Earnings call transcript: Stoke Therapeutics beats Q2 2025 expectations

Stoke Therapeutics Inc (NASDAQ:STOK) exceeded analyst expectations in its Q2 2025 earnings report, posting a narrower-than-anticipated loss and stronger revenue. The company’s EPS was -$0.40, compared to the forecasted -$0.50, while revenue reached $13.8 million, surpassing the expected $9.39 million. Following the announcement, the stock rose 2.81% to $13.16, with aftermarket trading showing a further increase of 1.98%. According to InvestingPro data, the company maintains an EXCELLENT financial health score of 3.9 out of 5, with particularly strong metrics in cash flow management and relative value.

Key Takeaways

• Stoke Therapeutics reported a significant earnings and revenue beat for Q2 2025.
• The company maintains a strong cash position, ensuring operations through mid-2028.
• Positive clinical developments in lead drug Zorivanersen for Dravet syndrome.
• Stock price increased post-earnings, reflecting investor confidence.

Company Performance

Stoke Therapeutics demonstrated robust performance in Q2 2025, driven by substantial revenue from its collaborations with ACADIA and Biogen. The company’s financial health is underpinned by a strong cash position, projected to support operations until mid-2028. With a current ratio of 8.41 and more cash than debt on its balance sheet, this performance is particularly notable amidst ongoing challenges within the biotech sector. InvestingPro analysis reveals 12 additional key insights about STOK’s financial position and growth prospects, available to subscribers.

Financial Highlights

• Revenue: $13.8 million, up from the forecasted $9.39 million.
• Earnings per share: -$0.40, better than the forecasted -$0.50.
• Net loss: $23.5 million, reflecting ongoing R&D and G&A investments.

Earnings vs. Forecast

Stoke Therapeutics exceeded expectations with a 20% positive EPS surprise and a 47.18% revenue surprise. This marks a significant achievement compared to previous quarters, indicating effective management of collaborations and operational expenses.

Market Reaction

The stock’s post-earnings rise of 2.81%, with an additional aftermarket gain of 1.98%, suggests a positive reception from investors. Trading at a P/E ratio of 15.4, STOK has shown strong momentum with a 31.87% return over the past six months. This movement highlights confidence in the company’s strategic direction and future growth prospects. For deeper insights into STOK’s valuation and momentum indicators, InvestingPro subscribers can access the comprehensive Pro Research Report, part of our coverage of 1,400+ US stocks.

Outlook & Guidance

Stoke Therapeutics continues to focus on advancing its clinical pipeline, particularly the Phase III EMPEROR study for Zorivanersen. The company anticipates completing enrollment in 2026, with top-line data expected in 2027. This long-term outlook is supported by a solid financial foundation and strategic partnerships. Analyst consensus is strongly bullish, with price targets ranging from $15 to $35, reflecting confidence in the company’s pipeline potential. The stock’s Fair Value assessment and detailed financial analysis are available through InvestingPro’s extensive metrics and expert insights.

Executive Commentary

"The era of disease modification is upon us," stated Ian Smith, Interim CEO, highlighting the company’s pioneering efforts in creating disease-modifying therapies. Barry Tico, Chief Medical Officer, emphasized, "These data support the long-term potential of zurivanersen to modify the course of Dravet syndrome," underlining the promising clinical results.

Risks and Challenges

• High R&D and G&A expenses could impact profitability.
• Lengthy timelines for clinical trials and commercialization.
• Potential regulatory hurdles and competitive pressures in the biotech industry.

Q&A

During the earnings call, analysts inquired about the potential for accelerated approval pathways and the impact of European study cohort additions. The company clarified that these additions do not affect the overall study design, reinforcing confidence in their strategic approach.

Full transcript - Stoke Therapeutics Inc (STOK) Q2 2025:

Tommy Leggett, Chief Financial Officer, Stokes Therapeutics: Good afternoon and welcome to Stokes Therapeutics second quarter twenty twenty five conference call. I’m Tommy Leggett, Chief Financial Officer at Stokes. Joining me for prepared remarks are Ian Smith, our Interim Chief Executive Officer Doctor. Barry Tico, Chief Medical Officer and Doctor. Kimberly Parkerson, Head of Neurology Clinical Development.

In addition, Jason Hoyt, our Chief Patient Officer will participate in Q and A. As a reminder, today’s webcast slides are available in the Investors section of our website. This webcast is being recorded and 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 the filings of the SEC for additional information. With that, I’ll turn the call over to Ian.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Welcome, everyone, and thank you for joining us today. I’ve been working with Stowe Therapeutics for two years as a director and advisor, more recently as the CEO. It has been a great opportunity to get to know the team, the medicines, and the disease areas, and to support the company through this growth period. The key priority is obviously Dravet syndrome and zorrevonercin as we work to deliver a disease modifying medicine to patients. What we’re seeing with zorrevonercin may be new to the field of epilepsy, but I’m struck with the familiarity of the feeling of being part of something very special, again, which is creating a new first in class disease modifying medicine for patients who desperately need it, potentially changing the lives of these children suffering from Dravet syndrome.

Let me start by saying that Stokes is in a strong growth position, defined by a late stage registrational medicine, well capitalized balance sheet, expanding pipeline of potential medicines, and a very strong partner in Biogen with expansive capabilities to support zurivanersen outside of North America. Our Phase III EMPORER study in patients with Dravet syndrome is off to a strong start with sites initiated in The U. S, U. K, and Japan and Europe expected to initiate in early twenty twenty six. The first patient is now dosed, and we anticipate rapid enrollment based on the high level of awareness of the study, competitive participation among the study sites, and importantly, the urgent patient need.

We continue to generate data that supports our understanding of zurifenursen from our Phase III and OLE studies. We have prioritized sharing this information broadly as the field begins to transition from a symptomatic treatment to a potentially disease modifying medicine for Dravet syndrome. We continue to educate around reductions with our medicine, and those reductions are on top of standard care anti seizure medicines. More recently, we shared data that was used to inform the assessments of behavior and cognition and the powering of our Phase III study, specifically the substantial improvements in cognition and behavior indicated with a dosing level that is similar to and consistent with the one we are using in our Phase III study. And today, we are sharing with you top line results from the third year of our open label extension studies.

