year data. These meetings normally take place around early data, and so we're excited. As I mentioned in the prepared remarks, we're going down there before the end of the year. We're actually going down in December. We've already submitted our briefing book, and we're looking forward to that discussion with the FDA.

And what are some of the potential scenarios, like outcomes?

Yeah, another good question, Pete. as you've heard a number of times now when I've spoken to you, I call it bookends. There is one bookend which is you get on the most expedited path through to filing an NDA and that outcome would be defined as the FDA saying everything is a review issue based on our questions in that briefing book. When the FDA says it's a review issue, that means that you can file your NDA and everything would be a discussion and a review issue in your NDA.

The other end of the outcome with those discussions with the FDA could be, please proceed, perform your Phase 3. And again, as I just mentioned, one of the differences in other companies going to the FDA with the multidisciplinary meeting is they don't usually have an ongoing recruiting Phase 3 program. We do. And as Barry mentioned on his remarks, we've already -- randomized over 20 patients into that study. And so the other bookend to the outcomes is actually run the Phase 3, which is progressing very nicely.

There are iterations in between. And for those of you that are listening today, you've probably heard me say the iterations in between will be a process of discussion with the FDA about how you may amend the trial, cut the data, use other types of data, but basically use the data you have and use the ongoing Phase 3 in a different way, potentially cutting data earlier at different endpoints with different powerings in agreement with the FDA. And if we go down that pathway, obviously we'll communicate that at the time.

All right, thank you, very helpful. Just one additional question, Tom. You know, just the data presented at the recent medical conferences, you know, can you just help us understand the magnitude of the cognitive and behavioral improvements on the Vineland-3 data?

And just, you know, I know you touched that on slide 9, but, you know, just help us better understand how clinically meaningful these changes are and how has it been received by physicians and KOLs that treat these patients?

Yes, so I'll take the initial part of that question and Barry will follow up. I think the key piece of data for investors to focus on, because what I hear in your question, Pete, is you're asking how can we get comfortable that you'll hit your key secondary endpoint with Vineland, and is there data you've presented at conferences that could correlate to that possibility or probability of hitting the endpoints?

And the data we provided at CNS is probably the most appropriate data. The CNS data that Barry was referring to in his slides is based on a dosing that's similar and consistent to that that we're using in the Phase 3. And with that data, we did see significant responses in the five key domains in Vineland.

Maybe, Barry, you want to talk about the context of those data and what those actually mean when you start to score a 9 and a 10.

Yeah, Pete, so the question you're asking is a question we asked ourselves as well. And so we went out and asked clinicians and caregivers directly and said, what point change on this scale would be meaningful as a change to the child with Dravet syndrome? And we published these data in a peer-reviewed journal that said that change of one to three points would be meaningful.

And especially when we talked to the families, they said, changes in communication were especially important. And these families have gone actually to the FDA and told the FDA directly that changes in communication would be important. And notably, that's where we're seeing some of the largest changes, not just after one year, but as Ian said, after two years, after three years, we continue to see improvements in these subdomains that are important to the families as well as to the clinicians.

Laura Chico, Wedbush.

I actually just have two. So one that we've fielded from investor centers on the EMPEROR design and whether you could pursue an early approval solely based on the primary endpoint of seizure reduction alone. I guess I'm curious, would that be an option?

I'm trying to understand the impact on secondary measures like Finland. Obviously, that's carrying a lot of weight there. And then I have a follow-up.

So I mean, the answer to your question, Laura, is yes, we could seek an approval based on seizure reduction. And we could cut the data at week 20 -- you know, for week 28 primary endpoint. But the broader answer is we will not do that. We believe the medicine is a disease-modifying therapy for Dravet syndrome. The underlying pathophysiology of this disease is we need to increase expression of NAV1.1. The way that our medicine works is that it increases expression of NAV1.1 and therefore affects the whole syndrome.

And so for the sake of an expedited process that might save six months because you're talking about a week 28 primary endpoint versus a week 52 endpoint. We would not go for an approval for reductions in seizures in Dravet syndrome. This is a disease-modifying therapy and we will be looking for a label to treat Dravet syndrome based on the data that we have so far and we expect to receive from our Phase 3 study.

Understood. That makes sense. My follow-up then, you're guiding to enrollment completion by the second half of '26. If you were to leverage a rolling submission, when would you be in a position to initiate that process?

Well, the timeline broadly at this point in time is to complete enrollment of 170 patients in the Phase 3 in the second half of 2026, which means on a 52-week study that we would have data in the second half of 2027, and probably within 2027, late 2027, early 2028, we would be filing an NDA.

