Q2 2025 Stoke Therapeutics Inc Earnings Call

Speaker #2: Good afternoon, and welcome to Stoke Therapeutics' second quarter 2025 conference call. I'm Tommy Leggett, Chief Financial Officer at Stoke. Joining me for prepared remarks are Ian Smith, our Interim Chief Executive Officer; Dr. Barry Tico, Chief Medical Officer; and Dr. Kimberly Parkerson, Head of Neurology Clinical Development.

Thomas Leggett: Good afternoon, welcome to Stoke Therapeutics' Q2 2025 Conference Call. I'm Thomas Leggett, Chief Financial Officer at Stoke. Joining me for prepared remarks are Ian F. Smith, our Interim Chief Executive Officer; Dr. Barry Ticho, Chief Medical Officer; and Dr. Kimberly Parkerson, Head of Neurology Clinical Development. In addition, Jason Hoyt, our Chief Patient Officer, will participate in Q&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, 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.

Barry Ticho: Good afternoon and welcome to Stoke Therapeutics' second quarter 2025 conference call. I'm Tommy Leggett, Chief Financial Officer at Stoke. Joining me for prepared remarks are Ian Smith, our Interim Chief Executive Officer; Dr. Barry Tico, Chief Medical Officer; and Dr. Kimberly Parkerson, Head of Neurology Clinical Development. In addition, Jason Hoyt, our Chief Patient Officer, will participate in Q&A. As a reminder, today's webcast slides are available in the Investor 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.

Speaker #2: In addition, Jason Hoyt, our Chief Patient Officer, will participate in a Q&A. As a reminder, today's webcast slides are available in the Investors section of our website.

Speaker #2: 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.

Speaker #2: Please refer to the filings of the SEC for additional information. With that, I'll turn the call over to Ian.

Speaker #3: Welcome, everyone, and thank you for joining us today. I've been working with Stoke Therapeutics for two years as a Director and Advisor, and more recently as the CEO.

Ian F. Smith: Welcome, everyone, and thank you for joining us today. I've been working with Stoke Therapeutics for 2 years as a Director and Advisor, more recently as the CEO. There's 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 zorevunersen, as we work to deliver a disease-modifying medicine to patients. What we're seeing with zorevunersen 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.

Dr. Kimberly Parkerson: Welcome, everyone, and thank you for joining us today. I've been working with Stoke 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 Zoriba Nursin, as we work to deliver a disease-modifying medicine to patients. What we're seeing with Zoriba Nursin 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, a game 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.

Speaker #3: 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.

Speaker #3: The key priority is obviously Drug A syndrome and Zorebinursin, as we work to deliver a disease-modifying medicine to patients. What we're seeing with Zorebinursin may be new to the field of epilepsy, but I'm struck by 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 Drug A syndrome.

Speaker #3: Let me start by saying that Stoke is in a strong growth position, defined by a late-stage registrational medicine, a wealth-capitalized balance sheet, an expanding pipeline of potential medicines, and a very strong partner in Biogen with expansive capabilities to support Zorebinursin outside of North America.

Ian F. Smith: Let me start by saying that Stoke 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 zorevunersen outside of North America. Our Phase III EMPEROR study in patients with Dravet syndrome is off to a strong start, with sites initiated in the US, UK, Japan, and Europe expected to initiate in early 2026. 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 zorevunersen from our Phase I, II, and OLE studies.

Dr. Kimberly Parkerson: Let me start by saying that Stoke is in a strong growth position, defined by a late-stage registration medicine, well-capitalized balance sheet, expanding pipeline of potential medicines, and a very strong partner in Biogen with expansive capabilities to support Zoriba Nursin outside of North America. Our Phase III EMPEROR study in patients with Dravet Syndrome is off to a strong start, with sites initiated in the US, UK, and Japan, and Europe expected to initiate in early 2026. 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 Zoriba Nursin from our Phase I, II, and OLE studies.

Speaker #3: Our Phase III Emperor study in patients with drug A syndrome is off to a strong start. This site initiated in the US, UK, and Japan and Europe expected to initiate in early 2026.

Speaker #3: 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.

Speaker #3: We continue to generate data that support our understanding of Zorebinursin from our Phase I-II 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 drug A syndrome.

Ian F. Smith: 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 the seizure 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. Today, we are sharing with you top-line results from the third year of our open-label extension studies.

Dr. Kimberly Parkerson: 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 the seizure 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.

Speaker #3: We continue to educate around the seizure 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.

Speaker #3: 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 Zorebinursin to modify the course of drug A 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.

Ian F. Smith: These data support the long-term potential of zorevunersen 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 Dravet, we see significant potential to develop disease-modifying medicines for additional genetic diseases. We've advanced STK-002 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.

Dr. Kimberly Parkerson: These data support the long-term potential of Zoriba Nursin 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 Dravet, we see significant potential to develop disease-modifying medicines for additional genetic diseases. We've advanced STK-002 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.

Speaker #3: Importantly, these long-term follow-up data continue to demonstrate a favorable safety profile. Beyond drug A, we see significant potential to develop disease-modifying medicines for additional genetic diseases.

Speaker #3: We have advanced STKOO2 into Phase I clinical development for autosomal dominant optic atrophy. Like Drug A, ADOA is a haploinsufficient disease, and we are uniquely positioned to treat it by restoring naturally occurring OPA1 protein expression using our antisense oligonucleotide approach, with the goal of preventing further loss of eyesight and possibly improving vision.

Speaker #3: Now to our collaboration with Biogen. Band in February, this brings global expertise, commercializing high-value disease-modifying medicines for rare genetic diseases and strengthens our balance sheet.

Speaker #3: The terms of the collaboration retain significant value to Stoke while enhancing our ability to deliver Zorebinursin to patients globally. We have a strong balance sheet and are well-funded through Phase III readout, which is anticipated in the second half of 2027.

Dr. Kimberly Parkerson: The terms of the collaboration retain significant value to Stoke while enhancing our ability to deliver Zoriba Nursin to patients globally. We have a strong balance sheet and are well-funded through Phase III readout, which is anticipated in the second half of 2027. Our balance sheet and projected investment support a cash runway through to mid-2028. We continue to build Stoke's 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.

Ian F. Smith: The terms of the collaboration retain significant value to Stoke while enhancing our ability to deliver zorevunersen to patients globally. We have a strong balance sheet and are well-funded through Phase III readout, which is anticipated in H2 2027, and our balance sheet and projected investment support a cash runway through to mid-2028. We continue to build Stoke's 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.

Speaker #3: Our balance sheet and projected investment support a cash runway through to mid-2028. We continue to build Stoke's 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.

Speaker #3: 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.

Speaker #4: Thank you, Ian. This is a very exciting time here at Stoke. As we take Zorebinursin into this next phase of clinical development, and potential registration and approval, drug A syndrome is a severe lifelong developmental and epileptic encephalopathy that becomes symptomatic around one year of age.

Barry Ticho: Thank you, Ian. This is a very exciting time here at Stoke as we take zorevunersen into this next phase of clinical development and potential registration and approval. Dravet syndrome is a severe, lifelong developmental and epileptic encephalopathy that becomes symptomatic around 1 year of age. For the vast majority of patients, the cause is insufficient levels of the NaV1.1 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, they just aren't enough. Most patients continue to suffer from seizures, 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.

Barry Ticho: Thank you, Ian. This is a very exciting time here at Stoke. As we take Zoriba Nursin into this next phase of clinical development and potential registration and approval, Dravet Syndrome is a severe, lifelong developmental and epileptic encephalopathy that becomes symptomatic around one year of age. For the vast majority of patients, the cause is insufficient levels of the NAD-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.

Speaker #4: For the vast majority of patients, the cause is insufficient levels of the NAD 1.1 protein in the brain. There are many medicines available to treat the seizures associated with drug A syndrome.

Speaker #4: 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.

Speaker #4: Furthermore, side effects of the anti-seizure regimen also present their own challenges for patients and their caregivers. While Drug A syndrome may be best known for its seizure burden, the effects go far beyond seizures.

Speaker #4: Nearly all patients suffer from one or more behavioral and cognitive effects. The anti-seizure medicines were not intended to address these effects. We intend to change that.

Barry Ticho: The anti-seizure medicines were not intended to address these effects. We intend to change that. Zoriba Nursin is an antisense oligonucleotide designed to restore naturally occurring NAD-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 dataset 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 I, II study among patients treated with initial doses of 70 milligrams of Zoriba Nursin on top of standard anti-seizure medicines. The most substantial reductions were observed among patients who received either two or three doses of 70 milligrams.

Barry Ticho: The anti-seizure medicines were not intended to address these effects. We intend to change that. zorevunersen is an antisense oligonucleotide designed to restore naturally occurring NaV1.1 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 8, you see the dramatic reductions in seizures demonstrated in our Phase I, II studies among patients treated with initial doses of 70mg of zorevunersen on top of standard anti-seizure medicines. The most substantial reductions were observed among patients who received either two or three doses of 70mg.

Speaker #4: Zorebinursin is an antisense oligonucleotide designed to restore naturally occurring NAD 1.1 protein levels. As such, it has the potential to be the first disease-modifying therapy for drug A syndrome.

Speaker #4: As we designed our Phase III study, we were fortunate to have a large dataset available to inform key decisions related to dose level, dose frequency, study endpoint assessments, and powering.

Speaker #4: Here on slide 8, you see the dramatic reductions in seizures demonstrated in our Phase I-II study among patients treated with initial doses of 70 milligrams of Zorebinursin on top of standard anti-seizure medicines.

Speaker #4: The most substantial reductions were observed among patients who received either two or three doses of 70 milligrams, based on these data and additional modeling analysis, we selected a two-dose loading regimen for Phase III.

Barry Ticho: Based on these data and additional modeling analysis, we selected a two-dose loading regimen, Phase III, with seizures as our primary endpoint for the trial. After receiving their last Phase I, II 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 effect.

Barry Ticho: Based on these data and additional modeling analysis, we selected a 2-dose loading regimen, phase III, with seizures as our primary endpoint for the trial. After receiving their last phase I, II dose, patients were followed for at least 6 months before restarting treatment in the open-label extension study. When designing our phase III program, we used the initial 8 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.

Speaker #4: The seizures, as our primary endpoint for the trial, after receiving their last Phase I-II dose, patients were followed for at least six months before restarting treatment in the open-label extension study.

Speaker #4: 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.

Speaker #4: 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 later; these data later in the call.

Speaker #4: 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 III design.

Barry Ticho: On slide 10, you see one of the key analyses that informed our thinking on the Phase III 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 effect on cognition and behavior using data from patients treated with dose levels that were similar to and consistent with our Phase III 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 Zoriba Nursin showed cognition and behavioral benefits in the five key subdomains that comprise our key secondary endpoints in Epic. On this slide, you can see the Phase III design. Patients who enroll in EMPEROR will be randomized one-to-one to Zoriba Nursin or to SHAM.

Barry Ticho: On slide 10, you see one of the key analyses that informed our thinking on the phase III 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 III dose regimen. Little to no change was detected in the natural history that patients treated with zorevunersen showed cognition and behavioral benefits in the five key subdomains that comprise our key secondary endpoints in EMPEROR. On this slide, you can see the phase III design. Patients who enroll in EMPEROR would be randomized 1-to-1 to zorevunersen or to sham.