These data support the long term potential of zurivanersen to modify the course of Dravet syndrome as indicated by durable seizure reductions on top of what can be achieved with anti seizure regimens, as well as continuing improvements in cognition and behavior. Importantly, these long term follow-up data continue to demonstrate a favorable safety profile. Beyond we see significant potential to develop disease modifying medicines for additional genetic diseases. We’ve advanced STK002 into Phase I clinical development for autosomal dominant optic atrophy. Like Dravet, ADOA is a haploinsufficient disease, and we are uniquely positioned to treat by restoring naturally occurring OPA1 protein expression using our antisense oligonucleotide approach toward the goal of preventing further loss of eyesight and possibly improving vision.

Now to our collaboration with Biogen. Found in February, this brings global expertise commercializing high value disease modifying medicines for rare genetic diseases and strengthens our balance sheet. In terms of the collaboration, we tend significant value to Stokes while enhancing our ability to deliver Zarifenursen to patients globally. We have a strong balance sheet and are well funded through Phase III readout, which is anticipated in the 2027. And our balance sheet and projected investment supports a cash runway through to mid-twenty twenty eight.

We continue to build Stokes’ internal capabilities by enhancing our leadership team and strengthening key functions, including regulatory, medical affairs and commercial, all fundamentally important functions at our stage of growth. In short, we are establishing a clear trajectory for value creation for patients, for employees, and for our investors. With that, I’ll turn the call over to Barry, who will discuss our Phase III study design and progress.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Thank you, Ian. This is a very exciting time here at Scope as we take zerivaneursen into this next phase of clinical development and potential registration and approval. Dravet syndrome is a severe lifelong developmental encephalopathy that becomes symptomatic around one year of age. For the vast majority of patients, the cause is insufficient levels of the NAB1.1 protein in the brain. There are many medicines available to treat the seizures associated with Dravet syndrome.

These medicines have undoubtedly made a difference for patients, but they just aren’t enough. Most patients continue to suffer from seizures, and few achieve seizure freedom. Furthermore, side effects of the anti seizure regimen also present their own challenges for patients and their caregivers. While Dravet syndrome may be best known for its seizure burden, the effects go far beyond seizures. Nearly all patients suffer from one or more behavioral and cognitive effects.

Antiseizure medicines were not intended to address these effects. We intend to change that. Arrevonerstin is an antisense oligonucleotide designed to restore naturally occurring MAD1.1 protein levels. As such, it has the potential to be the first disease modifying therapy for Dravet syndrome. As we designed our Phase III study, we were fortunate to have a large data set available to inform key decisions related to dose level, dose frequency, study endpoint assessments, and powering.

Here on slide eight, you see the dramatic reductions in seizures demonstrated in our phase onetwo studies among patients treated with initial doses of seventy milligrams of zirubinescent on top of standard anti seizure medicine. The most substantial reductions were observed among patients who received either two or three doses of seventy milligrams. Based on these data and additional modeling analysis, we selected a two dose loading regimen, phase three, with seizures as our primary endpoint for the trial. After receiving their last Phase III dose, patients were followed for at least six months before restarting treatment in the open label extension study. When designing our Phase III program, we used the initial eight months of data from the OLE that showed substantial and durable reductions in seizures and a favorable safety profile to inform our maintenance dose.

We now have an additional year of data on these patients, which are shown here, and support the long term durable reductions in seizures. Kim will discuss these data later in the call. These new long term data give us confidence in our loading and maintenance dosing, as well as the durability of effects. On slide 10, you see one of the key analyses that informed our thinking on the phase three design, which Ian referenced earlier, and was presented at EPNS in Munich last month. The analysis shown on the left was performed to assess potential effects on cognition and behavior using data from patients treated with dose levels that were similar to and consistent with our phase three dose regimen.

The effects are striking, particularly in the context of the results from a matched cohort of patients followed in our natural history study. Little to no change was detected in the natural history, that patients treated with cerebrosynurgin showed cognition and behavioral benefits in the five key subdomains that comprise our key secondary endpoints in effort. On this slide, you can see the phase three design. Patients who enroll in EMPORER will be randomized one to one to zirivaneurcin or to sham. In both study arms, patients will continue to receive standard of care anti seizure medicine.

Consistent with the data I just reviewed, patients in the zirivaneurcin arm will receive two loading doses of seventy milligrams, followed by two maintenance doses of forty five milligrams. An open label extension treatment period will allow all patients the opportunity to receive treatment with cerebundersen following fifty two weeks of treatment in this study. I will now review the EMPRA study design and conduct in more detail on slide 12. Primary endpoint is changed from baseline in major motor seizure frequency at week twenty eight. Durability of effect on seizures will be measured as a secondary endpoint at week fifty two.

Ceremonersen is a potential first in class disease modifying medicine. So EMPRA will also measure effects on behavior and cognition. Powering for these secondary endpoints is robust and designed with the intent to show statistical significance on both individual subdomain and composite specimens. We were pleased with the level of interaction and input from global regulatory agencies and our advisors as we worked together to design the EMPEROR trial. Through these discussions, we aligned around a double blind, SAM controlled study with lumbar puncture for all patients.

As individual European countries got involved later in the process, they required a modification to the sham arm to proceed. In order to ensure our commitment to patients in Europe, we now plan to add a cohort of at least 20 patients in Europe where sham will be administered via needle prick. This cohort of patients will be in addition to and complement the originally planned group of approximately 150 patients who will be randomized to receive zolivoneurcin or sham with lumbar puncture in The U. S, U. K, and Japan.

We expect to activate at least half of the 70 study sites by year end, and European sites to initiate by early twenty twenty six. We see significant and growing global interest in EMPEROR, which supports our expectation to complete enrollment in the 2026 with a Phase III data readout in the 2027. EMPORER is off to a great start. We have had a high degree of confidence in the study design based on a large data set and the ongoing patient needs. Our natural history study has proven invaluable in understanding the effects that Dravet syndrome has on patients over time, as well as the limitations of the current standard of care medicine.