Andrew Tsai, Jefferies

Congrats on the progress. This is John. I'm for Andrew. Thanks for taking our questions. Two from us, if we can. First, just a little bit of a follow-up on the prior question. Based on your progress with EMPEROR for enrollment, it seems like it could actually be tracking ahead. Is there a potential earlier outcome at which you think you could fully enroll the study?

And then maybe for the second one, to get a better sense of what kind of percent improvement is zorevunersen is showing on Vineland, when you're seeing such strong 8- to 14-point benefits, would you be able to share or do you have plans to share at AEF, for example, the baseline Vineland scores from the Phase 1/2 for the five domains you're going to be assessing? And then maybe any color around if the Phase 3 baseline scores are expected to look similar.

Thanks. So first, a number of questions there. So if we missed them, please ask them again. But firstly, you're correct that the trial is proceeding ahead of our expectations, both with trial sites opening and the recruiting of patients -- the screening and recruiting of patients. And we anticipate that it will continue that way. This has been a wonderful effort by the Stoke team in terms of medical affairs and communication and the clinical team and to help with awareness of the medicine and also the disease. And I think that is all helping accelerate that Phase 3 recruitment timeline.

At this stage, we're not moving our guidance. I think we're still at the beginning stage. As we said, we've randomized over 20 patients into the study, or 170 patients. And as we move through it and we have a better visibility of the recruitment timeline, we'll update at that time.

And Barry, do you have a comment on the Vineland data regarding the Phase 1/2? I think what you're referring to is the do we have the Vineland data from the Phase 1 and 2 data that was a nine-month study? And have we disclosed that? Was that the question?

Just more about the baseline Vineland scores for that study.

So the answers there are, first of all, in the Phase 1/2, again, only in the UK study, where we're measuring the baseline data. In the US study, we did not look at Vineland at the baseline. So most of the baseline data come for all patients from the open-label extension study, and that's where we're showing the changes, again, these dramatic changes and improvements in the scores over time.

As a reminder, as we mentioned, for the Natural History, those patients, their scores hardly change at all over time, over one or two years. So this is a dramatic difference from that. But in terms of overall baseline data, we're not going to be showing those data at AES for the actual scores.

Maybe I'll pick up from Barry, but a key part of our briefing book and data to the FDA is actually our natural history study that was run over 24 months, and we have disclosed that. In fact, I think it was recently published as well. And so that'll be a key piece of the comparison to the Phase 1/2 and the three-year OLE data. And then also to your question in terms of AES, yes, we'll continue to provide you data as we go through these medical conferences with AES being a very important conference for us.

Tom Shrader, BTIG.

Good luck with the big meeting. I wanted to ask a little bit about patient-level data. If you look at slide 7, even far out, the seizure reductions seem fairly noisy. And I'm just wondering, do you see, is that patients that get benefit for a while and then reverse?

Do you see any evidence that the treatment is transient or does an individual patient sort of better behave when it's kind of monotonically down? And then I have a pipeline follow-up.

So I'll answer, maybe Barry will follow up, but part of the, I'm going to say noise in those error bars, as you go further out, it's a low number of patients. Whereas what's interesting, Tom, is when you take a look at on slide 7, and that is the OLE data, which is after the nine-month Phase 1/2 and if you think about these patients now moving through into the OLE data, when you look at the earlier data, both on the seizure reductions, whether it's the Lower dose group or the Higher dose group, it becomes tighter because you've got more patients. And so that data actually is not noisy when you have a lot more patients.

When you get further out to the far right of that slide with the one you're referring to, yeah, there's a couple of wide arrow bars, but that's where you have the least number of patients. And then I would just say that even where you do see the error bars, and I would focus on the left-hand side of that slide, You still see, even with the low dose, you still see if the median is around 75 or 70, you still see 60 to 85, if not bigger, reductions in seizures. All of that is a dramatic benefit to these patients that, remember, are taking three, four, and sometimes five standard of care anti-seizure medicines.

And I'll just add, again, Tom, that in actual history, that zero line that you see there, that's where the change that we would see on these same anti-seizure medications patients are on. We're seeing almost no change in their seizures. So that's a dramatic difference from what would be patients who are just on anti-seizure medications alone.

Okay, if I can follow up, as you start to think about a pipeline, As you head into a program, is the odds that you'll find a lead candidate? I remember you had something like 200 candidates early on. Is the odds you'll find success high, or is it low?