Speaker #4: 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 III dose regimen.

Speaker #4: 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, yet patients treated with Zorebinursin showed cognition and behavioral benefits in the five key subdomains that comprise our key secondary endpoints in epilepsy.

Speaker #4: On this slide, you can see the Phase III design. Patients who enroll in Emperor would be randomized one-to-one to Zorebinursin or to SHAM. In both study arms, patients will continue to receive standard of care anti-seizure medicine.

Barry Ticho: 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 Zoriba Nursin arm will receive two loading doses of 70 milligrams, followed by two maintenance doses of 45 milligrams. An open-label extension treatment period will allow all patients the opportunity to receive treatments with Zoriba Nursin following 52 weeks of treatment in this study. I will now review the EMPEROR study design and conduct in more detail on slide 12. Primary endpoint is changed from baseline in major motor seizure frequency at week 28. Durability of effect on seizures will be measured as a secondary endpoint at week 52. Zoriba Nursin is a potential first-in-class disease-modifying medicine, so EMPEROR will also measure effect on behavior and cognition.

Barry Ticho: 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 zorevunersen arm will receive 2 loading doses of 70 milligrams followed by 2 maintenance doses of 45 milligrams. An open-label extension treatment period will allow all patients the opportunity to receive treatment with zorevunersen following 52 weeks of treatment in this study. I will now review the EMPEROR study design and conduct in more detail on slide 12. Primary endpoint is change from baseline in major motor seizure frequency at week 28. Durability of effect on seizures will be measured as a secondary endpoint at week 52. zorevunersen is a potential first-in-class disease-modifying medicine, so EMPEROR 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 assessments.

Speaker #4: Consistent with the data I just reviewed, patients in the Zorebinursin arm will receive two loading doses of 70 milligrams, followed by two maintenance doses of 45 milligrams.

Speaker #4: In the open-label extension treatment period, all patients will have the opportunity to receive treatment with Zorebinursin following 52 weeks of treatment in this study. I will now review the Emperor study design.

Speaker #4: At conduct, in a more detail on slide 12. Primary endpoint is change from baseline in major motor seizure frequency at week 28. Durability of effect on seizures will be measured as a secondary endpoint at week 52.

Speaker #4: Zorebinursin is a potential first-in-class disease-modifying medicine. Though Emperor 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.

Barry Ticho: Powering for these secondary endpoints is robust and designed with the intent to show statistical significance on both individual subdomain and composite assessment. 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 and 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 arms of pursuit. 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 prep.

Speaker #4: 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.

Barry Ticho: 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 and 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 zorevunersen or Sham with lumbar puncture in the US, UK, and Japan.

Speaker #4: 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.

Speaker #4: 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.

Speaker #4: 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 Zorebinursin or SHAM with lumbar puncture in the US, UK, and Japan.

Barry Ticho: 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 Zoriba Nursin or SHAM with lumbar puncture in the US, UK, and Japan. We expect to activate at least half of the 70 study sites by year-end and European sites to initiate by early 2026. We see significant and growing global interest in EMPEROR, which supports our expectation to complete enrollment in the second half of 2026 with a Phase III data readout in the second half of 2027. EMPEROR is off to a great start. We have had a high degree of confidence in the study design based on a large dataset and the ongoing patient need.

Speaker #4: We expect to activate at least half of the 70 study sites by year-end. And European sites to initiate by early 2026. We see significant and growing global interest in Emperor.

Barry Ticho: We expect to activate at least half of the 70 study sites by year-end and European sites to initiate by early 2026. We see significant and growing global interest in EMPEROR, which supports our expectation to complete enrollment in H2 2026 with a phase III data readout in H2 2027. EMPEROR is off to a great start. We have had a high degree of confidence in the study designed based on a large data set and the ongoing patient need. 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 zorevunersen in phase I, II, and the ongoing OLEs has helped us understand the initial and ongoing effects of zorevunersen and has demonstrated an encouraging long-term safety profile.

Speaker #4: Which supports our expectation to complete enrollment in the second half of 2026. For the Phase III data readout, in the second half of 2027.

Speaker #4: Emperor is off to a great start. We have had a high degree of confidence in the study design based on a large dataset and the ongoing patient need.

Speaker #4: Our natural history study has proven invaluable in understanding the effects that drug A syndrome has on patients over time. As well as the limitations of the current standard of care medicine.

Barry Ticho: Our natural history study has proven invaluable in understanding the effect that Dravet Syndrome has on patients over time, as well as the limitations of its current standard-of-care medicine. Our experience with Zoriba Nursin in Phase I, II and the ongoing OLEs has helped us understand the initial and ongoing effects of Zoriba Nursin and has demonstrated an encouraging long-term safety profile. Our assessments of behavior and cognition have been validated, and our endpoints and powering are informed by our years of experience and data. As announced yesterday, the first patient was dosed in EMPEROR. Study investigators have identified approximately 130 potential participants, and that number continues to increase. More than 10 clinical sites have initiated across the US, UK, 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.

Speaker #4: Our experience with Zorebinursin in Phase I-II and the ongoing OLEs has helped us understand the initial and ongoing effects of Zorebinursin and has demonstrated an encouraging long-term safety profile.

Speaker #4: Our assessments of behavior and cognition have been validated, and our endpoints and powering are informed by our years of experience and data. As announced yesterday, the first patient was dosed in Emperor.

Barry Ticho: Our assessments of behavior and cognition have been validated, and our endpoints in powering are informed by our years of experience and data. As announced yesterday, the first patient was dosed in EMPEROR. Study investigators have identified approximately 130 potential participants. That number continues to increase. More than 10 clinical sites have initiated across the US, UK, and Japan, with more coming online weekly. This is exactly the kind of start we were hoping for. 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 extension data.

Speaker #4: 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.

Speaker #4: 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 extension data.

Barry Ticho: With that, I would like to turn the call over to Kim for a review of the new three-year open-label extension data.

Speaker #5: Thanks, Barry. Before I share the new data, I want to express my gratitude to the patients, caregivers, advocates, clinicians, and Stoke employees who have brought Zorebinursin to where it is today.

Kimberly Parkerson: Thanks, Barry. Before I share the new data, I want to express my gratitude to the patients, caregivers, advocates, clinicians, and Stoke employees who have brought zorevunersen 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 36-month data. More than 90%, or 75, eligible patients who completed treatment in the phase I, II studies continue treatment with zorevunersen in the open-label extension studies.

Tommy Leggett: Thanks, Barry. Before I share the new data, I want to express my gratitude to the patients, caregivers, advocates, clinicians, and Stoke employees who have brought Zoriba Nursin 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 36-month data. More than 90% or 75 eligible patients who completed treatment in the Phase I, II studies continue treatment with Zoriba Nursin in the open-label extension studies.

Speaker #5: Having treated patients with drug-resistant epilepsy 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.

Speaker #5: 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.

Speaker #5: With that, it's my honor to share the new 36-month data. More than 90% or 75% eligible patients who completed treatment in the Phase I-II studies continue treatment with Zorebinursin in the open-label extension studies.

Speaker #5: The high 77% retention to date in the OLEs has provided us with a robust dataset to assess the long-term effects of Zorebinursin in these patients.

Tommy Leggett: The high 77% retention to date in the OLEs has provided us with a robust dataset to assess the long-term effects of Zoriba Nursin in these patients. Here on slide 15, you see the three-year effects on seizures observed across patients treated with Zoriba Nursin in our OLE studies following treatment in the Phase I, II studies. I'd like to call your attention to the top blue line, which shows patients treated with less than 70 milligram loading doses in the Phase I, II studies before continuing treatment in the OLEs. As patients transition to more stable 45 milligram dosing, you begin to see on the right side of the graph a trend toward further reductions in seizures.

Kimberly Parkerson: The high 77% retention to date in the OLEs has provided us with a robust data set to assess the long-term effects of zorevunersen in these patients. Here on slide 15, you see the 3-year effects on seizures observed across patients treated with zorevunersen in our OLE studies following treatment in the phase I, II studies. I'd like to call your attention to the top blue line, which shows patients treated with less than 70 mg loading doses in the phase I, II studies before continuing treatment in the OLEs. As patients transition to more stable 45 mg dosing, you begin to see on the right side of the graph a trend toward further reductions in seizures.

Speaker #5: Here on slide 15, you see the three-year effects on seizures observed across patients treated with Zorebinursin in our OLE studies following treatment in the Phase I-II studies.

Speaker #5: I'd like to call your attention to the top blue line, which shows patients treated with less than 70 mg loading doses in the Phase I-II studies before continuing treatment in the OLEs.

Speaker #5: As patients transition to more stable 45 mg dosing, you begin to see on the right side of the graph a trend toward further reductions in seizures.

Speaker #5: Turning our attention to the orange line, you see the substantial and durable effects for the patients treated with loading doses of 70 milligrams followed by continued dosing of 30 milligrams or 45 milligrams every four months in the OLEs.

Kimberly Parkerson: Turning our attention to the orange line, you see the substantial and durable effects for the patients treated with loading doses of 70 milligrams, followed by continued dosing of 30 milligrams or 45 milligrams every 4 months in the OLEs. For these patients, we observed a median reduction of 59% to 91% in major motor seizure frequency across each time point through month 20. The durability of effect is consistent with what we would expect for a disease-modifying medicine and supports our EMPEROR Phase III registrational study. 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 impacts on patient health and well-being. For most, seizures remain the primary comorbidity.

Tommy Leggett: Turning our attention to the orange line, you see the substantial and durable effect for the patients treated with loading doses of 70 milligrams, followed by continued dosing of 30 milligrams or 45 milligrams every four months in the OLEs. For these patients, we observed a median reduction of 59% to 91% in major motor seizure frequency across each time point through month 20. The durability of effect is consistent with what we would expect for a disease-modifying medicine and supports our EMPEROR Phase III registration 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 impacts on patient health and well-being. For most, seizures remain the primary comorbidity.

Speaker #5: For these patients, we observed a median reduction of 59% to 91% in major motor seizure frequency across each time point through month 20. The durability of effect is consistent with what we would expect for a disease-modifying medicine and supports our Emperor Phase III registrational study.

Speaker #5: But we know Drug A syndrome is more than just a seizure disorder. Drug A syndrome is a complex disease that presents daily and life-altering challenges for patients, their families, and their caregivers.

Speaker #5: On the left, you see the impact on patient health and well-being. For most, seizures remain the primary comorbidity. However, drug A impacts all aspects of life for patients and their families, some of which are shown on the right.

Kimberly Parkerson: 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 experience minimal improvements in cognition and behavior. Overall, patient development begins to plateau within the first several years of their life. Over time, they fall further and further behind their neurotypical peers in their ability to achieve developmental milestones. The Vineland-III 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.

Tommy Leggett: 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 experience minimal improvement 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 in their ability to achieve developmental milestones. The Vineland 3 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.

Speaker #5: 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 Drug A syndrome, shown with the bottom line.

Speaker #5: Consistent with findings from natural history data, including results from our two-year butterfly study, patients with drug A syndrome experience minimal improvements in cognition and behavior.

Speaker #5: 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.

Speaker #5: The violent reassessment is helping us measure changes in cognition and behavior in patients with drug A syndrome. I'll now review what the assessment is and how it works.

Speaker #5: As summarized on slide 18, violent 3 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.