Our experience with ziribunirsen in Phase onetwo and ongoing OLEs has helped us understand the initial and ongoing effects of ziribunirsen and has demonstrated an encouraging long term safety proof. Our assessment of behavior and cognition have been validated, and our endpoints empowering are informed by our years of experience and data. As announced yesterday, the first patient was dosed in EMPORER. Study investigators have identified approximately 130 potential participants, and that number continues to increase. More than 10 clinical sites have initiated across The U.

S, U. K, and Japan, with more coming online weekly. This is exactly the kind of start we were hoping for, And it positions us well for continued enrollment success. With that, I would like to turn the call over to Kim for a review of the new three year open label expansion data.

Kimberly Parkerson, Head of Neurology Clinical Development, Stokes Therapeutics: Thanks, Barry. Before I share the new data, I want to express my gratitude to the patients, caregivers, advocates, clinicians, and Stokes employees who have brought ZarifaNursing to where it is today. Having treated patients with drug resistant epilepsies for many years in my clinical practice, I can tell you that these data are profound and meaningful. The community has been waiting a long time for something that would address the syndrome, not just the seizures. We remain confident that we may very well see a significant advance in treatment for patients, which would have impacts for them and also for their families.

With that, it’s my honor to share the new thirty six month data. More than ninety percent or seventy five eligible patients who completed treatment in the Phase onetwo studies continued treatment with zurivanersen in the open label extension studies. The high seventy seven percent retention to date in the OLEs has provided us with a robust data set to assess the long term effects of zurivanersen in these patients. Here on slide 15, you see the three year effects on seizures observed across patients treated with Zarivamersen in our OLE studies following treatment in the Phase onetwo studies. I’d like to call your attention to the top blue line, which shows patients treated with less than seventy milligram loading doses in the phase onetwo studies before continuing treatment in the OLEs.

As patients transition to more stable forty five milligram dosing, you begin to see on the right side of the graph a trend toward further reductions in seizures. Turning our attention to the orange line, you see the substantial and durable effect for the patients treated with loading doses of seventy milligrams followed by continued dosing of thirty milligrams or forty five milligrams every four months in the OLEs. For these patients, we observed a median reduction of 59 percent to ninety one percent in major motor seizure frequency across each time point through month twenty. The durability of effect is consistent with what we would expect for a disease modifying medicine and supports our EMPEROR Phase III registrational study. But we know Dravet syndrome is more than just a seizure disorder.

Dravet syndrome is a complex disease that presents daily and life altering challenges for patients, their families and their caregivers. On the left, you see the impact on patient health and well-being. For most, remain the primary comorbidity. However, Dravet impacts all aspects of life for patients and their families, some of which are shown on the right. On slide 17, you see a graph that illustrates expectations for the development of a neurotypical child, shown with the top line, and a child with Dravet syndrome, shown with the bottom line.

Consistent with findings from natural history data, including results from our two year butterfly study, patients with Dravet syndrome experienced minimal improvements in cognition and behavior. Overall, patient development begins to plateau within the first several years of their life. And over time, they fall further and further behind their neurotypical peers and their ability to achieve developmental milestones. The Vineland-three assessment is helping us measure changes in cognition and behavior in patients with Dravet syndrome. I’ll now review what the assessment is and how it works.

As summarized on slide 18, Vineland-three is a clinically validated and widely used tool for assessing neurodevelopment over time. It is typically administered through a semi structured interview with the patient’s caregiver that is conducted by neuropsychologists or other trained raters. There are four domains evaluated with communication, motor skills, socialization, and daily living. These domains are broken down into a series of sub domains which are evaluated on a point system scale. We use the Vineland-three across multiple of our clinical studies and it is now being used to evaluate key secondary endpoints in our Phase III EMPORER study.

Our natural history study also helped in the selection of Vineland-three as an assessment for our clinical studies. So now today, we are showing data on slide 19, which are quite remarkable and striking. What you see here is the progression of Vineland-three results for patients treated in the OLE studies with zurivanersen over one, two and three years following treatment in the phase onetwo studies. For this analysis, patients were measured against their own baseline scores at entry into the OLE and demonstrated improvements through year one of the OLEs and continuing improvements in year two and year three. The improvements you see here are in addition to any improvements the patients may have experienced during the nine month phase onetwo treatment period.

Notably, some patients received doses as low as ten milligrams upon entering the OLEs. As a reminder, small changes on the Vineland-three are considered meaningful to clinicians and caregivers of patients with Dravet syndrome. To give you context, our published survey indicated raw score improvements ranging from one to three points over a year across individual sub domains would be considered clinically meaningful to at least half of caregivers. The thirty six month data show profound changes, addressing the underlying protein deficiency appears to restore function and help patients achieve more of their developmental milestones. In effect, zurivanersen appears to be narrowing the gap between the normal course of disease and neurotypical development that I showed you earlier.

While these graphs get clinicians like me really excited, hearing caregivers and clinicians talk about what these data mean in real life only increases the sense of urgency we feel here at Stokes to advance the reaversions to patients. In addition to compelling efficacy data, we are highly encouraged by the safety profile observed across our studies to date. This safety summary represents over four years of clinical data, including the first year of treatment in the phase onetwo studies, followed by over three years of treatment in the OLEs. Over this time period, zurivoneurcin has been generally well tolerated. Eighty one patients received at least one dose of zurivoneurcin.

In the Phase I2a studies, thirty percent of patients experienced the treatment emergent adverse event related to the study drug. The most common were CSF protein elevations, which we continue to observe in the OLEs. Approximately eighty six percent of patients have developed elevated CSF protein levels, of which forty five percent have been classified as a treatment emergent adverse event due to the laboratory values. Importantly, no clinical manifestations have been associated with CSF protein elevations. Only one patient has discontinued treatment due to elevated CSF protein levels.

Treatment emergent serious adverse events have been reported in twenty nine percent of patients in the OLEs and none have been attributed to study drug. Across all studies only one patient experienced two SARS. To date more than 700 doses of Zarivamersen have been administered across the studies. Patients have received up to fifteen doses of Zarivamersen with forty one patients having received 10 or more doses. This is highly encouraging as we think about the Phase III design and ongoing treatment.