Maybe you can comment on what you learned from Rett, which is an important one that I guess didn't work out. So as you go into the pipeline, is SYNGAP just the best disease, or do you have data that it's one that's likely to work?

Thanks for that question, Tom. I'll just rewind the clock maybe six or seven months when I started in the position of CEO. And I asked the team pretty much that question. And I wanted to do a full strategic review of certain disease areas. And what I mean by a strategic review, start with the market, start with can you develop the medicine in terms of its end points to potential accelerated pathways. And then preclinical safety and efficacy models and models that are more human-like in the proof of concept in animal but also causing the company to really focus on haploid sufficiency.

And we came away, I can tell you, with a number of new disease areas that are touched on in our slides and that's cardiac, and a couple of other areas. And so we are working, those are the earliest stages. Now if I go to the mid parts of our pipeline, which is SYNGAP and ADOA, those are both haploin-sufficient diseases. RETT is not. RETT is a little different. And we may have learned a lot from RETT in terms of maybe creating kind of more functional protein, but it's still mutated. and so there was some challenges in RETT.

But as far as SYNGAP is concerned, ADOA is concerned, and then in cardiac and a couple of other disease areas that we're looking at, those are all haploin-sufficient areas, which is our platform to focus on those disease areas.

Mark Goodman, Levering Partners.

This is [Basma]. I'm for Mark. Thank you for taking our questions. Our first question is on the BUTTERFLY study. Could you please remind us whether the company has received alignment from the FDA on the study design and the goals of the study, just to make sure that the study is robust enough? And also, we have a follow-up question.

I'm sorry, but I couldn't quite -- I don't understand the slide you were referring to. If you're asking about --

The BUTTERFLY Natural History studies.

Barry, do you want to --. So I'll take the first part of that question, and maybe Barry will follow up. When in discussion with the FDA, I can tell you how they focus on Natural History studies and how they're utilized.

I'll tell you what the FDA does not like. The FDA does not like a retrospective analysis of real-world data or Natural History studies to try and realign with what your primary and secondary endpoints are in your study. So they like endpoints to be pre-specified and consistent with the studies that you're running. That is exactly what we've done with BUTTERFLY. BUTTERFLY looked at seizure reductions as well as the Vineland, and that is consistent with how we've run all our studies. And that's most important.

And I'll refer to, it's called RDEP, it's real-world evidentiary principles that the FDA put guidance out on, and that specifically talks about being aligned and not being retrospective analysis, being more predetermined analysis as you go into these studies if you want to use them as comparisons or control arms.

Great. We have one quick clarifying question regarding the EMPEROR study. Could you remind us again whether the patients are required to stay on stable dose for the background ASM throughout the 52 weeks or after the 26-week, I'm sorry, the 26- or 28-week primary endpoint they can actually change the dosing of that background ASM.

Yeah, this is Barry again. So the study requires that for the first 28 weeks, the patients do not change their background anti-seizure medications. After that, because some of the variability of the disease, we do allow some changes. But for that primary key endpoint there, there are no changes allowed.

Yarin Warber, TD Securities.

Hi, this is Jaina on for your own. Congrats on the quarter and thanks for taking our question. For us, your Phase 1/2 studies and your Phase 3 have slightly different dosing schedules. So I was wondering how that was going to factor into how you design a label for zorevunersen if you do pursue this kind of accelerated pathway.

Also, just to follow up on one of the earlier questions, you said that one of the potential aspects of your discussions with the FDA are how you can iterate on how to amend your trial, cut the data, use other cuts of data from your Phase 3 trial to also accelerate approval. What do you think are the most kind of promising possibilities among those scenarios?

So good questions. First one, in terms of the dosing, absolutely correct. It is a fact that there is not a patient that is dosed on the exact schedule that we're using in the Phase 3. And just to be clear on that, there are patients that were -- that did receive two doses of 70 milligrams of zorevunersen, but then had a six-month gap before they went into the OLE study and then received 45 milligrams every four months in the OLE. That dosing in terms of 270s and then 45 milligrams maintenance dose is consistent with what's in the Phase 3, what the piece that's inconsistent is a six-month gap instead of a four-month gap.

Yes, we understand the point that you're making. It is something that could be a discussion with the FDA. However, we would point to the data from the Phase 1/2 and the OLE in terms of its consistency and durability from the Phase 1/2, the six-month gap in dosing, and then into the OLE where those seizure reductions are durable and are maintained. Plus, you see the same with Vineland. where you get an improvement in cognition and behavior as mentioned by the Vineland scores. And that continues into the OLE study as well.