Tommy Leggett: As summarized on slide 18, Vineland 3 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 Vineland 3: communication, motor skills, socialization, and daily living. These domains are broken down into a series of subdomains, which are evaluated on a point system scale. We use the Vineland 3 across multiple of our clinical studies, and it is now being used to evaluate key secondary endpoints in our Phase III EMPEROR study. Our natural history study also helped in the selection of Vineland 3 as an assessment for our clinical studies. So now today, we are showing data on slide 19, which are quite remarkable and striking.

Kimberly Parkerson: As summarized on slide 18, Vineland-III 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 Vineland-III: communication, motor skills, socialization, and daily living. These domains are broken down into a series of subdomains, which are evaluated on a point system scale. We use the Vineland-III across multiple of our clinical studies, and it is now being used to evaluate key secondary endpoints in our Phase III EMPEROR study. Our natural history study also helped in the selection of Vineland-III as an assessment for our clinical studies. Now today, we are showing data on slide 19, which are quite remarkable and striking.

Speaker #5: There are four domains evaluated with violent 3: communication, motor skills, socialization, and daily living. These domains are broken down into a series of subdomains which are evaluated on a point system scale.

Speaker #5: We use the violent 3 across multiple of our clinical studies and it is now being used to evaluate key secondary endpoints in our Phase III Emperor study.

Speaker #5: Our natural history study also helps in the selection of violent 3 as an assessment for our clinical studies. So now, today, we are showing data on slide 19, which are quite remarkable and striking.

Speaker #5: What you see here is the progression of violent 3 results for patients treated in the OLE studies with Zorebinursin over one, two, and three years following treatment in the Phase I-II studies.

Kimberly Parkerson: What you see here is the progression of Vineland-III results for patients treated in the OLE studies with zorevunersen over 1, 2, and 3 years following treatment in the phase I/II studies. For this analysis, patients were measured against their own baseline scores at entry into the OLE and demonstrated improvements through year 1 of the OLEs and continuing improvements in year 2 and year 3. The improvements you see here are in addition to any improvements the patients may have experienced during the 9-month phase I/II treatment period. Notably, some patients received doses as low as 10 milligrams upon entering the OLEs. As a reminder, small changes on the Vineland-III are considered meaningful to clinicians and caregivers of patients with Dravet syndrome.

Tommy Leggett: What you see here is the progression of Vineland 3 results for patients treated in the OLE studies with Zoriba Nursin over one, two, and three years following treatment in the Phase I, II 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 I, II treatment period. Notably, some patients received doses as low as 10 milligrams upon entering the OLEs. As a reminder, small changes on the Vineland 3 are considered meaningful to clinicians and caregivers of patients with Dravet Syndrome.

Speaker #5: 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, with continuing improvements in year two and year three.

Speaker #5: The improvements you see here are in addition to any improvements the patients may have experienced during the nine-month Phase I-II treatment period. Notably, some patients received doses as low as 10 milligrams upon entering the OLEs.

Speaker #5: As a reminder, small changes on the violent 3 are considered meaningful to clinicians and caregivers of patients with drug A syndrome. To give you context, our published survey indicated ROS score improvements ranging from one to three points over a year across individual subdomains would be considered clinically meaningful to at least half of caregivers.

Kimberly Parkerson: To give you context, our published survey indicated raw score improvements ranging from 1 to 3 points over a year across individual subdomains would be considered clinically meaningful to at least half of caregivers. The 36-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, zorevunersen 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 Stoke to advance zorevunersen to patients. In addition to compelling efficacy data, we are highly encouraged by the safety profile observed across our studies to date.

Tommy Leggett: To give you context, our published survey indicated raw score improvements ranging from one to three points over a year across individual subdomains would be considered clinically meaningful to at least half of caregivers. The 36-month data show profound changes, addressing the underlying protein deficiency, appear to restore function and help patients achieve more of their developmental milestones. In effect, Zoriba Nursin 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 Stoke to advance Zoriba Nursin to patients. In addition to compelling efficacy data, we are highly encouraged by the safety profile observed across our studies to date.

Speaker #5: The 36-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, Zorebinursin appears to be narrowing the gap between the normal course of disease and neurotypical development that I showed you earlier.

Speaker #5: 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 Stoke.

Speaker #5: To advance Zorebinursin to patients. In addition to compelling efficacy data, we are highly encouraged by the safety profile observed across our studies to date.

Speaker #5: This safety summary represents over four years of clinical data, including the first year of treatment in the Phase I-II studies followed by over three years of treatment in the OLEs.

Tommy Leggett: This safety summary represents over four years of clinical data, including the first year of treatment in the Phase I, II studies, followed by over three years of treatment in the OLEs. Over this time period, Zoriba Nursin has been generally well tolerated. 81 patients received at least one dose of Zoriba Nursin. In the Phase I, IIa studies, 30% of patients experienced a 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 86% of patients have developed elevated CSF protein levels, of which 45% 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.

Kimberly Parkerson: This safety summary represents over 4 years of clinical data, including the first year of treatment in the phase I, II studies, followed by over 3 years of treatment in the OLEs. Over this time period, zorevunersen has been generally well-tolerated. 81 patients received at least 1 dose of zorevunersen. In the phase I, II-A studies, 30% of patients experienced a 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 86% of patients have developed elevated CSF protein levels, of which 45% 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 1 patient has discontinued treatment due to elevated CSF protein levels.

Speaker #5: Over this time period, Zorebinursin has been generally well tolerated. Eighty-one patients received at least one dose of Zorebinursin. In the Phase I-IIA studies, 30% of patients experienced a treatment-emergent adverse event related to the study drug.

Speaker #5: The most common were CSF protein elevations, which we continue to observe in the OLEs. Approximately 86% of patients have developed elevated CSF protein levels.

Speaker #5: Of which 45% 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.

Speaker #5: Only one patient has discontinued treatment due to elevated CSF protein levels. Treatment emergent serious adverse events have been reported in 29% of patients in the OLEs.

Kimberly Parkerson: Treatment-emergent serious adverse events have been reported in 29% of patients in the OLEs, and none have been attributed to study drug. Across all studies, only one patient experienced SUSARs. To date, more than 700 doses of zorevunersen have been administered across the studies. Patients have received up to 15 doses of zorevunersen, with 41 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.

Tommy Leggett: Treatment-emergent serious adverse events have been reported in 29% of patients in the OLEs, and none have been attributed to study drug. Across all studies, only one patient experienced QTAR. To date, more than 700 doses of Zoriba Nursin have been administered across the studies. Patients have received up to 15 doses of Zoriba Nursin, with 41 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.

Speaker #5: And none have been attributed to the study drug. Across all studies, only one patient experienced suicide. To date, more than 700 doses of Zorebinursin have been administered across the studies.

Speaker #5: Patients have received up to 15 doses of Zorebinursin, with 41 patients having received 10 or more doses. This is highly encouraging as we think about the Phase III design and ongoing treatment.

Speaker #5: I will now turn the call back over to Barry.

Speaker #4: Thank you, Kim. Stoke has long believed in the potential of its platform, and today, I'm pleased to share that we have initiated a Phase I study of STKOO2 for autosomal dominant optic atrophy for the most common inherited optic nerve disorder.

Barry Ticho: Thank you, Kim. Stoke has long believed in the potential of its platform, and today, I'm pleased to share that we have initiated a phase I study of STK-002 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 a mutation in the OPA1 gene, which leads to diminished protein function or haploinsufficiency 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, reduced 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.

Barry Ticho: Thank you, Kim. Stoke has long believed in the potential of its platform, and today, I'm pleased to share that we have initiated a Phase I study of STK-002 or 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 a mutation in the OPA1 gene, which leads to diminished protein function or haploinsufficiency 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 demand and gradually degenerate. The result is optic nerve atrophy and progressive vision loss.

Speaker #4: From a genetic and mechanistic perspective, ADOA shares a lot of similarity with drug A. The majority of cases of ADOA are caused by mutation in the OPA1 gene, which leads to diminished protein function due to haploinsufficiency related to OPA1 protein deficiency.

Speaker #4: 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 pairs mitochondrial function and results in decreased energy production.

Speaker #4: 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.

Speaker #4: Approximately 80% of patients are symptomatic by age 10, and about half of all patients are legally blind. About one out of every 30,000 people around the world are estimated to have ADOA, with a higher incidence of approximately one out of 10,000 in Denmark, due to a founder effect.

Barry Ticho: Approximately 80% of patients are symptomatic by age 10, and about half of all patients are legally blind. About one out of every 30,000 people around the world are estimated to have ADOA, with a higher incidence of approximately one out of 10,000 in Denmark due to a founder effect. We estimate that approximately 13,000 patients are currently living with ADOA across seven key geographies, including the US, EU5, and Denmark. As described on slide 23, we have generated compelling preclinical findings that support advancements of STK-002 into the clinic. We have observed increased OPA1 protein levels and improved mitochondrial function in ADOA patient fibroblasts treated with STK-002. Increases in OPA1 protein have been demonstrated with STK-002 in vitro and in vivo, including dose-related increases in OPA1 protein expression in non-human primate retinal ganglion cells following intravitreal injection. STK-002 has been found to be well tolerated across multiple species.

Barry Ticho: Approximately 80% of patients are symptomatic by age 10, and about half of all patients are legally blind. About one out of every 30,000 people around the world are estimated to have ADOA, with a higher incidence of approximately one out of 10,000 in Denmark due to a founder effect. We estimate that approximately 13,000 patients are currently living with ADOA across seven key geographies, including the US, EU5, and Denmark. As described on slide 23, we have generated compelling preclinical findings that support advancement of STK-002 into the clinic. We have observed increased OPA1 protein levels and improved mitochondrial function in ADOA patient fibroblasts treated with STK-002. Increases in OPA1 protein have been demonstrated with STK-002 in vitro and in vivo, including dose-related increases in OPA1 protein expression in non-human primate retinal ganglion cells following intravitreal injection. STK-002 has been found to be well-tolerated across multiple species.

Speaker #4: We estimate that approximately 13,000 patients are currently living with ADOA across seven key geographies, including the US, EU5, and Denmark. As described on slide 23, we have generated compelling preclinical findings that support advancements of STKOO2 into the clinic.

Speaker #4: We have observed increased OPA1 protein levels and improved mitochondrial function in ADOA patient fibroblasts treated with STKOO2. Increases in OPA1 protein have been demonstrated with STKOO2 in vitro and in vivo including dose-related increases in OPA1 protein expression in non-human primate retinal ganglion cells following intravitreal injection.

Speaker #4: STKOO2 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 STKOO2 conducted in a non-human primate model of ADOA that has a mutation in OPA1 gene resulting in insufficient protein in the mitochondria.

Barry Ticho: In addition, today, we are sharing new efficacy and safety data from a study of STK-002 conducted in a non-human 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-002. 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-002 in an NHP model of ADOA. Intravitreal injections of single doses of STK-002 were well tolerated in disease NHP eyes. These data suggest the potential for STK-002 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-002 in ADOA patients.

Barry Ticho: In addition, today, we are sharing new efficacy and safety data from a study of STK-002 conducted in a non-human 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-002. 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-002 in an NHP model of ADOA. Intravitreal injections of single doses of STK-002 were well-tolerated in diseased NHP eyes. These data suggest the potential for STK-002 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-002 in ADOA patients.