I will now turn the call back over to Barry.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Thank you, Kim. STOKE has long believed in the potential of its platform, and today I am pleased to share that we have initiated a phase one study of STK-two for autosomal dominant optic atrophy, the most common inherited optic nerve disorder. From a genetic and mechanistic perspective, ADOA shares a lot of similarity with Dravet. The majority of cases of ADOA are caused by mutation in the OPA1 gene, which leads to diminished protein function for haploid deficiency related to OPA1 protein deficiency. In a healthy eye, the OPA1 protein plays a key role in maintaining mitochondrial structure and function.

Patients with ADOA reduce levels or function of the OPA1 protein impairs mitochondrial function and results in decreased energy production. Without sufficient OPA1 protein, the retinal ganglion cells cannot meet their metabolic demands and gradually degenerate. The result is optic nerve atrophy and progressive vision loss. Approximately eighty percent of patients are symptomatic by age 10, and about half of all patients are legally blind. About one out of every thirty thousand people around the world are estimated to have ADAway, with a higher incidence of approximately one out of ten thousand in Denmark due to a founder effect.

We estimate that approximately thirteen thousand patients are currently living with ADOA across seven key geographies, including The U. S, EU5, and Denmark. As described on slide 23, we have generated compelling preclinical findings that support advancements for STK-two into the clinic. We have observed increased OPA1 protein levels and improved mitochondrial function in ADOA patient fibroblasts treated with STK-two. Increases in OPA1 protein have been demonstrated with STK-two in vitro and in vivo, including dose related increases in OPA1 protein expression in nonhuman primate retinal ganglion cells following intravitreal injection.

STK-two has been found to be well tolerated across multiple species. In addition, today we are sharing new efficacy and safety data from a study of STK-two conducted in a nonhuman primate model of ADOA that has a mutation in the OPA1 gene resulting in insufficient protein in the mitochondria. These NHPs have disease characteristics similar to humans with ADOA, and therefore represent a unique opportunity to evaluate STK-two. The new data we are sharing today on slide 24 show improvement in mitochondrial and retinal function three and five months after treatment with STK-two in an NHP model of ADAOA. Intravitreal injections of single doses of STK-two were well tolerated in diseased NHBIs.

These data suggest the potential for STK-two to stabilize or perhaps even improve vision by restoring functional protein levels. Based on these data, we have initiated a Phase I study of STK-two in ADOA patients. OSFIRE is an open label single ascending dose study designed primarily to evaluate safety, but which will include assessments of clinical activity. Study initiated in The UK last week, and we expect sites in Europe to initiate later this year. There are currently no treatments approved for ADOA.

We believe our approach represents a unique opportunity to address the underlying cause of ADOA by restoring naturally occurring protein function.

Tommy Leggett, Chief Financial Officer, Stokes Therapeutics: I will now hand the call over to Tommy to discuss our financial summary. Thank you, Barry. For those following along, I’ll be speaking to Stokes’ financial results as provided in the 10 Q and earnings release. Stoke is in a strong financial position as we enter Phase three and expand our platform into new disease areas, starting with ADOA. We ended the second quarter with $355,000,000 in cash, cash equivalents and marketable securities, which we continue to expect will fund operations beyond the Phase three readout and into launch readiness to mid-twenty twenty eight.

Total revenue for the quarter was $13,800,000 which is driven by revenue from our ACADIA and Biogen collaborations of 10,600,000 and $3,200,000 respectively. We expect revenue from Biogen to increase going forward as we continue to execute on EMPEROR and our other Zareva Nursing related activities. Our net loss for the quarter was $23,500,000 or $0.40 per share, slightly improved from the prior year period despite a $6,900,000 year over year increase in operating expenses. Operating expenses during the second quarter were comprised of R and D expense of 25,900,000.0 which reflects continued investment in our Dravet program and key areas of our business, namely medical affairs, while also expanding our pipeline. G and A expenses of $15,300,000 were largely driven by the continued expansion of our commercial team and capabilities.

In summary, our strong balance sheet enabled us to invest in zuribonursen, our pipeline, including ADAOA and capabilities while maintaining our cash runway to mid-twenty twenty eight. I’ll now turn the call back over to Ian for closing remarks.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Thanks, Tommy. Our recent progress and overwhelmingly positive response to the start of EMPRA underscore the unique potential of zuriva nurse. The era of disease modification is upon us. There is a palpable feeling within Stokes as we work together to create something truly special, a medicine that will transform the lives of patients and their families and realize the potential of our platform. We have the unique opportunity to build a company around the technology, which can create even more medicines to help even more patients.

I am energized and committed to doing everything I can to support the team as they embark on this journey. Thank you. And I will now open the call for questions.

Conference Call Operator: Your first question comes from the line of Laura Chico from Wedbush. Please go ahead.

Laura Chico, Analyst, Wedbush: Good afternoon. Thanks for taking the question. I wanted to start with a regulatory question for Zorba Nirsen. Ian, first, you’ve got three year OLE data now in hand along with natural history data. Second, if I’m understanding this correctly, you’ve got 130 patients already in pre screening for a Phase three study that’s got a target enrollment of 170 patients.

And then third, you’ve got breakthrough therapy designation. So I guess my question is, looking at the guidance documents for accelerated approval for serious conditions, I’m wondering if you could help us understand how could you explore a faster path to market for zirvanirsen?

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Laura, thank you for the call. I want to first of all start by reminding everybody that zurifenursen has breakthrough designated class. We applied for breakthrough designation last year in 2024, and we’re granted it towards the end of 2024. We were granted breakthrough designation for Dravet syndrome. What that means is the FDA reviewed our safety and efficacy data as of last year and saw the safety efficacy data and efficacy specifically for seizures, as well as cognition and behavioral benefits.

That’s really important to understand. So the FDA has already seen a lot of data. We chose to wait under the normal process of breakthrough designation to collect further data. And the key piece of data being this extension of the OLE being into thirty six months now, with the hope that the seizures continue to be reduced and durable and durably reduced, as well as the cognition and behavioral benefits continue to extend. Were thrilled that that’s how it played out.