And we presented that data to you over three years in terms of looking at it from a longitudinal basis where you see an improvement in year one and then year two and year three in the OLE in most of the domains. and so that is the data that we'll be using to support the dosing regimen that is in the phase three design that we would be seeking approval for.

Jess Fye, JPMorgan

I had a few here. kind of long questions, but maybe short answers. So first, you talked about the FDA meeting scheduled in December. When will we know the outcome of that meeting? Would you plan to wait for the minutes before communicating to the street on the path forward? Or are there scenarios where you think the feedback would be clear enough to communicate before receiving the minutes?

Second one is, I think you had 130 patients in pre-screening this summer, and then that grew and grew, and now I think you mentioned 200. But of the 130 from August, how many of those folks are still in pre-screening versus screening versus screened out for some reason? Trying to tie that 20 patients randomized back to these large pre-screening numbers.

Third, to the extent you're able to see blinded safety data from Phase 3, anything you can say about the patients treated so far? Is the safety consistent there?

And lastly, looks like you raised about $50 million via the ATM this quarter. Can you just refresh our understanding of the balance sheet?

Okay, Jess, I think I got all those down. I will, number three, blinded safety data from our Phase 3, no commentary. It's a blinded study and it's an ongoing Phase 3 study.

The other three questions, you asked about disclosure coming out of the December meeting with the FDA. Disclosure will be driven by when we believe that we are moving the timeline that we're currently communicating to you this evening, and that is to complete enrollment in the second half of 2026, and then with data coming in the second half of 2027. The moment that we're confident that we are moving off that timeline, whether it's an expedited pathway, an accelerated recruitment, we will then provide a communication.

You asked specifically about minutes. I believe you should always wait for the minutes. My experience over years now is that you can have good and bad meetings with the FDA, but you should always wait for the minutes to see exactly how they recorded it. It is your document of record and allows you further discussion with the FDA. And so we will be waiting for those minutes and we will then understand those minutes to allow us to communicate and update if necessary to you all.

In terms of the pre-screen, think of it as in kind of an upside down triangle where you've got 200 patients or 150 patients in pre-screen. They then flow into the screening part of the study. And to reference what that means, there is a six-week pre-screen period in front of dosing or randomization in the EMPEROR study. So 60 of those pre-screen patients -- approximately 60, have gone into screening. Once they go through screening, and they're acceptable patients for our study because there are certain criteria that is consistent to the Phase 1/2 and the OLE patient recruitment, then you move through to randomization in the EMPEROR study.

And there is over 20 of those 60 that have moved through screening that have moved into randomization. And just so you can continue to do the math or the kind of like the equation of how many patients you could expect in the near term to move into the study. We expect probably about an 80% success rate in screening patients. So there are patients that do fail screening for certain criteria, but we anticipate an 80% screening success rate. And so 80% of those 60 should move into randomization of the trial very shortly.

And the last question you had was regarding, can you remind you of the strength of the balance sheet?

Yes, so Jess, I'll take that. Thanks, Ian. So we ended the quarter with $328.6 million in cash, Jess, so we have a very, very strong financial position and as you mentioned, we raised 487 -- $448.7 million by a single block trade through our ATM. These funds not only push us further into mid-2020, but they also support the continued investment in our organizational capabilities, and importantly, our earlier stage programs. So at this time, we're not providing any changes to our runway, but we will update our guidance once it does change.

Joseph Stringer, Needham & Co.

Just as a follow-up, what are some of the most common reasons for screen failure? And then secondly, for the Vinland-3, you said that European regulators will consider the composite score that's different from FDA.

So can you just walk us through the details of that particular analysis? Are the same five subdomains being used or being analyzed as part of the composite, and are they equally weighted?

Hi, thanks. Hi, Joey. This is Barry. Thanks for the call. So in terms of the screen fail reasons, there are a few. One is that there is a minimum number of seizures that the patients have to have before they enroll in a trial. The primary endpoint is seizures, so we want to make sure that we can measure a change from baseline in those patients. Some of the patients, if they get sick for whatever reason in that period of time, then they may not be able to enroll right away and we have to wait until they recover.

And sometimes it's just for family reasons that once they're in the trial and they realize that for whatever reason they're not going to be able to meet all the commitments, then they may not do. So those are the primary reasons. But again, as Ian said, the screen fail rate is actually quite low and very gratifying for us.