Speaker #4: These NHPs have disease characteristics similar to humans with ADOA. And therefore, represent a unique opportunity to evaluate STKOO2. The new data we are sharing today on slide 24 show improvement in mitochondrial and retinal function in pre and five-month after treatment with STKOO2 in an NHP model of ADOA.

Speaker #4: Intravitreal injections of single doses of STKOO2 were well tolerated in diseased NHPIs. These data suggest the potential for STKOO2 to stabilize or perhaps even improve vision.

Speaker #4: By restoring functional protein levels, based on these data, we have initiated a Phase I study of STKOO2 in ADOA patients. Phase III is an open-label, single ascending dose study designed primarily to evaluate safety.

Barry Ticho: OC3 is an open-label single ascending dose study designed primarily to evaluate safety, which will include assessment of clinical activity. The 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. I will now hand the call over to Tommy to discuss our financial summary.

Barry Ticho: OSPRE is an open-label single ascending dose study designed primarily to evaluate safety, but which will include assessments of clinical activity. The 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. I will now hand the call over to Tommy to discuss our financial summary.

Speaker #4: But which will include assessments of clinical activities. Study initiated in the UK last week and we expect sites in Europe to initiate later this year.

Speaker #4: 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.

Speaker #4: I will now hand the call over to Tommy to discuss our financial summary.

Speaker #6: Thank you, Barry. For those following along, I'll be speaking to Stoke's financial results as provided in the 10-Q and earnings release. Stoke is in a strong financial position as we enter Phase III and expand our platform into new disease areas, starting with ADOA.

Barry Ticho: Thank you, Barry. For those following along, I'll be speaking to Stoke's financial results as provided in the 10-Q and earnings release. Stoke is in a strong financial position as we enter phase III and expand our platform into new disease areas, starting with ADOA. We ended Q2 with $355 million in cash equivalents in marketable securities, which we continue to expect will fund operations beyond the phase III readout and into launch readiness to mid-2028. Total revenue for the quarter was $13.8 million, which is driven by revenue from our Acadia and Biogen collaborations of $10.6 million and $3.2 million, respectively. We expect revenue from Biogen to increase going forward as we continue to execute on EMPEROR and our other zorevunersen-related activities.

Jason Hoyt: Thank you, Barry. For those following along, I'll be speaking to Stoke's financial results as provided in the 10-Q and earnings release. Stoke is in a strong financial position as we enter Phase III and expand our platform into new disease areas, starting with ADOA. We ended the second quarter with 355 million in cash, cash equivalent to marketable securities, which we continue to expect will fund operations beyond the Phase III readout and into launch readiness to mid-2028. Total revenue for the quarter was 13.8 million, which is driven by revenue from our Arcadia and Biogen collaborations of 10.6 million and 3.2 million, respectively. We expect revenue from Biogen to increase going forward as we continue to execute on EMPEROR and our other Zoriba Nursin-related activities.

Speaker #6: We ended the second quarter with $355 million in cash, cash equivalents, and marketable securities, which we continue to expect will fund operations beyond the Phase III readout and into launch readiness to mid-2028.

Speaker #6: Total revenue for the quarter was $13.8 million, which is driven by revenue from our Acadia and Biogen collaborations of $10.6 million and $3.2 million, respectively.

Speaker #6: We expect revenue from Biogen to increase going forward as we continue to execute on Emperor and our other Zorebinursin-related activities. Our net loss for the quarter was $23.5 million, or 40 cents per share.

Barry Ticho: Our net loss for Q2 was $23.5 million or $0.40 per share, slightly improved from the prior year period despite a $6.9 million year-over-year increase in operating expenses. Operating expenses during Q2 were comprised of R&D expense of $25.9 million, which reflects continued investment in our Dravet program and key areas of our business, namely medical affairs, while also expanding our pipeline. G&A expenses of $15.3 million were largely driven by the continued expansion of our commercial team and capabilities. In summary, our strong balance sheet enables us to invest in zorevunersen, our pipeline, including ADOA, and capabilities while maintaining our cash runway to mid-2028. I'll now turn the call back over to Ian for closing remarks.

Jason Hoyt: Our net loss for the quarter was $23.5 million or 40 cents per share, slightly improved from the prior year period, despite a 6.9 million year-over-year increase in operating expenses. Operating expenses during the second quarter were comprised of R&D expense of 25.9 million, which reflects continued investment in our Dravet program and key areas of our business, namely medical affairs, while also expanding our pipeline. G&A expenses of 15.3 million were largely driven by the continued expansion of our commercial team and capabilities. In summary, our strong balance sheet enabled us to invest in Zoriba Nursin, our pipeline, including ADOA, and capabilities while maintaining our cash runway to mid-2028. I'll now turn the call back over to Ian for closing remarks.

Speaker #6: Slightly improved from the prior year period despite a $6.9 million year-over-year increase in operating expenses. Operating expenses during the second quarter were comprised of R&D expense of $25.9 million, which reflects continued investment in our drug A program, and key areas of our business, namely medical affairs, while also expanding our pipeline.

Speaker #6: GA expenses of $15.3 million were largely driven by the continued expansion of our commercial team and capabilities. In summary, our strong balance sheet enabled us to invest in Zorebinursin, our pipeline, including ADOA, and capabilities while maintaining our cash runway to mid-2028.

Speaker #6: I'll now turn the call back over to Ian for closing remarks.

Speaker #3: Thanks, Tommy. Our recent progress and overwhelmingly positive response to the start of Emperor underscore the unique potential of Zorebinursin. The era of disease-modification is upon us.

Ian F. Smith: Thanks, Tommy. Our recent progress and overwhelmingly positive response to the starts of EMPEROR underscore the unique potential of zorevunersen. The era of disease modification is upon us. There is a palpable feeling within Stoke 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 a 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. I will now open the call for questions.

Dr. Kimberly Parkerson: Thanks, Tommy. Our recent progress and overwhelmingly positive response to the start of EMPEROR underscore the unique potential of Zoriba Nursin. The era of disease modification is upon us. There is a palpable feeling within Stoke 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 a 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.

Speaker #3: There is a palpable feeling within Stoke 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.

Speaker #3: We have the unique opportunity to build a company around a 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.

Speaker #3: Thank you. I will now open the call for questions.

Speaker #7: At this time, I would like to remind everyone in order to ask a question, press star. The number one on your telephone keypad. Please limit your questions to one and one follow-up.

Operator 2: At this time, I would like to remind everyone, in order to ask a question, press star, the number one on your telephone keypad. Please limit your questions to one and one follow-up. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Laura Chico from Wedbush. Please go ahead.

Speaker 6: At this time, I would like to remind everyone in order to ask a question, press star with the number one on your telephone keypad. Please limit your questions to one and one follow-up. We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Laura Chico from Wedbush. Please go ahead.

Speaker #7: We will pause for just a moment to compile the Q&A roster. Your first question comes from the line of Laura Chico from Wedbush. Please go ahead.

Speaker #8: Good Good afternoon. Thanks for taking the question. I wanted to start with a regulatory question for Zorebinursin. And Ian, you know, first, you've got three-year OLE data now in hand along with natural history data.

Laura Chico: Good afternoon. Thanks for taking the question. I wanted to start with a regulatory question for zorevunersen. Ian, first, you've got 3-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 prescreening for a phase III study that's got a target enrollment of 170 patients. Third, you've got Breakthrough Therapy designation. 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 zorevunersen?

Speaker 7: Good afternoon. Thanks for taking the question. I wanted to start with a regulatory question for Zoriba Nursin. And Ian, you know, 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 prescreening for a Phase III 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, you know, 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 Zoriba Nursin?

Speaker #8: Second, if I'm understanding this correctly, you've got 130 patients already in pre-screening for a Phase III study that's got a target enrollment of 170 patients.

Speaker #8: And then third, you've got breakthrough therapy designation. So I guess my question is, you know, 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 Zorebinursin?

Speaker #3: Laura, thank you for the call. I want to, first of all, start by reminding everybody that Zorebinursin has breakthrough designated class. We applied for breakthrough designation last year in 2024 and were granted it towards the end of 2024.

Dr. Kimberly Parkerson: Laura, thank you for the call. I want to, first of all, start by reminding everybody that Zoriba Nursin has the 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 class or designation for Dravet Syndrome. What that means is the FDA reviewed our safety and efficacy data as of last year and saw the safety and 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.

Ian F. Smith: Laura, thank you for the call. I want to, first of all, start by reminding everybody that zorevunersen has a 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. The FDA has already seen a lot of data.

Speaker #3: We were granted breakthrough designation class or designation for drug A syndrome. What that means is the FDA reviewed our safety and efficacy data as of last year.

Speaker #3: 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.

Speaker #3: 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 36 months now.

Ian F. Smith: We chose to wait under the normal process of Breakthrough Therapy designation to collect further data, and the key piece of data being this extension of the OLE being into 36 months now with the hope that the seizures continue to be reduced and durably reduced as well as the cognition and behavioral benefits continue to extend. We were thrilled that that's how it played out. We will take all of this data to the 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. That will all be part of a discussion with the FDA in H2 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.

Dr. Kimberly Parkerson: 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 36 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. We were very, we were thrilled that that's how it played out. We will take all of this data to the 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.

Speaker #3: 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.

Speaker #3: We were very, we were thrilled that that's how it played out. We will take all of this data to the 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.

Speaker #3: 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.

Speaker #3: We have begun the Phase III study. Not changing timelines in terms of recruitments and getting the medicine to patients through a validated Phase III study.

Ian F. Smith: We have begun the Phase III study, not changing timelines in terms of recruitment and getting the medicine to patients through a validated Phase III study. If things change, we'll let you know at that time. Yes, we are very excited about this data. Under Breakthrough designation, we'll have all kinds of discussions with the FDA.

Dr. Kimberly Parkerson: We have begun the Phase III study, not changing timelines in terms of recruitments and getting the medicine to patients through a validated Phase III study. And if things change, we'll let you know at that time. But yes, we are very excited about this data, and under the breakthrough designation, we'll have all kinds of discussions with the FDA.

Speaker #3: And if things change, we'll let you know at that time. But yes, we are very excited about this data and under the breakthrough designation will have all kinds of discussions with the FDA.

Speaker #8: Oh, 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?

Speaker 7: Oh, 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 I guess maybe if you could walk through that, that'd be helpful. And I'll hop back in queue. Thank you.

Laura Chico: Thank you, Ian. Maybe one quick follow-up, if I could. In terms of what is the range of outcomes then, I guess, in terms of the H2 following the meeting? Would this be a potential earlier-than-expected filing? I guess maybe if you could walk through that'd be helpful. I'll hop back in queue. Thank you.

Speaker #8: Would this be a potential earlier than expected filing or, I guess, maybe if you could walk through that, that'd be helpful. And I'll hop back in queue.

Speaker #8: Thank you.

Speaker #3: Yeah, it's difficult to answer that question, Laura. Somebody actually asked me a very similar question just the other day. Internally. And you know, 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.

Ian F. Smith: Yeah, it's difficult to answer that question, Laura. Somebody actually asked me a very similar question just the other day internally. 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. You ask a number of different questions to the FDA. Sometimes you get support, and sometimes you get pushback, and sometimes you get amendments and changes, and you continue the process forward. It's very difficult for me to say what is the potential outcome of those discussions. It is all really a backwards and forwards with the FDA. If anything changes from our current timelines, we'll advise you at that time.