We will take all of this data FDA. We have a responsibility to the FDA to discuss all of our data, to discuss the disease itself and how our medicine may address this disease. And that will all be part of a discussion with the FDA in the second half of this year. We have a responsibility to see whether we can get this medicine to patients as fast as possible, given the data that we’ve seen. We have begun the Phase three study, not changing timelines in terms of recruitments and getting the medicine to patients through a validated Phase three study.

And if things change, we’ll let you know at that time. But yes, we are very excited about this data and the breakthrough designation, we’ll have all kinds of discussions with the FDA.

Laura Chico, Analyst, Wedbush: Thank you, Ian. And maybe one quick follow-up if I could. In terms of what is the range of outcomes then I guess in terms of the second half following the meeting? Would this be a potential earlier than expected filing? Or guess maybe if you could walk through that, that’d be helpful.

I’ll hop back in queue. Thank you.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Yeah, it’s difficult to answer that question, Laura. Somebody actually asked me a very similar question just the other day internally. And there is no answer because the answer is actually so broad. Because the way it works with the process is we create a briefing book, we go down to the FDA and we share all data, as well as the magnitude of benefits and also safety that we’re having in these patients. And you ask a number of different questions to the FDA and sometimes you support and sometimes you get pushback and sometimes you get amendments and changes you continue the process forward.

So it’s very difficult for me to say what is the potential outcome of those discussions. Is all really a backwards and forwards with the FDA. And if anything changes from our current timelines, we’ll advise you at that time.

Laura Chico, Analyst, Wedbush: Thanks very much.

Conference Call Operator: Our next question comes from the line of Mark Goodman from Leerink. Please go ahead.

Tommy Leggett, Chief Financial Officer, Stokes Therapeutics: Hey, guys. Can you help us understand the magnitude of the cognition of behavior improvements in the Vinland-three data in this OLE data that you’re showing. Just talk about the clinically meaningfulness of the changes and in context of what these changes mean in real life for the patients please and the caregivers.

Kimberly Parkerson, Head of Neurology Clinical Development, Stokes Therapeutics: Thanks Mark for the question. I’ll try to address that. So really, as regards cognitive and behavioral outcomes, I think first it’s really important to recognize that patients with Dravet, really there’s not one size fits all for all these patients. I think that they all come in a bit heterogeneous at baseline. I think that being said, I would say that we’re all beginning to learn more about what these changes look like.

And I think that’s through a few things. One is we certainly have anecdotes from investigators of how these patients have changed over time. And then I think that we had one of our investigators present videos of one patient in December. That certainly was something I think that was really emotional for all of us. And I think a lot of that, you know, on my mind, I’ve certainly seen patients in clinic with Dravet syndrome and really this change, I think that we saw at least in that patient was something that is not something we would expect in a normal course of disease with Dravet.

I know that certainly this won’t help you at the moment, but I think that over the course of our phase three study, I think we’re going to get a good handle on what these patients look like and what they do over time. And I really think that’s going to be informative for the community as a whole across a lot of different DEEs and neurodevelopmental disorders. I think if we really focus on the numbers in particular, the numbers from the data across this three years, in particular, for those five key sub domains, but certainly across even others that we didn’t see early change in. These points are really eight to 10 ish points of change. And if we think about the data that caregivers have really given us through the survey we did with them, they identified even, you know, one to three points as something clinically meaningful.

So I think in short, I can’t paint a perfect picture, I think, of what a before and after looks like, but I think the magnitude of change across these violent subdomains will be things that families can see in the daily life of these patients across multiple developmental areas, and I think that with time, hopefully they’ll have significant impact in really the quality of life of patients and their families both.

Tommy Leggett, Chief Financial Officer, Stokes Therapeutics: Were you surprised just at the changes from twenty four months to thirty six months? I mean, on some of these domains, was pretty amazing.

Kimberly Parkerson, Head of Neurology Clinical Development, Stokes Therapeutics: Yeah, I think we all looked at it, I have to say, I think several people internally had almost tears come to their eyes to say, hey, we’re really continuing to see improvements here. So, think it was really remarkable for all of us and I certainly am looking forward to replicating this in a larger group of patients as we really get this Phase three done.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Mark, this is Barry. I’ll just add, in addition to the cognition and behavior effects that we saw, over the three years, what we were seeing is that as the patients were on the maintenance dose of forty five milligrams, those patients started to move more and more towards a greater degree of seizure reduction, a trend towards reduction. And so that tells us also that, first of all, the medicine is working according to the mechanism of action of the medicine to reduce seizures, as well as the effects of the NAV1.1 deficiency. But also that as we continue patients for long enough and observe them for long enough, they’re seeing a benefit as we get to the higher dose. Thanks.

Conference Call Operator: Your next question comes from the line of Andrew Tsai from Jefferies. Please go ahead.

Andrew Tsai, Analyst, Jefferies: Hey, good afternoon. Thanks for the updates and sharing the data. So in the past you’ve mentioned how you’ve done various analyses to help you design the Phase III EMPOR study. So can you explain what data you’ve used exactly and give us a sense of how those data helped inform your powering assumptions on Vineland specifically? Thank you.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Why don’t you take the question? Focus on seizures and cognition and behavior.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Yeah, thanks Andrew for the question. So the data that we use to determine the power calculations for the phase three partially came from an analysis that we presented earlier this year at the European Pediatric Neurologist Society where we looked at a response in a group of patients who had a dosing regimen that was similar to and consistent with the phase three study. And when we looked at those responses on the Vineland, we saw that when we modeled it out for one year, those patients had all had substantial improvements in the cognition and behavior based on the Vineland score. That was especially in contrast to a matched group of patients from our natural history study who showed very little change at all in that score. So that was a substantial contrast and shows the effect.

And we then powered the study based on that response. And we did give a change in the point score based on what we expected to be a potential placebo response. So we reduced it by 20% and use that to power. That’s where we came up with the 150 patient score. I’ll note that we also have long term data from open label extension studies, which gives us very much confidence on the safety long term.