In terms of the endpoints for Vineland, yes, those five key endpoints that we measured. Again, those are the ones that we heard from investigators, from families. Those are the ones that are most important to see a change. Those are part of the composite and also would be individual endpoints that we would measure as part of the study.

I think there was a question on composite versus hierarchical.

Thank you. So the composite, yeah, so the composite, well, those endpoints will be assessed both as part of the composite as well as separately, individually for the study.

Sumant Kulkarni, Canaccord Genuity.

It's nice to see all the progress, and thanks for taking our questions. I have three. First, what specific aspects of the data that you've generated already for zorevunersen do you think would be the key for FDA to allow an earlier filing?

Sumant, it's a good question, and I often use phrase in our industry is I love all my children the same. And what I mean by that is there's not really a key part of the data. It is actually the totality of the data. And I actually think about it as in what is most important within this data set because obviously it's seizure reductions and then this continuous improvement in Vineland scores over a period of nearly four years now.

It's actually the magnitude and longevity of the responses that are so different than baseline and Natural History. That's what I would point to as being one of the most compelling aspects of this data set. Yes, it is up to 90 patients of data. Not all of those 90 are still on medicine in the OLE, but a lot of them are. But it's the fact that that data set goes for four years and has that durability of response that you've seen, whether it is the reduction in seizures or whether it is the improvement in cognition and behavior for these patients that unfortunately plateau after two years of age.

I'll ask the second and third questions in one shot here. Could Biogen's expertise with the FDA or experience with the FDA on antisense oligonucleotides help you with your interactions with the agency? And second, given you have some launch readiness efforts already underway, could you share your latest thoughts around potential pricing for a product that is currently uniquely positioned to modify the progression of?

Yes. So firstly, to clarify our relationship with Biogen. Biogen is a wonderful partner. They were the partner of choice before they became the partner of choice because of their capabilities outside of North America. We retain rights -- commercial rights, in North America. However, we've retained worldwide development rights.

So Biogen is a wonderful partner because of their experience outside North America, particularly with commercialization, and they have capabilities such as manufacturing, and they've got Spinraza, which is also an SMA, and they have treatment centers -- they work with treatment centers around the globe, and so that is highly beneficial to us as a company.

As far as the regulatory processes are concerned, both in the US and Europe and Japan, we work collaboratively with Biogen. We are the lead, I'll just say that. We are the lead. We have a whole governance structure set up between the two companies where you have employees and leaders and executives on those governance committees that share the execution of the plans and how we go to the agencies. And the relationship between ourselves and Biogen has been very good for the nine months that we've been together now and I anticipate it will continue.

Yeah, and on the pricing question, Sumant, I think first it's important to note that we're pretty far away from setting a price here. We haven't done a formal pricing project yet. But I think even just the way you asked the question is right on target in the sense that we anticipate bringing a rare disease-modifying treatment to the market, and we want to make sure that we're, number one, maximizing patient access to treatment, and number two, maximizing the value of the asset and reflecting the value that it's bringing to the Dravet treatment landscape.

And so I think other rare genetically targeted disease-modifying treatments are the appropriate analogs. I think things like Spinraza, the CF treatments from Vertex, and other disease-modifying treatments looking at rare genetic diseases are probably the right place to focus if you're looking for a place to anchor to before we actually set a price.

Ananda Ghosh, HC Wainwright.

Congrats on the quarter. I have three questions. Maybe the first one, you know, given the durability of the CSER reduction plus the cognitive and behavioral improvement seen in the 36-month OLE, you know, how confident are you in meeting the EMPEROR Phase 3 endpoint for major motor seizure frequency, given that it's just sham-controlled.

And a follow-up question on the same aspect is that, let's say the secondary endpoints, such as Vineland-3 score, kind of get shy of achieving statistical significance. What are the plans existing for regulatory strategy and positioning of the level?

You know, just so you understand, I have Barry, our Chief Medical Officer, sitting right next to me here, and I cannot tell you that I've dug into the Phase 3 design and the powering and the data and worked closely with our clinical team, and so our confidence is high. This is an exquisitely designed Phase 3 study with a powering to a p-value of 0.01, confidence level, the p-value of 0.01.

The seizure reduction primary endpoint, which is what approval will be based upon in terms of a result from the Phase 3, obviously you can see that we reduce seizures with this regimen that's similar to this to the extent of 80% on top of standard care medicines. And so our confidence in seizure reductions is very high.