Dr. Kimberly Parkerson: Yeah, it's difficult to answer that question, Laura. Somebody actually asked me a very similar question just the other day internally. And you know, 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 get support, and sometimes you get pushback, and sometimes you get amendments and changes, and you continue the process forward. So it's very difficult for me to say what is the potential outcome of those discussions. It is all really a backwards and forwards with the FDA.

Speaker #3: We go down to the FDA and we share all data, as well as the magnitude of benefits and safety that we're having in these patients.

Speaker #3: And you ask a number of different questions to the FDA, and sometimes you get support, and sometimes you get pushback, and sometimes you get amendments and changes.

Speaker #3: And you continue the process forward. So it's very difficult for me to say what is the potential outcome of those discussions. It is all really a backwards and forwards with the FDA.

Speaker #3: And if anything changes from our current timelines, we'll advise you at that time.

Dr. Kimberly Parkerson: And if anything changes from our current timelines, we'll advise you at that time.

Speaker #8: Thanks very much.

Laura Chico: Thanks very much.

Speaker 7: Thanks very much.

Speaker #7: Our next question comes from the line of Mark Goodman from Leering. Please go ahead.

Speaker 6: Our next question comes from the line of Mark Goodman from Lering. Please go ahead.

Operator 2: Our next question comes from the line of Marc Goodman from Leerink Partners. Please go ahead.

Speaker #9: Yes, hey guys. Can you help us understand the magnitude of the cognition and behavior improvements in the Vinland III data? In this OLE data that you're showing, just talk about the clinically meaningfulness of the changes and any I don't know, context of what these changes mean in real life.

Marc Goodman: Yes. Hey, guys. Can you help us understand the magnitude of the cognition and behavior improvements in the Vineland-III data in this OLE data that you're showing? Just talk about the clinically meaningfulness of the changes and any, I don't know, context of what these changes mean in real life for the patients, please, and the caregivers.

Speaker 8: Yes. Hey, guys. Can you help us understand the magnitude of the cognition and behavior improvements in the Vineland 3 data in this OLE data that you're showing? Just talk about the clinically meaningfulness of the changes and in the, I don't know, context of what these changes mean in real life for the patients, please, and the caregivers.

Speaker #9: For the patients, please, and the caregivers.

Speaker #5: Sure. Thanks, Mark, for the question. I'll try to address that. So really, you know, as regards I think cognitive and behavioral outcomes, I think first it's really important to recognize that patients with drug A really there's not one-size-fits-all for all these patients.

Tommy Leggett: Thanks, Mark, for the question. I'll try to address that. So really, you know, as regards, I think, 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, you know, at baseline. You know, I think that 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, you know, anecdotes from investigators of how these patients have changed over time. And then I think that, you know, we had one of our investigators present videos of one patient in December last year. That certainly was something I think that was really emotional for all of us.

Kimberly Parkerson: Thanks, Marc, for the question. I'll try to address that. Really, as regards, I think, 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. I think that's through a few things. One is we certainly have anecdotes from investigators of how these patients have changed over time. I think that we had one of our investigators present videos of one patient in December last year that certainly was something, I think, that was really emotional for all of us.

Speaker #5: I think that they all come in a bit heterogeneous, you know, at baseline. You know, I think that that being said, I would say that we're all beginning to learn more about what these changes look like.

Speaker #5: And I think that's through a few things. One is we certainly have have, you know, anecdotes from investigators of how these patients have changed over time.

Speaker #5: And then I think that, you know, we had one of our investigators present videos of one patient in December last year that certainly was something I think was really emotional for all of us.

Speaker #5: And I think a lot of that, you know, on my mind, I've certainly seen patients in clinic with drug A syndrome and really this change I think that we saw at least in that patient was something that is not something we would expect.

Kimberly Parkerson: I think a lot of that, on my mind, I've certainly seen patients in clinic with Dravet syndrome. 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 III study, I think we're going to get a good handle on what these patients look like and what they do over time. I really think that's going to be informative for the community as a whole across a lot of different DEEs and neurodevelopmental disorders.

Tommy Leggett: 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. So I know that, you know, certainly this won't help you at the moment, but I think that over the course of our Phase III 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, you know, for the community as a whole across a lot of different DEs and neurodevelopmental disorders.

Speaker #5: In a normal course of disease with drug A. So I know that, you know, certainly this won't help you at the moment. But I think that over the course of our Phase III study, I think we're going to get a good handle on what these patients look like and what they do over time.

Speaker #5: And I really think that's going to be informative for the community as a whole across a lot of different DEs and neurodevelopmental disorders. I think if we really focus on the numbers, in particular, the numbers, you know, from the data across this three years and particularly, you know, for those five key subdomains, but certainly across even others that we didn't see early change in, these points are really eight to ten-ish points of change.

Kimberly Parkerson: I think if we really focus on the numbers in particular, the numbers from the data across the 3 years, in particular for those 5 key subdomains, but certainly across even others that we didn't see early change in, these points are really 8 to 10-ish points of change. If we think about the data that caregivers have really given us through the survey we did with them, they identified even 1 to 3 points as something clinically meaningful. I think, in short, I can't paint a perfect picture, I think, of what a before and after looks like. I think the magnitude of change across these Vineland subdomains will be things that families can see in the daily life of these patients across multiple developmental areas.

Tommy Leggett: I think if we really focus on the numbers in particular, the numbers, you know, from the data across just three years, in particular, you know, for those five key subdomains, but certainly across even others that we didn't see early change in, these points are really, you know, eight to ten-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 Vineland subdomains will be things that families can see in the daily life of these patients across multiple developmental areas.

Speaker #5: And if we think about the data that caregivers have really given us through the survey we've been with them, they identified even one to three points as something clinically meaningful.

Speaker #5: 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.

Speaker #5: Across multiple developmental areas. And I think that with time, hopefully they'll have significant impacts, you know, in really the quality of life of patients and their families both.

Tommy Leggett: And I think that with time, hopefully, they'll have significant impacts, you know, in really the quality of life of patients and their families both.

Kimberly Parkerson: I think that with time, hopefully, they'll have significant impacts in really the quality of life of patients and their families, both.

Speaker #3: I mean, we're surprised just at the changes from 24 months to 36 months. I mean, on some of these domains, it was pretty amazing.

Marc Goodman: I mean, were you surprised just at the changes from 24 months to 36 months? I mean, on some of these domains, it was pretty amazing.

Dr. Kimberly Parkerson: I mean, were you surprised just at the changes from 24 months to 36 months? I mean, on some of these domains, it was pretty amazing.

Speaker #5: Yeah, I think we all looked at it and I have to say I think, you know, several people internally had, you know, almost tears come to their eyes to say, hey, we're really continuing to see improvements here.

Kimberly Parkerson: 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. I think it was really remarkable for all of us. I certainly am looking forward to replicating this in a larger group of patients as we really get this phase III done.

Tommy Leggett: Yeah, I think we all looked at it. And I have to say, I think, you know, several people internally had, you know, almost tears come to their eyes to say, "Hey, we're really continuing to see improvements here." So I think it was really, you know, 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 III done.

Speaker #5: So I think it was really, you know, 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 III done.

Speaker 8: Yeah. Thanks.

Marc Goodman: Yeah. Thanks.

Speaker #9: Thanks.

Speaker #3: 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 45 milligrams, those patients started to move more and more towards a greater degree of seizure reduction, a trend towards reduction.

Dr. Kimberly Parkerson: 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 45 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 NAD-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.

Barry Ticho: Marc, this is Barry. I'll just add, in addition to the cognition and behavior effects that we saw over the 3 years, what we were seeing is that as the patients were on the maintenance dose of 45 milligrams, those patients started to move more and more towards a greater degree of seizure reduction, a trend towards reduction. 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.

Speaker #3: 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 NAD 1.1 deficiency.

Speaker #3: But also that as we continue to observe patients for long enough, they're seeing a benefit as we get to the higher dose.

Speaker #9: Thanks.

Marc Goodman: Thanks.

Speaker 8: Thanks.

Speaker #7: Your next question comes from the line of Andrew Tai from Jeffries. Please go ahead.

Speaker 6: Your next question comes from the line of Andrew Tai from Jeffrey. Please go ahead.

Operator 2: Your next question comes from the line of Andrew Tsai from Jefferies. Please go ahead.

Speaker #10: 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 Emperor study.

Andrew Tsai: Hey, good afternoon. Thanks for the updates and sharing the data. In the past, you've mentioned how you've done various analyses to help you design the Phase III EMPEROR study. 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.

Speaker 9: 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 EMPEROR 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.

Speaker #10: 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 Vinland specifically?

Speaker #10: Thank you.

Speaker #9: Okay.

Speaker #3: Barry, why didn't you take that question? I mean, focus on seizures and cognition and behavior. Yeah, thanks, Andrew, for the question. So the data that we used to determine the power calculations for the Phase III partially came from an analysis that we presented earlier this year at the European Pediatric Neurology Society.

Dr. Kimberly Parkerson: Barry, why don't you take that question? I mean, yeah, focus on seizures and cognition and behavior.

Ian F. Smith: I think, Barry, why don't you take that question? I mean, focus on seizures and cognition and behavior.

Barry Ticho: Thanks, Andrew Tsai, for the question. The data that we used to determine the power calculations for the Phase III partially came from an analysis that we presented earlier this year at the European Paediatric Neurology 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 III study. When we looked at those responses on the Vineland, we saw that when we modeled it out for 1 year, those patients 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. That was a substantial contrast and shows the effect.

Barry Ticho: Yeah, thanks, Andrew, for the question. So the data that we used to determine the power calculations for the Phase III partially came from an analysis that we presented earlier this year at the European Pediatric Neurology 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 III 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.

Speaker #3: 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 III study.

Speaker #3: And when we looked at those responses on the Vinland, 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 Vinland score.

Speaker #3: That was especially in contrast to a matched group of patients in the from our natural history study who showed very little change at all.

Speaker #3: In that score, we observed a substantial contrast that illustrated the effect. We then powered the study based on that response and did give a change in the point score based on what we expected to be a potential placebo response. We reduced it by 20% and used that to power the study.

Barry Ticho: 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 used 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 Zoriba Nursin in our studies. And we have patients who've gotten multiple doses, over 15, some of them up to 15 doses of the drug. So that safety profile is also helping us with the design of the study.

Barry Ticho: We then powered the study based on that response. We did give a change in the point score based on what we expected to be a potential placebo response. We reduced it by 20% and used 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 4 years. We've given almost 800 doses of zorevunersen in our studies. We have patients who've gotten multiple doses, some of them up to 15 doses of the drug. That safety profile is also helping us with the design of the study.

Speaker #3: 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.

Speaker #3: We have now patients who've been dosed for over four years. We've given almost 800 doses of Zorebinursin in our studies. And we have patients who've received multiple doses, with some of them up to 15 doses of the drug.

Speaker #3: 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 45 milligram dosing. We also powered that very conservatively with a 0.01 p-value and a 90% power, and a generous placebo effect as well.

Barry Ticho: And then finally, for the seizure endpoints, we also looked at the response based on the two-dose loading regimen, as well as the 45 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.