We have now patients who’ve been dosed for over four years. We’ve given almost 800 doses of Zarivamersen in our studies. And we have patients who’ve gotten multiple doses over 15, some of them up to fifteen doses of the drug. So that safety profile is also helping us with the design of the study. And then finally for the seizure endpoints, we also looked at the response based on the two dose loading regimen as well as the forty five milligram dosing.

And we also powered that very conservatively with a 0.01 p value and a 90% power and a generous placebo effect as well. So we’re very confident in the powering of the study.

Andrew Tsai, Analyst, Jefferies: Yeah, thank you. And let’s just say second half twenty twenty seven when the data arrives, can describe what constitutes STAT SIG in Vineland? How many of the five individual sub domains need to hit stat sig and for each sub domain, what kind of placebo adjusted delta do you need to see to be stat sig? Thanks.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Yeah, we’ve powered the study based on what we think is a clinically meaningful change. So that power is based on response that we had from a survey that we mentioned was a two to three point sorry, one to three point change in the raw score of the Vineland. And so statistically significant would be a change in that range. But we think that based on our data that we have, we will potentially have greater changes than that. So again, this was a conservative assessment with a powering that was used to allow for a generous potential placebo effect.

Andrew Tsai, Analyst, Jefferies: Thank you.

Conference Call Operator: Our next question comes from the line of Pete Stavropoulos from Cantor Fitzgerald. Please go ahead.

Pete Stavropoulos, Analyst, Cantor Fitzgerald: Mary, Tommy and team, congrats on the progress and the data for the OLE, and thanks for taking our questions. First question is, are there any trends in terms of degree of seizure reduction and benefit measured by the neurodevelopmental scale, you know, Vineland-three. And I’m curious to know if younger patients, you know, are driving improvements, you know, on the scale on the sub domains, you know, versus older patients.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Maybe I’ll take the first part of that question, Barry, Kim, and then ask you guys to talk about kind of the subsets and individual not individual, but groups of patients’ reactions. One of the striking results from the thirty six month data from the OLE study was actually month 24 to month 36, where our low dose patients, it’s on the slide number 15, where the lower dose patients continued to see a reduction in seizures. And what I mean by continued to see a reduction in seizures, they continued to go lower. So they came in to the study with reduced seizures, but the seizure reduction for those low dose patients was not as significant. But as they continued through the one year, two year, and three year on a consistent dose of forty five milligrams every four months, we saw those seizures actually further reduce.

It’s on the slide as you can see, but it was one of the most striking responses that we see that goes to the mechanism of action of this drug and restoring NaP1.1 in the brain and therefore causing these children to respond better to our drug over a longer duration of time. That is one of the trends that we were very excited about. As for trends with different patient demographics, Barry Kim, do you? Yeah,

Jessica Fye, Analyst, JPMorgan: so I think you had

Kimberly Parkerson, Head of Neurology Clinical Development, Stokes Therapeutics: a couple of other kind of points in that question. One, I think had to do with kind of the seizure reduction and the Vineland responses. And I think that’s a really difficult kind of correlation I think to do particularly with, you know, the overall kind of small sample size and total kind of for a phase one study across different doses. If you really look at, you know, the seventy milligram patients, the vast majority of those patients, you know, had over fifty percent seizure reduction. So then when you try to go to some of the lower doses, there’s a lot more variability in their seizure response.

And so really being able to correlate, you know, seizure responses and violence are really tough, right now. I think that’s something we can try to do more with certainly phase three. I think with respect to the younger and older patients, for the phase three, we’ve elected to put in patients two to eighteen years of age because we’ve seen changes, you know, across the spectrum of ages in our phase onetwo study. And so I think that, you know, certainly looking across the different sub domains, some do have appear at least by kind of a covariant to have some preference towards, you know, younger and older versus older, you know, than younger. But I think that, you know, we’re confident that we can really move the bar, I think, across all of, you know, these patients from young to older.

I think that, you know, from the mechanism of action, you know, of the drug, we’re up regulating the fundamental problem, you know, of this disease, and there’s really no reason to think that maybe it’s going to take, you know, more time. We don’t know. There may be changes in the neural networks, those sorts of things, but there’s really no fundamental reason why up regulating NAV 1.1, even at a later age, cannot produce, you know, benefits in these patients. And so that’s why we’re studying, you know, two to 18, at least, you know, right now, and certainly the phase three is going to give us more insights, I think, into that.

Pete Stavropoulos, Analyst, Cantor Fitzgerald: All right. Yeah, I mean, I definitely agree that, you know, may see benefit across all the ages, but, you know, my assumption is, and many investors are assuming that the younger you go, more sort of dramatic outcome you may have on these neurodevelopmental sort of outcomes. So curious, know, out of the 150 plus 20 patients that you’re enrolling in Phase III, are you sort of capping the number of older patients or enrolling a certain, you know, a minimum number of younger patients in the study?

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: So Pete, maybe I’ll take the kind of the front end of your second question, which is what we’re seeing here in the data is definitely a rush to treat patients as young as possible. If you treat a two year old, for example, you may have the possibility of changing the course of their lives. Treating a 15 year old that may have more advanced disease, whether you can recover them, may be challenging. I mentioned in my prepared remarks that I have a familiarity in terms of feeling for zurivanersen for my prior role in cystic fibrosis. And we always try to get the medicine to the children at the earliest age as possible because if you can correct the fundamental causal biology of Dravet, then you may put these kids on a more normal path of developments and prevent the seizures.

And so it is a goal of the program, but as far as saying, do patients respond differently at different ages? The fundamental mechanism of action, we should have responses. They may have different responses at different ages, but the way that clinical trial has been designed is in the tight group of two through 18. There is a slight loading of patients seven through ten, I believe it is. But it should be beneficial for the patients in age group two through 18.

Pete Stavropoulos, Analyst, Cantor Fitzgerald: Thank you for taking our questions and congrats again.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Thanks.

Conference Call Operator: Our next question comes from the line of Rudi Lee from Chardan. Please go ahead.