In terms of the secondary endpoints, I think the data to look to understand the confidence in hitting the key secondary endpoints is actually the CNS data that we showed in August. I can't remember the number of the slide it's on, but it's in the deck, and you can take a look at that. But on that slide, you do see Vineland scores over a period of, I believe, 68 weeks of scores between 8 and 11 points. And so you can compare that to how the study is powered.

The study is powered for a two-point improvement in Vineland to, again, a 90% confidence level of 0.01 for a two-point improvement compared to the sham control. And so when you compare that to the CNS data that is on slide -- and Barry's going to read it to me because slide 11, I don't have my glasses on. So but yes, our confidence is high based on that data. And so, yeah.

Got it.

Did I get all your questions?

Yes, for the first part. I have two follow-up questions, if I may. The second question is on safety. You know, with the elevated CSF protein, which has been consistently observed and you have reported. One question is, you know, are there any data suggesting long-term impact of the elevated CSF protein, like across any patient population? And the second -- and a follow-up on that would be, like, you know, what additional safety data or mitigation strategies will you present to the regulators?

So I'll quickly give you a summary, and then Barry can go into more detail. But what we present to the regulators is the detail that is behind the summary that is in the slide in the deck again. And somebody's going to give me the number of the slide while I keep talking to you. But that's slide 12 in the deck. And so when we share the patient-level data, with the -- in the briefing book. And it's that patient-level data over this four-year period that we share in over 800 doses. And that's what we're sharing with the FDA.

And the summary of that is the drug is well-tolerated. I think it's one of the strengths in terms of the briefing book and the package is the safety profile over a four-year period that we can take to the FDA and then potentially focus the discussions on efficacy measures.

And Barry, do you have anything to add in regards to CSF?

I'll just mention again that we do see the elevated CSF protein levels in the Open Label Extension study at various time points. What we have not seen are any clinical manifestations associated with it, specifically looking at things like hydrocephalus that might be associated with that. So we track it very carefully. and regardless of how long the patients have been on treatment, and as we said, we have patients that have gotten more than 15 doses, we have not seen any of those manifestations in the patients who had elevated CSF protein.

Correct, thanks. Maybe the last question on the OPA1 program. You showed us some encouraging FALCON Natural History study recently. and the question, but then one aspect of it is that, you know, the slow progression of the disease in itself. So you know, how does it kind of, you know, how do you kind of mitigate that slow progression aspect of the disease as you kind of plan your trials, like the human clinical trials?

Yeah, it's a really good question and that earlier on this call, I mentioned that when I started as the CEO eight months ago, I asked the team, to go through a kind of a strategic assessment of different disease areas that we may take drugs forward in. One of the questions I posed to the team is, how do you develop drugs in the area? And it's exactly for the reason that you're mentioning, which is sometimes the endpoint in a slowly progressing or deteriorating disease, such as losing eyesight over a long period of time, it's very difficult to run studies with them unless you actually improve eyesight.

And so ADOA was a great example where the team did extensive work in animal models and I referred to human-like animal models for safety and efficacy earlier in this call as well and what the team did, which was incredible, they ran a non-human primate model with a control and what we found when, and it's a non-human primate model that has actually ADOA, it's not actually a created model. It's actually a non-human primate with ADOA.

And in that data, we found that the eye that was injected actually improved eyesight as measured by a neurofilament measure, fluorescent filament measure. And that showed kind of more activity in the eye. And we compared that to the control arm, which showed deterioration of control eye and another monkey, and that showed deterioration. And that was actually the data that pushed us forward into the clinic.

And I've mentioned it now in a couple of calls and also at conferences, but that data gave us the confidence that as we go through clinical development, we will be looking for an improvement in vision, not a slowing of progression of eyesight. And recently, there was a company that put out some data that validated the OPA1 target. and so it's a very interesting area.

And Barry, do you have further comments?

Well, I can just say that the measures that we had in the monkey study were functional measures of the nerve function -- the optic nerve function, and also measures of mitochondrial function. So that's something called flavor protein fluorescence. And we showed that that is -- we know that in our natural history study that that's elevated in patients with ADOA. It's above normal. And in the monkey study, we showed that those levels were reduced. So that would go along with potential for improving vision in patients.

This concludes the question-and-answer session. I will now turn it over to Ian Smith for closing remarks.

Yeah, thank you. I just want to say thank you for you all taking time out to listen to us. We appreciate the questions and our opportunity to respond to those questions and help you more understand Stoke Therapeutics and I look forward to keeping you updated as we progress along. Thank you for your time this evening.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.