Barry Ticho: Finally, for the seizure endpoints, we also looked at the response based on the 2-dose loading regimen as well as the 45 mg dosing. We also powered that very conservatively with a 0.01 p-value and a 90% power and a generous placebo effect as well.

Speaker #10: Great.

Speaker #3: So

Speaker #3: So we're very confident in the powering of the study.

Barry Ticho: Great.

Barry Ticho: We're very confident in the powering of the study.

Speaker #7: Yeah, thank you. And you know, let's just say come second half of 2027 when the data arrives. Can you describe what constitutes statsig in Vinland?

Andrew Tsai: Yeah. Thank you. Let's just say come H2 2027 when the data arrives, can you describe what constitutes stat sig in Vineland? How many of the 5 individual subdomains need to hit stat sig? For each subdomain, what kind of placebo-adjusted delta do you need to see to be stat sig? Thanks.

Speaker 9: Yeah. Thank you. And you know, let's just say come second half 2027 when the data arrives, can you describe what constitutes STAT-CIG in Vineland? How many of the five individual subdomains need to hit STAT-CIG? And for each subdomain, what kind of placebo-adjusted delta do you need to see to be STAT-CIG? Thanks.

Speaker #7: How many of the five individual subdomains need to hit statsig? And for each subdomain, what kind of placebo-adjusted delta do you need to see to be statsig?

Speaker #7: Thanks.

Speaker #3: Yeah, we've powered the study based on what we think is a clinically meaningful change. So that power is based on the response that we had from a survey that we mentioned was a two to three point, or sorry, one to three point change in the ROS score of the Vinland.

Barry Ticho: Yeah. We've powered the study based on what we think is a clinically meaningful change. That power is based on response that we had from a survey that we mentioned was a 2 to 3 point or sorry, 1 to 3 point change in the raw score of the Vineland. Statistically significant would be a change in that range. We think that based on our data that we have, we will potentially have greater changes than that. Again, this was a conservative assessment with a powering that was used to allow for a generous potential placebo effect.

Barry Ticho: Yeah, we've powered the study based on what we think is a clinically meaningful change. So that power is based on a response that we had from a survey that we mentioned was a two to three point, or 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.

Speaker #3: 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.

Speaker #3: So again, this was a conservative assessment with a powering that was used to allow for a generous potential placebo effect.

Speaker #10: Thank you.

Operator 2: Thank you. Our next question comes from the line of Pete Stavropoulos from Cantor Fitzgerald. Please go ahead.

Speaker 9: Thank you.

Speaker #7: Our next question comes from the line of Pete Stavropolos. From Kantor Fitzgerald, please go ahead.

Speaker 6: Our next question comes from the line of Pete Stavropoulos from Kantor Fitzgerald. Please go ahead.

Speaker #3: Barry, Tommy, and team. Congrats on the progress and the data for the OLE. And thanks for taking our questions. First question is, you know, are there any trends in terms of, you know, degree of seizure reduction and, you know, benefit measured by the neurodevelopmental scale, you know, Vinland III?

Pete Stavropoulos: Mary, Tommy, and team, congrats on the progress and the data for the OLE. 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 at Vineland-III? I'm curious to know if younger patients are driving improvements on the subdomains versus older patients.

Speaker 10: Barry, Tommy, and team, congrats on the progress and the data for the OLE, and thanks for taking our questions. Our first question is, you know, are there any trends in terms of, you know, degree of seizure reduction and, you know, benefit measured by the neurodevelopmental scale, you know, Vineland 3? And I'm curious to know if younger patients, you know, are driving improvements, you know, on the scale on the subdomains, you know, versus older patients.

Speaker #3: And I'm curious to know if younger patients, you know, are driving improvements, you know, on the scale on the subdomains, you know, versus older patients.

Speaker #3: Maybe I'll take the first part of that question, Barry, Kim, and then ask you guys to kind of talk about kind of the subsets and individual not individual, but groups of patients' reactions.

Ian F. Smith: Maybe I'll take the first part of that question, Barry, Kim, and then ask you guys to kind of talk about kind of the subsets and individual not individual, but groups of patients' reactions. One of the striking results from the 36-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. What I mean by continued to see a reduction in seizures, they continued to go lower. They came into the study with reduced seizures, the seizure reduction for those low-dose patients was not as significant. As they continued through the 1 year, 2 year, and 3 year on a consistent dose of 45 mg every 4 months, we saw those seizures actually further reduce.

Dr. Kimberly Parkerson: Maybe I'll take the first part of that question, Barry, Kim, and then ask you guys to kind of talk about kind of the subsets and individual, not individual, but groups of patients' reactions. One of the striking results from the 36-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 continue to see a reduction in seizures, they continued to go lower. So they came into the study with reduced seizures, but you know, 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 45 milligrams every four months, we saw those seizures actually further reduce. It's on the slide, as you can see.

Speaker #3: One of the striking results from the 36-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.

Speaker #3: And what I mean by continued to see a reduction in seizures is that they continued to go lower. They came into the study with reduced seizures, but you know, the seizure reduction for those low-dose patients was not as significant.

Speaker #3: But as they continued through the one year, two year, and three year marks, on a consistent dose of 45 milligrams every four months, we saw those seizures actually further reduce.

Speaker #3: It's on the slide, as you can see, but it was one of those more striking responses that we see that goes to the mechanism of action of this drug and restoring NAD 1.1 in the brain.

Ian F. Smith: It's on the slide, as you can see. It was one of the more striking responses that we see that goes to the mechanism of action of this drug and restoring NaV1.1 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?

Dr. Kimberly Parkerson: But it was one of the more striking responses that we see that goes to the mechanism of action of this drug and restoring NAD-1 in the brain and therefore, you know, 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?

Speaker #3: And therefore, you know, 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.

Speaker #3: As for trends with different patient demographics, Barry, Kim, do you?

Speaker #5: Yeah, so I think you had a couple of other kind of points in that question. One, I think had to do with kind of the seizure reduction and the, you know, Vinland responses.

Tommy Leggett: Yeah. So I think you had 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 I study across different doses. If you really look at, you know, the 70 milligram patients, the vast majority of those patients, you know, had over 50% 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 Vineland are really tough, you know, right now.

Kimberly Parkerson: I think you had 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. I think that's a really difficult kind of correlation, I think, to do, particularly with the overall kind of small sample size and total kind of for a phase I study across different doses. If you really look at the 70 milligram patients, the vast majority of those patients had over 50% seizure reduction. When you try to go to some of the lower doses, there's a lot more variability in their seizure response. Really being able to correlate seizure responses in Vineland are really tough right now. I think that's something we can try to do more with, certainly, phase III.

Speaker #5: 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 I study across different doses.

Speaker #5: If you really look at, you know, the 70 milligram patients, the vast majority of those patients, you know, had over 50% 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.

Speaker #5: And so really being able to correlate, you know, seizure responses and Vinland are really tough, you know, right now. I think that's something, you know, we can try to do more with certainly Phase III.

Tommy Leggett: I think that's something, you know, we can try to do more with certainly Phase III. I think with respect to the, you know, younger and older patients, you know, for the Phase III, we've elected to put in patients 2 to 18 years of age because we've seen changes, you know, across the spectrum of ages in our Phase I, II study. And so I think that, you know, certainly looking across the different subdomains, some do have a peer, 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 could really move the bar, I think, across all of, you know, these patients from young to older.

Speaker #5: I think with respect to the, you know, younger and older patients, you know, for the Phase III, we've elected to put in patients two to 18 years of age.

Kimberly Parkerson: I think with respect to the younger and older patients, for the phase III, we've elected to put in patients 2 to 18 years of age because we've seen changes across the spectrum of ages in our phase I, II study. I think that certainly looking across the different subdomains, some do appear at least by kind of a covariate to have some preference towards younger and older versus older than younger. I think that we're confident that we could really move the bar, I think, across all of these patients from young to older. I think that from the mechanism of action of the drug, we're upregulating the fundamental problem of this disease. There's really no reason to think that maybe it's going to take more time. We don't know. There may be changes in the neural networks, those sorts of things.

Speaker #5: Because we've seen changes, you know, across the spectrum of ages in our Phase I-II study. And so I think that, you know, certainly looking across the different subdomains, some do have appear at least by kind of a covariance to have some preference towards younger and older versus older, you know, than younger.

Speaker #5: But I think that, you know, we're confident that we could really move the bar, I think, across all of, you know, these patients from young to older.

Speaker #5: I think that, you know, from the mechanism of action, you know, of the drug, we're upregulating the fundamental problem of this disease. And there's really no reason to think that maybe it's going to take, you know, more time.

Tommy Leggett: I think that, you know, from the mechanism of action, you know, of the drug, we're upregulating 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 upregulating NAD-1, even at a later age, cannot produce, you know, benefits in these patients. And so that's why we're studying, you know, 2 to 18 at least, you know, right now. And certainly, the Phase III is going to give us more insights, I think, into that.

Speaker #5: We don't know. There may be changes in the neural networks, those sorts of things. But there's really no fundamental reason why upregulating NAD 1.1, even in a later age, cannot produce, you know, benefits in these patients.

Kimberly Parkerson: There's really no fundamental reason why upregulating NaV1.1, even at a later age, cannot produce benefits in these patients. That's why we're studying 2 to 18 at least right now. Certainly, the phase III is going to give us more insights, I think, into that.

Speaker #5: And so, that's why we're studying, you know, ages two to eighteen at least, you know, right now. And certainly, the Phase III is going to give us more insights, I think, into that.

Speaker #3: All right. Yeah, I mean, I definitely agree that, you know, you may see benefits across all ages. But, you know, my assumption is, and many investors are assuming that the younger you go, the more sort of dramatic outcomes you may have on these neurodevelopmental sort of outcomes.

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

Speaker 10: All right. Yeah. I mean, I definitely agree that, you know, we may see benefit across all ages. But, you know, my assumption is, and many investors are assuming that the younger you go, the more sort of dramatic outcome you may have on these neurodevelopmental sort of outcomes. So curious, you 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?

Speaker #3: So, I'm curious. Out of the 150 plus 20 patients that you're enrolling in the 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?

Speaker #3: So, Pete, maybe I'll take the front end of your second question, which is, you know, what we're seeing here in the data is definitely a rush to treat patients as young as possible.

Ian F. Smith: Pete, maybe I'll take 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 2-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 zorevunersen for my prior role in cystic fibrosis. 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 syndrome, you may put these kids on a more normal path of developments and prevent their seizures. It is a goal of the program.

Dr. Kimberly Parkerson: So, Pete, maybe I'll take the kind of the front end of your second question, which is, you know, 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. You know, I mentioned in my prepared remarks that I have a familiarity in terms of feeling for Zoriba Nursin from 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 development and prevent their seizures.

Speaker #3: 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.

Speaker #3: You know, I mentioned in my prepared remarks that I have a familiarity in terms of feeling for Zorebinursin from my prior role in cystic fibrosis.

Speaker #3: And we always tried to get the medicine to the children at the earliest age as possible because if you can correct the fundamental causal biology of drug A, then you may put these kids on a more normal path of development and prevent their seizures.

Speaker #3: 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.

Dr. Kimberly Parkerson: 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 the clinical trial has been designed is in the tight group of 2 through 18. There is a slight loading of patients 7 through 10, I believe it is. But it should be beneficial for the patients in the age group 2 through 18.