Rudi Lee, Analyst, Chardan: Thanks for taking my question and congrats on the Phase III progress. I have a question regarding the OLE data. So, can you talk about the higher incidence of CSF protein elevations in the OLE part? Any specific concern, especially for the forty five percent patients classified as treatment emergent AEs? Just curious what can be attributed to the higher levels in the OLE study?

Thanks.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Hi, Rudy. Thanks. Good to hear from you. Thanks for the question. As far as the CSF protein levels go, first of all, as a reminder, that is a laboratory finding.

And it occurs as a standard measure every time a child has or one of the patients has a CSF lumbar puncture done. We do that as a routine test. Most importantly, we’ve looked specifically for any effects, clinical effects of the elevated CSF protein, and we have not seen any in the in the eighty one patients that we’ve dosed so far. The elevated CSF proteins, those are a class effect. So they’re known to occur in other intrathecally administered oligonucleotides, approved ones as well.

And so the reason that we see it now later with additional dosing, it may be more of a procedure related effect. And again, the point is that we now have long term data with patients dosed for some of them for over four years. And the safety profile continues to support moving into phase three. And again, we have from the CSF protein perspective not seen any reason that that should prevent us from moving into the study.

Rudi Lee, Analyst, Chardan: Got it. Very helpful. Thanks.

Conference Call Operator: Our next question comes from the line of Jeannie Kim for Tom Schroeder from BTIG. Please go ahead.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics0: Good afternoon. Thank you for taking my question. I want to ask a little bit more about the decision to explore STK-two in autosomal dominant optic atrophy. What prompted this decision to pursue this now in this condition? And any comments on the most key data outcomes from your nonhuman primate study that contributed to the rationale would be super helpful.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Ginny, I’ll take the front end of that question and then maybe Barry can tell you about the data we collected. But over the last six months, when asked by investors and analysts, I’ve talked about a process that the company went through. And that was a process where you effectively do an evaluation of the opportunity in ADOA. What that means is understanding patients that you may treat and provide benefit to, it’s how you may run the clinical studies and what your preclinical safety efficacy package is. It’s the complete assessment of the disease area And following assessment and frankly the data that we received relating to the nonhuman primates, that gave us the confidence and frankly excitement to go into study ADOA with STK-two.

I will just point out that in these genetic diseases where you have a slowly progressing disease and with ADOA you have a slowly progressing loss of eyesight, you really want to have significant efficacy to be able to run the clinical trial, because you’re trying to separate from natural history. And so when we saw the non human primate data where we potentially improved vision, it gave us the confidence to move into clinical development knowing that we can study these patients with STK002. And maybe Barry, if you want to specifically talk to that nonhuman primate data, which really was the trigger.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: Jeannie, thanks again for the question. And we are very excited about these data. We’re very excited about the opportunity to treat this disease. I’ll tell you both my father’s an ophthalmologist, my brother’s an ophthalmologist. And when I told him that we were treating patients or trying to find a treatment for patients with ADOH, he said to me, well, that’s great because I have several families I follow and we cannot do anything for them.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics1: And since I mentioned it to him,

Barry Tico, Chief Medical Officer, Stokes Therapeutics: he keeps every few weeks he calls me and says, I found another patient. So this is a large group of patients that are undiagnosed and have no treatment options at all. It’s a very exciting time for us here at the company. And what made us even more exciting were the data from this monkey model. This monkey model was a spontaneously occurring, naturally occurring monkey that had a family monkey that had the same mutation in the OPA1 gene that we find in some patients with ADOA.

And they had a very similar profile in terms of some of the testing that we did in our natural history study of patients with ADOA. We found those very similar ones in monkeys with ADOA. So when we looked at a few specific tests, one of them being something called the flavor protein fluorescence, which measures mitochondrial function. We found that just as we found in people with ADOA, we found in the monkeys that they had high levels of this FPF because their mitochondria were not functioning well. And when we injected two into the monkeys, we saw that the FPF levels either stabilized or actually improved within a short time, within less than half a year.

That gave us a lot of encouragement that we might be able to see this as a biomarker in a clinical trial. And then we also looked using something called the electroretinogram at the functioning of the nerve because this is an optic nerve disease. And when we looked at the patients, we see we know that those patients have abnormal ERGs. And now when we looked in the monkeys after they were dosed with two, we saw that the ERG pattern improved. The nerve function was improving.

So these are the best measures that we could have in an animal model since we can’t actually measure vision. But it gives us a high degree of confidence that when we start treatment in people that we may be able to see actual visual improvement after treatment with two.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics0: Sounds great. Thank you so much.

Conference Call Operator: Our next question comes from the line of Jessica Fye from JPMorgan. Please go ahead.

Jessica Fye, Analyst, JPMorgan: Hey, guys. Good afternoon. Thanks for taking our question. I was curious, with one hundred and thirty patients identified in prescreening in the 170 target enrollment for your Phase III trial in Dravet, can you talk about how you’re going to be communicating enrollment updates? Should we expect sort of quarterly progress updates?

And how do you think about the possibility of delivering Phase III data prior to the ’7, given how many patients are in pre screening? Thank you.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Thanks Jess. I’ll take your question. If you don’t mind, I’ll broaden it in terms of really, you’re asking about timelines and disclosures. So we are very excited the demand from the patients’ families to push their children into the trial and the speed that they want to go through screening. But the rate limiting feature is actually opening of the clinical trial sites.

And so we’re going through that process and we’re making good progress. As of now, it’s still early in the trial, everything’s pointing positively. But at the point that we do see a change in what we’ve communicated as being recruitment will complete in the 2026. When we see a change from that, we will actually communicate that at the time in an appropriate forum. That same goes for the data.

Obviously, it’s a one year trial. So if we’ve got a one year recruitment period, that means it’s one year from ending of recruitment. So we’re still maintaining the delivery of the top line data in the 2027. The other thing I want to refer to is in terms of disclosure is, as you’re seeing the company is taking the opportunity, whether it’s a medical conference, it’s a quarterly conference call here, and we’re providing data to you to understand the medicine. We think it’s our responsibility to help our investors and the analyst community understand the medicine that the company has created.