Ian F. Smith: 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. The way that clinical trial has been designed is in the tight group of 2 through 18. There is a slight loading of patients 7 through 10, I believe it is. It should be beneficial for the patients in the age group 2 through 18.

Speaker #3: They may have different responses at different ages. However, the way that the clinical trial has been designed is in a tight group of ages 2 through 18, with a slight loading of patients between ages 7 and 10, I believe.

Speaker #3: But it should be beneficial for the patients in the age group two through 18. Thank you for taking our questions, and congrats again.

Pete Stavropoulos: Thank you for taking our questions. Congrats again.

Speaker 10: Thank you for taking our questions and congrats again.

Ian F. Smith: Thanks.

Speaker #10: Thanks.

Dr. Kimberly Parkerson: Thanks.

Speaker #7: Our next question comes from the line of Rudy Lee from Chardon. Please go ahead.

Speaker 6: Our next question comes from the line of Rudy Lee from Chardon. Please go ahead.

Operator 2: Our next question comes from the line of Rudy Li from Chardan. Please go ahead.

Speaker #10: Hey, thanks for taking my question. And congrats on the Phase III progress. So I have a question regarding the OLE data. So can you talk about the higher incidence of CSF protein elevations in the OLE part?

Speaker 11: Thanks for taking my question and congrats on the Phase III progress. So 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 45% patients classified as treatment-emergent AEs? Just curious, what can be attributed to the higher levels in the OLE study? Thanks.

Rudy Li: Hey. Thanks for taking my question. Congrats on the Phase III progress. I have a question regarding the OLE data. Can you talk about the higher incidence of CSF protein elevations in the OLE part? Any specific concern, especially for the 45% patients classified as treatment-emergent AEs? Just curious, what can be attributed to the higher levels in the OLE study? Thanks.

Speaker #10: Any specific concern, especially for the 45% patients classified as treatment emergent AEs? Just curious, what can be attributed to the higher levels in the OLE study?

Speaker #10: Thanks.

Speaker #3: 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.

Barry Ticho: 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 patients, in the 81 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.

Barry Ticho: Hi, Rudy Li. 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. 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 clinical effects of the elevated CSF protein. We have not seen any in the 81 patients that we've dosed so far. The elevated CSF proteins, those are a class effect. They're known to occur in other intrathecally administered oligonucleotides, approved ones as well. The reason that we see it now later with additional dosing, it may be more of a procedure-related effect.

Speaker #3: 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.

Speaker #3: Most importantly, we've looked specifically for any effects clinical effects of the elevated CSF protein. And we have not seen any in the patients in the 81 patients that we've dosed so far.

Speaker #3: 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.

Speaker #3: 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 III.

Barry Ticho: 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 III. And again, we have, from the CSF protein perspective, not seen any reason that that should prevent us from moving into the study.

Barry Ticho: Again, the point is that we now have long-term data with patients dosed for some of them for over 4 years. The safety profile continues to support moving into phase III. Again, we have, from the CSF protein perspective, not seen any reason that that should prevent us from moving into the study.

Speaker #3: And again, we have from the CSF protein perspective not seen any reason that that should prevent us from moving into the study.

Speaker #10: Got it. Very helpful. Thanks.

Rudy Li: Got it. Very helpful. Thanks.

Dr. Kimberly Parkerson: Got it.

Barry Ticho: Very helpful. Thanks.

Speaker #7: Our next question comes from the line of Jeanne Kim for Thomson Reuters from BTIG. Please go ahead.

Operator 2: Our next question comes from the line of Jinnie Kim for Thom Schroeder from BTIG. Please go ahead.

Speaker 6: Our next question comes from the line of Jeanne Kim for Tom Schrader from BPIG. Please go ahead.

Speaker #11: Good Good afternoon. Thank you for taking my question. I want to ask a little bit more about the decision to explore STKOO2 in autosomal dominant optic atrophy.

Jinnie Kim: Good afternoon. Thank you for taking my question. I want to ask a little bit more about the decision to explore STK-002 and Autosomal Dominant Optic Atrophy. What prompted this decision to pursue this now in this condition? Any comments on the most key data outcomes from your non-human primate study that contributed to the rationale would be super helpful.

Speaker 7: Good afternoon. Thank you for taking my question. I want to ask a little bit more about the decision to explore STK-002 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 non-human primate study that contributed to the rationale would be super helpful.

Speaker #11: What prompted this decision to pursue this now in this condition? And any comments on the most key data outcomes from your non-human primate study that contributed to the rationale would be super helpful.

Speaker #3: Jeanne, 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.

Ian F. Smith: Jinnie, I'll take the front end of that question. Then maybe Barry can tell you about the data we collected. Over the last 6 months, when asked by investors and analysts, I've talked about a process that the company went through. 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 a complete assessment of the disease area. Following that assessment and frankly, the data that we received relating to the non-human primates, that gave us the confidence and frankly, excitement to go into study ADOA with STK-002.

Dr. Kimberly Parkerson: Jeanne, 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. And you know, it's a complete assessment of the disease area. And following that assessment, and frankly, the data that we received relating to the non-human primates, that gave us the confidence and, frankly, excitement to go into study ADOA with STK-002.

Speaker #3: 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.

Speaker #3: It's how you may run the clinical studies. And what your preclinical safety-efficacy package is. And you know, it's a complete assessment of the disease area and following that assessment, and frankly, the data that we received relating to the non-human primates that gave us the confidence.

Speaker #3: And frankly, excitement to go into study ADOA with STKOO2. I will just point out that in the genetic diseases where you have a slowly progressing disease and with ADOA, you have a slowly progressing loss of eyesight.

Ian F. Smith: I will just point out that in the 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. 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 STK-002. Maybe, Barry, if you want to specifically talk to that non-human primate data, which really was the trigger.

Dr. Kimberly Parkerson: I will just point out that in the 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 STK-002. And maybe, Barry, if you want to specifically talk to that non-human primate data, which really was the trigger.

Speaker #3: You really want to have significant efficacy to be able to run the clinical trial because you're trying to separate from natural history. When we saw the non-human primate data, where we potentially improved vision, it gave us the confidence to move into clinical development.

Speaker #3: Knowing that we can study these patients with STKOO2. And maybe, Barry, if you want to specifically talk to that non-human primate data, which really was the trigger.

Speaker #3: Yeah, Jeanne, thanks again for the question. And we are very excited about these data. We're very excited about the opportunity to treat this disease.

Barry Ticho: Yeah. Jinnie, thanks again for the question. We are very excited about these data. We are very excited about the opportunity to treat this disease. I will tell you, both my father is an ophthalmologist, my brother is an ophthalmologist. When I told them that we were treating patients or trying to find a treatment for patients with ADOA, he said to me, Wow, that is great because I have several families I follow, and we cannot do anything for them. Since I mentioned it to him, every few weeks, he calls me and says, I found another patient. This is a large group of patients that are undiagnosed and have no treatment options at all. This is a very exciting time for us here at the company. What made us even more exciting were the data from this monkey model.

Barry Ticho: Yeah, Jeanne, 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 ADOA, he said to me, "Wow, that's great because I have several families I follow, and we cannot do anything for them." And since I mentioned it to him, 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. This is a very exciting time for us here at the company. And what made us even more exciting was the data from this monkey model.

Speaker #3: I'll tell you, both my father is an ophthalmologist. My brother is an ophthalmologist. And when I told him that we were treating patients or trying to find a treatment for patients with ADOA, he said to me, well, that's great because I have several families I follow and we cannot do anything for them.

Speaker #3: And since I mentioned it to him, he keeps calling me every few weeks and says, "I found another patient." So, this is a large group of patients that are undiagnosed and have no treatment options at all.

Speaker #3: This is a very exciting time for us here at the company. What makes us even more excited is the data from this monkey model; this monkey model was a spontaneously occurring, naturally occurring monkey that had a family member who had the same mutation in the OPA1 gene.

Barry Ticho: 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 flavoprotein 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 002 into the monkeys, we saw that the FPF levels either stabilized or actually improved within a short time, within less than half a year.

Barry Ticho: This monkey model was a spontaneously occurring, naturally occurring monkey that had a family of monkey that had the same mutation in the OPA1 gene that we find in some patients with ADOA. 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. When we looked at a few specific tests, one of them being something called the flavoprotein 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.

Speaker #3: 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.

Speaker #3: 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 flavoprotein fluorescence.

Speaker #3: 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.

Speaker #3: And when we injected 002 into the monkeys, we saw that the FPF levels either stabilized or actually improved within a short time—less than half a year.

Barry Ticho: When we injected STK-002 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. Then we also looked, using something called the electroretinogram, at the functioning of the nerve because this is an optic nerve disease. When we looked at the patients, we know that those patients have abnormal ERGs. Now when we looked in the monkeys after they were dosed with STK-002, we saw that the ERG pattern improved. The nerve function was improving. These are the best measures that we could have in an animal model since we can't actually measure vision.

Speaker #3: That gave us a lot of encouragement that we might be able to see this as a biomarker in a clinical trial. Then, we also looked at using something called the electroretinogram to assess the functioning of the nerve.

Barry Ticho: 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 at 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 002, 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 the 002.

Speaker #3: Because this is an optic nerve disease, when we looked at the patients we see, we know that those patients have abnormal ERGs. Now, when we looked at the monkeys after they were dosed with 002, we saw that the ERG pattern improved.

Speaker #3: 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.

Speaker #3: 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 002.

Barry Ticho: 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 the 002.

Speaker #11: Sounds great. Thank you so much.

Speaker 7: So great. Thank you so much.

Jinnie Kim: Sounds great. Thank you so much.

Speaker #7: Our next question comes from the line of Jessica Phi from J.P. Morgan. Please go ahead.

Operator 2: Our next question comes from the line of Jessica Fye from J.P. Morgan. Please go ahead.

Speaker 6: Our next question comes from the line of Jessica Fye from JP Morgan. Please go ahead.

Speaker #5: Hey guys, good afternoon. Thanks for taking our question. I was curious, with 130 patients identified in pre-screening in the 170 target enrollment for your Phase III trial and drug A, can you talk about how you're going to be communicating enrollment updates?

Jessica Fye [Managing Director, Equity Research Analyst: Hey, guys. Good afternoon. Thanks for taking our question. I was curious, with 130 patients identified in prescreening and 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? How do you think about the possibility of delivering phase III data prior to the back half of 2027, just given how many patients are in prescreening? Thank you.

Speaker 7: Hey, guys. Good afternoon. Thanks for taking our question. I was curious, with 130 patients identified in prescreening and the 170 target enrollment through 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 back half of '27, given how many patients are in prescreening? Thank you.

Speaker #5: Should we expect sort of quarterly progress updates? And how do you think about the possibility of delivering Phase III data prior to the back half of '27?

Speaker #5: Just given how many patients are in pre-screening. Thank you.

Speaker #3: 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.

Ian F. Smith: 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. 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. The rate-limiting feature is actually opening of the clinical trial sites. 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. At the point that we do see a change in what we've communicated as being recruitment will complete in the H2 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 1-year trial.

Dr. Kimberly Parkerson: 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. And 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. You know, 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 second half of 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.

Speaker #3: The demand from the patients' families to push their children into the trial and the speed at which they want to go through screening is quite high. However, the rate-limiting factor is actually the opening of the clinical trial sites.