And so we’re taking the opportunity to provide data as we move along, including the thirty six month OLE data today, which is striking. And we have medical conferences coming up. We’ve got a medical conference coming in Labor Day weekend and we have one later in the year that we will be present at and we’ll be providing further data. And so, please expect us to continue to communicate, the benefits and safety around this drug as we progress. And as far as timelines are concerned, if they do move, we will communicate at that time.

Conference Call Operator: Your next question comes from the line of Yaron Werber from TD Securities. Please go ahead.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics2: Great. Thanks for taking my question. I got two. Maybe the first one, Barry, for the phase three for EMPOR, the 20 patients in Europe specifically, I imagine you can lump them right into the overall study and treat them sort of indistinctly. And do you need to enroll one to one in the EU, just given their requirements for the way the sham injection is going be?

Is it going to be one to one drug versus placebo? And then for the, the ADA, so it’s a single injection up to forty eight weeks. So clearly, you’re expecting from your nonhuman primates very stable sort of protein expression. Do you think it’s going to last longer than forty eight weeks overall long term? And how many patients would you enroll in that Phase I?

Thank you.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: You’re on, I’ll take the first question in terms of the regulatory authorities and ask Barry to respond to you on ADUA and it’s good to hear from you again. Maybe if I give you the kind of the broader picture, this was a study that was agreed and aligned with the major regulatory authorities globally. And what I mean by that is The U. S, Europe, Japan and UK. And it’s a long arduous process that includes getting clinical trial designs approved in individual countries as well.

Later on in the process, we actually had feedback from certain European countries that required needle prick sham control, to be part of the study as opposed to a lumbar puncture sham control. And so what we simply did is we added 20 patients in a separate cohort in those four European countries. And we just increased the number for lumbar puncture and maintained one hundred and fifty patients. What we’re doing overall is kind of maintaining the integrity of the study in the event that there is a separate analysis that is required, but we want to maintain that powering of one hundred and fifty with lumbar puncture and patients being blinded through a lumbar puncture sham control. And so, simply put, we added 20 patients, at least 20 patients in Europe.

It doesn’t change our timeline and it doesn’t change our regulatory filings nor the pairing of the study.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: And I’ll just add, so your question about one to one. So yeah, it is one to one balance. So one to one for sham and for active. And that applies to the number of patients in Europe as well. Sorry, there was one other question about the two.

And as you know, Yaron, these oligonucleotides do have long half lives. And we have already some data from our animal model showing that the oligonucleotides can have a half life of nine months or longer. So a single injection could have an effect over that full twelve months of the clinical trial. And so that’s why we’re going to be following these patients and observing them that entire period of time.

Conference Call Operator: Our next question comes from the line of Joseph Stringer from Needham. Please go ahead.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics3: Good afternoon. This is Eddie on for Joey. Thanks for taking our questions and congrats on starting the enrollment in EPIR. Just a couple from us. When do you anticipate beginning some of the North America commercial build out?

And what do you expect the sales force composition and cost to be at peak? And then elaborating a little bit more on the ADA01 Phase I program, is there any requirement for OPA1 genetic screening? And what might be the cadence of some of this data after a forty eight week duration for the primary endpoint, but when might see some interim data or final data and then progression into Phase II? Thank you.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics1: Yeah, thanks for the question, Eddie. This is Jason. On the commercial front, right now, we’re a relatively small team. We have expertise in marketing, market access and new product planning. We intend to slowly build the team over time as we start engaging in efforts like a disease awareness campaign later this year, starting to educate the market and better understand the market through insight generation.

At peak, we anticipate somewhere in the neighborhood of about 20 salespeople with additional kind of cross functional support functions in the field to support reimbursement, patient education and site activation for the intrathecal administration on the commercial front. So relatively modest overall field based infrastructure for this rare disease.

Andrew Tsai, Analyst, Jefferies: Just

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: add to Jason’s comment. In terms of being involved with medicines, disease modifying genetic medicines like ZorivaNursen and other CF medicines, you don’t sell a medicine. You actually help with access and reimbursement for patients and families. The medicine by the time it’s approved is usually very well understood and known because as you conduct your trial, you’re actually utilizing most of the treatment centers globally for major geographies. And so the commercial build is focused on access and reimbursement and understanding the market.

And it’s why I made a comment in my own remarks that medical affairs is fundamentally important for the stage of the company right now, where

Barry Tico, Chief Medical Officer, Stokes Therapeutics: we

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: educate both families and advocacy groups and also the physicians as terms of the medicine. And so it’s more of a science education than it is a commercial cell. So I just want to reiterate that and that’s why Jason refers to the kind of the low build. As far as the ADOA study is concerned, it’s a phase one study which is dose escalating and it goes through multiple doses. And so I always view those studies as no news is good news because primary endpoint is actually safety as you escalate the dose.

But at the point that we may see data that causes us to act beyond just the study we’re running, then we’ll inform you That could be over the next year. It could be over a longer period. It all depends on what dose we get to that we start having safety maintaining safety and start having efficacious outcomes. And so we’ll let you know when we see that.

Barry Tico, Chief Medical Officer, Stokes Therapeutics: And I’ll just add on your question about the genetic testing. So OPA1 gene is included in many panels for inherited retinal disease and other vision issues. So it does not require a separate test. The issue is that many of these patients either never get tested, or even if they do get tested, there’s nothing available, so they get lost to follow-up. So we’re hoping to do an extensive education campaign.

Jason’s gonna be part of that. And also encourage genetic testing for children who have vision problems when they’re young.

Conference Call Operator: I will now turn the call back over to Ian Smith for closing remarks.

Ian Smith, Interim Chief Executive Officer, Stokes Therapeutics: Yes. Thank you. Thank you for all that participated in the call today. Thank you for the questions and thank you for those people that were on the line and listening. We’re very happy to provide this update to you all.

And we will be available in our offices post call to answer any further follow-up questions. Thank you for attending the call today.

Conference Call Operator: Ladies and gentlemen, that concludes today’s call. Thank you all for joining. You may now

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