Speaker #3: And so we're going through that process and we're making good progress. As of now, it's still early in the trial. You know, 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 second half of 2026.

Speaker #3: 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.

Speaker #3: 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 second half of 2027.

Ian F. Smith: If we've got a 1-year recruitment period, that means it's 1 year from ending of recruitment. We're still maintaining the delivery of the top-line data in H2 2027. The other thing I want to refer to 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. We're taking the opportunity to provide data as we move along, including the 36-month OLE data today, which is striking. We have medical conferences coming up. We've got a medical conference coming in Labor Day weekend.

Dr. Kimberly Parkerson: 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 second half of 2027. The other thing I want to refer to 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 36-month OLE data today, which is striking. And we have medical conferences coming up.

Speaker #3: 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.

Speaker #3: 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 36-month OLE data today, which is striking.

Speaker #3: And we have medical conferences coming up. We've got a medical conference coming in at Labor Day weekend. And we have one later in the year.

Dr. Kimberly Parkerson: 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 will 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,

Ian F. Smith: We have one later in the year that we will be present at and will be providing further data. Please expect us to continue to communicate benefits and safety around this drug as we progress. As far as timelines are concerned, if they do move, we will communicate at that time.

Speaker #3: That we will be present at and we'll be providing further data. And so please expect us to continue to communicate. Benefits and safety around this drug as we progress.

Speaker #3: And as far as timelines are concerned, if they do move, we will communicate at that time.

Ian Smith: we will communicate at that time.

Speaker #7: Your next question comes from the line of Yaron Werber from TD Securities. Please go ahead.

Operator 2: Your next question comes from the line of Yaron Werber from TD Securities. Please go ahead.

Barry Ticho: Your next question comes from the line of Jaron Werber from TD Securities. Please go ahead.

Speaker #9: Great. Thanks for taking my question. I got two. Maybe the first one, Barry, for the Phase III for Emperor. The 20 patients in Europe specifically, I imagine you can lump them right into the overall study and treat them sort of indistinctly.

Yaron Werber: Great. Thanks for taking my question. I got two. Maybe the first one, Barry, for the phase III for EMPEROR, the 20 patients in Europe specifically, I imagine you can lump them right into the overall study and treat them sort of indistinctly. Do you need to enroll one-to-one in the EU just given their requirements for the way the sham injection's going to be? Is it going to be one-to-one drug versus placebo? For the ADOA, it's a single injection, not the 48 weeks. Clearly, you're expecting from your non-human primates, very stable sort of protein expression. Do you think it's going to last longer than 48 weeks overall, long-term? How many patients would you enroll in that phase I? Thank you.

Dr. Kimberly Parkerson: Great. Thanks for taking my question. I got two. Maybe the first one, Barry, for the phase three for EMPEROR, 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 the requirements of the way the sham injection is going to be? It's going to be one-to-one drug versus placebo. And then for the ADOA, so it's a single injection out to 48 weeks. So clearly, you're expecting from your non-human primates very stable sort of protein expression. Do you think it's going to last longer than 48 weeks overall long term? And how many patients would you enroll in that phase one? Thank you.

Speaker #9: And do you need to enroll one to one in the EU just given their requirements for the way the sham injection is going to be?

Speaker #9: Is it going to be one to one drug versus placebo? And then for the ADOA so it's a single injection, not the 48 weeks.

Speaker #9: So clearly you're expecting from your non-human primates a very stable sort of protein expression. Do you think it's going to last longer than 48 weeks overall, long-term?

Ian Smith: So, you're on. I'll take the first question in terms of the regulatory authorities and ask Barry to respond to you on ADOA. 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 US, 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 a 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.

Ian F. Smith: Yaron, I'll take the first question in terms of the regulatory authorities. Ask Barry Ticho to respond to you on ADOA. It's good to hear from you again. Maybe if I give you kind of the broader picture. This was a study that was agreed and aligned with the major regulatory authorities globally. What I mean by that is the US, Europe, Japan, and UK. 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 a needle prick sham control to be part of the study as opposed to a lumbar puncture sham control. What we simply did is we added 20 patients in a separate cohort in those four European countries.

Ian Smith: And we just increased the number for lumbar puncture and maintained our 150 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 150 with lumbar puncture and patients being blinded through a lumbar puncture sham control. And so, you know, simply part, 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 powering of the study.

Ian F. Smith: We just increased the number for lumbar puncture and maintained our 150 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. We wanted to maintain that powering of 150 with lumbar puncture and patients being blinded through a lumbar puncture sham control. Simply put, we added 20 patients, at least 20 patients in Europe. It doesn't change our timeline. It doesn't change our regulatory filings nor the powering of the study.

Dr. Kimberly Parkerson: And I'll just add, Jaron--so yeah, 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.

Barry Ticho: I'll just add, Yaron, yeah, your question about one-to-one. Yeah, it is one-to-one balance. One-to-one for sham and for active. That applies to the number of patients in Europe as well.

Barry Ticho: Our next question is about the--

Operator 2: Our next question comes from.

Dr. Kimberly Parkerson: Sorry, sorry. There was one other question. You had one other question about the 002. And as you know, Jaron, 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 12 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.

Barry Ticho: There was one other question. He had one other question about STK-002. As you know, Yaron, these oligonucleotides do have long half-lives. We have already some data from our animal model showing that the oligonucleotides can have a half-life of 9 months or longer. A single injection could have an effect over that full 12 months of the clinical trial. That is why we are going to be following these patients and observing them that entire period of time.

The 002. And as you know, you're on these these Auto nucleotides have do have long, half lives. And we have already some data from our animal model showing that the auto nucleotides can have a half-life of of 9 months or longer. So a single injection could have an effect over that full 12 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.

Operator 2: Our next question comes from the line of Joseph Stringer from Needham. Please go ahead.

Barry Ticho: Our next question comes from the line of Joseph Stringer from NEHDM. Please go ahead.

Our next question comes from the line of Joseph Stringer from Nidam. Please go ahead.

Eddie Offer Joy: Good afternoon. This is Eddie Offer Joy. Thanks for taking our questions. Congrats on starting the enrollment in EMPEROR. Just a couple from us. When do you anticipate beginning some of the North America commercial buildout? What do you expect the sales force composition and cost to be at peak? Elaborating a little bit more on the ADOA phase I program, is there any requirement for OPA1 genetic screening? What might be the cadence of some of this data after you have a 48-week duration for the primary endpoint? When might we see some interim data or final data and then progression into phase II? Thank you.

Tommy Leggett: Good afternoon. This is Eddie Opper Joey. Thanks for taking our questions and congrats on starting the enrollment in EMPEROR. Just a couple from us. When do you anticipate beginning some of the North America commercial buildout? And what do you expect the sales force composition and cost to be at peak? And then elaborating a little bit more on the ADO1 phase one program, is there any requirement for OPA1 genetic screening? And what might be the cadence of some of this data? I have to have a 48-week duration for the primary endpoint. But when might we see some interim data or final data and then progression into phase two? Thank you.

Good afternoon. This is Eddie on for Joey, thanks for taking our questions and, uh, congrats on starting the enrollment and effort, um, just a couple from us. Um, when do you anticipate beginning some of the North America commercial buildout, um, and what do you expect? The sales force composition and cost to be at Peak and then, uh, elaborating a little bit more on the Ada. 01 base 1 program. Um, is there any requirement for opa1 genetic screening and what might be the Cadence of

Of this data. Uh, after you have a 48 week,

Uh, duration for the primary endpoint. Um, will we see some interim data or final data and then progress into Phase 2? Thank you.

Jason Hoyt: Yeah. Thanks for the question, Eddie. This is Jason. On the commercial front, right now, we are 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. A relatively modest overall field-based infrastructure for this rare disease.

Jason Hoyt: 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 a relatively modest overall field-based infrastructure for this rare disease.

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.

On the commercial front, there is relatively modest overall field-based infrastructure for this rare disease.

Ian F. Smith: I'll just add to Jason's comment. In terms of being involved with disease-modifying genetic medicines like zorevunersen 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 your major geographies. The commercial build is focused on access and reimbursement and understanding the market. 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 we educate both families and advocacy groups and also the physicians as terms of the medicine. It's more of a science education than it is a commercial sell.

Ian Smith: I'll just add to Jason's comment. I'll just add to Jason's comments. In terms of being involved with medicines, disease-modifying genetic medicines like siruvinir 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 your 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 we 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 sell.

Jason's comment.

I'll just add to Jason's comments in terms of, you know.

Being involved with medicine's disease, modifying genetic medicines like or even nurse and and other CF medicines. You don't sell a medicine. Um, you actually help with access and reimbursement for patients and families. Um, the medicine by the time is approved is usually very well understood and known because as you conduct your trial, you're actually utilizing most of the treatment centers globally, um, for your, for your major major geographies. And so, the, the, the commercial build is focused on access and reimbursement, and understanding the market and, uh, and it's why I made a comment in my own remarks that uh, medical Affairs is fundamentally important for the stage of the company right now where we educate um you know, both families and

Ian F. Smith: I just want to reiterate that. That's why Jason refers to kind of the low build. As far as the ADOA study is concerned, it's a phase I study, which is dose escalating. It goes through multiple doses. I always view those studies as known news is good news because primary endpoint is actually safety as you escalate the dose. 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 maintaining safety and start having efficacious outcomes. We'll let you know when we see that.

Ian Smith: 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 the 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.

Um, advocacy groups and also the physicians, uh, as terms of the medicine. And so it's more of a science education than it is, uh, a commercial sell. So I just want to reiterate that and that's why, um, Jason refers to the kind of the low build.

Um, as far as the ADUA study is concerned, it's a Phase 1 study, which is dose escalating. It goes through multiple doses and so, um,

Dr. Kimberly Parkerson: 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. And Jason's going to be part of that and also encourage genetic testing for children who have vision problems when they're young.

Barry Ticho: I'll just add on your question about the genetic testing. OPA1 gene is included in many panels for inherited retinal disease and other vision issues. 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. We're hoping to do an extensive education campaign. Jason's going to be part of that and also encourage genetic testing for children who have vision problems when they're young.

I, I always view those studies as no news is good news, because the primary endpoint is actually safety as you escalate the dose. Um, 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. Um, that could be over the next year. It could be over a longer period. Um, it all depends on what dose we get to that we start having safety as maintaining safety and starting application outcomes. And we'll let you know when we see that.

And I'll just add on to your question about the genetic testing. So, the 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, and Jason's going to be part of that. We are also encouraging genetic testing for children who have vision problems when they're young.

Operator 2: I will now turn the call back over to Ian Smith for closing remarks.

Barry Ticho: I will now turn the call back over to Ian Smith for closing remarks.

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

Ian F. Smith: Yeah. Thank you. Thank you for all that participated in the call today. Thank you for the questions. Thank you for those people that were on the line and listening. We're very happy to provide this update to you all. We will be available in our offices post-call to answer any further follow-up questions. Thank you for attending the call today.

Ian Smith: Yeah, thank you. And thank you for all the participants 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.

Yeah, thank you. And thank you for all the participate 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 uh, to provide this uh update uh to you all. And uh we will be available in our offices uh post call to answer any further follow-up questions. Thank you for attending the call today.

Barry Ticho: Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

Operator 2: Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

Ladies and gentlemen, that concludes today's call, thank you all for joining. You may now disconnect

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